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DOI 10.1378/chest.11-2301 2012;141;e419S-e494SChest
Michael K. Gould, Francesco Dentali, Mark Crowther and Susan R. KahnBounameaux, Samuel Z. Goldhaber, Michael E. Nelson, Philip S. Wells, Clive Kearon, Elie A. Akl, Anthony J. Comerota, Paolo Prandoni, Henri Practice GuidelinesChest Physicians Evidence-Based Clinical Thrombosis, 9th ed: American College ofAntithrombotic Therapy and Prevention of Antithrombotic Therapy for VTE Disease :
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CHEST Supplement
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e419S
ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: ACCP GUIDELINES
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Recommendations that remain unchanged are not shaded.
2.1. In patients with acute DVT of the leg treated with vitamin K antagonist (VKA) therapy, we
Background: This article addresses the treatment of VTE disease. Methods: We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence. Results: For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagu-lant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a fi rst proximal DVT or PE that is provoked by surgery or by a nonsurgical tran-sient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsur-gical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivar-oxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superfi cial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C). Conclusion: Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences. CHEST 2012; 141(2)(Suppl):e419S–e494S
Abbreviations: CALISTO 5 Comparison of ARIXTRA in Lower Limb Superfi cial Thrombophlebitis With Placebo; CDT 5 catheter-directed thrombolysis; CTPH 5 chronic thromboembolic pulmonary hypertension; HR 5 hazard ratio; INR 5 international normalized ratio; IVC 5 inferior vena cava; LMWH 5 low-molecular-weight heparin; PE 5 pulmo-nary embolism; PESI 5 Pulmonary Embolism Severity Index; PREPIC 5 Prevention du Risque d’Embolie Pulmonaire par Interruption Cave; PTS 5 postthrombotic (phlebitic) syndrome; RR 5 risk ratio; rt-PA 5 recombinant tissue plasminogen activator; SC 5 subcutaneous; SVT 5 superfi cial vein thrombosis; tPA 5 tissue plasminogen activator; UEDVT 5 upper-extremity DVT; UFH 5 unfractionated heparin; VKA 5 vitamin K antagonist
Antithrombotic Therapy for VTE Disease Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Clive Kearon , MD , PhD ; Elie A. Akl , MD , MPH , PhD ; Anthony J. Comerota , MD ; Paolo Prandoni , MD , PhD ; Henri Bounameaux , MD ; Samuel Z. Goldhaber , MD , FCCP ; Michael E. Nelson , MD , FCCP ; Philip S. Wells , MD ; Michael K. Gould , MD , FCCP ; Francesco Dentali , MD ; Mark Crowther, MD ; and Susan R. Kahn , MD
Summary of Recommendations
Note on Shaded Text: Throughout this guideline, shading is used within the summary of recommenda-tions sections to indicate recommendations that are newly added or have been changed since the publica-tion of Antithrombotic and Thrombolytic Therapy:
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of diagnostic tests, provided test results are expected within 24 h (Grade 2C) .
2.3.1. In patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, we suggest serial imaging of the deep veins for 2 weeks over initial antico-agulation (Grade 2C) .
2.3.2. In patients with acute isolated distal DVT of the leg and severe symptoms or risk factors for extension (see text), we suggest initial anti-coagulation over serial imaging of the deep veins (Grade 2C) .
Remarks: Patients at high risk for bleeding are more likely to benefi t from serial imaging. Patients who place a high value on avoiding the inconvenience of repeat imaging and a low value on the inconvenience of treatment and on the potential for bleeding are likely to choose initial anticoagulation over serial imaging.
2.3.3. In patients with acute isolated distal DVT of the leg who are managed with initial anti-coagulation, we recommend using the same approach as for patients with acute proximal DVT (Grade 1B) .
2.3.4. In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we recommend no anticoagulation if the throm-bus does not extend (Grade 1B) ; we suggest anti-coagulation if the thrombus extends but remains confi ned to the distal veins (Grade 2C) ; we rec-ommend anticoagulation if the thrombus extends into the proximal veins (Grade 1B) .
2.4. In patients with acute DVT of the leg, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anti-coagulation for a minimum of 5 days and until the international normalized ratio (INR) is 2.0 or above for at least 24 h (Grade 1B) .
2.5.1. In patients with acute DVT of the leg, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) .
Remarks: Local considerations such as cost, availability, and familiarity of use dictate the choice between fondaparinux and LMWH.
LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH .
recommend initial treatment with parenteral anticoagulation (low-molecular-weight heparin [LMWH], fondaparinux, IV unfractionated hep-arin [UFH], or subcutaneous [SC] UFH) over no such initial treatment (Grade 1B) .
2.2.1. In patients with a high clinical suspicion of acute VTE, we suggest treatment with paren-teral anticoagulants compared with no treat-ment while awaiting the results of diagnostic tests (Grade 2C) .
2.2.2. In patients with an intermediate clinical suspicion of acute VTE, we suggest treatment with parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C) .
2.2.3. In patients with a low clinical suspicion of acute VTE, we suggest not treating with paren-teral anticoagulants while awaiting the results
Revision accepted August 31, 2011. Affi liations: From the Departments of Medicine and Clinical Epidemiology and Biostatistics (Dr Kearon), Michael De Groote School of Medicine, McMaster University, Hamilton, ON, Can-ada; Departments of Medicine, Family Medicine, and Social and Preventive Medicine (Dr Akl), State University of New York at Buffalo, Buffalo, NY; Department of Surgery (Dr Comerota), Jobst Vascular Center, Toledo, OH; Department of Cardiotho-racic and Vascular Sciences (Dr Prandoni), University of Padua, Padua, Italy; Department of Medical Specialties (Dr Bounameaux), University Hospitals of Geneva, Geneva, Switzerland; Department of Medicine (Dr Goldhaber), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; Department of Medicine (Dr Nelson), Shawnee Mission Medical Center, Shawnee Mission, KS; Department of Medicine (Dr Wells), University of Ottawa, Ottawa, ON, Canada; Departments of Medicine and Preventive Medicine (Dr Gould), Keck School of Medicine, University of Southern California, Los Angeles, CA; Department of Medicine (Dr Dentali), University of Insubria, Varese, Italy; Department of Medicine (Dr Crowther), Michael De Groote School of Med-icine, McMaster University, Hamilton, ON, Canada; and Depart-ments of Medicine and Clinical Epidemiology and Biostatistics (Dr Kahn), McGill University, Montreal, QC, Canada. Funding/Support : The Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines received support from the National Heart, Lung, and Blood Institute [R13 HL104758] and Bayer Schering Pharma AG. Support in the form of educational grants were also provided by Bristol-Myers Squibb; Pfi zer, Inc; Canyon Pharmaceuticals; and sanofi -aventis US. Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://chestjournal.chestpubs.org/content/141/2_suppl/1S. Correspondence to: Elie A. Akl, MD, MPH, PhD, Department of Medicine, State University of New York at Buffalo, ECMC-CC 142, 462 Grider St, Buffalo, NY 14215 ; e-mail: [email protected] © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http://www.chestpubs.org/site/misc/reprints.xhtml ). DOI: 10.1378/chest.11-2301
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2.13.1. In patients with acute DVT of the leg, we recommend against the use of an inferior vena cava (IVC) fi lter in addition to anticoagulants (Grade 1B) .
2.13.2. In patients with acute proximal DVT of the leg and contraindication to anticoagulation, we recommend the use of an IVC fi lter (Grade 1B) .
2.13.3. In patients with acute proximal DVT of the leg and an IVC fi lter inserted as an alterna-tive to anticoagulation, we suggest a conven-tional course of anticoagulant therapy if their risk of bleeding resolves (Grade 2B) .
Remarks: We do not consider that a permanent IVC fi lter, of itself, is an indication for extended anti-coagulation.
2.14. In patients with acute DVT of the leg, we suggest early ambulation over initial bed rest (Grade 2C) .
Remarks: If edema and pain are severe, ambula-tion may need to be deferred. As per section 4.1, we suggest the use of compression therapy in these patients.
3.0. In patients with acute VTE who are treated with anticoagulant therapy, we recommend long-term therapy (see section 3.1 for recom-mended duration of therapy) over stopping anti-coagulant therapy after about 1 week of initial therapy (Grade 1B) .
3.1.1. In patients with a proximal DVT of the leg provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treat-ment of a shorter period (Grade 1B) , (ii) treat-ment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , or (iii) extended therapy (Grade 1B regardless of bleeding risk) .
3.1.2. In patients with a proximal DVT of the leg provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , and (iii) extended therapy if there is a high bleeding risk (Grade 1B) . We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Grade 2B) .
3.1.3. In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical
2.5.2. In patients with acute DVT of the leg treated with LMWH, we suggest once- over twice-daily administration (Grade 2C) .
Remarks: This recommendation only applies when the approved once-daily regimen uses the same daily dose as the twice-daily regimen (ie, the once-daily injection contains double the dose of each twice-daily injection). It also places value on avoiding an extra injection per day.
2.7. In patients with acute DVT of the leg and whose home circumstances are adequate, we recommend initial treatment at home over treatment in hospital (Grade 1B) .
Remarks: The recommendation is conditional on the adequacy of home circumstances: well-maintained living conditions, strong support from family or friends, phone access, and ability to quickly return to the hospital if there is deterioration. It is also condi-tional on the patient feeling well enough to be treated at home (eg, does not have severe leg symptoms or comorbidity).
2.9. In patients with acute proximal DVT of the leg, we suggest anti coagulant therapy alone over catheter-directed thrombolysis (CDT) (Grade 2C) .
Remarks: Patients who are most likely to benefi t from CDT (see text), who attach a high value to prevention of postthrombotic syndrome (PTS), and a lower value to the initial complexity, cost, and risk of bleeding with CDT, are likely to choose CDT over anticoagu-lation alone.
2.10. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over systemic thrombolysis (Grade 2C) .
Remarks: Patients who are most likely to benefi t from systemic thrombolytic therapy (see text), who do not have access to CDT, and who attach a high value to prevention of PTS, and a lower value to the initial complexity, cost, and risk of bleeding with systemic thrombolytic therapy, are likely to choose systemic thrombolytic therapy over anticoagulation alone.
2.11. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over operative venous thrombectomy (Grade 2C) .
2.12. In patients with acute DVT of the leg who undergo thrombosis removal, we recommend the same intensity and duration of anticoagu-lant therapy as in comparable patients who do not undergo thrombosis removal (Grade 1B) .
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Remarks (3.1.3, 3.1.4, 3.1.4.3): Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anti-coagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be prescribed anticoagulants (see section 2.3).
In all patients who receive extended anticoagu-lant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually).
3.2. In patients with DVT of the leg who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR , 2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B) .
3.3.1. In patients with DVT of the leg and no cancer, we suggest VKA therapy over LMWH for long-term therapy (Grade 2C) . For patients with DVT and no cancer who are not treated with VKA therapy, we suggest LMWH over dab-igatran or rivaroxaban for long-term therapy (Grade 2C) .
3.3.2. In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade 2B) . In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dab-igatran or rivaroxaban for long-term therapy (Grade 2B) .
Remarks (3.3.1-3.3.2): Choice of treatment in patients with and without cancer is sensitive to the individual patient’s tolerance for daily injections, need for labo-ratory monitoring, and treatment costs.
LMWH, rivaroxaban, and dabigatran are retained in patients with renal impairment, whereas this is not a concern with VKA.
Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these guide-lines were being prepared (October 2011), postmar-keting studies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak recommenda-tion in favor of VKA and LMWH therapy over dab-igatran and rivaroxaban, and we have not made any recommendations in favor of one of the new agents over the other.
3.4. In patients with DVT of the leg who receive extended therapy, we suggest treatment with the
transient risk factor (see remark), we suggest treatment with anticoagulation for 3 months over treatment of a shorter period (Grade 2C) and recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) or extended therapy (Grade 1B regardless of bleeding risk) .
3.1.4. In patients with an unprovoked DVT of the leg (isolated distal [see remark] or proximal), we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B) . After 3 months of treatment, patients with unprovoked DVT of the leg should be evaluated for the risk-benefi t ratio of extended therapy.
3.1.4.1. In patients with a fi rst VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B) .
3.1.4.2. In patients with a fi rst VTE that is an unprovoked proximal DVT of the leg and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy (Grade 1B) .
3.1.4.3. In patients with a fi rst VTE that is an unprovoked isolated distal DVT of the leg (see remark), we suggest 3 months of anticoag-ulant therapy over extended therapy in those with a low or moderate bleeding risk (Grade 2B) and recommend 3 months of anticoagulant treatment in those with a high bleeding risk (Grade 1B) .
3.1.4.4. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (Grade 1B), and we sug-gest extended anticoagulant therapy in those with a moderate bleeding risk (Grade 2B) .
3.1.4.5. In patients with a second unprovoked VTE who have a high bleeding risk, we sug-gest 3 months of anticoagulant therapy over extended therapy (Grade 2B) .
3.1.5. In patients with DVT of the leg and active cancer, if the risk of bleeding is not high, we recommend extended anticoagulant therapy over 3 months of therapy (Grade 1B) , and if there is a high bleeding risk, we suggest extended anticoagulant therapy (Grade 2B) .
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of diagnostic tests, provided test results are expected within 24 h (Grade 2C) .
5.3. In patients with acute PE, we recommend early initiation of VKA (eg, same day as paren-teral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the INR is 2.0 or above for at least 24 h (Grade 1B) .
5.4.1. In patients with acute PE, we suggest LMWH or fondaparinux over IV UFH (Grade 2C for LMWH; Grade 2B for fondaparinux) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) .
Remarks: Local considerations such as cost, availability, and familiarity of use dictate the choice between fondaparinux and LMWH.
LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH.
In patients with PE where there is concern about the adequacy of SC absorption or in patients in whom thrombolytic therapy is being considered or planned, initial treatment with IV UFH is preferred to use of SC therapies.
5.4.2. In patients with acute PE treated with LMWH, we suggest once- over twice-daily admin-istration (Grade 2C) .
Remarks: This recommendation only applies when the approved once-daily regimen uses the same daily dose as the twice-daily regimen (ie, the once-daily injection contains double the dose of each twice-daily injection). It also places value on avoiding an extra injection per day.
5.5. In patients with low-risk PE and whose home circumstances are adequate, we suggest early discharge over standard discharge (eg, after fi rst 5 days of treatment) (Grade 2B) .
Remarks: Patients who prefer the security of the hospi-tal to the convenience and comfort of home are likely to choose hospitalization over home treatment.
5.6.1.1. In patients with acute PE associated with hypotension (eg, systolic BP , 90 mm Hg) who do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2C) .
5.6.1.2. In most patients with acute PE not asso-ciated with hypotension, we recommend against
same anticoagulant chosen for the fi rst 3 months (Grade 2C) .
3.5. In patients who are incidentally found to have asymptomatic DVT of the leg, we suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic DVT (Grade 2B) .
4.1. In patients with acute symptomatic DVT of the leg, we suggest the use of compression stockings (Grade 2B) .
Remarks: Compression stockings should be worn for 2 years, and we suggest beyond that if patients have developed PTS and fi nd the stockings help ful.
Patients who place a low value on preventing PTS or a high value on avoiding the inconvenience and discomfort of stockings are likely to decline stockings.
4.2.1. In patients with PTS of the leg, we sug-gest a trial of compression stockings (Grade 2C) .
4.2.2. In patients with severe PTS of the leg that is not adequately relieved by compression stock-ings, we suggest a trial of an intermittent com-pression device (Grade 2B) .
4.3. In patients with PTS of the leg, we suggest that venoactive medications (eg, rutosides, defi -brotide, and hidrosmin) not be used (Grade 2C) .
Remarks: Patients who value the possibility of response over the risk of side effects may choose to undertake a therapeutic trial.
5.1. In patients with acute PE, we recommend initial treatment with parenteral anticoagula-tion (LMWH, fondaparinux, IV UFH, or SC UFH) over no such initial treatment (Grade 1B) .
5.2.1. In patients with a high clinical suspicion of acute PE, we suggest treatment with paren-teral anticoagulants compared with no treat-ment while awaiting the results of diagnostic tests (Grade 2C) .
5.2.2. In patients with an intermediate clinical suspicion of acute PE, we suggest treatment with parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C) .
5.2.3. In patients with a low clinical suspicion of acute PE, we suggest not treating with paren-teral anticoagulants while awaiting the results
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6.1. In patients with PE provoked by surgery, we recommend treatment with anticoagula-tion for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , or (iii) extended therapy (Grade 1B regardless of bleeding risk) .
6.2. In patients with PE provoked by a nonsur-gical transient risk factor, we recommend treat-ment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , and (iii) extended therapy if there is a high bleeding risk (Grade 1B) . We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Grade 2B) .
6.3. In patients with an unprovoked PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter dura-tion (Grade 1B) . After 3 months of treatment, patients with unprovoked PE should be evaluated for the risk-benefi t ratio of extended therapy.
6.3.1. In patients with a fi rst VTE that is an unprovoked PE and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B) .
6.3.2. In patients with a fi rst VTE that is an unprovoked PE and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy (Grade 1B) .
6.3.3. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (Grade 1B) , and we sug-gest extended anticoagulant therapy in those with a moderate bleeding risk (Grade 2B) .
6.3.4. In patients with a second unprovoked VTE who have a high bleeding risk, we sug-gest 3 months of therapy over extended therapy (Grade 2B) .
6.4. In patients with PE and active cancer, if there is a low or moderate bleeding risk, we rec-ommend extended anticoagulant therapy over 3 months of therapy (Grade 1B) , and if there is a high bleeding risk, we suggest extended anti-coagulant therapy (Grade 2B) .
Remarks: In all patients who receive extended anticoag-ulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually).
systemically administered thrombolytic therapy (Grade 1C) .
5.6.1.3. In selected patients with acute PE not associated with hypotension and with a low bleeding risk whose initial clinical presentation, or clinical course after starting anticoagulant therapy, suggests a high risk of developing hypo-tension, we suggest administration of thrombo-lytic therapy (Grade 2C) .
5.6.2.1. In patients with acute PE, when a throm-bolytic agent is used, we suggest short infusion times (eg, a 2-h infusion) over prolonged infu-sion times (eg, a 24-h infusion) (Grade 2C) .
5.6.2.2. In patients with acute PE when a throm-bolytic agent is used, we suggest administration through a peripheral vein over a pulmonary artery catheter (Grade 2C) .
5.7. In patients with acute PE associated with hypotension and who have (i) contraindica-tions to thrombolysis, (ii) failed thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are available, we suggest catheter-assisted thrombus removal over no such inter-vention (Grade 2C) .
5.8. In patients with acute PE associated with hypotension, we suggest surgical pulmonary embolectomy over no such intervention if they have (i) contraindications to thrombolysis, (ii) failed thrombolysis or catheter-assisted embolectomy, or (iii) shock that is likely to cause death before thrombolysis can take effect (eg, within hours), provided surgical expertise and resources are available (Grade 2C) .
5.9.1. In patients with acute PE who are treated with anticoagulants, we recommend against the use of an IVC fi lter (Grade 1B) .
5.9.2. In patients with acute PE and contraindi-cation to anticoagulation, we recommend the use of an IVC fi lter (Grade 1B) .
5.9.3. In patients with acute PE and an IVC fi l-ter inserted as an alternative to anticoagulation, we suggest a conventional course of anticoagu-lant therapy if their risk of bleeding resolves (Grade 2B) .
Remarks: We do not consider that a permanent IVC fi lter, of itself, is an indication for extended anticoagulation.
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8.1.1. In patients with superfi cial vein thrombo-sis (SVT) of the lower limb of at least 5 cm in length, we suggest the use of a prophylactic dose of fondaparinux or LMWH for 45 days over no anticoagulation (Grade 2B) .
Remarks: Patients who place a high value on avoiding the inconvenience or cost of anticoagulation and a low value on avoiding infrequent symptomatic VTE are likely to decline anticoagulation.
8.1.2. In patients with SVT who are treated with anticoagulation, we suggest fondaparinux 2.5 mg daily over a prophylactic dose of LMWH (Grade 2C) .
9.1.1. In patients with acute upper-extremity DVT (UEDVT) that involves the axillary or more proximal veins, we recommend acute treatment with parenteral anticoagulation (LMWH, fonda-parinux, IV UFH, or SC UFH) over no such acute treatment (Grade 1B) .
9.1.2. In patients with acute UEDVT that involves the axillary or more proximal veins, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B) .
9.2.1. In patients with acute UEDVT that involves the axillary or more proximal veins, we sug-gest anticoagulant therapy alone over throm-bolysis (Grade 2C) .
Remarks: Patients who (i) are most likely to benefi t from thrombolysis (see text); (ii) have access to CDT; (iii) attach a high value to prevention of PTS; and (iv) attach a lower value to the initial complexity, cost, and risk of bleeding with thrombolytic therapy are likely to choose thrombolytic therapy over anticoagu-lation alone.
9.2.2. In patients with UEDVT who undergo thrombolysis, we recommend the same inten-sity and duration of anticoagulant therapy as in similar patients who do not undergo thromboly-sis (Grade 1B) .
9.3.1. In most patients with UEDVT that is asso-ciated with a central venous catheter, we sug-gest that the catheter not be removed if it is functional and there is an ongoing need for the catheter (Grade 2C) .
9.3.2. In patients with UEDVT that involves the axillary or more proximal veins, we sug-gest a minimum duration of anticoagulation of 3 months over a shorter period (Grade 2B) .
6.5. In patients with PE who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR , 2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B) .
6.6. In patients with PE and no cancer, we sug-gest VKA therapy over LMWH for long-term therapy (Grade 2C) . For patients with PE and no cancer who are not treated with VKA therapy, we suggest LMWH over dabigatran or rivaroxa-ban for long-term therapy (Grade 2C) .
6.7. In patients with PE and cancer, we suggest LMWH over VKA therapy (Grade 2B) . In patients with PE and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2C) .
Remarks (6.6-6.7): Choice of treatment in patients with and without cancer is sensitive to the individual patient’s tolerance for daily injections, need for labo-ratory monitoring, and treatment costs.
Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes than VKA and LMWH therapy. When these guide-lines were being prepared (October 2011), postmar-keting studies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak recommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban, and we have not made any recommen-dation in favor of one of the new agents over the other.
6.8. In patients with PE who receive extended therapy, we suggest treatment with the same anticoagulant chosen for the fi rst 3 months (Grade 2C) .
6.9. In patients who are incidentally found to have asymptomatic PE, we suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic PE (Grade 2B) .
7.1.1. In patients with chronic thromboem-bolic pulmonary hypertension (CTPH), we rec-ommend extended anticoagulation over stopping therapy (Grade 1B) .
7.1.2. In selected patients with CTPH, such as those with central disease under the care of an experienced throm boendarterectomy team, we suggest pulmonary thromboendarterectomy over no pulmonary thromboendarterectomy (Grade 2C) .
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
e426S Antithrombotic Therapy for VTE
which are collectively referred to as VTE. We also provide recommendations for patients with (1) post-thrombotic syndrome (PTS), (2) chronic thromboem-bolic pulmonary hypertension (CTPH), (3) incidentally diagnosed (asymptomatic) DVT or PE, (4) acute upper-extremity DVT (UEDVT), (5) superfi cial vein thrombosis (SVT), (6) splanchnic vein thrombosis, and (7) hepatic vein thrombosis.
Table 1 describes the populations, interventions, comparators, and outcomes (ie, PICO elements) for the questions addressed in this article and the design of the studies used to address them. Refer to Garcia et al, 1 Ageno et al, 2 and Holbrook et al 3 in these guidelines for recommendations on the man-agement of parenteral anticoagulation (dosing and monitoring) and oral anticoagulation (dosing and mon itoring). Refer to Bates et al 4 and Monagle et al 5 in these guidelines for recommendations for preg-nancy and neonates and children. The current article builds on previous versions of these guidelines and, most recently, the eighth edition. 6
1.0 Methods
1.1 Presentation as DVT or PE
In addressing DVT, we fi rst review studies that included (1) only patients who presented with symptomatic DVT or (2) patients who presented with DVT or PE (ie, meeting the broader criterion of VTE). For the PE components, we review studies (and sub-groups within studies) that required patients to have presented with symptomatic PE (who may also have had symptoms of DVT). For this reason and because more patients with VTE present with symptoms of DVT alone than with symptoms of PE (including those who also have symptoms of DVT), the DVT section deals with a larger body of evidence than the PE section.
In the evaluation of anticoagulant therapy, there are a number of justifi cations for inclusion of patients who present with DVT and PE in the same study, and for extrapolating evidence obtained in patients with one presentation of VTE (eg, DVT) to the other presentation (eg, PE). First, a majority of patients with symp-tomatic DVT also have PE (symptomatic or asymptomatic), and a majority of those with symptomatic PE also have DVT (symp-tomatic or asymptomatic). 7,8 Second, clinical trials of anticoagu-lant therapy have yielded similar estimates for effi cacy and safety in patients with DVT alone, in those with both DVT and PE, and in those with only PE. Third, the risk of recurrence appears to be similar after PE and after proximal DVT. 7,9 Consequently, the results of all studies of VTE have been considered when formu-lating recommendations for short- and long-term anticoagula-tion of proximal DVT and PE ( Fig 1 ), and these recommendations are essentially the same for proximal DVT or PE.
There are, however, some important differences between patients who present with PE and those who present with DVT that justify separate consideration of some aspects of the treatment of PE. First, the risk of early death (within 1 month) from VTE due to either the initial acute episode or recurrent VTE is much greater after presenting with PE than after DVT 9 ; this difference may justify more aggressive initial treatment of PE (eg, thrombo-lytic therapy, insertion of an inferior vena cava (IVC) fi lter, more intensive anticoagulant therapy) compared with DVT. Second, recurrent episodes of VTE are about three times as likely to be
Remarks: This recommendation also applies if the UEDVT was associated with a central venous cath-eter that was removed shortly after diagnosis.
9.3.3. In patients who have UEDVT that is asso-ciated with a central venous catheter that is removed, we recommend 3 months of antico-agulation over a longer duration of therapy in patients with no cancer (Grade 1B) , and we sug-gest this in patients with cancer (Grade 2C) .
9.3.4. In patients who have UEDVT that is asso-ciated with a central venous catheter that is not removed, we recommend that anticoagulation is continued as long as the central venous cath-eter remains over stopping after 3 months of treatment in patients with cancer (Grade 1C) , and we suggest this in patients with no cancer (Grade 2C) .
9.3.5. In patients who have UEDVT that is not associated with a central venous catheter or with cancer, we recommend 3 months of anticoagula-tion over a longer duration of therapy (Grade 1B) .
9.4. In patients with acute symptomatic UEDVT, we suggest against the use of compression sleeves or venoactive medications (Grade 2C) .
9.5.1. In patients who have PTS of the arm, we suggest a trial of compression bandages or sleeves to reduce symptoms (Grade 2C) .
9.5.2. In patients with PTS of the arm, we sug-gest against treatment with venoactive medica-tions (Grade 2C) .
10.1. In patients with symptomatic splanch-nic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we recommend anti-coagulation over no anticoagulation (Grade 1B) .
10.2. In patients with incidentally detected splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we suggest no anticoagulation over anticoagulation (Grade 2C) .
11.1. In patients with symptomatic hepatic vein thrombosis, we suggest anticoagulation over no anticoagulation (Grade 2C) .
11.2. In patients with incidentally detected hepatic vein thrombosis, we suggest no antico-agulation over anticoagulation (Grade 2C) .
This article provides recommendations for the use of antithrombotic agents as well as the use of
devices or surgical techniques in the treatment of patients with DVT and pulmonary embolism (PE),
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e 1—
Stru
ctu
red
Cli
nica
l Q
ues
tion
s
Stru
ctur
ed P
ICO
Que
stio
n
Issu
e (I
nfor
mal
Que
stio
n)Po
pula
tion
Inte
rven
tion
Com
para
tors
Out
com
eM
etho
dolo
gy
Patie
nt w
ith a
cute
DV
T o
f the
leg
(2.0
-3.0
)
Initi
al a
ntic
oagu
lant
(2.1
)Pa
tient
s w
ith a
cute
DV
T o
f th
e le
gA
ntic
oagu
latio
nN
o an
ticoa
gula
tion
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts
Whe
ther
to tr
eat w
hile
aw
aitin
g th
e re
sults
of t
he d
iagn
ostic
wor
k-up
(2
.2.1
- 2.2
.3)
Patie
nts
with
sus
pect
ed a
cute
D
VT
of t
he le
g aw
aitin
g th
e re
sults
of d
iagn
ostic
test
s
Ant
icoa
gula
tion
No
antic
oagu
latio
nPE
, maj
or b
leed
ing,
and
m
orta
lity
RC
Ts a
nd
coho
rt
stud
ies
Whe
ther
to tr
eat i
sola
ted
dist
al
thro
mbo
sis
(2.3
.1-2
.3.4
)Pa
tient
with
acu
te is
olat
ed
dist
al D
VT
of t
he le
gA
ntic
oagu
latio
nN
o an
ticoa
gula
tion
DV
T e
xten
sion
, PE
, maj
or
blee
ding
, mor
talit
y,
QO
L, a
nd P
TS
RC
Ts a
nd
coho
rt
stud
ies
Tim
ing
of in
itiat
ion
of V
KA
rel
ativ
e to
the
initi
atio
n of
par
ente
ral
antic
oagu
latio
n (2
.4)
Patie
nts
with
acu
te D
VT
of
the
leg
Ear
ly in
itiat
ion
of V
KA
Del
ayed
initi
atio
n of
VK
AD
VT
ext
ensi
on, P
E, m
ajor
bl
eedi
ng, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts a
nd
coho
rt
stud
ies
Dur
atio
n of
initi
al
antic
oagu
latio
n (2
.4)
Patie
nts
with
acu
te D
VT
of
the
leg
Lon
ger
dura
tion
Shor
ter
dura
tion
DV
T e
xten
sion
, PE
, maj
or
blee
ding
, mor
talit
y,
QO
L, a
nd P
TS
RC
Ts a
nd
coho
rt
stud
ies
Cho
ice
and
rout
e of
initi
al
antic
oagu
lant
(2.5
.1, 2
.5.2
, 2.6
)Pa
tient
s w
ith a
cute
DV
T
of th
e le
gU
FH
IV
or
SQL
MW
H, f
onda
pari
nux,
ri
varo
xaba
nD
VT
ext
ensi
on, P
E, m
ajor
bl
eedi
ng, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts
Sett
ing
of in
itial
an
ticoa
gula
tion
(2.7
)Pa
tient
s w
ith a
cute
DV
T
of th
e le
gIn
-hos
pita
l tre
atm
ent
At-
hom
e tr
eatm
ent
DV
T e
xten
sion,
PE
, maj
or b
leed
ing,
m
orta
lity,
QO
L, a
nd P
TSR
CTs
Rol
e of
thro
mbo
lytic
and
mec
hani
cal
inte
rven
tions
(2.9
-2.1
2)Pa
tient
s w
ith a
cute
pro
xim
al
DV
T o
f the
leg
Cat
hete
r di
rect
ed
thro
mbo
lysi
sN
o ac
tive
thro
mbu
s re
mov
al o
r an
othe
r m
etho
d of
thro
mbu
s re
mov
al
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, PT
S, s
hort
er I
CU
an
d ho
spita
l sta
ys, a
nd
acut
e co
mpl
icat
ions
RC
Ts a
nd
coho
rt
stud
ies
Syst
emic
thro
mbo
lytic
th
erap
yO
pera
tive
veno
us
thro
mbe
ctom
yR
ole
of I
VC
fi lte
rs in
add
ition
to
antic
oagu
latio
n (2
.13.
1)Pa
tient
s w
ith a
cute
DV
T
of th
e le
g st
arte
d on
an
ticoa
gula
tion
IVC
fi lte
rN
o IV
C fi
lter
Rec
urre
nt D
VT
and
PE
, maj
or
blee
ding
, mor
talit
y, Q
OL
, PT
S,
and
com
plic
atio
ns o
f pro
cedu
re
RC
Ts
Rol
e of
IV
C fi
lters
whe
n an
ticoa
gula
tion
is c
ontr
aind
icat
ed
(2.1
3.2)
Patie
nts
with
acu
te D
VT
of
the
leg
and
a co
ntra
indi
catio
n to
ant
icoa
gula
tion
IVC
fi lte
rN
o IV
C fi
lter
Rec
urre
nt D
VT
and
PE
, maj
or
blee
ding
, mor
talit
y, Q
OL
, PT
S,
and
com
plic
atio
ns o
f pro
cedu
re
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
ant
icoa
gula
tion
in p
atie
nts
who
initi
ally
rec
eive
d an
IV
C
fi lte
r w
hen
cont
rain
dica
tion
to
antic
oagu
latio
n re
solv
es (2
.13.
3)
Patie
nts
with
acu
te D
VT
of t
he
leg
who
initi
ally
rec
eive
d an
IV
C fi
lter,
now
con
trai
ndic
atio
n to
ant
icoa
gula
tion
reso
lved
Ant
icoa
gula
tion
in
addi
tion
to I
VC
fi lte
rN
o an
ticoa
gula
tion
in
addi
tion
to I
VC
fi lte
rR
ecur
rent
DV
T a
nd P
E, m
ajor
bl
eedi
ng, m
orta
lity,
QO
L, P
TS,
an
d co
mpl
icat
ions
of p
roce
dure
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
ear
ly a
mbu
latio
n (2
.14)
Patie
nts
with
acu
te D
VT
of t
he
leg
star
ted
on a
ntic
oagu
lant
tr
eatm
ent
Ear
ly a
mbu
latio
nIn
itial
bed
res
tR
ecur
rent
DV
T a
nd P
E, m
ajor
bl
eedi
ng, m
orta
lity,
QO
L, P
TS,
an
d co
mpl
icat
ions
of p
roce
dure
RC
Ts a
nd
coho
rt
stud
ies
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
e428S Antithrombotic Therapy for VTE
Stru
ctur
ed P
ICO
Que
stio
n
Issu
e (I
nfor
mal
Que
stio
n)Po
pula
tion
Inte
rven
tion
Com
para
tors
Out
com
eM
etho
dolo
gy
Lon
g-te
rm a
ntic
oagu
latio
n th
erap
y (3
.0)
Patie
nts
with
acu
te V
TE
of
the
leg
Lon
g-te
rm a
ntic
oagu
latio
n th
erap
yN
o lo
ng-t
erm
an
ticoa
gula
tion
ther
apy
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts
Dur
atio
n of
long
-ter
m
antic
oagu
latio
n (3
.1.1
- 3.1
.5)
Patie
nts
with
an
acut
e D
VT
of
the
leg
Lon
ger
dura
tion
Shor
ter
dura
tion
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts
Inte
nsity
of V
KA
(3.2
)Pa
tient
s w
ith a
cute
DV
T
of th
e le
gIN
R 2
-3H
ighe
r or
low
er I
NR
ra
nges
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts
Cho
ice
of lo
ng-t
erm
ant
icoa
gula
nt
(3.3
.1, 3
.3.2
, 3.4
)Pa
tient
s w
ith a
cute
DV
T
of th
e le
g.L
MW
H, d
abig
atra
n,
riva
roxa
ban
VK
AR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts
Whe
ther
to tr
eat a
n in
cide
ntal
ly
diag
nose
d as
ympt
omat
ic a
cute
D
VT
of t
he le
g (3
.5)
Patie
nts
with
inci
dent
ally
di
agno
sed
asym
ptom
atic
D
VT
of t
he le
g
Ant
icoa
gula
tion
No
antic
oagu
latio
nR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts
Patie
nts
with
PT
S of
the
leg
Rol
e of
com
pres
sion
sto
ckin
g in
pr
even
ting
PTS
(4.1
)Pa
tient
s w
ith a
cute
DV
T o
f the
le
g st
arte
d on
ant
icoa
gula
nt
trea
tmen
t
Com
pres
sion
sto
ckin
gsN
o co
mpr
essi
on
stoc
king
sQ
OL
, PT
S, a
nd r
ecur
rent
D
VT
RC
Ts
Rol
e of
com
pres
sion
sto
ckin
g in
PT
S (4
.2.1
)Pa
tient
s w
ith P
TS
of th
e le
gC
ompr
essi
on s
tock
ings
No
com
pres
sion
st
ocki
ngs
QO
L, s
ympt
omat
ic r
elie
f, ul
cera
tion
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
inte
rmitt
ent p
neum
atic
co
mpr
essi
on in
PT
S (4
.2.2
)Pa
tient
s w
ith P
TS
of th
e le
gIn
term
itten
t pne
umat
ic
com
pres
sion
No
inte
rmitt
ent
pneu
mat
ic
com
pres
sion
QO
L, s
ympt
omat
ic r
elie
f, ul
cera
tion
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
ven
oact
ive
med
icat
ions
in
PTS
(4.3
)Pa
tient
s w
ith P
TS
of th
e le
gVe
noac
tive
med
icat
ions
No
veno
activ
e m
edic
atio
nsQ
OL
, PT
S, a
nd r
ecur
rent
D
VT
RC
Ts a
nd
coho
rt
stud
ies
Patie
nt w
ith a
cute
PE
Initi
al a
ntic
oagu
lant
(5.1
)Pa
tient
s w
ith a
cute
PE
Ant
icoa
gula
tion
No
initi
al
antic
oagu
latio
nR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts
Whe
ther
to tr
eat w
hile
aw
aitin
g th
e re
sults
of t
he d
iagn
ostic
wor
k-up
(5
.2.1
-5.2
.3)
Patie
nts
with
sus
pect
ed a
cute
PE
aw
aitin
g th
e re
sults
of
the
diag
nost
ic te
sts
Ant
icoa
gula
tion
No
antic
oagu
latio
nR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts a
nd
coho
rt
stud
ies
Tim
ing
of in
itiat
ion
of V
KA
rel
ativ
e to
the
initi
atio
n of
par
ente
ral
antic
oagu
latio
n (5
.3)
Patie
nts
with
acu
te P
EE
arly
initi
atio
n of
VK
AD
elay
ed in
itiat
ion
of V
KA
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts a
nd
coho
rt
stud
ies
Dur
atio
n of
initi
al
antic
oagu
latio
n (5
.3)
Patie
nts
with
acu
te P
EL
onge
r du
ratio
nSh
orte
r du
ratio
nR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts a
nd
coho
rt
stud
ies
Tabl
e 1—
Con
tinu
ed
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e429S
(Con
tinu
ed)
Tabl
e 1—
Con
tinu
ed
Stru
ctur
ed P
ICO
Que
stio
n
Issu
e (I
nfor
mal
Que
stio
n)Po
pula
tion
Inte
rven
tion
Com
para
tors
Out
com
eM
etho
dolo
gy
Cho
ice
and
rout
e of
initi
al
antic
oagu
lant
(5.4
.1, 5
.4.2
)Pa
tient
s w
ith a
cute
DV
T
of th
e le
gU
FH
IV
or
SQL
MW
H, f
onda
pari
nux,
an
d ri
varo
xaba
nR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts
Sett
ing
of in
itial
an
ticoa
gula
tion
(5.5
)Pa
tient
s w
ith a
cute
PE
In-h
ospi
tal t
reat
men
tA
t-ho
me
trea
tmen
tR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts
Thr
ombo
lytic
ther
apy
in p
atie
nts
with
acu
te P
E (5
.6.1
.1, 5
.6.1
.2,
5.6.
1.3)
Patie
nts
with
acu
te P
ET
hrom
boly
tic th
erap
yN
o th
rom
boly
tic
ther
apy
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts
Infu
sion
tim
e fo
r th
rom
boly
tic
ther
apy
(5.6
.2.1
)Pa
tient
s w
ith a
cute
PE
re
quir
ing
thro
mbo
lytic
th
erap
y
Lon
ger
infu
sion
tim
eSh
orte
r in
fusi
on ti
me
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts a
nd
coho
rt
stud
ies
Veno
us a
cces
s fo
r th
rom
boly
tic
ther
apy
(5.6
.2.2
)Pa
tient
s w
ith a
cute
PE
re
quir
ing
thro
mbo
lytic
th
erap
y
Peri
pher
al v
ein
Pulm
onar
y ca
thet
erR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
cat
hete
r-as
sist
ed th
rom
bus
rem
oval
(5.7
)Pa
tient
s w
ith a
cute
PE
Use
of c
athe
ter-
assi
sted
th
rom
bus
rem
oval
No
use
of
cath
eter
-ass
iste
d th
rom
bus
rem
oval
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
sur
gica
l pul
mon
ary
embo
lect
omy
(5.8
)Pa
tient
s w
ith a
cute
PE
Surg
ical
pul
mon
ary
embo
lect
omy
No
surg
ical
pul
mon
ary
embo
lect
omy
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
IV
C fi
lter
in a
dditi
on to
an
ticoa
gula
tion
in p
atie
nts
with
acu
te P
E (5
.9.1
)
Patie
nts
with
acu
te P
E s
tart
ed
on a
ntic
oagu
latio
nIV
C fi
lter
No
IVC
fi lte
rR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
IV
C fi
lters
whe
n an
ticoa
gula
tion
is c
ontr
aind
icat
ed
(5.9
.2)
Patie
nts
with
acu
te P
E a
nd
a co
ntra
indi
catio
n to
an
ticoa
gula
tion
IVC
fi lte
rN
o IV
C fi
lter
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
ant
icoa
gula
tion
in p
atie
nts
who
initi
ally
rec
eive
d an
IV
C
fi lte
r w
hen
cont
rain
dica
tion
to
antic
oagu
latio
n re
solv
es (5
.9.3
)
Patie
nts
with
acu
te P
E w
ho
initi
ally
rec
eive
d an
IV
C
fi lte
r, no
w c
ontr
aind
icat
ion
to a
ntic
oagu
latio
n re
solv
ed
Ant
icoa
gula
tion
in
addi
tion
to I
VC
fi lte
rN
o an
ticoa
gula
tion
in
addi
tion
to I
VC
fi lte
rR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts a
nd
coho
rt
stud
ies
Dur
atio
n of
long
-ter
m
antic
oagu
latio
n in
pat
ient
s w
ith
acut
e PE
(6.1
-6.4
)
Patie
nts
with
acu
te P
EL
onge
r du
ratio
nSh
orte
r du
ratio
nR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts a
nd
coho
rt
stud
ies
Inte
nsity
of V
KA
(6.5
)Pa
tient
s w
ith a
cute
PE
INR
2-3
Hig
her
or lo
wer
IN
R r
ange
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts a
nd
coho
rt
stud
ies
Cho
ice
of lo
ng-t
erm
ant
icoa
gula
nt
(6.6
, 6.7
, 6.8
)Pa
tient
s w
ith a
cute
PE
LM
WH
, dab
igat
ran,
ri
varo
xaba
nV
KA
Rec
urre
nt D
VT
and
PE
, maj
or
blee
ding
, mor
talit
y, Q
OL,
and
PTS
RC
Ts
Whe
ther
to tr
eat a
n in
cide
ntal
ly
diag
nose
d as
ympt
omat
ic a
cute
PE
(6.9
)Pa
tient
s w
ith in
cide
ntal
ly
diag
nose
d as
ympt
omat
ic P
EA
ntic
oagu
latio
nN
o an
ticoa
gula
tion
Rec
urre
nt D
VT
and
PE
, maj
or
blee
ding
, mor
talit
y, Q
OL
, and
PTS
RC
Ts a
nd
coho
rts
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
e430S Antithrombotic Therapy for VTE
Stru
ctur
ed P
ICO
Que
stio
n
Issu
e (I
nfor
mal
Que
stio
n)Po
pula
tion
Inte
rven
tion
Com
para
tors
Out
com
eM
etho
dolo
gy
Patie
nt w
ith C
TPH
Rol
e of
ora
l ant
icoa
gula
tion
in
CT
PH (7
.1.1
)Pa
tient
s w
ith C
TPH
Ora
l ant
icoa
gula
tion
No
oral
ant
icoa
gula
tion
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
pul
mon
ary
thro
mbo
enda
rter
ecto
my
in C
TPH
(7.1
.2)
Patie
nts
with
CT
PHPu
lmon
ary
thro
mbo
enda
rter
ecto
my
No
pulm
onar
y th
rom
boen
dart
erec
tom
yR
ecur
rent
DV
T a
nd P
E,
maj
or b
leed
ing,
mor
talit
y,
QO
L, a
nd P
TS
RC
Ts a
nd
coho
rt
stud
ies
Patie
nt w
ith S
VT
Rol
e of
ant
icoa
gula
tion
in S
VT
(8
.1.1
, 8.1
.2)
Patie
nts
with
SV
TA
ntic
oagu
latio
nN
o an
ticoa
gula
tion
or
othe
r an
ticoa
gula
ntD
VT
and
PE
, maj
or
blee
ding
, mor
talit
y, Q
OL
, sy
mpt
omat
ic r
elie
f, an
d PT
S
RC
Ts a
nd
coho
rt
stud
ies
Patie
nt w
ith a
cute
UE
DV
TA
cute
ant
icoa
gula
tion
(9.1
.1, 9
.1.2
)Pa
tient
s w
ith U
ED
VT
Pare
nter
al a
ntic
oagu
latio
nN
o an
ticoa
gula
tion
Rec
urre
nt D
VT
and
PE
, m
ajor
ble
edin
g, m
orta
lity,
Q
OL
, and
PT
S
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
thro
mbo
lytic
ther
apy
(9.2
.1, 9
.2.2
)Pa
tient
s w
ith U
ED
VT
Syst
emic
thro
mbo
lytic
th
erap
yN
o sy
stem
ic th
rom
boly
tic
ther
apy
Rec
urre
nt D
VT
and
PE
, maj
or
blee
ding
, mor
talit
y, Q
OL
, PT
S, sh
orte
r IC
U a
nd h
ospi
tal
stay
s, an
d ac
ute
com
plic
atio
ns
RC
Ts a
nd
coho
rt
stud
ies
Whe
ther
indw
ellin
g ce
ntra
l ve
nous
cat
hete
r sh
ould
be
rem
oved
(9.3
.1)
Patie
nts
with
UE
DV
T a
nd
indw
ellin
g ce
ntra
l ven
ous
cath
eter
Rem
oval
of i
ndw
ellin
g ce
ntra
l ven
ous
cath
eter
No
rem
oval
of
indw
ellin
g ce
ntra
l ve
nous
cat
hete
r
Rec
urre
nt D
VT
and
PE
, maj
or
blee
ding
, mor
talit
y, Q
OL
, PT
S, sh
orte
r IC
U a
nd h
ospi
tal
stay
s, an
d ac
ute
com
plic
atio
ns
RC
Ts a
nd
coho
rt
stud
ies
Dur
atio
n of
long
-ter
m
antic
oagu
latio
n (9
.3.2
-9.3
.5)
Patie
nts
with
UE
DV
T a
nd
indw
ellin
g ce
ntra
l ven
ous
cath
eter
Lon
ger
dura
tion
Shor
ter
dura
tion
Rec
urre
nt D
VT
and
PE
, maj
or
blee
ding
, mor
talit
y, Q
OL
, PT
S, sh
orte
r IC
U a
nd h
ospi
tal
stay
s, an
d ac
ute
com
plic
atio
ns
RC
Ts a
nd
coho
rt
stud
ies
Prev
entio
n of
PT
S of
the
arm
(9.4
)Pa
tient
s w
ith U
ED
VT
Com
pres
sion
sle
eves
or
ven
oact
ive
med
icat
ions
No
com
pres
sion
sle
eves
or
ven
oact
ive
med
icat
ions
QO
L, P
TS,
and
re
curr
ent D
VT
RC
Ts a
nd
coho
rt
stud
ies
Trea
tmen
t of P
TS
of th
e ar
m
(9.5
.1, 9
.5.2
)Pa
tient
s w
ith P
TS
of
the
arm
Com
pres
sion
sle
eves
or
ven
oact
ive
med
icat
ions
No
com
pres
sion
sle
eves
or
ven
oact
ive
med
icat
ions
QO
L, s
ympt
omat
ic r
elie
f, an
d ul
cera
tion
RC
Ts a
nd
coho
rt
stud
ies
Patie
nt w
ith th
rom
bosi
s in
unu
sual
site
sR
ole
of a
ntic
oagu
latio
n in
spl
anch
nic
vein
thro
mbo
sis
(10.
1, 1
0.2)
Patie
nts
with
spl
anch
nic
vein
thro
mbo
sis
Ant
icoa
gula
tion
No
antic
oagu
latio
nM
orta
lity,
bow
el is
chem
ia,
maj
or b
leed
ing,
QO
L,
and
sym
ptom
atic
rel
ief
RC
Ts a
nd
coho
rt
stud
ies
Rol
e of
ant
icoa
gula
tion
in h
epat
ic
vein
thro
mbo
sis
(11.
1, 1
1.2)
Patie
nts
with
hep
atic
ve
in th
rom
bosi
sA
ntic
oagu
latio
nN
o an
ticoa
gula
tion
Mor
talit
y, li
ver
failu
re, P
E,
maj
or b
leed
ing,
QO
L,
and
sym
ptom
atic
rel
ief
RC
T s a
nd
coho
rt
stud
ies
CT
PH 5
chro
nic
thro
mbo
embo
lic p
ulm
onar
y hy
pert
ensi
on;
INR
5 in
tern
atio
nal
norm
aliz
ed r
atio
; IV
C 5
infe
rior
ven
a ca
va;
LM
WH
5 lo
w-m
olec
ular
-wei
ght
hepa
rin,
PE
5 p
ulm
onar
y em
bolis
m;
PIC
O 5
pop
ulat
ion,
inte
rven
tion,
com
para
tor,
outc
ome;
PT
S 5
pos
tthr
ombo
tic s
yndr
ome,
QO
L 5
qua
lity
of li
fe; R
CT
5 ra
ndom
ized
con
trol
led
tria
l; SV
T 5
supe
rfi c
ial v
ein
thro
mbo
sis;
UE
DV
T 5
upp
er-
extr
emity
DV
T; U
FH
5 u
nfra
ctio
nate
d he
pari
n, V
KA
5 vi
tam
in K
ant
agon
ist.
Tabl
e 1—
Con
tinu
ed
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e431S
Figure 1. Phases of anticoagulation. LMWH 5 low-molecular-weight heparin.
and preferences for the most part were obtained from ratings that all panelists for these guidelines provided in response to standardized descriptions of different outcomes and treatments, supplemented with the fi ndings of a systematic review of the literature on this topic. 15 However, we also took into account that values and preferences vary markedly among individual patients and that often there is appreciable uncertainty about the average patient values we used.
On average, we assumed that patients attach equal value (or dislike [disutility]) to nonfatal thromboembolic and major bleeding events. Concern that the panelist rating exercise that attached a similar disutility to vitamin K antagonist (VKA) therapy (frequent blood testing and telephone or clinic visits, attention to changes in other medications) and long-term low-molecular-weight-heparin (LMWH) therapy (daily subcutaneous [SC] injection, injection site bruising or nodules) may have been misguided led us to request a review of this issue at the fi nal meeting of all panelists. Our judgment that, on average, patients would prefer VKA therapy to long-term LMWH therapy was confi rmed at that meeting.
1.4 Infl uence of Bleeding Risk and Cost
Usually, we did not assess how an individual patient’s risk of bleeding would infl uence each recommendation because (1) we considered that most recommendations would be unlikely to change based on differences in risk of bleeding (eg, anticoagula-tion vs no anticoagulation for acute VTE, comparison of anticoag-ulant regimens), (2) there are few data assessing outcomes in patients with different risks of bleeding, and (3) there is a lack of well-validated tools for stratifying risk of bleeding in patients with VTE. However, for a small number of the recommendations in which the risk of bleeding is very infl uential (eg, use of extended-duration anticoagulation), we stratifi ed recommendations based on this risk ( Table 2 ). Unless otherwise stated, the cost (eg, to the patient, a third-party payer, or society) associated with different treatments did not infl uence our recommendations. In most situ-ations of uncertain benefi t of a treatment, particularly if it was potentially harmful, we took the position of primum non nocere (fi rst do no harm) and made a weak recommendation against the treatment.
2.0 Treatment of Acute DVT
2.1 Initial Anticoagulation of Acute DVT of the Leg
The fi rst and only randomized trial that compared anticoagulant therapy with no anticoagulant therapy in patients with symptomatic DVT or PE was pub-lished in 1960 by Barritt and Jordan. 50 Trial results suggested that 1.5 days of heparin and 14 days of
PE after an initial PE than after an initial DVT (ie, about 60% after a PE vs 20% after a DVT) 7,9,10 ; this difference may justify more aggressive, or more prolonged, long-term therapy. Third, the long-term sequelae of PE are cardiorespiratory impairment, especially due to pulmonary hypertension, rather than PTS of the legs or arms. These differences are most important for recommen-dations about the use of thrombus removal procedures (eg, thrombo-lytic therapy) in patients who present with DVT and PE.
1.2 Outcomes Assessed
The outcomes important to patients we considered for most rec-ommendations are recurrent VTE, major bleeding, and all-cause mortality. These outcomes are categorized in two different ways in the evidence profi les. Whenever data were available, fatal epi-sodes of recurrent VTE and bleeding were included in the mor-tality outcome, and nonfatal episodes of recurrent VTE and bleeding were reported separately in their own categories to avoid reporting an outcome more than once in an evidence profi le. However, many original reports and published meta-analyses did not report fatal and nonfatal events separately. In this situa-tion, we have reported the outcome categories of mortality, recur-rent VTE, and major bleeding, with fatal episodes of VTE and bleeding included in both mortality and two specifi c outcomes (ie, fatal episodes of VTE and bleeding are included in two out-comes of the evidence profi le).
With both ways of reporting outcomes, we tried to specifi cally identify deaths from recurrent VTEs and major bleeds. As part of the assessment of the benefi ts and harms of a therapy, we gener-ally assume that � 5% of recurrent episodes of VTE are fatal 11,12 and that � 10% of major bleeds are fatal, 12-14 and if we deviated from these estimates, we noted the reasons for so doing. We did not consider surrogate outcomes (eg, vein patency) when there were adequate data addressing the corresponding outcome of importance to patients (eg, PTS).
When developing evidence profi les, we tried to obtain the baseline risk of outcomes (eg, risk of recurrent VTE or major bleeding) from observational studies because these estimates are most likely to refl ect real-life incidence. In many cases, however, we used data from randomized trials because observational data were lacking or were of low quality. Methodologic issues specifi c to duration of anticoagulation are addressed in the section 3.1 under the subsection on general consideration in weighing the benefi ts and risks of different durations of anticoagulant therapy.
1.3 Patient Values and Preferences
In developing our recommendations, we took into account average patient values for each outcome and preferences for different types of antithrombotic therapy. As described in MacLean et al 15 and Guyatt et al 16 in these guidelines, these values
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
e432S Antithrombotic Therapy for VTE
“S” before the number denote supplementary tables not contained in the body of the article and avail-able instead in an online data supplement. See the “Acknowledgments” for more information.) The need for an initial course of heparin is also supported by the observation that there are high rates of recur-rent VTE during 3 months of follow-up in patients
VKA therapy markedly reduced recurrent PE (0/16 vs 10/19) and appeared to reduce mortality (1/16 vs 5/19) in patients with acute PE. In the early 1990s, a single randomized trial established the need for an initial course of heparin in addition to VKA as com-pared with starting treatment with VKA therapy alone 51 ( Table 3 , Table S1). (Tables that contain an
Table 2—[Section 2.3, 3] Risk Factors for Bleeding With Anticoagulant Therapy and Estimated Risk of Major Bleeding in Low-, Moderate-, and High-Risk Categories
Risk Factorsa
Age . 65 y17-25
Age . 75 y17-21,23,25-34
Previous bleeding18,24,25,30,33-36
Cancer20,24,30,37
Metastatic cancer36.38,
Renal failure18,24,25,28,30,33
Liver failure19,21,27,28
Thrombocytopenia27,36
Previous stroke18,25,27,39
Diabetes18,19,28,32,34
Anemia18,21,27,30,34
Antiplatelet therapy19,27,28,34,40
Poor anticoagulant control22,28,35
Comorbidity and reduced functional capacity24,28,36
Recent surgery21,41,b
Frequent falls27
Alcohol abuse24,25,27,34
Estimated Absolute Risk of Major Bleeding, %Categorization of Risk of Bleedingc Low Riskd (0 Risk Factors) Moderate Riskd (1 Risk Factor) High Riskd (� 2 Risk Factors) Anticoagulation 0-3 moe
Baseline risk (%) 0.6 1.2 4.8 Increased risk (%) 1.0 2.0 8.0 Total risk (%) 1.6e 3.2 12.8f
Anticoagulation after fi rst 3 mog
Baseline risk (%/y) 0.3h 0.6 � 2.5 Increased risk (%/y) 0.5 1.0 � 4.0 Total risk (%/y) 0.8i 1.6i � 6.5
See Table 1 legend for expansion of abbreviations.aThe increase in bleeding associated with a risk factor will vary with (1) severity of the risk factor (eg, location and extent of metastatic disease, platelet count), (2) temporal relationships (eg, interval from surgery or a previous bleeding episode),29 and (3) how effectively a previous cause of bleeding was corrected (eg, upper-GI bleeding).bImportant for parenteral anticoagulation (eg, fi rst 10 d) but less important for long-term or extended anticoagulation.cAlthough there is evidence that risk of bleeding increases with the prevalence of risk factors,20,21,25,27,30,33,34,36,42,43 this categorization scheme has not been validated. Furthermore, a single risk factor, when severe, will result in a high risk of bleeding (eg, major surgery within the past 2 d, severe thrombocytopenia).dCompared with low-risk patients, moderate-risk patients are assumed to have a twofold risk and high-risk patients an eightfold risk of major bleeding.18,20,21,27,28,30,36,44
eThe 1.6% corresponds to the average of major bleeding with initial UFH or LMWH therapy followed by VKA therapy (Table S6 Evidence Profi le: LMWH vs IV UFH for initial anticoagulation of acute VTE). We estimated baseline risk by assuming a 2.6 relative risk of major bleeding with anticoagulation (footnote g in this table).fConsistent with frequency of major bleeding observed by Hull et al41 in high-risk patients.gWe estimate that anticoagulation is associated with a 2.6-fold increase in major bleeding based on comparison of extended anticoagulation with no extended anticoagulation (Table S27 Evidence Profi le: extended anticoagulation vs no extended anticoagulation for different groups of patients with VTE and without cancer). The relative risk of major bleeding during the fi rst 3 mo of therapy may be greater that during extended VKA therapy because (1) the intensity of anticoagulation with initial parenteral therapy may be greater than with VKA therapy; (2) anticoagulant control will be less stable during the fi rst 3 mo; and (3) predispositions to anticoagulant-induced bleeding may be uncovered during the fi rst 3 mo of therapy.22,30,35 However, studies of patients with acute coronary syndromes do not suggest a � 2.6 relative risk of major bleeding with parenteral anticoagulation (eg, UFH or LMWH) compared with control.45,46
hOur estimated baseline risk of major bleeding for low-risk patients (and adjusted up for moderate- and high-risk groups as per footnote d in this table).iConsistent with frequency of major bleeding during prospective studies of extended anticoagulation for VTE22,44,47,48,49 (and Table S27 Evidence Profi le: extended anticoagulation vs no extended anticoagulation for different groups of patients with VTE and without cancer and Table S24).
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account that starting anticoagulant therapy in patients who ultimately have DVT excluded is costly and is a burden to patients and the health-care system. Poor cardiopulmonary reserve may also encourage the use of anticoagulant therapy while awaiting diagnostic testing. If clinicians choose to administer anticoagu-lant therapy and diagnostic testing will be completed within 12 h, we suggest using a 12-h over a 24-h dose of LMWH. VKA therapy usually should not be started before VTE has been confi rmed.
Recommendations
2.2.1. In patients with a high clinical suspicion of acute VTE, we suggest treatment with paren-teral anticoagulants compared with no treat-ment while awaiting the results of diagnostic tests (Grade 2C) .
2.2.2. In patients with an intermediate clinical suspicion of acute VTE, we suggest treatment with parenteral anticoagulants compared with no treat-ment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C) .
2.2.3. In patients with a low clinical suspicion of acute VTE, we suggest not treating with paren-teral anticoagulants while awaiting the results of diagnostic tests, provided test results are expected within 24 h (Grade 2C) .
2.3 Whether and How to Prescribe Anticoagulants to Patients With Isolated Distal DVT
Whether to Look for Isolated Distal DVT and When to Prescribe Anticoagulants if Distal DVT Is Found:
with acute VTE treated with suboptimal heparin therapy. 1,3,52,53 We discuss whether isolated distal (calf) DVT should be sought and if isolated distal DVT is diagnosed, whether and how it should be treated in section 2.3.
Recommendation
2.1. In patients with acute DVT of the leg treated with VKA therapy, we recommend initial treat-ment with parenteral anticoagulation (LMWH, fondaparinux, IV unfractionated heparin [UFH], or SC UFH) over no such initial treatment (Grade 1B) .
2.2 Whether to Treat With Parenteral Anticoagulation While Awaiting the Results of Diagnostic Work-up for VTE
We identifi ed no trial addressing this question. The decision regarding treatment while awaiting test results requires balancing (1) minimizing thrombotic complications in patients with VTE and (2) avoiding bleeding in those without VTE. Our recommenda-tions are based on two principles. First, the higher the clinical suspicion for VTE (use of validated predic-tion models for probability of having DVT 54 or PE 55,56 can usefully inform this assessment, 57 the shorter the acceptable interval without treatment until results of diagnostic testing become available. Second, the higher the risk of bleeding, the longer the acceptable interval without treatment until results are available.
Our recommendations assume that patients do not have major risk factors for bleeding, such as recent surgery. The recommendations also take into
Table 3—[Section 2.1] Summary of Findings: Parenteral Anticoagulation vs No Parenteral Anticoagulation in Acute VTEa, 51
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated absolute effects
Risk With No Parenteral Anticoagulation
Risk Difference With Parenteral Anticoagulation (95% CI)
Mortality 120 (1 study), 6 mo Moderateb,c due to imprecision
RR 0.5 (0.05-5.37)
33 per 1,000 16 fewer per 1,000 (from 31 fewer to 144 more)
VTE symptomatic extension or recurrence
120 (1 study), 6 mo Moderateb,d due to imprecision
RR 0.33 (0.11-0.98)
200 per 1,000 134 fewer per 1,000 (from 4 fewer to 178 fewer)
Major bleeding 120 (1 study), 6 mo Moderateb,c due to imprecision
RR 0.67 (0.12-3.85)
50 per 1,000 16 fewer per 1,000 (from 44 fewer to 142 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. GRADE 5 Grades of Recommendations, Assessment, Development, and Evaluation; RR 5 risk ratio.aBoth groups treated with acenocoumarol.bStudy described as double blinded; outcome adjudicators blinded. None of the study participants were lost to follow-up. Intention-to-treat analysis. Study was stopped early for benefi t.cCI includes values suggesting no effect as well as values suggesting either appreciable benefi t or appreciable harm.dLow number of events caused by the early stoppage of the trial.
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the risk for thrombus extension (the greater the risk, the stronger the indication for anticoagula-tion), we suggest either (1) anticoagulation or (2) withholding of anticoagulation while performing sur-veillance ultrasound examinations to detect thrombus extension. We consider the following to be risk fac-tors for extension: positive D -dimer, thrombosis that is extensive or close to the proximal veins (eg, . 5 cm in length, involves multiple veins, . 7 mm in max-imum diameter), no reversible provoking factor for DVT, active cancer, history of VTE, and inpatient status. 7,60,63,64 Thrombosis that is confi ned to the mus-cular veins has a lower risk of extension than true iso-lated distal DVT. 63,65 We anticipate that isolated distal DVT detected using a selective approach to whole-leg ultrasound often will satisfy criteria for initial anti-coagulation, whereas distal DVT detected by routine whole-leg ultrasound often will not. A high risk for bleeding ( Table 2 ) favors ultrasound surveillance over initial anticoagulation, and the decision to use sur-veillance or initial anticoagulation is expected to be sensitive to patient preferences. The evidence sup-porting recommendations to prescribe anticoagu-lants for isolated calf DVT is low quality because it is not based on direct comparisons of the two man-agement strategies, and the ability to predict exten-sion of distal DVT is limited.
How to Treat With Anticoagulants: A single con-trolled trial of 51 patients with symptomatic isolated distal DVT, all of whom were initially treated with heparin, found that 3 months of VKA therapy pre-vented DVT extension and recurrent VTE (29% vs 0%, P , .01). 66 The evidence in support of parenteral anti-coagulation and VKA ther apy for isolated distal DVT, which includes indirect evidence from patients with acute proximal DVT and PE that is presented else-where in this article, is of moderate quality (there is high-quality evidence that anticoagulation is effec-tive, but uncertainty that benefi ts outweigh risks). There have not been evaluations of alternatives to full-dose anticoagulation of symptomatic isolated dis-tal DVT, and it is possible that less-aggressive anti-coagulant strategies may be adequate. Duration of anticoagulation for isolated distal DVT is discussed in section 3.1.
Recommendations
2.3.1. In patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension (see text), we suggest serial imaging of the deep veins for 2 weeks over ini-tial anticoagulation (Grade 2C) .
2.3.2. In patients with acute isolated distal DVT of the leg and severe symptoms or risk factors
Whether patients with isolated distal DVT (DVT of the calf [peroneal, posterior tibial, anterior tibial veins] without involvement of the popliteal or more proximal veins) are identifi ed depends on how suspected DVT is investigated. 57 If all patients with suspected DVT have ultrasound examination of the calf veins (whole-leg ultrasound), isolated distal DVT accounts for about one-half of all DVT diagnosed. 58 If a diagnostic approach is used that does not include ultrasound examination of the calf veins or that only performs ultrasound examination of the calf veins in selected patients, isolated distal DVT is rarely diagnosed. 59
The primary goal of diagnostic testing for DVT is to identify patients who will benefi t from anticoagulant therapy. This does not mean that all symptomatic DVT need to be identifi ed. Isolated distal DVT do not need to be sought and treated provided that (1) there is strong evidence that the patient does not have a distal DVT that will extend into the proximal veins (ie, the patient is unlikely to have a distal DVT, and if a distal DVT is present, it is unlikely to extend); (2) if this crite-rion is not satisfi ed, a follow-up proximal ultrasound is done after 1 week to detect distal DVT that has extended into the proximal veins, in which case antico-agulant therapy is started; and (3) the patient does not have severe symptoms that would require anticoagu-lant therapy if the symptoms were due to a distal DVT.
Diagnostic approaches to suspected DVT that do not examine the calf veins (eg, use of a combination of clinical assessment, D-dimer testing, single and serial proximal vein ultrasound examination to man-age patients) or only examine the calf veins in selected patients (eg, those who cannot have DVT excluded using the previously noted tests) have been proven safe and are presented in Bates et al 57 in these guide-lines. If the calf veins are imaged (usually with ultra-sound) and isolated distal DVT is diagnosed, there are two management options: (1) treat patients with anticoagulant therapy or (2) do not treat patients with anticoagulant therapy unless extension of the DVT is detected on a follow-up ultrasound examination (eg, after 1 and 2 weeks or sooner if there is concern [there is no widely accepted protocol for surveil-lance ultrasound testing]). 60 Natural history studies suggest that when left untreated, � 15% of symptom-atic distal DVT will extend into the proximal veins and that if extension does not occur within 2 weeks, it is unlikely to occur subsequently. 7,60-62 The risk of extension of isolated distal DVT will vary among patients (see later discussion).
As noted in Bates et al, 57 these guidelines favor diagnostic approaches to suspected DVT other than routine whole-leg ultrasound. If isolated dis-tal DVT is diagnosed, depending on the severity of patient symptoms (the more severe the symptoms, the stronger the indication for anticoagulation) and
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2.5 Choice of Initial Anticoagulant Regimen in Patients With Proximal DVT
Initial anticoagulant regimens vary according to the drug, the route of administration, and whether dose is adjusted in response to laboratory tests of coagulation. Six options are available for the initial treatment of DVT: (1) SC LMWH without moni-toring, (2) IV UFH with monitoring, (3) SC UFH given based on weight initially, with monitoring, (4) SC UFH given based on weight initially, without monitoring, (5) SC fondaparinux given without monitoring, and (6) rivaroxaban given orally. We considered the SC UFH options as a single category because results were similar in studies that used SC UFH with and with-out laboratory monitoring ( Table 5 , Tables S3-S5). Rivaroxaban is used in the acute treatment of VTE without initial parenteral therapy; studies of its use for the acute treatment of VTE are reviewed under long-term treatment of DVT (section 3.1) and PE (section 6) of this article. Recommendations for dosing and monitoring of IV UFH, SC UFH, and SC LMWH are addressed in Garcia et al 1 and Holbrook et al 3 in these guidelines. Because LMWH, fondaparinux, and rivaroxaban have substantial renal excretion, these agents should be avoided (eg, use UFH instead) or should be used with coagulation monitoring (test selection is specifi c to each agent and requires expert interpretation) in patients with marked renal impair-ment (eg, estimated creatinine clearance , 30 mL/min [in a 70-year-old weighing 70 kg, a creatinine clear-ance of 30 mL/min corresponds to a serum creati-nine of about 200 m mol/L (2.3 mg/dL) in a man and 175 m mol/L (2.0 mg/dL) in a woman] http://www.nephron.com/cgi-bin/CGSIdefault.cgi).
LMWH Compared With IV UFH for the Initial Treatment of DVT: A number of meta-analyses 72-75 have summarized the trials addressing this question. The evidence suggests that LMWH is associated with decreased mortality, lower recurrence of VTE, and decreased incidence of major bleeding compared with IV UFH ( Table 6 , Table S6). However, the qual-ity of supporting evidence is low due to a high risk of bias in the primary studies, and evidence of publica-tion bias in favor of LMWH. LMWH has the advan-tage over IV UFH that it is much easier to administer (which makes outpatient treatment feasible) and that it has a lower potential for heparin-induced thrombocytopenia, 69 but the disadvantage is that it accumulates in patients with renal failure.
SC UFH Compared With LMWH for the Initial Treatment of DVT: Four randomized trials have compared SC UFH with SC LMWH ( Table 6 , Tables S3-S5). 70,71,76,77 This evidence suggests that SC UFH is associated with a similar frequency of
for extension (see text), we suggest initial anti-coagulation over serial imaging of the deep veins (Grade 2C) .
Remarks: Patients at high risk for bleeding are more likely to benefi t from serial imaging. Patients who place a high value on avoiding the inconvenience of repeat imaging and a low value on the inconve-nience of treatment and on the potential for bleeding are likely to choose initial anticoagulation over serial imaging.
Recommendations
2.3.3. In patients with acute isolated distal DVT of the leg who are managed with initial anti-coagulation, we recommend using the same approach as for patients with acute proximal DVT (Grade 1B) .
2.3.4. In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we recommend no anticoagulation if the thrombus does not extend (Grade 1B) ; we suggest anticoagulation if the thrombus extends but remains confi ned to the distal veins (Grade 2C) ; we recommend anticoagulation if the thrombus extends into the proximal veins (Grade 1B) .
2.4 Timing of Initiation of VKA and Associated Duration of Parenteral Anticoagulant Therapy
Until � 20 years ago, initiation of VKA therapy was delayed until patients had received about 5 days of heparin therapy, which resulted in patients remain-ing in the hospital until they had received � 10 days of heparin. Three randomized trials 41,67,68 provided moderate-quality evidence that early initiation of VKA, with shortening of heparin therapy to � 5 days, is as effective as delayed initiation of VKA with about a 10-day course of heparin ( Table 4 , Table S2). Short-ening the duration of initial heparin therapy from about 10 to 5 days is expected to have the added advan-tage of reducing the risk of heparin-induced throm-bocytopenia. 69 If the international normalized ratio (INR) exceeds the therapeutic range (ie, INR . 3.0) prematurely, it is acceptable to stop parenteral therapy before the patient has received 5 days of treatment.
Recommendation
2.4. In patients with acute DVT of the leg, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral antico-agulation for a minimum of 5 days and until the INR is 2.0 or above for at least 24 h (Grade 1B) .
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equivalence of fondaparinux to LMWH for the treat-ment of acute VTE.
Fondaparinux Compared With IV UFH for the Ini-tial Treatment of DVT: In the absence of direct evi-dence in patients with DVT, indirect evidence in patients with acute PE (section 5.4) suggests that fondaparinux is equivalent to IV UFH. 79 As noted previously, we judge that fondaparinux and LMWH are equivalent; fondaparinux also shares the advan-tages that LMWH has over IV UFH and the disad-vantage that it is renally excreted (section 2.5). The quality of the evidence regarding the comparison of fondaparinux and UFH is moderate as, although there is some indirectness, it is minor.
Fondaparinux Compared With SC UFH for the Initial Treatment of DVT: There is no direct evidence for this comparison in any patient population. Our recommendation is based on our assessment that
mortality, recurrent VTE, and major bleeding as LMWH. However, the quality of the evidence is mod erate because of imprecision. LMWH has the disadvantage of a higher cost but is more conve-nient to use (LMWH can be administered once daily [see later discussion]), is more widely available for use in outpatients, has a lower potential for heparin-induced thrombocytopenia, 69 and there is much more experience with its use than with SC UFH.
Fondaparinux Compared With LMWH for the Initial Treatment of DVT: The Matisse-DVT trial 78 compared fondaparinux with LMWH for short-term treatment of DVT ( Table 7 , Table S7). This study sug-gests that fondaparinux is associated with a similar frequency of mortality, recurrent VTE, and major bleeding as LMWH. However, the quality of the evidence from this study was moderate because of imprecision. Evidence that fondaparinux is effective for the treatment of PE 79 (section 5.4) supports the
Table 4—[Recommendation 2.4] Summary of Findings: Early Warfarin (and Shorter Duration Heparin) vs Delayed Warfarin (and Longer Duration Heparin) for Acute VTEa-d,41,67,68
OutcomesNo. of Participants
(Studies), Follow-up
Quality of the Evidence (GRADE)
Relative Effect (95%
CI)
Anticipated Absolute Effects
Risk With Delayed Warfarin Initiation (and Longer
Duration Heparin)
Risk Difference With Early Warfarin Initiation (and Shorter Duration
Heparin) (95% CI)
Mortality 688 (3 studies), 3 moe Moderatef,g due to imprecision
RR 0.9 (0.41-1.95)
24 per 1,000h 2 fewer per 1,000 (from 14 fewer to 23 more)
Recurrent VTE 688 (3 studies), 3 moe Moderatef,g due to imprecision
RR 0.83 (0.4-1.74)
47 per 1,000h 8 fewer per 1,000 (from 28 fewer to 35 more)
Major bleeding 688 (3 studies), 3 moi Highf,j,k RR 1.48 (0.68-3.23)
16 per 1,000h 14 more per 1,000 (from 9 fewer to 66 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aMost patients had proximal DVT, some had isolated distal DVT, most DVT were symptomatic (asymptomatic DVT included in Hull et al41), and few had PE (only included in Gallus et al67).bThe early initiation of VKA was associated with a fewer number of days of heparin therapy (4.1 vs 9.5 in Gallus et al67; 5 vs 10 in Hull et al41) and a fewer number of days of hospital stay (9.1 vs 13.0 in Gallus et al; 11.7 vs 14.7 in Hull et al; 11.9 vs 16.0 in Leroyer et al68).cVKA therapy started within 1 day of starting heparin therapy (UFH in two studies and LMWH in one study).dVKA therapy delayed for 4 to 10 d.eOutcome assessment was at hospital discharge in the study by Gallus et al67 (although there was also extended follow-up) and 3 mo in the studies by Hull et al41 and Leroyer et al.68
fPatients and investigators were not blinded in two studies (Gallus et al67 and Leroyer et al68) and were blinded in one study (Hull et al41). Concealment was not clearly described but was probable in the three studies. Primary outcome appears to have been assessed after a shorter duration of follow-up in the shorter treatment arm of one study because of earlier discharge from hospital, and 20% of subjects in this study were excluded from the fi nal analysis postrandomization (Gallus et al).gThe 95% CI on relative effect includes both clinically important benefi t and clinically important harm.hEvent rate corresponds to the median event rate in the included studies.iBleeding was assessed early (in hospital or in the fi rst 10 d) in two studies (Gallus et al67 and Hull et al41) and at 3 mo in one study (Leroyer et al68).jIt is unclear whether bleeding was assessed at 10 d in all subjects or just while heparin was being administered, which could yield a biased estimate in favor of short-duration therapy in one study (Hull et al41).kBecause the shorter duration of heparin therapy is very unlikely to increase bleeding, the wide 95% CIs around the relative effect of shorter therapy on risk of bleeding is not a major concern.
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Table 6—[Section 2.5.1] Summary of Findings: LMWH vs IV UFH for Initial Anticoagulation of Acute VTE74
OutcomesNo. of Participants (Studies),
Follow-upQuality of the Evidence
(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With IV UFHRisk Difference With
LMWH (95% CI)
All-cause mortality
7,908 (17 studies), 3 mo Lowa,b due to risk of bias, publication bias
RR 0.79 (0.66-0.95) 46 per 1,000c 10 fewer per 1,000 (from 2 fewer to 16 fewer)
Recurrent VTE 7,976 (17 studies), 3 mo Lowa,b due to risk of bias, publication bias
RR 0.72 (0.58-0.89) 55 per 1,000c 15 fewer per ,1000 (from 6 fewer to 23 fewer)
Major bleeding 6,910 (20 studies), 3 mo Lowa,b,d due to risk of bias, publication bias
RR 0.67 (0.45-1) 15 per 1,000c 5 fewer per 1,000 (from 8 fewer to 0 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aOf the 20 trials, allocation was concealed in nine and was unclear whether concealed in the remaining 11. In 18 trials, outcome assessors were blinded. Seven trials did not have any postrandomization exclusions or losses to follow-up. Ten trials reported the number of participants lost to follow-up, which ranged from 1.0% to 12.7%. One trial did not report the drop-outs.bInverted funnel plot very suggestive of publication bias. Many of the included studies are of small size, and all were funded by industry.cEvent rate corresponds to the median event rate in the included studies.dCI includes values suggesting signifi cant benefi t and no effect.
fi ve of these studies 83-87 that had unconfounded com-parisons. This evidence suggests that LMWH once daily and twice daily are associated with similar mor-tality, recurrent VTE, and major bleeding. However, the quality of the evidence is low because of impre-cision and inconsistency. The sixth study that used a lower total daily dose of LMWH with once-daily compared with twice-daily administration (enox-aparin 1.5 mg/kg once daily vs 1.0 mg/kg bid; enox-aparin 2 mg/kg once daily is not used) suggested that outcomes might be inferior with this once-daily regimen. 85
fondaparinux and LMWH are equivalent and that fondaparinux shares the advantages that LMWH has over SC UFH (section 2.5). This recommendation does not take into account difference in purchase cost between SC UFH and fondaparinux and is based on low-quality evidence.
Once- vs Twice-Daily Administration of LMWH for Initial Treatment of DVT: Two meta-analyses 80,81 summarized six studies comparing once-daily and twice-daily administrations of the same LMWH. 82-87 Table 8 and Table S8 summarize the fi ndings of
Table 5—[Section 2.5.1] Summary of Findings: LMWH vs SC UFH for Initial Anticoagulation of Acute VTE70,71,76,77
OutcomesNo. of Participants (Studies),
Follow-upQuality of the Evidence
(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With SC UFHRisk Difference With
LMWH (95% CI)
All-cause mortality
1,566 (3 studies), 3 mo Moderatea,b due to imprecision
RR 1.1 (0.68-1.76) 33 per 1,000c 3 more per 1,000 (from 11 fewer to 25 more)
Recurrent VTE 1,563 (3 studies), 3 mo Moderatea,b due to imprecision
RR 0.87 (0.52-1.45) 42 per 1,000c 5 fewer per 1,000 (from 20 fewer to 19 more)
Major bleeding 1,634 (4 studies), 3 mo Moderatea,b due to imprecision
RR 1.27 (0.56-2.9) 16 per 1,000c 4 more per 1,000 (from 7 fewer to 30 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. SC 5 subcutaneous. See Table 1 and 3 legends for expansion of abbreviations.aIn the two largest trials (Prandoni et al,70 Kearon et al;71 87% of patients), allocation was concealed, outcome adjudicators and data analysts were concealed, analysis was intention to treat, and there were no losses to follow-up.bPrecision judged from the perspective of whether SC heparin is noninferior to LMWH. The total number of events and the total number of participants were relatively low.cEvent rate corresponds to the median event rate in the included studies.
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Remarks: Local considerations such as cost, avail-ability, and familiarity of use dictate the choice between fondaparinux and LMWH. LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH.
Recommendations
2.5.1. In patients with acute DVT of the leg, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) .
Table 7—[Section 2.5.1] Summary of Findings: Fondaparinux vs LMWH for Initial Anticoagulation of Acute DVTa-c,78
OutcomesNo. of Participants (Studies),
Follow-upQuality of the Evidence
(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With LMWHRisk Difference With
Fondaparinux (95% CI)
Mortality 2,205 (1 study), 3 mo Moderated,e due to imprecision
RR 1.25 (0.8-1.97) 30 per 1,000 7 more per 1,000 (from 6 fewer to 29 more)
Recurrent VTE 2,205 (1 study), 3 mo Moderated,e due to imprecision
RR 0.96 (0.64-1.45) 41 per 1,000f 2 fewer per 1,000 (from 15 fewer to 18 more)
Major bleeding 2,205 (1 study), 3 mo Moderated,e due to imprecision
RR 0.93 (0.43-2.03) 12 per 1,000g 1 fewer per 1,000 (from 7 fewer to 12 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aAll patients had acute symptomatic DVT.bFondaparinux 7.5 mg (5.0 mg in patients weighing , 50 kg and 10.0 mg in patients weighing . 100 kg) SC once daily for at least 5 d and until VKAs induced an INR . 2.0.cEnoxaparin 1 mg/kg of body weight SC bid for at least 5 d and until VKAs induced an INR . 2.0.dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Analysis excluded 0.6% of randomized patients. Not stopped early for benefi t.eCI includes values suggesting no effect and values suggesting either benefi t or harm; relatively low number of events.fFive fatal VTE in fondaparinux group and fi ve fatal VTE in LMWH group.g Twelve patients in the fondaparinux group and 13 in the LMWH group had a major bleeding event during the initial period (7 d). Of these, two in the fondaparinux group and none in the LMWH group were fatal.
Table 8—[Section 2.5.2] Summary of Findings: LMWH Once vs Twice Daily for Initial Anticoagulation of Acute VTEa,b,81
OutcomesNo. of Participants
(Studies), Follow-upQuality of the Evidence
(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With Twice Daily
Risk Difference With LMWH Once Daily (95% CI)
Mortality 1,261 (3 studies), 3 mo Lowc-e due to inconsistency and imprecision
RR 1.05 (0.57-1.94) 31 per 1,000 2 more per 1,000 (from 13 fewer to 29 more)
VTE recurrence 1,261 (3 studies), 3 mo Lowc,e,f due to inconsistency and imprecision
RR 0.86 (0.52-1.42) 49 per 1,000 7 fewer per 1,000 (from 24 fewer to 21 more)
Major bleeding 1,522 (5 studies), 10 d Moderatec,e due to imprecision
RR 1.13 (0.48-2.66) 12 per 1,000 2 more per 1,000 (from 6 fewer to 20 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aOf the fi ve included studies, one included patients with PE and DVT and four included only patients with DVT. All studies addressed the initial management of VTE.bThe fi ve included studies used four brands of LMWH (enoxaparin, tinzaparin, dalteparin, and nadroparin). In Merli et al,85 enoxaparin 1 mg/kg bid was compared with 1.5 mg/kg once daily. Holmström et al84 adjusted the dose to anti-Xa levels, which resulted in different daily doses after a number of days. In the remaining studies, the dose of the once-daily administration was double the dose of the twice-daily administration (equal total daily dose).cAll included studies concealed allocation. Two studies had a double-blind design, and two others were single blind. One study did not mention blinding. Intention to treat likely used in all studies. Participants were lost to follow-up in only two studies (0.3% and 2.2%).dI2 5 37%; point effect estimate in favor of twice-daily dose in Merli et al85 and in favor of once-daily dose in Charbonnier et al.83
eImprecision judged relative to no difference.fI2 5 65%; point effect estimate in favor of twice-daily dose in Merli et al85 and in favor of once-daily dose in Charbonnier.83
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conditional on the patient feeling well enough to be treated at home (eg, does not have severe leg symp-toms or comorbidity).
2.8 Treatment Strategies of Thrombus Removal for Acute DVT
Treatments that actively remove thrombus in patients with acute DVT have the potential to reduce acute symptoms and the risk of developing PTS. Patients with DVT that involves the iliac and common femoral veins are at highest risk for PTS and, therefore, are the subset with the greatest potential to benefi t from thrombus removal strategies. 102 Thrombus removal strategies are indicated in patients with the very rare complication of impending venous gangrene despite optimal anticoagulant therapy; such patients are not the focus of the following sections. A recent trial that randomized 183 patients with proximal DVT to per-cutaneous endovascular intervention or to anticoagu-lant therapy alone reported reduced acute symptoms, hospital stay, recurrent VTE, and PTS at 6 months in the thrombus removal group. 103 This trial, which had a high potential for bias (randomization not described, no blinding), is not considered further because it was not possible to determine outcomes in patients treated with mechanical thrombectomy alone and in those treated with thrombolytic therapy.
2.9 Catheter-Directed Thrombolysis for Acute DVT
The rationale for catheter-directed thrombolysis (CDT) is that compared with systemic thromboly-sis, it will achieve lysis of thrombus more rapidly and with lower doses of thrombolytic therapy, thereby reducing serious bleeding. The addition of mechan-ical thrombus fragmentation (collectively referred to as pharmacomechanical thrombolysis) with or with-out aspiration can further reduce the dose of throm-bolytic therapy and shorten the procedure. 104
One randomized trial of CDT has been com-pleted, 105 and a second has reported short-term outcomes (but not the development of PTS). 106,107 Table 10 and Table S10 present the combined fi nd-ings from these studies (see also Tables S11 and S12). This evidence suggests that CDT may reduce PTS and improve quality of life without being associated with an unacceptable increase in bleeding. However, the quality of evidence is low for mortality, recur-rent VTE, and major bleeding because of very serious imprecision, and is low for PTS because of indirect-ness (ie, use of surrogate outcome [PTS has yet to be measured directly during follow-up]).
In addition to the two randomized trials, 105,106 fi ndings of observational studies suggest that CDT improves venous patency and preserves venous valve function (Tables S11 and S12). Use of CDT, however, requires
2.5.2. In patients with acute DVT of the leg treated with LMWH, we suggest once- over twice-daily administration (Grade 2C) .
Remarks: This recommendation only applies when the approved once-daily regimen uses the same daily dose as the twice-daily regimen (ie, the once-daily injection contains double the dose of each twice-daily injection). It also places value on avoiding an extra injection per day.
2.6 Initial Treatment With Rivaroxaban vs Parenteral Therapy
One trial directly compared short- and long-term rivaroxaban (without initial parenteral anticoagula-tion) with parenteral anticoagulation (LMWH) and VKA in patients with acute DVT. 88 The fi ndings of this study and associated recommendations are pre-sented in section 3.3.
2.7 At-Home vs In-Hospital Initial Treatment of DVT
One trial of 201 patients directly compared outpa-tient and inpatient administration of the same initial anticoagulant regimen (three LMWH preparations were used); there were few recurrent VTE and major bleeds in each group. 89 A number of trials 90-94 have compared LMWH administered at home (without hospital admis-sion or after early discharge) in a substantial proportion of patients, with IV UFH administered in the hospital ( Table 9 , Table S9). This evidence suggests that home treatment is not associated with an increase in mortality, recurrent VTE, or major bleeding and may be asso-ciated with improved outcomes. However, the quality of the evidence is moderate because of indirectness (patients were not explicitly randomized to home therapy in most studies) and imprecision.
Health economic evaluations that have assessed initial treatment of DVT at home, although they have weaknesses (eg, industry funded, not derived from trials in which LMWH was used both in the hospital and at home, short time horizon (ie, � 3 months), and limited use of sensitivity analyses), all conclude that home treatment is cost-saving (about US $500-$2,500 per patient). 95-101
Recommendation
2.7. In patients with acute DVT of the leg and whose home circumstances are adequate, we rec-ommend initial treatment at home over treat-ment in hospital (Grade 1B) .
Remarks: The recommendation is conditional on the adequacy of the following home circumstances: well-maintained living conditions, strong support from family or friends, phone access, and ability to quickly return to hospital if there is deterioration. It is also
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assess the benefi t or risk of inserting an IVC fi lter in patients who have CDT performed (recommended by manufacturer with some endovascular devices and techniques, whereas not with others). Percutaneous mechanical venous thrombectomy without concomi-tant thrombolysis has not been evaluated in random-ized trials, and its use is discouraged because small retrospective studies suggest that it often fails to remove much of the thrombus 115,116 and is associated with a high risk of PE. 117,118
Recommendation
2.9. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over CDT (Grade 2C) .
substantial resources and expertise. Patients who are most likely to benefi t from CDT have iliofemoral DVT, symptoms for , 14 days, good functional status, life expectancy of � 1 year, and a low risk of bleeding ( Table 11 ). Because the balance of risks and benefi ts with CDT is uncertain, anticoagulant therapy alone is an acceptable alternative to CDT in all patients with acute DVT who do not have impending venous gangrene.
There is no single standardized approach to per-forming CDT or pharmacomechanical thrombolysis. If these interventions are performed, the technique used will vary with local resources and expertise. If CDT has been successful but there are residual lesions in the common femoral or more proximal veins, balloon angioplasty and stenting often are used to relieve obstruction. There are inadequate data to
Table 9—[Section 2.7] Summary of Findings: Home Treatment vs Hospital Treatment of Acute DVTa-d,442
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With Hospital Treatment
Risk Difference With Home Treatment (95% CI)
Mortality 1,708 (6 studies), 3 mo
Lowc-f due to indirectness and imprecision
RR 0.72 (0.45-1.15) 46 per 1,000 13 fewer per 1,000 (from 25 fewer to 7 more)
Recurrent VTE 1,708 (6 studies), 3 mo
Moderatec-e due to indirectness RR 0.61 (0.42-0.9) 74 per 1,000 29 fewer per 1,000 (from 7 fewer to 43 fewer)
Major bleeding 1,708 (6 studies), 3 mo
Moderatec-e,g due to indirectness RR 0.67 (0.33-1.36) 21 per 1,000 7 fewer per 1,000 (from 14 fewer to 8 more)
QOL 0 (3 studiesh), 3 mo
Lowi-k due to indirectness and imprecision
Not estimable … h
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aStudies included in the systematic review should have recruited patients whose home circumstances were adequate.bAll studies included patients with lower-extremity DVT and excluded patients with suspected or confi rmed PE. Studies also excluded patients who were pregnant.cFour studies had partial hospital treatment of many in the home arm: Koopman et al92 (mean hospital stay, 2.7 in home arm vs 8.1 d in hospital arm), Levine et al93 (2.1 vs 6.5 d), Boccalon et al89 (1 vs 9.6 d), and Ramacciotti et al94 (3 vs 7 d). In Daskalopoulos et al,91 there was no hospital stay at all in the home group. Chong et al90 did not report duration of hospital stay.dOnly one study (Boccalon et al89) used LMWH in both treatment arms. Remaining studies used UFH in the inpatient arm and LMWH in the outpatient arm.eOut of six studies, allocation was clearly concealed in three (unclear in remaining three), outcome adjudicators were blinded in the two largest studies (unclear in remaining four), loss to follow-up was signifi cant in only one small study, intention-to-treat analysis was conducted in four (unclear in remaining two), and no study was stopped early for benefi t. Overall, the judgment was that these limitations would not warrant downgrading of quality; it has already been downgraded by at least one level based on other factors.fThe CI includes values suggesting benefi t and harm.gJudged as precise based on the narrow CI around absolute effect.hBäckman et al95 reported evaluation of health-related QOL using the EQ-5D. They found no differences in mean QOL scores or in the proportion of patients showing improvement in self-rated health state. Koopman et al92 evaluated health-related QOL using the Medical Outcome Study Short Form-20 and an adapted version of the Rotterdam Symptom Checklist. The changes over time were similar in both groups, except that the patients receiving LMWH had better scores for physical activity (P 5 .002) and social functioning (P 5 .001) at the end of the initial treatment. The authors did not report enough data to assess precision and clinical signifi cance of results. O’Brien et al96 assessed changes in QOL using the Medical Outcome Study Short Form-36 in 300 patients participating in Levine et al.93 They found that the change in scores from baseline to day 7 was not signifi cantly different between the treatment groups for seven of the eight domains. The one exception was the domain of social functioning, where a greater improvement was observed for the outpatient group.iPotential inconsistency as Bäckman et al95 showed no effect, whereas Koopman et al92 and O’Brien et al96 showed potential benefi t.jTwo of the three studies had partial hospital treatment of many in the home arm: Koopman et al92 (mean hospital stay, 2.7 in home arm vs 8.1 d in hospital arm) and Levine et al93 (2.1 vs 6.5 d).kNot able to evaluate, but imprecision is possible. Taken together with the potential inconsistency, we downgraded the quality of evidence by one level.
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bleeding, and PTS ( Table 12 , Table S15). This evi-dence suggests that systemic thrombolysis has the potential to reduce PTS at the expense of an increase in major bleeding. However, the overall quality of this evidence is low because of imprecision and risk of bias.
There have been no direct comparisons of different thrombolytic agents; however, prolonged infusions of streptokinase that were used predominantly in the earlier studies appear to be associated with higher bleeding rates than other regimens. No random-ized trial has compared systemic thrombolysis with CDT, but a single-center, retrospective study 127 sug-gested that systemic thrombolysis achieves less
Remarks: Patients who are most likely to benefi t from CDT (see text) and attach a high value to prevention of PTS and a lower value to the initial complexity, cost, and risk of bleeding with CDT are likely to choose CDT over anticoagulation alone.
2.10 Systemic Thrombolytic Therapy for Acute DVT
Many trials of systemic thrombolysis for the treat-ment of DVT assessed early lysis, often reported bleeding, but rarely reported recurrent VTE or development of PTS (Table S13 and S14). 119-137 A meta-analysis 138 summarized the fi ndings of trials that assessed mortality, recurrent VTE, major
Table 10—[Section 2.9] Summary of Findings: CDT vs No CDT for Extensive Acute DVT of the Lega,b,105,106
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No CDT
Risk Difference With CDT (95% CI)
Mortality 153 (2 studies), 3 mo Lowc,d due to imprecision
RR 0.14 (0.01-2.71) 39 per 1,000e 34 fewer per 1,000 (from 39 fewer to 67 more)
Nonfatal recurrent VTE 153 (1 study), 3 mo Lowc,d due to imprecision
RR 0.35 (0-8.09) 48 per 1,000f 31 fewer per 1,000 (from 48 fewer to 340 more)
Nonfatal major bleeding 153 (2 studies), 7 d Lowc,d due to imprecision
RR 2.00 (0.19-19.46) 29 per 1,0006,7 29 more per 1,000 (from 23 fewer to 535 more)
PTS (complete lysis on venography [Elsharawy et al73]; patency on ultrasound and air plethysmography [Enden et al74])
138 (2 studies), 2 y Moderatec,g due to indirectness
RR 0.46 (0-0.79) 588 per 1,000h 318 fewer per 1,000 (from 123 fewer to 588 fewer)i
QOL (SF-12, HUI Mark version 2/3 questionnaires)
98 (1 studyj), 16 mo Lowk,l See footnotem
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. HUI 5 Health Utilities Index; SF-12 5 Medical Outcomes Survey Short Form-12; VETO 5 Venous Thrombosis Outcomes. See Table 1 and 3 legends for expansion of other abbreviations.aIn selected patients with extensive acute proximal DVT (eg, iliofemoral DVT, symptoms for , 14 d, good functional status, life expectancy � 1 y) who have a low risk of bleeding.bAll patients prescribed anticoagulants per protocol, but the intervention group receives CDT in addition to anticoagulation.cAllocation was concealed in Enden et al106 but unclear in Elsharawy et al.105 Outcome assessor blinded in both studies. Follow-up rates were 87% in Enden et al and 100% in Elsharawy et al. Neither of the studies was stopped early for benefi t.dCI includes values suggesting both benefi t and harm.eThree control patients died of cancer.fBaseline risks for nonfatal recurrent VTE and for major bleeding derived from Douketis et al.108
gSurrogate outcome: absence of patency at 6 mo in Enden et al106 study; absence of complete lysis at 6 mo in Elsharawy et al105 study.hThis estimate is based on the fi ndings of the VETO study.102 This probably underestimates PTS baseline risk given that overall, 52% of patients reported the current use of compression stockings during study follow-up.iSevere PTS: assuming the same RR of 0.46 and a baseline risk of 13.8%,102 the absolute reduction is 75 fewer severe PTS per 1,000 (from 29 fewer to 138 fewer) over 2 y.jCamerota et al.109
kParticipation rate was 65%.lRecall was used to measure QOL prior to the thrombotic event; we did not consider these measurements.mAt the initial follow-up (mean, 16 mo), patients treated with CDT reported a trend toward a higher mental summary scale (P 5 .087) and improved HUI (P 5 .078). They reported better overall role physical functioning (P 5 .046), less stigma (P 5 .033), less health distress (P 5 .022), and fewer overall symptoms (P 5 .006) compared with patients who were treated with anticoagulation alone.
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lysis (31% vs 50%) and less preservation of valve function (13% vs 44%) (Tables S13 and S14), and the higher doses of thrombolytic agent used with
sys temic thrombolysis are expected to be associ-ated with a higher risk of nonprocedure-related bleeding.
We believe that systemic thrombolysis should be considered only in patients who meet all of the following criteria: iliofemoral DVT, symptoms for , 14 days, good functional status, life expec-tancy of � 1 year, and low risk of bleeding ( Table 11 ). Based on low-quality evidence of greater effective-ness and less bleeding, if resources and expertise are available to perform CDT, we consider it the preferable approach. Because the balance of risks and benefi ts with systemic thrombolysis is uncertain, and particularly because of concerns about major bleeding, anticoagulant therapy alone is an accept-able alternative to systemic thrombolysis in all patients with acute DVT who do not have impending venous gangrene.
Recommendation
2.10. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over systemic thrombolysis (Grade 2C) .
Remarks: Patients who are most likely to benefi t from systemic thrombolytic therapy (see text), who do not have access to CDT, and who attach a high value to prevention of PTS and a lower value to the initial complexity, cost, and risk of bleeding with systemic thrombolytic therapy are likely to choose systemic thrombolytic therapy over anticoagulation alone.
2.11 Operative Venous Thrombectomy for Acute DVT
Operative venous thrombectomy, with contempo-rary operative techniques 140 and more effective anti-coagulant regimens, appears to achieve improved outcomes compared with earlier reports. 141,142 A single small randomized trial with extended follow-up com-pared iliofemoral venous thrombectomy with a tem-porary arteriovenous fi stula plus anticoagulation with anticoagulation alone. 143-145 Results at 6 months, 5 years, and 10 years suggested improved iliac vein patency, less leg swelling, and fewer leg ulcers with throm-bectomy ( Table 13 , Tables S16-S18). 143-145 Evidence from this trial is of low quality because of impreci-sion and risk of bias.
We believe that operative venous thrombec-tomy should be considered only if all of the following criteria are met: iliofemoral DVT, symp-toms for , 7 days (criterion used in the single randomized trial), good functional status, life expec-tancy of � 1 year, and both resources and expertise are available. Based on low-quality evidence of greater effectiveness and less bleeding, we consider
Table 11—[Section 2.9, 2.10, 5.6, 9.2] Risk Factors for Bleeding With and Contraindications to Use of Thrombolytic Therapy (Both Systemic and Locally
Administered)
Major contraindicationsa
Structural intracranial disease Previous intracranial hemorrhage Ischemic stroke within 3 mo Active bleeding Recent brain or spinal surgery Recent head trauma with fracture or brain injury Bleeding diathesisRelative contraindicationsb
Systolic BP . 180 mm Hg Diastolic BP . 110 mm Hg Recent bleeding (nonintracranial) Recent surgery Recent invasive procedure Ischemic stroke more that 3 mo previously Anticoagulation (eg, VKA therapy) Traumatic cardiopulmonary resuscitation Pericarditis or pericardial fl uid Diabetic retinopathy Pregnancy Age . 75 y Low body weight (eg, , 60 kg) Female sex Black race
Among 32,000 Medicare patients (� 65 y) with myocardial infarc-tion who were treated with thrombolytic therapy, the following fac-tors were independently associated with intracranial hemorrhage: age � 75 y (OR, 1.6), black race (OR, 1.6), female sex (OR, 1.4), previous stroke (OR, 1.5), systolic BP � 160 mm Hg (OR, 1.8), women weighing � 65 kg or men weighing � 80 kg (OR, 1.5), and INR . 4 (OR, 2.2).110 The rate of intracranial hemorrhage increased from 0.7% with none or one of these risk factors to 4.1% with fi ve or more of these risk factors. Among 32,000 patients with myocardial infarction who were treated with thrombolytic therapy in fi ve clini-cal trials, the following factors were independently associated with moderate or severe bleeding: older age (OR, 1.04 per year), black race (OR, 1.4), female sex (OR, 1.5), hypertension (OR, 1.2), and lower weight (OR, 0.99/kg).111 We estimated that systemic thrombolytic therapy is associated with a relative risk of major bleeding of 3.5 within 35 d (RR, �7 for intracranial bleeding); about three-fourths of the excess of major bleeds with thrombolytic therapy occur in the fi rst 24 h.112 See Table 1 legend for expansion of abbreviations.aThe presence of major contraindications usually precludes use of thrombolytic therapy and, consequently, these factors have not been well studied as risk factors for bleeding associated with thrombolytic therapy. The factors listed in this table are consistent with other recommendations for the use of thrombolytic therapy in patients with PE.72,259,260,454 104,111,113,114
bRisk factors for bleeding during anticoagulant therapy noted in Table 10 that are not included in this table are also likely to be relative contraindications to thrombolytic therapy. The increase in bleeding associated with a risk factor will vary with (1) severity of the risk factor (eg, extent of trauma or recent surgery) and (2) temporal relationships (eg, interval from surgery or a previous bleeding episode believed to decrease markedly after �2 wk). Risk factors for bleeding at critical sites (eg, intracranial, intraocular) or noncompressible sites are stronger contraindications for thrombolytic therapy.
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method of thrombus removal (including systemic thrombolysis). Mechanical components of these procedures are associated with a high early risk of early recurrent thrombosis, and thrombus removal is not known to alter the long-term risk of recurrent VTE. We used evidence from patients with DVT who did not have thrombus removal to guide anti-coagulant decisions in those who had thrombus removal. This evidence is rated down to moderate quality because of its indirectness in this patient population.
Recommendation
2.12. In patients with acute DVT of the leg who undergo thrombosis removal, we recommend
CDT preferable to the operative venous thrombec-tomy approach.
Recommendation
2.11. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over operative venous thrombectomy (Grade 2C) .
2.12 Anticoagulation in Patients Who Have Had Any Method of Thrombus Removal Performed
There are no randomized trials or observational studies that have compared different anticoagulant regimens or durations of therapy in patients with acute proximal DVT of the leg who have had any
Table 12—[Section 2.10] Summary of Findings: Systemic Lysis vs No Systemic Lysis for Extensive Acute DVT of the Leg138
OutcomesNo. of Participants
(Studies), Follow-upQuality of the Evidence
(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No Systemic Lysis
Risk Difference With Systemic Lysis (95% CI)
Mortality 688 (5 studies), 3 moa Lowb-e due to imprecision RR 0.86 (0.27-2.68) 21 per 1,000 3 fewer per 1,000 (from 16 fewer to 36 more)
Nonfatal recurrent VTE
687 (3 studies), 3 mof Lowd,e,g due to imprecision RR 1.28 (0.25-6.68) 48 per 1,000h 13 more per 1,000 (from 36 fewer to 273 more)
Nonfatal major bleeding
688 (10 studies), 3 mof Moderatec,d,i due to imprecision
RR 1.84 (0.94-3.59) 29 per 1,000h,j 24 more per 1,000 (from 2 fewer to 75 more)
PTS 678 (2 studies), 2 yk Lowd,e,l,m due to risk of bias and imprecision
RR 0.71 (0.49-1.04) 588 per 1,000n 171 fewer per 1,000 (from 300 fewer to 24 more)o
QOL not measured
… … … … …
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1, 3, and 10 legends for expansion of abbreviations.aRange of follow-up in included studies, 1 to 72 mo.bAllocation was concealed in three of fi ve studies. Follow-up inadequate in one of fi ve studies (Common et al139). Excluding this study from the analysis does not change the effect estimate. All studies had blinded outcome assessors. None of the studies used a placebo control.cThe population of one study (Schulman et al131) comprised patients with calf vein thrombosis.dInterventions varied across studies with regard to agent (eg, tissue plasminogen activator, streptokinase, urokinase), dose, use of the pedal vein administration, duration of treatment, and concomitant drugs (eg, steroids). However, we did not downgrade for indirectness given that there was no standard regimen and all analyses showed no heterogeneity in results.eCI included both no effect and a potentially signifi cant effect.fRange of follow-up in included studies, 1 to 30 d.gAllocation was concealed in two of three studies. Follow-up adequate in all studies. All studies had blinded outcome assessors. None of the studies used a placebo control.hBaseline risks for nonfatal recurrent VTE and for major bleeding derived from Douketis et al.108
iAllocation was concealed in seven of 10 studies. Follow-up inadequate in one of 10 studies (Common et al139). Excluding this study from the analysis does not affect the effect estimate. All studies had blinded outcome assessors. Two studies used placebo (Turpie et al135 and Verhaeghe et al136).jOnly 4% of all major bleeding events were intracranial bleeds.kRange of follow-up in included studies, 1 to 6 y.lAllocation was concealed in two of two studies. Follow-up adequate in both studies. Both studies had blinded outcome assessors. Neither study used placebo control.mNo use of a standardized validated tool reported.nThis estimate is based on the fi ndings of the VETO study.102 This probably underestimates PTS baseline risk, given that overall, 52% of patients reported the current use of compression stockings during study follow-up.oSevere PTS: Assuming the same RR of 0.71 and a baseline risk of 13.8%,102 the absolute reduction is 40 fewer severe PTS per 1,000 (from 70 fewer to 6 more) over 2 y.
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bleeding), we assume that the relative risk of out-comes will be the same as in patients who received anticoagulant therapy in the Prevention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC) study. However, their absolute rate of symptomatic PE and recurrent DVT will be higher compared with the PREPIC participants who were prescribed antico-agulants. A comprehensive review of mostly retrospec-tive case series of IVC fi lter insertions (6,500 patients in 89 reports) suggested that venous thrombosis at the site of fi lter insertion occurs in � 10% of patients and that fi lters can be placed above the renal veins and in the superior vena cava if necessary. 150 A prospec-tive observational study also suggested that symp-tomatic VTE and asymptomatic fi lter thrombosis are common, 151 and a systematic review suggested that the prevalence of PTS may be increased 152 in patients with permanent IVC fi lters. A small single-center randomized trial suggested a higher complication rate with the Trapease compared with the Green-fi eld permanent fi lter. 153
the same intensity and duration of anticoagu-lant therapy as in similar patients who do not undergo thrombosis removal (Grade 1B) .
2.13 Vena Caval Filters for the Initial Treatment of DVT
No randomized trial or prospective observational study has evaluated IVC fi lters as sole therapy (ie, without concurrent anticoagulation) in patients with DVT. A single, large, randomized controlled trial evaluated permanent IVC fi lter insertion as an adjunct to anticoagulant therapy in patients with acute DVT who were considered to be at high risk for PE ( Table 14 , Table S19). The fi ndings at 2 years 146 and 8 years 149 of follow-up, suggest that IVC fi lters increase the risk of recurrent DVT, reduce the risk of PE, do not alter the combined frequency of DVT and PE (ie, recurrent VTE), do not increase the risk of PTS, and do not alter mortality.
In assessing the role of an IVC fi lter in patients who cannot receive anticoagulant therapy (eg, actively
Table 13—[Section 2.11] Summary of Findings: Surgical Thrombectomy vs No Surgical Thrombectomy for Extensive Acute DVT of the Lega,144
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No Surgical Thrombectomy
Risk Difference With Surgical Thrombectomy (95% CI)
Mortality not reported
… … … … …
Nonfatal recurrent VTE
51 (1 study), 3 mo Lowb,c due to risk of bias and imprecision
RR 0.37 (0.02-8.75)
48 per 1,000d,e 30 fewer per 1,000 (from 47 fewer to 372 more)
Nonfatal major bleeding
51 (1 study), 3 mo Lowb,c due to risk of bias and imprecision
Not estimable (no events)
… -
PTS 51 (1 study), 2 y Lowf,g due to risk of bias and imprecision
RR 0.63 (0.44-0.9)h
588 per 1,000i 218 fewer per 1,000 (from 59 fewer to 329 fewer)j
QOL not measured
… … … … …
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1, 3 and 10 legends for expansion of abbreviations.aThe study included patients with DVT with symptoms of leg swelling not exceeding 7 d and a proximal extension of the thrombus above the inguinal ligament but not into the vena cava.bNot clear whether allocation was concealed. No blinding reported. Not clear whether analysis was intention to treat. Follow-up rate was 88% at 6 mo. Study not stopped early for benefi t.cCI includes values suggesting either harm or benefi t.dBaseline risks for nonfatal recurrent VTE derived from Douketis et al.108
eOne event was a symptomatic PE.fIn addition to other study limitations, this outcome was assessed by those who did the surgery and anticoagulation. No standardized tool was used. One surgical patient had an amputation secondary to venous gangrene and was not counted in the PTS assessment.gFew number of events. This warrants rating down the quality of evidence by a second level when considered along with study limitations.hThe RR is based on the 6-mo data.iThis estimate is based on the fi ndings of the VETO study.102 This probably underestimates PTS baseline risk, given that overall, 52% of patients reported the current use of compression stockings during study follow-up.jSevere PTS: assuming the same RR of 0.63 and a baseline risk of 13.8% over 2 y,102 the absolute reduction is 51 fewer severe PTS per 1,000 (from 14 fewer to 77 fewer) over 2 y.
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be treated for the same length of time as if the same patient had not had an IVC fi lter inserted (see section 3.1). The duration of anticoagulation, therefore, will vary according to whether the DVT was provoked by a temporary risk factor, was unprovoked, or was asso-ciated with cancer, and may be infl uenced by the patient’s ongoing risk of bleeding and preferences.
Our recommendation to treat patients with an IVC fi lter with anticoagulants when contraindications to anticoagulation resolve is weaker than for anticoagu-lation of most patients with VTE because the risks of bleeding may remain elevated, and the patient’s risk of recurrence is expected to be lower if the acute episode of thrombosis occurred remotely. The evidence for IVC fi lter use in patients with acute proximal DVT who cannot be treated with anticoagulation is mod-erate because of serious imprecision and indirectness (ie, extrapolated from the PREPIC study in which
If an IVC fi lter is indicated in a patient with acute DVT or PE because anticoagulant therapy is temporarily contraindicated (eg, active bleeding), there is the option of inserting a retrievable fi lter and removing it when it is safe to start anticoagu-lant therapy. However, most retrievable fi lters are not removed; retrievable fi lters that are not removed may have a higher long-term complication rate than permanent fi lters, and there currently is no good evidence that retrievable IVC fi lters improve patient outcomes. 104,147,154,155
Insertion of an IVC fi lter does not eliminate the risk of PE and increases the risk of DVT ( Table 14 , Table S19). Consequently, we suggest that patients who have an IVC fi lter inserted should receive a con-ventional course of anticoagulation (eg, parenteral and long-term anticoagulation) if the contraindica-tion to anticoagulation resolves. Such patients should
Table 14—[Section 2.13] Summary of Findings: Vena Cava Filter vs No Vena Cava Filter for Acute Proximal DVT of the Leg Treated With Anticoagulationa,b,146,443
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No vena cava Filters
Risk Difference With Vena cava Filters (95% CI)
Mortality 400 (1 study), 8 y Moderatec,d due to imprecision
RR 0.95 (0.78-1.16)e
515 per 1,000 26 fewer per 1,000 (from 113 fewer to 82 more)
Symptomatic PE 304 (1 study), 8 y Moderatec,f due to imprecision
RR 0.41 (0.2-0.86)g
151 per 1,000 89 fewer per 1,000 (from 21 fewer to 121 fewer)
Recurrent DVT 310 (1 study), 8 y Moderatec,f due to imprecision
RR 1.3 (0.93-1.82)h
273 per 1,000 82 more per 1,000 (from 19 fewer to 224 more)
Major bleeding 337 (1 study), 8 y Moderatec,d due to imprecision
RR 0.83 (0.52-1.34)i
185 per 1,000 31 fewer per 1,000 (from 89 fewer to 63 more)
PTS 308 (1 study), 8 y Lowd,j due to risk of bias and imprecision
RR 0.87 (0.66-1.13)
699 per 1,000 91 fewer per 1,000 (from 238 fewer to 91 more)
Complications 379 (1 study), 2 y Moderatef due to imprecision
… … k
QOL not reported … … … … …
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. PREPIC 5 Prevention du Risque d’Embolie Pulmonaire par Interruption Cave. See Table 1 and 3 legends for expansion of other abbreviations.aAnticoagulation consisted of LMWH or UFH initially (according to a 2 3 2 factorial design) followed by oral anticoagulation for at least 3 mo.bFour types of permanent vena cava fi lters were used: Vena Tech LGM (B. Braun Melsugen AG), titanium Greenfi eld (Boston Scientifi c Corporation), Cardial (C.R. Bard, Inc), and Bird’s Nest (Cook Group Incorporated).cAllocation was concealed. Data collectors and outcome adjudicators were blinded. Intention-to-treat analysis. Data missing for 4% at 2 y and 1% at 8 y. Enrollment was stopped at 400 instead of targeted 800 because of slow recruitment.dCI includes both negligible effect and appreciable benefi t or appreciable harm.eRR, 1.0 (95% CI, 0.29-3.4) at 12 d; RR, 1.08 (95% CI, 0.73-1.58) at 2 y.fSmall number of events.gRR. 0.23 (95% CI, 0.05-1.05) at 12 d (both symptomatic and asymptomatic PE). RR, 0.54 (0.21-1.41) at 2 y (symptomatic PE).hRR, 1.78 (95% CI, 1.09-2.94) at 2 y.iRR, 1.5 (95% CI, 0.54-4.14) at 12 d. RR, 0.74 (95% CI, 0.41-1.36) at 2 y.jNo standardized validated tool used to measure PTS.kNo complications directly related to the fi lter or its insertion reported in the PREPIC trial.146 Mismetti et al147 (prospective study) reported an incidence of 3.2% (excluding fi lter tilting and puncture site hematoma) among 220 patients receiving a retrievable vena cava fi lter for secondary prevention of VTE, whereas Athanasoulis et al148 (retrospective study) reported an incidence of 0.3% for major complications among 1,731 patients receiving vena cava fi lters predominantly for secondary prevention of VTE.
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2.14 Early Ambulation of Patients With Acute DVT
Treatment of acute DVT with bed rest and antico-agulation (originally IV UFH) has given way to early mobilization with anticoagulation (often administered SC). Two meta-analyses 156,157 summarized evidence from four relevant trials ( Table 15 , Tables S20-S22). This evidence is of low quality because of risk of bias and imprecision. We suggest early ambulation (eg, with-out a period of bed rest) when feasible because of its potential to decrease PTS and improve quality of life.
Recommendation
2.14. In patients with acute DVT of the leg, we suggest early ambulation over initial bed rest (Grade 2C) .
Remarks: If edema and pain are severe, ambulation may need to be deferred. As per section 4.1, we rec-ommend the use of compression therapy in these patients.
patients were routinely treated with anticoagulants; this indirectness, however, is minor).
Recommendations
2.13.1. In patients with acute DVT of the leg, we recommend against the use of an IVC fi lter in addition to anticoagulants (Grade 1B) .
2.13.2. In patients with acute proximal DVT of the leg and contraindication to anticoagulation, we recommend the use of an IVC fi lter (Grade 1B) .
2.13.3. In patients with acute proximal DVT of the leg and an IVC fi lter inserted as an alterna-tive to anticoagulation, we suggest a conventional course of anticoagulant therapy if their risk of bleeding resolves (Grade 2B) .
Remarks: We do not consider that a permanent IVC fi lter, of itself, is an indication for extended anticoagulation.
Table 15—[Section 2.14] Summary of Findings: Early Ambulation vs Delayed Ambulation for Acute DVT of the Lega,b,273,309,310,314,315
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With Delayed Ambulation
Risk Difference With Early Ambulation (95% CI)
Mortality 385 (4 studies), 3 moc Lowd,e due to risk of bias, imprecision
RR 1.3 (0.23-7.55)
11 per 1,000 3 more per 1,000 (from 8 fewer to 70 more)
PE (symptomatic or asymptomatic)
385 (4 studies), 4-12 d Lowd-g due to risk of bias, imprecision
RR 1.16 (0.66-2.05)
118 per 1,000 19 more per 1,000 (from 40 fewer to 124 more)
QOL questionnaire in chronic limb venous insuffi ciency (CIVIQ)
53 (1 study), 2 y Lowh,i due to risk of bias, indirectness
See footnotej
PTS Villata-Prandoni scores (value, . 5)
37 (1 study), 2 y Lowe,h due to risk of bias, imprecision
RR 0.66 (0.42-1.03)
400 per 1,000 136 fewer per 1,000 (from 232 fewer to 12 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. CIVIQ 5 ChronIc Venous Insuffi ciency Questionnaire. See Table 1 and 3 legends for expansion of other abbreviations.aTwo of four eligible studies excluded patients with symptomatic PE; in the third study, 24% of participants had symptomatic PE at baseline. It was not clear whether the fourth study excluded patients with symptomatic PE.bIn two of four eligible trials, all patients received early compression therapy (bandages or stockings). In the two other trials, only patients randomized to early ambulation received early compression therapy.cThree studies reporting acute-phase mortality reported no deaths.dConcealment of allocation was reported in one of four studies; blinding of outcome assessors was reported in two of four studies; intention-to-treat analysis reported in two of four studies. Follow-up was 97% to 100%. In two of four trials, only patients randomized to early ambulation received early compression therapy (bandages or stockings). In the other two trials, all patients received early compression therapy.eCI includes both values of clinically signifi cant benefi t and values of clinically signifi cant harms.fPE assessed as both symptomatic and asymptomatic PE.gFunnel plot reported as not asymmetrical by Aissaoui et al.156
hConcealment of allocation was not reported; outcome assessors were not blinded for this outcome. Seventy percent follow-up rate; compression stockings used on patients with early mobilization but not in patients with delayed mobilization.iNo explanation was provided.jPsychologic and overall somatic QOL did not differ signifi cantly between the treatment groups, whereas DVT-related items, especially those refl ecting the ease of locomotion, showed signifi cantly greater improvement with compression than with bed rest (P , .001 for bandages, P , .05 for stockings).
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continued until (1) the reduction of recurrent VTE no longer clearly outweighs the increase in bleeding or (2) it is patient preference (which may be infl uenced by fi nancial burden) to stop treatment, even if the reduc-tion in VTE would outweigh the increase in bleeding.
Increase in Risk of Recurrent VTE After Stopping Therapy— Current evidence suggests that the risk of recurrence after stopping therapy is largely deter-mined by two factors: (1) whether the acute episode of VTE has been effectively treated (duration of therapy) and (2) the patient’s intrinsic risk of having a new episode of VTE (individual risk of recurrence).
Duration of therapy: The primary goal of trials that compare different time-limited durations of antico-agulation is to identify the shortest duration of therapy that results in a posttreatment risk of recurrence that is as low as can be achieved. The fi ndings of these trials generally are not sensitive to differences in indi-vidual patient risk of bleeding.
Individual risk of recurrence: Primary factors for estimating risk of recurrence: Presence of a reversible provoking risk factor, 47,159,160,162-168,169,170 unprovoked VTE, 47,159,160,162-168,169,170 and presence of active cancer 9,47,165,166 are the most important factors that infl uence risk of recurrent VTE after stopping VKA. Among patients with VTE provoked by a reversible factor, the risk of recurrence is much lower if the provoking factor was recent surgery com-pared with a nonsurgical trigger (eg, estrogen therapy, pregnancy, leg injury, fl ight of . 8 h). 162,171 In patients with proximal DVT and PE, the estimated cumula-tive risk of recurrent VTE after stopping anticoagu-lant therapy of each of these categories is as follows: VTE provoked by surgery, 1% after 1 year and 3% after 5 years; VTE provoked by a nonsurgical revers-ible risk factor, 5% after 1 year and 15% after 5 years; and unprovoked VTE, 10% recurrence after 1 year and 30% after 5 years.
There are sparse data addressing the risk of recur-rent VTE after stopping therapy in patients with cancer because treatment is rarely stopped in these patients because of a high risk for recurrence. 38,47,165,166,172 A reasonable estimate for this risk, expressed as an annualized rate, may be 15%. However, the risk of recurrence is expected to vary according to whether the cancer is metastatic, being treated with chemo-therapy, or rapidly progressing. 38,165 The high mortality in patients with VTE and cancer (40% at 6 months in one large study 173 ) precludes estimating the cumu-lative risk of recurrence after long-term follow-up. We categorize patients with VTE according to these primary individual risk factors for recurrence when we make recommendations for duration of anticoag-ulant therapy.
Secondary factors for estimating risk of recurrence: Additional factors that infl uence the risk of recurrence
3.0 Long-term Anticoagulation of Acute DVT of the Leg
In this review, the term long-term treatment refers to treatments (eg, VKA therapy, LMWH, dabigatran) that are continued after initial therapy (eg, parenteral anticoagulation, thrombolytic therapy) ( Fig 1 ). In addition, we consider treatment with rivaroxaban, which is used without initial parenteral therapy. Long-term therapy has two goals: (1) to complete treat-ment of the acute episode of VTE and (2) to prevent new episodes of VTE that are not directly related to the acute event. During the early phase of long-term treatment (ie, fi rst 3 months), treatment of the acute episode of VTE predominates. During the late phase of long-term treatment (ie, after the fi rst 3 months), prevention of new episodes of VTE predominates. We use the term extended anticoagulation to refer to anticoagulation that is continued beyond 3 months without a scheduled stop date. However, regular (eg, yearly) reassessments are needed to assess whether a patient’s risk of bleeding increased or the patient’s preferences changed.
Three lines of evidence from randomized trials sup-port the need for long-term anticoagulant treatment of DVT (ie, after 5-10 days of initial heparin therapy): (1) a randomized controlled trial of long-term anti-coagulant therapy in 51 patients with symptomatic calf-vein thrombosis that documented a 25% rate of symptomatic extension of thrombosis within 3 months in the control group, 66 (2) a randomized trial com-paring long-term SC low-dose UFH (5,000 units bid) with VKA therapy in patients with proximal DVT that found that low-dose UFH was ineffective and resulted in a high rate of recurrent VTE (47% within 3 months), 158 and (3) randomized trials in which reduced durations of treatment of 4 or 6 weeks resulted in important increases in recurrent VTE compared with conventional durations of treat-ment of 3 or 6 months (section 3.1). 159-161 This evi-dence is of moderate quality because of imprecision and indirectness.
Recommendation
3.0. In patients with acute VTE who are treated with anticoagulant therapy, we recommend long-term therapy (see section 3.1 for recommended duration of therapy) over stopping anticoag-ulant therapy after 1 week of initial therapy (Grade 1B) .
3.1 Duration of Long-term Anticoagulant Therapy
Weighing the Benefi ts and Risks of Different Dura-tions of Anticoagulant Therapy: General Consider-ations: Anticoagulant therapy for VTE should be
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e448S Antithrombotic Therapy for VTE
VKA therapy targeted to an INR of 2.5 was the anti-coagulant regimen in all comparisons.
Short vs Intermediate Durations of Therapy—Five trials have evaluated shortening the duration of oral anticoagulant therapy from 3 or 6 months to 4 or 6 weeks in patients with mostly fi rst episodes of VTE ( Table 16 , Tables S23-S25). 159,160,167,169 This evidence, which is high quality, indicates that with the shorter duration of therapy, the absolute decrease in bleeding was small compared with the absolute increase in recurrent VTE. Patients with isolated distal DVT provoked by a major transient risk factor have a very low risk of recurrence after anticoagulant therapy is stopped ( � 1% per year 170 ). It is uncertain whether this risk is lowered by treating for 3 months compared with 4 or 6 weeks (hazard ratio [HR] for 4 or 6 weeks vs � 3 months at 2 years after stopping therapy, 0.36; 95% CI, 0.09-1.54 170 ). For this reason, we make a weaker recommendation for 3 months compared with a shorter duration of therapy in patients with isolated distal DVT that was provoked by a reversible risk factor. The evidence supporting this weaker rec-ommendation is rated down to low quality because of serious imprecision and because it is a post hoc observation.
Different Intermediate Durations of Therapy (6 or 12 months vs 3 months)—We considered trials that randomized patients with VTE to 3 months vs to 6 or 12 months of treatment to determine, when using a time-limited duration of therapy, whether there was any benefi t to treating for . 3 months. Five reports, which included six randomized comparisons, con-tributed to this analysis ( Table 17 , Tables S24-S26). 167,194,203-205 These studies found that 6 or 12 months of therapy did not convincingly lower risk of recurrence but increased major bleeding about 2.5-fold. In a meta-analysis of individual patient data from randomized trials, during the 2 years after stop-ping anticoagulant therapy, treatment of 3 months compared with � 6 months was associated with an HR of 1.19 (95% CI, 0.86-1.65) in all patients and an HR of 1.39 (95% CI, 0.96-2.01) in patients with unprovoked DVT or PE. 170 Therefore, although anti-coagulants are very effective at preventing recurrence while patients are receiving therapy, when anticoagu-lants are stopped, there is a similar risk of recurrence whether patients have been treated for 3 months or longer. 170 This evidence is of moderate quality because of serious imprecision.
As an alternative to comparing two time-limited durations of anticoagulant therapy, the AESOPUS (Ultrasound Findings to Adjust the Duration of Anti-coagulation) trial compared a predefi ned duration of therapy with a fl exible duration of therapy that depended on whether there was residual thrombo-sis during follow-up in patients with a fi rst proximal
strongly enough to modify some recommendations about duration of therapy include (1) whether DVT was confi ned to the distal veins (isolated distal [or calf] DVT), which is estimated to be associated with about one-half of the risk of recurrence of proximal DVT and PE, 10,164,167,169,170 and (2) whether the VTE was a second or subsequent episode of VTE, which is estimated to be associated with about a 50% higher risk of recurrence compared with a fi rst VTE. 9,173,175
Additional factors for estimating risk of recur-rence: Other factors predict risk of recurrence, but not strongly or consistently enough to infl uence rec-ommendations on duration of therapy once the pri-mary and secondary factors noted previously have been considered. These factors, which have mostly been evaluated in patients with unprovoked VTE, include negative D -dimer testing 1 month after withdrawal of VKA (risk ratio [RR], � 0.4), 48,176-181 antiphospholipid antibody (RR, � 2), 182-185 heredi-tary thrombophilia (RR, � 1.5), 162,163,174,177,180-182,185-190 male vs female sex (RR, � 1.6), 191,192 Asian ethnicity (RR, � 0.8), 193 and residual thrombosis in the prox-imal veins (RR, � 1.5). 149,182,185,194-198 Combinations of factors have the potential to be more important predictions of recurrence risk than single factors (eg, low risk of recurrence in women with unpro-voked proximal DVT or PE who have a negative D -dimer test before 185 or 1 month after 180,199 stop-ping anticoagulant therapy). PTS may be a risk factor for recurrent VTE, 183,185,200 and recurrent ipsilateral DVT is a risk factor for development of PTS. 201,202 Both associations may contribute to a decision to use extended therapy in a patient with established PTS.
Increase in Risk of Bleeding While Remaining on Anticoagulant Therapy— Although the decision to treat patients with different time-limited durations of anticoagulant therapy generally are insensitive to an individual’s risk of bleeding, the decision to use extended anticoagulation, particularly in patients with an unprovoked proximal DVT or PE, is sensitive to risk of bleeding. There is no validated prediction tool to stratify the risk of major bleeding during extended anticoagulant therapy specifi cally in patients with VTE, but this risk appears to increase with the prevalence of the factors noted in Table 2 . This table also provides our estimate of the absolute risk of bleeding without anticoagulation (baseline risk), the increase with anticoagulation, and the sum of these two risks (ie, risk of bleeding on therapy).
Comparisons of Time-Limited Durations of Therapy: Randomized trials have compared either a short (eg, 4 or 6 weeks) with an intermediate (eg, 3 or 6 months) duration of therapy, or two intermediate durations of therapy, (eg, 3 months vs 6 or 12 months).
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bleeding. The quality of evidence for the reduction in recurrent VTE with extended therapy is high but is rated down to moderate for bleeding and mortality because of imprecision.
Weighing the Benefi ts and Risks of Extended VKA Therapy— The decision to extend anticoagulation therapy beyond 3 months is sensitive to both baseline risks of recurrent VTE and major bleeding. We did not identify a validated prediction tool for either outcome that takes into account all relevant risk fac-tors. As an alternative, for patients without cancer, we chose to stratify our recommendations according to four primary risk groups for recurrent VTE (sec-tion 3.1) and three risk groups for major bleeding (section 3.1) ( Table 2 ). This approach resulted in a total of 12 combinations of risk profi les. Table 19 shows the estimated total (and fatal) number of recurrent episodes of VTE prevented and the number of major bleeds caused by 5 years of extended therapy for each of the 12 combinations. In the absence of robust trial data for mortality for recurrent VTE and
Table 16—[Section 3.1.1-3.1.4] Summary of Findings: Four or Six Weeks vs Three or Six Months as Minimum Duration of Anticoagulation for VTEa,b,16,159,167,169,195
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With Control
Risk Difference With 4 or 6 wk vs 3 or 6 mo Months of Anticoagulation (95% CI)
Recurrent VTE 2,185 (5 studiesc), 1-2 yd Highe-g RR 1.83 (1.39-2.42)
64 per 1,000 53 more per 1,000 (from 25 more to 91 more)
Major bleeding 2,185 (5 studies), 1-2 y Highf RR 0.54 (0.22-1.32)
12 per 1,000 5 fewer per 1,000 (from 9 fewer to 4 more)
Mortality 2,098 (5 studies), 1-2 y Highe,f,h RR 0.97 (0.68-1.38)
55 per 1,000 2 fewer per 1,000 (from 18 fewer to 21 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confidence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aPopulations varied among studies: fi rst provoked isolated distal DVT, proximal DVT, or PE provoked in Kearon et al195; fi rst isolated distal DVT in Pinede et al167; fi rst isolated distal DVT, proximal DVT, or PE in Schulman et al169; proximal DVT (21% had cancer) in Levine et al159; DVT or PE (29% not objectively confi rmed) in British Thoracic Society.160
bShort vs longer duration of anticoagulation was 6 wk vs 6 mo for Schulman et al169, 6 wk vs 3 mo for Pinede et al,167 and 4 wk vs 3 mo for the other three studies.cTiming of randomization relative to the start of treatment varied across studies: Pinede et al,167 Schulman et al,169 and British Thoracic Society160 randomized at diagnosis, and Kearon et al195 and Levine et al159 randomized to stop or to continue treatment for 2 mo more after the initial 4 wk of treatment.dFollow-up was for �1 y in all studied except for Schulman et al169 in which it was 2 y.eGenerally, study design was strong. No study stopped early for benefi t; two stopped early because of slow recruitment (Kearon et al,195 Pinede et al167). In one study (British Thoracic Society160), 44 randomized patients were excluded centrally as they did not satisfy eligibility criteria. Patients and caregivers were blinded in two studies (Kearon et al, Levine et al159). Adjudicators of outcomes were blinded in all but one study (British Thoracic Society). All studies appear to have used effective randomization concealment, intention-to-treat analysis, and a low unexplained drop-out frequency.fNo heterogeneity with I2 5 0%.gNo imprecision for overall estimates. However, for the subgroup of patients with isolated distal DVT, who are known to have a very low risk of recurrence, there is imprecision and the possibility that the shorter duration of anticoagulation is adequate and not associated with a clinically important higher risk of recurrence.hDifferences in mortality are expected to be mediated by differences in recurrent VTE and bleeding.
DVT 206 (Tables S24 and S25). Its fi ndings suggest that the latter approach may be helpful for tailoring the duration of therapy.
Extended vs Time-Limited Anticoagulant Therapy: Five trials compared extended anticoagulation with VKA therapy (target INR 2.0-2.85, 161 2.0-3.0, 48,182,207 and 1.5-2.0 174 ) with stopping VKA therapy at 3 or 6 months in patients who were judged to have a high risk of recurrence ( Table 18 , Table S24, S25, and S27). The results indicate that randomization to indefi nite treatment with conventional-intensity VKA (target INR 2.5) reduces recurrent VTE by about 90% (RR for the four studies, 0.12; 95% CI, 0.05-0.25 48,161,182,207 ), and randomization to low-intensity therapy (target INR 1.75) reduces VTE by 64% (95% CI for HR, 23%-81%), 174 with about one-half of recurrent VTE in the active treatment groups in these studies occurring in patients who had prematurely stopped VKA therapy. Extended anticoagulant therapy was associated with about a 2.6-fold increase in major
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e450S Antithrombotic Therapy for VTE
others fi nd it a major burden that greatly erodes their sense of well-being. 210
The presence of additional risk factors for VTE recurrence (section 3.1), the patient’s relative value for the different outcome of interest (recurrence of VTE, major bleeding, PTS), and the patient’s per-ceived burden of anticoagulant therapy may infl uence decisions about the use of extended anticoagulant therapy in patient groups for which we provide a weak recommendation but are unlikely to infl uence this decision in patients groups for which we provide a strong recommendation. 16 Similarly, the costs of therapy and how those costs are paid (eg, patient, third party) are more likely to infl uence treatment decisions when there is a weak recommendation (Grade 2) in favor of extended therapy.
Patients With VTE and Cancer: As previously noted (section 3.1), because they have a high risk of recur-rence, patients with active cancer (eg, treated within the past 6 months, persistent or progressive) should benefi t from extended anticoagulant therapy unless they have a very high risk of bleeding. The quality of the evidence supporting this recommendation is moderate because of indirectness (the relative effects of anticoagulation are based, in part, on evidence
bleeding, we assumed that 3.6% of recurrent VTE and 11.3% of major bleeds will be fatal. 12
We make (1) a strong recommendation for extended therapy when it is associated with a reduction in VTE that is substantially more frequent than the increase in major bleeding and with a mortality advantage, (2) a weak recommendation for extended therapy when it is associated with a reduction in VTE that is more frequent than the increase in major bleeding but the magnitude of this difference and the suggested mortality advantage are more modest, (3) a weak recommendation against extended therapy when extended therapy is associated with a reduc-tion in VTE that is less frequent than the increase in major bleeding and no mortality advantage exists, and (4) a strong recommendation against extended therapy when extended therapy is associated with a reduction in VTE that is less frequent than the increase in major bleeding and a mortality disadvan-tage may exist. We assume that on average, extended anticoagulation with VKA therapy is a modest burden to patients. 15 However, this differs markedly among patients; some do not fi nd anticoagulant therapy a burden and have an enhanced feeling of well-being because they feel protected from recurrence, whereas
Table 17—[Section 3.1.1-3.1.4] Summary of Findings: Six or Twelve Months vs Three Months as Minimum Duration of Anticoagulation for VTEa,b,167,203,204
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With 3 moRisk Difference With 6 or
12 mo (95% CI)
Recurrent VTE 2,061 (6 studies), 1-3 y Moderatec-e due to imprecision
RR 0.89 (0.69-1.14)
115 per 1,000 13 fewer per 1,000 (from 36 fewer to 16 more)
Major bleeding 2,061 (6 studies), 1-3 y Highf RR 2.49 (1.2-5.16)
9 per 1,000 13 more per 1,000 (from 2 more to 37 more)
Mortalityg 1,331 (5 studies), 1-3 y Moderated due to imprecision
RR 1.3 (0.81-2.08)
44 per 1,000 13 more per 1,000 (from 8 fewer to 47 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of other abbreviations.aStudy populations varied across studies: Pinede et al167 enrolled provoked and unprovoked proximal DVT and PE; Campbell et al203 enrolled provoked and unprovoked isolated distal DVT, proximal DVT, and PE; Agnelli et al194 had separate randomizations for provoked PE (3 vs 6 mo) and unprovoked (3 vs 12 mo); and Agnelli et al204 enrolled unprovoked proximal DVT.bTiming of randomization relative to the start of treatment and length of treatment in the non-3 mo group varied across studies: Pinede et al167 and Campbell et al203 randomized at diagnosis; and Agnelli et al194,204 randomized after the initial 3 mo of treatment to stop or continued treatment. The longer duration of treatment was 6 mo in Agnelli et al194 (provoked PE) and 12 mo in Agnelli et al204 and Agnelli et al194 (unprovoked PE).cGenerally, study design was strong. No study stopped early for benefi t; two stopped early because of slow recruitment (Campbell et al,203 Pinede et al167) and one because of lack of benefi t (Agnelli et al204). In one study (Campbell et al), 20% of VTE outcomes were not objectively confi rmed. Patients and caregivers were not blinded in any study. Adjudicators of outcomes were blinded in all but one study (Campbell et al). All studies used effective randomization concealment, intention-to-treat analysis, and a low unexplained drop-out frequency.dCIs include both values suggesting no effect and values suggesting either benefi t or harm.eLow number of events and a total number of participants , 2,000.fOne study may have confi ned the assessment of bleeding to when subjects were receiving anticoagulant therapy, which could have infl ated the increase in bleeding associated with the longer duration of therapy (Campbell et al203).gDifferences in mortality are expected to be mediated by differences in recurrent VTE and bleeding.
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Table 18—[Section 3.1.1-3.1.4] Summary of Findings: Extended Anticoagulation vs No Extended Anticoagulation for Different Groups of Patients with VTE and Without Cancera,b,48,161,182,207
OutcomesNo. of Participants
(Studies), Follow-up
Quality of the Evidence
(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No Extended Duration
Oral Anticoagulation
Risk Difference With Extended Duration Oral Anticoagulation (95% CI)
Mortality 1,184 (4 studies), 10-36 mo
Moderatec-e due to imprecision
RR 0.57 (0.31-1.03) 63 per 1,000 27 fewer per 1,000 (from 44 fewer to 2 more)
Recurrent VTE at 1 y
1,184 (4 studies), 10-36 mo
High RR 0.12 (0.09-0.38) First VTE provoked by surgeryf-j
10 per 1,000 10 fewer per 1,000 (from 6 fewer to 9 fewer)
First proximal DVT or PE provoked nonsurgical/fi rst unprovoked distal DVTf-j
50 per 1,000 44 fewer per 1,000 (from 31 fewer to 45 fewer)
First unprovoked VTEf-j
100 per 1,000 88 fewer per 1,000 (from 62 fewer to 91 fewer)
Second unprovoked VTEf-j
150 per 1,000 132 fewer per 1,000 (from 93 fewer to 137 fewer)
Major bleeding at 1 y
1,184 (4 studies), 10-36 mo
Moderate due to imprecision
RR 2.63 (1.02-6.76) Lowk,l (see Table 2)3 per 1,000 5 more per 1,000 (from
0 more to 15 more)Moderatek,l (see Table 2)
6 per 1,000 10 more per 1,000 (from 1 more to 29 more)
Highk,l (see Table 2)25 per 1,000 40 more per 1,000 (from
3 more to 122 more)Recurrent VTE
at 5 y1,184 (4 studies),
10-36 moHigh RR 0.12 (0.09-0.38) First VTE provoked by surgeryf-j
30 per 1,000 26 fewer per 1,000 (from 19 fewer to 27 fewer)
First proximal DVT or PE provoked nonsurgical/fi rst unprovoked distal DVTf-j
150 per 1,000 132 fewer per 1,000 (from 93 fewer to 137 fewer)
First unprovoked VTEf-j
300 per 1,000 264 fewer per 1,000 (from 186 fewer to 273 fewer)
Second unprovoked VTEf-j
450 per 1,000 396 fewer per 1,000 (from 279 fewer to 409 fewer)
Major bleeding at 5 y
1,184 (4 studies), 10-36 mo
Moderate due to imprecision
RR 2.63 (1.02-6.76) Lowk,l (see Table 2)15 per 1,000 24 more per 1,000 (from
2 more to 73 more)Moderatek,l (see Table 2)
30 per 1,000 48 more per 1,000 (from 4 more to 146 more)
Highk,l (see Table 2)125 per 1,000 199 more per 1,000
(from 17 more to 609 more)
(Continued)
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e452S Antithrombotic Therapy for VTE
from patients without cancer). Presence of factors associated with a lower risk of recurrence that may support stopping anticoagulant therapy, particularly if the risk of bleeding was high, include the following: (1) VTE was associated with a superimposed revers-ible risk factor (eg, recent surgery, chemotherapy), (2) the cancer has responded to treatment, (3) the cancer has not metastasized, and (4) the VTE was an isolated distal DVT.
Follow-up of Patients on Extended Therapy: Patients who are treated with extended anticoagulant therapy should be reviewed regularly (eg, annually) to ensure that (1) they have not developed contraindications to extended therapy, (2) their preferences have not changed (eg, anticoagulation has become an exces-sive burden), (3) they can benefi t from improved ways
OutcomesNo. of Participants
(Studies), Follow-up
Quality of the Evidence
(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No Extended Duration
Oral Anticoagulation
Risk Difference With Extended Duration Oral Anticoagulation (95% CI)
Burden of anticoagulation not reported
… … … Warfarin: daily medication, dietary and activity restrictions, frequent blood testing/monitoring, increased hospital/clinic visitsm
…
PTS not reported … … … n …
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. PREVENT 5 Prevention of Recurrent Venous Thromboembolism. See Table 1 and 3 legends for expansion of other abbreviations.aStudies vary in follow-up duration (10 mo to 3 y) and in duration of time-limited VKA (3-6 mo).bWe excluded PREVENT trial because target INR was 1.75 (low intensity), which has been shown in an RCT44 to be less effective than a target of 2.5.cI2 5 0%.dCI includes both values suggesting no effect and values suggesting either appreciable harms or appreciable benefi t.eSmall number of events. Decision to rate down also takes into account that two studies were stopped early for benefi t.fAnnual risk of VTE recurrence after discontinuing oral anticoagulation therapy in patients with fi rst VTE provoked by surgery: 1% (Iorio et al171); we assumed a 0.5% yearly risk thereafter (3% over 5 y).gAnnual risk in patients with fi rst VTE provoked by nonsurgical factor: �5% the fi rst year (Iorio et al171); we assumed a 2.5% yearly thereafter (15% over 5 y).hAnnual risk in patients with fi rst episode of unprovoked VTE: 9.3% over 1 y in Rodger et al185; 11.0% over 1 y, 19.6% over 3 y, and 29.1% over 5 y in Prandoni et al.208 We assumed a risk of 10% the fi rst year after discontinuation and 5% yearly thereafter (30% over 5 y).iAnnual risk in patients with second episode of unprovoked VTE: we assumed an RR of 1.5 compared with a fi rst episode of unprovoked VTE: 15% the fi rst year after discontinuation, 7.5% yearly thereafter (45% over 5 y).jCase fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier et al12).kAnnual risk of major bleeding is based on three risk levels: low, intermediate, and high. The corresponding 0.3%, 0.6%, and 1.2% risks are estimates based on control arms of included studies (see Table 2).lCase fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al12) (no data available for after discontinuing oral anticoagulation therapy).mBurden of anticoagulation: endured by all patients who continue extended-duration anticoagulation (100%) and applies to patients who stop anticoagulation (no extended duration anticoagulation) who subsequently experienced a recurrent VTE (5%/10%/15% at 1 y; 15%/30%/45% at 5 y).nPTS: baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (Kahn et al102). There was a threefold (Prandoni et al202) to 10-fold (van Dongen et al209) increase in PTS with recurrent VTE in the ipsilateral leg.
Table 18—Continued
of selecting a patient for extended therapy if these have become available, and (4) they are being treated with the anticoagulant regimen that best suits them.
LMWH for Extended Therapy: We identifi ed no direct evidence for LMWH compared with (1) VKA, (2) other anticoagulant strategies, or (3) control for the extended phase of anticoagulation in patients who were treated with a standardized initial long-term anticoagulant regimen. Based on indirect evidence from comparisons of LMWH with VKA therapy during the initial 3 or 6 months of long-term therapy, we judged LMWH to be at least as effective in terms of recurrent VTE and as safe in terms of major bleeding ( Table 20 , Table S28). The potential for drug-induced osteoporosis, however, may be greater with extended therapy LMWH than with VKA therapy. 1
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Table 19—[Section 3.1.1-3.1.4] Estimated Absolute Difference in Recurrent VTE and Major Bleeding Events (Including Fatal Events) With 5 Years of vs No Extended Anticoagulation
Outcomes After 5 y of Treatment
Risk of Bleeding
Low Intermediate Higha
First VTE provoked by surgery
Recurrent VTE reduction per 1,000
↓ 26 (19-27) (1 fatal)b ↓ 26 (19-27) (1 fatal)b ↓ 26 (19-27) (1 fatal)b
Major bleeding increase per 1,000
↑ 24 (2-73) (3 fatal)b ↑ 49 (1-173) (5 fatal)b ↑ 98 (1-346) (11 fatal)b
First VTE provoked by a nonsurgical factor/fi rst unprovoked distal DVT
Recurrent VTE reduction per 1,000
↓ 132 (93-137) (5 fatal)c ↓ 132 (93-137) (5 fatal)c ↓ 132 (93-137) (5 fatal)b
Major bleeding increase per 1,000
↑ 24 (2-73) (3 fatal)c ↑ 49 (1-173) (5 fatal)c ↑ 98 (1-346) (11 fatal)b
First unprovoked proximal DVT or PE
Recurrent VTE reduction per 1,000
↓ 264 (186-273) (10 fatal)d ↓ 264 (186-273) (10 fatal)d ↓ 264(186-273) (10 fatal)b
Major bleeding increase per 1,000
↑ 24 (2-73) (3 fatal)d ↑ 49 (1-173) (5 fatal)d ↑ 98 (1-346) (11 fatal)b
second unprovoked VTE Recurrent VTE reduction per 1,000
↓ 396 (279-409) (14 fatal)e ↓ 396 (279-409) (14 fatal)d ↓ 396 (279-409) (14 fatal)c
Major bleeding increase per 1,000
↑ 24 (2-73) (3 fatal)e ↑ 49 (1-173) (5 fatal)d ↑ 98 (1-346) (11 fatal)c
Recommendations:Risk of dying in patients with a recurrent VTE or a major bleed:• Case fatality rate of recurrent VTE after discontinuing oral anticoagulation therapy: 3.6% (Carrier et al12).• Case fatality rate of major bleeding during initial oral anticoagulation therapy: 11.3% (Carrier et al12) (no data available for after discontinuing oral
anticoagulation therapy).Annual risks of recurrent VTE after discontinuation of anticoagulation:• First VTE provoked by surgery: 1% (Iorio et al171); we assumed a 0.5% yearly risk thereafter (3% over 5 y).• First episode of VTE provoked by nonsurgical factor: �5% the fi rst year (Iorio et al171); we assumed a 2.5% yearly thereafter (15% over 5 y)• First episode of unprovoked VTE: 9.3% over 1 y (Rodger et al185); 11.0% over 1 y, 19.6% over 3 y, 29.1% over 5 y (Prandoni et al208). We assumed
a risk of 10% the fi rst year after discontinuation and 5% yearly thereafter (30% over 5 y).• Second episode of unprovoked VTE: we assumed that this infl icts 1.5 the risk of recurrent VTE relative to fi rst episode of unprovoked VTE: 15%
the fi rst year after discontinuation, 7.5% yearly thereafter (45% over 5 y).Relative risk reduction with extended anticoagulant therapy:• 82% based on Table 18Annual risks of major bleeding in patients not on anticoagulant therapy:• Low risk, 0.3%/y; intermediate risk 0.6%/y; high risk, 2.4%/y (Table 2).Relative risk of major bleeding with extended anticoagulant therapy:• 2.6 based on Table 18.Criteria used to decide on direction and strengths of recommendations:• Criterion for a strong recommendation against whenever the estimated number of fatal bleeding events exceeded the estimated number of fatal
recurrent VTE prevented.• Criterion to go from a strong recommendation against to weak recommendation against: difference between the lower boundary of increased
major bleeding and upper boundary of reduction in recurrent VTE , 2% (risk over 5 y averaged per year).• Criterion to go from a weak recommendation against to a weak recommendation in favor of: difference between point estimate of reduction of recurrent
VTE and point estimate for increase in major bleeding is . 2% (risk over 5 y averaged per year) (2% to account for the burden and cost of VKA).• Criterion to go from a weak recommendation for to strong recommendation for: difference between the lower boundary of reduction in VTE and
upper boundary of increased major bleeding . 4% (risk over 5 y averaged per year).Another way of interpreting the direction and strength of recommendation based on the number of deaths (related to either bleeding or recurrent VTE) is as follows:• A strong recommendation against: extended anticoagulation is estimated to be associated with an increase in deaths.• A weak recommendation against: extended anticoagulation is estimated to be associated with from no effect on deaths to only a very small
reduction in deaths (0-4/1,000 prevented over 5 y or , 0.5%/patient-y).• A weak recommendation for: extended anticoagulation is estimated to be associated with a small reduction in deaths (5 to 9/1,000 prevented over
5 y or 0.5%-0.9%/patient-y).• A strong recommendation for: extended anticoagulation is estimated to be associated with a large reduction in deaths (. 10/1,000 prevented over
5 y or . 1%/patient-y).aWith an eightfold risk of bleeding in the high-risk group compared with the low-risk group, a strong recommendation against extended anticoagulation for a second unprovoked VTE is justifi ed. The high-risk group, however, includes patients who have a risk of bleeding that is less than this estimate (eg, patients aged . 75 y without additional risk factors for bleeding [Table 2]) and, therefore, may benefi t from extended anticoagulant therapy. For this reason, we provide a weak rather than a strong recommendation against extended anticoagulation for patients with a second unprovoked VTE in the high-bleeding-risk group.bStrong againstcWeak againstdWeak in favoreStrong in favor
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e454S Antithrombotic Therapy for VTE
Rivaroxaban for Extended Therapy: Use of rivar-oxaban compared with initial parenteral therapy followed by VKA therapy for the short- and long-term treatment of DVT is reviewed in section 3.3 ( Table 21 , Table S29). In the current section, we con-sider rivaroxaban compared with no anticoagulation in patients with proximal DVT or PE who have com-pleted 6 or 12 months of anticoagulant therapy, which has been evaluated in a single study ( Table 22 , Table S30). 127 This study found that rivaroxaban markedly reduced recurrent VTE at the expense of a modest absolute increase in major bleeding. The evi-dence from this one study is of moderate quality because of serious imprecision.
Dabigatran for Extended Therapy: There are no completed studies that have compared dabigatran with no anticoagulation for extended treatment of VTE.
Choice of Anticoagulant Regimen for Extended Therapy: This question is addressed in section 3.3.
Recommendations
3.1.1. In patients with a proximal DVT of the leg provoked by surgery, we recommend treatment with anticoagulation for 3 months over: (i) treat-ment of a shorter period (Grade 1B) , (ii) treat-ment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , or (iii) extended therapy (Grade 1B regardless of risk of bleeding) .
3.1.2. In patients with a proximal DVT of the leg provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , and (iii) extended therapy if there is a high bleeding risk ( Table 2 ) (Grade 1B) . We suggest treatment with anticoagulation for 3 months over extended ther apy if there is a low or mod-erate bleeding risk ( Table 2 ) (Grade 2B) .
3.1.3. In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor (see remark), we suggest treatment with anticoagulation for 3 months over treatment of a shorter period (Grade 2C) and recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) or extended therapy (Grade 1B regardless of bleeding risk) .
3.1.4. In patients with an unprovoked DVT of the leg (isolated distal [see remark] or prox-imal), we recommend treatment with anticoagu-
lation for at least 3 months over treatment of a shorter duration (Grade 1B). After 3 months of treatment, patients with unprovoked DVT of the leg should be evaluated for the risk-benefi t ratio of extended therapy.
3.1.4.1. In patients with a fi rst VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk ( Table 2 ), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B) .
3.1.4.2. In patients with a fi rst VTE that is an unprovoked proximal DVT of the leg and who have a high bleeding risk ( Table 2 ), we recom-mend 3 months of anticoagulant therapy over extended therapy (Grade 1B) .
3.1.4.3. In patients with a fi rst VTE that is an unprovoked isolated distal DVT of the leg (see remark), we suggest 3 months of anticoagulant therapy over extended therapy in those with a low bleeding risk ( Table 2 ) (Grade 2B) , and recommend 3 months of anticoagulant treat-ment in those with a moderate or high bleeding risk ( Table 2 ) (Grade 1B) .
3.1.4.4. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk ( Table 2 ) (Grade 1B) , and we suggest extended anticoagulant therapy in those with a moderate bleeding risk ( Table 2 ) (Grade 2B) .
3.1.4.5. In patients with a second unprovoked VTE who have a high bleeding risk ( Table 2 ), we suggest 3 months of anticoagulant therapy over extended therapy (Grade 2B) .
3.1.5. In patients with DVT of the leg and active cancer, if the risk of bleeding is not high ( Table 2 ), we recommend extended anti-coagulant therapy over 3 months of therapy (Grade 1B) , and if there is a high bleeding risk ( Table 2 ), we suggest extended anticoagulant therapy (Grade 2B) .
Remarks (3.1.3, 3.1.4, 3.1.4.3): Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anti-coagulant therapy; however, it is anticipated that not all patients who are given a diagnosis of isolated distal DVT will be prescribed anticoagulants (see section 2.3). In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually).
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Table 20—[Section 3.3] Summary of Findings: LMWH vs VKA for Long-term Treatment of VTEa-c,173,211,213,223,224,226-228
Outcomes
No. of Participants
(Studies), Follow-up
Quality of the Evidence (GRADE)
Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With VKARisk Difference With
LMWH (95% CI)
Death 2,496 (7 studies), 6 mo
Moderated,e due to imprecision
RR 0.96 (0.81-1.13)
164 per 1,000 7 fewer per 1,000 (from 31 fewer to 21 more)
Recurrent VTE 2,727 (8 studies), 6 mo
Moderatef due to risk of bias
RR 0.62 (0.46-0.84)
No cancerg
30 per 1,000 11 fewer per 1,000 (from 5 fewer to 16 fewer)
Nonmetastatic cancerg
80 per 1,000 30 fewer per 1,000 (from 13 fewer to 43 fewer)
Metastatic cancerg
200 per 1,000 76 fewer per 1,000 (from 32 fewer to 108 fewer)
Major bleeding 2,737 (8 studies), 6 mo
Moderateh,i due to imprecision
RR 0.81 (0.55-1.2)
No cancer or nonmetastatic cancerj
20 per 1,000 4 fewer per 1,000 (from 9 fewer to 4 more)
Metastatic cancerj
80 per 1,000 15 fewer per 1,000 (from 36 fewer to 16 more)
Burden of anticoagulation
… Highk … Warfarin: daily medication, dietary restrictions, frequent blood testing/monitoring, increased hospital/clinic visits
LMWH: daily injection, no dietary restrictions, no frequent blood testing/monitoring
PTS (self-reported leg symptoms and signs)
100 (1 study), 2 y Lowl,m due to risk of bias, indirectness
RR 0.85 (0.77-0.94)
200 per 1,000n 30 fewer per 1,000 (from 12 fewer to 46 fewer)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aTwo of these studies enrolled only patients without cancer, three enrolled only patients with cancer, and three enrolled both patients with and without cancer (separate data provided for patients with cancer and without cancer in one study).bLimited to LMWH regimens that used � 50% of the acute treatment dose during the extended phase of treatment.cThe initial parenteral anticoagulation was similar in both arms for all except one study (Hull et al211) in which patients randomized to LMWH initially received the same LWMH, whereas patients randomized to VKA received initially UFH.dOne study did not report deaths, which is unusual and could refl ect selective reporting of outcomes.eCI includes both no effect and harm with LMWH.fNone of the studies were blinded, whereas the diagnosis of recurrent VTE has a subjective component and there could be a lower threshold for diagnosis of recurrent VTE in VKA-treated patients because switching the treatment of such patients to LMWH is widely practiced. At the same time, there is reluctance to diagnose recurrent VTE in patients who are already taking LMWH because there is no attractive alternative treatment option.gRisk of recurrent VTE: low corresponds to patients without cancer (3% estimate taken from recent large RCTs of acute treatment), intermediate corresponds to patients with local or recently resected cancer (based on average rate across the six studies in this analysis and appears to be consistent with Prandoni et al38 [particularly if low risk is increased to 4%]), and high corresponds to patients with locally advanced or distant metastatic cancer (Prandoni et al).hNo study was blinded; diagnosis of major bleeding has a subjective component.iThe 95% CIs for the RR for major bleeding includes a potentially clinically important increase or decrease with LMWH and may vary with the dose of LMWH used during the extended phase of therapy.jRisk of bleeding: low corresponds to patients without risk factor for bleeding (ie, age . 75 y, cancer, metastatic disease; chronic renal or hepatic failure; platelet count , 80,0000; requirement for antiplatelet therapy; history of bleeding without a reversible cause) (Table 2). Based on Prandoni et al38 and Beyth et al212 and adjusted to a 6-mo time frame.kHull et al213 reported no signifi cant difference in QOL but suggested greater satisfaction with LMWH over VKA (questionnaire did not directly assess the burden of injections).lPatients and investigators not blinded. Self-reported leg symptoms and signs after 3 mo of treatment.mThe association between leg symptoms and signs at 3 mo and long-term PTS is uncertain.nBaseline risk assumes that patients all wear pressure stockings. Control event rate comes from observational studies in a review by Kahn et al,214 adjusted to a 2-y time frame.
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3.2 Intensity of Anticoagulant Effect
Ageno et al 2 and Holbrook et al 3 in these guidelines present evidence for the optimal intensity of VKA therapy (ie, target INR) during the long-term (eg, fi rst 3 months of treatment) and extended phases of treatment of VTE.
Recommendation
3.2. In patients with DVT of the leg who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR , 2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B) .
3.3 Choice of Anticoagulant Regimen for Long-term Therapy
VKA therapy has been the standard method of anticoagulant therapy for VTE. Adjusted-dose SC UFH is an effective alternative to VKA therapy, but it has never been popular because it requires initial
laboratory monitoring and twice-daily injection and is associated with osteoporosis. 215,216 SC LMWH has advantages over SC UFH in that it does not require laboratory monitoring, is less likely to cause osteoporosis, 216 and can be given once a day. For these reasons, LMWH has been used for the long-term treatment of VTE. The synthetic pentasaccha-ride, fondaparinux, has not been evaluated or widely used for long-term treatment of VTE. Idraparinux, a long-acting pentasaccharide, is effective for the long-term treatment of VTE, 217 but it is not being marketed because of concerns about bleeding given its prolonged duration of action (once weekly injec-tion) and lack of reversibility. The direct antithrombin dabigatran and the direct factor Xa inhibitors apixa-ban and rivaroxaban have been evaluated for treat-ment of VTE and are now available in many countries. In this section, we compare VKA therapy (target INR 2.5), LMWH, dabigatran, and rivaroxaban for the long-term treatment of VTE (ie, fi rst 3 months and extended therapy).
Table 21—[Section 3.3] Summary of Findings: Rivaroxaban vs LMWH and VKA Therapy for Acute and Long-term Treatment of VTEa-c,88
Outcomes
No. of Participants
(Studies), Follow-up
Quality of the Evidence
(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With LMWH and VKA Therapy
Risk Difference With Rivaroxaban (95% CI)
Mortality 3,449 (1 study), 6-12 mod
Moderatee,f due to imprecision
HR 0.67 (0.44-1.02)
29 per 1,000 9 fewer per 1,000 (from 16 fewer to 1 more)
Recurrent VTE 3,449 (1 study), 6-12 mod
Moderatee,g due to imprecision
HR 0.68 (0.44-1.04)
30 per 1,000h 9 fewer per 1,000 (from 17 fewer to 1 more)
Major bleeding 3,429 (1 study), 6-12 mod
Moderatee,g due to imprecision
HR 0.68 (0.34-1.38)i
11 per 1,000j 4 fewer per 1,000 (from 7 fewer to 4 more)
Burden of anticoagulation not reported
… … … Warfarin: daily medication, dietary restrictions, frequent blood testing/monitoring, increased hospital/clinic visits
Rivaroxaban: daily medication, no dietary restrictions, no frequent blood testing/monitoring
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. HR 5 hazard ratio. See Table 1 and 3 legends for expansion of other abbreviations.aIncluded patients had acute, symptomatic, and objectively verifi ed proximal DVT of the legs (unprovoked, 62%; cancer, 6%; previous, VTE 19%).bRivaroxaban 15 mg bid for 3 wk and then 20 mg/d for a total of 3 (12%), 6 (63%), or 12 (25%) mo.cEnoxaparin 1 mg/kg bid for �8 d and then VKA therapy targeted to an INR of 2.5 for 3, 6, or 12 mo.dFollow-up was prespecifi ed to be 3 (12%), 6 (63%), or 12 (25%) mo.eAllocation was concealed. Patients, providers, and data collectors were not blinded, but outcome adjudicators were blinded. Intention-to-treat analysis; 1.0% were loss to follow-up. Not stopped early for benefi t.fCI includes values suggesting benefi t or no effect; relatively low number of events.gCI includes values suggesting benefi t and harm.hOne defi nite or possible fatal VTE in the rivaroxaban group and one in the LMWH/VKA group.iCalculated from reported data.jBleeds contributing to death: one in the rivaroxaban group and fi ve in the warfarin group.
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LMWH vs VKA Therapy for the Long-term Treat-ment of DVT: Two meta-analyses compared LMWH in widely differing doses with VKAs. 218,219 In an analysis by Iorio and colleagues, 218 which included seven studies 168,221-225 and a total of 1,379 patients, among study differences of mean daily dose of LMWH, little effect on the effi cacy of LMWH compared with VKA therapy was found, but the dose of LMWH appeared to infl uence the risk of major bleeding (OR, � 0.2 with � 4,000 International Units/d to � 0.7 with 12,000 International Units/d, relative to the VKA groups; P 5 .03 for dose-dependent interac-tion). Because prophylactic doses of LMWH are rarely used as an alternative to VKA therapy in patients with VTE, we restricted our analysis to eight studies that used � 50% of the full therapeutic dose of LMWH for long-term treatment of VTE ( Table 20 , Table S28). 173,211,213,223,224,226-228 This evidence suggests that compared with VKA therapy, LMWH is associated with a reduction of recurrent VTE and a similar frequency of major bleeding and mor-tality. The quality of this evidence is moderate because of potential for bias in the assessment of recurrent VTE (nonblinded outcome assessment) and serious imprecision for major bleeding and mortality.
Cancer vs No Cancer— There are differences between patients with and without cancer with VTE that may infl uence response to anticoagulant ther-apies. These include about a 10-fold higher risk of dying and a threefold higher risk of recurrent VTE and major bleeding during the fi rst 3 or 6 months of treatment 38 ; different mechanisms of thrombosis that may be associated with a poor response to VKA ther-apy 229 ; use of cancer chemotherapy that is associated with thrombocytopenia, vomiting, and anorexia and may have other interactions with VKA therapy; and the need for invasive therapeutic interventions (eg, drainage procedures) that require reversal of antico-agulation. Many of these factors make LMWH more attractive and VKA therapy less attractive in patients with VTE and cancer and suggest that cancer may alter the response of VTE to LMWH vs VKA therapy (ie, presence of an interaction).
Among the eight studies included in Table 20 and Table S28, separate data are provided for 1,114 patients with cancer and 660 patients with-out cancer. Subgroup analyses suggest the possi-bility that the response to LMWH vs VKA therapy may differ between patients with cancer and with-out cancer (recurrent VTE: RR, 0.52 with cancer
Table 22—[Section 3.3] Summary of Findings: Rivaroxaban vs Placebo for Extended Anticoagulation of VTEa,b,88
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With PlaceboRisk Difference With Rivaroxaban (95% CI)
Mortality 1,196 (1 study), 6 or 12 moc
Moderated,e due to imprecision
RR 0.49 (0.04-5.4)f
3 per 1,000 2 fewer per 1,000 (from 3 fewer to 15 more)
Recurrent VTE 1,196 (1 study), 6 or 12 moc
Highd HR 0.18 (0.09-0.39)
71 per 1,000g 58 fewer per 1,000 (from 43 fewer to 64 fewer)
Major bleeding 1,188 (1 study), 6 or 12 mo
Moderated,h due to imprecision
RR 4.9 (0.58-42)f
i 7 more per 1,000 (from 3 more to 16 more)
Burden of anticoagulation not reported
… Rivaroxaban: daily medication
PTS not reported … … … … j
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1, 3, and 21 legends for expansion of abbreviations.aIncluded patients had acute, symptomatic, and objectively verifi ed proximal DVT of the legs or PE (unprovoked, 73%; cancer, 5%; previous VTE, 19%).bRivaroxaban 20 mg/d for 6 or 12 mo after initial long-term therapy.cFollow-up was prespecifi ed to be 6 (60%) or 12 (40%) mo.dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Intention-to-treat analysis; 0.2% were loss to follow-up. Not stopped early for benefi t.eCI includes values suggesting benefi t or no effect; relatively low number of events.fCalculated from reported data with addition of one event to each event rate because event rate was 0 in the control group.gOne defi nite or possible fatal VTE in the rivaroxaban group and one in the LMWH/VKA group.hCI includes values suggesting benefi t and harm.iBleeds contributing to death: none in the rivaroxaban group and none in the warfarin group.jPTS: baseline risk over 2 y of 58.8% for PTS and 13.8% for severe PTS (Kahn et al102). There is threefold (Prandoni et al202) to 10-fold (van Dongen et al209) increase in PTS with recurrent VTE in the ipsilateral leg.
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e458S Antithrombotic Therapy for VTE
[95% CI, 0.36-0.76] vs 0.99 without cancer [95% CI, 0.46-2.13]); major bleeding: RR, 0.92 with cancer [95% CI, 0.59-1.44] vs 0.43 without cancer [95% CI, 0.16-1.17]); mortality: RR, 0.93 with cancer [95% CI, 0.79-1.09] vs 1.85 without cancer [95% CI, 0.59-5.77]). However, none of these differences is sta-tistically signifi cant, making it less likely that there is a true difference in response to LMWH vs VKA in the two patient populations. For this reason, we have applied the same relative effects for LMWH vs VKA in patients with and without cancer. The baseline risks of events, however, are clearly different in the two populations.
Patient Preferences— As discussed in the Methods section, the ultimate judgment of the entire Anti-thrombotic Therapy and Prevention of Thrombo-sis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (AT9) panel is that most patients prefer VKA therapy over LMWH therapy. The higher purchase cost of LMWH compared with VKA therapy is an additional barrier to the long-term use of LMWH.
Quality of Evidence and Strength of Recommen-dations— Evidence for the comparison of long-term LMWH vs VKA therapy in patients without cancer is of low quality. The subgroup effect discussed previ-ously was not suffi ciently convincing to allow us to generate an effect estimate specifi cally for patients without cancer, but still reduced our confi dence that the overall effect estimate applies to the noncancer subgroup that contributed a minority of data. Consid-erations favoring use of VKA over LMWH in patients without cancer include (1) the evidence of benefi t with LMWH is of low quality, (2) the estimated abso-lute reductions in recurrent VTE events with LMWH compared with VKA therapy is small, (3) the high cost of LMWH, and (4) our assessment that LMWH is a greater burden to patients than VKA therapy. Considerations favoring use of LMWH over warfarin in patients with cancer include (1) a large absolute reduction in recurrent VTE with LMWH over VKA therapy and (2) that LMWH is better suited to the care of patients with cancer than is VKA therapy. Among patients with VTE and cancer, the advan-tages of LMWH over VKA therapy are expected to be greatest in patients (1) with metastatic disease, (2) being treated with aggressive chemotherapy, (3) presenting with extensive VTE, (4) with liver dysfunction, (5) with poor or unstable nutritional status, and (6) who wish to avoid laboratory moni-toring of coagulation.
Dabigatran vs VKA Therapy for the Long-term Treatment of DVT: One completed study has directly compared dabigatran and VKA for the fi rst 6 months of treatment of VTE ( Table 23 , Table S31 ). 343 Like
patients treated with VKA therapy, patients treated with dabigatran initially received parenteral therapy (usually IV UFH or LMWH). This study suggests that treatment with dabigatran or VKA therapy is associated with a similar frequency of recurrent VTE, major bleeding, and death. This evidence is of mod-erate quality because of serious imprecision for each outcome and lack of long-term safety data for dab-igatran in this patient population. Because the study included few patients with cancer, we were unable to assess whether its fi ndings apply equally to patients with and without cancer. In the absence of evidence of such an interaction, however, we have not further rated down the quality of evidence for patients with VTE and cancer.
Rivaroxaban vs VKA Therapy for the Long-term Treatment of DVT: A single study has directly com-pared rivaroxaban (without initial parenteral antico-agulation) with parenteral anticoagulation and VKA in patients with acute DVT ( Table 21 , Table S29). 88 Results suggested that treatment with rivaroxaban and VKA therapy are associated with a similar fre-quency of recurrent VTE, major bleeding, and death. This evidence is of moderate quality because of serious imprecision for each outcome. Because the study included few patients with cancer, we were unable to assess whether its fi ndings apply equally to patients with and without cancer. In the absence of evidence of such an interaction, however, we have not further rated down the quality of evidence for patients with VTE and cancer.
Comparisons Among LMWH, Dabigatran, and Rivaroxaban for the Long-term Treatment of DVT: There are no direct comparisons of these three agents for the long-term treatment of VTE. Recommendations about the use of one of these agents over the other are based on indirect comparisons, and the evidence is low quality.
Recommendations
3.3.1. In patients with DVT of the leg and no cancer, we suggest VKA therapy over LMWH for long-term therapy (Grade 2C) . For patients with DVT and no cancer who are not treated with VKA therapy, we suggest LMWH over dab-igatran or rivaroxaban for long-term therapy (Grade 2C) .
3.3.2. In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Grade 2B) . In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2B) .
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Remarks (3.3.1-3.3.2): Choice of treatment in patients with and without cancer is sensitive to individual patient’s tolerance for daily injections, need for labo-ratory monitoring, and treatment costs. LMWH, rivar-oxaban, and dabigatran are retained in patients with renal impairment, whereas this is not a concern with VKA. Treatment of VTE with dabigatran or rivaroxa-ban, in addition to being less burdensome to patients, may prove to be associated with better clinical out-comes than VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketing studies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak rec-ommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban, and we have not made any recommendations in favor of one of the new agents over the other.
3.4 Choice of Anticoagulant Regimen for Extended Therapy
Other than a comparison of low-intensity (target INR 1.75) with conventional-intensity VKA therapy 44 (Table S24 and S25), there are no completed stud ies that have compared different anticoagulant agents or regimens for extended therapy after a standard-ized initial period (eg, � 3 months) of anticoagulation in either patients without or with cancer. Because a
decision about using extended therapy occurs after an initial period of anticoagulation (eg, 3 months) and because the relative effi cacy and safety of anticoagulant regimens are expected to be similar during the early and extended phases of therapy, we anticipate that most patients will continue to use their initial antico-agulant regimen for extended therapy. Possible rea-sons for switching from LMWH to VKA therapy include the following: cancer becomes less active, chemotherapy is completed, patient tires of SC injec-tions, development of renal impairment causes con-cern about accumulation of LMWH (also applies to rivaroxaban and dabigatran), and LMWH costs become prohibitive . Reasons for switching from VKA therapy to LMWH could include diffi culty with INR control and need for repeated invasive proce-dures. New anticoagulant therapies may expand indi-cations for extended anticoagulant therapy because they are less burdensome than VKA or LMWH therapy and because they may be associated with improved clinical outcomes (ie, more effective or safer).
Recommendation
3.4. In patients with DVT of the leg who choose extended therapy, we suggest treatment with the same anticoagulant chosen for the fi rst 3 months (Grade 2C) .
Table 23—[Section 3.3] Summary of Findings: Dabigatran vs VKA Therapy for Long-term Treatment of VTEa-c,343
OutcomesNo. of Participants
(Studies), Follow-up
Quality of the Evidence
(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With WarfarinRisk Difference With Dabigatran (95% CI)
Mortality 2,539 (1 study), 6 mo
Moderated,e due to imprecision
HR 0.98 (0.53-1.79)
17 per 1,000 0 fewer per 1,000 (from 8 fewer to 13 more)
Recurrent VTE 2,539 (1 study), 6 mo
Moderated,e due to imprecision
HR 1.01 (0.65-1.84)
19 per 1,000f 0 more per 1,000 (from 7 fewer to 16 more)
Major bleeding 2,539 (1 study), 6 mo
Moderated,e due to imprecision
HR 0.82 (0.45-1.48)
19 per 1,000g 3 fewer per 1,000 (from 10 fewer to 9 more)
Burden of anticoagulation not reported
… … … Warfarin: daily medication, dietary restrictions, frequent blood testing/monitoring, increased hospital/clinic visits
Dabigatran: daily medication, no dietary restrictions, no frequent blood testing/monitoring
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1, 3, and 21 legends for expansion of abbreviations.aIncluded patients had acute, symptomatic, and objectively verifi ed proximal DVT of the legs or PE.bDabigatran 150 mg bid taken orally for 6 mo after an initial treatment with LMWH or IV UFH.cWarfarin adjusted to achieve an INR of 2.0 to 3.0 for 6 mo after an initial treatment with LMWH or IV UFH.dAllocation was concealed. Patients, providers, data collectors, and outcome adjudicators were blinded. Modifi ed intention-to-treat analysis; 1.1% loss to follow-up. Not stopped early for benefi t.eCI includes values suggesting no effect and values suggesting either benefi t or harm; relatively low number of events.fOne fatal VTE in dabigatran group and three fatal VTE in warfarin group.gOne fatal major bleeding in dabigatran group and one fatal major bleeding in warfarin group.
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3.5 Treatment of Asymptomatic DVT of the Leg
Rather than screen postoperative patients for the presence of asymptomatic DVT, clinicians should prescribe primary prophylaxis for VTE to surgical patients. 230,231 If imaging studies performed for other reasons (eg, CT scanning for staging of cancer) inci-dentally detect asymptomatic proximal DVT, the high frequency of false-positive results in patients without a prior suspicion of DVT dictates caution in assuming that a DVT is truly present. Reasons for a high rate of false-positive results include (1) the imaging tech-nique may not have been optimal for the diagnosis of DVT, (2) incidentally diagnosed DVT often is seen in the pelvis where DVT is harder to image (eg, unable to be assessed with compression ultrasound), and (3) the prevalence of DVT in asymptomatic patients is much lower than in symptomatic patients. Conse-quently, when there is evidence of incidental DVT, additional diagnostic testing (eg, ultrasound) to con-fi rm the presence of DVT may be necessary. Because many cases of asymptomatic VTE are detected as PE, see also section 6.9 of this article for recommenda-tions on the management of this condition.
No randomized trials have evaluated anticoagu-lant therapy in patients with incidental VTE; there-fore, evidence is of moderate quality because of indirectness. Moreover, benefi ts of anticoagulant therapy may be less than in symptomatic patients because asymptomatic DVT may be chronic or less extensive and because the prevalence of false-positive results will be higher than in patients who were sus-pected of having DVT.
Factors that justify a more-aggressive approach to anticoagulation in patients with incidentally diagnosed DVT include certainty of diagnosis, extensive throm-bosis that appears to be acute (eg, not present on a previous imaging study), progression of thrombosis on a follow-up imaging study, ongoing risk factors for VTE (eg, cancer), and a low risk of bleeding. A less-aggressive approach to anticoagulation could include (1) withholding of anticoagulation with surveillance to detect DVT extension or (2) limiting anticoagulant therapy to 3 months in patients with continuing risk factors for VTE (eg, cancer). Many patients have left the hospital by the time incidental DVT is reported. If it would be diffi cult for patients to return the same day, it is often reasonable to defer further assessment and anticoagulant therapy until the next day.
Recommendation
3.5. In patients who are incidentally found to have asymptomatic DVT of the leg, we suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic DVT (Grade 2B) .
4.0 PTS of the Leg
PTS is a cluster of leg symptoms and signs attribut-able to previous DVT. PTS occurs in about one-third of patients after acute DVT and up to two-thirds who have had an iliofemoral DVT. 102,232 The initial treat-ment of acute DVT, particularly with the use of thrombus removal strategies, may infl uence the risk of developing PTS (section 2.8). The most prominent symptoms are chronic dependent swelling and pain, discomfort on walking, and skin discoloration. The severity of symptoms may vary over time, and the most severe manifestation is a venous ulcer of the lower leg. In this section, we address prevention of PTS fi rst and then its treatment. Unlike the last edition of these guidelines, 6 we do not address treatment of leg ulcers associated with venous insuffi ciency.
4.1 Compression Stockings and Bandages to Prevent PTS
Five randomized trials evaluated compression stock-ings used at various times after diagnosis of acute DVT for the prevention of PTS (Tables S32 and S33). 201,202,233-235 Two of these trials 163,164 randomized patients soon after diagnosis of a fi rst episode of symptomatic proximal DVT to prolonged use of stockings (30-40 mm Hg pressure at the ankles) or no stockings and otherwise treated patients the same way ( Table 24 , Table S34). These trials suggest that compression stockings started within 2 weeks of DVT and continued for 2 years reduce PTS by about 50% and do not alter the frequency of recurrent VTE. Patients with proximal DVT and a previous DVT in the same leg and who have marked symptoms are expected to gain the most benefi t from compression stockings. 102,201,202 The evidence is of moderate quality because the assessment of PTS, which includes a large subjective component, was not blinded, and the estimate for recurrent VTE was imprecise.
Compression stockings applying an ankle pressure of 30 to 40 mm Hg and a lower pressure higher up the leg (ie, graduated pressure) should be started as soon as feasible after starting anticoagulant therapy. Bandages may be used to provide initial compressive therapy because it may not be possible to fi t compres-sion stockings immediately and if stockings can be worn, a rapid decrease in leg swelling will require them to be refi tted. The fi ndings from a randomized trial of 69 patients suggest that immediate compression ban-daging improves acute symptoms but does not reduce PTS at 1 year (RR, 0.9; 95% CI, 0.4-1.8). 236 Patients or their caregivers need to be able to apply and remove stockings for their use to be feasible. Alternative approaches to the use of stockings, such as routinely wearing stockings after acute DVT but stopping them if there are no symptoms of PTS after 6 months 235,237 or
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quality of the evidence is low because of imprecision and risk of bias. There is anecdotal evidence that compression therapy is of benefi t in many patients with PTS, and the potential benefi t of a trial of com-pression stockings in individual patients is likely to outweigh its harm and cost. We suggest below-knee stockings in most patients, but thigh-length stockings may be preferable in those with marked thigh swelling.
Two small crossover randomized trials have evalu-ated the treatment of severe PTS with intermittent compression devices 239,240 ( Table 26 , Table S36). Both studies suggested benefi t from intermittent compres-sion therapy. The quality of the evidence, however, is moderate because of imprecision. The goal of inter-mittent compression therapy is to reduce PTS symp-toms rather than to alter the natural history of its development. These devices can be used with or without compression stockings, depending on patient preference. Leg swelling and associated symptoms (eg, heaviness, tightness) are more likely to respond to compression stockings or intermittent compres-sion devices than are other symptoms.
only wearing stockings if there is persistent leg swell-ing, have not been adequately evaluated.
Recommendation
4.1. In patients with acute symptomatic DVT of the leg, we suggest the use of compression stockings (Grade 2B) .
Remarks : Compression stockings should be worn for 2 years, and we suggest beyond that if patients have developed PTS and fi nd the stockings helpful. Patients who place a low value on preventing PTS or a high value on avoiding the inconvenience and dis-comfort of stockings are likely to decline stockings.
4.2 Physical Treatment of PTS
Treatment of PTS with compression stockings has only been evaluated in two small trials 233, 238 ( Table 25 , Tables S35 and S37) (all patients received rutosides in one study 238 ). These studies did not fi nd compression stockings to be of benefi t. However, the
Table 24—[Section 4.1] Summary of Findings: Elastic Compression Stockings vs No Elastic Compression Stockings to Prevent PTS of the Lega,b,451
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No Elastic Compression Stockings
Risk Difference With Elastic Compression Stockings (95% CI)
PTS 421 (2 studies), 2 y Moderatec due to risk of bias
RR 0.46 (0.34-0.63)d
479 per 1,000e,f 259 fewer per 1,000 (from 177 fewer to 316 fewer)g
Recurrent VTE
374 (2 studies), 5 y Moderateh,i due to imprecision
RR 1.01 (0.61-1.67)d
210 per 1,000j 2 more per 1,000 (from 82 fewer to 141 more)
QOL not reported
… … k …
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1, 3 and 10 legends for expansion of abbreviations.aPrandoni et al202 excluded patients with recurrent ipsilateral DVT, preexisting leg ulcers, or signs of chronic venous insuffi ciency, bilateral thrombosis, a short life expectancy or a contraindication for use of stockings (eg, advanced-stage peripheral arterial insuffi ciency). Brandjes et al201 excluded patients with short life expectancy, paralysis of the leg, bilateral thrombosis, leg ulcers, or extensive varicosis.bBrandjes201 used graded elastic compression stockings (40 mm Hg of pressure at the ankle, 36 mm Hg at the lower calf, and 21 mm Hg at the upper calf); stockings were applied 2 to 3 wk after the fi rst episode of proximal DVT. Prandoni et al202 used fl at-knitted stockings (30 to 40 mm Hg of pressure at the ankle); stockings were started at hospital discharge, an average of 1 wk after admission. In both studies, stockings were used for 2 y.cPatients were not blinded to the treatment assignment, and outcomes were partly based on subjective report of symptoms.dThe effect estimate shown here results from a meta-analysis (Mantel-Haenszel fi xed-effects model) of the two relevant trials. A fi xed-effects model was chosen because of the small number of studies available.eThis estimate is based on the fi ndings of the VETO study.70 This probably underestimates PTS baseline risk given that overall, 52% of patients reported the current use of compression stockings during study follow-up.fIn Prandoni et al,202 most events occurred during the fi rst 6 mo. The cumulative incidence of the PTS in the control group was 40% after 6 mo, 47% after 1 y, and 49% after 2 y.gSevere PTS: assuming the same RR of 0.46 and a baseline risk of 8.1% over 2 y, the absolute reduction is 44 fewer severe PTS per 1,000 (from 30 fewer to 53 fewer) over 2 y.hWe did not rate down the quality of evidence for recurrent VTE for the lack of blinding because this a more objective outcome than PTS.iCI includes both negligible effect and appreciable benefi t or appreciable harm.jThis estimate is the mean of two estimates derived from two studies: 12.4% probable/defi nite VTE (Heit et al165) and 29.1% confi rmed VTE (Prandoni et al208).kThis is an important outcome that should be considered in future studies.
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e462S Antithrombotic Therapy for VTE
sion. Furthermore, rutosides may be associated with important side effects.
Recommendation
4.3. In patients with PTS of the leg, we suggest that venoactive medications (eg, rutosides, defi -brotide, and hidrosmin) not be used (Grade 2C) .
Remarks: Patients who value the possibility of response over the risk of side effects may choose to undertake a therapeutic trial
5.0 Initial Treatment of Acute PE
As we noted in Methods (section 1.1), recommenda-tions for management of patients with PE, particu-larly those addressing anticoagulant therapy and IVC fi lter insertion, are based on studies that enrolled patients with only DVT , patients with both DVT and PE, and patients with only symptoms of PE. The following sections emphasize studies that enrolled only patients with symptoms of PE (who could also have symptoms of DVT), emphasize differences in
Recommendations
4.2.1. In patients with PTS of the leg, we sug-gest a trial of compression stockings (Grade 2C) .
4.2.2. In patients with severe PTS of the leg that is not adequately relieved by compres-sion stockings, we suggest a trial of an inter-mittent compression device (Grade 2B) .
4.3 Pharmacologic Treatment of PTS
Hydroxyrutosides, a class of fl avonoid drug pro-duced from plant glycosides, may reduce capillary permeability, reduce infl ammation, improve lym-phatic function, and promote ulcer healing in patients with chronic venous insuffi ciency. 6,241,242 Two studies compared treatment of PTS (without ulceration) with rutosides vs control 238,243 (all patients wore compres-sion stockings in one study 238 ), and one study com-pared rutosides with hidrosmina 244 (Table S37). The two controlled studies suggest that rutosides do not reduce most symptoms of PTS, although they may reduce ankle swelling ( Table 27 ). This evidence is of low quality because of inconsistency and impreci-
Table 25—[Section 4.2.1] Summary of Findings: Compression Stockings vs No Compression Stockings for Patients With PTSa-c,233,238
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No Compression Stockings
Risk Difference With Compression Stockings
(95% CI)
Symptomatic relief treatment successg
115 (2 studies), 12 to 26 mo
Lowd-f due to risk of bias and imprecision
RR 0.96 (0.70-1.31)
579 per 1,000 23 fewer per 1,000 (from 174 fewer to 179 more)
QOL not reported … Not estimableRecurrent VTE not
reported… Not estimable
Ulcerationh not reported
… Not estimableh
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. CLOTS1 5 Clots in Legs or Stocking After Stroke. See Table 1 and 3 legends for expansion of other abbreviations.aGinsberg et al233 included patients with PTS 1 y after chronic, typical proximal DVT. Frulla et al238 included patients with clinical symptoms and signs suggestive of PTS.bGinsberg et al233: Graduated compression stockings (30-40 mm Hg, calf or thigh length, depending on symptoms). Patients were encouraged to wear stockings as much as possible during waking hours. Frulla et al238: below-knee graded elastic compression stockings (ECS) (30-40 mm Hg at the ankle). Patients in both study arms received hydroxyethylrutosides (HR) (we considered the ECS 1 HR vs HR comparison).cGinsberg et al233: placebo stockings (calf or thigh length, depending on symptoms).dGinsberg et al233: Adequacy of sequence generation and allocation concealment were unclear; patients and outcome assessors were adequately blinded; unclear whether analysis followed the intention-to-treat principle; unclear whether follow-up was complete. Frulla et al238: outcome assessors were blinded; follow-up was complete; intention-to-treat principle was adhered to, but sequence generation and allocation concealment were unclear, and patients were not blinded.eVery small number of patientsfPublication bias was not detected but not ruled out given that we identifi ed only one small study partially supported by industry (provision of graduated compression stockings).gGinsberg et al233 reported treatment failure (defi ned a priori based on any of fi ve clinical criteria, including symptoms and ulcer development). Treatment success refers to the absence of treatment failure. Frulla et al238 used the Villalta scale.hIndirect evidence from the CLOTS1 trial suggests that compression stockings is associated with an RR of 4 for skin complications.
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the management of patients who present with PE compared with DVT, and make recommendations for the management of patients with PE. We do not repeat evidence that was presented in the corre-sponding section that addresses treatment of DVT; instead, the reader is directed to those sections of the article and to the related tables. We do not comment in the text on the quality of the evidence that under-lies treatment recommendations for PE unless the quality of this evidence differs from that for patients who present with DVT.
5.1 Initial Anticoagulation for Acute PE
See section 2.1, Table 3 , and Table S1.
Recommendation
5.1. In patients with acute PE, we recommend initial treatment with parenteral anticoagula-tion (LMWH, fondaparinux, IV UFH, or SC UFH) over no such initial treatment (Grade 1B) .
5.2 Whether to Treat With Parenteral Anticoagulation While Awaiting the Results of Diagnostic Work-up for PE
See section 2.2. For the purpose of implement-ing this recommendation, validated prediction rules help with estimation of clinical probability of having PE. 55,56
Table 26—[Section 4.2.2] Summary of Findings: Intermittent Compression Device vs No Intermittent Compression Device for Patients With Severe PTSa-c,233,240
Outcomes
No. of Participants (Studies), Follow-up
Quality of the Evidence
(GRADE)
Relative Effect (95%
CI)
Anticipated Absolute Effects
Risk With No Intermittent
Compression Device
Risk Difference With Intermittent Compression
Device (95% CI)
Symptomatic relief: symptom score includes scoring of pain, swelling, and limitation of activity on a scale of 10-70
82 (2 studiesd), 8 wk
Moderatee-i due to imprecision
The mean symptomatic relief in the control groups was 0
The mean symptomatic relief in the intervention groups was 0.41 SDs higher (0.02 lower to 0.85 higher)
QOL: VEINES-QOL scale of 0-100.
0 (1 studyd,j), 8 wk
Moderateg-i,k,l due to imprecision
The mean QOL in the control groups was 50.2
The mean QOL in the intervention groups was 2.3 higher (1.04 lower to 5.64 higher)
Recurrent VTEm not reported … Not estimablem
Ulcerationn not reported … Not estimablen
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. VEINES 5 Venous Insuffi ciency Epidemiological and Economic Study. See Table 1, 3, and 25 legends for expansion of other abbreviations.aPatients with previous DVT with symptoms of severe PTS.bIntervention group: Ginsberg et al239: Extremity pump used bid for 20 min each session; 50 mm Hg (therapeutic pressure) for 1 mo. O’Donnell et al240: Venowave lower-limb venous return assist device to wear for most of the day for 8 wk.cControl group: Ginsberg et al239: Extremity pump used bid for 20 min each session; 15 mm Hg (placebo pressure) for 1 mo. O’Donnell et al240: Venowave lower-limb venous return assist device with no connection between motor and planar sheet for 8 wk.dCrossover RCTs.eIn both studies, sequence generation was adequate; patients were blinded, analysis adhered to intention-to-treat principle, and there were no missing outcome data. In Ginsberg et al239 (but not O’Donnell et al240), outcome assessors were not blinded, and it was not clear whether allocation was concealed.fI2 5 0%.gSome concerns with indirectness, given relatively short follow-up (8 wk).hVery small number of patients. CI includes both values suggesting no effect and values suggesting a benefi cial effect.iPublication bias not detected but not ruled out given that we identifi ed only two small studies, with one (Ginsberg et al239) partially supported by industry (provision of devices).jO’Donnell et al et al.240
kSequence generation was adequate; patients were blinded, analysis adhered to intention-to-treat principle, and there were no missing outcome data. However, outcome assessors were not blinded, and it was not clear whether allocation was concealed.lPublication bias was not detected but not ruled out given that we identifi ed only a small study.mO’Donnell et al240 indicated no cases of recurrent VTE by the end of this study but judged the follow-up period to be short.nO’Donnell et al240 indicated that one patient in the control group developed a venous ulceration. Three other participants developed nonserious skin-related side effects. Indirect evidence from the CLOTS1 suggests that compression stockings are associated with an RR of 4 for skin complications. Common side effects attributed to Venowave were heat sensation, skin irritation, and increased sweating.
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e464S Antithrombotic Therapy for VTE
Recommendations
5.2.1. In patients with a high clinical suspicion of acute PE, we suggest treatment with paren-teral anticoagulants compared with no treat-ment while awaiting the results of diagnostic tests (Grade 2C) .
5.2.2. In patients with an intermediate clinical suspicion of acute PE, we suggest treatment with parenteral anticoagulants compared with no treatment if the results of diagnostic tests are expected to be delayed for more than 4 h (Grade 2C) .
5.2.3. In patients with a low clinical suspicion of acute PE, we suggest not treating with parenteral anticoagulants while awaiting the results of diagnostic tests provided that test results are expected within 24 h (Grade 2C) .
5.3 Timing of Initiation of VKA and Associated Duration of Parenteral Anticoagulant Therapy
See section 2.4, Table 4 , and Table S2.
Recommendation
5.3. In patients with acute PE, we recommend early initiation of VKA (eg, same day as paren-teral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the INR is 2.0 or above for at least 24 h (Grade 1B) .
5.4 Choice of Initial Parenteral Anticoagulant Regimen in Patients With PE
See section 2.5.
LMWH Compared With IV UFH for the Initial Treatment of PE: See section 2.5 and Table 6 . Con-sistent with fi ndings in patients with DVT, LMWH has been found to be as effective and safe as IV UFH in studies that included both patients with PE and DVT or only in patients with PE ( Table 6 ). A meta-analysis of 12 studies 85,146,245-254 that included a total of 1,951 patients with either submassive symp-tomatic PE or asymptomatic PE in conjunction with symptomatic DVT failed to demonstrate or
Table 27—[Section 4.3] Summary of Findings: Venoactive Medication vs No Venoactive Medication for Patients With PTSa,b,202,238
Outcomes
No. of Participants (Studies), Follow-up
Quality of the Evidence
(GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No Venoactive Medication
Risk Difference With Venoactive
Medication (95% CI)
Symptomatic relief: PTS score (Villalta scale) , 5 or decreased by 30% at 12 mo compared with baseline in Frulla et al238; improved tiredness of the leg at 8 wk in de Jongste et al243,c
163 (2 studies) Lowd-g due to inconsistency, imprecision
RR 1.14 (0.85-1.52) 476 per 1,000 67 more per 1,000 (from 71 fewer to 247 more)
QOL not reported … Not estimableRecurrent VTE not reported … Not estimableUlceration not reported … Not estimableSide effects 203 (2 studies) Moderated,f-h due
to imprecisionRR 2.04 (0.76-5.51) 61 per 1,000 63 more per 1,000
(from 15 fewer to 275 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aPatients with PTS and history of DVT in PTS leg.bIncluded studies that assessed rutosides.cInvestigators assessed other symptoms (pain, heaviness, swelling feeling, restless legs, and cramps) but did not report a composite score. The symptom we chose to report showed the most benefi t; the effect estimates for the other symptoms ranged from 0.8 to 1.4, and none were statistically signifi cant.dIn both studies, sequence generation and allocation concealment were unclear. Both studies blinded outcome assessors and had complete follow-up. Although de Jongste et al243 blinded patients, the authors did not adhere to the intention-to-treat principle and did not use a validated scale to measure symptomatic relief. Although Frulla et al238 adhered to the intention-to-treat principle, the author did not blind patients.eI2 5 77%.fSmall number of patients. CI included both values suggesting harms and values suggesting benefi ts.gPublication bias was not detected but not ruled out given that we identifi ed only two small studies, and it unclear whether they were funded by industry.hI2 5 7%.
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exclude a benefi cial or detrimental effect of LMWH on recurrent VTE (OR, 0.63; 95% CI, 0.33-1.18), major bleeding (OR, 0.67; 95% CI, 0.36-1.27), and all-cause mortality (OR, 1.20; 95% CI, 0.59-2.45). 255
SC UFH Compared With SC LMWH for the Ini-tial Treatment of PE: See section 2.5, Table 5 , and Tables S3 through S5.
Fondaparinux Compared With IV UFH for the Ini-tial Treatment of PE: The Matisse-PE trial compared fondaparinux with IV UFH for acute treatment of PE 79 ( Table 28 , Table S38). This study suggested that fondaparinux is associated with a similar frequency of mortality, recurrent VTE, and major bleeding as LMWH. The quality of this evidence is moderate because of imprecision. In making recommendations, we also considered evidence that fondaparinux is equiv-alent to LMWH for the treatment of DVT (see sec-tion 2.5, Table 7 , and Table S38) and that fondaparinux shares the advantages that LMWH has over IV UFH.
Fondaparinux Compared With LMWH for the Ini-tial Treatment of PE: In the absence of direct evi-dence in patients with PE, indirect evidence in patients with acute DVT (see section 2.5, Table 7 , and Table S7) suggests that fondaparinux is equiva-lent to LMWH.
Fondaparinux Compared With SC UFH for the Initial Treatment of PE: There is no direct evidence
for this comparison. In making recommendations, we considered that fondaparinux and LMWH are equiv-alent and that fondaparinux shares the advantages that LMWH has over IV UFH. We did not take into account the lower purchase cost of SC UFH com-pared with fondaparinux.
Once- vs Twice-Daily Administration of LMWH for Initial Treatment of PE: See section 2.5, Table 8 , and Table S8. Patients who presented with PE were included in only one of the fi ve studies with an unconfounded comparison of once- and twice-daily LMWH 85 and in one additional large study that com-pared once-daily LMWH therapy with IV UFH in patients who presented with PE. 252
Recommendations
5.4.1. In patients with acute PE, we suggest LMWH or fondaparinux over IV UFH (Grade 2C for LMWH; Grade 2B for fondaparinux) , and over SC UFH (Grade 2B for LMWH; Grade 2C for fondaparinux) .
Remarks: Local considerations such as cost, avail-ability, and familiarity of use dictate the choice between fondaparinux and LMWH. LMWH and fondaparinux are retained in patients with renal impairment, whereas this is not a concern with UFH. In patients with PE where there is concern about the adequacy of SC absorption or in patients in whom
Table 28—[Section 5.4] Summary of Findings: Fondaparinux vs IV UFH for Initial Anticoagulation of Acute PEa-c,79
OutcomesNo. of Participants
(Studies), Follow-up
Quality of the Evidence (GRADE)
Relative Effect (95% CI)
Anticipated Absolute Effects
Risk With UFHRisk Difference With
Fondaparinux (95% CI)
Mortality 2,213 (1 study), 3 mo Moderated,e due to imprecision
RR 1.20 (0.82-1.74) 43 per 1,000 9 more per 1,000 (from 8 fewer to 32 more)
Recurrent VTE 2,213 (1 study), 3 mo Moderated,e due to imprecision
RR 0.75 (0.51-1.12) 50 per 1,000f 13 fewer per 1,000 (from 25 fewer to 6 more)
Major bleeding 2,213 (1 study), 3 mo Moderated,e due to imprecision
RR 0.85 (0.49-1.49) 23 per 1,000g 4 fewer per 1,000 (from 12 fewer to 11 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aAll patients had acute, symptomatic, hemodynamically stable PE.bFondaparinux (5.0, 7.5, or 10.0 mg in patients weighing , 50, 50 to 100, or . 100 kg, respectively) SC once daily given for at least 5 days and until the use of VKAs resulted in an INR . 2.0.cUFH continuous IV infusion (ratio of the activated partial thromboplastin time to a control value of 1.5-2.5) given for at least 5 days and until the use of VKAs resulted in an INR . 2.0.dAllocation was concealed. Patients, providers, and data collectors were not blinded. Outcome adjudicators were blinded; 0.6% of randomized patients were lost to follow-up. Not stopped early for benefi t.eCI includes values suggesting no effect and values suggesting either benefi t or harm; relatively low number of events.fSixteen fatal VTE in fondaparinux group and 15 fatal VTE in UFH group.gFourteen patients in the fondaparinux group and 12 patients in the LMWH group had a major bleeding event during the initial period (6-7 d). Of these, one in the fondaparinux group and one in the UFH group were fatal.
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e466S Antithrombotic Therapy for VTE
thrombolytic therapy is being considered or planned, initial treatment with IV UFH is preferred to use of SC therapies.
5.4.2. In patients with acute PE treated with LMWH, we suggest once- over twice-daily admin-istration (Grade 2C) .
Remarks: This recommendation only applies when the approved once-daily regimen uses the same daily dose as the twice-daily regimen (ie, the once-daily injec-tion contains double the dose of each twice-daily injection). It also places value on avoiding an extra injection per day.
5.5 Early vs Standard Discharge of Patients With Acute PE
Consistent with our discussion of outpatient treat-ment of acute DVT (section 2.7), LMWH has made it feasible to treat acute PE at home either without admission to the hospital (ie, discharge from the emergency department) or with admission and early discharge. However, because acute PE is associated with much higher short-term mortality than acute DVT, the safety of treating PE at home is uncertain. Consequently, PE is treated at home much less often than DVT, and the proportion of outpatients with PE that clinical centers treat at home varies from almost none to about 50%.
Two studies randomized patients with acute PE and a low risk of complications to receive LMWH either (1) in the hospital for only 3 days vs entirely in the hospital 256 or (2) entirely out of the hospital (dis-charged within 24 h) vs at least partly in hospital 257 ( Table 29 , Table S39). This evidence suggests that treating appropriately selected patients with acute PE at home does not increase recurrent VTE, bleeding, or mortality.
There are a number of prediction rules for identi-fying patients with acute PE who have a low risk of serious complications and may be suitable for treat-ment at home. 258-263 Of these, the PE Severity Index (PESI) is best validated 261,262,264-266 and was used to select patients for home treatment in the larger of the previously noted clinical trials ( Table 29 , Table S39). Patients with acute PE who meet the following criteria appear to be suitable for treatment out of the hospital: (1) Clinically stable with good car-diopulmonary reserve (eg, PESI score of , 85 257 or simplifi ed PESI score of 0, 262 including none of hypoxia, systolic BP , 100, recent bleeding, severe chest pain, platelet count , 70,000/mm 3 , PE while on anticoagulant therapy, and severe liver or renal disease) 257 , (2) good social support with ready access to medical care, and (3) expected to be compliant with follow-up. Patients also need to feel well enough
to be treated at home (eg, absence of severe symp-toms or comorbidity).
Consistent with the fi ndings of these two trials, a systematic review of 11 observational studies (seven prospective, four retrospective; 928 patients) 267 and four more recent observational studies (two retro-spective with 584 patients 268,269 ; two prospective with 449 patients 270,271 ) reported a very low frequency of complications in low-risk patients with acute PE who were initially treated partially or entirely at home. About one-third to one-half of outpatients with acute PE appear to be in this low-risk group. 272 The evidence from the randomized trials is of moderate quality (rated down for serious imprecision), with additional supportive fi ndings from the observational studies.
Recommendation
5.5. In patients with low-risk PE and whose home circumstances are adequate, we suggest early discharge over standard discharge (eg, after the fi rst 5 days of treatment) (Grade 2 B) .
Remarks: Patients who prefer the security of the hos-pital to the convenience and comfort of home are likely to choose hospitalization over home treatment.
5.6 Systemic Thrombolytic Therapy for PE
5.6.1 Systemic Thrombolytic Therapy vs Anticoag-ulation Alone for PE: Randomized trials have estab-lished that, at 24 h, thrombolytic therapy improves (1) pulmonary artery hemodynamic measurements (eg, mean pulmonary artery pressure improvement, 4.4 mm Hg; 95% CI, 2 4.6-4.2 mm Hg), (2) arterio-venous oxygen (difference of 2 0.3 [ 2 0.4 to 2 0.2] ), (3) pulmonary perfusion (50% early improvement in perfusion scan, OR, 3.8; 95% CI, 0.9-15.7), and (4) echo-cardiographic assessment (OR for improved right ventricular wall movement, 3.1; 95% CI, 1.5-6.3). 273 Thrombolytic therapy, however, does not appear to reduce the extent of residual thrombosis. It is uncer-tain whether the benefi ts of more-rapid resolution of PE outweigh the risk of increased bleeding associ-ated with thrombolytic therapy. In patients with PE, severity of presentation is expected to depend on the extent of embolism (ie, degree of pulmonary artery obstruction) and the presence and severity of chronic cardiopulmonary impairment. 104,274,275 Patients with the most severe presentations who have the highest risk of dying from an acute PE have the most to gain from thrombolysis.
Prognosis in Patients With Acute PE— Of patients who are diagnosed with PE and start treatment, � 5% die of the initial PE or another PE within the next 7 days. 9,104,276-279 However, although the risk of dying of PE differs markedly among patients, no validated
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risk prediction tool is available. Risk of dying of PE is estimated to be � 70% if cardiopulmonary arrest occurs ( � 1% of patients at presentation), 30% if there is shock requiring inotropic support ( � 5% of patients), and � 2% in patients who are not hypotensive. 104,276-278,280,281 In the presence of normal systemic arterial pressure, prognosis can also differ, depending on (1) clinical evaluation, 276 (2) cardiac biomarkers such as troponin or brain natriuretic peptide, 279,282-291 and (3) assessment of right ventric-ular size and function. 279,280,283,285,290-295
Clinical evaluation involves assessment of general appearance, BP, heart rate, respiratory rate, temper-ature, pulse oximetry, and signs of right ventricular dysfunction (eg, distended jugular veins, tricuspid regurgitation, accentuated P 2 ). 104 Clues on the ECG include right bundle branch block, S 1 Q 3 T 3 , and T-wave inversion in leads V 1 through V 4 . 296 Elevation of cardiac troponins indicates right ventricular micro-infarction, and echocardiography may show right ven-tricular hypokinesis; both are risk factors for early mortality and are associated with a worse outcome when they occur together. 238,241-245,250 Right ventricular enlargement on the CT pulmonary angiogram, defi ned as a right ventricular diameter � 90% than the left ventricular diameter may also be an independent risk factor for death and nonfatal complications. 279,291,293,295,297
Risk of Bleeding With Thrombolytic Therapy— We have not identifi ed any validated risk predic-
tion tool for bleeding with thrombolytic therapy in patients with PE. However, we assume that the assessment of bleeding risk with thrombolytic ther-apy is similar in patients with PE and with acute ST-segment elevation myocardial infarction. 104,110-113,298,299 Table 11 lists risk factors for bleeding with thrombolytic therapy, categorized as major and relative contra-indications.
Trials Evaluating Thrombolytic Therapy in Patients With Acute PE— The fi ndings of 13 randomized trials that compared thrombolytic therapy to antico-agulant therapy alone in patients with acute PE are summarized in Table 30 and Tables S40 through S42. 300-313 A number of meta-analyses of these studies have been performed. 104,273,315,315 This evidence sug-gests that thrombolysis may be associated with a reduc-tion in mortality and recurrent PE and is associated with an increase in major bleeding, as has been estab-lished in patients with myocardial infarction. 112 The quality of evidence regarding mortality and recurrent PE is low because of risk of bias, serious imprecision, and suspected publication bias. A previous meta-analysis that categorized studies as either including, or not including, patients with cardiopulmonary com-promise, suggested that thrombolytic therapy reduced the composite outcome of death and recurrent PE in studies that included the sickest patients. 315 However, we found that the data available from these studies are not suffi ciently detailed to enable a subgroup
Table 29—[Section 5.5] Summary of Findings: Early Discharge vs Standard Discharge in the Treatment of Acute PEa,b,256,257
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With Standard Discharge
Risk Difference With Early Discharge (95% CI)
Mortality 471 (2 studies), 3 mo Moderatec,d due to imprecision
RR 0.58 (0.17-1.97) 26 per 1,000 11 fewer per 1,000 (from 22 fewer to 26 more)
Nonfatal recurrent PE 471 (2 studies), 3 mo Moderatec,d due to imprecision
RR 1.23 (0.25-6.03) 9 per 1,000 2 more per 1,000 (from 7 fewer to 44 more)
Major bleeding 471 (2 studies), 3 mo Moderatec,d due to imprecision
RR 2.74 (0.45-16.71) 4 per 1,000 8 more per 1,000 (from 2 fewer to 69 more)
QOL not reported … … … … …PTS not reported … … … … …
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aThe two RCTs included only patients with low risk: risk classes I or II on the Pulmonary Embolism Severity Index in Aujesky et al216; low risk on clinical prediction rule by Uresandi et al.258
bMean length of hospital stay: 3.4 (SD 1.1) vs 9.3 (SD 5.7) d in Otero et al256 and 0.5 (SD 1.0) vs 3.9 (SD 3.1) d in Aujesky et al257; low risk on clinical prediction rule by Uresandi et al258 in Otero et al.cOtero et al256: allocation concealed; no patients lost to follow-up; intention-to-treat analysis; no blinding of outcome assessors reported; study stopped early because the rate of short-term mortality was unexpectedly high in the early discharge group (2 [2.8%] vs 0 [0%]). Aujesky et al257: unclear whether allocation was concealed; three (1%) patients had missing outcome data; intention-to-treat analysis; blinding of outcome adjudicators; no early stoppage.dCI includes both values suggesting no effect and values suggesting appreciable harm or appreciable benefi t.
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analysis evaluating outcomes in patients with hemo-dynamic compromise or other markers of heightened risk of death (eg, right ventricular dysfunction).
Balancing Benefi ts and Harms of Thrombolytic Therapy— In patients who present with PE and hypotension (eg, systolic pressure BP , 90 mm Hg or a documented drop in systolic BP . 40 mm Hg with evidence of poor perfusion), especially if they have a low risk of bleeding, even modest effi cacy of throm-bolytic therapy is likely to reduce deaths from PE more than it would increase fatal bleeds and nonfatal intracranial bleeds ( Table 30 , Tables S40-S42). The ultimate judgment of the entire AT9 panel was to issue a weak recommendation for patients with PE and hypotension given the uncertainty of the benefi t. In most patients with PE, given the certain risks of bleeding and less-certain benefi ts, thrombolysis is likely to be harmful. Selected patients without hypo-tension may benefi t from thrombolysis because their initial clinical presentation or clinical course after starting anticoagulant therapy suggest that they are at high risk of dying.
There is no explicit clinical prediction rule that identifi es this subgroup of patients. We suggest that such patients are identifi ed predominantly by clinical evidence of instability (eg, a decrease in systolic BP that still remains . 90 mm Hg, tachycardia, elevated jugular venous pressure, clinical evidence of poor tissue perfusion, hypoxemia) and failure to improve on anticoagulant therapy. As noted previously, labo-ratory (eg, troponin, brain natriuretic peptide), ECG, echocardiography, and CT evidence of right ventric-ular dysfunction or enlargement, can supplement the clinical evaluation of instability; however, they are not suffi ciently predictive to serve as indications for thrombolytic therapy on their own, 289 and we do not recommend that they are routinely measured.
Recommendations
5.6.1.1. In patients with acute PE associated with hypotension (eg, systolic BP , 90 mm Hg) who do not have a high risk of bleeding, we sug-gest systemically administered thrombolytic therapy over no such therapy (Grade 2C) .
5.6.1.2. In most patients with acute PE not asso-ciated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1C) .
5.6.1.3. In selected patients with acute PE not associated with hypotension and with a low risk of bleeding whose initial clinical presentation or clinical course after starting anticoagulant therapy suggests a high risk of developing hypo-
tension, we suggest administration of thrombo-lytic therapy (Grade 2C) .
5.6.2 Systemic Thrombolytic Therapy Regimen for PE: Twelve randomized trials (total of 938 patients) have compared the rate of thrombus resolution achieved with various IV thrombolytic regimens. 316-327 These regimens included urokinase given over 2 h 319,326 or 12 h 316,321,326 ; streptokinase given over 2 h, 12 h, 320 or 24 h 316 ; and recombinant tPA (rt-PA) given over 15 min 317,322,325 or 2 h, 317-325,327 reteplase in two boluses 30 min apart, 325 and desmoteplase in three different doses as a bolus 323 .
An additional study compared IV with pulmonary artery catheter administration of rt-PA (50 mg over 2 h). 328 The results of studies that compared different approaches to thrombolysis in patients with PE (noted previously) suggest that (1) prolonged infusions of thrombolytic agents (eg, � 12 h) are associated with higher rates of bleeding 316,318 ; (2) 2-h infu-sions achieve more rapid clot lysis than 12- or 24-h infusions 318,320,321 ; (3) when a high-concentration 2-h infusion of thrombolysis is administered, there is no clear difference in the effi cacy or safety of rt-PA vs streptokinase 327 ; (4) bolus rt-PA regimens (eg, � 50 mg in � 15 min) appears to be as effective and safe as a 2-h infusion of 100 mg of rt-PA 313,317,322,325 ; and (5) infusion of rt-PA directly into a pulmonary artery as opposed to a peripheral vein does not accelerate thrombolysis but does cause more frequent bleeding at the catheter insertion site (there was no attempt to infuse rt-PA directly into or to mechanically dis-rupt the thrombus in this study from 1988). 328 When a lytic agent is appropriate for PE, current evidence supports that thrombolytic therapy should be infused into a peripheral vein over � 2 h. At a dose of 100 mg over 2 h, rt-PA is currently the most widely used and evaluated regimen. In patients with imminent or actual cardiac arrest, bolus infusion of thrombolytic therapy is indicated.
The quality of evidence for comparisons of systemic thrombolytic agents and regimens (eg, different doses or durations of infusion) is low based on very serious imprecision and risk of bias. In addition, there is substantial potential for publication bias. Based on this evidence, we provide only weak rec-ommendations for all comparisons of thrombolytic agents and regimens in the short-term treatment of PE.
Recommendations
5.6.2.1. In patients with acute PE, when a throm-bolytic agent is used, we suggest short infusion times (eg, a 2-h infusion) over prolonged infu-sion times (eg, a 24-h infusion) (Grade 2C) .
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5.6.2.2. In patients with acute PE, when a throm-bolytic agent is used, we suggest administration through a peripheral vein over a pulmonary artery catheter (Grade 2C) .
5.6.3 Initial Anticoagulant Therapy in Patients Treated With Thrombolytic Therapy: Trials that evaluated thrombolysis for PE used IV UFH in
conjunction with thrombolytic therapy ( Table 30 , Tables S40-S42), and no randomized trials have com-pared different regimens of IV UFH in this setting. IV UFH should be given in full therapeutic doses 1,3 before thrombolytic therapy is administered, and it is acceptable to either continue or suspend the UFH infusion during administration of thrombo-lytic therapy (these two practices have never been
Table 30—[Section 5.6.1] Summary of Findings: Systemic Thrombolytic Therapy vs Anticoagulation Alone in Patients With Acute PEa-d,273,309,310,314,315
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No Systemically Administered
Thrombolytic Therapy
Risk Difference With Systemically Administered
Thrombolytic Therapy (95% CI)
Mortality 847 (12 studies), 30 d
Lowe-h due to risk of bias and imprecision
RR 0.7 (0.37-1.31)
Lowi,j
11 per 1,000 3 fewer per 1,000 (from 7 fewer to 3 more)
Highi,j
89 per 1,000 27 fewer per 1,000 (from 56 fewer to 28 more)
Recurrent PE 801 (9 studies), 30 d
Lowe-h due to risk of bias and imprecision
RR 0.7 (0.4-1.21)
57 per 1,000 17 fewer per 1,000 (from 34 fewer to 12 more)
Major bleeding 847 (12 studies), 10 d
Moderatee,f,h,k due to risk of bias and imprecision
RR 1.63 (1-2.68)l
Lowm
1 per 1,000 1 more per 1000 (from 0 more to 2 more)
Highm
62 per 1,000 39 more per 1,000 (from 0 more to 104 more)
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aOne study included exclusively patients with hemodynamic compromise (shock), six excluded them, whereas the rest either included a number of such patients or did not specify related eligibility criteria. Of studies not restricted to patients with hemodynamic compromise (n 5 11), only three were clearly restricted to patients with right ventricular dysfunction; the rest either did not specify related eligibility criteria or included both patients with and without right ventricular dysfunction. As a result, it was not possible to perform reliable categorization of studies to conduct subgroup analyses based on the presence or absence of right ventricular dysfunction or hemodynamic compromise.bStudies included patients at low risk for bleeding.cIncluded studies that used different thrombolytic agents with varying doses and durations of administration; no statistical heterogeneity was noted.dThrombolysis was in addition to anticoagulation (most of the studies used heparin followed by warfarin; three studies used warfarin only).eReport of methodologic quality was poor in most studies. Of the 12 eligible studies, allocation was concealed in fi ve, three were single blind (outcome assessor), six were double blind, and three were not blinded. Most studies did not report on missing outcome data. None of the studies were stopped early for benefi t. For the increase in bleeding with thrombolytic therapy, quality of evidence is increased from low to moderate because there is high quality evidence of this association in patients with myocardial infarction and the indirectness of this evidence to patients with PE is minor.fI2 5 0%.gCI includes values suggesting both benefi t and no effect or harm; small number of events.hInverted funnel plots suggestive of possible publication bias in favor of thrombolytics.iRecurrent PE stratifi cation based on the simplifi ed Pulmonary Embolism Severity Index validated in the RIETE (RegistroInformatizado de la Enfermedad Tromboembólica) cohort.262
jSome studies suggested that the baseline risk of mortality in patients with hemodynamic instability is as high as 30%.274 In that case, the absolute number of deaths associated with thrombolytics would be 90 fewer per 1,000 (from 189 fewer to 93 more).kCI includes values suggesting both harm and no effect; small number of events.lMajor bleeding risk stratifi cation derived from the RIETE cohort.30 The median risk of bleeding over the fi rst 10 d reported in the eligible trials was 3.1%. In that case, the absolute number of major bleeding events with thrombolysis would be 20 more per 1,000 (from 0 more to 52 more).mIndirect evidence from studies of thrombolysis for myocardial infarction and acute stroke provide more precise estimates of increase major bleeding with thrombolytics use.
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compared). During a 2-h infusion of 100 mg of tPA, US regulatory bodies recommend suspension of IV UFH, whereas IV UFH is continued during the tPA infusion in many other countries. US authorities rec-ommend checking the activated partial thrombo-plastin time immediately after completion of the tPA infusion and, provided that the activated antithrombin time is not . 80 s, restarting IV UFH without a bolus at the same infusion rate as before tPA was started.
5.7 Catheter-Based Thrombus Removal for the Initial Treatment of PE
Interventional catheterization techniques for mas-sive PE include mechanical fragmentation of throm-bus with a standard pulmonary artery catheter, clot pulverization with a rotating basket catheter, percu-taneous rheolytic thrombectomy, or pigtail rotational catheter embolectomy. 329-336 Pharmacologic throm-bolysis and mechanical interventions are usually combined unless bleeding risk is high. Catheter embolectomy does not result in extraction of intact pulmonary arterial thrombus; instead, clot fragments are suctioned through the catheter or displaced dis-tally with modest angiographic improvement.
No randomized trials have evaluated interventional catheterization techniques for PE. Most observation studies are retrospective series of , 30 patients. 334 Consequently, evidence for the use of interventional catheter techniques in patients with acute PE is of low quality, and our recommendations are weak. Catheter selection, catheter deployment, and adjunc-tive thrombolytic regimen should be based on local expertise and resources.
Recommendation
5.7. In patients with acute PE associated with hypotension and who have (i) contraindications to thrombolysis, (ii) failed thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are avail-able, we suggest catheter-assisted thrombus removal over no such intervention (Grade 2C) .
5.8 Surgical Embolectomy for the Initial Treatment of PE
Emergency surgical embolectomy with cardio-pulmonary bypass is another management strategy for acute PE associated with hypotension. 337-340 This operation is also suited for patients with acute PE who require surgical excision of a right atrial thrombus, paradoxical arterial embolism, or clo-sure of a patent foramen ovale. Surgical embolec-tomy also can be performed to rescue patients in
whom thrombolysis has been unsuccessful. The procedure is best performed on a warm, beating heart, without aortic cross-clamping, cardioplegia, or fi brillatory arrest.
No randomized trials or prospective observational studies have evaluated surgical embolectomy in patients with acute PE. Consequently, evidence related to surgical embolectomy in patients with acute PE is of low quality, and our recommendations are weak.
Recommendation
5.8. In patients with acute PE associated with hypotension, we suggest surgical pulmonary embolectomy over no such intervention if they have (i) contraindications to thrombolysis, (ii) failed thrombolysis or catheter-assisted embolectomy, or (iii) shock that is likely to cause death before thrombolysis can take effect (eg, within hours), provided surgical expertise and resources are available (Grade 2C) .
5.9. Vena Caval Filters for the Initial Treatment of PE
As previously noted in section 2.13, IVC fi lters can be used instead of initial anticoagulant therapy in patients with acute PE if there is an unacceptable risk of bleeding or as an adjunct to anticoagulation. As in DVT, no randomized trials or prospective cohort studies have evaluated IVC fi lters as sole therapy for acute PE (ie, without concurrent antico-agulation). As described in section 2.13, the PREPIC study, which evaluated IVC fi lters as an adjunct to anticoagulation in 400 high-risk patients with prox-imal DVT, showed that fi lters reduced PE, increased DVT, and did not change overall frequency of VTE (DVT and PE combined) or mortality 146,149 ( Table 14 ; Table S19).
The PREPIC study included 145 (36%) patients with symptomatic PE and 52 (13%) patients with asymptomatic PE at enrollment. If a patient has an acute PE and a short-term contraindication to anticoagulation, provided there is no proximal DVT on ultrasound, it is reasonable not to insert an IVC fi lter immediately; serial ultrasound examina-tions can be performed to ensure that the patient remains free of proximal DVT while anticoagulation is withheld.
There is uncertainty about the risk and benefi ts of inserting IVC fi lters as an adjunct to anticoagulant and thrombolytic therapy in patients with PE and hypotension. Among patients with hemodynamic compromise in the International Cooperative Pulmo-nary Embolism Registry, insertion of an IVC fi lter was associated with a reduction of early recurrent PE and death. 280 Consequently, our recommendation
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against insertion of an IVC fi lter in patients with acute PE who are treated with anticoagulants may not apply to this select subgroup of patients.
Recommendations
5.9.1. In patients with acute PE who are treated with anticoagulants, we recommend against the use of an IVC fi lter (Grade 1B) .
5.9.2. In patients with acute PE and contraindi-cation to anticoagulation, we recommend the use of an IVC fi lter (Grade 1B) .
5.9.3. In patients with acute PE and an IVC fi l-ter inserted as an alternative to anticoagulation, we suggest a conventional course of anticoagu-lant therapy if their risk of bleeding resolves (Grade 2B) .
Remarks: We do not consider that a permanent IVC fi lter of itself is an indication for extended anticoagulation.
6.0 Long-term Treatment of PE
In the following sections, we emphasize studies that were performed exclusively in patients with PE and patients with PE who were enrolled in other studies. For the reasons noted in section 1.1, we make the same recommendations for long-term treatment of PE as for DVT and rate the quality of the under-lying evidence as the same (see corresponding sec-tions for treatment of DVT).
VKA for the Long-term Treatment of PE: There has been only one evaluation of duration of VKA therapy exclusively in patients with PE. After 3 months of initial treatment, patients with PE pro-voked by a temporary risk factor were randomized to stop or to receive 3 more months of therapy, and those with unprovoked PE were randomized to stop or to receive 6 more months of therapy (WODIT PE [Warfarin Optimal Duration Italian Trial in patients with Pulmonary Embolism]) (Table S24 and S25). 194 Consistent with studies that included patients who presented with DVT, extended VKA therapy was effective while treatment was being received. How-ever, extending the duration of treatment beyond 3 months did not lower the rates of recurrence that were observed when anticoagulants were subsequently stopped.
LMWH for the Long-term Treatment of PE: Two small studies from the same investigator group have compared long-term LMWH (enoxaparin 1 mg/kg SC bid for � 14 days followed by 1.5 mg/kg SC daily)
with long-term VKA exclusively in patients who pre-sented with PE. 341,342 The two studies combined found a similar frequency of recurrent VTE (enoxaparin, 4/60; VKA, 1/40) and major bleeding (enoxaparin, 1/60; VKA, 2/40) with the two treatments. 341 Of the 12 other studies that compared LMWH with VKA therapy for long-term treatment of VTE (see section 3.3), only two 173,227 included patients with PE. In these two studies, all patients had cancer, and 295 had PE (36% of all enrolled patients; some PE may have been asymptomatic in one study 227 ); subgroup analyses were not reported for the patients with PE.
Dabigatran for the Long-term Treatment of PE: In the one completed study that compared dabigatran with VKA therapy after initial parenteral therapy ( Table 23 , Table S31), 786 (31%) patients had symp-tomatic PE at enrollment. 343 Subgroup analysis did not suggest that patients with symptomatic PE have a different response to dabigatran vs VKA therapy in terms of either recurrent VTE or bleeding.
Rivaroxaban for the Long-term Treatment of PE: In the Einstein Extension study that compared rivar-oxaban with placebo after an initial period of long-term anticoagulation ( Table 22 , Table S30), 454 (38%) patients had symptomatic PE at enrollment. 88 Sub-group analysis did not suggest that patients with symptomatic PE had a different response to rivaroxa-ban vs VKA therapy in terms of either recurrent VTE or bleeding.
Recommendations
6.1. In patients with PE provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , or (iii) extended therapy (Grade 1B regardless of bleeding risk) .
6.2. In patients with PE provoked by a nonsur-gical transient risk factor, we recommend treat-ment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Grade 1B) , and (iii) extended therapy if there is a high bleeding risk ( Table 2 ) (Grade 1B) . We suggest treatment with antico-agulation for 3 months over extended therapy if there is a low or moderate bleeding risk ( Table 2 ) (Grade 2B) .
6.3. In patients with an unprovoked PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter
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duration (Grade 1B) . After 3 months of treat-ment, patients with unprovoked PE should be evaluated for the risk-benefi t ratio of extended therapy.
6.3.1. In patients with a fi rst VTE that is an unprovoked PE and who have a low or moderate bleeding risk ( Table 2 ), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B) .
6.3.2. In patients with a fi rst VTE that is an unprovoked PE and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy (Grade 1B) .
6.3.3. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk ( Table 2 ) (Grade 1B) , and we suggest extended anticoagulant therapy in those with a moderate bleeding risk ( Table 2 ) (Grade 2B) .
6.3.4. In patients with a second unprovoked VTE who have a high bleeding risk ( Table 2 ), we suggest 3 months of therapy over extended therapy (Grade 2B) .
6.4. In patients with PE and active cancer, if the risk of bleeding is not high ( Table 2 ), we rec-ommend extended anticoagulant therapy over 3 months of therapy (Grade 1B) , and if there is a high bleeding risk ( Table 2 ), we suggest extended anticoagulant therapy (Grade 2B) .
Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treat-ment should be reassessed at periodic intervals (eg, annually).
6.5. In patients with PE who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR , 2) or higher (INR 3.0-5.0) range for all treatment durations (Grade 1B) .
6.6. In patients with PE and no cancer, we suggest VKA therapy over LMWH for long-term therapy (Grade 2C) . For patients with PE and no cancer who are not treated with VKA therapy, we suggest LMWH over dabigatran or rivaroxaban for long-term therapy (Grade 2C) .
6.7. In patients with PE and cancer, we suggest LMWH over VKA therapy (Grade 2B) . In patients with PE and cancer who are not treated with
LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Grade 2C) .
Remarks (6.6-6.7): Choice of treatment in patients with and without cancer is sensitive to individual patient tolerance for daily injections, need for labora-tory monitoring, and treatment costs. Treatment of VTE with dabigatran or rivaroxaban, in addition to being less burdensome to patients, may prove to be associated with better clinical outcomes that VKA and LMWH therapy. When these guidelines were being prepared (October 2011), postmarketing stud-ies of safety were not available. Given the paucity of currently available data and that new data are rapidly emerging, we give a weak recommendation in favor of VKA and LMWH therapy over dabigatran and rivaroxaban, and we have not made any recommen-dations in favor of one of the new agents over the other.
6.8. In patients with PE who receive extended therapy, we suggest treatment with the same anticoagulant chosen for the fi rst 3 months (Grade 2C) .
6.9 Treatment of Asymptomatic PE
Diagnosis of asymptomatic PE occurs in � 1% of outpatients and � 4% of inpatients who have contrast-enhanced CT scans, with a majority being in patients with known malignancy. 40,344-355 When PE is diagnosed unexpectedly in patients with cancer, in retrospect, the clinical history may reveal symptoms that were aggravated by the PE (eg, an increase in fatigue). 345 About one-half of such incidental PE involve the lobar or more central pulmonary arteries, whereas the other one-half are more distal. 40,353
When there is evidence of an asymptomatic PE, the fi rst priority is to review the CT scans to deter-mine whether the fi ndings are convincing for acute PE. Other recent CT scans may be available for com-parison, or the current scan may also reveal DVT in the central deep veins (eg, subclavian vein, IVC, iliac vein). If there is any uncertainty about the pres-ence of an acute PE, additional diagnostic testing is required (eg, ultrasonography of the deep veins, dedicated CT pulmonary angiography, D -dimer).
Consistent with recommendations for the treat-ment of asymptomatic DVT (section 3.5) in patients in whom clinicians are convinced that an asymptom-atic PE has occurred, based on moderate-quality evidence, we suggest the same initial and long-term anticoagulation as for similar patients with symp-tomatic PE. The indication for anticoagulation is most compelling when the presence of PE is unequivocal, PE involves the lobar and more central
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pulmonary arteries, PE is a new fi nding on CT, ultrasound reveals proximal DVT, there are ongoing risk factors for VTE such as active cancer, and the patient is not at high risk for bleeding ( Table 2 ). Many patients have left the hospital by the time an incidental PE is reported. If PE is less extensive and it would be diffi cult for patients to return the same day, it often is reasonable to defer further assessment and anticoagulant therapy until the next day.
Recommendation
6.9. In patients who are incidentally found to have asymptomatic PE, we suggest the same ini-tial and long-term anticoagulation as for similar patients with symptomatic PE (Grade 2B) .
7.0 Chronic Thromboembolic Pulmonary Hypertension
Prospective studies suggest that CTPH occurs in � 3% of patients who are treated for PE. 104,354-358 About one-third of patients have a history of VTE, whereas two-thirds have had single or recurrent epi-sodes of PE that were not diagnosed and may have been asymptomatic. 359 Patients with CTPH are likely to have a high risk of recurrent VTE because they have had previous VTE and have cardiopulmonary impairment. Recurrent VTE may be fatal more often in patients with severe cardiopulmonary impairment than in those without such impairment . After PE ini-tiates CTPH, pulmonary vascular remodeling may cause severe pulmonary hypertension out of propor-tion with pulmonary vascular thrombosis. 104,359,360
7.1 Pulmonary Thromboendarterectomy, Anticoagulant Therapy, and Vena Caval Filter for the Treatment of CTPH
Primary therapy for CTPH is pulmonary throm-boendarterectomy, which, if successful, can reduce or cure pulmonary hypertension and associated symp-toms. 104,359-367 The operation is lengthy and complex, requiring a median sternotomy, cardio pulmonary bypass, deep hypothermia with periods of circu-latory arrest, and exploration of both pulmonary arteries. At the most experienced centers, mortality is � 5%. 104,360,363,365-367 Management often includes inser-tion of a permanent IVC fi lter before or during pul-monary endarterectomy and indefi nite anticoagulant therapy. 359,361,363,365 Patients with CTPH who are not candidates for pulmonary endarterectomy because of comorbid disease or surgically inaccessible lesions may be candidates for vasodilator therapy, balloon pulmonary angioplasty, or lung transplantation and may benefi t from referral to a center with expertise in pulmonary hypertension. 359,363-365,368-370
There are no randomized trials of CTPH therapy and, overall, evidence is low quality. There is, how-ever, high-quality indirect evidence that anticoagu-lant therapy is very effective at preventing recurrent VTE in other patient populations (see section 3.1; Table 18 ; and Tables S24, S25, and S27). Conse-quently, the evidence supporting long-term antico-agulation in patients with CTPH is of moderate quality (rated down for indirectness). Features that are expected to be associated with greater benefi t with pulmonary thromboendarterectomy include younger age, central disease, progressive clinical deteriora-tion, and access to an expert multidisciplinary throm-boendarterectomy team.
Recommendations
7.1.1. In patients with CTPH, we recommend extended anticoagulation over stopping therapy (Grade 1B) .
7.1.2. In selected patients with CTPH, such as those with central disease under the care of an experienced thromboendarterectomy team, we suggest pulmonary thromboendarterectomy over no pulmonary thromboendarterectomy (Grade 2C) .
8.0 Superficial Vein Thrombosis
SVT has been less well studied than DVT but is estimated to occur more often. 371,372 It usually affects the lower limbs; often involves a varicose vein; is associated with chronic venous insuffi ciency, malig-nancy, thrombophilia, pregnancy or estrogen therapy, obesity, sclerotherapy, long-distance travel, and a his-tory of VTE; or may be unprovoked. 371-373 The long saphenous vein is involved in about two-thirds of lower-limb SVT. 374
Although traditionally considered a benign disease, a number of studies indicate that the consequences of SVT may be more serious. 371,372 A prospective study of 844 patients with acute SVT of � 5 cm found that at initial presentation, � 4% of patients had symp-tomatic PE, and routine ultrasound detected prox-imal DVT in 10% and distal DVT in an additional 13% of patients. 374 In patients without VTE at presen-tation, despite 90% being treated with anticoagulant therapy (therapeutic doses in two-thirds, prophylac-tic doses in one-third, median duration of 11 days), 3.1% developed symptomatic VTE (0.5% PE, 1.2% proximal DVT, 1.4% distal DVT), 1.9% had recur-rent SVT (different location), and 3.3% had an exten-sion of SVT (same location) at 3 months. Male sex, history of VTE, cancer, and absence of varicose veins each was associated with about a doubling of the risk of VTE during follow-up.
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is low because there is no direct comparison in patients with SVT. Factors that favor the use of anticoagulant therapy in patients with SVT (see Recommendation 8.1.1) include: extensive SVT; involvement above the knee, particularly if close to the saphenofemoral junction; severe symptoms; involvement of the greater saphenous vein; history of VTE or SVT; active cancer; and recent surgery. An economic evaluation found that treatment of SVT with fondaparinux was not cost-effective; it cost $500,000 per quality-adjusted life year gained com-pared with no treatment. 383
Graduated compression stockings often are used in patients with SVT (eg, 83% of patients in the CALI-STO study). Oral nonsteroidal antiinfl ammatory agents may be used to alleviate symptoms if patients are not treated with anticoagulants. Topical nonste-roidal antiinfl ammatory agents may reduce symptoms and can be used with anticoagulant therapy. Sur-gical therapy, with ligation of the saphenofemoral junction or stripping of thrombosed superfi cial veins appears to be associated with higher rates of VTE than treatment with anticoagulants. 380,384,385 Anticoag-ulant therapy generally is not used to treat SVT that occurs in association with an IV infusion (ie, infusion thrombophlebitis).
Recommendations
8.1.1. In patients with SVT of the lower limb of at least 5 cm in length, we suggest the use of a prophylactic dose of fondaparinux or LMWH for 45 days over no anticoagulation (Grade 2B) .
Remarks: Patients who place a high value on avoid-ing the inconvenience or cost of anticoagulation and a low value on avoiding infrequent symptomatic VTE are likely to decline anticoagulation.
8.1.2. In patients with SVT who are treated with anticoagulation, we suggest fondaparinux 2.5 mg daily over a prophylactic dose of LMWH (Grade 2C) .
9.0 Acute Upper-Extremity DVT
About 5% to 10% of VTE involve the upper extre m-ities. 386-390 UEDVT includes two etiologic groups: primary (unprovoked with or without thrombophilia, effort-related and thoracic outlet syndrome) and sec-ondary (provoked by central venous catheters, pace-makers, or cancer). Secondary UEDVT accounts for � 75% of cases. 386,388,389,391-394
UEDVT involves the subclavian, axillary, or bra-chial veins and may include extension to the bra-chiocephalic vein, superior vena cava, or the internal
Given the high prevalence of concomitant prox-imal DVT in patients with SVT and the need to treat such patients with higher doses of anticoagulant therapy (ie, therapeutic doses), patients with SVT above the knee should have ultrasonography to exclude proximal DVT. Ultrasound can also help with the diagnosis of SVT if the clinical presentation is uncertain. With greater appreciation of the serious-ness of SVT, investigators have evaluated anticoagu-lant therapy, often in prophylactic or intermediate doses, as a way to reduce acute symptoms, extension, recurrence, and progression to VTE ( Table 31 , Tables S43-S45). 375
8.1 Treatment of SVT
Most studies that have evaluated anticoagulant therapy for SVT have been small (eg, � 100 patients per treatment group), with additional methodologic weaknesses 376-381 (Tables S44, S45). Although these studies suggest that prophylactic-dose LMWH, inter-mediate-dose UFH or LMWH, warfarin therapy, and oral nonsteroidal antiinfl ammatory agents are benefi -cial in patients with SVT, the supporting evidence is of low quality. The recently published Comparison of ARIXTRA™ in lower LImb Superfi cial Thrombo-phlebitis with placebo (CALISTO) study, which com-pared fondaparinux (2.5 mg/d for 45 days) with placebo in 3,000 patients with SVT ( � 5 cm in length), has helped to clarify the role of anticoagulants for the treatment of SVT ( Table 31 , Table S43), and the nat-ural history of this condition. 382
CALISTO found that fondaparinux is very effec-tive at reducing VTE, recurrent SVT, extension of SVT, and the need for venous surgery, and is associ-ated with little bleeding. In the placebo group, throm-botic complications occurred more often if SVT involved the greater saphenous vein (92% of patients in the control group), extended to within 10 cm from the saphenofemoral junction (9% of patients), and involved veins above the knee (46% of patients) and if VTE (7% of patients) or SVT (12% of patients) had occurred previously. 382 Age, sex, and presence of var-icose veins were not convincingly associated with the frequency of thrombotic complications, and there were too few patients with cancer in CALISTO to assess that association.
The evidence is moderate quality. We have inter-preted the fi ndings of the CALISTO study as evi-dence for anticoagulation in general and assume that prophylactic doses of LMWH and fondaparinux have similar antithrombotic effi cacy and safety. Because it is direct and more extensive, the evidence in support of fondaparinux is higher quality than the evidence in support of LMWH. Quality of the evi-dence for comparison of fondaparinux with LMWH
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jugular vein. Clinical manifestations include acute and chronic arm pain, swelling, discoloration, and dilated collateral veins over the arm, neck, or chest. UEDVT may lead to complications, including symp-tomatic PE ( � 5% of patients 387-389,393,395 ), recurrent UEDVT ( � 8% at 5 years of follow-up 389,390,395 ), and PTS of the arm ( � 20% of patients). 386,387,395,396 In the absence of a central venous catheter, the dominant arm is more often affected. 387 Complications of UEDVT are expected to occur much more often and to be more severe when UEDVT involves the axillary or more-proximal veins than if thrombosis is confi ned to the brachial vein. In general, when we refer to UEDVT, we are referring to thrombosis that involves the axillary or more-proximal veins.
The most frequent risk factor for UEDVT is a cen-tral venous catheter. 386,388,397,398 If UEDVT occurs in association with a central venous catheter and the catheter is no longer required, it should be removed. There are no data to guide whether catheter removal should be preceded by an initial period of anticoagu-lation, and we do not have a preference for imme-diate or deferred removal. If UEDVT occurs in association with a central venous catheter and there is a continuing need for the catheter, the catheter need
not be removed. If the catheter is not functioning and cannot be made to function (even after a period of systemic anticoagulation), it should be removed .
As with treatment of leg DVT and PE, treatment of UEDVT may be divided into acute (eg, parenteral anticoagulants, thrombolytic therapy) and long-term phases (eg, anticoagulation, treatment of upper-extremity PTS). Because no randomized trials have evaluated treatment of UEDVT, recommendations are based on indirect evidence from studies performed in patients with leg DVT, observational studies (gen-erally small), and understanding of the natural his-tory of UEDVT. Therefore, quality of evidence is, at best, moderate.
9.1 Acute Anticoagulation for UEDVT
No randomized controlled studies have evaluated acute anticoagulation for initial treatment of UEDVT. Several small prospective cohort studies have reported low rates of recurrent DVT, PE, and major bleeding when UEDVT was treated similarly to leg DVT (Tables S46 and S47). 395,399-401 Anticoagulant therapy is used to treat UEDVT because (1) UEDVT causes acute symptoms, can cause PE (including fatal
Table 31—[Section 8.1] Summary of Findings: Fondaparinux vs Placebo for Acute SVTa-c,382
OutcomesNo. of Participants
(Studies), Follow-upQuality of the
Evidence (GRADE)Relative Effect
(95% CI)
Anticipated Absolute Effects
Risk With No Fondaparinux
Risk Difference With Fondaparinux (95% CI)
Mortality 3,002 (1 study), 3 mo Moderated-g due to imprecision
RR 1.99 (0.18-21.87) 4 per 1,000h 4 more per 1,000 (from 3 fewer to 83 more)
VTE 3,002 (1 study), 3 mo Highd RR 0.18 (0.06-0.53) 33 per 1,000h 27 fewer per 1,000 (from 16 fewer to 31 fewer)
SVT recurrence 3,002 (1 study), 3 mo Highd RR 0.31 (0.14-0.68) 19 per 1,000h 13 fewer per 1,000 (from 6 fewer to 16 fewer)
Major bleeding 2,987(1 study), 47 d Moderated,e,i due to imprecision
RR 0.99 (0.06-15.86)e 1 per 1,000 0 fewer per 1,000 (from 1 fewer to 10 more)
QOL not measured … … … … …
The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Working group grades of evidence are as follow: High quality, further research is very unlikely to change our confi dence in the estimate of effect; moderate quality, further research is likely to have an important impact on our confi dence in the estimate of effect and may change the estimate; low quality, further research is very likely to have an important impact on our confi dence in the estimate of effect and is likely to change the estimate; very-low quality, we are very uncertain about the estimate. See Table 1 and 3 legends for expansion of abbreviations.aPatients with infusion-related SVT were excluded from CALISTO (Comparison of ARIXTRA in lower Limb Superfi cial Thrombophlebitis with Placebo).bFondaparinux 2.5 mg for 45 d.cPatients in the two treatment groups benefi ted from close clinical monitoring with adequate diagnostic procedures in the event of new or persistent symptoms.dAllocation concealed. Outcome adjudicators, steering committee, patients, providers, and data collectors blinded. Follow-up rate was 98%. Intention-to-treat analysis for effi cacy outcomes. Not stopped early for benefi t.eCI includes values suggesting large benefi t and values suggesting large harm.fWe rated down by only one level because of the low event rate and large sample size.gSmall number of events.hBaseline risk derived from a large prospective cohort study.374
iThe upper limit of the CI for absolute effect (10 more bleeds) is not low enough to suggest a clear balance of benefi ts vs harms.
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episodes), and is associated with PTS; (2) observa-tional studies support its use; and (3) there is strong evidence for benefi t in patients with leg DVT.
Uncertainty exists about the need to prescribe antico-agulants to patients with thrombosis confi ned to the brachial vein. Acceptable alternatives to full-dose anti-coagulation in such patients include clinical or ultra-sound surveillance to detect extension of UEDVT while withholding anticoagulation, or treatment with prophylactic-dose anticoagulation, or treatment with therapeutic doses of anticoagulation for , 3 months. We favor anticoagulation if isolated brachial vein thrombosis is symptomatic, associated with a central venous catheter that will remain in place, or associ-ated with cancer in the absence of a central venous catheter. A high risk of bleeding argues against full-dose anticoagulation.
Recommendations
9.1.1. In patients with acute UEDVT that involves the axillary or more proximal veins, we recommend acute treatment with paren-teral anticoagulation (LMWH, fondaparinux, IV UFH, or SC UFH) over no such acute treat-ment (Grade 1B) .
9.1.2. In patients with acute UEDVT that involves the axillary or more proximal veins, we suggest LMWH or fondaparinux over IV UFH (Grade 2C) and over SC UFH (Grade 2B) .
9.2 Thrombolytic Therapy for the Initial Treatment of UEDVT
No randomized controlled studies have evaluated thrombolytic therapy compared with anticoagula-tion alone in patients with UEDVT. A number of retrospective and small prospective observational studies have evaluated streptokinase, urokinase, or rt-PA administered with varying doses, methods of administration (IV, catheter directed), and infu-sion durations. 402-409 Three of these studies included nonrandomized control groups who received antico-agulation alone. 402,407,408 In some studies, a few patients also had venous angioplasty 405 or surgical decom-pression 402,405,408 (Tables S48 and S49).
These studies suggest that thrombolysis can improve early and late venous patency but is associ-ated with increased bleeding. However, it is not known whether thrombolytic therapy reduces PTS of the arm or recurrent VTE. PTS of the arm appears to be a less common complication of thrombosis than PTS of the leg. 386-388,393,395,410 We believe that throm-bolysis should be considered only in patients who meet all of the following criteria: severe symptoms, thrombus involving most of the subclavian vein and
the axillary vein, symptoms for , 14 days, good func-tional status, life expectancy of � 1 year, and low risk for bleeding ( Table 11 ). If thrombolysis is used, in order to reduce the dose of thrombolytic therapy and the associated risk of bleeding, we encourage cath-eter-based therapy over systemic thrombolysis. In addition, because the balance of risks and benefi ts with all forms of thrombolytic therapy is uncertain, anticoagulant therapy alone is acceptable initial ther-apy in all patients with UEDVT. There is no evidence to suggest that thrombolysis reduces the risk of recur-rent VTE.
Resection of the fi rst rib has been advocated when UEDVT is believed to have been due to entrapment of the subclavian vein as it passes between the clav-icle and the fi rst rib. 6,386,411-421 Insertion of a fi lter in the superior vena cava has also been used in patients with acute UEDVT who cannot be given anticoagu-lants. Complications, however, may be more than with IVC fi lters. 389,413,422 The evidence in support of these procedures is of low quality, and because there is the potential to cause harm, their use should be confi ned to exceptional circumstances in specialized centers.
Recommendations
9.2.1. In patients with acute UEDVT that involves the axillary or more proximal veins, we suggest anticoagulant therapy alone over throm-bolysis (Grade 2C) .
Remarks: Patients who (i) are most likely to benefi t from thrombolysis (see text); (ii) have access to CDT; (iii) attach a high value to prevention of PTS; and (iv) attach a lower value to the initial complexity, cost, and risk of bleeding with thrombolytic therapy are likely to choose thrombolytic therapy over anticoagu-lation alone.
9.2.2. In patients with UEDVT who undergo thrombolysis, we recommend the same inten-sity and duration of anticoagulant therapy as in similar patients who do not undergo thromboly-sis (Grade 1B) .
9.3 Long-term Anticoagulation for UEDVT
No randomized studies have evaluated duration or intensity of long-term anticoagulation in patients with UEDVT. In prospective observational studies, patients with UEDVT generally were treated with VKA (target INR 2.5) for periods of 3 to 6 months. 393,399-
401,423 Rates of recurrent VTE and PTS varied (Tables S50 and S51), but as previously noted, these rates generally were lower than those observed in patients with leg DVT.
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The factors that infl uence long-term anticoagu-lation in patients with leg DVT (section 3.1) are relevant to long-term treatment of UEDVT. Some differences between UEDVT and leg DVT are wor-thy of emphasis, especially that UEDVT often is asso-ciated with a central venous catheter that may or may not be removed (section 9.0). The most important continuing risk factors for UEDVT are (1) the pres-ence of a central venous catheter in the same arm and (2) active cancer in patients with UEDVT not associ-ated with a central venous catheter.
Another important distinction between UEDVT and leg DVT relates to long-term anticoagulation in patients with unprovoked thrombosis. Because the risk of recurrent VTE is substantially lower in patients with UEDVT compared with in those with proximal leg DVT, 387,388,393,395 we discourage extended anticoag-ulant therapy (ie, beyond 3 months) in patients with an unprovoked UEDVT.
No data are available for the long-term use of LMWH monotherapy or newer anticoagulants for the long-term treatment of UEDVT. We make the same recommendations for choice of initial, long-term, and extended anticoagulant regimens for UEDVT as for leg DVT (recommendations 3.1.1, 3.1.2, and 3.1.4) and note that the supporting evidence for these weak recommendations is further weakened in this population because of indirectness.
Recommendations
9.3.1. In most patients with UEDVT that is asso-ciated with a central venous catheter, we sug-gest that the catheter not be removed if it is functional and there is an ongoing need for the catheter (Grade 2C) .
9.3.2. In patients with UEDVT that involves the axillary or more proximal veins, we suggest a minimum duration of anticoagulation of 3 months over a shorter period (Grade 2B) .
Remarks: This recommendation also applies if the UEDVT is associated with a central venous catheter that was removed shortly after diagnosis.
9.3.3. In patients who have UEDVT that is asso-ciated with a central venous catheter that is removed, we recommend 3 months of antico-agulation over a longer duration of therapy in patients with no cancer (Grade 1B) , and we sug-gest this in patients with cancer (Grade 2C) .
9.3.4. In patients who have UEDVT that is asso-ciated with a central venous catheter that is not removed, we recommend that anticoagulation is continued as long as the central venous cath-
eter remains over stopping after 3 months of treatment in patients with cancer (Grade 1C) , and we suggest this in patients with no cancer (Grade 2C) .
9.3.5. In patients who have UEDVT that is not associated with a central venous catheter or with cancer, we recommend 3 months of anti-coagulation over a longer duration of therapy (Grade 1B) .
9.4 Prevention of PTS of the Arm
PTS of the arm occurs in � 20% of patients after treatment for UEDVT 38,395,396 and can be a disabl-ing condition that adversely affects quality of life, particularly if the dominant arm is involved. 410,424 No randomized trials have evaluated compression bandages, compression sleeves, or venoactive drugs to prevent PTS after UEDVT. We have not con-sidered indirect evidence from the legs for use of compression therapy to prevent PTS of the arms because (1) the pathophysiology of PTS is believed to be different in the arms than in the legs (less dependent venous hypertension), (2) arm sleeves are more diffi cult to fi t than stockings, and (3) PTS occurs less often after UEDVT than after leg DVT.
Recommendation
9.4. In patients with acute symptomatic UEDVT, we suggest against the use of compression sleeves or venoactive medications (Grade 2C) .
9.5 Treatment of PTS of the Arm
Symptoms of PTS of the arm include swelling, heaviness, and limb fatigue with exertion. 395,410 No randomized trials have evaluated compression ban-dages, compression sleeves (as are used for lym-phedema), or venoactive drugs to treat PTS after UEDVT. We considered anecdotal evidence that compression therapy benefi ts some patients with PTS of the arm and that the benefi ts of a trial of compres-sion therapy will outweigh its harms and costs. There is no evidence that venoactive drugs are of benefi t in PTS of the arm.
Recommendations
9.5.1. In patients who have PTS of the arm, we suggest a trial of compression bandages or sleeves to reduce symptoms (Grade 2C) .
9.5.2. In patients with PTS of the arm, we sug-gest against treatment with venoactive medica-tions (Grade 2C) .
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10.0 Splanchnic Vein Thrombosis
Thrombosis in the portal venous system, which includes the superior mesenteric, inferior mesen-teric, splenic, and portal veins, is collectively termed splanchnic vein thrombosis . Depending on the location and extent of thrombosis, how rapidly thrombosis develops, speed and extent of thrombus recannula-tion, presence of collateral portal venous drainage, and adequacy of arterial inflow, splanchnic vein thrombosis may result in bowel or splenic infarction and chronic portal hypertension. 425-430 Acute and chronic splanchnic vein thrombosis may be symp-tomatic, but many episodes are detected incidentally in imaging studies performed for other indications, such as assessing response to surgical or medical therapy in patients with cancer. 348,429 Limited under-standing of the natural history of both symptomatic and incidentally detected splanchnic vein thrombosis in patients who are not treated with anticoagulants (ie, frequency of bowel infarction, development of portal hypertension, recurrence), a paucity of data from prospective cohort studies, 428,431 and a lack of randomized trials of standardized anticoagulant therapy for splanchnic vein thrombosis result in uncertainty about the role of anticoagulation for this condition. Increased risk of bleeding associated with esophageal varices (secondary to portal hypertension), thrombo-cytopenia (secondary to hypersplenism), and the pres-ence of cirrhosis and malignancy (which predispose to splanchnic vein thrombosis) add to this uncertainty.
A number of retrospective, 425,429,430 and two pro-spective, 428,431 studies suggested that bowel ischemia is uncommon in patients with symptomatic splanchnic vein thrombosis who are treated with anticoagulants ( � 2% 428 ), that recurrent venous thrombosis (both involving the splanchnic and nonsplanchnic veins) is common without anticoagulation or after stopping anticoagulation ( � 5% per year 425,429,430 ), and that anti-coagulation is effective at preventing progression and recurrent thrombosis, 425,428-431 although it is asso-ciated with an increased (particularly GI), but usually acceptable, frequency of bleeding. 428-431 Effi cacy of anticoagulant therapy in other forms of symptom-atic venous thrombosis also provides indirect evi-dence for anticoagulation of patients with symptomatic splanchnic vein thrombosis and, supported by the previously noted observational studies, this evidence is of moderate quality. We are not aware of studies of treated or untreated asymptomatic splanchnic vein thrombosis.
Factors that may encourage anticoagulant therapy in patients with incidental splanchnic vein thrombo-sis include extensive thrombosis that appears to be acute (eg, not present on a previous imaging study, presence of an intraluminal fi lling defect, lack of cav-
ernous transformation), progression of thrombosis on a follow-up imaging study, and ongoing cancer che-motherapy. Esophageal varices secondary to acute portal vein thrombosis are not necessarily a contrain-dication to anticoagulant therapy because such treat-ment may improve the portal hypertension. LMWH may be preferred over VKA if there is active malig-nancy, liver disease, or thrombocytopenia. 431 The pres-ence of a reversible provoking factor for splanchnic vein thrombosis, such as intraabdominal sepsis or recent surgery, supports stopping anticoagulant therapy after 3 months. Absence of a reversible risk factor (eg, “unprovoked” thrombosis or presence of a per-sistent risk factor, such as myeloproliferative disease) and a low risk of bleeding support extended anticoag-ulant therapy.
Recommendations
10.1. In patients with symptomatic splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we recommend anti-coagulation over no anticoagulation (Grade 1B) .
10.2. In patients with incidentally detected splanchnic vein thrombosis (portal, mesenteric, and/or splenic vein thromboses), we suggest no anticoagulation over anticoagulation (Grade 2C) .
11.0 Hepatic Vein Thrombosis
Hepatic vein thrombosis, particularly Budd-Chiari syndrome with occlusion of the main hepatic vein, can result in impairment of liver function and an associated coagulopathy. 432,433 Because there is limited understanding of the natural history of this condition and a paucity of prospective studies that have evalu-ated anticoagulant therapy, the role of anticoagulant therapy is uncertain. 432
In a prospective registry of 163 patients with Budd-Chiari syndrome of variable extent, of whom 86% were treated with anticoagulation, one-half of patients did not require invasive interventions (ie, transjugu-lar intrahepatic portosystemic shunting in 34% of all patients, surgical portosystemic shunting in 2% of patients, liver transplantation in 12% of patients), and survival was 82% after 2 years. 432 In an earlier retro-spective study of 237 patients with Budd-Chiari syn-drome performed when use of surgical portosystemic shunting was common (49% of patients), use of anti-coagulant therapy (72% of patients) had no apparent effect on survival (RR, 1.05; 95% CI, 0.62-1.76).
Factors that encourage anticoagulant therapy in patients with incidental hepatic vein thrombosis include extensive thrombosis that appears to be acute (eg, not present on a previous imaging study, pres-ence of an intraluminal fi lling defect), progression
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of thrombosis on a follow-up imaging study, and ongoing cancer chemotherapy. Coagulopathy due to liver dysfunction caused by hepatic vein thrombosis is not a contraindication to anticoagulant therapy because anticoagulants may improve hepatic func-tion. LMWH usually will be preferred to VKA therapy when there is hepatic dysfunction and if there is active malignancy. Presence of a reversible provoking factor for hepatic vein thrombosis, such as oral con-traceptive therapy, encourages a time-limited course of therapy. Absence of a reversible risk factor encour-ages the use of extended therapy. Treatment of hepatic vein obstruction is complex and best under-taken by a multidisciplinary team.
Recommendations
11.1. In patients with symptomatic hepatic vein thrombosis, we suggest anticoagulation over no anticoagulation (Grade 2C) .
11.2. In patients with incidentally detected hepatic vein thrombosis, we suggest no antico-agulation over anticoagulation (Grade 2C) .
12.0 Future Research
Several questions in the treatment of VTE need to be answered. Current evidence relating to these questions is of moderate or low quality. We list the questions roughly as they arise in this article rather than in order of importance. We do not present the rationale for each question because this is addressed in the corresponding sections of the article. We have confi ned ourselves to the primary question (eg, Should patients with proximal DVT be treated with antico-agulant therapy alone, or should they be treated with pharmacomechanical CDT?); however, once the primary question is answered, we anticipate that secondary questions will need to be addressed (eg, Which patients with proximal DVT should, or should not, be treated with CDT?) . We are pleased to note that many of the these questions are being addressed in ongoing trials.
• Should patients with an isolated distal DVT rou-tinely be treated with anticoagulant therapy, or should they have serial testing to determine whether the DVT is extending and only be treated if extension is detected?
• Should patients with proximal DVT be treated with anticoagulant therapy alone, or should they be treated with pharmacomechanical CDT?
• Which patients with unprovoked proximal DVT or PE or cancer-associated VTE should stop anticoagulant therapy at 3 months, and which should remain on extended anticoagulant therapy?
• Which patients with unprovoked VTE or cancer-associated VTE have an unacceptable risk of bleeding if they remain on extended anticoagu-lant therapy?
• How should risk of recurrent VTE if anticoagu-lant therapy is stopped be balanced against risk of bleeding is anticoagulant therapy is continued?
• What is the preferred anticoagulant regimen for the short- and long-term treatment of VTE in patients with and without cancer?
• Should patients receiving an incidental diagno-sis of asymptomatic VTE routinely be treated with anticoagulant therapy, or should they have serial testing to determine whether they have evolving DVT and only be treated if this is detected?
• Should patients with symptomatic DVT rou-tinely wear graduated compression stockings from the time of diagnosis, or should stockings be used selectively (eg, in selected patients, in patients whose symptoms do not rapidly resolve)?
• Should patients with PE that causes right ven-tricular dysfunction be treated with anticoagu-lant therapy alone, or should they be treated with thrombolytic therapy?
• If patients have catheter-associated UEDVT and the catheter is removed, should they be treated with anticoagulant therapy or can they be treated without anticoagulant therapy?
• Can UEDVT be treated with less-intense or a shorter duration of anticoagulant therapy than leg DVT?
Acknowledgments Author contributions: As Topic Editor, Dr Akl oversaw the development of this article, including the data analysis and subse-quent development of the recommendations contained herein. Dr Kearon: served as Deputy Editor . Dr Akl: served as Topic Editor. Dr Comerota: served as a panelist. Dr Prandoni: served as a panelist. Dr Bounameaux: served as a panelist. Dr Goldhaber: served as a panelist. Dr Nelson: served as a frontline clinician. Dr Wells: served as a panelist. Dr Gould: served as a resource consultant. Dr Dentali: served as a panelist. Dr Crowther: served as a panelist. Dr Kahn: served as a panelist. Financial/nonfi nancial disclosures: The authors of this guide-line provided detailed confl ict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal.chestpubs.org/content/141/2_suppl/e419S/suppl/DC1. In summary, the authors have reported to CHEST the following confl icts of interest: Dr Kearon is a consultant to Boehringer Ingelheim and has received peer-reviewed funding for studies in the treatment of VTE. Dr Bounameaux has received grant monies and honoraria for consultancy or lec-tures from Bayer Schering Pharma AG; Daiichi-Sankyo Co, Ltd; Sanofi -Aventis LLC; Pfi zer Inc; Bristol-Myers Squibb; Servier; and Canonpharma Production Ltd. Dr Goldhaber has received funds from Eisai Co, Ltd; EKOS Corporation; Sanofi -Aventis LLC;
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and Johnson & Johnson. He serves as a consultant for Boeh-ringer Ingelheim GmbH; Bristol-Myers Squibb; Daiichi San-kyo Co, Ltd; Eisai Co, Ltd; EKOS Corporation; Medscape; Merck & Co, Inc; Portola Pharmaceuticals, Inc; and Sanofi -Aventis LLC. Dr Wells has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombo-sis treatment. He has received honoraria for industry-sponsored (Bayer, Boehringer-Ingelheim, Pfi zer, BioMerieux, sanofi -aventis) talks pertaining to venous thrombosis and has attended advisory boards for Bayer, Boehringer-Ingelheim, Pfi zer and Bristol-Myers-Squibb. Dr Crowther has served on various advisory boards, has assisted in the preparation of educational materials, has sat on data safety management boards, and his institution has received research funds from the following companies: Leo Pharma A/S, Pfi zer Inc, Boerhinger Ingelheim GmbH, Bayer Healthcare Pharmaceuticals, Octapharm AG, CSL Behring, and Artisan Pharma. Personal total compensation for these activities over the past 3 years totals less than US $10,000. Dr Kahn has received peer-reviewed and investigator-initiated industry research funding for projects related to venous thrombosis and postthrombotic syndrome pre-vention and treatment. She has received honoraria for industry-sponsored talks pertaining to venous thrombosis. Dr Akl is a member of and prominent contributor to the GRADE Working Group. Dr Comerota discloses that he is a consultant to and speaker for Covidien, Inc. Drs Prandoni, Nelson, Gould, and Dentali have reported that no potential confl icts of interest exist with any companies/organizations whose products or services may be dis-cussed in this article . Role of sponsors: The sponsors played no role in the develop-ment of these guidelines. Sponsoring organizations cannot recom-mend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Sci-ence Policy Committee are blinded to the funding sources. Fur-ther details on the Confl ict of Interest Policy are available online at http://chestnet.org . Other contributions: We acknowledge the contributions of the writing groups of previous editions of this guideline and thank Gordon H. Guyatt , MD, FCCP, for his comments and suggestions and Aman Rajpal, MD, for his help with reviewing the proofs. Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clin-ical Pharmacy, the American Society of Health-System Pharma-cists, the American Society of Hematology, and the International Society of Thrombosis and Hematosis. Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/content/141/2_suppl/e419S/suppl/DC1.
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Online Data SupplementCHEST
1 © 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http :// www . chestpubs . org / site / misc / reprints . xhtml ). DOI: 10.1378/chest.11-2301
Antithrombotic Therapy for VTE Disease
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines
Clive Kearon, MD, PhD; Elie A. Akl, MD, MPH, PhD; Anthony J. Comerota, MD; Paolo Prandoni, MD; Henri Bounameaux, MD; Samuel Z. Goldhaber, MD, FCCP; Michael Nelson, MD, FCCP; Philip Wells, MD; Michael K. Gould, MD, MS, FCCP; Francesco Dentali, MD; Mark Crowther, MD; and Susan R. Kahn, MD
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
2© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S1
—[S
ecti
on 2
.1]
Evi
denc
e P
rofi l
e: P
aren
tera
l A
ntic
oagu
lati
on v
s N
o P
aren
tera
l A
ntic
oagu
lati
on i
n A
cute
VT
E a
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Ove
rall
Qua
lity
of E
vide
nce
With
No
Pare
nter
al
Ant
icoa
gula
tion
With
Par
ente
ral
Ant
icoa
gula
tion
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith N
o Pa
rent
eral
A
ntic
oagu
latio
n
Ris
k D
iffer
ence
W
ith P
aren
tera
l A
ntic
oagu
latio
n (9
5% C
I)
Mor
talit
y (im
port
ant o
utco
me)
120
(1 s
tudy
), 6
mo
No
seri
ous
risk
of b
ias b
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s c U
ndet
ecte
dM
oder
ate b,
c du
e to
im
prec
isio
n
2/60
(3.3
)1/
60 (1
.7)
RR
0.5
(0
.05-
5.37
)33
per
1,0
0016
few
er
per
1,00
0 (f
rom
31
few
er
to 1
44 m
ore)
Rec
urre
nt V
TE
(cri
tical
out
com
e; a
sses
sed
with
sym
ptom
atic
ext
ensi
on o
r re
curr
ence
)
120
(1 s
tudy
), 6
mo
No
seri
ous
risk
of b
ias b
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s d U
ndet
ecte
dM
oder
ate b,
d du
e to
im
prec
isio
n
12/6
0 (2
0)4/
60 (6
.7)
RR
0.3
3 (0
.11-
0.98
)20
0 pe
r 1,
000
134
few
er
per
1,00
0 (f
rom
4 fe
wer
to
178
few
er)
Maj
or b
leed
ing
(cri
tical
out
com
e)
120
(1 s
tudy
), 6
mo
No
seri
ous
risk
of b
ias b
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s c U
ndet
ecte
dM
oder
ate b,
c du
e to
im
prec
isio
n
3/60
(5)
2/60
(3.3
)R
R 0
.67
(0.1
2-3.
85)
50 p
er 1
,000
16 fe
wer
pe
r 1,
000
(fro
m 4
4 fe
wer
to
142
mor
e)
Bib
liogr
aphy
: Bra
ndje
s et
al. 1 R
R 5
risk
rat
io.
a Bot
h gr
oups
trea
ted
with
ace
noco
umar
ol.
b Stu
dy d
escr
ibed
as
doub
le b
linde
d; o
utco
me
adju
dica
tors
blin
ded.
Non
e of
the
stud
y pa
rtic
ipan
ts w
ere
lost
to fo
llow
-up.
Int
entio
n-to
-tre
at a
naly
sis.
Stu
dy w
as s
topp
ed e
arly
for
bene
fi t.
c CI
incl
udes
val
ues
sugg
estin
g no
eff
ect a
s w
ell a
s va
lues
sug
gest
ing
eith
er a
ppre
ciab
le b
enefi
t or
app
reci
able
har
m.
d Low
num
ber
of e
vent
s ca
used
by
the
earl
y st
oppa
ge o
f the
tria
l.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
3© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S2
—[S
ecti
on 2
.4]
Evi
denc
e P
rofi l
e: E
arly
War
fari
n (a
nd S
hort
er D
ura
tion
Hep
arin
) vs
Del
ayed
War
fari
n (a
nd L
onge
r D
ura
tion
Hep
arin
) fo
r A
cute
VT
E a-d
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Stud
y E
vent
Rat
es (%
)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
e
With
Del
ayed
W
arfa
rin
Initi
atio
n (a
nd L
onge
r D
urat
ion
Hep
arin
)
With
Ear
ly
War
fari
n In
itiat
ion
(and
Sho
rter
D
urat
ion
Hep
arin
)
Ris
k W
ith
Del
ayed
W
arfa
rin
Initi
atio
n (a
nd
Lon
ger D
urat
ion
Hep
arin
)
Ris
k D
iffer
ence
W
ith E
arly
W
arfa
rin
Initi
atio
n (a
nd S
hort
er
Dur
atio
n H
epar
in)
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me e )
688
(3 s
tudi
es),
3 m
o f N
o se
riou
s ri
sk
of b
ias g
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s h U
ndet
ecte
dM
oder
ate g,
h du
e to
im
prec
isio
n
13/3
38 (3
.8)
12/3
50 (3
.4)
RR
0.9
(0
.41-
1.95
)24
per
1,0
00 i
2 fe
wer
pe
r 1,
000
(fro
m 1
4 fe
wer
to
23
mor
e)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
688
(3 s
tudi
es),
3 m
o f N
o se
riou
s ri
sk
of b
ias g
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s h U
ndet
ecte
dM
oder
ate g,
h du
e to
im
prec
isio
n
14/3
38 (4
.1)
12/3
50 (3
.4)
RR
0.8
3 (0
.4-1
.74)
47 p
er 1
,000
i 8
few
er
per
1,00
0 (f
rom
28
few
er
to 3
5 m
ore)
Maj
or b
leed
ing
(cri
tical
out
com
e)
688
(3 s
tudi
es),
3 m
o j N
o se
riou
s ri
sk
of b
ias g,
k N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
No
seri
ous
impr
ecis
ion l
Und
etec
ted
Hig
h g,k,
l 10
/338
(3.0
)15
/350
(4.3
)R
R 1
.48
(0.6
8-3.
23)
16 p
er 1
,000
i 14
mor
e pe
r 1,
000
(fro
m 9
few
er
to 6
6 m
ore)
Bib
liogr
aphy
: Gal
lus
et a
l, 2 H
ull e
t al
, 3 L
eroy
er e
t al
. 4 E
xclu
ded
Moh
iudd
in e
t al
5 be
caus
e 34
% o
f su
bjec
ts h
ad m
ural
thr
ombu
s ra
ther
tha
n V
TE
, in
addi
tion
to
maj
or m
etho
dolo
gic
limit
atio
ns).
LM
WH
5 lo
w-m
olec
ular
-wei
ght h
epar
in; P
E 5
pul
mon
ary
embo
lism
; UF
H 5
unf
ract
iona
ted
hepa
rin;
VK
A 5
vita
min
K a
ntag
onis
t. Se
e Ta
ble
S1 le
gend
for
expa
nsio
n of
oth
er a
bbre
viat
ion.
a V
KA
ther
apy
star
ted
with
in 1
day
of s
tart
ing
hepa
rin
ther
apy
(UF
H in
two
stud
ies
and
LM
WH
in o
ne s
tudy
). b V
KA
ther
apy
dela
yed
for
4 to
10
d.
c Mos
t pat
ient
s ha
d pr
oxim
al D
VT,
som
e ha
d is
olat
ed d
ista
l DV
T; m
ost D
VT
wer
e sy
mpt
omat
ic (a
sym
ptom
atic
DV
T in
clud
ed in
Hul
l et a
l), a
nd fe
w h
ad P
E (o
nly
incl
uded
in G
allu
s et
al).
d T
he e
arly
initi
atio
n of
VK
A w
as a
ssoc
iate
d w
ith a
low
er n
umbe
r of
day
s of
hep
arin
ther
apy
(4.1
vs
9.5
in G
allu
s et
al;
5 vs
10
in H
ull e
t al)
and
a lo
wer
num
ber
of d
ays
of h
ospi
tal s
tay
(9.1
vs
13.0
in G
allu
s;
11.7
vs
14.7
in H
ull;
11.9
vs
16.0
in L
eroy
er e
t al).
e D
iffer
ence
s in
dea
th, i
ndep
ende
ntly
of d
iffer
ence
s in
rec
urre
nt V
TE
and
maj
or b
leed
ing,
is u
nlik
ely.
f O
utco
me
asse
ssm
ent w
as a
t hos
pita
l dis
char
ge in
the
stud
y by
Gal
lus
et a
l (al
thou
gh th
ere
was
als
o ex
tend
ed fo
llow
-up)
and
3 m
o in
the
stud
ies
by H
ull e
t al a
nd L
eroy
er e
t al.
g Pat
ient
s an
d in
vest
igat
ors
wer
e no
t blin
ded
in tw
o st
udie
s (G
allu
s et
al a
nd L
eroy
er e
t al)
and
wer
e bl
inde
d in
one
stu
dy (H
ull e
t al)
. Con
ceal
men
t was
not
cle
arly
des
crib
ed b
ut w
as p
roba
ble
in th
e th
ree
stud
ies.
Pri
mar
y ou
tcom
e ap
pear
s to
hav
e be
en a
sses
sed
afte
r a
shor
ter
dura
tion
of f
ollo
w-u
p in
the
sho
rter
tre
atm
ent
arm
of
one
stud
y be
caus
e of
ear
lier
disc
harg
e fr
om t
he h
ospi
tal,
and
20%
of
subj
ects
in th
is s
tudy
wer
e ex
clud
ed fr
om th
e fi n
al a
naly
sis
post
rand
omiz
atio
n (G
allu
s).
h The
95%
CI
on r
elat
ive
effe
ct in
clud
es b
oth
clin
ical
ly im
port
ant b
enefi
t an
d cl
inic
ally
impo
rtan
t har
m.
i Eve
nt r
ate
corr
espo
nds
to th
e m
edia
n ev
ent r
ate
in th
e in
clud
ed s
tudi
es.
j Ble
edin
g w
as a
sses
sed
earl
y (in
hos
pita
l or
in th
e fi r
st 1
0 d)
in tw
o st
udie
s (G
allu
s et
al,
Hul
l et a
l) an
d at
3 m
o in
one
stu
dy (L
eroy
er e
t al).
k I
t is u
ncle
ar w
heth
er b
leed
ing
was
ass
esse
d at
10
d in
all
subj
ects
or j
ust w
hile
hep
arin
was
bei
ng a
dmin
iste
red,
whi
ch c
ould
yie
ld a
bia
sed
estim
ate
in fa
vor o
f sho
rt-d
urat
ion
ther
apy
in o
ne st
udy
(Hul
l et a
l).
l Bec
ause
the
shor
ter
dura
tion
of h
epar
in th
erap
y is
ver
y un
likel
y to
incr
ease
ble
edin
g, th
e w
ide
95%
CIs
aro
und
the
rela
tive
effe
ct o
f sho
rter
ther
apy
on r
isk
of b
leed
ing
is n
ot a
maj
or c
once
rn.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S3
—[S
ecti
on 2
.5.1
] E
vide
nce
Pro
fi le:
LM
WH
vs
SC U
FH
for
Ini
tial
Ant
icoa
gula
tion
of
Acu
te V
TE
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith S
C U
FH
With
LM
WH
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
SC
U
FH
Ris
k D
iffer
ence
W
ith L
MW
H
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me)
1,56
6 (3
stu
dies
), 3
mo
No
seri
ous
risk
of b
ias a
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s b U
ndet
ecte
dM
oder
ate a,
b du
e to
im
prec
isio
n
31/7
80 (4
)34
/786
(4.3
)R
R 1
.1
(0.6
8-1.
76)
33 p
er 1
,000
c 3
mor
e pe
r 1,
000
(fro
m 1
1 fe
wer
to
25
mor
e)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
1,56
3 (3
stu
dies
), 3
mo
No
seri
ous
risk
of b
ias a
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s b U
ndet
ecte
dM
oder
ate a,
b du
e to
im
prec
isio
n
31/7
77 (4
)26
/786
(3.3
)R
R 0
.87
(0.5
2-1.
45)
42 p
er 1
,000
c 5
few
er
per
1,00
0 (f
rom
20
few
er
to 1
9 m
ore)
Maj
or b
leed
ing
(cri
tical
out
com
e)
1,63
4 (4
stu
dies
), 3
mo
No
seri
ous
risk
of b
ias a
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s b U
ndet
ecte
dM
oder
ate b,
c du
e to
im
prec
isio
n
15/8
15 (1
.8)
19/8
19 (2
.3)
RR
1.2
7 (0
.56-
2.9)
16 p
er 1
,000
c 4
mor
e pe
r 1,
000
(fro
m 7
few
er
to 3
0 m
ore)
Bib
liogr
aphy
: Lop
aciu
k et
al, 21
Fai
vre
et a
l, 2 Pra
ndon
i et a
l, 23 K
earo
n et
al. 24
SC
5 su
bcut
aneo
us. S
ee T
able
S1
and
S2 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a In
the
two
larg
est t
rial
s (P
rand
oni e
t al a
nd K
earo
n et
al,
87%
of p
atie
nts)
, allo
catio
n w
as c
once
aled
, out
com
e ad
judi
cato
rs a
nd d
ata
anal
ysts
wer
e co
ncea
led,
ana
lysi
s w
as in
tent
ion
to tr
eat,
and
ther
e w
ere
no lo
sses
to fo
llow
-up.
b P
reci
sion
judg
ed fr
om th
e pe
rspe
ctiv
e of
whe
ther
SC
hep
arin
is n
onin
feri
or to
LM
WH
. The
tota
l num
ber
of e
vent
s an
d th
e to
tal n
umbe
r of
par
ticip
ants
are
rel
ativ
ely
low
. c E
vent
rat
e co
rres
pond
s to
the
med
ian
even
t rat
e in
the
incl
uded
stu
dies
.
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Tabl
e S4
—[S
ecti
on 2
.5.1
] L
MW
H v
s SC
UF
H f
or I
niti
al A
ntic
oagu
lati
on o
f A
cute
VT
E: C
lini
cal
Des
crip
tion
and
Res
ult
s
Aut
hor/
Year
(Acr
onym
)In
terv
entio
nsPa
tient
s A
naly
zed a
Rec
urre
nt D
VT
or
PEM
ajor
Ble
edin
gTo
tal M
orta
lity
Com
men
ts
Lop
aciu
k et
al 21
/199
2U
FH
5,0
00 u
nits
IV
follo
wed
by
250
uni
ts/k
g SC
bid
in
itial
ly a
nd a
djus
ted
to
aPT
T fo
r 10
d
72/7
51/
72 (1
.4%
)1/
72 (1
.4%
)3/
72 (4
.2%
)Po
pula
tion:
Fem
oral
DV
T in
81
% a
nd p
oplit
eal o
r m
ore
dist
al D
VT
in 1
9%. P
rim
ary
outc
ome
was
rep
eat
veno
grap
hy.
F
raxi
pari
ne 9
7 In
tern
atio
nal
Uni
ts/k
g SC
bid
for
10 d
74/7
40/
74 R
R 3
.1 (0
.1-7
.5)
0/74
RR
3.1
(0.1
-7.5
)0/
74R
R 7
.2 (0
.4-1
37)
Fai
vree
t al 22
/198
8U
FH
5,0
00 u
nits
IV
follo
wed
by
250
uni
ts/k
g SC
bid
and
adj
uste
d to
aP
TT
for
10 d
29/3
51/
353/
351/
35Po
pula
tion:
DV
T (p
ropo
rtio
n of
pro
xim
al a
nd d
ista
l not
re
port
ed).
Prim
ary
outc
ome
was
rep
eat v
enog
raph
y.
C
Y222
2,0
00 I
nter
natio
nal
Uni
ts I
V fo
llow
ed b
y 15
0 In
tern
atio
nal U
nits
/kg
SC b
id fo
r 10
d
30/3
31/
33 R
R 0
.9 (0
.1-1
4.5)
0/33
RR
6.6
(0.3
-123
)0/
33 R
R 2
.8 (0
.1-6
7)
Pran
doni
et a
l 23 /2
004
(Gal
ilei)
UF
H I
V ( ,
50
kg: 4
,000
uni
ts;
50-7
0 kg
: 5,0
00 u
nits
; .
70
kg: 6
,000
uni
ts)
follo
wed
by
SC b
id d
oses
(in
itial
ly ,
50
kg: 1
2,50
0 un
its;
50-7
0 kg
: 15,
000
units
; .
70
kg: 1
7,50
0 un
its)
adju
sted
to a
PTT
fo
r �
6.5
d
360/
360
15/3
60 (4
.2%
)5/
360
(1.4
%)
12/3
60 (3
.3%
)Po
pula
tion:
Pro
xim
al D
VT
in
65%
, dis
tal D
VT
in 1
8%,
and
PE in
17%
.
N
adro
parin
85
Inte
rnat
iona
l U
nits
/kg
SC b
id fo
r � 6.
5 d
360/
360
14/3
60 (3
.9%
) RR
1.1
(0
.5-2
.2)
7/36
0 (1
.9%
) RR
0.7
(0
.2-2
.2)
12/3
60 (3
.3%
) RR
1.0
(0.5
-2.2
)
Kea
ron
et a
l 24 /2
006
(FID
O)
UF
H 3
33 u
nits
/kg
SC
follo
wed
by
250
units
/kg
SC b
id (n
o ad
just
men
t)
for
6.3
d
345/
355
13/3
45 (3
.8%
)6/
348
(1.7
%)
18/3
48 (5
.2%
)Po
pula
tion:
Pro
xim
al D
VT
in
77%
, asy
mpt
omat
ic o
r di
stal
D
VT
in 4
%, a
nd P
E in
19%
. Se
vent
y pe
rcen
t of p
atie
nts
wer
e tr
eate
d en
tirel
y as
an
outp
atie
nt (7
6% o
f DV
T
and
39%
of P
E) P
ostr
an-
dom
izat
ion
excl
usio
ns in
10
pat
ient
s re
ceiv
ing
UF
H
and
one
patie
nt r
ecei
ving
L
MW
H.
D
alte
pari
n (n
5 2
61)
or e
noxa
pari
n (n
5 9
1)
100
Inte
rnat
iona
l Uni
ts/k
g SC
bid
for
7.1
d
352/
353
12/3
52 (3
.4%
) RR
1.1
(0
.5-2
.3)
12/3
52 (3
.4%
) RR
0.5
(0
.2-1
.3)
22/3
52 (6
.3%
) RR
0.8
(0.4
-1.5
)
aPT
T 5
activ
ated
pro
thro
mbi
n tim
e; F
IDO
5 F
ixed
Dos
e H
epar
in. S
ee T
able
S1
and
S2 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Fol
low
-up
was
for
3 m
o ex
cept
for
the
stud
y by
Fai
vre
et a
l 22 in
whi
ch it
was
10
d.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
6© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S5
—[S
ecti
on 2
.5.1
] L
MW
H v
s SC
UF
H f
or I
niti
al A
ntic
oagu
lati
on o
f A
cute
VT
E: M
etho
dolo
gic
Qu
alit
y
Aut
hor/
Year
(Acr
onym
)In
terv
entio
nsSt
udy
Des
ign
Ran
dom
izat
ion
Con
ceal
edB
lindi
ngL
oss
to F
ollo
w-u
pA
naly
sis
Com
men
ts
Lop
aciu
k et
al 21
/199
2U
FH
5,0
00 u
nits
IV
follo
wed
by
250
units
/kg
SC b
id in
itial
ly a
nd
adju
sted
to a
PTT
for
10 d
RC
TPY
Patie
nts:
CN
Car
egiv
ers:
CN
Adj
udic
ator
s: C
ND
ata
Ana
lyst
s: P
N
Not
des
crib
edIT
T
F
raxi
pari
ne 9
7 In
tern
atio
nal
units
/kg
SC b
id fo
r 10
d
Fai
vre
et a
l 22 /1
988
UF
H 5
,000
uni
ts I
V fo
llow
ed b
y 25
0 un
its/k
g SC
bid
and
ad
just
ed to
aPT
T fo
r 10
d
RC
TPN
Patie
nts:
PN
Car
egiv
ers:
PN
Adj
udic
ator
s: P
ND
ata
Ana
lyst
s: P
N
Thr
ee o
f CY2
22 g
roup
and
six
of
UF
H g
roup
who
did
not
ha
ve r
epea
t ven
ogra
phy
are
assu
med
to h
ave
com
plet
ed
clin
ical
follo
w-u
p
ITT
CY2
22 2
,000
Int
erna
tiona
l Uni
ts
IV fo
llow
ed b
y 15
0 In
tern
atio
nal
Uni
ts/k
g SC
bid
for
10 d
Pran
doni
et a
l 23 /2
004
(Gal
ilei)
UF
H I
V ( ,
50
kg: 4
,000
uni
ts;
50-7
0 kg
: 5,0
00 u
nits
; . 7
0 kg
: 6,
000
units
) fol
low
ed b
y SC
bid
do
ses
(initi
ally
, 5
0 kg
: 12,
500
units
; 50-
70 k
g: 1
5,00
0 un
its;
. 7
0 kg
: 17,
500
units
) adj
uste
d to
aPT
T fo
r �
6.5
d
RC
TC
YPa
tient
s: C
NC
areg
iver
s: C
NA
djud
icat
ors:
CY
Dat
a A
naly
sts:
PY
Nil
ITT
Nad
ropa
rin
85 I
nter
natio
nal
Uni
ts/k
g SC
bid
for
� 6
.5 d
Kea
ron
et a
l 24 /2
006
(FID
O)
UF
H 3
33 u
nits
/kg
SC fo
llow
ed
by 2
50 u
nits
/kg
SC b
id (n
o ad
just
men
t) fo
r 6.
3 d
RC
TC
YPa
tient
s: C
NC
areg
iver
s: C
NA
djud
icat
ors:
CY
Dat
a A
naly
sts:
PY
Nil
ITT
Post
rand
omiz
atio
n ex
clus
ions
fr
om th
e ef
fi cac
y an
alys
is
wer
e 10
(2.8
%) f
or th
e U
FH
an
d on
e (0
.2%
) for
the
LM
WH
gro
up.
Dal
tepa
rin
(n 5
261
) or
enox
apar
in
(n 5
91)
100
Int
erna
tiona
l U
nits
/kg
SC b
id fo
r 7.
1 d
CN
5 ce
rtai
nly
no;
CY
5 ce
rtai
nly
yes;
IT
T 5
inte
ntio
n to
tre
at;
PN 5
pro
babl
y no
; PY
5 p
roba
bly
yes;
RC
T 5
rand
omiz
ed c
ontr
olle
d tr
ial.
See
Tabl
e S1
, S2
, an
d S4
leg
ends
for
exp
ansi
on o
f ot
her
abbr
evia
tions
.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
7© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S6
—[S
ecti
on 2
.5.1
] E
vide
nce
Pro
fi le:
LM
WH
vs
IV U
FH
for
Ini
tial
Ant
icoa
gula
tion
of
Acu
te V
TE
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Ove
rall
Qua
lity
of
Evi
denc
eW
ith I
V U
FH
With
LM
WH
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
IV
U
FH
Risk
Diff
eren
ce W
ith
LM
WH
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me)
7,90
8 (1
7 st
udie
s),
3 m
o
Seri
ous a
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nR
epor
ting
bias
st
rong
ly
susp
ecte
d b
Low
a,b d
ue to
ri
sk o
f bia
s,
publ
icat
ion
bias
232/
3,78
9 (6
.1)
187/
4,11
9 (4
.5)
RR
0.7
9 (0
.66-
0.95
)46
per
1,0
00 c
10 fe
wer
per
1,0
00
(fro
m 2
few
er to
16
few
er)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
7,97
6 (1
7 st
udie
s),
3 m
o
Seri
ous a
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nR
epor
ting
bias
st
rong
ly
susp
ecte
d b
Low
a,b d
ue to
ri
sk o
f bia
s,
publ
icat
ion
bias
208/
3,86
9 (5
.4)
151/
4,10
7 (3
.7)
RR
0.7
2 (0
.58-
0.89
)55
per
1,0
00 c
15 fe
wer
per
1,0
00
(fro
m 6
few
er to
23
few
er)
Maj
or b
leed
ing
(cri
tical
out
com
e)
6,91
0 (2
0 st
udie
s),
3 m
o
Seri
ous a
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
n d R
epor
ting
bias
st
rong
ly
susp
ecte
d b
Low
a,b,
d due
to
risk
of b
ias,
pu
blic
atio
n bi
as
69/3
,517
(2)
41/3
,393
(1.2
)R
R 0
.67
(0.4
5-1)
15 p
er 1
,000
c 5
few
er p
er 1
,000
(f
rom
8 fe
wer
to 0
m
ore)
Bib
liogr
aphy
: van
Don
gen
et a
l. 6 Inc
lude
d st
udie
s. 7,
20 S
ee T
able
S1
and
S2 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a O
f the
20
tria
ls, a
lloca
tion
was
con
ceal
ed in
nin
e an
d w
as u
ncle
ar w
heth
er c
once
aled
in th
e re
mai
ning
11.
Eig
htee
n tr
ials
had
blin
ded
outc
ome
asse
ssor
s. S
even
tria
ls d
id n
ot h
ave
any
post
rand
omiz
atio
n ex
clus
ions
or
loss
es to
follo
w-u
p. T
en tr
ials
rep
orte
d th
e nu
mbe
r of
par
ticip
ants
lost
to fo
llow
-up,
whi
ch r
ange
d fr
om 1
.0%
to 1
2.7%
. One
tria
l did
not
rep
ort t
he d
rop-
outs
. b I
nver
ted
funn
el p
lot v
ery
sugg
estiv
e of
pub
licat
ion
bias
. Man
y of
the
incl
uded
stu
dies
are
of s
mal
l siz
e, a
nd a
ll ar
e fu
nded
by
indu
stry
. c E
vent
rat
e co
rres
pond
s to
the
med
ian
even
t rat
e in
the
incl
uded
stu
dies
. d C
I in
terv
al in
clud
es v
alue
s su
gges
ting
sign
ifi ca
nt b
enefi
t an
d no
eff
ect.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
8© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S7
—[S
ecti
on 2
.5.1
] E
vide
nce
Pro
fi le:
Fon
dapa
rinu
x vs
LM
WH
for
Ini
tial
Ant
icoa
gula
tion
of
Acu
te D
VT
a-c
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith L
MW
HW
ith
Fon
dapa
rinu
xR
elat
ive
Eff
ect
(95%
CI)
Ris
k W
ith
LM
WH
Ris
k D
iffer
ence
W
ith F
onda
pari
nux
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me)
2,20
5 (1
stu
dy),
3 m
oN
o se
riou
s ri
sk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dM
oder
ate d,
e due
to
impr
ecis
ion
33/1
,107
(3.0
)41
/1,0
98 (3
.7)
RR
1.2
5 (0
.8-1
.97)
30 p
er 1
,000
7 m
ore
per
1,00
0 (f
rom
6 fe
wer
to
29 m
ore)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
2,20
5 (1
stu
dy),
3 m
oN
o se
riou
s ri
sk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dM
oder
ate d,
e due
to
impr
ecis
ion
45/1
,107
(4.1
) f 43
/1,0
98 (3
.9) f
RR
0.9
6 (0
.64-
1.45
)41
per
1,0
00 f
2 fe
wer
per
1,0
00
(fro
m 1
5 fe
wer
to
18
mor
e)
Maj
or b
leed
ing
(cri
tical
out
com
e)
2,20
5 (1
stu
dy),
3 m
oN
o se
riou
s ri
sk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dM
oder
ate d,
e due
to
impr
ecis
ion
13/1
,107
(1.2
) g 12
/1,0
98 (1
.1) g
RR
0.9
3 (0
.43-
2.03
)12
per
1,0
00 g
1 fe
wer
per
1,0
00
(fro
m 7
few
er to
12
mor
e)
Bib
liogr
aphy
: Bül
ler
et a
l. 25 I
NR
5 in
tern
atio
nal n
orm
aliz
ed r
atio
. See
Tab
le S
1 an
d S2
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a F
onda
pari
nux
7.5
mg
(5.0
mg
in p
atie
nts
wei
ghin
g ,
50
kg a
nd 1
0.0
mg
in p
atie
nts
wei
ghin
g .
100
kg)
SC
onc
e da
ily fo
r at
leas
t 5 d
and
unt
il V
KA
s in
duce
d an
IN
R .
2.0
. E
noxa
pari
n 1
mg/
kg o
f bod
y w
eigh
t SC
bid
for
at le
ast 5
d a
nd u
ntil
VK
As
indu
ced
an I
NR
. 2
.0.
c All
patie
nts
had
acut
e sy
mpt
omat
ic D
VT.
d A
lloca
tion
was
con
ceal
ed. P
atie
nts,
pro
vide
rs, d
ata
colle
ctor
s, a
nd o
utco
me
adju
dica
tors
wer
e bl
inde
d. A
naly
sis
excl
uded
0.6
% o
f ran
dom
ized
pat
ient
s. N
ot s
topp
ed e
arly
for
bene
fi t.
e CI
incl
udes
val
ues
sugg
estin
g no
eff
ect a
nd v
alue
s su
gges
ting
eith
er b
enefi
t or
har
m; r
elat
ivel
y lo
w n
umbe
r of
eve
nts.
f F
ive
fata
l VT
E in
fond
apar
inux
gro
up a
nd fi
ve fa
tal V
TE
in L
MW
H g
roup
. g T
wel
ve p
atie
nts
in th
e fo
ndap
arin
ux g
roup
and
13
in th
e L
MW
H g
roup
had
a m
ajor
ble
edin
g du
ring
the
initi
al p
erio
d (7
d).
Of t
hese
, tw
o in
the
fond
apar
inux
gro
up a
nd n
one
in th
e L
MW
H g
roup
wer
e fa
tal.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
9© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S8
—[S
ecti
on 2
.5.2
] E
vide
nce
Pro
fi le:
LM
WH
Onc
e vs
Tw
ice
Dai
ly f
or I
niti
al A
ntic
oagu
lati
on o
f A
cute
VT
E a,b
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith B
idW
ith L
MW
H
Onc
eR
elat
ive
Eff
ect
(95%
CI)
Ris
k W
ith B
id
Ris
k D
iffer
ence
W
ith L
MW
H
Onc
e (9
5% C
I)
Mor
talit
y (im
port
ant o
utco
me)
1,26
1 (3
stu
dies
), 3
mo
No
seri
ous
risk
of
bia
s c Se
riou
s d N
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dL
ow c-
e due
to
inco
nsis
tenc
y,
impr
ecis
ion
20/6
47 (3
.1)
20/6
14 (3
.3)
RR
1.0
5 (0
.57-
1.94
)31
per
1,0
002
mor
e pe
r 1,
000
(fro
m 1
3 fe
wer
to
29
mor
e)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
1,26
1 (3
stu
dies
), 3
mo
No
seri
ous
risk
of
bia
s c Se
riou
s f N
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dL
ow c,
e,f d
ue to
in
cons
iste
ncy,
im
prec
isio
n
32/6
47 (4
.9)
26/6
14 (4
.2)
RR
0.8
6 (0
.52-
1.42
)49
per
1,0
007
few
er p
er 1
,000
(f
rom
24
few
er
to 2
1 m
ore)
Maj
or b
leed
ing
(cri
tical
out
com
e)
1,52
2 (5
stu
dies
), 10
dN
o se
riou
s ri
sk
of b
ias c
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dM
oder
ate c,
e due
to
impr
ecis
ion
9/77
2 (1
.2)
10/7
50 (1
.3)
RR
1.1
3 (0
.48-
2.66
)12
per
1,0
002
mor
e pe
r 1,
000
(fro
m 6
few
er to
20
mor
e)
Bib
liogr
aphy
: van
Don
gen
et a
l. 26 S
ee T
able
S1,
S2,
and
S5
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a T
he fi
ve in
clud
ed s
tudi
es u
sed
four
bra
nds
of L
MW
H (e
noxa
pari
n, ti
nzap
arin
, dal
tepa
rin,
and
nad
ropa
rin)
. In
Mer
li et
al,
enox
apar
in 1
mg/
kg b
id w
as c
ompa
red
with
1.5
mg/
kg o
nce
daily
. Hol
mst
röm
27 e
t al
adju
sted
the
dose
to a
nti-X
a le
vels
, whi
ch r
esul
ted
in d
iffer
ent d
aily
dos
es a
fter
a n
umbe
r of
day
s. I
n th
e re
mai
ning
stu
dies
, the
dos
e of
the
once
-dai
ly a
dmin
istr
atio
n w
as d
oubl
e th
e do
se o
f the
twic
e-da
ily
adm
inis
trat
ion
(equ
al to
tal d
aily
dos
e).
b Of t
he fi
ve in
clud
ed s
tudi
es, o
ne in
clud
ed p
atie
nts
with
PE
and
DV
T, a
nd fo
ur in
clud
ed o
nly
patie
nts
with
DV
T. A
ll st
udie
s ad
dres
sed
the
initi
al m
anag
emen
t of V
TE
. c A
ll in
clud
ed s
tudi
es c
once
aled
allo
catio
n. T
wo
stud
ies
had
a do
uble
-blin
d de
sign
, and
two
othe
rs w
ere
sing
le b
lind.
One
stu
dy d
id n
ot m
entio
n bl
indi
ng. I
TT
like
ly u
sed
in a
ll st
udie
s. P
artic
ipan
ts w
ere
lost
to
follo
w-u
p in
onl
y tw
o st
udie
s (0
.3%
and
2.2
%).
d I 2 5
37%
; poi
nt e
ffec
t est
imat
e in
favo
r of
bid
dos
e in
Mer
li et
al 16
and
in fa
vor
of o
nce-
daily
dos
e in
Cha
rbon
nier
et a
l. 28
e Im
prec
isio
n ju
dged
rel
ativ
e to
no
diff
eren
ce.
f I 2 5
65%
; poi
nt e
ffec
t est
imat
e in
favo
r of
bid
dos
e in
Mer
li et
al 16
and
in fa
vor
of o
nce-
daily
dos
e in
Cha
rbon
nier
et a
l. 28
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
10© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S9
—[S
ecti
on 2
.7]
Evi
denc
e P
rofi l
e: H
ome
Tre
atm
ent
vs H
ospi
tal
Tre
atm
ent
of A
cute
DV
T a-d
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith H
ospi
tal
Trea
tmen
tW
ith H
ome
Trea
tmen
t
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith H
ospi
tal
Trea
tmen
t
Ris
k D
iffer
ence
W
ith H
ome
Trea
tmen
t (95
% C
I)
Mor
talit
y (im
port
ant o
utco
me)
1,70
8 (6
stu
dies
), 3
mo
No
seri
ous
risk
of
bia
s e N
o se
riou
s in
cons
iste
ncy
Seri
ous a,
b Se
riou
s f U
ndet
ecte
dL
ow a,
b,e,
f due
to
indi
rect
ness
, im
prec
isio
n
39/8
51 (4
.6)
28/8
57 (3
.3)
RR
0.7
2 (0
.45-
1.15
)46
per
1,0
0013
few
er p
er 1
,000
(f
rom
25
few
er to
7
mor
e)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
1,70
8 (6
stu
dies
), 3
mo
No
seri
ous
risk
of
bia
s e N
o se
riou
s in
cons
iste
ncy
Seri
ous a,
b N
o se
riou
s im
prec
isio
nU
ndet
ecte
dM
oder
ate a,
b,e d
ue
to in
dire
ctne
ss63
/851
(7.4
)39
/857
(4.6
)R
R 0
.61
(0.4
2-0.
9)74
per
1,0
0029
few
er p
er 1
,000
(f
rom
7 fe
wer
to
43 fe
wer
)
Maj
or b
leed
ing
(cri
tical
out
com
e)
1,70
8 (6
stu
dies
), 3
mo
No
seri
ous
risk
of
bia
s e N
o se
riou
s in
cons
iste
ncy
Seri
ous a,
b Se
riou
sfU
ndet
ecte
dM
oder
ate a,
b,e,
g du
e to
in
dire
ctne
ss
18/8
51 (2
.1)
12/8
57 (1
.4)
RR
0.6
7 (0
.33-
1.36
)21
per
1,0
007
few
er p
er 1
,000
(f
rom
14
few
er to
8
mor
e)
Qua
lity
of li
fe (i
mpo
rtan
t out
com
e)
0 (3
stu
dies
h ),
3 m
oN
o se
riou
s ri
sk
of b
ias
No
seri
ous
inco
nsis
tenc
y i Se
riou
s j Se
riou
skU
ndet
ecte
dL
ow i-k
due
to
indi
rect
ness
, im
prec
isio
n
……
Not
poo
led
See
com
men
th-k
See
com
men
th-k
Bib
liogr
aphy
: Oth
ieno
et a
l 29 ; i
nclu
ded
stud
ies.
13,1
4,30
-33 Q
ualit
y of
life
. 13,3
4,35
See
Tab
le S
1 an
d S2
for
expa
nsio
n of
abb
revi
atio
ns.
a Fou
r stu
dies
had
par
tial h
ospi
tal t
reat
men
t of m
any
in th
e ho
me
arm
: Koo
pman
et a
l (m
ean
hosp
ital s
tay
2.7
in h
ome
arm
vs 8
.1 d
in h
ospi
tal a
rm),
Lev
ine
et a
l (2.
1 vs
6.5
d),
Boc
calo
n et
al (
1 vs
9.6
d),
and
Ram
acci
otti
et a
l (3
vs 7
d).
In D
aska
lopo
ulos
et a
l, th
ere
was
no
hosp
ital s
tay
at a
ll in
the
hom
e gr
oup.
Cho
ng e
t al d
id n
ot r
epor
t dur
atio
n of
hos
pita
l sta
y.
b Onl
y on
e st
udy
(Boc
calo
n et
al)
used
LM
WH
in b
oth
trea
tmen
t arm
s. R
emai
ning
stu
dies
use
d U
FH
in th
e in
patie
nt a
rm a
nd L
MW
H in
the
outp
atie
nt a
rm.
c Stu
dies
incl
uded
in th
e sy
stem
atic
rev
iew
sho
uld
have
rec
ruite
d pa
tient
s w
hose
hom
e ci
rcum
stan
ces
wer
e ad
equa
te.
d All
stud
ies
incl
uded
pat
ient
s w
ith lo
wer
-ext
rem
ity D
VT
and
exc
lude
d pa
tient
s w
ith s
uspe
cted
or
confi
rm
ed P
E. S
tudi
es a
lso
excl
uded
pat
ient
s w
ho w
ere
preg
nant
. e O
ut o
f six
stu
dies
, allo
catio
n w
as c
lear
ly c
once
aled
in th
ree
(unc
lear
in r
emai
ning
thre
e). O
utco
me
adju
dica
tors
wer
e bl
inde
d in
the
two
larg
est s
tudi
es (u
ncle
ar in
rem
aini
ng).
Fou
r re
port
ed lo
ss to
follo
w-u
p (w
as s
igni
fi can
t in
onl
y a
smal
l stu
dy).
ITT
ana
lysi
s w
as c
ondu
cted
in f
our
(unc
lear
in r
emai
ning
tw
o). N
o st
udy
was
sto
pped
ear
ly f
or b
enefi
t. O
vera
ll, t
he ju
dgm
ent
was
tha
t th
ese
limita
tions
wou
ld n
ot
war
rant
dow
ngra
ding
of q
ualit
y be
caus
e it
has
alre
ady
been
dow
ngra
ded
by a
t lea
st o
ne le
vel b
ased
on
othe
r fa
ctor
s.
f The
CI
incl
udes
bot
h va
lues
sug
gest
ing
bene
fi t a
nd h
arm
. g J
udge
d as
pre
cise
bas
ed o
n th
e na
rrow
CI
arou
nd a
bsol
ute
effe
ct.
h Bäc
kman
et
al 34
rep
orte
d ev
alua
tion
of h
ealth
-rel
ated
qua
lity
of li
fe u
sing
the
EQ
-5D
. The
y fo
und
no d
iffer
ence
s in
mea
n qu
ality
-of-
life
scor
es o
r in
the
pro
port
ion
of p
atie
nts
show
ing
impr
ovem
ent
in
self-
rate
d he
alth
sta
te. K
oopm
an e
t al e
valu
ated
hea
lth-r
elat
ed q
ualit
y of
life
usi
ng th
e M
edic
al O
utco
me
Stud
y Sh
ort F
orm
-20
and
an a
dapt
ed v
ersi
on o
f the
Rot
terd
am S
ympt
om C
heck
list.
The
cha
nges
ov
er ti
me
wer
e si
mila
r in
bot
h gr
oups
exc
ept t
hat t
he p
atie
nts
rece
ivin
g L
MW
H h
ad b
ette
r sc
ores
for
phys
ical
act
ivity
( P
5 .0
02)
and
soci
al fu
nctio
ning
( P
5 .0
01)
at th
e en
d of
the
initi
al tr
eatm
ent.
The
au
thor
s di
d no
t rep
ort e
noug
h da
ta to
ass
ess
prec
isio
n an
d cl
inic
al s
igni
fi can
ce o
f res
ults
. O’B
rien
et a
l 35 a
sses
sed
chan
ges
in q
ualit
y of
life
usi
ng th
e M
edic
al O
utco
me
Stud
y Sh
ort F
orm
-36
in 3
00 p
atie
nts
part
icip
atin
g in
Lev
ine
et a
l. 14 T
hey
foun
d th
at, t
he c
hang
e in
sco
res
from
bas
elin
e to
day
7 w
as n
ot s
igni
fi can
tly d
iffer
ent b
etw
een
the
trea
tmen
t gro
ups
for
seve
n of
the
eigh
t dom
ains
. The
one
exc
eptio
n w
as th
e do
mai
n of
soc
ial f
unct
ioni
ng, w
here
a g
reat
er im
prov
emen
t was
obs
erve
d fo
r th
e ou
tpat
ient
gro
up.
i Pot
entia
l inc
onsi
sten
cy a
s B
äckm
an e
t al 34
sho
wed
no
effe
ct, w
here
as K
oopm
an e
t al 13
and
O’B
rien
et a
l 35 s
how
ed p
oten
tial b
enefi
t.
j Tw
o of
the
thre
e st
udie
s ha
d pa
rtia
l hos
pita
l tre
atm
ent o
f man
y in
the
hom
e ar
m: K
oopm
an e
t al 13
(mea
n ho
spita
l sta
y 2.
7 in
hom
e ar
m v
s 8.
1 d
in h
ospi
tal a
rm) a
nd L
evin
e et
al (
2.1
vs 6
.5 d
). k N
ot a
ble
to e
valu
ate
but i
mpr
ecis
ion
is p
ossi
ble.
Tak
en to
geth
er w
ith th
e po
tent
ial i
ncon
sist
ency
, we
dow
ngra
ded
the
qual
ity o
f evi
denc
e by
one
leve
l.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
11© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S1
0 —[S
ecti
on 2
.9]
Evi
denc
e P
rofi l
e: C
athe
ter-
Dir
ecte
d T
hrom
bol
ysis
vs
No
Cat
hete
r-D
irec
ted
Thr
omb
olys
is f
or E
xten
sive
Acu
te D
VT
of
the
Leg
ab
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Cat
hete
r-D
irec
ted
Thr
ombo
lysis
With
Cat
hete
r-D
irec
ted
Thr
ombo
lysi
sR
elat
ive
Eff
ect
(95%
CI)
Ris
k W
ith N
o C
athe
ter-
Dir
ecte
d T
hrom
boly
sis
Ris
k D
iffer
ence
W
ith C
athe
ter-
Dir
ecte
d T
hrom
boly
sis
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me)
153
(2 s
tudi
es),
3 m
oN
o se
riou
s ri
sk
of b
ias c
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssVe
ry s
erio
us d
Und
etec
ted
Low
c,d d
ue to
im
prec
isio
n3/
76 (3
.9) e
0/77
(0)
RR
0.1
4
(0.0
1-2.
71)
39 p
er 1
,000
e 34
few
er p
er 1
,000
(f
rom
39
few
er to
67
mor
e)
Non
fata
l rec
urre
nt V
TE
(cri
tical
out
com
e)
153
(1 s
tudy
), 3
mo
No
seri
ous
risk
of
bia
s c N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Very
ser
ious
d U
ndet
ecte
dL
ow c,
d due
to
impr
ecis
ion
1/76
(1.3
)0/
77 (0
)R
R 0
.35
(0
-8.0
9)48
per
1,0
00 f
31 fe
wer
per
1,0
00
(fro
m 4
8 fe
wer
to
340
mor
e)
Non
fata
l maj
or b
leed
ing
(cri
tical
out
com
e)
153
(2 s
tudi
es),
7 d
No
seri
ous
risk
of
bia
s c N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Very
ser
ious
d U
ndet
ecte
dL
ow c,
d due
to
impr
ecis
ion
0/76
(0)
1/77
(1.3
) g R
R 2
.00
(0
.19-
19.4
6)29
per
1,0
00 f,h
29
mor
e pe
r 1,
000
(fro
m 2
3 fe
wer
to
535
mor
e)
Post
thro
mbo
tic s
yndr
ome
(cri
tical
out
com
e; a
sses
sed
with
: com
plet
e ly
sis
on v
enog
raph
y (E
lsha
raw
y et
al);
pat
ency
on
ultr
asou
nd a
nd a
ir p
leth
ysm
ogra
phy
(End
en e
t al))
138
(2 s
tudi
es),
2 y
No
seri
ous
risk
of
bia
s c N
o se
riou
s in
cons
iste
ncy
Seri
ous i
No
seri
ous
impr
ecis
ion
Und
etec
ted
Mod
erat
e c,i d
ue
to in
dire
ctne
ss49
/70
(70)
23/6
8 (3
3.8)
RR
0.4
6
(0-0
.79)
588
per
1,00
0 j 31
8 fe
wer
per
1,0
00
(fro
m 1
23 fe
wer
to
588
few
er) k
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
12© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Cat
hete
r-D
irec
ted
Thr
ombo
lysis
With
Cat
hete
r-D
irec
ted
Thr
ombo
lysi
sR
elat
ive
Eff
ect
(95%
CI)
Ris
k W
ith N
o C
athe
ter-
Dir
ecte
d T
hrom
boly
sis
Ris
k D
iffer
ence
W
ith C
athe
ter-
Dir
ecte
d T
hrom
boly
sis
(95%
CI)
Qua
lity
of li
fe (i
mpo
rtan
t out
com
e; m
easu
red
with
the
Med
ical
Out
com
e Su
rvey
Sho
rt F
orm
-12,
Hea
lth U
tiliti
es I
ndex
MA
RK
ver
sion
2/3
que
stio
nnai
res;
bet
ter
indi
cate
d by
low
er v
alue
s)
98 (1
stu
dy l ),
16
mo
No
seri
ous
risk
of
bia
s m,n
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dL
ow m
,n
3068
...Se
e fo
otno
te o
Bib
liogr
aphy
: Els
hara
wy
et a
l, 36 E
nden
et a
l, 37 C
omer
ota
et a
l. 38 C
DT
5 ca
thet
er-d
irec
ted
thro
mbo
lysi
s; P
TS
5 p
ostt
hrom
botic
syn
drom
e. S
ee T
able
S1
lege
nd fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a All
patie
nts
wer
e an
ticoa
gula
ted
per
prot
ocol
, but
the
inte
rven
tion
grou
p re
ceiv
ed C
DT
in a
dditi
on to
ant
icoa
gula
tion.
b I
n se
lect
ed p
atie
nts
with
ext
ensi
ve a
cute
pro
xim
al D
VT
(eg,
ilio
fem
oral
DV
T, s
ympt
oms
for
, 1
4 d,
goo
d fu
nctio
nal s
tatu
s, li
fe e
xpec
tanc
y �
1 y
) who
hav
e a
low
ris
k of
ble
edin
g .
c Allo
catio
n w
as c
once
aled
in E
nden
et
al a
nd u
ncle
ar in
Els
hara
wy
et a
l. O
utco
me
asse
ssor
blin
ded
in b
oth
stud
ies.
Fol
low
-up
rate
s w
ere
87%
in E
nden
et
al a
nd 1
00%
in E
lsha
raw
y et
al.
Non
e of
the
st
udie
s w
as s
topp
ed e
arly
for
bene
fi t.
d CI
incl
udes
val
ues
sugg
estin
g bo
th b
enefi
t an
d ha
rm.
e Thr
ee c
ontr
ol p
atie
nts
died
of c
ance
r. f B
asel
ine
risk
s fo
r no
nfat
al r
ecur
rent
VT
E a
nd fo
r m
ajor
ble
edin
g de
rive
d fr
om D
ouke
tis e
t al. 39
g I
n th
e E
nden
et a
l stu
dy, o
ne p
atie
nt h
ad “
dura
ble
and
part
ial i
mpa
irm
ent o
f sen
sibi
lity
of th
e fo
ot”
imm
edia
tely
aft
er r
ecei
ving
CD
T, a
nd n
ine
patie
nts
had
min
or b
leed
ing
com
plic
atio
ns.
h Mos
t of b
leed
ing
even
ts o
ccur
dur
ing
the
fi rst
7 d
. i S
urro
gate
out
com
e: a
bsen
ce o
f pat
ency
at 6
mo
in E
nden
et a
l stu
dy; a
bsen
ce o
f com
plet
e ly
sis
at 6
mo
in E
lsha
raw
y et
al s
tudy
. j T
his
estim
ate
is b
ased
on
the
fi ndi
ngs
of th
e V
ET
O (V
enou
s T
hrom
bosi
s O
utco
mes
) stu
dy. 40
Thi
s pr
obab
ly u
nder
estim
ates
PT
S ba
selin
e ri
sk g
iven
that
ove
rall,
52%
of p
atie
nts
repo
rted
the
curr
ent u
se o
f co
mpr
essi
on s
tock
ings
dur
ing
stud
y fo
llow
-up.
k S
ever
e PT
S: a
ssum
ing
the
sam
e R
R o
f 0.4
6 an
d a
base
line
risk
of 1
3.8%
, the
abs
olut
e re
duct
ion
is 7
5 fe
wer
sev
ere
PTS
per
1,00
0 (f
rom
29
few
er to
138
few
er) o
ver
2 y.
l C
amer
ota
et a
l. 38
m P
artic
ipat
ion
rate
was
65%
. n R
ecal
l was
use
d to
mea
sure
qua
lity
of li
fe p
rior
to th
e th
rom
botic
eve
nt; w
e di
d no
t con
side
r th
ese
mea
sure
men
ts.
o At t
he in
itial
follo
w-u
p (m
ean,
16
mo)
, pat
ient
s tre
ated
with
CD
T re
port
ed a
tren
d to
war
d a
high
er m
enta
l sum
mar
y sc
ale
( P 5
.087
) and
impr
oved
Hea
lth U
tiliti
es In
dex
( P 5
.078
). T
hey
repo
rted
bet
ter o
vera
ll ro
le p
hysi
cal f
unct
ioni
ng ( P
5 .0
46),
less
stig
ma
( P 5
.033
), le
ss h
ealth
dis
tres
s ( P
5 .0
22),
and
few
er o
vera
ll sy
mpt
oms (
P 5
.006
) com
pare
d w
ith p
atie
nts w
ho w
ere
trea
ted
with
ant
icoa
gula
tion
alon
e.
Tabl
e S1
0—C
onti
nued
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Tabl
e S1
1 —[S
ecti
on 2
.9]
CD
T v
s N
o C
DT
for
Ext
ensi
ve A
cute
DV
T o
f th
e L
eg: C
lini
cal
Des
crip
tion
and
Res
ult
s (A
ll R
ando
miz
ed T
rial
s an
d P
rosp
ecti
ve
Ob
serv
atio
nal
Stu
dies
of
at L
east
20
Pat
ient
s)
Aut
hor/
Year
Type
of P
ublic
atio
nPa
rtic
ipan
tsIn
terv
entio
nsO
utco
mes
Fol
low
-up
Res
ults
Sem
ba e
t al 41
/199
4Pr
ospe
ctiv
e re
gist
ry21
pat
ient
s (2
7 lim
bs) w
ith
iliof
emor
al D
VT
� 1
4 d
(20)
or
. 1
4 d
(7) d
urat
ion
4.9
mill
ion
units
uro
kina
se
(mea
n) in
fuse
d ov
er 3
0 h
(mea
n),
follo
wed
by
hepa
rin
and
then
w
arfa
rin
for
8-12
wk
Adj
unct
ive
ther
apy:
lim
bs w
ith
resi
dual
ste
nose
s .
50%
rec
eive
d an
giop
last
y (2
) or
sten
ting
(14)
Clo
t lys
is,
com
plic
atio
ns3
mo
Sign
ifi ca
nt ly
sis:
18/
25 a (
72%
) Pa
rtia
l lys
is: 5
/25
(20%
) N
o ly
sis:
2/2
5 (8
%)
Com
plic
atio
ns: 1
sm
all h
emat
oma
at p
unct
ure
site
, no
inte
rven
tion/
tran
sfus
ion
Verh
aegh
e et
al 42
/199
7Pr
ospe
ctiv
e st
udy
24 p
atie
nts
with
ilio
fem
oral
D
VT
� 1
4 d
(16)
or
. 1
4 d
(8) d
urat
ion
3 m
g/h
rt-P
A (m
ean
86 m
g) in
fuse
d w
ith 1
,000
U/h
IV
hep
arin
, fo
llow
ed b
y he
pari
n, a
djus
ted
to A
PTT
Adj
unct
ive
ther
apy:
hyd
rody
nam
ic
thro
mbe
ctom
y (3
) and
ste
nts
(9)
Clo
t lys
is, b
leed
ing
13 m
o (m
ean)
Sign
ifi ca
nt ly
sis:
19/
24 (7
9%)
Part
ial l
ysis
: 5/2
4 (2
1%)
Ble
edin
g: 6
/24
(25%
) Pa
tenc
y:
3
mo:
84%
1
y: 7
8%
Bja
rnas
on e
t al 43
/199
7Pr
ospe
ctiv
e re
gist
ry77
pat
ient
s (8
7 lim
bs) w
ith
iliof
emor
al D
VT
� 1
4 d
(69)
or
. 1
4 d
(18)
dur
atio
n
2,00
0-2,
500
units
/kg
per
h ur
okin
ase
infu
sed
for
75 h
(mea
n)
with
5,0
00 I
nter
natio
nal U
nits
bol
us
hepa
rin
plus
infu
sion
ad
just
ed to
aPT
TA
djun
ctiv
e th
erap
y: a
ngio
plas
ty
(52
limbs
), st
ent (
38),
AVF
(15)
, su
rgic
al th
rom
bect
omy
(13)
, m
echa
nica
l thr
ombe
ctom
y (4
), su
rgic
al b
ypas
s (3
)
Clo
t lys
is, P
E,
blee
ding
1 y
Ear
ly r
esul
ts:
Si
gnifi
cant
lysi
s: 6
9/87
(79%
)
Il
iac
(63%
)
F
emor
al (4
0%)
N
o ly
sis:
18/
87 (2
1%)
PE
: 1 (1
%)
B
leed
ing:
maj
or, 5
/77
(6%
);
m
inor
, 11/
77 (1
4%)
Pate
ncy
at 1
y:
Il
iac:
63%
F
emor
al, 4
0%
(Con
tinu
ed)
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Tabl
e S1
1—C
onti
nued
Aut
hor/
Year
Type
of P
ublic
atio
nPa
rtic
ipan
tsIn
terv
entio
nsO
utco
mes
Fol
low
-up
Res
ults
Mew
isse
n et
al 44
/199
9 (N
atio
nal M
ultic
ente
r R
egis
try)
Pros
pect
ive
mul
ticen
ter
regi
stry
287
patie
nts
(312
infu
sion
s)
with
low
er li
mb
DV
T �
10
d (1
88) o
r .
10
d (9
9) d
urat
ion
7.8
mill
ion
units
uro
kina
se
(mea
n) in
fuse
d fo
r 53
.4 h
(m
ean)
in 2
97 li
mbs
In 6
lim
bs, o
nly
syst
emic
infu
sion
(n
o C
DT
)A
djun
ctiv
e th
erap
y: s
tent
s (1
04),
syst
emic
infu
sion
(54)
Clo
t lys
is, P
E,
blee
ding
, dea
th1
yE
arly
res
ults
:
50%
-100
% ly
sis:
258
/312
(83%
) ,
50%
lysi
s: 5
4/31
2 (1
7%)
PE: 6
/473
b (1%
) B
leed
ing:
54/
473 b (
11%
) D
eath
: 2/4
73 b (
, 1
%)
Pate
ncy
at 1
y:
Il
iac:
64%
F
emor
al: 4
7%
Abu
Rah
ma
et a
l 45 /2
001
Pros
pect
ive
stud
y51
pat
ient
s (5
1 lim
bs) w
ith
iliof
emor
al D
VT
giv
en c
hoic
e be
twee
n co
nven
tiona
l the
rapy
(h
epar
in 1
war
fari
n) o
rlys
is
1 a
ngio
/ste
nt (i
f nee
ded)
. L
ysis
off
ered
onl
y to
pat
ient
s w
ith D
VT
� 1
4 d
dura
tion
and
no c
ontr
aind
icat
ions
Ant
icoa
gula
tion:
33
patie
nts
give
n 1,
000-
2000
uni
ts/h
hep
arin
in
fusi
on fo
r 5-
7 d.
Clo
t lys
is, P
E,
blee
ding
Ant
icoa
g: 6
mo
Ant
icoa
gula
tion:
30-d
sig
nifi c
ant l
ysis
: 1/3
3 (3
%)
6-m
o pa
tenc
y: 8
/33
(24%
) B
leed
ing:
2/3
3 (6
%)
PE: 2
/33
(6%
)
C
DT:
18
patie
nts
give
n lo
adin
g do
se 4
,500
uni
ts u
roki
nase
fo
llow
ed b
y 4,
500
units
/kg
per
h fo
r 24-
48 h
or 4
-8-m
g bo
lus o
f rt-
PA fo
llow
ed b
y 2-
4-m
g/h
infu
sion
CD
T: 6
mo?
CD
T:
30
-d si
gnifi
cant
lysi
s: 15
/18
(83%
)6-
mo
pate
ncy:
15/
18 (8
3%)
Ble
edin
g: 2
/18
(11%
)
A
djun
ctiv
e th
erap
y: p
atie
nts
with
re
sidu
al s
teno
sis
. 5
0% r
ecei
ved
sten
ts (1
0)
Els
hara
wy
et a
l 36 /2
002)
R
CT,
sin
gle
cent
er35
pat
ient
s w
ith D
VT
, 1
0 d
dura
tion
rand
omiz
ed to
C
DT
or
antic
oagu
latio
n al
one
CD
T: 1
8 pa
tient
s re
ceiv
ed �
1
mill
ion
units
SK
pul
se-s
pray
for
1 h,
follo
wed
by
100,
000
units
/h S
K in
fusi
on u
ntil
com
-pl
ete
lysi
s, n
o ch
ange
in 1
2 h,
or
com
plic
atio
nA
djun
ctiv
e th
erap
y:
angi
opla
sty/
sten
t (1)
Clo
t lys
is, P
E,
blee
ding
1 w
k an
d 6
mo
CD
T, 1
wk
C
ompl
ete
lysi
s: 1
1/18
(61%
) N
o ly
sis:
0 (0
%)
PE: 0
Ble
edin
g: 0
A
ntic
oagu
latio
n, 1
wk:
Com
plet
e ly
sis:
0/1
7 (0
%)
No
lysi
s: 1
7/17
(100
%)
PE: 1
/17
(6%
) B
leed
ing:
0
(Con
tinu
ed)
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Aut
hor/
Year
Type
of P
ublic
atio
nPa
rtic
ipan
tsIn
terv
entio
nsO
utco
mes
Fol
low
-up
Res
ults
A
ntic
oagu
latio
n: 1
7 pa
tient
s re
ceiv
ed 5
,000
uni
ts h
epar
in
bolu
s, fo
llow
ed b
y he
pari
n ad
just
ed to
aPT
T
CD
T, 6
mo
Com
plet
e ly
sis:
13/
18 (7
2%)
No
lysi
s: 0
(0%
) A
ntic
oagu
latio
n, 6
mo
Sign
ifi ca
nt ly
sis:
2/17
(12%
) N
o ly
sis:
7/1
7 (4
1%)
End
en e
t al 37
/200
9 (C
aVen
T)
RC
T, m
ultic
ente
rIl
iofe
mor
al D
VT
, 2
1 d
dura
tion
CD
T: tP
A 0
.01
mg/
kg p
er h
, m
axim
um o
f 20
mg/
24 h
for
4 d.
Tr
eate
d in
four
ref
erra
l cen
ters
Clo
t lys
is, P
E,
blee
ding
(PT
S at
24
mo
pend
ing)
1 w
k an
d 6
mo
CD
T, 1
wk
�
50%
lysi
s: 4
4/50
(68%
) PE
: 0
Maj
or b
leed
ing:
1/5
0
Ant
icoa
gula
tion
alon
e: u
sual
pr
actic
e, a
dmin
iste
red
loca
llyA
ntic
oagu
latio
n, 1
wk:
Lys
is n
ot a
sses
sed
PE: 0
M
ajor
ble
edin
g: 0
(p
unct
ure
site
ner
ve d
amag
e: 0
)
CD
T, 6
mo
Il
iofe
mor
al p
aten
cy:
32/5
0 (6
4%)
Ant
icoa
gula
tion,
6 m
o
Ilio
fem
oral
pat
ency
: 19
/53
(36%
)
Ear
ly p
rosp
ectiv
e ob
serv
atio
nal s
tudi
es w
ith ,
20
patie
nts
and
retr
ospe
ctiv
e st
udie
s ar
e de
scri
bed
in T
able
3 o
f th
e ei
ghth
edi
tion
of t
hese
gui
delin
es. 46
AV
F 5
arte
riov
enou
s fi s
tula
; CaV
enT
5 C
athe
ter-
Dir
ecte
d Ve
nous
Thr
ombo
lysi
s in
Acu
te I
liofe
mor
al V
ein
Thr
ombo
sis;
rt-
PA 5
reco
mbi
nant
tiss
ue p
lasm
inog
en a
ctiv
ator
; SK
5 st
rept
okin
ase.
See
Tab
le S
2, S
4, S
5, a
nd S
10 le
gend
s fo
r ex
pans
ion
of o
ther
ab
brev
iatio
ns.
a Tw
enty
-fi ve
of 2
7 lim
bs tr
eate
d w
ith C
DT;
two
coul
d no
t be
cros
sed
with
the
guid
ewir
e.
b Cal
cula
ted
from
tota
l num
ber
of p
atie
nts
in V
enou
s R
egis
try.
Tabl
e S1
1—C
onti
nued
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Table S12 —[Section 2.9] CDT vs No CDT for Extensive Acute DVT of the Leg: Methodologic Quality
Author/Year Randomization Allocation Concealment Blinding Loss to follow-up
Semba et al 41 /1994 N/A N/A N/A N/A
Verhaeghe et al 42 /1997 N/A N/A N/A N/A
Bjarnason et al 43 /1997 N/A N/A N/A N/A
Mewissen et al 44 /1999 N/A N/A N/A N/A
AbuRahma et al 45 /2001 N/A N/A N/A N/A
Elsharawy et al 36 /2002 Computer-designated cards
PN N for patients, caregivers, and probably data analysts. Y for vascular imaging
0
Enden et al 37 /2009 Computer-designated cards
Y No for patients and caregivers. Yes for vascular imaging.
One loss to follow-up (CDT), fi ve
withdrawals, fi ve postrandomization
exclusions
N 5 no; N/A 5 not applicable; Y 5 yes. See Table S10 legend for expansion of other abbreviation.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S1
3 —[S
ecti
on 2
.10]
Sys
tem
ic L
ysis
vs
No
Syst
emic
Lys
is f
or E
xten
sive
Acu
te D
VT
of
the
Leg
: Cli
nica
l D
escr
ipti
on a
nd R
esu
lts
(Ran
dom
ized
Tri
als
Tha
t C
ompa
red
Syst
emic
Thr
omb
olyt
ic T
hera
py W
ith
No
Thr
omb
olyt
ic T
hera
py)
Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Bro
wse
et a
l 52 /1
968
R
CT,
sin
gle
cent
er10
pat
ient
s w
ith
low
er-e
xtre
mity
D
VT
con
fi rm
ed
by p
hleb
ogra
phy
Lys
is: 6
00,0
00 u
nits
SK
plu
s 10
0 m
g hy
droc
ortis
one
for
fi rst
hou
r, th
en
cont
inue
d ev
ery
6 h
for
3 d
(5 p
atie
nts)
Ant
icoa
gula
tion:
4-6
hou
rly
dose
s of
hep
arin
5,
000
units
for
48 h
fo
llow
ed b
y w
arfa
rin
(5 p
atie
nts)
Clo
t lys
is, P
E,
blee
ding
7-10
dT
hrom
boly
sis:
C
ompl
ete
clot
lysi
s: 3
/5 (6
0%)
Part
ial l
ysis
: 1/5
(20%
) N
o ly
sis:
1 (2
0%)
PE: 0
B
leed
ing:
0
Ant
icoa
gula
tion:
C
ompl
ete
clot
lysi
s: 0
/5
Part
ial l
ysis
: 0/5
N
o ly
sis:
5/5
(100
%))
PE
: 0
Ble
edin
g: 0
Rob
erts
on e
t al 53
/196
8
RC
T, s
ingl
e ce
nter
16 p
atie
nts
with
D
VT
Thr
ombo
lysi
s: S
K 2
00,0
00
units
ove
r 90
min
, the
n 10
0,00
0 un
its a
s m
aint
enan
ce d
ose
for
22.5
h; h
epar
in 5
00 m
g gi
ven
duri
ng 2
4 h,
plu
s pr
edni
sone
(8 p
atie
nts)
Ant
icoa
gula
tion:
Hep
arin
pl
us p
redn
ison
e (8
pat
ient
s)
Clo
t lys
is,
blee
ding
7 d
Thr
ombo
lysi
s:
Sign
ifi ca
nt ly
sis:
5/8
(63%
) Pa
rtia
l lys
is: 2
/8 (2
5%)
No
lysi
s: 1
/8 (1
2%)
Ble
edin
g: M
ajor
: 2/8
(25%
) M
inor
: 2/8
(25%
) A
ntic
oagu
latio
n:
Sign
ifi ca
nt ly
sis:
1/8
(12%
) Pa
rtia
l lys
is: 2
/8 (2
5%)
No
lysi
s: 5
/8 (6
3%)
Ble
edin
g: M
ajor
: 1/8
(12%
) M
inor
: 1/8
(12%
)
Kak
kar
et a
l 54 /1
969
RC
T, s
ingl
e ce
nter
30 p
atie
nts
with
D
VT
of ,
4 d
Thr
ombo
lysi
s: S
K 5
00,0
00 u
nits
IV
ove
r 30
min
; 900
,000
uni
ts
ever
y 6
h 3
5 d
(1
0 pa
tient
s)
Clo
t lys
is, P
E,
blee
ding
, dea
th6-
12 m
oT
hrom
boly
sis:
C
ompl
ete
clot
lysi
s: 6
/9 (6
7%)
Part
ial l
ysis
: 1/9
(11%
) N
o ly
sis:
2/9
(22%
) PE
: 0
Ble
edin
g: 4
/10
(40%
) D
eath
: 2/9
(22%
) N
ote:
(1 p
atie
nt e
xclu
ded
from
trea
tmen
t)
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
18© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S1
3—C
onti
nued
Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
A
rvin
: Arv
in lo
adin
g do
se
80 u
nits
IV
ove
r 6
h;
80 u
nits
ove
r 15
min
; 40
-80
units
eve
ry
6 h
3 5
d (1
0 pa
tient
s)A
ntic
oagu
latio
n: H
epar
in
10,0
00 u
nits
IV
ove
r 5
min
, the
n 10
,000
-15,
000
units
eve
ry 6
h 3
5 d
(1
0 pa
tient
s)
Arv
in:
Com
plet
e ly
sis:
1/1
0 (1
0%)
Part
ial l
ysis
: 3/1
0 (3
0%)
No
lysi
s: 6
/10
(60%
) PE
: 0
Ble
edin
g: 0
D
eath
: 0
Ant
icoa
gula
tion:
C
ompl
ete
clot
lysi
s: 2
/9 (2
2%)
Part
ial l
ysis
: 2/9
(22%
) N
o ly
sis:
5/9
(55%
) PE
: 1/1
0 D
eath
: 2/9
(22%
) B
leed
ing:
2/9
(22%
) N
ote:
(1 p
atie
nt e
xclu
ded
from
trea
tmen
t)
Tsap
ogas
et a
l 55 /1
973
R
CT,
sin
gle
cent
er34
pat
ient
s w
ith
DV
T o
f , 5
dT
hrom
boly
sis:
titr
ated
in
itial
dos
e of
SK
IV,
th
en S
K 1
00,0
00 u
nits
/h
mai
ntai
ned
and
adju
sted
up
to 7
2 h
IV h
epar
in fo
r 1
wk
6-12
h p
ost S
K
(19
patie
nts)
Ant
icoa
gula
tion:
Hep
arin
IV
in
to a
ffec
ted
limb,
7,0
00 u
nits
bo
lus
then
1,5
00 u
nits
/h
adju
sted
; con
tinue
d fo
r 7
d (1
5)
Clo
t lys
is, P
E,
blee
ding
7 d
Thr
ombo
lysi
s:
Com
plet
e/pa
rtia
l lys
is: 1
0/19
(53%
) N
o ly
sis:
9/1
9 (4
7%)
PE: 0
M
inor
ble
edin
g: 3
(16%
) A
ntic
oagu
latio
n:
Com
plet
e/pa
rtia
l lys
is: 1
/15
(7%
) N
o ly
sis:
14/
15 (9
3%)
PE: 1
/15
(7%
) B
leed
ing:
0
Duc
kert
et a
l 56 /1
975
Pr
ospe
ctiv
e st
udy
134
patie
nts
with
acu
te
or s
ubac
ute
DV
TT
hrom
boly
sis:
initi
al d
ose
SK c
alcu
late
d ac
cord
ing
to to
lera
nce
inje
cted
ove
r 15
-30
min
; mai
nten
ance
do
se a
t 30
mL
/h w
as
two-
thir
ds o
f fi r
st d
ose
(92
patie
nts)
Ant
icoa
gula
tion:
5,0
00 u
nits
he
pari
n fo
r in
itial
dos
e fo
llow
ed b
y 25
,000
uni
ts/2
4 h
infu
sion
(42
patie
nts)
.
Clo
t lys
is, P
E,
blee
ding
� 7
dT
hrom
boly
sis:
Si
gnifi
cant
lysi
s: 3
9/92
(42%
) Pa
rtia
l lys
is: 2
3/92
(25%
) N
o ly
sis:
30/
92 (3
3%)
PE: 7
(8%
) M
ajor
ble
edin
g: 5
8 (6
2%)
Min
or b
leed
ing:
24
(26%
) s
Ant
icoa
gula
tion:
Si
gnifi
cant
lysi
s: 0
/42
(0%
) Pa
rtia
l lys
is: 4
/42
(10%
) N
o ly
sis:
38/
42 (9
0%)
PE: 5
/42
(12%
) M
ajor
ble
edin
g: 2
/42
(5%
) M
inor
ble
edin
g: 4
/42
(10%
) (C
onti
nued
)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
19© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Port
er e
t al 57
/197
5
RC
T, s
ingl
e ce
nter
50 p
atie
nts
with
D
VT
, 1
4 d
dura
tion
Thr
ombo
lysi
s: S
K 2
50,0
00 u
nits
IV
ov
er 3
0 m
in, t
hen
100,
000
units
/h ti
trat
ed
for
72 h
follo
wed
by
IV h
epar
in ti
trat
ed o
ver
7 d
(23
patie
nts)
Ant
icoa
gula
tion:
IV
hep
arin
15
0 un
its/k
g lo
adin
g do
se
then
titr
ated
for
10 d
(2
6 pa
tient
s)
Clo
t lys
is, P
E,
blee
ding
, de
ath
due
to
trea
tmen
t
10 d
Thr
ombo
lysi
s C
ompl
ete
lysi
s: 6
/23
(26%
) Pa
rtia
l lys
is: 1
5/23
(65%
) N
o ly
sis:
2/2
3 (9
%)
PE: 0
B
leed
ing:
4/2
3 (1
7%)
Dea
th: 1
(4%
) A
ntic
oagu
latio
n:
Com
plet
e ly
sis:
1/2
6 (4
%)
Part
ial l
ysis
: 20/
26 (7
7%)
No
lysi
s: 5
/26
(19%
) PE
: 0
Ble
edin
g: 1
/26
(4%
) D
eath
: 0
Mar
der
et a
l 58 /1
977
RC
T, s
ingl
e ce
nter
24 p
atie
nts
with
D
VT
Thr
ombo
lysi
s: in
itial
dos
e of
25
0,00
0 un
its S
K fo
r 20
min
, fol
low
ed b
y 10
0,00
0 un
its/h
for
72 h
(12
patie
nts)
Ant
icoa
gula
tion:
initi
al d
ose
hepa
rin
150
units
/kg
IV,
follo
wed
by
titra
ted
infu
sion
for
72 h
Cot
reat
men
t: 10
0 m
g bo
lus
hydr
ocor
tison
e pr
ior
to tr
eatm
ent
Clo
t lys
is,
deat
h du
e to
tr
eatm
ent
5 d
Thr
ombo
lysi
s:
Sign
ifi ca
nt ly
sis:
5/1
2 (4
2%)
Part
ial l
ysis
: 2/1
2 (1
6%)
No
lysi
s: 5
/12
(42%
) D
eath
: 1/1
2 (8
%)
Ant
icoa
gula
tion:
Si
gnifi
cant
lysi
s: 0
/12
(0%
) Pa
rtia
l lys
is: 3
/12
(25%
) N
o ly
sis:
9/1
2 (7
5%)
Dea
th: 0
Arn
esen
et a
l 59 /1
978
R
CT,
sin
gle
cent
er42
pat
ient
s w
ith
prox
imal
DV
T
of ,
5 d
.
Thr
ombo
lysi
s: lo
adin
g do
se
of S
K 2
50,0
00 u
nits
IV,
th
en 1
00,0
00 I
nter
natio
nal
Uni
ts/h
IV
for
72-9
6 h
(21
patie
nts)
Ant
icoa
gula
tion:
hep
arin
15
,000
Int
erna
tiona
l Uni
ts
IV b
olus
, the
n to
tal o
f 30
,000
Int
erna
tiona
l Uni
ts
IV in
fusi
on fo
r 72
-90
h (2
1 pa
tient
s)
Clo
t lys
is, P
E,
blee
ding
21 d
-6 y
Thr
ombo
lysi
s:
Sign
ifi ca
nt ly
sis:
15/
21 (7
1%)
No
lysi
s: 6
/21
(29%
) PE
: 1/2
1 (5
%)
Ble
edin
g: 2
/21
(9%
) A
ntic
oagu
latio
n:
Sign
ifi ca
nt ly
sis:
5/2
1 (2
4%)
No
lysi
s: 1
6/21
(76%
) PE
: 0
Ble
edin
g: 2
/21
(9%
)
Tabl
e S1
3—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
20© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Elli
ot e
t al 60
/197
9
RC
T, s
ingl
e ce
nter
51 p
atie
nts
with
cl
inic
al h
isto
ry
of D
VT
of ,
8 d
Thr
ombo
lysi
s: lo
adin
g do
se
of S
K 6
00,0
00 u
nits
infu
sed
over
30
min
, fol
low
ed b
y 10
0,00
0/h
for
3 d;
hep
arin
fo
r 4
d fo
llow
ing
SK
(26
patie
nts)
Ant
icoa
gula
tion:
hep
arin
10
,000
uni
ts I
V in
itial
ly,
follo
wed
by
10,0
00 u
nits
IV
dai
ly fo
r a
6-h
infu
sion
to
mai
ntai
n cl
ottin
g tim
e of
2.5
-3 ti
mes
nor
mal
for
7 d
(25
patie
nts)
Imm
edia
te:
clot
lysi
s,
PE, b
leed
ing
Lon
g te
rm:
sym
ptom
free
Imm
edia
te: 5
dL
ong
term
: 19
mo
(mea
n)
Imm
edia
te:
Thr
ombo
lysi
s:
Sign
ifi ca
nt ly
sis:
17/2
6 (6
5%)
Part
ial l
ysis
: 1/2
6 (4
%)
No
lysi
s: 8
/26
(31%
) PE
: 0
Ble
edin
g: 2
(8%
) A
ntic
oagu
latio
n:
Sign
ifi ca
nt ly
sis:
0/2
5 (0
%)
Part
ial l
ysis
: 0/2
5 (0
%)
No
lysi
s: 2
5/25
(100
%)
PE: 0
B
leed
ing:
2/2
1 (9
%)
Lon
g te
rm:
Thr
ombo
lysi
s:
Sym
ptom
-fre
e: 1
2/20
a (60
%)
Trea
tmen
t 2
Sym
ptom
-fre
e: 2
/21 b (
9%)
Wat
z et
al 61
/197
9
Pros
pect
ive
stud
y35
pat
ient
s w
ith
DV
TT
hrom
boly
sis:
initi
al d
ose
of
SK 2
50,0
00 u
nits
in 3
0 m
in,
follo
wed
by
mai
nten
ance
10
0,00
0 un
its/h
(18
patie
nts)
Ant
icoa
gula
tion:
hep
arin
45
,000
uni
ts d
aily
with
w
arfa
rin
(17)
Clo
t lys
is, P
E,
blee
ding
1-2
mo
Thr
ombo
lysi
s:
Sign
ifi ca
nt ly
sis:
8/1
8 (4
4%)
Part
ial l
ysis
: 4/1
8 (2
2%)
No
lysi
s: 6
/18
(34%
) PE
: 1/1
8 (5
%)
Min
or b
leed
ing:
3/1
8 (1
2%)
Ant
icoa
gula
tion:
Si
gnifi
cant
lysi
s: 1
/17
(6%
) Pa
rtia
l lys
is: 5
/17
(29%
) N
o ly
sis:
11/
17 (6
5%)
PE: 1
/17
(6%
) M
inor
ble
edin
g: 2
/17
(12%
)
Tabl
e S1
3—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
21© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Kiil
et a
l 62 /1
981
R
CT,
sin
gle
cent
er20
pat
ient
s w
ith
DV
T o
f , 7
2 h
Thr
ombo
lysi
s: u
roki
nase
20
0,00
0 un
its I
V fo
r 24
h;
afte
r 18
h, h
epar
in lo
adin
g do
se o
f 15,
000
units
, the
n 40
,000
uni
ts/d
for
5 d
(11
patie
nts)
Ant
icoa
gula
tion:
hep
arin
40
,000
uni
ts/d
ay 4
for
6 d
(9 p
atie
nts)
Clo
t lys
is, P
E,
blee
ding
2 w
kT
hrom
boly
sis:
Pa
rtia
l lys
is: 1
/11
(9%
) N
o ly
sis:
10/
11 (9
1%)
PE: 0
B
leed
ing:
3/1
1 (2
7%)
Ant
icoa
gula
tion:
Pa
rtia
l lys
is: 1
/8 (1
2%)
No
lysi
s: 7
/8 (8
8%)
PE: 0
B
leed
ing:
3/9
(33%
) N
ote:
1 p
atie
nt e
xclu
ded
from
gro
up
Arn
esen
et a
l 63 /1
982
F
ollo
w-u
p to
RC
T o
f A
rnes
en
(197
8)
35/4
2 pa
tient
s fr
om
RC
TPh
lebo
grap
hy a
nd c
linic
al
exam
inat
ion
by b
linde
d ev
alua
tors
Nor
mal
legs
, PT
S sy
mpt
oms
6.5
yT
hrom
boly
sis:
N
orm
al le
gs: 1
3/17
(77%
) PT
S sy
mpt
oms
(mod
erat
e): 4
/17
(24%
) A
ntic
oagu
latio
n:
Nor
mal
legs
: 6/1
8 (3
3%)
PTS
sym
ptom
s (m
oder
ate)
: 9/1
8 (5
0%)
Schu
lman
et a
l 49 /1
986
R
CT,
sin
gle
cent
er36
pat
ient
s w
ith c
alf
DV
T o
f , 7
dT
hrom
boly
sis:
SK
50,
000
Inte
rnat
iona
l Uni
ts I
V
over
15
min
, the
n 10
0,00
0 In
tern
atio
nal U
nits
ove
r 12
h fo
r up
to 7
d, t
itrat
ed;
give
n w
ith h
epar
in 5
,000
In
tern
atio
nal U
nits
IV
ove
r 12
h (1
7 pa
tient
s)A
ntic
oagu
latio
n: h
epar
in
5,00
0 In
tern
atio
nal U
nits
IV
for
15 m
in th
en 3
0,00
0 In
tern
atio
nal U
nits
/d,
titra
ted
over
7 d
(1
9 pa
tient
s)
Clo
t lys
is,
blee
ding
, PE
5 y
Thr
ombo
lysi
s:
Com
plet
e ly
sis:
7/1
7 (4
1%)
Ble
edin
g:3/
17 (1
8%)
PE: 0
A
ntic
oagu
latio
n:
Com
plet
e ly
sis:
2/1
9 (1
0%)
Ble
edin
g: 1
/19
(5%
) PE
: 0
Verh
aegh
e et
al 51
/198
9Pr
ospe
ctiv
e co
hort
stu
dy
(A) a
nd m
ultic
ente
r R
TC
(B)
32 p
atie
nts
with
D
VT
of ,
10
dSt
udy
A: o
pen-
labe
l stu
dy
with
rt-
PA 1
00 m
g ov
er
IV 8
h (d
ay 1
), 50
mg
rt-P
A
over
8 h
(day
2);
10%
dos
e as
bol
us (1
1 pa
tient
s)
Clo
t lys
is,
blee
ding
72 h
Not
e: A
utho
rs a
ssig
ned
vein
s a
rela
tive
valu
e re
fl ect
ing
degr
ee o
f thr
ombo
sis
(max
imum
, 40
units
: com
plet
e th
rom
bosi
s). T
he u
nit s
core
s re
fl ect
the
redu
ctio
n in
thro
mbo
sis
post
lysi
s.
Tabl
e S1
3—C
onti
nued
(Con
tinu
ed)
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Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
St
udy
B: r
t-PA
100
mg:
IV
of
100
mL
con
tain
ing
rt-P
A
100
mg
infu
sed
over
8 h
(d
ay 1
), IV
of 1
00 m
L
cont
aini
ng 5
0 m
g rt
-PA
in
fuse
d ov
er 8
h (d
ay 2
); 10
% d
ose
as b
olus
(8
pat
ient
s)rt
-PA
50
mg:
IV
of 1
00 m
L
cont
aini
ng r
t-PA
50
mg
infu
sed
over
8 h
on
both
da
ys 1
and
2; 1
0% d
ose
as b
olus
(6 p
atie
nts)
Plac
ebo:
IV
of 1
00 m
L
cont
aini
ng p
lace
bo in
fuse
d ov
er 8
h o
n bo
th d
ays
1 an
d 2
(7 p
atie
nts)
Co-
trea
tmen
t: he
pari
n 5,
000
units
IV
bol
us th
en c
ontin
uous
in
fusi
on 1
,000
uni
ts/h
fo
r up
to 7
2 h
Stud
y A
C
hang
e in
uni
t sco
re: 2
3.2
St
udy
B
rt-P
A 1
00 m
g:
Cha
nge
in u
nit s
core
: 2 2
4.3
Ble
edin
g: 6
rt
-PA
50
mg:
C
hang
e in
uni
t sco
re: 2
34.
3 B
leed
ing:
3
Plac
ebo:
C
hang
e in
uni
t sco
re: 2
2.8
B
leed
ing:
0
Gol
dhab
er e
t al 64
/199
0R
CT,
m
ultic
ente
r64
pat
ient
s (6
5 ra
ndom
izat
ions
) w
ith D
VT
of ,
14
d
rt-P
A: r
t-PA
0.0
5 m
g/kg
per
h
IV fo
r 24
h, t
hen
hepa
rin
100
units
/kg
bolu
s, th
en
1,00
0 un
its/h
, adj
uste
d (3
6 pa
tient
s)rt
-PA
1 h
epar
in: r
t-PA
as
in g
roup
1 p
lus
hepa
rin
conc
omita
ntly
(17
patie
nts)
Ant
icoa
gula
tion:
hep
arin
10
0 un
its/k
g bo
lus,
then
1,
000
units
/h (1
2 pa
tient
s)
Clo
t lys
is,
blee
ding
36 h
rt-P
A:
Com
plet
e ly
sis:
2/3
2 (6
%)
Part
ial l
ysis
: 18/
32 (5
7%)
No
lysi
s: 1
2/32
(38%
) B
leed
ing:
1/3
2 (3
%)
rt-P
A 1
hep
arin
: C
ompl
ete
lysi
s: 1
/17
(6%
) Pa
rtia
l lys
is: 8
/17
(48%
) N
o ly
sis:
8/17
(48%
) B
leed
ing:
0
Ant
icoa
gula
tion:
Pa
rtia
l lys
is: 2
/11
(18%
) N
o ly
sis:
9/1
1 (8
9%)
Ble
edin
g: 0
N
ote:
5/6
5 ve
nogr
ams
not a
naly
zed
Tabl
e S1
3—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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(Con
tinu
ed)
Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Turp
ie e
t al 50
/199
0R
CT,
m
ultic
ente
r83
pat
ient
s w
ith
DV
T o
f , 7
dPh
ase
1: L
ysis
1 h
epar
in:
two-
chai
n rt
-PA
0.5
mg/
kg
IV fo
r 4
h (1
2 pa
tient
s)
Clo
t lys
is,
blee
ding
24-4
8 h
Phas
e 1:
L
ysis
1 h
epar
in:
� 5
0% ly
sis:
7/1
2 (5
8%)
, 5
0% ly
sis:
2/1
2 (1
7%)
No
lysi
s: 3
/12
(25%
) B
leed
ing:
4/1
2 (3
3%)
Pl
aceb
o 1
hep
arin
(1
2 pa
tient
s)Pl
aceb
o 1
hep
arin
: ,
50%
lysi
s: 2
/12
(17%
) N
o ly
sis:
10/
12 (8
3%)
Ble
edin
g: 1
/12
(8%
)
Ph
ase
2: L
ysis
1 h
epar
in:
one-
chai
n rt
-PA
0.5
mg/
kg
IV fo
r 8
h an
d re
peat
ed
in 2
4 h
(29
patie
nts)
Phas
e 2:
L
ysis
1 h
epar
in:
� 5
0% ly
sis:
6/2
9 (2
1%)
, 5
0% ly
sis:
7/2
9 (2
4%)
No
lysi
s: 1
5/29
(52%
) B
leed
ing:
1/2
9 (3
%)
Pl
aceb
o 1
hep
arin
(30
pts)
Plac
ebo
1 h
epar
in
� 5
0% ly
sis:
2/3
0 (7
%)
, 5
0 ly
sis:
5/30
(17%
) N
o ly
sis:
23/
30 (7
7%)
Ble
edin
g: 1
/30
(3%
)
C
otre
atm
ent:
hepa
rin
5,00
0-un
it IV
bol
us th
en
30,0
00 u
nits
/24
h,
adju
sted
for
7-10
d
Schw
eize
r et
al 65
/199
8R
CT,
sin
gle
cent
er69
pat
ient
s w
ith
DV
T o
f , 7
drt
-PA
20
mg
IV in
to p
edal
ve
in 4
h/d
for
7 d;
hep
arin
IV
giv
en c
onco
mita
ntly
; w
arfa
rin
day
7-12
mo
Uro
kina
se 1
00,0
00
Inte
rnat
iona
l Uni
ts/h
r IV
into
ped
al v
ein
cont
inuo
usly
7 d
; hep
arin
IV
7 d
; pla
smin
ogen
m
onito
red;
war
fari
n da
y 7-
12 m
o
7 d:
clo
t lys
is,
blee
ding
1 y:
PT
S sy
mpt
oms
7 d
and
1 y
rt-P
A:
Com
plet
e ly
sis:
6/2
2 (2
7%)
Ble
edin
g: 1
/22
(5%
) PT
S sy
mpt
oms:
14/
22 (6
4%)
Uro
kina
se:
Com
plet
e ly
sis:
11/
22 (5
0%)
Ble
edin
g: 1
/22
(5%
) PT
S sy
mpt
oms:
9/2
2 (4
1%)
Tabl
e S1
3—C
onti
nued
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Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
A
ntic
oagu
latio
n: h
epar
in I
V
adju
sted
for
7 d;
war
fari
n da
y 1-
12 m
o
Ant
icoa
gula
tion:
C
ompl
ete
lysi
s: 0
B
leed
ing:
0 P
TS
Sym
ptom
s: 1
5/22
(68%
)
Schw
eize
r et
al 66
/200
0R
CT,
m
ultic
ente
r25
0 pa
tient
s w
ith
DV
T o
f , 9
drt
-PA
: loc
oreg
iona
l rt-
PA
20 m
g/da
y fo
r 4
h th
roug
h pe
dal v
ein
for
4-7
d;
IV h
epar
in g
iven
si
mul
tane
ousl
y at
1,0
00
Inte
rnat
iona
l Uni
ts/h
, adj
uste
d
Clo
t lys
is,
blee
ding
, m
orta
lity
1 y
rt-P
A:
Com
plet
e ly
sis:
10/
50 (2
0%)
� 5
0% ly
sis:
7/5
0 (1
4%)
, 5
0% ly
sis:
16/
50 (3
2%)
No
lysi
s: 1
3/50
(26%
) B
leed
ing:
2/5
0 (4
%)
U
roki
nase
: loc
oreg
iona
l ur
okin
ase
100,
000
Inte
rnat
iona
l Uni
ts in
fuse
d co
ntin
uous
ly; fi
bri
noge
n an
d pl
asm
inog
en m
onito
red;
IV
hep
arin
giv
en c
onco
mita
ntly
Uro
kina
se:
Com
plet
e ly
sis:
10/
50 (2
0%)
� 5
0% ly
sis:
9/5
0 (1
8%)
, 5
0% ly
sis:
17/
50 (3
4%)
No
lysi
s: 1
1/50
(22%
) B
leed
ing:
1/5
0 (2
%)
Sy
stem
ic S
K: 3
mill
ion
units
/d
for
6 h
with
hep
arin
for
up to
7
d. P
rem
edic
atio
ns:
hydr
ocor
tison
e 10
0 m
g,
rani
tidin
e 50
mg,
cl
emas
tine
2 m
g
Syst
emic
SK
: C
ompl
ete
lysi
s: 2
0/50
(40%
) �
50%
lysi
s: 7
/50
(14%
) ,
50%
lysi
s: 1
3/50
(26%
) N
o ly
sis:
8/5
0 (1
6%)
Ble
edin
g: 5
/50
(10%
) PE
: 5/5
0 (1
0%)
Sy
stem
ic u
roki
nase
: 5 m
illio
n In
tern
atio
nal U
nits
/d fo
r 4
h up
to 7
d; I
V h
epar
in g
iven
co
ncom
itant
ly
Syst
emic
uro
kina
se:
Com
plet
e ly
sis:
17/
50 (3
4%)
� 5
0% ly
sis:
10/5
0 (2
0%)
, 5
0% ly
sis:
13/
50 (2
6%)
No
lysi
s: 8
/50
(16%
) B
leed
ing:
4/5
0 (8
%)
PE: 4
/50
(8%
)
Ant
icoa
gula
tion:
hep
arin
IV,
ad
just
ed.
C
otre
atm
ent:
bed
rest
, co
mpr
essi
on b
anda
ges,
co
mpr
essi
on th
erap
y,
war
fari
n fo
r 12
mo
See
Tabl
e S1
, S2,
and
S11
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Fou
r de
aths
, oth
er c
ause
s, tw
o lo
st to
follo
w-u
p.
b Fou
r de
aths
, tw
o PE
s, tw
o ot
her
caus
es.
Tabl
e S1
3—C
onti
nued
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Table S14 —[Section 2.10] Systemic Lysis vs No Systemic Lysis for Extensive Acute DVT of the Leg: Methods
Author/Year Randomization Allocation concealment Blinding Loss to follow-up
Browse et al 52 /1968 N/A N/A N/A 0
Robertson et al 53 /1968 Patients given consecutive code numbers and divided into equal groups of 2—not truly randomized
Labels on SK and heparin coded
Y, data assessors; unclear for patients, caregivers, analysts
0
Kakkar et al 54 /1969 Sequential sealed envelope Adequate Y, patients No, caregivers, assessors, analysts
0
Tsapogas et al 55 /1973 Sealed envelope Adequate Not blinded 0
Duckert et al 56 /1975 N/A N/A N/A N/A
Porter et al 57 /1975 Assigned at random to one of two groups
N/A N/A N/A
Marder et al 58 /1977 Assigned at random to one of two groups. Five-day follow-up venograms were not performed in 3 of the SK patients, so an additional 3 patients were added to SK group in nonrandomized fashion.
Unclear Not blinded 23
Arnesen et al 59 /1978 Assigned at random to either group by sealed envelope
Adequate Y, radiologic assessors No, patients, caregivers, analysts
0
Elliot et al 60 /1979 Assigned at random to one of two groups
Unclear Y, assessors N, patients, caregivers, analysts
N/A
Watz et al 61 /1979 N/A N/A N/A N/A
Kiil et al 62 /1981 Assigned at random to either group
Unclear Y, assessors, analysts N, patients, caregivers
0
Arnesen et al 63 /1982 N/A N/A Evaluator blinded 7
Schulman et al 49 /1986 Assigned at random to either group by sealed envelope
Adequate Single blind 0
Verhaeghe et al 51 /1989 Assigned at random to one of three groups
Unclear Y, patients, assessors N, caregivers, analysts
0
Goldhaber et al 64 /1990 Assigned at random to one of three groups through sealed envelope
2:2:1 allocation scheme
Not blinded 0
Turpie et al 50 /1990 Assigned at random to one of two groups in each phase of study
Unclear Y, patients, assessors N, caregivers, analysts
37
Schweizer et al 65 /1998 Assigned at random to one of three groups
Adequate Y, assessors N, patients, caregivers, analysts
1
Schweizer et al 66 /2000 Assigned at random to one of fi ve groups
Unclear Single blind—not sure who 12
Y 5 yes. See Table S5 and S12 legends for expansion of other abbreviations.
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Tabl
e S1
5 —[S
ecti
on 2
.10]
Evi
denc
e P
rofi l
e: S
yste
mic
Lys
is v
s N
o Sy
stem
ic L
ysis
for
Ext
ensi
ve A
cute
DV
T o
f th
e L
eg
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith N
o Sy
stem
ic L
ysis
With
Sy
stem
ic
Lys
isR
elat
ive
Eff
ect
(95%
CI)
Ris
k W
ith
No
Syst
emic
L
ysis
Ris
k D
iffer
ence
W
ith S
yste
mic
L
ysis
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me)
688
(5 s
tudi
es),
3 m
o a N
o se
riou
s ri
sk
of b
ias b
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ss c,
d Ve
ry s
erio
us e
Und
etec
ted
Low
b-e d
ue to
im
prec
isio
n5/
233
(2.1
)4/
455
(0.9
)R
R 0
.86
(0.2
7-2.
68)
21 p
er 1
,000
3 fe
wer
per
1,
000
(fro
m
16 fe
wer
to
36 m
ore)
Non
fata
l rec
urre
nt V
TE
(cri
tical
out
com
e)
687
(3 s
tudi
es),
3 m
o f N
o se
riou
s ri
sk
of b
ias g
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ss d
Very
ser
ious
e U
ndet
ecte
dL
ow d,
e,g d
ue to
im
prec
isio
n2/
233
(0.9
)10
/454
(2.2
)R
R 1
.28
(0.2
5-6.
68)
48 p
er 1
,000
h 13
mor
e pe
r 1,
000
(fro
m
36 fe
wer
to
273
mor
e)
Non
fata
l maj
or b
leed
ing
(cri
tical
out
com
e)
688
(10
stud
ies)
, 3
mo f
No
seri
ous
risk
of
bia
s i N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
c,d
Seri
ous
Und
etec
ted
Mod
erat
e c,d,
i due
to
impr
ecis
ion
10/2
34 (4
.3)
38/4
54 (8
.4)
RR
1.8
4 (0
.94-
3.59
)29
per
1,0
00 h,
j 24
mor
e pe
r 1,
000
(fro
m
2 fe
wer
to 7
5 m
ore)
(C
onti
nued
)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith N
o Sy
stem
ic L
ysis
With
Sy
stem
ic
Lys
isR
elat
ive
Eff
ect
(95%
CI)
Ris
k W
ith
No
Syst
emic
L
ysis
Ris
k D
iffer
ence
W
ith S
yste
mic
L
ysis
(95%
CI)
Post
thro
mbo
tic s
yndr
ome
(cri
tical
out
com
e)
678
(2 s
tudi
es),
2 y k
Seri
ous l,m
N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
d3 Se
riou
s e4
Und
etec
ted
Low
d,e,
l,m d
ue to
ri
sk o
f bia
s,
impr
ecis
ion
24/2
30 (1
0.4)
27/4
48 (6
)R
R 0
.71
(0.4
9-1.
04)
588
per
1,00
0 n 171
few
er p
er
1,00
0 (f
rom
30
0 fe
wer
to
24 m
ore)
o
Qua
lity
of li
fe n
ot m
easu
red
……
……
……
……
…-
……
Bib
liogr
aphy
: Wat
son
et a
l. 47 W
e ex
clud
ed E
lsha
raw
y et
al 36
fro
m t
he a
naly
sis
beca
use
it us
ed c
athe
ter
dire
cted
thr
ombo
lysi
s. 36
We
iden
tifi e
d no
stu
dies
pub
lishe
d si
nce
the
sear
ch d
ate
of t
he s
yste
mat
ic
revi
ew. S
ee T
able
S1,
S10
, and
S11
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Ran
ge o
f fol
low
-up
in in
clud
ed s
tudi
es, 1
to 7
2 m
o.
b Allo
catio
n co
ncea
led
in t
hree
of
fi ve
stud
ies.
Fol
low
-up
inad
equa
te in
one
of
fi ve
(Com
mon
et
al 48
). E
xclu
ding
thi
s st
udy
from
the
ana
lysi
s do
es n
ot c
hang
e th
e ef
fect
est
imat
e. A
ll st
udie
s ha
d bl
inde
d ou
tcom
e as
sess
ors.
Non
e of
the
stud
ies
used
a p
lace
bo c
ontr
ol.
c The
pop
ulat
ion
of o
ne s
tudy
(Sch
ulm
an e
t al 49
) con
sist
ed o
f pat
ient
s w
ith c
alf v
ein
thro
mbo
sis.
d I
nter
vent
ions
var
ied
acro
ss s
tudi
es w
ith r
egar
d to
age
nt (e
g, tP
A, S
K, u
roki
nase
), do
se, u
se o
f the
ped
al v
ein
adm
inis
trat
ion,
dur
atio
n of
trea
tmen
t, an
d co
ncom
itant
dru
gs (e
g, s
tero
ids)
. How
ever
, we
did
not d
owng
rade
for
indi
rect
ness
giv
en th
at th
ere
is n
o st
anda
rd r
egim
en, a
nd a
ll an
alys
es s
how
ed n
o he
tero
gene
ity in
res
ults
. e C
I in
clud
ed b
oth
no e
ffec
t and
a p
oten
tially
sig
nifi c
ant e
ffec
t. f R
ange
of f
ollo
w-u
p in
incl
uded
stu
dies
, 1 to
30
d.
g Allo
catio
n co
ncea
led
in tw
o of
thre
e st
udie
s. F
ollo
w-u
p ad
equa
te in
all
stud
ies.
All
stud
ies
had
blin
ded
outc
ome
asse
ssor
s. N
one
of th
e st
udie
s us
ed a
pla
cebo
con
trol
. h B
asel
ine
risk
s fo
r no
nfat
al r
ecur
rent
VT
E a
nd f
or m
ajor
ble
edin
g de
rive
d fr
om D
ouke
tis e
t al
. 39i A
lloca
tion
conc
eale
d in
sev
en o
f 10
stu
dies
. Fol
low
-up
inad
equa
te in
one
10
stud
ies
(Com
mon
et
al 48
). E
xclu
ding
this
stu
dy fr
om th
e an
alys
is d
oes
not a
ffec
t the
eff
ect e
stim
ate.
All
stud
ies
had
blin
ded
outc
ome
asse
ssor
s. T
wo
stud
ies
used
pla
cebo
(Tur
pie
et a
l; 50
Verh
aegh
e et
al 51
). j O
nly
4% o
f all
maj
or b
leed
ing
even
ts w
ere
intr
acra
nial
ble
eds.
k R
ange
of f
ollo
w-u
p in
incl
uded
stu
dies
: 1 to
6 y
. l A
lloca
tion
conc
eale
d in
two
of tw
o st
udie
s. F
ollo
w-u
p ad
equa
te in
all
stud
ies.
All
stud
ies
had
blin
ded
outc
ome
asse
ssor
s. N
one
of th
e st
udie
s us
ed p
lace
bo c
ontr
ol.
m N
o us
e of
a s
tand
ardi
zed
valid
ated
tool
rep
orte
d.
n Thi
s es
timat
e is
bas
ed o
n th
e fi n
ding
s of
the
VE
TO
(Ven
ous
Thr
ombo
sis
Out
com
es) s
tudy
. 40 T
his
prob
ably
und
eres
timat
es P
TS
base
line
risk
giv
en th
at o
vera
ll, 5
2% o
f pat
ient
s re
port
ed th
e cu
rren
t use
of
com
pres
sion
sto
ckin
gs d
urin
g st
udy
follo
w-u
p.
o Sev
ere
PTS:
ass
umin
g th
e sa
me
RR
of 0
.71
and
a ba
selin
e ri
sk o
f 13.
8%, 40
the
abso
lute
red
uctio
n is
40
few
er s
ever
e PT
S pe
r 1,
000
(fro
m 7
0 fe
wer
to 6
mor
e) o
ver
2 y.
Tabl
e S1
5—C
onti
nued
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
28© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S1
6 —[2
.11]
Evi
denc
e P
rofi l
e: S
urg
ical
Thr
omb
ecto
my
Vs
No
Surg
ical
Thr
omb
ecto
my
for
Ext
ensi
ve A
cute
DV
T o
f th
e L
eg a
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Surg
ical
T
hrom
bect
omy
With
Sur
gica
l T
hrom
bect
omy
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
No
Surg
ical
T
hrom
bect
omy
Ris
k D
iffer
ence
W
ith S
urgi
cal
Thr
ombe
ctom
y (9
5% C
I)
Mor
talit
y no
t rep
orte
d
……
……
……
...…
……
......
Non
fata
l rec
urre
nt V
TE
(cri
tical
out
com
e)
51 (1
stu
dy),
3 m
oSe
riou
s b N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
c Ve
ry s
erio
us c
Und
etec
ted
Low
b,c d
ue to
ri
sk o
f bia
s,
impr
ecis
ion
1/27
(3.7
) d 0/
24 (0
)R
R 0
.37
(0.0
2-8.
75)
48 p
er 1
,000
d,e
30 fe
wer
per
1,
000
(fro
m
47 fe
wer
to
372
mor
e)
Non
fata
l maj
or b
leed
ing
(cri
tical
out
com
e)
51 (1
stu
dy),
3 m
oSe
riou
s b N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Very
ser
ious
c U
ndet
ecte
dSe
e co
mm
ent
0/27
(0)
0/24
(0) f
Not
est
imab
leSe
e co
mm
ent
…
PTS
(cri
tical
out
com
e)
51 (1
stu
dy),
2 y
Seri
ous g
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s h U
ndet
ecte
dL
ow g,
h due
to
risk
of b
ias,
im
prec
isio
n
25/2
7 (9
2.6)
14/2
4 (5
8.3)
RR
0.6
3 (0
.44-
0.9)
i 58
8 pe
r 1,
000 j
218
few
er p
er
1,00
0 (f
rom
59
few
er to
32
9 fe
wer
) k
Qua
lity
of li
fe n
ot m
easu
red
……
……
……
……
…-
……
Bib
liogr
aphy
: Pla
te e
t al. 67
See
Tab
le S
1, S
5, a
nd S
10 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a T
he s
tudy
incl
uded
pat
ient
s w
ith D
VT
with
sym
ptom
s of
leg
swel
ling
not e
xcee
ding
7 d
and
a p
roxi
mal
ext
ensi
on o
f the
thro
mbu
s ab
ove
the
ingu
inal
liga
men
t, bu
t not
into
the
vena
cav
a.
b Not
cle
ar w
heth
er a
lloca
tion
was
con
ceal
ed. N
o bl
indi
ng r
epor
ted.
Not
cle
ar w
heth
er a
naly
sis
was
IT
T. F
ollo
w-u
p ra
te 8
8% a
t 6 m
o. S
tudy
not
sto
pped
ear
ly fo
r be
nefi t
. c C
I in
clud
es v
alue
s su
gges
ting
eith
er h
arm
or
bene
fi t.
d One
eve
nt, w
hich
was
a s
ympt
omat
ic P
E.
e Bas
elin
e ri
sks
for
nonf
atal
rec
urre
nt V
TE
der
ived
from
Dou
ketis
et a
l. 39
f No
seve
re b
leed
ing
com
plic
atio
ns w
ere
reco
rded
in e
ither
gro
up. T
hree
pat
ient
s in
thro
mbe
ctom
y gr
oup
deve
lope
d lo
cal w
ound
hem
atom
a.
g In
addi
tion
to o
ther
stu
dy li
mita
tions
, thi
s ou
tcom
e w
as a
sses
sed
by th
ose
who
did
the
surg
ery
and
antic
oagu
latio
n. N
o st
anda
rdiz
ed to
ol w
as u
sed.
One
sur
gica
l pat
ient
had
an
ampu
tatio
n se
cond
ary
to
veno
us g
angr
ene
and
was
not
cou
nted
in th
e PT
S as
sess
men
t. h F
ew n
umbe
r of
eve
nts.
Thi
s w
arra
nts
ratin
g do
wn
the
qual
ity o
f evi
denc
e by
a s
econ
d le
vel w
hen
cons
ider
ed a
long
with
stu
dy li
mita
tions
. i T
he R
R is
bas
ed o
n th
e 6-
mo
data
. j T
his
estim
ate
is b
ased
on
the
fi ndi
ngs
of th
e V
ET
O (V
enou
s T
hrom
bosi
s O
utco
mes
stu
dy. 40
Thi
s pr
obab
ly u
nder
estim
ates
PT
S ba
selin
e ri
sk g
iven
that
ove
rall,
52%
of p
atie
nts
repo
rted
the
curr
ent u
se o
f co
mpr
essi
on s
tock
ings
dur
ing
stud
y fo
llow
-up.
k S
ever
e PT
S: a
ssum
ing
the
sam
e R
R o
f 0.6
3 an
d a
base
line
risk
of 1
3.8%
ove
r 2
y, 40
the
abso
lute
red
uctio
n is
51
few
er s
ever
e PT
S pe
r 1,
000
(fro
m 1
4 fe
wer
to 7
7 fe
wer
) ove
r 2
y.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
29© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S1
7 —[S
ecti
on 2
.11]
Su
rgic
al T
hrom
bec
tom
y vs
No
Surg
ical
Thr
omb
ecto
my
for
Ext
ensi
ve A
cute
DV
T o
f th
e L
eg: C
lini
cal
Des
crip
tion
and
Res
ult
s (A
ll R
ando
miz
ed T
rial
s an
d P
rosp
ecti
ve O
bse
rvat
iona
l St
udi
es o
f at
Lea
st 2
0 P
atie
nts)
Aut
hor/
Year
Type
of P
ublic
atio
nPa
rtic
ipan
tsIn
terv
entio
nsO
utco
mes
Fol
low
-up
Res
ults
Plat
e et
al 67
/198
4R
CT,
mul
ticen
ter
58 p
atie
nts
with
acu
te
iliof
emor
al v
enou
s th
rom
bosi
s
Med
ical
: 5,0
00-u
nit b
olus
hep
arin
fo
llow
ed b
y 50
0 un
its/k
g pe
r 24
h a
djus
ted
to a
PTT,
and
ora
l an
ticoa
gula
tion
(31
patie
nts)
PTS
sequ
elae
: ilio
fem
oral
pa
tenc
y, v
alve
com
pete
nce
6 m
oM
edic
al:
PTS
sequ
elae
: 25/
27 (9
3%)
Ilio
fem
oral
pat
ency
: 9/2
6 (3
5%)
Valv
e co
mpe
tenc
e: 7
/27
(26%
) (P
E in
1 p
atie
nt)
Su
rgic
al: o
pera
tive
veno
us th
rom
-be
ctom
y w
ith te
mpo
rary
AV
F
plus
ant
icoa
gula
tion
as a
bove
(2
7 pa
tient
s)
Surg
ical
: PT
S se
quel
ae: 1
4/24
(58%
, P ,
.005
) Il
iofe
mor
al p
aten
cy: 1
6/21
(76%
, P ,
.025
) Va
lve
com
pete
nce:
13/
23, (
52%
P ,
.05)
(ven
ous
gang
rene
in 1
pat
ient
)
Ein
arss
on e
t al 68
/198
6Pr
ospe
ctiv
e re
gist
ry70
pat
ient
s (7
1 le
gs) w
ith
iliof
emor
al D
VT
(age
of
clot
mea
n, 3
d)
Ilio
fem
oral
ven
ous
thro
mbe
ctom
y w
ith te
mpo
rary
AV
F c
lose
d at
6-8
wk,
hep
arin
pre
oper
ativ
ely
and
post
oper
ativ
ely
plus
w
arfa
rin
post
oper
ativ
ely
Veno
us p
aten
cy, h
emat
oma,
AV
F p
aten
cy, P
E, w
ound
in
fect
ion
56 d
(mea
n)Pa
tent
ilia
c ve
in: 8
8%
Hem
atom
a: 1
1%
AVF
pat
ency
: 86%
PE
: 4%
W
ound
infe
ctio
n: 2
6%:
Ein
arss
on e
t al 69
/198
657
pat
ient
s (5
8 lim
bs) w
ith
prio
r op
erat
ive
veno
us
thro
mbe
ctom
y an
d AV
F
clos
ed a
t 6-8
wk
for
iliof
emor
al D
VT
Clin
ical
PT
S, v
enog
raph
y,
veno
us p
ress
ure,
ve
nous
ple
thys
mog
raph
y,
foot
vol
umet
ry
Veno
us in
suffi
cien
cy:
Goo
d, fa
ir, p
oor
9-10
mo
Veno
us in
suffi
cien
cy:
Goo
d: 7
5%
Fai
r: 2
0%
Poor
: 5%
Ve
nogr
aphy
(vei
n se
gmen
t):
Nor
mal
, pos
tthr
ombo
tic,
occl
uded
Veno
grap
hy (i
liofe
mor
al):
Nor
mal
: 61%
Po
stth
rom
botic
: 23%
O
cclu
ded:
39%
Veno
us p
ress
ure:
Nor
mal
, ab
norm
alIV
pre
ssur
e:
Nor
mal
: 82%
A
bnor
mal
: 18%
Plet
hysm
ogra
phy:
Nor
mal
, ab
norm
alPl
ethy
smog
raph
y:
Nor
mal
: 29%
A
bnor
mal
: 71%
Foo
t vol
umet
ry: N
orm
al,
abno
rmal
Foo
t vol
umet
ry:
Nor
mal
: 29%
A
bnor
mal
: 71%
Plat
e et
al 70
/199
0F
ive-
year
follo
w-
up to
RC
T (P
late
, 19
8467
)
41/5
8 pa
tient
s (2
2 m
edic
al,
19 s
urgi
cal)
avai
labl
e fo
r ev
alua
tion
at 5
y
Prio
r tr
eatm
ent:
Med
ical
: an
ticoa
gula
tion
alon
e vs
Su
rgic
al: o
pera
tive
veno
us
thro
mbe
ctom
y pl
us
antic
oagu
latio
n
PTS
sequ
elae
, ilia
c pa
tenc
y,
veno
us p
ress
ure
5 y
Med
ical
: PT
S se
quel
ae: 6
/22
(27%
) Il
iac
pate
ncy:
11/
22 (5
0%)
Veno
us p
ress
ure:
60
mm
Hg
(mea
n)
(Con
tinu
ed)
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Aut
hor/
Year
Type
of P
ublic
atio
nPa
rtic
ipan
tsIn
terv
entio
nsO
utco
mes
Fol
low
-up
Res
ults
Su
rgic
al:
PTS
sequ
elae
: 2/1
9 (1
1%)
Ilia
c pa
tenc
y: 1
5/19
(78%
) Ve
nous
pre
ssur
e: 4
3 m
m H
g (m
ean,
P ,
.05)
Neg
lén
et a
l 71 /1
991
Pros
pect
ive
regi
stry
48 p
atie
nts
with
ilio
fem
oral
D
VT
of 1
-14
dO
pera
tive
veno
us th
rom
bect
omy
with
tem
pora
ry A
VF
(c
lose
d 6-
12 w
k po
stop
erat
ive)
Pate
ncy,
PE
, clin
ical
sy
mpt
oms,
nor
mal
ph
otop
leth
ysm
ogra
phy,
su
cces
sful
AV
F c
losu
re
24 m
o (m
ean)
Pate
ncy:
Il
iofe
mor
al: 8
8%
Popl
iteal
: 94%
PE
: 16%
sym
ptom
atic
, 31%
asym
ptom
atic
Sym
ptom
-fre
e: 8
1%
Nor
mal
pho
topl
ethy
smog
raph
y
(no
refl u
x): 5
6% A
VF
clo
sure
su
cces
s ra
te: 8
7%
A
djun
ctiv
e th
erap
y: tr
ansv
enou
s pe
rcut
aneo
us d
ilata
tion
of
seve
re il
iac
sten
osis
(3 p
atie
nts)
Plat
e et
al 72
/199
7Te
n-ye
ar fo
llow
-up
to R
CT
(Pla
te,
1984
[10]
and
19
90 [2
0])
30/5
8 pa
tient
s (1
7 fr
om
med
ical
arm
, 13
from
su
rgic
al a
rm) a
vaila
ble
for
eval
uatio
n
Prio
r tr
eatm
ent M
edic
al:
antic
oagu
latio
n al
one
vs S
urgi
cal:
oper
ativ
e ve
nous
thro
mbe
ctom
y pl
us a
ntic
oagu
latio
n
PTS
sequ
elae
, ilia
c pa
tenc
y,
veno
us p
ress
ure
10 y
Med
ical
: PT
S se
quel
ae: 1
5/17
(88%
) Il
iac
pate
ncy:
7/1
7 (4
1%)
Veno
us p
ress
ure:
63
mm
Hg
(mea
n)
Su
rgic
al:
PTS
sequ
elae
: 7/1
3 (5
4%)
Ilia
c pa
tenc
y: 1
0/12
(83%
) Ve
nous
pre
ssur
e: 5
5 m
m H
g (m
ean)
Ear
ly p
rosp
ectiv
e ob
serv
atio
nal s
tudi
es w
ith ,
20
patie
nts
and
retr
ospe
ctiv
e st
udie
s ar
e de
scri
bed
in T
able
5 o
f th
e ei
ghth
edi
tion
of t
hese
gui
delin
es. 46
See
Tab
le S
1, S
2, S
4, S
10, a
nd S
11 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
.
Tabl
e S1
7—C
onti
nued
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Table S18 —[Section 2.11 ] Surgical Thrombectomy vs No Surgical Thrombectomy for Extensive Acute DVT of the Leg: Methodologic Quality
Author/Year Randomization Allocation Concealment Blinding Loss to Follow-up
Plate et al 67 /1984 ND PN N, patients, caregivers, assessors, and data analysts
7
Einarsson et al 68 /1986 N/A N/A N/A N/A
Einarsson et al 69 /1986 N/A N/A N/A N/A
Plate et al 70 /1990 N/A N/A N/A 17
Neglén et al 71 /1991 N/A N/A N/A N/A
Plate et al 72 /1997 N/A N/A N/A 28
See Table S5 and S12 legends for expansion of abbreviations.
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Tabl
e S1
9 —[S
ecti
on 2
.13]
Evi
denc
e P
rofi l
e: V
ena
Cav
a F
ilte
r vs
No
Ven
a C
ava
Fil
ter
for
Acu
te P
roxi
mal
DV
T o
f th
e L
eg T
reat
ed W
ith
Ant
icoa
gula
tion
a,b
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Vena
Cav
a F
ilter
sW
ith V
ena
Cav
a F
ilter
s
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith N
o Ve
na C
ava
Filt
ers
Ris
k D
iffer
ence
W
ith V
ena
Cav
a F
ilter
s (9
5% C
I)
Mor
talit
y (im
port
ant o
utco
me)
400
(1 s
tudy
), 8
yN
o se
riou
s ri
sk
of b
ias c
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s d U
ndet
ecte
dM
oder
ate c,
d due
to
impr
ecis
ion
103/
200
(51.
5)98
/200
(49.
0)R
R 0
.95
(0.7
8-1.
16) e
515
per
1,00
026
few
er p
er 1
,000
(f
rom
113
few
er
to 8
2 m
ore)
Sym
ptom
atic
PE
(cri
tical
out
com
e)
304
(1 s
tudy
), 8
yN
o se
riou
s ri
sk
of b
ias c
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s f U
ndet
ecte
dM
oder
ate c,
f due
to
impr
ecis
ion
24/1
59 (1
5.1)
9/14
5 (6
.2)
RR
0.4
1 (0
.2-0
.86)
g 15
1 pe
r 1,
000
89 fe
wer
per
1,0
00
(fro
m 2
1 fe
wer
to
121
few
er)
Rec
urre
nt D
VT
(im
port
ant o
utco
me)
310
(1 s
tudy
), 8
yN
o se
riou
s ri
sk
of b
ias c
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s f U
ndet
ecte
dM
oder
ate c,
f due
to
impr
ecis
ion
41/1
50 (2
7.3)
57/1
60 (3
5.6)
RR
1.3
(0
.93-
1.82
) h 27
3 pe
r 1,
000
82 m
ore
per
1,00
0 (f
rom
19
few
er
to 2
24 m
ore)
Maj
or b
leed
ing
(impo
rtan
t out
com
e)
337
(1 s
tudy
), 8
yN
o se
riou
s ri
sk
of b
ias c
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s d U
ndet
ecte
dM
oder
ate c,
d due
to
impr
ecis
ion
31/1
68 (1
8.5)
26/1
69 (1
5.4)
RR
0.8
3 (0
.52-
1.34
) i 18
5 pe
r 1,
000
31 fe
wer
per
1,0
00
(fro
m 8
9 fe
wer
to
63
mor
e)
(Con
tinu
ed)
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Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Vena
Cav
a F
ilter
sW
ith V
ena
Cav
a F
ilter
s
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith N
o Ve
na C
ava
Filt
ers
Ris
k D
iffer
ence
W
ith V
ena
Cav
a F
ilter
s (9
5% C
I)
PTS
(impo
rtan
t out
com
e)
308
(1 s
tudy
), 8
ySe
riou
s j N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous d
Und
etec
ted
Low
d,j d
ue to
ri
sk o
f bia
s,
impr
ecis
ion
107/
153
(69.
9)10
9/15
5 (7
0.3)
RR
0.8
7 (0
.66-
1.13
)69
9 pe
r 1,
000
91 fe
wer
per
1,0
00
(fro
m 2
38 fe
wer
to
91
mor
e)
Com
plic
atio
ns (i
mpo
rtan
t out
com
e)
379
(1 s
tudy
), 2
yN
o se
riou
s ri
sk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s f U
ndet
ecte
dM
oder
ate f d
ue to
im
prec
isio
n0/
186
(0)
0/19
3 (0
)…
……
k
Qua
lity
of li
fe n
ot r
epor
ted
……
……
……
……
…-
……
Bib
liogr
aphy
: Dec
ousu
s et
al, 8 T
he P
RE
PIC
Inv
estig
ator
s. 73
See
Tab
le S
1, S
2, S
5, a
nd S
10 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a F
our
type
s of
per
man
ent
vena
cav
a fi l
ters
wer
e us
ed: V
ena
Tech
LG
M (
B. B
raun
Mel
suge
n A
G),
titan
ium
Gre
enfi e
ld (
Bos
ton
Scie
ntifi
c C
orpo
ratio
n), C
ardi
al (
C.R
. Bar
d, I
nc),
and
Bir
d’s
Nes
t (C
ook
Gro
up I
ncor
pora
ted)
. b A
ntic
oagu
latio
n co
nsis
ted
of L
MW
H o
r U
FH
initi
ally
(acc
ordi
ng to
a 2
3 2
fact
oria
l des
ign)
follo
wed
by
oral
ant
icoa
gula
tion
for
at le
ast 3
mo.
c A
lloca
tion
conc
eale
d. D
ata
colle
ctor
s an
d ou
tcom
e ad
judi
cato
rs b
linde
d. I
TT
ana
lysi
s. D
ata
mis
sing
for
4%
at
2 y
and
1% a
t 8
y. E
nrol
lmen
t w
as s
topp
ed a
t 40
0 in
stea
d of
tar
gete
d 80
0 du
e to
slo
w
recr
uitm
ent.
d CI
incl
udes
bot
h ne
glig
ible
eff
ect a
nd a
ppre
ciab
le b
enefi
t or
app
reci
able
har
m.
e RR
, 1.0
(95%
CI,
0.2
9-3.
4) a
t 12
d; R
R, 1
.08
(95%
CI,
0.7
3-1.
58) a
t 2 y
. f S
mal
l num
ber
of e
vent
s.
g RR
, 0.2
3 (9
5% C
I, 0
.05-
1.05
) at 1
2 d
(bot
h sy
mpt
omat
ic a
nd a
sym
ptom
atic
PE
). R
R, 0
.54
(95%
CI,
0.2
1-1.
41) a
t 2 y
(sym
ptom
atic
PE
) h R
R, 1
.78
(95%
CI,
1.0
9-2.
94) a
t 2 y
. i R
R, 1
.5 (9
5% C
I, 0
.54-
4.14
) at 1
2 d.
RR
, 0.7
4 (9
5% C
I, 0
.41-
1.36
) at 2
y.
j No
stan
dard
ized
val
idat
ed to
ol u
sed
to m
easu
re P
TS.
k N
o co
mpl
icat
ions
dir
ectly
rel
ated
to
the
fi lte
r or
its
inse
rtio
n re
port
ed in
the
PR
EPI
C (
Prev
entio
n du
Ris
que
d’E
mbo
lie P
ulm
onai
re p
ar I
nter
rupt
ion
Cav
e) t
rial
. 8 M
ism
etti
et a
l 74 (
pros
pect
ive
stud
y)
repo
rted
an
inci
denc
e of
3.2
% (
excl
udin
g fi l
ter
tilt
ing
and
punc
ture
sit
e he
mat
oma)
am
ong
220
pati
ents
rec
eivi
ng r
etri
evab
le v
ena
cava
fi lt
er f
or s
econ
dary
pre
vent
ion
of V
TE
, w
here
as w
hile
A
than
asou
lis e
t al 75
(ret
rosp
ectiv
e st
udy)
rep
orte
d an
inci
denc
e of
0.3
% fo
r m
ajor
com
plic
atio
ns a
mon
g 1,
731
patie
nts
rece
ivin
g ve
na c
ava
fi lte
rs p
redo
min
antly
for
seco
ndar
y pr
even
tion
of V
TE
.
Tabl
e 19
—C
onti
nued
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S2
0 —[S
ecti
on 2
.14]
Evi
denc
e P
rofi l
e: E
arly
Am
bu
lati
on v
s D
elay
ed A
mb
ula
tion
for
Acu
te D
VT
of
the
Leg
a,b
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Ove
rall
Qua
lity
of E
vide
nce
With
Del
ayed
A
mbu
latio
nW
ith E
arly
A
mbu
latio
n
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
Del
ayed
A
mbu
latio
n
Ris
k D
iffer
ence
W
ith E
arly
A
mbu
latio
n (9
5% C
I)
Mor
talit
y (im
port
ant o
utco
me)
385
(4 s
tudi
es),
3 m
o c Se
riou
s d N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Very
se
riou
s e U
ndet
ecte
dL
ow d,
e due
to
risk
of b
ias,
im
prec
isio
n
2/18
6 (1
.1)
3/19
9 (1
.5)
RR
1.3
(0.2
3-7.
55)
11 p
er 1
,000
3 m
ore
per
1,00
0 (f
rom
8
few
er to
70
mor
e)
PE (c
ritic
al o
utco
me;
ass
esse
d w
ith s
ympt
omat
ic o
r as
ympt
omat
ic P
E)
385
(4 s
tudi
es),
4-12
dSe
riou
s d N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
f Se
riou
s e U
ndet
ecte
d g L
ow d-
g due
to
risk
of b
ias,
im
prec
isio
n
22/1
86 (1
1.8)
27/1
99 (1
3.6)
RR
1.1
6 (0
.66-
2.05
)11
8 pe
r 1,
000
19 m
ore
per
1,00
0 (f
rom
40
few
er to
124
mor
e)
Qua
lity
of li
fe (i
mpo
rtan
t out
com
e; m
easu
red
with
qua
lity
of li
fe q
uest
ionn
aire
in c
hron
ic li
mb
veno
us in
suffi
cien
cy [C
IVIQ
]; be
tter
indi
cate
d by
low
er v
alue
s)
53 (1
stu
dy ),
2 y
Seri
ous h
No
seri
ous
inco
nsis
tenc
ySe
riou
s i N
o se
riou
s im
prec
isio
nU
ndet
ecte
dL
ow h,
i due
to
risk
of b
ias,
in
dire
ctne
ss
1736
-Se
e fo
otno
te j
PTS
(impo
rtan
t out
com
e; a
sses
sed
with
Vill
ata-
Pran
doni
sco
re [v
alue
. 5
])
37 (1
stu
dy) 2
ySe
riou
s h N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous e
Und
etec
ted
Low
e,h d
ue to
ri
sk o
f bia
s,
impr
ecis
ion
9/11
(81.
8)14
/26
(53.
8)R
R 0
.66
(0.4
2-1.
03)
Mod
erat
e
400
per
1,00
013
6 fe
wer
per
1,0
00 (f
rom
23
2 fe
wer
to 1
2 m
ore)
Bib
liogr
aphy
: Kah
n et
al, 76
Ais
saou
i et a
l. 77 I
nclu
ded
stud
ies.
78-8
2 See
Tab
le S
1, S
2, S
5, a
nd S
10 le
gend
s ex
pans
ion
of o
ther
abb
revi
atio
ns.
a In
two
of f
our
elig
ible
tri
als,
all
patie
nts
rece
ived
ear
ly c
ompr
essi
on t
hera
py (
band
ages
or
stoc
king
s). I
n th
e tw
o ot
her
tria
ls, o
nly
patie
nts
rand
omiz
ed t
o ea
rly
ambu
latio
n re
ceiv
ed e
arly
com
pres
sion
th
erap
y.
b Tw
o of
four
elig
ible
stu
dies
exc
lude
d pa
tient
s w
ith s
ympt
omat
ic P
E; i
n th
e th
ird
stud
y, 2
4% o
f par
ticip
ants
had
sym
ptom
atic
PE
at b
asel
ine.
It w
as n
ot c
lear
whe
ther
the
four
th s
tudy
exc
lude
d pa
tient
s w
ith s
ympt
omat
ic P
E.
c Thr
ee s
tudi
es r
epor
ting
acut
e ph
ase
mor
talit
y re
port
ed n
o de
aths
. d C
once
alm
ent o
f allo
cati
on re
port
ed in
one
of f
our s
tudi
es; b
lindi
ng o
f out
com
e as
sess
ors r
epor
ted
in tw
o of
four
stud
ies;
IT
T a
naly
sis r
epor
ted
in tw
o of
four
stud
ies.
Fol
low
-up
97%
-100
%. I
n tw
o of
fo
ur tr
ials
, onl
y pa
tient
s ra
ndom
ized
to e
arly
am
bula
tion
rece
ived
ear
ly c
ompr
essi
on th
erap
y (b
anda
ges
or s
tock
ings
). In
the
two
othe
r tr
ials
, all
patie
nts
rece
ived
ear
ly c
ompr
essi
on th
erap
y.
e CI
incl
udes
bot
h va
lues
of c
linic
ally
sig
nifi c
ant b
enefi
t an
d va
lues
of c
linic
ally
sig
nifi c
ant h
arm
s.
f PE
ass
esse
d as
bot
h sy
mpt
omat
ic a
nd a
sym
ptom
atic
PE
. g F
unne
l plo
t rep
orte
d as
not
asy
mm
etri
cal b
y A
issa
oui e
t al. 77
h C
once
alm
ent o
f allo
catio
n no
t rep
orte
d, o
utco
me
asse
ssor
s no
t blin
ded
for
this
out
com
e; 7
0% fo
llow
-up
rate
; com
pres
sion
sto
ckin
gs u
sed
on p
atie
nts
with
ear
ly m
obili
zatio
n bu
t in
patie
nts
with
del
ayed
m
obili
zatio
n.
iNo
expl
anat
ion
was
pro
vide
d.
j Psy
chol
ogic
and
ove
rall
som
atic
qua
lity
of li
fe d
id n
ot d
iffer
sig
nifi c
antly
bet
wee
n th
e tr
eatm
ent g
roup
s, w
here
as D
VT-
rela
ted
item
s, e
spec
ially
thos
e re
fl ect
ing
the
ease
of l
ocom
otio
n, s
how
ed s
igni
fi can
tly
grea
ter
impr
ovem
ent w
ith c
ompr
essi
on th
an w
ith b
ed r
est (
P ,
.001
for
band
ages
, P ,
.05
for
stoc
king
s).
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Tabl
e S2
1 —[S
ecti
on 2
.14]
Ear
ly A
mb
ula
tion
vs
Del
ayed
Am
bu
lati
on f
or A
cute
DV
T o
f th
e L
eg: C
lini
cal
Des
crip
tion
and
Res
ult
s
Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Sche
llong
et a
l 82 /1
999
RC
T, s
ingl
e ce
nter
126
patie
nts
with
ac
ute
prox
imal
D
VT
Am
bula
tion:
leg
elev
atio
n un
til
day
2, th
en a
mbu
latio
n an
d co
mpr
essi
on (6
4 pa
tient
s)
PE b
y /
sca
n10
dA
mbu
latio
n: P
E: 1
0/59
(17%
)
B
ed r
est f
or 8
d w
ith le
g el
evat
ion
and
com
pres
sion
(6
2 pa
tient
s)
Bed
Res
t: PE
: 14/
63 (2
2%)
Part
sch
et a
l 81 /2
000
RC
T,
mul
ticen
ter
45 p
atie
nts
with
pr
oxim
al D
VT
,
14
d du
ratio
n
Am
bula
tion
1 b
anda
ges:
in
elas
tic U
nna
boot
ba
ndag
es p
lus
wal
king
ex
erci
ses
(15
patie
nts)
Wal
king
dis
tanc
e, p
ain
leve
ls, l
eg c
ircu
mfe
renc
e,
clin
ical
sco
res,
PE
, sid
e ef
fect
s
9 d
Sum
mar
y re
sults
bet
wee
n gr
oups
: Wal
king
dis
tanc
e, p
ain,
le
g ci
rcum
fere
nce
and
clin
ical
sco
res
sign
ifi ca
ntly
impr
oved
in
gro
ups
A a
nd B
com
pare
d w
ith g
roup
C
A
mbu
latio
n 1
sto
ckin
gs:
elas
tic c
ompr
essi
on
stoc
king
s pl
us w
alki
ng
exer
cise
s (1
5 pa
tient
s)
PE, g
roup
A: 2
/15
(13%
) PE
, gro
up B
: 1/1
5 (7
%)
PE, g
roup
C: 1
/15
(7%
)
B
ed r
est,
no c
ompr
essi
on,
LM
WH
(15
patie
nts)
Asc
hwan
den
et a
l 78 /2
001
RC
T, s
ingl
e ce
nter
129
patie
nts
with
ac
ute
DV
TA
mbu
latio
n �
4 h
/d fo
r 4
d un
der
supe
rvis
ion,
LM
WH
(6
9 pa
tient
s)
New
PE
bet
wee
n ba
selin
e an
d da
y 4
by
/ s
can
3 m
oA
mbu
latio
n: P
E: 1
0/69
(14%
)
B
ed r
est f
or 4
d (6
0 pa
tient
s)B
ed r
est:
PE: 6
/60
(10%
)
Not
e: n
ew P
Es
wer
e as
ympt
omat
ic; 1
2/16
pat
ient
s ha
d ba
selin
e PE
s
Part
sch
et a
l 83 /2
001
Pros
pect
ive
stud
y1,
289
patie
nts
with
ac
ute
DV
TA
ll tr
eate
d w
ith L
MW
H,
com
pres
sion
, and
im
med
iate
am
bula
tion
PE o
n /
sca
n at
ad
mis
sion
and
aft
er
10 d
of t
reat
men
t,
10 d
PE a
t adm
issi
on: 6
29/1
,270
(50%
) PE
at 1
0 d:
77/
1,25
6 (6
1%)
Not
e: in
itial
lung
sca
ns w
ere
perf
orm
ed in
1,2
70/1
,289
pat
ient
s;
follo
w-u
p sc
ans
wer
e pe
rfor
med
in 1
,256
/1,2
89 p
atie
nts
Blä
ttle
r et
al 79
/200
3R
CT
53 p
atie
nts
with
pr
oxim
al D
VT
Am
bula
tion
1 b
anda
ges:
fi r
m in
elas
tic b
anda
ges,
am
bula
tion
(18
patie
nts)
Am
bula
tion
1 s
tock
ings
: el
astic
com
pres
sion
st
ocki
ngs,
am
bula
tion
(18
patie
nts)
Wal
king
dis
tanc
e,
wel
l-bei
ng, a
nd
DV
T-re
late
d qu
ality
of
life,
leg
pain
by
visu
al
anal
og s
cale
, ede
ma,
cl
inic
al s
core
s, th
rom
bus
prog
ress
ion
9 d
Wel
l-bei
ng/q
ualit
y of
life
: Im
prov
ed w
ith s
tock
ings
( P ,
.05)
, ba
ndag
es ( P
, .0
1)
Leg
pai
n: D
ecre
ased
fast
er d
urin
g fi r
st 4
d w
/ ban
dage
s an
d st
ocki
ngs
vs b
ed r
est (
P ,
.01)
; nea
r ab
senc
e of
pai
n at
9 d
ach
ieve
d w
ith b
anda
ges
only
(Con
tinu
ed)
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Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
B
ed r
est o
nly
(17
patie
nts)
Ede
ma:
Mar
ked
redu
ctio
n in
leg
size
with
ban
dage
s an
d st
ocki
ngs
vs b
ed r
est (
P ,
.001
)
Clin
ical
sco
res:
Im
prov
ed w
ith b
anda
ges
and
stoc
king
s vs
bed
re
st ( P
, .0
01)
T
hrom
bus
prog
ress
ion:
Im
prov
ed w
ith b
anda
ges
and
stoc
king
s vs
bed
res
t ( P
, .0
1)
PE
: No
diff
eren
ce b
etw
een
grou
ps
Part
sch
et a
l 84 /2
004
2-y
follo
w-u
p to
RC
T (7
7)37
pat
ient
s fo
llow
ed u
p 2
y po
st-R
CT
Ant
icoa
gula
tion
and
bed
rest
vs
antic
oagu
latio
n an
d am
bula
tion
with
com
pres
sion
ba
ndag
es o
r st
ocki
ngs
PTS
asse
ssm
ent
(Vill
alta
-Pra
ndon
i sca
le)
2 y
PTS
scor
es: A
mbu
lato
ry g
roup
(mea
n sc
ore,
5.1
) had
impr
oved
ou
tcom
e vs
bed
res
t gro
up (m
ean
scor
e, 8
.2; P
, .0
1)
Pa
in a
sses
smen
t by
visu
al
anal
og s
cale
and
mod
ifi ed
L
owen
berg
test
Pain
: Low
er p
ain
leve
ls in
mob
ile g
roup
vs
bed
rest
(ns)
T
hrom
bus
regr
essi
onT
hrom
bus
exte
nsio
n: N
o di
ffer
ence
in th
rom
bus
regr
essi
on o
f th
rom
bus
rem
nant
s be
twee
n gr
oups
Truj
illo-
Sant
os e
t al 85
/200
5
Pros
pect
ive
stud
y2,
650
patie
nts
with
ac
ute
DV
T
(2,0
38 [7
7%])
or
PE (6
12 [2
3%])
DV
T g
roup
, bed
res
t or
ambu
latio
n: 1
,050
(52%
) pa
tient
s re
ceiv
ed b
ed r
est,
and
988
(48%
) am
bula
ted.
A
ll re
ceiv
ed L
MW
H.
PE g
roup
, bed
res
t or
ambu
latio
n: 3
85 (6
3%)
patie
nts
rece
ived
bed
res
t, an
d 22
7 (3
7%) a
mbu
late
d.
All
rece
ived
LM
WH
.
Sym
ptom
atic
, con
fi rm
ed
PE d
urin
g fi r
st 1
5 d
of
ther
apy
3 m
oD
VT
gro
up, b
ed r
est:
PE: 7
/105
0 (0
.7%
) D
VT
gro
up, a
mbu
late
: PE
: 4/9
88 (0
.4%
) PE
gro
up, b
ed r
est:
PE: 2
/385
(0.5
%)
PE g
roup
, am
bula
te: P
E: 2
/227
(0.9
%)
Jüng
er e
t al 80
/200
6R
CT,
mul
ticen
ter
open
des
ign
stra
tifi e
d by
age
103
patie
nts
with
pr
oxim
al D
VT
Bed
res
t: 50
pat
ient
s re
ceiv
ed
5 d
of s
tric
t bed
res
t, L
MW
H, c
ompr
essi
on
band
ages
.
PE, p
rogr
essi
on o
f or
new
th
rom
bosi
s, in
fect
ion
or
seri
ous
adve
rse
even
t
5 d
New
PE
bed
res
t: 8/
50 (1
6%) a
mbu
latio
n: 2
/52
(4%
)
A
mbu
latio
n: 5
2 pa
tient
s am
bula
ted
for
5 d,
LM
WH
, co
mpr
essi
on b
anda
ges
Prim
ary
targ
et v
aria
ble:
Bed
res
t: 14
/50
(28%
) A
mbu
latio
n: 7
/52
(13%
)
ns 5
not
sig
nifi c
ant;
/ 5
vent
ilatio
n/pe
rfus
ion.
See
Tab
le S
2, S
5, a
nd S
10 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
Tabl
e S2
1—C
onti
nued
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Table S22 —[Section 2.14] Early Ambulation vs Delayed Ambulation for Acute DVT of the Leg: Methodologic Quality
Author/Year RandomizationAllocation
Concealment Blinding Loss to Follow-up
Schellong et al 82 /1999 Patients randomized to 1 of 2 study groups Unclear Y, assessors N, patients, caregivers, analysts
4
Partsch et al 81 /2000 Patients randomized to 1 of 3 study groups by sealed envelope
Unclear Y, assessors N, patients, caregivers, analysts
0
Aschwanden et al 78 /2001 Patients randomized to 1 of 2 study groups Sealed envelope Not blinded 5
Partsch et al 83 /200 N/A N/A N/A N/A
Blättler et al 79 /2003 Patients randomized to 1 of 3 study groups by sealed envelope
Not specifi ed Y, assessors N, patients, caregivers, analysts
0
Partsch et al 84 /2004 N/A N/A N/A 21
Trujillo-Santos et al 85 /2005 N/A N/A N/A N/A
Jünger et al 80 /2006 Patients randomized to 1 of 2 study groups by sealed envelope
Unclear Y, analysts N, patients, caregivers, assessors
See Table S5 and S12 legends for expansion of abbreviations.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S2
3 —[S
ecti
ons
3.1.
1-3.
1.4]
Evi
denc
e P
rofi l
e: F
our
or S
ix W
eeks
vs
Thr
ee o
r Si
x M
onth
s as
Min
imu
m D
ura
tion
of
Ant
icoa
gula
tion
for
VT
E a,b
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
up
Ris
k of
B
ias
Inco
nsis
tenc
yIn
dire
ctne
ssIm
prec
isio
nPu
blic
atio
n B
ias
Ove
rall
qual
ity o
f E
vide
nce
With
Con
trol
With
4 o
r 6
wk
vs 3
or
6 m
o of
A
ntic
oagu
latio
n
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
C
ontr
ol
Ris
k D
iffer
ence
With
4
or 6
wk
vs 3
or
6 m
o of
A
ntic
oagu
latio
n (9
5% C
I)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
2,18
5 (5
stu
dies
c ),
1-2
y d N
o se
riou
s ri
sk o
f bia
s e N
o se
riou
s in
cons
iste
ncy f
No
seri
ous
indi
rect
ness
No
seri
ous
impr
ecis
ion g
Und
etec
ted
Hig
h e-g
70/1
,090
(6.4
)12
7/1,
095
(11.
6)R
R 1
.83
(1.3
9-2.
42)
64 p
er 1
,000
53 m
ore
per
1,00
0 (f
rom
25
mor
e to
91
mor
e)
Maj
or b
leed
ing
(cri
tical
out
com
e)
2,18
5 (5
stu
dies
), 1-
2 yd
No
seri
ous
risk
of
bia
sN
o se
riou
s in
cons
iste
ncy f
No
seri
ous
indi
rect
ness
No
seri
ous
impr
ecis
ion
Und
etec
ted
Hig
h f 13
/1,0
90 (1
.2)
7/1,
095
(0.6
)R
R 0
.54
(0.2
2-1.
32)
12 p
er 1
,000
5 fe
wer
per
1,0
00 (f
rom
9
few
er to
4 m
ore)
Mor
talit
y (im
port
ant o
utco
me)
2,09
8 (5
stu
dies
), 1-
2 yd
No
seri
ous
risk
of
bia
s e N
o se
riou
s in
cons
iste
ncy f
No
seri
ous
indi
rect
ness
No
seri
ous
impr
ecis
ion h
Und
etec
ted
Hig
h e,f,h
55
/998
(5.5
)57
/1,1
00 (5
.2)
RR
0.9
7 (0
.68-
1.38
)55
per
1,0
002
few
er p
er 1
,000
(fro
m
18 fe
wer
to 2
1 m
ore)
Bib
liogr
aphy
: Kea
ron
et a
l, 86 P
ined
e et
al, 87
Sch
ulm
an e
t al, 88
Lev
ine
et a
l, 89 B
ritis
h T
hora
cic
Soci
ety.
90 S
ee T
able
S1,
S5,
and
S2
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Sho
rt v
s lo
nger
dur
atio
n of
ant
icoa
gula
tion
was
6 w
k vs
6 m
o fo
r Sc
hulm
an e
t al,
6 w
k vs
3 m
o fo
r Pi
nede
et a
l, an
d 4
wk
vs 3
mo
for
the
othe
r th
ree
stud
ies.
b P
opul
atio
ns v
arie
d am
ong
stud
ies:
fi rs
t pro
voke
d is
olat
ed d
ista
l DV
T, p
roxi
mal
DV
T o
r PE
pro
voke
d in
Kea
ron
et a
l; fi r
st is
olat
ed d
ista
l DV
T in
Pin
ede
et a
l; fi r
st is
olat
ed d
ista
l DV
T, p
roxi
mal
DV
T, o
r PE
in
Sch
ulm
an e
t al;
prox
imal
DV
T (2
1% h
ad c
ance
r) in
Lev
ine
et a
l; an
d D
VT
or
PE (2
9% n
ot o
bjec
tivel
y co
nfi r
med
) in
Bri
tish
Tho
raci
c So
ciet
y.
c Tim
ing
of ra
ndom
izat
ion
rela
tive
to th
e st
art o
f tre
atm
ent v
arie
d ac
ross
stud
ies:
Pin
ede
et a
l, Sc
hulm
an e
t al,
and
Bri
tish
Tho
raci
c So
ciet
y ra
ndom
ized
at d
iagn
osis
; Kea
ron
et a
l and
Lev
ine
et a
l ran
dom
ized
to
sto
p or
to c
ontin
ue tr
eatm
ent o
f 2 m
ore
mon
ths
afte
r th
e in
itial
4 w
k of
trea
tmen
t. e G
ener
ally
, stu
dy d
esig
n w
as s
tron
g. N
o st
udy
stop
ped
earl
y fo
r be
nefi t
; tw
o st
oppe
d ea
rly
beca
use
of s
low
rec
ruitm
ent (
Kea
ron
et a
l, Pi
nede
et a
l). I
n on
e st
udy
(Bri
tish
Tho
raci
c So
ciet
y), 4
4 ra
ndom
ized
pa
tient
s w
ere
excl
uded
cen
tral
ly a
s th
ey d
id n
ot s
atis
fy e
ligib
ility
cri
teri
a. P
atie
nts
and
care
give
rs w
ere
blin
ded
in tw
o st
udie
s (K
earo
n et
al,
Lev
ine
et a
l). A
djud
icat
ors
of o
utco
mes
wer
e bl
inde
d in
all
but
one
stud
y (B
ritis
h T
hora
cic
Soci
ety)
. All
stud
ies
appe
ared
to h
ave
used
eff
ectiv
e ra
ndom
izat
ion
conc
ealm
ent,
ITT
ana
lysi
s, a
nd a
ppea
rs to
hav
e a
low
une
xpla
ined
dro
p-ou
t fre
quen
cy.
f No
hete
roge
neity
with
I 2 5
0%
. g N
o im
prec
isio
n fo
r ov
eral
l est
imat
es. H
owev
er, f
or th
e su
bgro
up o
f pat
ient
s w
ith is
olat
ed d
ista
l DV
T, w
ho a
re k
now
n to
hav
e a
very
low
ris
k of
rec
urre
nce,
ther
e is
impr
ecis
ion
and
the
poss
ibili
ty th
at th
e sh
orte
r du
ratio
n of
ant
icoa
gula
tion
is a
dequ
ate
and
not a
ssoc
iate
d w
ith a
clin
ical
ly im
port
ant h
ighe
r ri
sk o
f rec
urre
nce.
d F
ollo
w-u
p w
as fo
r �
1 y
in a
ll st
udie
d ex
cept
for
Schu
lman
et a
l in
whi
ch it
was
2 y
. h D
iffer
ence
s in
mor
talit
y ar
e ex
pect
ed to
be
med
iate
d by
diff
eren
ces
in r
ecur
rent
VT
E a
nd b
leed
ing.
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Tabl
e S2
4 —[S
ecti
ons
3.1.
1-3.
1.4]
Com
pari
son
of D
ura
tion
s of
Ant
icoa
gula
nt T
hera
py f
or D
VT
and
PE
: Cli
nica
l D
escr
ipti
on a
nd R
esu
lts
Aut
hor/
Year
(Acr
onym
)In
terv
entio
nN
o. P
atie
nts
Ana
lyze
dL
engt
h F
ollo
w-u
pR
ecur
rent
DV
T o
r PE
Maj
or B
leed
ing
Tota
l Mor
talit
yC
omm
ents
Shor
t (4
or 6
wk)
vs
inte
rmed
iate
(3 o
r 6
mo)
dur
atio
ns o
f ant
icoa
gula
tion
Kea
ron
et a
l 86 /2
004
(SO
FAST
)V
KA
sto
pped
(pla
cebo
)84
/84
11 m
o5/
84 (6
%)
0/84
0/84
Popu
latio
n: fi
rst D
VT
or
PE.
Trea
ted
for
1 m
o. V
TE
was
as
ympt
omat
ic in
9%
and
isol
ated
ca
lf D
VT
in 1
8%. O
ne V
TE
oc
curr
ed w
hile
on
war
fari
n.
V
KA
(IN
R 2
.0-3
.0)
For
2 m
ore
mo.
81/8
111
mo
3/81
(4%
) RR
0.6
(0
.1-2
.5)
0/81
RR
1.0
(0
.0-5
1.6)
1/81
(1%
) RR
3.1
(0
.1-7
4.4)
Pine
de e
t al 87
/200
1 (D
OTA
VK
)V
KA
(IN
R 2
.0-3
.0)
for
1.5
mo
105/
105
15 m
o2/
105
(2%
)1/
105
(1%
)N
ot s
peci
fi ed
Popu
latio
n: fi
rst i
sola
ted
calf
DV
T.
V
KA
(IN
R 2
.0-3
.0)
for
3 m
o92
/92
3/92
RR
1.7
(0
.3-1
0.0)
3/92
RR
3.4
(0.4
-33.
4)
Schu
lman
et a
l 88 /1
995
(DU
RA
C 1
)V
KA
(IN
R 2
.0-2
.85)
fo
r 1.
5 m
o44
3/44
32
y80
/443
(18%
)1/
443
22/4
43 (5
%)
Fir
st V
TE
: DV
T (d
ista
l or
prox
imal
) or
PE
. Onl
y as
ked
abou
t ble
edin
g w
hile
on
VK
As.
VK
A (I
NR
2.0
-2.8
5)
for
6 m
o45
4/45
443
/454
(9%
) RR
0.5
(0
.4, 0
.7)
5/45
4 (1
%)
RR
4.9
(0.6
-41.
6)17
/454
(4%
) RR
(0
.7-1
.4)
Lev
ine
et a
l 89 /1
995
VK
A s
topp
ed (p
lace
bo)
105/
107
9 m
o12
/105
(11%
)0/
105
9/10
5 (9
%)
Prox
imal
DV
T (fi
rst
epi
sode
in
91%
). C
ance
r in
21%
.
VK
A (I
NR
2.0
-3.0
) fo
r 2
mor
e m
o.10
9/11
37/
109
(6%
) RR
0.6
(0
.2-1
.4)
1/10
9 (1
%) R
R 2
.9
(0.1
-70.
2) (w
ithin
2
mo
of r
ando
miz
atio
n)
9/10
9 (8
%) R
R 1
.0
(0.4
-2.5
)
Bri
tish
Tho
raci
c So
ciet
y et
al 90
/199
2V
KA
(IN
R 2
.0-3
.0)
For
1 m
o35
8/35
81
y28
/358
(11%
)5/
358
(1%
)26
/358
(7%
)Po
pula
tion:
DV
T o
r PE
; onl
y 71
%
obje
ctiv
ely
diag
nose
d; p
ropo
rtio
n w
ith a
pre
viou
s V
TE
not
kno
wn.
VK
A (I
NR
2.0
-3.0
) fo
r 3
mo
354/
354
1 y
14/3
54 (4
%) R
R
0.5
(0.3
-0.9
)
4/35
4 (1
%)
RR
0.8
(0.2
-3.0
)28
/354
(8) R
R 1
.1
(0.6
-1.8
)A
ll bl
eeds
wer
e on
VK
A. O
nly
1 re
curr
ent V
TE
am
ong
116
patie
nts
with
pos
tope
rativ
e V
TE
. (C
onti
nued
)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
40© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Aut
hor/
Year
(Acr
onym
)In
terv
entio
nN
o. P
atie
nts
Ana
lyze
dL
engt
h F
ollo
w-u
pR
ecur
rent
DV
T o
r PE
Maj
or B
leed
ing
Tota
l Mor
talit
yC
omm
ents
Diff
eren
t int
erm
edia
te d
urat
ions
(6 o
r 12
mo
vs 3
mo)
of a
ntic
oagu
latio
n
Cam
pbel
l et a
l 91 /2
007
VK
A (I
NR
2.0
.0-3
.5)
for
3 m
o36
9/39
61
y31
/369
(8%
)0/
369
(dur
ing
3 m
o.
trea
tmen
t)15
/369
(4%
)Po
pula
tion:
DV
T o
r PE
; pro
port
ion
with
cal
f DV
T n
ot k
now
n. O
nly
blee
ding
dur
ing
trea
tmen
t is
repo
rted
; 20%
of V
TE
out
com
es
wer
e no
t obj
ectiv
ely
veri
fi ed.
VK
A (I
NR
2.0
-3.5
) fo
r 6
mo
380/
414
1 y
29/3
80 (8
%) R
R0.
9 (0
.6-1
.5)
8/38
0 (2
%) (
duri
ng 6
mo.
tr
eatm
ent)
RR
16.
5 (1
.0-2
85)
19/3
69 (5
%) R
R 1
.3
(0.6
-2.5
)
Agn
elli
et a
l 92 /2
003
(WO
DIT
PE
)V
KA
sto
pped
91/9
12.
6 y
(mea
n)11
/91
(12%
)1/
91 (1
%)
7/91
(8%
)Po
pula
tion:
fi rs
t unp
rovo
ked
PE.
Trea
ted
for
� 3
mo.
Am
ong
the
4 gr
oups
, onl
y 1
recu
rren
t VT
E
whi
le o
n V
KA
.
VK
A (I
NR
2.0
-3.0
) fo
r 9
mor
e m
o90
/90
2.9
y (m
ean)
11/9
0 (1
2%) R
R 1
.0
(0.5
-2.2
)2/
90 (2
%) R
R 2
.0
(0.5
-21.
9)8/
90 (9
%) R
R 1
.16
(0.4
-3.0
)
V
KA
sto
pped
70/7
02.
8 y
(mea
n)7/
70 (1
0%)
0/70
(0%
)0/
70 (0
%)
Popu
latio
n: fi
rst p
rovo
ked
PE.
Trea
ted
for
� 3
mo
(see
abo
ve)
V
KA
(IN
R 2
.0-3
.0)
for
3 m
ore
mo
75/7
52.
9 y
(mea
n)4/
75 (5
%) R
R 0
.5
(0.2
-1.7
)1/
75 (1
%) R
R 1
.9
(0.1
-56)
4/75
(5%
) RR
8.4
(0
.5-1
53)
Agn
elli
et a
l 93 /2
001
(WO
DIT
DV
T)
VK
A s
topp
ed13
3/13
33.
2 y
(mea
n)21
/133
(16%
)2/
133
(2%
)7/
133
(5%
)Po
pula
tion:
fi rs
t unp
rovo
ked
prox
-im
al D
VT
trea
ted
for
3 m
o. O
ne
patie
nt h
ad r
ecur
rent
VT
E o
n V
KA
. Ble
edin
g in
the
inte
rven
-tio
n gr
oup
was
whi
le o
n V
KA
.
VK
A (I
NR
2.0
-3.0
) fo
r 9
mo
134/
134
3.1
y (m
ean)
21/1
34 (1
6%) R
R 1
.0
(0.6
-1.7
)4/
134
(3%
) RR
2.0
(0
.4-1
0.7)
7/13
4 (5
%) R
R 1
.0
(0.4
-2.8
)
Pine
de e
t al 87
/200
1 (D
OTA
VK
)V
KA
(IN
R 2
.0-3
.0)
for
3 m
o27
0/27
015
mo
21/2
70 (8
%)
5/27
0 (2
%)
Not
spe
cifi e
dPo
pula
tion:
fi rs
t pro
xim
al D
VT
or
PE. R
ecur
rent
VT
E o
ccur
red
afte
r V
KA
in 2
6/28
of t
he s
hort
du
ratio
n gr
oups
and
21/
27 o
f the
lo
ng d
urat
ion
grou
ps.
V
KA
(IN
R 1
.0-3
.0)
for
6 m
o26
9/26
923
/269
(9%
) RR
1.1
(0
.6-1
.9)
7/26
9 (3
%))
RR
1.4
(0
.4-4
.4)
Sira
gusa
et a
l 94 /2
008
(DA
CU
S)V
KA
sto
pped
92/9
21.
8 y
27/9
2 (2
9%)
1/92
(1%
)N
ot s
peci
fi ed
(tot
al o
f 3 n
on-
VT
E/b
leed
dea
ths)
Popu
latio
n: fi
rst p
roxi
mal
DV
T
(pro
voke
d, 2
4%; u
npro
voke
d,
76%
) tre
ated
for
3 m
o an
d re
sidu
al D
VT
on
base
line
ultr
asou
nd
Tabl
e S2
4—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
41© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Aut
hor/
Year
(Acr
onym
)In
terv
entio
nN
o. P
atie
nts
Ana
lyze
dL
engt
h F
ollo
w-u
pR
ecur
rent
DV
T o
r PE
Maj
or B
leed
ing
Tota
l Mor
talit
yC
omm
ents
Inde
fi nite
vs
inte
rmed
iate
dur
atio
ns o
f ant
icoa
gula
tion
(IN
R �
2.0
-3.0
)
Pala
reti
et a
l 95 /2
006
(PR
OL
ON
G)
Rem
ain
off (
stop
) VK
A10
3/10
51.
4 y
(mea
n)18
/120
(15%
)0/
103
1/10
3 (1
%)
Popu
latio
n: fi
rst u
npro
voke
d pr
ox-
imal
DV
T o
r PE
. Tre
ated
for
� 3
m
o. V
KA
sto
pped
and
D-d
imer
po
sitiv
e 1
mo
late
r. E
ight
con
trol
pa
tient
. Res
tart
ed V
KA
, som
e af
ter
supe
rfi c
ial p
hleb
itis.
One
re
curr
ent V
TE
in V
KA
gro
up
afte
r V
KA
sto
pped
.
Res
tart
inde
fi nite
VK
A
(IN
R 2
.0-3
.0) (
not
blin
ded)
120/
122
(max
imum
, 1.
5 y)
2/10
3 (2
%) R
R 0
.1
(0.0
-0.4
)1/
120
(1%
) RR
2.6
(0
.1-6
2.6)
1/12
0 (1
%) R
R 0
.9
(0.1
-13.
6)
Kea
ron
et a
l 96 /1
999
(LA
FIT
)V
KA
sto
pped
(pla
cebo
)83
/83
10 m
o (m
ean)
17/8
3 (2
0%)
0/83
3/83
(4%
)Po
pula
tion:
fi rs
t unp
rovo
ked
prox
imal
DV
T o
r PE
(5%
had
pr
evio
us p
rovo
ked
VT
E).
The
re
curr
ent V
TE
in th
e V
KA
pa
tient
was
aft
er s
topp
ing
VK
A.
V
KA
(IN
R 2
.0-3
.0) f
or 2
m
ore
year
s79
/79
(max
imum
, 2 y
)1/
79 (1
%) R
R 0
.1
(0.0
-0.5
)3/
79 (4
%) R
R 7
.4 (0
.4-1
40)
1/79
(1%
) RR
0.3
(0
.0-3
.3)
Schu
lman
et a
l 97 /1
997
(DU
RA
C 2
)V
KA
(IN
R 2
.0-2
.85)
for
6 m
o11
1/11
14
y23
/111
(2%
)3/
111
(3%
)16
/111
(14%
)Se
cond
VT
E: D
VT
(dis
tal o
r pr
ox-
imal
) or
PE. A
ll re
curr
ent V
TE
in
the
inde
fi nite
VK
A g
roup
wer
e af
ter
stop
ping
VK
As.
Ble
edin
g du
ring
the
fi rst
6 m
o of
VK
A in
1
of 6
mo
grou
p an
d 6
of in
defi n
ite
grou
p (o
nly
aske
d ab
out b
leed
ing
whi
le o
n V
KA
s).
V
KA
(IN
R 2
.0-2
.85)
in
defi n
itely
116/
116
3/11
6 (3
%) R
R 0
.1
(0.0
-0.4
)10
/116
(9%
) RR
3.2
(0
.9-1
1.3)
10/1
16 (9
%) R
R 0
.6
(0.3
-1.3
)
Far
raj e
t al 98
/200
4V
KA
(IN
R 2
.0-3
.0) f
or
6 m
o32
/36
3 y
7/32
(22%
)2/
32 (6
%)
0/32
In to
tal:
2 V
TE
aft
er 2
4 m
o (2
4 m
o gr
oup)
; 1 V
TE
on
ther
apy
(24
mo
grou
p)
V
KA
(IN
R 2
.0-2
.85)
for
24 m
o32
/36
3/32
(3%
) RR
0.4
(0
.1-1
.5)
2/32
(6%
) RR
1.0
(0
.2-6
.7)
0/32
Tabl
e S2
4—C
onti
nued
(Con
tinu
ed)
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Aut
hor/
Year
(Acr
onym
)In
terv
entio
nN
o. P
atie
nts
Ana
lyze
dL
engt
h F
ollo
w-u
pR
ecur
rent
DV
T o
r PE
Maj
or B
leed
ing
Tota
l Mor
talit
yC
omm
ents
Fix
ed v
s fl e
xibl
e du
ratio
n, d
epen
ding
on
pres
ence
of r
esid
ual t
hrom
bosi
s on
follo
w-u
p ul
tras
ound
(IN
R 2
.0-3
.0)
Pran
doni
et a
l 99 /2
009
(AE
SOPU
S)V
KA
sto
pped
if p
rovo
ked
and
3 m
ore
mon
ths
if un
prov
oked
268/
268
33 m
o46
/268
(17%
)2/
268
(1%
)11
/268
(4%
)Po
pula
tion:
fi rs
t pro
voke
d (4
3%)
or u
npro
voke
d (5
7%) p
roxi
mal
D
VT
trea
ted
for
3 m
o. O
ne V
TE
in
eac
h gr
oup
whi
le o
n V
KA
s.
The
fl ex
ible
gro
up w
as tr
eate
d fo
r a
mea
n of
4 m
o (p
rovo
ked)
and
5
mo
(unp
rovo
ked)
long
er.
St
oppe
d if
no r
esid
ual v
ein
thro
mbo
sis
and
until
re
solv
ed o
r 9
mor
e m
o if
prov
oked
or
21 m
ore
mo
if un
prov
oked
270/
270
32/2
70 (1
2%) R
R 0
.7
(0.4
-1.1
)4/
270/
255
(1%
) R
R 2
.0 (0
.4-1
0.8)
4/25
5 (6
%) R
R 1
.5
(0.7
-3.2
)
Inde
fi nite
vs
inte
rmed
iate
dur
atio
ns o
f ant
icoa
gula
tion
(IN
R �
1.5
-2.0
, aft
er in
itial
IN
R 2
.0-3
.0 in
bot
h gr
oups
)
Rid
ker
et a
l 100 /2
003
(PR
EV
EN
T)
VK
A s
topp
ed o
r no
t re
star
ted
(pla
cebo
)25
3/25
32.
1 y
(mea
n)37
/253
(15%
)2/
253
(1%
)8/
253
(3%
)Po
pula
tion:
unp
rovo
ked
DV
T
(dis
tal o
r pr
oxim
al) o
r PE
(fi r
st
epis
ode
in 3
8%).
Eig
ht r
ecur
rent
V
TE
in th
e V
KA
gro
up a
fter
st
oppi
ng V
KA
s.
V
KA
IN
R 1
.5-2
.025
5/25
5(m
axim
um,
4.3
y)14
/255
(5%
) RR
0.4
(0
.2-0
.7)
5/25
5 (2
%) R
R 2
.5
(0.5
-12.
7)4/
255
(2%
) R
R 0
.5 (0
.1-1
.6)
Low
inte
nsity
(IN
R 1
.5-1
.9) v
s co
nven
tiona
l int
ensi
ty (I
NR
2.0
-3.0
)
Kea
ron
et a
l 101 /2
003
(EL
ATE
)V
KA
IN
R 1
.5-1
.936
9/36
92.
4 y
(mea
n)16
/369
(4%
)9/
369
(2%
)16
/369
(4%
)Po
pula
tion:
unp
rovo
ked
prox
imal
D
VT
or
PE (fi
rst
epi
sode
in
31%
). Tr
eate
d fo
r �
3 m
o. V
KA
(I
NR
2.0
-3.0
) (m
ean
12 m
o). F
ive
recu
rren
t VT
E in
IN
R 1
.5-1
.9
and
thre
e in
the
INR
2.0
-3.0
gr
oup
afte
r st
oppi
ng V
KA
s.
V
KA
IN
R 2
.0-3
.0
(blin
ded)
369/
369
6/36
9 (2
%)R
R 0
.4
(0.1
-0.9
)8/
369
(2%
) RR
0.9
(0
.3-2
.3)
8/36
9 (2
%) R
R 0
.5
(0.2
-1.2
)
AE
SOPU
S 5
Ultr
asou
nd F
indi
ngs
to A
djus
t the
Dur
atio
n of
Ant
icoa
gula
tion;
DA
CU
S 5
Dur
atio
n of
Ant
icoa
gula
tion
base
d on
Com
pres
sion
Ultr
aSon
ogra
phy;
DO
TAV
K 5
Dur
ée O
ptim
ale
du T
raite
men
t A
ntiV
itam
ines
K; D
UR
AC
5 D
urat
ion
of A
ntic
oagu
latio
n; E
LAT
E 5
Ant
icoa
gula
tion
for
Thr
ombo
-Em
bolis
m; L
AF
IT 5
Lon
g-te
rm A
ntic
oagu
latio
n fo
r a
Fir
st e
piso
de o
f Idi
opat
hic
veno
us T
hrom
boem
-bo
lism
; PR
EV
EN
T 5
Pre
vent
ion
of R
ecur
rent
Ven
ous
Thr
ombo
embo
lism
; SO
FAST
5 F
irst
Acu
te S
econ
dary
Thr
ombo
sis;
WO
DIT
DV
T 5
War
fari
n O
ptim
al D
urat
ion
Ital
ian
Tria
l in
patie
nts
with
DV
T;
WO
DIT
PE
5 W
arfa
rin
Opt
imal
Dur
atio
n It
alia
n Tr
ial i
n pa
tient
s w
ith P
ulm
onar
y E
mbo
lism
. See
Tab
le S
1, S
2, a
nd S
7 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
Tabl
e S2
4—C
onti
nued
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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(Con
tinu
ed)
Tabl
e S2
5 —[S
ecti
ons
3.1.
1-3.
1.4]
Com
pari
son
of D
ura
tion
s of
Ant
icoa
gula
nt T
hera
py f
or D
VT
and
PE
: Met
hodo
logi
c Q
ual
ity
Aut
hor/
Year
(Acr
onym
)In
terv
entio
nSt
udy
Des
ign
Ran
dom
izat
ion
Con
ceal
edB
lindi
ngL
oss
to F
ollo
w-u
pA
naly
sis
Com
men
ts
Kea
ron
et a
l 86 /2
004
(SO
FAST
)
VK
A s
topp
ed (p
lace
bo)
VK
A (I
NR
2.0
-3.0
)
for
2 m
ore
mo
RC
TC
YPa
tient
s: C
Y C
areg
iver
s: C
Y A
djud
icat
ions
: CY
Dat
a A
naly
sts:
CY
Plac
ebo:
0/8
4V
KA
: 0/8
1IT
TSt
oppe
d ea
rly
beca
use
of s
low
re
crui
tmen
t.
Pine
de e
t al 87
/200
1 (D
OT
AV
K)
VK
A (I
NR
2.0
-3.0
)
for
1.5
and
3 m
oV
KA
(IN
R 1
.0-3
.0) f
or
3
and
6 m
o
RC
TC
YPa
tient
s: C
N
Car
egiv
ers:
CN
A
djud
icat
ions
: CY
Dat
a A
naly
sts:
PN
Not
spe
cifi e
dPr
obab
ly lo
w o
r ni
lIT
TSt
oppe
d ea
rly
beca
use
of s
low
re
crui
tmen
t. Pa
tient
with
draw
als:
4
in s
hort
- and
16
in lo
ng-d
urat
ion
grou
ps. T
otal
of 2
2 pa
tient
s dr
oppe
d ou
t.
Schu
lman
et a
l 88 /1
995
(DU
RA
C 1
)V
KA
(IN
R2.
0-2.
85)
fo
r 1.
5 m
oV
KA
(IN
R 2
.0-2
.85)
for
6 m
o
RC
TC
YPa
tient
s: C
N
Car
egiv
ers:
CN
A
djud
icat
ions
: VT
E, C
Y O
ther
: PN
D
ata
Ana
lyst
s: P
N
Tota
l of 4
4 pa
tient
s
drop
ped
out d
urin
g fo
llow
-up
but p
artia
l fo
llow
-up
achi
eved
ITT
Fiv
e pa
tient
wer
e ex
clud
ed b
ecau
se
prot
ein
C fo
und
afte
r ra
ndom
izat
ion.
Lev
ine
et a
l 89 /1
995
VK
A s
topp
ed (p
lace
bo)
VK
A (I
NR
2.0
-3.0
)
for
2 m
ore
mo.
RC
TC
YPa
tient
s: C
Y C
areg
iver
s: C
Y A
djud
icat
ions
: VT
E, C
Y D
ata
Ana
lyst
s: P
N
Plac
ebo:
1/1
05
VK
A: 6
/109
(d
id n
ot c
ompl
ete
11
-mo
follo
w-u
p)
ITT
Two
plac
ebo
and
4 w
arfa
rin
patie
nts
with
drew
con
sent
sho
rtly
aft
er
rand
omiz
atio
n.
Bri
tish
Tho
raci
c So
ciet
y et
al 90
/199
2V
KA
(IN
R 2
.0-3
.0) F
or 1
mo
VK
A
(IN
R 2
.0-3
.0) f
or 3
mo
RC
TC
YPa
tient
s: C
N
Car
egiv
ers:
CN
A
djud
icat
ions
: CN
D
ata
Ana
lyst
s: P
N
No
VK
A: 2
7/35
4 V
KA
: 30/
358
ITT
For
ty-f
our
rand
omiz
ed p
atie
nts
excl
uded
cen
tral
ly a
s di
d no
t sat
isfy
en
try
crite
ria.
Cam
pbel
l et a
ll 91 /2
007
VK
A (I
NR
2.0
.0-3
.5) f
or 3
mo
VK
A (I
NR
2.0
-3.5
) for
6 m
oR
CT
CY
Patie
nts:
CN
C
areg
iver
s: C
N
Adj
udic
atio
ns: C
N
Dat
a A
naly
sts:
PN
3- m
o V
KA
: 6/3
69
6- m
o V
KA
: 4/3
80IT
TSi
xty-
one
rand
omiz
ed p
atie
nts
excl
uded
cen
tral
ly a
s di
d no
t sat
isfy
en
try
crite
ria.
Sto
pped
ear
ly b
ecau
se
of lo
w r
ecru
itmen
t.
Agn
elli
et a
l 92 /2
003
(WO
DIT
PE
)V
KA
sto
pped
VK
A (I
NR
2.0
-3.0
)
for
9 m
ore
mo.
RC
TC
YPa
tient
s: C
N
Car
egiv
ers:
CN
A
djud
icat
ions
: CY
Dat
a A
naly
sts:
PN
Not
spe
cifi e
d Pr
obab
ly lo
w o
r ni
lIT
TTw
o pa
tient
s in
the
cont
rol g
roup
s an
d 2
patie
nts
in th
e in
terv
entio
n gr
oups
cr
osse
d ov
er. F
ive
patie
nts
in th
e in
tend
ed g
roup
did
not
sto
p V
KA
. F
our
patie
nts
in th
e co
ntro
l gro
ups
rest
arte
d V
KA
s.
Agn
elli
et a
l 93 /2
001
(WO
DIT
DV
T)
VK
A s
topp
edV
KA
(IN
R 2
.0-3
.0) f
or 9
mo
RC
TC
YPa
tient
s: C
N
Car
egiv
ers:
CN
A
djud
icat
ions
: CY
Dat
a A
naly
sts:
PN
Not
spe
cifi e
d Pr
obab
ly lo
w o
r ni
lIT
TTr
ial s
topp
ed e
arly
for
lack
of a
dequ
ate
bene
fi t. F
our
patie
nts
in th
e in
terv
entio
n an
d 2
patie
nts
in th
e co
ntro
l gro
up c
ross
ed o
ver.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
44© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S2
5—C
onti
nued
Aut
hor/
Year
(Acr
onym
)In
terv
entio
nSt
udy
Des
ign
Ran
dom
izat
ion
Con
ceal
edB
lindi
ngL
oss
to F
ollo
w-u
pA
naly
sis
Com
men
ts
Sira
gusa
et a
l 94 /2
008
(DA
CU
S)V
KA
sto
pped
V
KA
(IN
R 1
.0-3
.0)
fo
r 9
mo.
RC
TPY
Patie
nts:
CN
C
areg
iver
s: C
N
Adj
udic
atio
ns: P
Y D
ata
Ana
lyst
s: P
N
Non
eIT
TN
ot k
now
n w
heth
er th
e m
any
post
enro
llmen
t exc
lusi
ons
wer
e po
stra
ndom
izat
ion.
Tri
al s
topp
ed
earl
y be
caus
e re
curr
ent V
TE
was
hi
gher
than
exp
ecte
d.
Pala
reti
et a
l 95 /2
006
(PR
OL
ON
G)
Rem
ain
off (
stop
) VK
AR
esta
rt in
defi n
itely
VK
A
(IN
R 2
.0-3
.0) (
not b
linde
d)
RC
TC
YPa
tient
s: C
N
Car
egiv
ers:
CN
A
djud
icat
ions
: CY
Dat
a A
naly
sts:
PN
No
VK
A: ,
3/1
05
VK
A: 0
/122
ITT
Fou
r pa
tient
s ex
clud
ed b
ecau
se
lupu
s an
ticoa
gula
nt fo
und
afte
r ra
ndom
izat
ion.
Kea
ron
et a
l 96 /1
999
(LA
FIT
)V
KA
sto
pped
(pla
cebo
)V
KA
(IN
R 2
.0-3
.0) f
or 2
mor
e y
RC
TC
YPa
tient
s: C
Y C
areg
iver
s: C
Y A
djud
icat
ions
: CY
Dat
a A
naly
sts:
CY
Non
eIT
TTr
ial s
topp
ed e
arly
bec
ause
of o
vera
ll be
nefi t
. Aft
er r
ecur
rent
VT
E,
patie
nts
wer
e no
t fol
low
ed. r
esul
ting
in s
hort
er fo
llow
-up
and
pote
ntia
l for
un
dere
stim
atio
n of
ble
edin
g in
the
no-V
KA
gro
up.
Schu
lman
et a
l 97 /1
997
(DU
RA
C 2
)V
KA
(IN
R 2
.0-2
.85)
for
6 m
oV
KA
(IN
R 2
.0-2
.85)
inde
fi nite
lyR
CT
CY
Patie
nts:
CN
C
areg
iver
s: C
N
Adj
udic
atio
ns: V
TE
, CY
Oth
er, P
N
Dat
a A
naly
sts:
PN
Tota
l of 1
4 pa
tient
s
drop
ped
out d
urin
g fo
llow
-up,
but
pa
rtia
l fol
low
-up
achi
eved
ITT
Act
ual m
ean
dura
tion
of V
KA
was
7.
7 m
o in
6-m
o gr
oup
and
42.7
mo
in in
defi n
ite (4
8 m
o) g
roup
.
Pran
doni
et a
l 99 /2
009
(AE
SOPU
S)V
KA
sto
pped
if p
rovo
ked
and
3
mor
e m
o if
unpr
ovok
edR
CT
CY
Patie
nts:
CN
C
areg
iver
s: C
N
Adj
udic
atio
ns: V
TE
, CY
Dat
a A
naly
sts:
PY
4 su
bjec
ts in
eac
h gr
oup
ITT
St
oppe
d if
no r
esid
ual v
ein
th
rom
bosi
s an
d un
til
reso
lved
or
9 m
ore
mo
if pr
ovok
ed o
r 21
mor
e m
o if
unpr
ovok
ed
Rid
ker
et a
l 100 /2
003
(PR
EV
EN
T)
VK
A s
topp
ed o
r no
t
rest
arte
d (p
lace
bo)
VK
A I
NR
1.5
-2.0
RC
TC
YPa
tient
s: C
Y C
areg
iver
s: C
Y A
djud
icat
ions
: CY
Dat
a A
naly
sts:
CY
Not
spe
cifi e
dIT
TTr
ial s
topp
ed e
arly
bec
ause
of o
vera
ll be
nefi t
. Num
ber
of c
ross
over
s no
t de
scri
bed.
Pr
obab
ly lo
w o
r ni
l
Far
raj e
t al 98
/200
4
VK
A (I
NR
2.0
-3.0
) for
6 m
o V
KA
(IN
R 2
.0-2
.85)
for
24 m
oR
CT
PYPa
tient
s: C
N
Car
egiv
ers:
CN
D
ata
Col
lect
ors:
PN
. A
djud
icat
ors:
PN
D
ata
Ana
lyst
s: P
N
0/32
ITT
Fou
r po
stra
ndom
izat
ion
excl
usio
ns
for
each
gro
up b
ecau
se o
f poo
r co
mpl
ianc
e.
0/32
(see
com
men
ts)
Kea
ron
et a
l 101 /2
003
(EL
ATE
)V
KA
IN
R 1
.5-1
.9 V
KA
IN
R 2
.0-3
.0 (b
linde
d)R
CT
CY
Patie
nts:
CY
Car
egiv
ers:
CY
Adj
udic
atio
ns: C
Y D
ata
Ana
lyst
s: C
Y
INR
1.5
-1.9
: � 1
/369
IN
R
1.5-
1.9:
� 1
/369
ITT
Cro
ssov
er to
IN
R 2
.0-3
.0 in
21
patie
nts
See
Tabl
e S1
, S2,
S7,
and
S24
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
45© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S2
6 —[S
ecti
ons
3.1.
1-3.
1.4]
Evi
denc
e P
rofi l
e: S
ix o
r Tw
elve
Mon
ths
vs T
hree
Mon
ths
as M
inim
um
Du
rati
on o
f A
ntic
oagu
lati
on f
or V
TE
a,b
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of E
vide
nce
With
3 m
oW
ith 6
or
12 m
oR
isk
With
3
mo
Ris
k D
iffer
ence
W
ith 6
or
12 m
o (9
5% C
I)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
2,06
1 (6
stu
dies
), 1-
3 y
No
seri
ous
risk
of b
ias c
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s d,e
Und
etec
ted
Mod
erat
e d-e
due
to
impr
ecis
ion
118/
1,02
5 (1
1.5)
105/
1,03
6 (1
0.1)
RR
0.8
9 (0
.69-
1.14
)11
5 pe
r 1,
000
13 fe
wer
per
1,0
00
(fro
m 3
6 fe
wer
to
16
mor
e)
Maj
or b
leed
ing
(cri
tical
out
com
e)
2,06
1 (6
stu
dies
), 1-
3 y
No
seri
ous
risk
of b
ias f
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dH
igh f
9/1,
025
(0.9
)24
/1,0
36 (2
.3)
RR
2.4
9 (1
.2-5
.16)
9 pe
r 1,
000
13 m
ore
per
1,00
0 (f
rom
2 m
ore
to
37 m
ore)
Mor
talit
y (im
port
ant o
utco
me g )
1,33
1 (5
stu
dies
), 1-
3 y
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s d U
ndet
ecte
dM
oder
ate d
due
to
impr
ecis
ion
29/6
63 (4
.4)
38/6
68 (5
.7)
RR
1.3
(0
.81-
2.08
)44
per
1,0
0013
mor
e pe
r 1,
000
(fro
m 8
few
er to
47
mor
e)
Bib
liogr
aphy
: Pin
ede
et a
l, 87 C
ampb
ell e
t al, 91
Agn
elli
et a
l, 93 A
gnel
li et
al, 92
Sir
agus
a. 94
See
Tab
le S
1, S
2, a
nd S
5 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a T
imin
g of
ran
dom
izat
ion
rela
tive
to th
e st
art o
f tre
atm
ent a
nd le
ngth
of t
reat
men
t in
the
non-
3-m
o gr
oup
vari
ed a
cros
s st
udie
s: P
ined
e et
al a
nd C
ampb
ell e
t al r
ando
miz
ed a
t dia
gnos
is, a
nd A
gnel
li et
al
rand
omiz
ed a
fter
the
initi
al 3
mo
of tr
eatm
ent t
o st
op, o
r con
tinue
, tre
atm
ent.
The
long
er d
urat
ion
of tr
eatm
ent w
as 6
mo
in P
ined
e, C
ampb
ell,
and
Agn
elli
et a
l (20
03) (
prov
oked
PE
), an
d 12
mo
in A
gnel
li (2
001)
and
Agn
elli
(200
3) (u
npro
voke
d PE
). b S
tudy
pop
ulat
ions
var
ied
acro
ss s
tudi
es: P
ined
e et
al e
nrol
led
prov
oked
and
unp
rovo
ked
prox
imal
DV
T a
nd P
E; C
ampb
ell e
t al e
nrol
led
prov
oked
and
unp
rovo
ked
isol
ated
dis
tal D
VT,
pro
xim
al D
VT
and
PE
; Agn
elli
et a
l (20
03) h
ad s
epar
ate
rand
omiz
atio
ns fo
r pr
ovok
ed P
E (3
vs
6 m
o) a
nd u
npro
voke
d (3
vs
12 m
o); a
nd A
gnel
li et
al (
2001
) enr
olle
d un
prov
oked
pro
xim
al D
VT.
c G
ener
ally
, stu
dy d
esig
n w
as s
tron
g. N
o st
udy
stop
ped
earl
y fo
r be
nefi t
; tw
o st
oppe
d ea
rly
beca
use
of s
low
rec
ruitm
ent (
Cam
pbel
l et a
l, Pi
nede
et a
l), a
nd o
ne s
topp
ed b
ecau
se o
f lac
k of
ben
efi t
(Agn
elli
et a
l [20
01])
. In
one
stud
y (C
ampb
ell),
20%
of V
TE
out
com
es w
ere
not o
bjec
tivel
y co
nfi r
med
. Pat
ient
s an
d ca
regi
vers
wer
e no
t blin
ded
in a
ny s
tudy
. Adj
udic
ator
s of
out
com
es w
ere
blin
ded
in a
ll bu
t one
st
udy
(Cam
pbel
l). A
ll st
udie
s us
ed e
ffec
tive
rand
omiz
atio
n co
ncea
lmen
t and
IT
T a
naly
sis
and
appe
ar to
hav
e a
low
une
xpla
ined
dro
p-ou
t fre
quen
cy.
d CIs
incl
ude
both
val
ues
sugg
estin
g no
eff
ect a
nd v
alue
s su
gges
ting
eith
er b
enefi
t or
har
m.
e Low
num
ber
of e
vent
s an
d a
tota
l num
ber
of p
artic
ipan
ts ,
2,0
00.
f One
stu
dy m
ay h
ave
confi
ned
the
asse
ssm
ent o
f ble
edin
g to
whe
n su
bjec
ts w
ere
rece
ivin
g an
ticoa
gula
nt th
erap
y, w
hich
cou
ld h
ave
infl a
ted
the
incr
ease
in b
leed
ing
asso
ciat
ed w
ith th
e lo
nger
dur
atio
n of
th
erap
y (C
ampb
ell e
t al).
g D
iffer
ence
s in
mor
talit
y ar
e ex
pect
ed to
be
med
iate
d by
diff
eren
ces
in r
ecur
rent
VT
E a
nd b
leed
ing.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S2
7 —[S
ecti
ons
3.1.
1-3.
1.4]
Ext
ende
d A
ntic
oagu
lati
on v
s N
o E
xten
ded
Ant
icoa
gula
tion
for
Dif
fere
nt G
rou
ps o
f P
atie
nts
Wit
h V
TE
and
Wit
hou
t C
ance
r a,b
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Ext
ende
d A
ntic
oagu
latio
nW
ith E
xten
ded
Ant
icoa
gula
tion
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
No
Ext
ende
d A
ntic
oagu
latio
n
Ris
k D
iffer
ence
W
ith E
xten
ded
Ant
icoa
gula
tion
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me)
1,18
4 (4
st
udie
s),
10-3
6 m
o
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
y c N
o se
riou
s in
dire
ctne
ssSe
riou
s d,e
Und
etec
ted
Mod
erat
e c-e
due
to
impr
ecis
ion
38/5
99 (6
.3)
16/5
85 (2
.7)
RR
0.5
7 (0
.31-
1.03
)63
per
1,0
0027
few
er p
er 1
,000
(fro
m
44 fe
wer
to 2
mor
e)
Rec
urre
nt V
TE
at 1
y (c
ritic
al o
utco
me)
1,18
4 (4
st
udie
s),
10-3
6 m
o
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dH
igh
102/
599
(17)
21/5
85 (3
.6)
RR
0.1
2 (0
.09-
0.38
)F
irst
VT
E p
rovo
ked
by s
urge
ry f-
j
10 p
er 1
,000
10 p
er 1
,000
F
irst
VT
E p
rovo
ked
nons
urgi
cal/fi
rst
un
prov
oked
dis
tal D
VT
f-j
50
per
1,0
0044
few
er p
er 1
,000
(fro
m
31 fe
wer
to 4
5 fe
wer
)
F
irst
unp
rovo
ked
VT
E f-
j
10
0 pe
r 1,
000
88 fe
wer
per
1,0
00 (f
rom
62
few
er to
91
few
er)
Se
cond
unp
rovo
ked
VT
E f-
j
15
0 pe
r 1,
000
132
few
er p
er 1
,000
(f
rom
93
few
er to
13
7 fe
wer
)
Maj
or b
leed
ing
at 1
y (c
ritic
al o
utco
me)
1,18
4 (4
st
udie
s),
10-3
6 m
o
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
sU
ndet
ecte
dM
oder
ate
due
to
impr
ecis
ion
7/59
9 (1
.2%
)21
/585
(3.6
%)
RR
2.6
3 (1
.02-
6.76
)L
ow r
isk
of b
leed
ing k,
l
3 pe
r 1,
000
5 m
ore
per
1,00
0 (f
rom
0
mor
e to
17
mor
e)
M
oder
ate
risk
of b
leed
ing k,
l
6
per
1,00
010
mor
e pe
r 1,
000
(fro
m
0 m
ore
to 3
5 m
ore)
H
igh
risk
of b
leed
ing k,
l
12
per
1,0
0020
mor
e pe
r 1,
000
(fro
m
0 m
ore
to 6
9 m
ore)
(C
onti
nued
)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
47© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S2
7—C
onti
nued
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Ext
ende
d A
ntic
oagu
latio
nW
ith E
xten
ded
Ant
icoa
gula
tion
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
No
Ext
ende
d A
ntic
oagu
latio
n
Ris
k D
iffer
ence
W
ith E
xten
ded
Ant
icoa
gula
tion
(95%
CI)
Rec
urre
nt V
TE
at 5
y (c
ritic
al o
utco
me)
1,18
4 (4
st
udie
s),
10-3
6 m
o
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dH
igh
102/
599
(17%
)21
/585
(3.6
%)
RR
0.1
2 (0
.09-
0.38
)F
irst
VT
E p
rovo
ked
by s
urge
ry f-
j
30 p
er 1
,000
26 fe
wer
per
1,0
00 (f
rom
19
few
er to
27
few
er)
F
irst
VT
E p
rovo
ked
nons
urgi
cal/fi
rst
un
prov
oked
dis
tal D
VT
f-j
15
0 pe
r 1,
000
132
few
er p
er 1
,000
(f
rom
93
few
er to
13
7 fe
wer
)
F
irst
unp
rovo
ked
VT
E f-
j
30
0 pe
r 1,
000
264
few
er p
er 1
,000
(f
rom
186
few
er to
27
3 fe
wer
)
Se
cond
unp
rovo
ked
VT
E f-
j
45
0 pe
r 1,
000
396
few
er p
er 1
,000
(f
rom
279
few
er to
40
9 fe
wer
)
Maj
or b
leed
ing
at 5
y (c
ritic
al o
utco
me)
1,18
4 (4
st
udie
s),
10-3
6 m
o
No
seri
ous
risk
of b
ias
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
sU
ndet
ecte
dM
oder
ate
due
to
impr
ecis
ion
7/59
9 (1
.2%
)21
/585
(3.6
%)
RR
2.6
3 (1
.02-
6.77
)L
ow r
isk
of b
leed
ing k,
l
15 p
er 1
,000
24 m
ore
per
1,00
0 (f
rom
0
mor
e to
87
mor
e)
M
oder
ate
risk
of b
leed
ing k,
l
30
per
1,0
0049
mor
e pe
r 1,
000
(fro
m
1 m
ore
to 1
73 m
ore)
H
igh
risk
of b
leed
ing k,
l
60
per
1,0
0098
mor
e pe
r 1,
000
(fro
m
1 m
ore
to 3
46 m
ore)
Bur
den
of a
ntic
oagu
latio
n no
t rep
orte
d
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
48© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Ext
ende
d A
ntic
oagu
latio
nW
ith E
xten
ded
Ant
icoa
gula
tion
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
No
Ext
ende
d A
ntic
oagu
latio
n
Ris
k D
iffer
ence
W
ith E
xten
ded
Ant
icoa
gula
tion
(95%
CI)
……
……
……
……
……
See
com
men
t m
See
com
men
t m
PTS
not r
epor
ted
……
……
……
……
……
See
com
men
t n Se
e co
mm
ent n
Bib
liogr
aphy
: Sch
ulm
an e
t al (
DU
RA
C 2
), 97 K
earo
n et
al (
LA
FIT
), 96 F
arra
j, 98 P
alar
eti (
PRO
LO
NG
). 95 S
ee T
able
S1,
S2,
S7,
and
S10
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Stu
dies
var
y in
follo
w-u
p du
ratio
n (1
0 m
o to
3 y
) and
in d
urat
ion
of ti
me-
limite
d V
KA
(3 to
6 m
o).
b We
excl
uded
Rid
ker
et a
l (PR
EV
EN
T) 10
0 bec
ause
targ
et I
NR
was
1.7
5 (lo
w in
tens
ity),
whi
ch h
as b
een
show
n in
an
RC
T to
be
less
eff
ectiv
e th
an a
targ
et o
f 2.5
. c I
2 5 0
%.
d CI
incl
udes
bot
h va
lues
sug
gest
ing
no e
ffec
t and
val
ues
sugg
estin
g ei
ther
app
reci
able
har
ms
or a
ppre
ciab
le b
enefi
t.
e Sm
all n
umbe
r of
eve
nts.
Dec
isio
n to
rat
e do
wn
also
take
s in
to a
ccou
nt th
at tw
o st
udie
s w
ere
stop
ped
earl
y fo
r be
nefi t
. f A
nnua
l ris
k of
VT
E re
curr
ence
aft
er d
isco
ntin
uing
ora
l ant
icoa
gula
tion
ther
apy
in p
atie
nts w
ith fi
rst V
TE
pro
voke
d by
surg
ery:
1%
(Ior
io A
, Kea
ron
C, F
ilipp
ucci
E, e
t al.
Ris
k of
recu
rren
ce a
fter
a fi
rst e
piso
de
of sy
mpt
omat
ic v
enou
s thr
ombo
embo
lism
pro
voke
d by
a tr
ansi
ent r
isk
fact
or: a
syst
emat
ic re
view
. Arc
h In
tern
Med
. 201
0;17
0(19
):171
0-17
16);
we
assu
med
a 0
.5%
yea
rly
risk
ther
eaft
er (3
% o
ver 5
y).
g Ann
ual r
isk
in p
atie
nts
with
fi rs
t VT
E p
rovo
ked
by n
on s
urgi
cal f
acto
r: a
bout
5%
the
fi rst
yea
r (I
orio
et a
l); w
e as
sum
ed 2
.5%
yea
rly
ther
eaft
er (1
5% o
ver
5 y)
. h A
nnua
l ris
k in
pat
ient
s with
fi rs
t epi
sode
of u
npro
voke
d V
TE
: 9.3
% o
ver 1
y in
Rod
ger M
A, K
ahn
SR, W
ells
PS,
et a
l. Id
entif
ying
unp
rovo
ked
thro
mbo
embo
lism
pat
ient
s at l
ow ri
sk fo
r rec
urre
nce
who
can
di
scon
tinue
ant
icoa
gula
nt th
erap
y. C
MA
J. 2
008;
179(
5):4
17-4
26; 1
1.0%
ove
r 1
y, 1
9.6%
ove
r 3
y, a
nd 2
9.1%
ove
r 5
y in
Pra
ndon
i et a
l (20
07).
We
assu
med
a r
isk
of 1
0% th
e fi r
st y
ear
afte
r di
scon
tinua
tion
and
5% y
earl
y th
erea
fter
(30%
ove
r 5
y).
i Ann
ual r
isk
in p
atie
nts w
ith se
cond
epi
sode
of u
npro
voke
d V
TE
: we
assu
med
an
RR
of 1
.5 c
ompa
red
with
a fi
rst e
piso
de o
f unp
rovo
ked
VT
E: 1
5% th
e fi r
st y
ear a
fter
dis
cont
inua
tion,
7.5
% y
earl
y th
erea
fter
(4
5% o
ver
5 y)
. j C
ase
fata
lity
rate
of r
ecur
rent
VT
E a
fter
dis
cont
inui
ng o
ral a
ntic
oagu
latio
n th
erap
y: 3
.6%
(Car
rier
201
0).
k Ann
ual r
isk
of m
ajor
ble
edin
g is
bas
ed o
n th
ree
risk
leve
ls: l
ow, i
nter
med
iate
, and
hig
h. T
he c
orre
spon
ding
0.3
%, 0
.6%
, and
1.2
% ri
sks a
re e
stim
ates
bas
ed o
n co
ntro
l arm
s of i
nclu
ded
stud
ies (
see
Tabl
e 3 )
. l C
ase
fata
lity
rate
of m
ajor
ble
edin
g du
ring
initi
al o
ral a
ntic
oagu
latio
n th
erap
y: 1
1.3%
(Car
rier
et a
l) (n
o da
ta a
vaila
ble
for
afte
r di
scon
tinui
ng o
ral a
ntic
oagu
latio
n th
erap
y).
m B
urde
n of
ant
icoa
gula
tion:
end
ured
by
all p
atie
nts
who
con
tinue
ext
ende
d-du
ratio
n an
ticoa
gula
tion
(100
%)
and
appl
ies
to p
atie
nts
who
sto
p an
ticoa
gula
tion
(no
exte
nded
-dur
atio
n an
ticoa
gula
tion)
who
su
bseq
uent
ly e
xper
ienc
e a
recu
rren
t VT
E (5
%, 1
0%, 1
5% a
t 1 y
; 15%
, 30%
, 45%
at 5
y).
n Bas
elin
e ri
sk o
ver
2 y
of 5
8.8%
for
PT
S an
d 13
.8%
for
sev
ere
PTS
(VE
TO
[Ve
nous
Thr
ombo
sis
Out
com
es s
tudy
]; A
nn I
nter
n M
ed. 2
008)
and
thr
eefo
ld (
Pran
doni
. Ann
Int
ern
Med
. 200
4) t
o 10
-fol
d (V
an D
onge
n. J
Thr
omb
Hae
mos
t. 20
05) i
ncre
ase
in P
TS .
Tabl
e S2
7—C
onti
nued
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
49© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
(Con
tinu
ed)
Tabl
e S2
8 —[S
ecti
on 3
.3]
Evi
denc
e P
rofi l
e: L
MW
H v
s V
KA
for
Lon
g-te
rm T
reat
men
t of
VT
E a-c
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith V
KA
With
LM
WH
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
V
KA
Ris
k D
iffer
ence
W
ith L
MW
H
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me)
2,49
6 (7
stu
dies
), 6
mo
No
seri
ous
risk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dM
oder
ate d,
e due
to
impr
ecis
ion
202/
1,23
1 (1
6.4)
204/
1,26
5 (1
6.1)
RR
0.9
6 (0
.81-
1.13
)16
4 pe
r 1,
000
7 fe
wer
per
1,0
00
(fro
m 3
1 fe
wer
to
21
mor
e)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
2,72
7 (8
stu
dies
), 6
mo
Seri
ous f
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dM
oder
ate f d
ue
to r
isk
of b
ias
105/
1,34
9 (7
.8)
67/1
,378
(4.9
)R
R 0
.62
(0.4
6-0.
84)
No
canc
er g
30 p
er 1
,000
11 fe
wer
per
1,0
00
(fro
m 5
few
er
to 1
6 fe
wer
)
N
onm
etas
tatic
can
cer g
80
per
1,0
0030
few
er p
er 1
,000
(f
rom
13
few
er
to 4
3 fe
wer
)
M
etas
tatic
can
cer g
20
0 pe
r 1,
000
76 fe
wer
per
1,0
00
(fro
m 3
2 fe
wer
to
108
few
er)
Maj
or b
leed
ing
(cri
tical
out
com
e)
2,73
7 (8
stu
dies
), 6
mo
No
seri
ous
risk
of b
ias h
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s i U
ndet
ecte
dM
oder
ate h,
i due
to
impr
ecis
ion
53/1
,351
(3.9
%)
45/1
,386
(3.2
%)
RR
0.8
1 (0
.55-
1.2)
No
canc
er o
r no
nmet
asta
tic
canc
er j
20 p
er 1
,000
4 fe
wer
per
1,0
00
(fro
m 9
few
er
to 4
mor
e)
M
etas
tatic
can
cer j
80
per
1,0
0015
few
er p
er 1
,000
(f
rom
36
few
er
to 1
6 m
ore)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
50© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith V
KA
With
LM
WH
Rel
ativ
e E
ffec
t (9
5% C
I)R
isk
With
V
KA
Ris
k D
iffer
ence
W
ith L
MW
H
(95%
CI)
Bur
den
of a
ntic
oagu
latio
n (im
port
ant o
utco
me)
k
…N
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
o se
riou
s lim
itatio
nsN
ot a
pplic
able
Hig
hW
arfa
rin:
dai
ly
med
icat
ion,
die
tary
in
tera
ctio
ns,
freq
uent
blo
od
test
ing/
mon
itori
ng,
incr
ease
d ho
spita
l/cl
inic
vis
its
LM
WH
: dai
ly
inje
ctio
n,
no d
ieta
ry
inte
ract
ions
, no
freq
uent
bl
ood
test
ing/
mon
itori
ng
……
PTS
(impo
rtan
t out
com
e; a
sses
sed
with
sel
f-re
port
ed le
g sy
mpt
oms
and
sign
s)
100 (1
stu
dy),
2 y
Seri
ous l
No
seri
ous
inco
nsis
tenc
ySe
riou
s m
No
seri
ous
impr
ecis
ion
Und
etec
ted
Low
l,m d
ue to
ri
sk o
f bia
s,
indi
rect
ness
31/4
4 (7
0.5%
)34
/56
(60.
7%)
RR
0.8
5 (0
.77-
0.94
)M
oder
ate n
200
per
1,00
030
few
er p
er 1
,000
(f
rom
12
few
er
to 4
6 fe
wer
)
Bib
liogr
aphy
: Inc
lude
d st
udie
s: D
eitc
her
et a
l, 102 H
ull e
t al, 10
3 Hul
l et a
l, 104 L
ee e
t al, 10
5 Lop
aciu
k et
al, 10
6 Lop
ez-B
eret
et a
l, 107 M
eyer
G e
t al, 10
8 Rom
era
et a
l 109 T
wo
of th
ese
stud
ies
enro
lled
only
pat
ient
s w
ithou
t can
cer, 10
4,10
7 3 e
nrol
led
only
pat
ient
s w
ith c
ance
r 108,
102,
105 ,
and
3 en
rolle
d bo
th p
atie
nts
with
and
with
out c
ance
r 103,
106,
109 (
sepa
rate
dat
a pr
ovid
ed fo
r ca
ncer
and
non
-can
cer
patie
nts
in o
ne s
tudy
103,
110 )
. E
xclu
ded
stud
ies
(less
than
50%
of t
hera
peut
ic d
ose
LM
WH
dur
ing
exte
nded
pha
se):
Pini
et a
l, 111 D
as e
t al, 11
2 Gon
zale
z-F
ajar
do e
t al, 11
3 Vei
ga e
t al, 11
4 Kak
kar
et a
l, 115 (
Ces
aron
e 20
03 C
irc
abst
ract
). PT
S da
ta fr
om: H
ull e
t al. 10
4 See
Tab
le S
1, S
2, S
5, a
nd S
10 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a L
imite
d to
LM
WH
reg
imen
s th
at u
sed
� 5
0% o
f the
acu
te tr
eatm
ent d
ose
duri
ng th
e ex
tend
ed p
hase
of t
reat
men
t. b T
he in
itial
par
ente
ral a
ntic
oagu
latio
n w
as s
imila
r in
bot
h ar
ms
for
all e
xcep
t on
e st
udy
(Hul
l et
al [
2007
]) in
whi
ch p
atie
nts
rand
omiz
ed t
o L
MW
H r
ecei
ved
initi
ally
the
sam
e LW
MH
, whe
reas
pat
ient
s ra
ndom
ized
to V
KA
rec
eive
d in
itial
ly U
FH
. c T
wo
of th
ese
stud
ies
enro
lled
only
pat
ient
s w
ithou
t can
cer,
thre
e en
rolle
d on
ly p
atie
nts
with
can
cer,
and
thre
e en
rolle
d bo
th p
atie
nts
with
and
with
out c
ance
r (s
epar
ate
data
pro
vide
d fo
r ca
ncer
and
non
-ca
ncer
pat
ient
s in
one
stu
dy).
d One
stu
dy d
id n
ot r
epor
t dea
ths,
whi
ch is
unu
sual
and
cou
ld r
efl e
ct s
elec
tive
repo
rtin
g of
out
com
es.
e CI
incl
udes
bot
h no
eff
ect a
nd h
arm
with
LM
WH
. f N
one
of th
e st
udie
s wer
e bl
inde
d, a
lthou
gh th
e di
agno
sis o
f rec
urre
nt V
TE
has
a su
bjec
tive
com
pone
nt a
nd th
ere
coul
d be
a lo
wer
thre
shol
d fo
r dia
gnos
is o
f rec
urre
nt V
TE
in V
KA
-tre
ated
pat
ient
s bec
ause
sw
itchi
ng th
e tr
eatm
ent o
f suc
h pa
tient
s to
LM
WH
is w
idel
y pr
actic
ed. A
t the
sam
e tim
e, th
ere
is re
luct
ance
to d
iagn
ose
recu
rren
t VT
E in
pat
ient
s who
are
alr
eady
on
LM
WH
bec
ause
ther
e is
no
attr
activ
e al
tern
ativ
e tr
eatm
ent o
ptio
n.
g Ris
k of
rec
urre
nt V
TE
: low
cor
resp
onds
to
patie
nts
with
out
canc
er (
3% e
stim
ate
take
n fr
om r
ecen
t la
rge
RC
Ts o
f ac
ute
trea
tmen
t), i
nter
med
iate
cor
resp
onds
to
patie
nts
with
loca
l or
rece
ntly
res
ecte
d ca
ncer
(bas
ed o
n av
erag
e ra
te a
cros
s th
e si
x st
udie
s in
this
ana
lysi
s an
d ap
pear
s to
be
cons
iste
nt w
ith P
rand
oni e
t al [
part
icul
arly
if lo
w r
isk
is in
crea
sed
to 4
%])
, and
hig
h to
pat
ient
s w
ith lo
cally
adv
ance
d or
di
stan
t met
asta
tic c
ance
r (P
rand
oni e
t al 11
6 ).
h No
stud
y w
as b
linde
d; d
iagn
osis
of m
ajor
ble
edin
g ha
s a
subj
ectiv
e co
mpo
nent
. i T
he 9
5% C
Is fo
r the
RR
for m
ajor
ble
edin
g in
clud
es a
pot
entia
lly c
linic
ally
impo
rtan
t inc
reas
e or
dec
reas
e w
ith L
MW
H a
nd m
ay v
ary
with
the
dose
of L
MW
H u
sed
duri
ng th
e ex
tend
ed p
hase
of t
hera
py.
j Ris
k of
ble
edin
g: lo
w c
orre
spon
ds to
pat
ient
s w
ithou
t ris
k fa
ctor
for
blee
ding
(ie,
. 7
5 y,
can
cer,
met
asta
tic d
isea
se; c
hron
ic r
enal
or
hepa
tic fa
ilure
; pla
tele
t cou
nt ,
800
,000
; req
uire
s an
tipla
tele
t the
rapy
; hi
stor
y of
ble
edin
g w
ithou
t a r
ever
sibl
e ca
use)
(Tab
le 2
) (ba
sed
on P
rand
oni e
t al 11
6 and
Bey
th e
t al, 11
7 adj
uste
d to
a 6
-mo
time
fram
e).
k Hul
l et a
l rep
orte
d no
sig
nifi c
ant d
iffer
ence
in q
ualit
y of
life
but
sug
gest
ed g
reat
er s
atis
fact
ion
with
LM
WH
ove
r V
KA
(que
stio
nnai
re d
id n
ot d
irec
tly a
sses
s th
e bu
rden
of i
njec
tions
). l P
atie
nts
and
inve
stig
ator
s no
t blin
ded.
Sel
f-re
port
ed le
g sy
mpt
oms
and
sign
s af
ter
3 m
o of
trea
tmen
t. m T
he a
ssoc
iatio
n be
twee
n le
g sy
mpt
oms
and
sign
s at
3 m
o an
d lo
ng-t
erm
PT
S is
unc
erta
in.
n Bas
elin
e ri
sk a
ssum
es th
at p
atie
nts
all w
ear
pres
sure
sto
ckin
gs. C
ontr
ol e
vent
rat
e co
mes
from
obs
erva
tiona
l stu
dies
in r
evie
w b
y K
ahn
et a
l, 118 a
djus
ted
to 2
-y ti
me
fram
e.
Tabl
e S2
8—C
onti
nued
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
51© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S2
9 —[S
ecti
on 3
.3]
Evi
denc
e P
rofi l
e: R
ivar
oxab
an v
s L
MW
H a
nd V
KA
The
rapy
for
Sho
rt-
and
Lon
g-te
rm T
reat
men
t of
VT
E a-c
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es)
Fol
low
up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
LM
WH
an
d V
KA
T
hera
pyW
ith
Riv
arox
aban
Ris
k W
ith
LM
WH
and
V
KA
The
rapy
Ris
k D
iffer
ence
W
ith R
ivar
oxab
an
(95%
CI)
Dea
th (i
mpo
rtan
t out
com
e)
3,44
9 (1
stu
dy),
6-12
mo d
No
seri
ous
risk
of b
ias e
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s f U
ndet
ecte
dM
oder
ate e,
f du
e to
im
prec
isio
n
49/1
,718
(2.9
)38
/1,7
31 (2
.2)
HR
0.6
7 (0
.44-
1.02
)29
per
1,0
009
few
er p
er 1
,000
(f
rom
16
few
er
to 1
mor
e)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
3,44
9 (1
stu
dy),
6-12
mo d
No
seri
ous
risk
of b
ias e
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s g U
ndet
ecte
dM
oder
ate e,
g du
e to
im
prec
isio
n
51/1
,718
(3) h
36/1
,731
(2.1
) h H
R 0
.68
(0.4
4-1.
04)
30 p
er 1
,000
h 9
few
er p
er 1
,000
(f
rom
17
few
er
to 1
mor
e)
Maj
or b
leed
ing
(cri
tical
out
com
e)
3,42
9 (1
stu
dy),
6-12
mo d
No
seri
ous
risk
of b
ias e
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s g U
ndet
ecte
dM
oder
ate e,
g du
e to
im
prec
isio
n
19/1
,711
(1.1
) i 13
/1,7
18 (0
.8) i
HR
0.6
8 (0
.34-
1.38
) j 11
per
1,0
00 i
4 fe
wer
per
1,0
00
(fro
m 7
few
er
to 4
mor
e)
Bur
den
of a
ntic
oagu
latio
n (im
port
ant o
utco
me)
not
rep
orte
d
……
……
……
…W
arfa
rin:
dai
ly
med
icat
ion,
di
etar
y in
tera
ctio
ns,
freq
uent
blo
od
test
ing/
mon
itori
ng,
incr
ease
d ho
spita
l/cl
inic
vis
its
Riv
aorx
aban
: dai
ly
med
icat
ion,
no
die
tary
in
tera
ctio
ns,
no fr
eque
nt
bloo
d te
stin
g/m
onito
ring
……
…
Bib
liogr
aphy
: Ein
stei
n D
VT.
119 H
R 5
haz
ard
ratio
. See
Tab
le S
1, S
2, S
5, a
nd S
7 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Riv
arox
aban
15
mg
bid
for
3 w
k an
d th
en 2
0 m
g/d
for
a to
tal o
f 3 (1
2%),
6 (6
3%),
or 1
2 (2
5%) m
onth
s.
b Eno
xapa
rin
1 m
g/kg
bid
for
� 8
d a
nd th
en V
KA
ther
apy
targ
eted
to I
NR
2.5
for
3, 6
, or
12 m
o.
c Inc
lude
d pa
tient
s ha
d ac
ute,
sym
ptom
atic
, obj
ectiv
ely
veri
fi ed
prox
imal
DV
T o
f the
legs
(unp
rovo
ked,
62%
; can
cer,
6%; p
revi
ous
VT
E, 1
9%).
d Fol
low
-up
was
pre
spec
ifi ed
to b
e 3
mo
(12%
), 6
mo
(63%
), or
12
mo
(25%
). e A
lloca
tion
was
con
ceal
ed. P
atie
nts,
pro
vide
rs, a
nd d
ata
colle
ctor
s w
ere
not b
linde
d, b
ut o
utco
me
adju
dica
tors
wer
e bl
inde
d. I
TT
ana
lysi
s; 1
.0%
loss
to fo
llow
-up.
Not
sto
pped
ear
ly fo
r be
nefi t
. f C
I in
clud
es v
alue
s su
gges
ting
bene
fi t o
r no
eff
ect;
rela
tivel
y lo
w n
umbe
r of
eve
nts.
g C
I in
clud
es v
alue
s su
gges
ting
bene
fi t a
nd h
arm
. h O
ne d
efi n
ite o
r po
ssib
le fa
tal V
TE
in r
ivar
oxab
an g
roup
and
one
in L
MW
H/V
KA
gro
up.
i Ble
eds
cont
ribu
ting
to d
eath
: one
in th
e ri
varo
xaba
n gr
oup
and
fi ve
in th
e w
arfa
rin
grou
p.
j Cal
cula
ted
from
rep
orte
d da
ta.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
52© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S3
0 —[S
ecti
on 3
.3]
Evi
denc
e P
rofi l
e: R
ivar
oxab
an v
s P
lace
bo
for
Ext
ende
d A
ntic
oagu
lati
on o
f V
TE
a,b
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith P
lace
boW
ith
Riv
arox
aban
Ris
k W
ith
Plac
ebo
Ris
k D
iffer
ence
W
ith R
ivar
oxab
an
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me)
1,19
6 (1
stu
dy),
6 or
12
mo c
No
seri
ous
risk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dM
oder
ate d,
e du
e to
im
prec
isio
n
2/59
4 (0
.34)
1/60
2 (0
.17)
RR
0.4
9 (0
.04-
5.4)
f 3
per
1,00
02
few
er p
er 1
,000
(f
rom
3 fe
wer
to
15
mor
e)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
1,19
6 (1
stu
dy),
6 or
12
mo c
No
seri
ous
risk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dH
igh d
42/5
94 (7
.1) g
8/60
2 (1
.3) g
HR
0.1
8 (0
.09-
0.39
)71
per
1,0
00 g
58 fe
wer
pe
r 1,
000
(fro
m 4
3 fe
wer
to
64
few
er)
Maj
or b
leed
ing
(cri
tical
out
com
e)
1,18
8 (1
stu
dy),
6 or
12
mo
No
seri
ous
risk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s h U
ndet
ecte
dM
oder
ate d,
h du
e to
im
prec
isio
n
0/59
0 (0
) i 4/
598
(0.7
) i R
R 4
.9
(0.5
8-42
) f i
7 m
ore
per
1,00
0 (f
rom
3 m
ore
to 1
6 m
ore)
Bur
den
of a
ntic
oagu
latio
n (im
port
ant o
utco
me)
not
rep
orte
d
……
……
……
……
Riv
arox
aban
: dai
ly
med
icat
ion,
no
die
tary
in
tera
ctio
ns,
no fr
eque
nt
bloo
d te
stin
g/m
onito
ring
……
PTS
(impo
rtan
t out
com
e) n
ot r
epor
ted
……
……
……
……
……
… j
Bib
liogr
aphy
: Ein
stei
n D
VT.
119 S
ee T
able
S1,
S2,
S5,
S10
, and
S29
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Riv
arox
aban
20
mg/
d fo
r 6
or 1
2 m
o af
ter
initi
al lo
ng-t
erm
ther
apy.
b I
nclu
ded
patie
nts
had
acut
e, s
ympt
omat
ic, o
bjec
tivel
y ve
rifi e
d pr
oxim
al D
VT
of t
he le
gs o
r PE
(unp
rovo
ked,
73%
; can
cer,
5%; p
revi
ous
VT
E, 1
9%).
c Fol
low
-up
was
pre
spec
ifi ed
to b
e 6
mo
(60%
) or
12 m
o (4
0%).
d Allo
catio
n w
as c
once
aled
. Pat
ient
s, p
rovi
ders
, dat
a co
llect
ors,
and
out
com
e ad
judi
cato
rs w
ere
blin
ded.
IT
T a
naly
sis;
0.2
% lo
ss to
follo
w-u
p. N
ot s
topp
ed e
arly
for
bene
fi t.
e CI
incl
udes
val
ues
sugg
estin
g be
nefi t
or
no e
ffec
t; re
lativ
ely
low
num
ber
of e
vent
s.
f Cal
cula
ted
from
rep
orte
d da
ta w
ith a
dditi
on o
f one
eve
nt to
eac
h ev
ent r
ate
as e
vent
rat
e 0
in c
ontr
ol g
roup
. g O
ne d
efi n
ite o
r po
ssib
le fa
tal V
TE
in r
ivar
oxab
an g
roup
and
one
in L
MW
H/V
KA
gro
up.
h CI
incl
udes
val
ues
sugg
estin
g be
nefi t
and
har
m.
i Ble
eds
cont
ribu
ting
to d
eath
: non
e in
the
riva
roxa
ban
grou
p an
d no
ne in
the
war
fari
n gr
oup.
j P
TS:
bas
elin
e ris
k ov
er 2
y o
f 58.
8% fo
r PT
S an
d 13
.8%
for s
ever
e PT
S (K
ahn
et a
l 40 ).
The
re is
thre
efol
d (P
rand
oni e
t al 12
0 ) to
10-
fold
(van
Don
gen
et a
l 121 )
incr
ease
in P
TS
with
recu
rren
t VT
E in
the
ipsil
ater
al le
g.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
53© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S3
1 —[S
ecti
on 3
.3]
Dab
igat
ran
vs V
KA
The
rapy
for
Lon
g-te
rm T
reat
men
t of
VT
E a-c
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith W
arfa
rin
With
D
abig
atra
n
Ris
k W
ith
War
fari
nR
isk
Diff
eren
ce
With
Dab
igat
ran
(95%
CI)
Dea
th (i
mpo
rtan
t out
com
e)
2,53
9 (1
stu
dy),
6 m
oN
o se
riou
s ri
sk o
f bia
s d N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous e
Und
etec
ted
Mod
erat
e d,e
due
to
impr
ecis
ion
21/1
,265
(1.7
)21
/1,2
74 (1
.6)
HR
0.9
8 (0
.53-
1.79
)17
per
1,0
000
few
er p
er 1
,000
(f
rom
8 fe
wer
to
13
mor
e)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
2,53
9 (1
stu
dy),
6 m
oN
o se
riou
s ri
sk o
f bia
s d N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous e
Und
etec
ted
Mod
erat
e d,e
due
to
impr
ecis
ion
24/1
,265
(1.9
) f 30
/1,2
74 (2
.4) f
HR
1.0
1 (0
.65-
1.84
)19
per
1,0
00 f
0 m
ore
per
1,00
0 (f
rom
7 fe
wer
to
16
mor
e)
Maj
or b
leed
ing
(cri
tical
out
com
e)
2,53
9 (1
stu
dy),
6 m
oN
o se
riou
s ri
sk o
f bia
s d N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous e
Und
etec
ted
Mod
erat
e d,e
due
to
impr
ecis
ion
24/1
,265
(1.9
) g 20
/1,2
74 (1
.6) g
HR
0.8
2 (0
.45-
1.48
)19
per
1,0
00 g
3 fe
wer
per
1,0
00
(fro
m 1
0 fe
wer
to
9 m
ore)
Bur
den
of a
ntic
oagu
latio
n (im
port
ant o
utco
me)
not
rep
orte
d
……
……
……
…W
arfa
rin:
dai
ly
med
icat
ion,
di
etar
y re
stri
ctio
ns,
freq
uent
blo
od
test
ing/
mon
itori
ng,
incr
ease
d ho
spita
l/cl
inic
vis
its
Dab
igat
ran:
dai
ly
med
icat
ion,
N
o di
etar
y re
stri
ctio
ns,
no fr
eque
nt
bloo
d te
stin
g/m
onito
ring
……
…
Bib
liogr
aphy
: Sch
ulm
an e
t al. 12
2 See
Tab
le S
2, S
5, a
nd S
29 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a D
abig
atra
n 15
0 m
g bi
d ta
ken
oral
ly fo
r 6
mo
afte
r an
initi
al tr
eatm
ent w
ith L
MW
H o
r IV
UF
H.
b War
fari
n ad
just
ed to
ach
ieve
an
INR
of 2
.0 to
3.0
for
6 m
o af
ter
an in
itial
trea
tmen
t with
LM
WH
or
IV U
FH
. c I
nclu
ded
patie
nts
had
acut
e, s
ympt
omat
ic, o
bjec
tivel
y ve
rifi e
d pr
oxim
al D
VT
of t
he le
gs o
r PE
. d A
lloca
tion
was
con
ceal
ed. P
atie
nts,
pro
vide
rs, d
ata
colle
ctor
s, a
nd o
utco
me
adju
dica
tors
wer
e bl
inde
d. M
odifi
ed I
TT
ana
lysi
s; 1
.1%
loss
to fo
llow
-up.
Not
sto
pped
ear
ly fo
r be
nefi t
. e C
I in
clud
es v
alue
s su
gges
ting
no e
ffec
t and
val
ues
sugg
estin
g ei
ther
ben
efi t
or h
arm
; rel
ativ
ely
low
num
ber
of e
vent
s.
f One
fata
l VT
E in
dab
igat
ran
grou
p an
d th
ree
fata
l VT
Es
in w
arfa
rin
grou
p.
g One
fata
l maj
or b
leed
ing
even
t in
dabi
gatr
an g
roup
and
one
fata
l maj
or b
leed
ing
even
t in
war
fari
n gr
oup.
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Tabl
e S3
2 —[S
ecti
on 4
.1]
Ela
stic
Sto
ckin
g fo
r P
reve
ntio
n of
PT
S: C
lini
cal
Des
crip
tion
and
Res
ult
s
Aut
hor/
Year
Type
of
Publ
icat
ion
Part
icip
ants
Inte
rven
tions
Out
com
esF
ollo
w-u
pR
esul
ts
Bra
ndje
s et
al 12
7 /199
7R
CT
194
patie
nts
with
fi rs
t sym
ptom
atic
pr
oxim
al D
VT
Com
pres
sion
sto
ckin
gs:
belo
w-k
nee
cust
omiz
ed
elas
tic c
ompr
essi
on
stoc
king
s w
ith a
nkle
pr
essu
re 3
0-40
mm
Hg
(96
patie
nts)
Cum
ulat
ive
inci
denc
e of
mild
to m
oder
ate
and
seve
re P
TS
3 an
d 6
mo,
th
en e
very
6 m
o to
a m
edia
n of
76
mo
Com
pres
sion
sto
ckin
gs:
Mild
-mod
erat
e PT
S: 2
0%
(RR
, 0.4
2; 9
5% C
I 0.
27-0
.66;
P
, .0
01) S
ever
e PT
S: 1
1%
(RR
, 0.4
9; 9
5% C
I, 0
.25-
0.95
; P
, .0
01)
C
ontr
ol g
roup
: no
inte
rven
tion
(98
patie
nts)
Con
trol
gro
up: M
ild-m
oder
ate
PTS:
47%
Sev
ere
PTS:
23%
Gin
sber
g et
al 12
4 /200
1R
CT
47 a
sym
ptom
atic
pat
ient
s w
ith v
alvu
lar
inco
mpe
tenc
e 1
y po
st-D
VT
Com
pres
sion
sto
ckin
gs:
belo
w-k
nee
elas
tic
com
pres
sion
sto
ckin
gs
20-3
0 m
m H
g (2
4 pa
tient
s)
PTS
sym
ptom
s57
mo
(mea
n)C
ompr
essi
on s
tock
ings
: PT
S sy
mpt
oms:
0%
Pl
aceb
o: p
lace
bo s
tock
ing
(23
patie
nts)
Plac
ebo:
PT
S sy
mpt
oms:
4%
Pran
doni
et a
l 120 /2
004
RC
T18
0 pa
tient
s w
ith fi
rst
epis
ode
of s
ympt
omat
ic,
acut
e pr
oxim
al D
VT
Com
pres
sion
sto
ckin
gs:
belo
w-k
nee
elas
tic
com
pres
sion
sto
ckin
gs
30-4
0 m
m H
g (9
0 pa
tient
s)
Cum
ulat
ive
inci
denc
e of
mild
to m
oder
ate
and
seve
re P
TS
3-5
yC
ompr
essi
on s
tock
ings
: PT
S sy
mpt
oms:
25%
(C
I, 1
5.6%
-33.
4%)
C
ontr
ol g
roup
: no
inte
rven
tion
(90
patie
nts)
Con
trol
gro
up: P
TS
sym
ptom
s:
49%
(CI,
38.
7%-5
9.4%
)
Part
sch
et a
l 84 /2
004
2-y
follo
w-u
p to
RC
T37
sym
ptom
atic
pat
ient
s w
ith a
cute
DV
T fo
llow
ed
long
term
All
antic
oagu
late
d w
ith
LM
WH
follo
wed
by
oral
ant
icoa
gula
tion
Ove
rall
leg
pain
2
yL
eg p
ain:
No
diff
eren
ce
betw
een
grou
ps
In
elas
tic b
anda
ges
1 e
arly
am
bula
tion
(13
patie
nts)
Leg
cir
cum
fere
nce
Cal
f cir
cum
fere
nce:
N
o di
ffer
ence
bet
wee
n gr
oups
E
last
ic s
tock
ings
(3
0 m
m H
g)
1 e
arly
am
bula
tion
(13
patie
nts)
PTS
scor
e (V
illal
ta-P
rand
oni)
PTS
scor
e: S
igni
fi can
tly
bett
er o
utco
me
with
am
bula
tion
and
band
agin
g or
sto
ckin
gs c
ompa
red
with
be
d re
st ( P
, .0
1)
B
ed r
est f
or 9
d,
no c
ompr
essi
on
(11
patie
nts)
Ash
wan
den
et a
l 130 /2
008
RC
T, s
ingl
e ce
nter
169
fi rst
or
recu
rren
t pr
oxim
al D
VT
with
out
PTS
afte
r 6
mo
of
com
pres
sion
sto
ckin
gs
Com
pres
sion
sto
ckin
gs:
belo
w-k
nee,
26
-36
mm
Hg
(84
patie
nts)
PTS
shin
cha
nges
( � C
4 on
C
EA
P)0-
7 y
(mea
n, 3
y)
PTS
com
pres
sion
st
ocki
ngs:
13%
C
ontr
ol g
roup
: sto
pped
st
ocki
ngs
(85
patie
nts)
Con
trol
gro
up: 2
0% H
R:
0.8
(95
% C
I, 0
.3-1
.3)
See
Tabl
e S1
, S2,
S5,
S10
, and
S29
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Table S33 —[Section 4.1] Elastic Stocking for Prevention of PTS: Methodologic Quality
Author/Year Randomization Allocation Concealment Blinding Loss to Follow-up
Brandjes et al 127 /1997 Y Y (sealed envelopes) Patients: N Caregivers: N Assessors: Y Data analysis: PY
Intervention group: 4 lost to follow-up, 19 died
Control group: 2 lost to follow-up, 18 died
Ginsberg et al 124 /2001 Y Probably, but not specifi ed
Patients: Y Caregivers: Y Assessors: Y data analysis: PY
Intervention: lost to follow-up not reported, 3 died
Control group: lost to follow-up not reported
Prandoni et al 120 /2004 Y Y Patients: N caregivers: N Assessors: Y Data analysis: PY
Intervention: 2 lost to follow-up, 6 died
Control group: 13 lost to follow-up
Ashwanden et al 130 /2008 Y Y Patients: N Caregivers: N Assessors: N Data analysis: N
Intervention: 19 (described)
Control group: 13 (described)
See Table S5 legend for expansion of abbreviations.
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Tabl
e S3
4 —[S
ecti
on 4
.1]
Evi
denc
e P
rofi l
e: E
last
ic C
ompr
essi
on S
tock
ings
vs
No
Ela
stic
Com
pres
sion
Sto
ckin
gs T
o P
reve
nt P
TS
of t
he L
eg a,b
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Stud
y E
vent
Rat
es (%
)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Ela
stic
C
ompr
essi
on
Stoc
king
s
With
Ela
stic
C
ompr
essi
on
Stoc
king
s
Ris
k W
ith
No
Ela
stic
C
ompr
essi
on
Stoc
king
s
Ris
k D
iffer
ence
With
E
last
ic C
ompr
essi
on
Stoc
king
s (9
5% C
I)
PTS
(cri
tical
out
com
e; a
sses
sed
with
Vill
alta
Sco
re)
421
(2 s
tudi
es),
2 y
Seri
ous c
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssN
o se
riou
s im
prec
isio
nU
ndet
ecte
dM
oder
ate c
due
to
risk
of b
ias
91/2
11 (4
3.1)
d 41
/210
(19.
5)R
R 0
.46
(0.3
4-0.
63) e
479
per
1,00
0 d,f
259
few
er p
er 1
,000
(f
rom
177
few
er
to 3
16 fe
wer
) g
Rec
urre
nt V
TE
(cri
tical
out
com
e)
374
(2 s
tudi
es),
5 y
No
seri
ous
risk
of b
ias h
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s i U
ndet
ecte
dM
oder
ate h,
i du
e to
im
prec
isio
n
26/1
88 (1
3.8)
26/1
86 (1
4)R
R 1
.01
(0.6
1-1.
67) e
210
per
1,00
0 j 2
mor
e pe
r 1,
000
(fro
m 8
2 fe
wer
to
141
mor
e)
Qua
lity
of li
fe (i
mpo
rtan
t out
com
e)
0 (0
k )…
……
See
com
men
t k …
Bib
liogr
aphy
: Kol
bach
et a
l. 123 W
e ex
clud
ed G
insb
erg
et a
l 124 a
nd B
elca
ro e
t al 12
5 bec
ause
they
res
pect
ivel
y ra
ndom
ized
pat
ient
s 7
and
12 m
o af
ter
thei
r D
VT
rat
her
than
at t
he ti
me
of th
e ac
ute
DV
T. W
e al
so e
xclu
ded
Arp
aia
et a
l 126 b
ecau
se th
ey r
ando
miz
ed p
atie
nts
to r
ecei
ve s
tock
ings
at t
he ti
me
of d
iagn
osis
of D
VT
vs
2 w
k la
ter. 12
6 See
Tab
le S
1 an
d S5
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Bra
ndje
s 127 u
sed
grad
ed e
last
ic c
ompr
essi
on s
tock
ings
(40
mm
Hg
of p
ress
ure
at th
e an
kle,
36
mm
Hg
at th
e lo
wer
cal
f, an
d 21
mm
Hg
at th
e up
per
calf)
; sto
ckin
gs w
ere
appl
ied
2 to
3 w
k af
ter
the
fi rst
ep
isod
e of
pro
xim
al D
VT.
Pra
ndon
i 120 u
sed
fl at-
knitt
ed s
tock
ings
(30
-40
mm
Hg
of p
ress
ure
at th
e an
kle)
; sto
ckin
gs w
ere
star
ted
at h
ospi
tal d
isch
arge
an
aver
age
of 1
wk
afte
r ad
mis
sion
. In
both
stu
dies
, st
ocki
ngs
wer
e us
ed fo
r 2
y.
b Pra
ndon
i 120 e
xclu
ded
patie
nts w
ith re
curr
ent i
psila
tera
l DV
T, p
reex
istin
g le
g ul
cers
, or s
igns
of C
VI,
bila
tera
l thr
ombo
sis,
a sh
ort l
ife e
xpec
tanc
y, o
r a c
ontr
aind
icat
ion
for u
se o
f sto
ckin
gs (e
g, a
dvan
ced-
stag
e pe
riph
eral
art
eria
l ins
uffi c
ienc
y). B
rand
jes
et a
l exc
lude
d pa
tient
s w
ith s
hort
life
, par
alys
is o
f the
leg,
bila
tera
l thr
ombo
sis,
leg
ulce
rs, o
r ex
tens
ive
vari
cosi
s.
c Pat
ient
s w
ere
not b
linde
d to
the
trea
tmen
t ass
ignm
ent,
and
outc
omes
wer
e pa
rtly
bas
ed o
n su
bjec
tive
repo
rt o
f sym
ptom
s.
d In
Pran
doni
, 120 m
ost e
vent
s oc
curr
ed d
urin
g th
e fi r
st 6
mo:
the
cum
ulat
ive
inci
denc
e of
PT
S in
the
cont
rol g
roup
was
40%
aft
er 6
mo,
47%
aft
er 1
y, a
nd 4
9% a
fter
2 y
. e T
he e
ffect
est
imat
e sh
own
here
resu
lts fr
om a
met
a-an
alys
is (M
ante
l-Hae
nsze
l fi x
ed-e
ffect
s mod
el) o
f the
two
rele
vant
tria
ls. A
fi xe
d-ef
fect
s mod
el w
as c
hose
n be
caus
e of
the
smal
l num
ber o
f stu
dies
ava
ilabl
e.
f Thi
s es
timat
e is
bas
ed o
n th
e fi n
ding
s of
the
VE
TO
(Ven
ous
Thr
ombo
sis
Out
com
es) s
tudy
. 40 T
his
prob
ably
und
eres
timat
es th
e PT
S ba
selin
e ri
sk g
iven
that
ove
rall,
52%
of p
atie
nts
repo
rted
the
curr
ent u
se
of c
ompr
essi
on s
tock
ings
dur
ing
stud
y fo
llow
-up.
g S
ever
e PT
S: a
ssum
ing
the
sam
e R
R o
f 0.4
6 an
d a
base
line
risk
of 8
.1%
ove
r 2
y, th
e ab
solu
te r
educ
tion
is 4
4 fe
wer
sev
ere
PTS
per
1,00
0 (f
rom
30
few
er to
53
few
er) o
ver
2 y.
h W
e di
d no
t rat
e do
wn
the
qual
ity o
f evi
denc
e fo
r re
curr
ent V
TE
for
the
lack
of b
lindi
ng b
ecau
se th
is a
mor
e ob
ject
ive
outc
ome
than
PT
S.
i CI
incl
udes
bot
h ne
glig
ible
eff
ect a
nd a
ppre
ciab
le b
enefi
t or
app
reci
able
har
m.
j Thi
s es
timat
e is
the
mea
n of
two
estim
ates
der
ived
from
two
stud
ies:
12.
4% p
roba
ble/
defi n
ite V
TE
(Hei
t 128 )
and
29.
1% c
onfi r
med
VT
E (P
rand
oni 12
9 ).
k Thi
s is
an
impo
rtan
t out
com
e th
at s
houl
d be
con
side
red
in fu
ture
stu
dies
.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S3
5 —[S
ecti
on 4
.2.1
] E
vide
nce
Pro
fi le:
Com
pres
sion
Sto
ckin
gs v
s N
o C
ompr
essi
on S
tock
ings
for
Pat
ient
s W
ith
PT
S a-c
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Stud
y E
vent
Rat
es (%
)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Com
pres
sion
St
ocki
ngs
With
Com
pres
sion
St
ocki
ngs
Ris
k W
ith N
o C
ompr
essi
on
Stoc
king
s
Ris
k D
iffer
ence
W
ith C
ompr
essi
on
Stoc
king
s (9
5% C
I)
Sym
ptom
atic
rel
ief (
criti
cal o
utco
me;
ass
esse
d w
ith tr
eatm
ent s
ucce
ss d )
115
(2 s
tudi
es),
12-2
6 m
oSe
riou
s e N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous f
Und
etec
ted g
Low
e-g d
ue to
ri
sk o
f bia
s,
impr
ecis
ion
33/5
7 (5
7.9)
32/5
8 (5
5.2)
RR
0.9
6 (0
.70-
1.31
)57
9 pe
r 1,
000
23 fe
wer
per
1,0
00
(fro
m 1
74 fe
wer
to
179
mor
e)
Qua
lity
of li
fe n
ot r
epor
ted
……
……
……
...…
……
......
Rec
urre
nt V
TE
not
rep
orte
d
……
……
……
...…
……
......
Ulc
erat
ion
not r
epor
ted h
……
……
……
...…
……
......
Bib
liogr
aphy
: Gin
sber
g 20
01 12
4 ; F
rulla
. 200
5 131 S
ee T
able
S1,
S2,
S5,
and
S10
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Gin
sber
g et
al:
grad
uate
d co
mpr
essi
on st
ocki
ngs,
30-
40 m
m H
g (c
alf o
r thi
gh le
ngth
, dep
endi
ng o
n sy
mpt
oms)
. Pat
ient
s wer
e en
cour
aged
to w
ear s
tock
ings
as m
uch
as p
ossi
ble
duri
ng w
akin
g ho
urs.
Fru
lla
(200
5): b
elow
-kne
e gr
aded
ela
stic
com
pres
sion
sto
ckin
gs (E
CS)
(30-
40 m
m H
g at
the
ankl
e). P
atie
nts
in b
oth
arm
s of
the
stud
y re
ceiv
ed h
ydro
xyet
hylr
utos
ides
(HR
) (w
e co
nsid
ered
the
EC
S 1
HR
vs
HR
co
mpa
riso
n).
b Gin
sber
g et
al:
plac
ebo
stoc
king
s (c
alf o
r th
igh
leng
th, d
epen
ding
on
sym
ptom
s).
c Gin
sber
g et
al i
nclu
ded
patie
nts
with
PT
S 1
y af
ter
chro
nic,
typi
cal p
roxi
mal
DV
T. F
rulla
(200
5) in
clud
ed p
atie
nts
with
clin
ical
sym
ptom
s an
d si
gns
sugg
estiv
e of
PT
S.
d Gin
sber
g et
al r
epor
ted
trea
tmen
t fai
lure
(defi
ned
a p
rior
i bas
ed o
n an
y of
fi ve
clin
ical
cri
teri
a, in
clud
ing
sym
ptom
s an
d ul
cer
deve
lopm
ent)
. Tre
atm
ent s
ucce
ss r
efer
s to
the
abse
nce
of tr
eatm
ent f
ailu
re.
Fru
lla u
sed
the
Vill
alta
sca
le.
e Gin
sber
g et
al:
Ade
quac
y of
seq
uenc
e ge
nera
tion
and
allo
catio
n co
ncea
lmen
t wer
e un
clea
r; p
atie
nts
and
outc
ome
asse
ssor
s w
ere
adeq
uate
ly b
linde
d; u
ncle
ar w
heth
er a
naly
sis
follo
wed
the
ITT
pri
ncip
le;
uncl
ear
whe
ther
follo
w-u
p w
as c
ompl
ete.
Fru
lla (2
005)
: out
com
e as
sess
ors
wer
e bl
inde
d; fo
llow
-up
was
com
plet
e. I
TT
pri
ncip
le w
as a
dher
ed to
, but
seq
uenc
e ge
nera
tion
and
allo
catio
n co
ncea
lmen
t wer
e un
clea
r, an
d pa
tient
s w
ere
not b
linde
d.
f Ver
y sm
all n
umbe
r of
pat
ient
s.
g Pub
licat
ion
bias
not
det
ecte
d bu
t not
rul
ed o
ut g
iven
that
we
iden
tifi e
d on
ly o
ne s
mal
l stu
dy p
artia
lly s
uppo
rted
by
indu
stry
(pro
visi
on o
f gra
duat
ed c
ompr
essi
on s
tock
ings
). h I
ndir
ect e
vide
nce
from
the
CL
OT
S1 (C
lots
in L
egs
Or
sToc
king
s af
ter
Stro
ke) t
rial
sug
gest
s th
at c
ompr
essi
on s
tock
ings
is a
ssoc
iate
d w
ith a
n R
R o
f 4 fo
r sk
in c
ompl
icat
ions
. i A
bsen
ce o
f ulc
er in
clud
ed in
the
trea
tmen
t suc
cess
out
com
e in
Gin
sber
g et
al.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
58© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S3
6 —[S
ecti
on 4
.2.2
] E
vide
nce
Pro
fi le:
Int
erm
itte
nt C
ompr
essi
on D
evic
e vs
No
Inte
rmit
tent
Com
pres
sion
Dev
ice
for
Pat
ient
s W
ith
Seve
re P
TS a
-c
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Stud
y E
vent
Rat
es (%
)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Inte
rmitt
ent
Com
pres
sion
D
evic
e
With
Int
erm
itten
t C
ompr
essi
on
Dev
ice
Ris
k W
ith N
o In
term
itten
t C
ompr
essi
on
Dev
ice
Ris
k D
iffer
ence
W
ith I
nter
mitt
ent
Com
pres
sion
D
evic
e (9
5% C
I)
Sym
ptom
atic
rel
ief (
criti
cal o
utco
me;
mea
sure
d w
ith s
ympt
om s
core
(inc
lude
s sc
orin
g of
pai
n, s
wel
ling,
and
lim
itatio
n of
act
ivity
); ra
nge
of s
core
s, 1
0-70
; bet
ter
indi
cate
d by
hig
her
valu
es)
82 (2
stu
dies
d ),
8 w
kN
o se
riou
s ri
sk o
f bia
s e N
o se
riou
s in
cons
iste
ncy f
No
seri
ous
indi
rect
ness
g Se
riou
s h U
ndet
ecte
d i M
oder
ate e-
i du
e to
im
prec
isio
n
41 d
41 d
…T
he m
ean
sym
ptom
atic
re
lief i
n th
e co
ntro
l gro
ups
was
0
The
mea
n sy
mpt
omat
ic
relie
f in
the
inte
rven
tion
grou
ps
was
0.4
1 SD
s hi
gher
(0.0
2 lo
wer
to
0.8
5 hi
gher
)
Qua
lity
of li
fe (c
ritic
al o
utco
me;
mea
sure
d w
ith V
EIN
ES-
QO
L; r
ange
of s
core
s, 0
-100
; bet
ter
indi
cate
d by
hig
her
valu
es)
0 (1
stu
dy d,
j ),
8 w
kN
o se
riou
s ri
sk o
f bia
s k N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
g Se
riou
s h U
ndet
ecte
d i,l M
oder
ate f-
h,k,
l du
e to
im
prec
isio
n
…0
…T
he m
ean
qual
ity
of li
fe in
the
cont
rol g
roup
s w
as 5
0.2
The
mea
n qu
ality
of l
ife in
the
inte
rven
tion
grou
ps
was
2.3
hig
her
(1.0
4 lo
wer
to
5.64
hig
her)
(C
onti
nued
)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
Stud
y E
vent
Rat
es (%
)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Inte
rmitt
ent
Com
pres
sion
D
evic
e
With
Int
erm
itten
t C
ompr
essi
on
Dev
ice
Ris
k W
ith N
o In
term
itten
t C
ompr
essi
on
Dev
ice
Ris
k D
iffer
ence
W
ith I
nter
mitt
ent
Com
pres
sion
D
evic
e (9
5% C
I)
Rec
urre
nt V
TE
not
rep
orte
d m
……
……
……
...…
……
......
Ulc
erat
ion
not r
epor
ted n
……
……
……
...…
……
......
Bib
liogr
aphy
: Gin
sber
g 19
99, 13
2 O’D
onne
ll, 2
008.
133 S
ee T
able
S1,
S5,
and
S10
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a G
insb
erg
et a
l: E
xtre
mity
pum
p us
ed b
id fo
r 20
min
eac
h se
ssio
n; 5
0 m
m H
g (t
hera
peut
ic p
ress
ure)
for
1 m
o. O
’Don
nell
et a
l: Ve
now
ave
low
er-li
mb
veno
us r
etur
n as
sist
dev
ice
to w
ear
for
mos
t of t
he d
ay
for
8 w
k.
b Gin
sber
g et
al:
Ext
rem
ity p
ump
used
bid
for
20 m
in e
ach
sess
ion;
15
mm
Hg
(pla
cebo
pre
ssur
e) fo
r 1
mo.
O’D
onne
ll et
al:
Veno
wav
e lo
wer
-lim
b ve
nous
ret
urn
assi
st d
evic
e w
ith n
o co
nnec
tion
betw
een
mot
or a
nd p
lana
r sh
eet f
or 8
wk.
c P
atie
nts
with
pre
viou
s D
VT
with
sym
ptom
s of
sev
ere
PTS.
d C
ross
over
RC
Ts.
e In
both
stu
dies
, seq
uenc
e ge
nera
tion
was
ade
quat
e; p
atie
nts
wer
e bl
inde
d. A
naly
sis
adhe
red
to I
TT
pri
ncip
le, a
nd th
ere
wer
e no
mis
sing
out
com
e da
ta. I
n G
insb
erg
et a
l (bu
t not
in O
’Don
nell
et a
l), o
ut-
com
e as
sess
ors
wer
e no
t blin
ded,
and
it w
as n
ot c
lear
whe
ther
allo
catio
n w
as c
once
aled
. f I 2 5
0%
. g S
ome
conc
erns
with
indi
rect
enes
s gi
ven
rela
tivel
y sh
ort f
ollo
w-u
p (8
wk)
. h V
ery
smal
l num
ber
of p
atie
nts.
CI
incl
udes
bot
h va
lues
sug
gest
ing
no e
ffec
t and
val
ues
sugg
estin
g a
bene
fi cia
l eff
ect.
i Pub
licat
ion
bias
not
det
ecte
d bu
t not
rul
ed o
ut g
iven
that
we
iden
tifi e
d on
ly tw
o sm
all s
tudi
es w
ith o
ne (G
insb
erg
et a
l) pa
rtia
lly s
uppo
rted
by
indu
stry
(pro
visi
on o
f dev
ices
). j O
’Don
nell
et a
l. k S
eque
nce
gene
ratio
n w
as a
dequ
ate;
pat
ient
s w
ere
blin
ded;
ana
lysi
s ad
here
d to
IT
T p
rinc
iple
; and
ther
e w
ere
no m
issi
ng o
utco
me
data
. How
ever
, out
com
e as
sess
ors
wer
e no
t blin
ded,
and
it w
as n
ot c
lear
w
heth
er a
lloca
tion
was
con
ceal
ed.
l Pub
licat
ion
bias
not
det
ecte
d bu
t not
rul
ed o
ut g
iven
that
we
iden
tifi e
d on
ly o
ne s
mal
l stu
dy.
m O
’Don
nell
et a
l ind
icat
ed n
o ca
ses
of r
ecur
rent
VT
E b
y th
e en
d of
this
stu
dy b
ut ju
dged
the
follo
w-u
p pe
riod
to b
e sh
ort.
n O’D
onne
ll et
al i
ndic
ated
that
one
pat
ient
in th
e co
ntro
l gro
up d
evel
oped
a v
enou
s ulc
erat
ion.
Thr
ee o
ther
par
ticip
ants
dev
elop
ed n
onse
riou
s ski
n-re
late
d si
de e
ffec
ts. I
ndir
ect e
vide
nce
from
the
CL
OT
S1
(Clo
ts in
Leg
s O
r sT
ocki
ngs
afte
r St
roke
) tr
ial s
ugge
sts
that
com
pres
sion
sto
ckin
gs a
re a
ssoc
iate
d w
ith a
n R
R o
f 4 fo
r sk
in c
ompl
icat
ions
: Com
mon
sid
e ef
fect
s ar
e at
trib
uted
to V
enow
ave
wer
e he
at s
en-
satio
n, s
kin
irri
tatio
n, a
nd in
crea
sed
swea
ting.
Tabl
e S3
6—C
onti
nued
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Tabl
e S3
7 —[S
ecti
on 4
.3]
Evi
denc
e P
rofi l
e: V
enoa
ctiv
e M
edic
atio
n vs
No
Ven
oact
ive
Med
icat
ion
for
Pat
ient
s W
ith
PT
S a,b
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Rel
ativ
e E
ffec
t (9
5% C
I)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Veno
activ
e M
edic
atio
nW
ith V
enoa
ctiv
e M
edic
atio
n
Ris
k W
ith N
o Ve
noac
tive
Med
icat
ion
Ris
k D
iffer
ence
With
Ve
noac
tive
Med
icat
ion
(95%
CI)
Sym
ptom
atic
relie
f (cr
itica
l out
com
e; a
sses
sed
with
PT
S sc
ore
(Vill
alta
scal
e) ,
5 or
dec
reas
ed b
y 30
% a
t 12
mo
com
pare
d w
ith b
asel
ine
in F
rulla
et a
l ; im
prov
ed ti
redn
ess o
f the
leg
at 8
wk
in d
e Jo
ngst
e et
al c )
163
(2 s
tudi
es )
No
seri
ous
risk
of b
ias d
Seri
ous e
No
seri
ous
indi
rect
ness
Seri
ous f
Und
etec
ted g
Low
d-g d
ue to
in
cons
iste
ncy,
im
prec
isio
n
39/8
2 (4
7.6)
44/8
1 (5
4.3)
RR
1.1
4 (0
.85-
1.52
)47
6 pe
r 1,
000
67 m
ore
per
1,00
0 (f
rom
71
few
er to
24
7 m
ore)
Qua
lity
of li
fe n
ot r
epor
ted
……
……
……
...
……
…...
...
Rec
urre
nt V
TE
not
rep
orte
d
……
……
……
...…
……
......
Ulc
erat
ion
not r
epor
ted
……
……
……
...…
……
......
Side
eff
ects
(cri
tical
out
com
e)
203
(2 s
tudi
es)
No
seri
ous
risk
of b
ias d
No
seri
ous
inco
nsis
tenc
y h N
o se
riou
s in
dire
ctne
ssSe
riou
s f U
ndet
ecte
d g M
oder
ate d,
f-h
due
to
impr
ecis
ion
5/82
(6.1
%)
13/1
21 (1
0.7%
)R
R 2
.04
(0.7
6-5.
51)
61 p
er 1
,000
63 m
ore
per
1,00
0 (f
rom
15
few
er to
27
5 m
ore)
Bib
liogr
aphy
: Fru
lla 2
005 13
1 de
Jong
ste
1989
. 134 S
ee T
able
S1,
S5,
and
S10
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Inc
lude
d st
udie
s as
sess
ed r
utos
ides
; we
excl
uded
Mon
real
et a
l 135 b
ecau
se it
com
pare
d tw
o ve
noac
tive
med
icat
ions
. b P
atie
nts
with
PT
S an
d hi
stor
y of
DV
T in
PT
S le
g.
c Inv
estig
ator
s ass
esse
d ot
her s
ympt
oms (
pain
, hea
vine
ss, s
wel
ling
feel
ing,
rest
less
legs
, and
cra
mps
) but
did
not
repo
rt a
com
posi
te sc
ore.
The
sym
ptom
we
chos
e to
repo
rt sh
owed
the
mos
t ben
efi t;
the
effe
ct
estim
ates
for
the
othe
r sy
mpt
oms
rang
ed fr
om 0
.8 to
1.4
, and
non
e w
as s
tatis
tical
ly s
igni
fi can
t. d I
n bo
th st
udie
s, se
quen
ce g
ener
atio
n an
d al
loca
tion
conc
ealm
ent w
ere
uncl
ear.
Bot
h st
udie
s blin
ded
outc
ome
asse
ssor
s and
had
com
plet
e fo
llow
-up.
Alth
ough
de
Jong
ste
et a
l blin
ded
patie
nts,
they
did
not
ad
here
to th
e IT
T p
rinc
iple
and
did
not
use
a v
alid
ated
sca
le to
mea
sure
sym
ptom
atic
rel
ief.
Alth
ough
Fru
lla (2
005)
adh
ered
to th
e IT
T p
rinc
iple
, it d
id n
ot b
lind
patie
nts.
e I
2 5 7
7%.
f Sm
all n
umbe
r of
pat
ient
s. C
I in
clud
ing
both
val
ues
sugg
estin
g ha
rms
and
valu
es s
ugge
stin
g be
nefi t
s.
g Pub
licat
ion
bias
not
det
ecte
d bu
t not
rul
ed o
ut g
iven
that
we
iden
tifi e
d on
ly tw
o sm
all s
tudi
es, a
nd it
was
unc
lear
whe
ther
they
wer
e fu
nded
by
indu
stry
. h I
2 5 7
%.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
61© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S3
8 —[S
ecti
on 5
.4]
Evi
denc
e P
rofi l
e: F
onda
pari
nux
vs I
V U
FH
for
Ini
tial
Ant
icoa
gula
tion
of
Acu
te P
E a-c
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith U
FH
With
F
onda
parin
uxR
elat
ive
Eff
ect
(95%
CI)
Ris
k W
ith
UF
H
Ris
k D
iffer
ence
With
F
onda
pari
nux
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me)
2,21
3 (1
stu
dy),
3 m
oN
o se
riou
s ri
sk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dM
oder
ate d,
e due
to
impr
ecis
ion
48/1
,110
(4.3
)57
/1,1
03 (5
.2)
RR
1.2
0 (0
.82-
1.74
)43
per
1,0
009
mor
e pe
r 1,
000
(fro
m 8
few
er to
32
mor
e)
Rec
urre
nt V
TE
(cri
tical
out
com
e)
2,21
3 (1
stu
dy),
3 m
oN
o se
riou
s ri
sk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dM
oder
ate d,
e due
to
impr
ecis
ion
56/1
,110
(5.0
) f 42
/1,1
03 (3
.8) f
RR
0.7
5 (0
.51-
1.12
)50
per
1,0
00 f
13 fe
wer
per
1,0
00
(fro
m 2
5 fe
wer
to
6 m
ore)
Maj
or b
leed
ing
(cri
tical
out
com
e)
2,21
3 (1
stu
dy),
3 m
oN
o se
riou
s ri
sk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s e U
ndet
ecte
dM
oder
ate d,
e due
to
impr
ecis
ion
26/1
,110
(2.3
) g 22
/1,1
03 (2
.0) g
RR
0.8
5 (0
.49-
1.49
)23
per
1,0
00 g
4 fe
wer
per
1,0
00
(fro
m 1
2 fe
wer
to
11 m
ore)
Bib
liogr
aphy
: Bül
ler
et a
l. 136 S
ee T
able
S1,
S2,
S4,
and
S7
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Fon
dapa
rinu
x (5
.0, 7
.5, o
r 10
.0 m
g in
pat
ient
s w
eigh
ing
, 5
0, 5
0 to
100
, or
> 10
0 kg
, res
pect
ivel
y) S
C o
nce
daily
giv
en fo
r at
leas
t 5 d
ays
and
until
the
use
of V
KA
s re
sulte
d in
an
INR
. 2
.0.
b UF
H c
ontin
uous
IV
infu
sion
(rat
io o
f the
aPT
T to
a c
ontr
ol v
alue
, 1.5
-2.5
) giv
en fo
r at
leas
t 5 d
ays
and
until
the
use
of V
KA
s re
sulte
d in
an
INR
. 2
.0.
c All
patie
nts
had
acut
e sy
mpt
omat
ic h
emod
ynam
ical
ly s
tabl
e PE
. d A
lloca
tion
was
con
ceal
ed. P
atie
nts,
pro
vide
rs, a
nd d
ata
colle
ctor
s no
t blin
ded.
Out
com
e ad
judi
cato
rs w
ere
blin
ded;
0.6
% o
f ran
dom
ized
pat
ient
s w
ere
lost
to fo
llow
-up.
Not
sto
pped
ear
ly fo
r be
nefi t
. e C
I in
clud
es v
alue
s su
gges
ting
no e
ffec
t and
val
ues
sugg
estin
g ei
ther
ben
efi t
or h
arm
; rel
ativ
ely
low
num
ber
of e
vent
s.
f Six
teen
fata
l VT
E in
fond
apar
inux
gro
up a
nd 1
5 fa
tal V
TE
in U
FH
gro
up.
g Fou
rtee
n pa
tient
s in
the
fond
apar
inux
gro
up a
nd 1
2 in
the
LM
WH
gro
up h
ad a
maj
or b
leed
ing
durin
g th
e in
itial
per
iod
(6-7
d).
Of t
hese
, one
in th
e fo
ndap
arin
ux g
roup
and
one
in th
e U
FH
gro
up w
ere
fata
l.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
62© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S3
9 —[S
ecti
on 5
.5]
Evi
denc
e P
rofi l
e: E
arly
Dis
char
ge v
s St
anda
rd D
isch
arge
in
the
Tre
atm
ent
of A
cute
PE
a,b
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
s
Ove
rall
Qua
lity
of
Evi
denc
eW
ith S
tand
ard
Dis
char
geW
ith E
arly
D
isch
arge
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith
Stan
dard
D
isch
arge
Ris
k D
iffer
ence
W
ith E
arly
Dis
char
ge
(95%
CI)
Mor
talit
y (c
ritic
al o
utco
me)
471
(2 s
tudi
es),
3 m
oSe
riou
s c N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous d
Und
etec
ted
Mod
erat
e c,d d
ue
to im
prec
isio
n6/
228
(2.6
)4/
243
(1.6
)R
R 0
.58
(0.1
7-1.
97)
26 p
er 1
,000
11 fe
wer
per
1,0
00
(fro
m 2
2 fe
wer
to
26
mor
e)
Non
fata
l rec
urre
nt P
E (c
ritic
al o
utco
me)
471
(2 s
tudi
es),
3 m
oSe
riou
s c N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous d
Und
etec
ted
Mod
erat
e c,d d
ue
to im
prec
isio
n2/
228
(0.9
)3/
243
(1.2
)R
R 1
.23
(0.2
5-6.
03)
9 pe
r 1,
000
2 m
ore
per
1,00
0 (f
rom
7 fe
wer
to
44
mor
e)
Maj
or b
leed
ing
(cri
tical
out
com
e)
471
(2 s
tudi
es),
3 m
oSe
riou
s c N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous d
Und
etec
ted
Mod
erat
e c,d d
ue
to im
prec
isio
n1/
228
(0.4
)4/
243
(1.6
)R
R 2
.74
(0.4
5-16
.71)
4 pe
r 1,
000
8 m
ore
per
1,00
0 (f
rom
2 fe
wer
to
69
mor
e)
Qua
lity
of li
fe n
ot r
epor
ted
……
……
……
……
……
…
Bib
liogr
aphy
: Ote
ro e
t al, 13
7 Auj
esky
et a
l. 138 S
ee T
able
S1,
S2,
and
S5
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Mea
n le
ngth
of h
ospi
tal s
tay:
3.4
(SD
1.1
) vs
9.3
(SD
5.7
) in
Ote
ro e
t al a
nd 0
.5 (S
D 1
.0) v
s 3.
9 (S
D 3
.1) i
n A
ujes
ky e
t al.
b The
two
RC
Ts in
clud
ed o
nly
patie
nts
with
low
ris
k: r
isk
clas
ses
I or
II
on th
e Pu
lmon
ary
Em
bolis
m S
ever
ity I
ndex
in A
ujes
ky e
t al 13
9 ; lo
w r
isk
on c
linic
al p
redi
ctio
n ru
le b
y U
resa
ndi e
t al 14
0 in
Ote
ro e
t al.
c Ote
ro e
t al:
allo
catio
n co
ncea
led,
no
patie
nts
lost
to fo
llow
-up,
IT
T a
naly
sis,
no
blin
ding
of o
utco
me
asse
ssor
s re
port
ed, s
tudy
sto
pped
ear
ly b
ecau
se th
e ra
te o
f sho
rt-t
erm
mor
talit
y w
as u
nexp
ecte
dly
high
in
the
earl
y di
scha
rge
grou
p (2
[2.
8%]
vs 0
[0%
]). A
ujes
ky e
t al:
uncl
ear
whe
ther
allo
catio
n w
as c
once
aled
, thr
ee (
1%)
patie
nts
had
mis
sing
out
com
e da
ta, I
TT
ana
lysi
s, o
utco
me
adju
dica
tors
blin
ded,
no
earl
y st
oppa
ge.
d CI
incl
udes
bot
h va
lues
sug
gest
ing
no e
ffec
t and
val
ues
sugg
estin
g ap
prec
iabl
e ha
rm o
r ap
prec
iabl
e be
nefi t
.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
63© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S4
0 —[S
ecti
on 5
.6.1
] E
vide
nce
Pro
fi le:
Sys
tem
ic T
hrom
bol
ytic
The
rapy
vs
Ant
icoa
gula
tion
Alo
ne i
n P
atie
nts
Wit
h A
cute
PE
a-d
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Syst
emic
ally
A
dmin
iste
red
Thr
ombo
lytic
T
hera
py
With
Sys
tem
ical
ly
Adm
inis
tere
d T
hrom
boly
tic
The
rapy
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith N
o Sy
stem
ical
ly
Adm
inis
tere
d T
hrom
boly
tic
The
rapy
Ris
k D
iffer
ence
W
ith S
yste
mic
ally
A
dmin
iste
red
Thr
ombo
lytic
T
hera
py (9
5% C
I)
Mor
talit
y (c
ritic
al o
utco
me)
847
(12
stud
ies)
, 30
dSe
riou
s e N
o se
riou
s in
cons
iste
ncy f
No
seri
ous
indi
rect
ness
Seri
ous g
Und
etec
ted h
Low
e-h d
ue
to r
isk
of
bias
and
im
prec
isio
n
26/4
23 (6
.1)
15/4
24 (3
.5)
RR
0.7
(0
.37-
1.31
)L
ow i,j
11 p
er 1
,000
3 fe
wer
per
1,0
00
(fro
m 7
few
er to
3
mor
e)
H
igh i,j
89
per
1,0
0027
few
er p
er 1
,000
(f
rom
56
few
er
to 2
8 m
ore)
Rec
urre
nt P
E (i
mpo
rtan
t out
com
e)
801
(9 s
tudi
es),
30 d
Seri
ous e
No
seri
ous
inco
nsis
tenc
y f N
o se
riou
s in
dire
ctne
ssSe
riou
s g U
ndet
ecte
d h L
ow e-
h due
to
ris
k of
bi
as a
nd
impr
ecis
ion
30/4
04 (7
.4)
18/3
97 (4
.5)
RR
0.7
(0
.4-1
.21)
57 p
er 1
,000
17 fe
wer
per
1,0
00
(fro
m 3
4 fe
wer
to
12
mor
e)
Maj
or b
leed
ing
(cri
tical
out
com
e)
847
(12
stud
ies)
, 10
dSe
riou
s e N
o se
riou
s in
cons
iste
ncy f
No
seri
ous
indi
rect
ness
Seri
ous k
Und
etec
ted h
Mod
erat
e e,f,h
,k
due
to r
isk
of b
ias
and
impr
ecis
ion
24/4
23 (5
.7)
38/4
24 (9
)R
R 1
.63
(1-2
.68)
l L
ow m
1 pe
r 1,
000
1 m
ore
per
1,00
0 (f
rom
0 m
ore
to
2 m
ore)
(C
onti
nued
)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
64© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S4
0—C
onti
nued
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
e
With
No
Syst
emic
ally
A
dmin
iste
red
Thr
ombo
lytic
T
hera
py
With
Sys
tem
ical
ly
Adm
inis
tere
d T
hrom
boly
tic
The
rapy
Rel
ativ
e E
ffec
t (9
5% C
I)
Ris
k W
ith N
o Sy
stem
ical
ly
Adm
inis
tere
d T
hrom
boly
tic
The
rapy
Ris
k D
iffer
ence
W
ith S
yste
mic
ally
A
dmin
iste
red
Thr
ombo
lytic
T
hera
py (9
5% C
I)
H
igh m
62
per
1,0
0039
mor
e pe
r 1,
000
(fro
m 0
mor
e to
10
4 m
ore)
Bib
liogr
aphy
: Nin
e ea
rlie
r stu
dies
141-
149 e
xtra
cted
from
thre
e sy
stem
atic
revi
ews (
Don
g et
al, 15
0 Wan
et a
l, 151 A
gnel
li et
al 15
2 ) a
nd tw
o re
cent
ly p
ublis
hed
stud
ies (
Bec
attin
i C e
t al, 15
3 Fas
sulo
et a
l 154 )
. See
Tab
le
S1 a
nd S
2 le
gend
s fo
r ex
pans
ion
of a
bbre
viat
ions
. a I
nclu
ded
stud
ies
used
diff
eren
t thr
ombo
lytic
age
nts
with
var
ying
dos
es a
nd d
urat
ions
of a
dmin
istr
atio
n; n
o st
atis
tical
het
erog
enei
ty w
as n
oted
. b T
hrom
boly
sis
was
in a
dditi
on to
ant
icoa
gula
tion
(mos
t of t
he s
tudi
es u
sed
hepa
rin
follo
wed
by
war
fari
n; th
ree
stud
ies
used
war
fari
n on
ly).
c One
stu
dy in
clud
ed e
xclu
sive
ly p
atie
nts
with
hem
odyn
amic
com
prom
ise
(sho
ck);
six
excl
uded
them
, whe
reas
the
rest
eith
er in
clud
ed a
num
ber
of s
uch
patie
nts
or d
id n
ot s
peci
fy r
elat
ed e
ligib
ility
. cri
teri
a.
Of s
tudi
es n
ot re
stri
cted
to p
atie
nts w
ith h
emod
ynam
ic c
ompr
omis
e (n
5 1
1), o
nly
thre
e w
ere
clea
rly
rest
rict
ed to
pat
ient
s with
righ
t ven
tric
ular
dys
func
tion;
the
rest
eith
er d
id n
ot sp
ecify
rela
ted
elig
ibili
ty
crite
ria
or in
clud
ed b
oth
patie
nts
with
and
with
out r
ight
ven
tric
ular
dys
func
tion.
As
a re
sult,
it w
as n
ot p
ossi
ble
to p
erfo
rm r
elia
ble
cate
gori
zatio
n of
stu
dies
to c
ondu
ct s
ubgr
oup
anal
yses
bas
ed o
n th
e pr
es-
ence
or
abse
nce
of r
ight
ven
tric
ular
dys
func
tion
or h
emod
ynam
ic c
ompr
omis
e.
d Stu
dies
incl
uded
pat
ient
s at
low
ris
k of
ble
edin
g.
e Rep
ort o
f met
hodo
logi
c qu
ality
was
poo
r in
mos
t stu
dies
. Of t
he 1
2 el
igib
le s
tudi
es, a
lloca
tion
was
con
ceal
ed in
fi ve
, thr
ee w
ere
sing
le b
linde
d (o
utco
me
asse
ssor
), si
x w
ere
doub
le b
linde
d, a
nd th
ree
wer
e no
t blin
ded.
Mos
t stu
dies
did
not
rep
ort o
n m
issi
ng o
utco
me
data
. Non
e of
the
stud
ies
was
sto
pped
ear
ly fo
r be
nefi t
. For
the
incr
ease
in b
leed
ing
with
thro
mbo
lytic
ther
apy,
qua
lity
of e
vide
nce
is in
crea
sed
from
low
to m
oder
ate
beca
use
ther
e is
hig
h qu
ality
evi
denc
e of
this
ass
ocia
tion
in p
atie
nts
with
myo
card
ial i
nfar
ctio
n an
d th
e in
dire
ctne
ss o
f thi
s ev
iden
ce to
pat
ient
s w
ith P
E is
min
or.
f I 2 5 0
%.
g CI
incl
udes
val
ues
sugg
estin
g bo
th b
enefi
t an
d no
eff
ect o
r ha
rm; s
mal
l num
ber
of e
vent
s.
h Inv
erte
d fu
nnel
plo
ts s
ugge
sted
pos
sibl
e pu
blic
atio
n bi
as in
favo
r of
thro
mbo
lytic
s.
i Rec
urre
nt P
E s
trat
ifi ca
tion
base
d on
the
sim
plifi
ed P
ulm
onar
y E
mbo
lism
Sev
erity
Ind
ex v
alid
ated
in th
e R
IET
E (R
egis
tro
Info
rmat
izad
o de
la E
nfer
med
ad T
rom
boem
bólic
a) c
ohor
t. 155
j Som
e st
udie
s su
gges
t th
at t
he b
asel
ine
risk
of
mor
talit
y in
pat
ient
s w
ith h
emod
ynam
ic in
stab
ility
is h
igh
as 3
0% (
Woo
d et
al).
156 I
n th
at c
ase,
the
abs
olut
e nu
mbe
r of
dea
th a
ssoc
iate
d w
ith t
hrom
boly
tics
wou
ld b
e 90
few
er p
er 1
,000
(fro
m 1
89 fe
wer
to 9
3 m
ore)
. k C
I in
clud
es v
alue
s su
gges
ting
both
har
m a
nd n
o ef
fect
; sm
all n
umbe
r of
eve
nts.
l In
dire
ct e
vide
nce
from
stu
dies
of t
hrom
boly
sis
for
myo
card
ial i
nfar
ctio
n an
d ac
ute
stro
ke p
rovi
de m
ore-
prec
ise
estim
ates
of i
ncre
ase
maj
or b
leed
ing
with
thro
mbo
lytic
s us
e.
m M
ajor
ble
edin
g ri
sk st
ratifi
cat
ion
deri
ved
from
the
RIE
TE
coh
ort. 15
7 The
med
ian
risk
of b
leed
ing
over
the
fi rst
10
d re
port
ed in
the
elig
ible
tria
ls w
as 3
.1%
. In
that
cas
e, th
e ab
solu
te n
umbe
r of m
ajor
ble
eds
with
thro
mbo
lysi
s w
ould
be
20 p
er 1
,000
(fro
m 0
mor
e to
52
mor
e).
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Tabl
e S4
1 —[S
ecti
on 5
.6.1
] Sy
stem
ic T
hrom
bol
ytic
The
rapy
vs
Ant
icoa
gula
tion
Alo
ne i
n P
atie
nts
Wit
h A
cute
PE
: Cli
nica
l D
escr
ipti
on a
nd R
esu
lts
Aut
hor/
Year
Inte
rven
tions
No.
Pat
ient
s A
naly
zed
Len
gth
of
Fol
low
-up
Rec
urre
nt D
VT
and
PE
(%) R
R (9
5% C
I)M
ajor
Ble
edin
g (%
) R
R (9
5% C
I)To
tal M
orta
lity
(%)
RR
(95%
CI)
Com
men
ts
SK 1
hep
arin
vs
hepa
rin
Tibb
utt e
t al 14
8 /197
4SK
600
,000
uni
ts
intr
apul
mon
ary
follo
wed
by
100
,000
uni
ts fo
r 72
h
SK: 1
1/13
(84.
6%)
72 h
SK: 0
/11
SL: 1
/11
(9.1
%)
SK: 0
/11
All
hydr
ocor
tison
e 10
0 m
g an
d at
60
h of
trea
tmen
t war
farin
in
itial
dos
e 25
mg
for 6
mo.
H
epar
in 5
,000
uni
ts
intr
apul
mon
ary
follo
wed
by
2,50
0 un
its fo
r 72
h
Hep
arin
: 12/
17
(70.
6%)
Hep
arin
: 0/1
2H
epar
in: 1
/12
(8.3
%)
RR
0.9
2 (0
.06-
12.9
5)H
epar
in: 0
/12
Seve
n pa
tient
s w
ho fa
iled
to
com
plet
e th
e tr
eatm
ent
regi
men
wer
e ex
clud
ed
from
the
anal
ysis
.
Pa
tient
s re
port
ing
maj
or
blee
ding
req
uire
d a
bloo
d tr
ansf
usio
n.
So
me
6-m
o fo
llow
-up
data
av
aila
ble
Ly
et a
l 146 /1
978
SK 2
50,0
00 u
nits
follo
wed
by
100
,000
uni
ts/h
for
72 h
SK: 1
4/14
10 d
SK: 1
/14
(7.1
%)
SK: 4
/14
(28.
6%)
SK: 1
/14
(7.1
%)
Prim
ary
outc
ome
was
ang
io-
grap
hic
repe
rfus
ion.
H
epar
in 1
5,00
0 un
its
follo
wed
by
1,25
0 un
its/h
fo
r 7
d
Hep
arin
: 11/
11H
epar
in: 2
/11
(18.
2%)
RR
2.5
5 (0
.26-
24.5
6)H
epar
in: 2
/11
(18.
2%)
RR
0.6
4 (0
.14-
2.86
)H
epar
in: 2
/11
(18.
2%)
RR
2.5
5 (0
.26-
24.5
6)F
ive
of th
e 25
pat
ient
s re
ceiv
ed n
onra
ndom
ized
th
erap
y. U
ncer
tain
if
deat
hs w
ere
in p
atie
nts
who
wer
e ra
ndom
ized
or
not r
ando
miz
ed.
Dot
ter
et a
l 143 /1
979
SK 2
50,0
00 u
nits
follo
wed
by
100,
000
units
/h fo
r 18
-72
hSK
: 15/
15In
hos
pita
lSK
: 0/1
5SK
: 3/1
5 (2
0.0%
)SK
: 1/1
5 (6
.7%
)A
ll: w
arfa
rin/
VK
A.
Prim
ary
outc
ome
was
an
giog
raph
ic r
eper
fusi
on
(not
cle
arly
sta
ted)
.
Hep
arin
1,5
00 u
nits
per
kg
for
2-7
dH
epar
in: 1
6/16
Hep
arin
: 1/1
6 (6
.3%
) R
R 2
.82
(0.1
2-64
.39)
Hep
arin
: 4/1
6 (2
5.0%
) R
R 1
.25
(0.3
3-4.
68)
Hep
arin
: 2/1
6 (1
2.5%
) R
R 1
.88
(0.1
9-18
.60)
Jerj
es-S
anch
ez
et a
l 145 /1
995
SK 1
,500
,000
uni
ts o
ver
1 h
follo
wed
by
a bo
lus
of
hepa
rin
10,0
00 u
nits
1
cons
tant
infu
sion
of 1
,000
un
its/h
SK: 4
/4In
hos
pita
lSK
: 0/4
(0%
)SK
: 0/4
(0%
)SK
: 0/4
(0%
)Pr
imar
y ou
tcom
e no
t sta
ted.
Tr
ial s
topp
ed e
arly
for
bene
fi t. A
ll pa
tient
s ha
d ca
rdio
geni
c sh
ock
at r
ando
miz
atio
n.
Hep
arin
-tre
ated
pat
ient
s ap
pear
to h
ave
faile
d he
pari
n th
erap
y be
fore
ra
ndom
izat
ion,
whe
reas
th
e SK
pat
ient
s ha
d no
t.
H
epar
in 1
0,00
0 un
its
follo
wed
by
1,00
0 un
its/h
Hep
arin
: 4/4
Hep
arin
: 4/4
(100
%)
RR
9.0
0 (0
.64-
126.
85)
Hep
arin
: 0/4
(0%
)H
epar
in: 4
/4 (1
00%
) R
R 9
.00
(0.6
4-12
6.85
)
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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(Con
tinu
ed)
Aut
hor/
Year
Inte
rven
tions
No.
Pat
ient
s A
naly
zed
Len
gth
of
Fol
low
-up
Rec
urre
nt D
VT
and
PE
(%) R
R (9
5% C
I)M
ajor
Ble
edin
g (%
) R
R (9
5% C
I)To
tal M
orta
lity
(%)
RR
(95%
CI)
Com
men
ts
Uro
kina
se v
s he
pari
n
UPE
T S
tudy
Gro
up
et a
l 141 /1
970
Uro
kina
se: i
nfus
ion
of 2
,000
C
TA u
nits
/lb fo
llow
ed b
y 2,
000
CTA
uni
ts/lb
per
h
Hep
arin
: inf
usio
n of
75
uni
ts/lb
follo
wed
by
10 u
nits
/lb p
er h
Uro
kina
se 8
2/82
Hep
arin
: 78/
78
2 w
kU
roki
nase
: 12/
82
(14.
6%)
Hep
arin
: 15/
78 (1
9.2%
) R
R 1
.31
(0.6
6-2.
63)
Uro
kina
se: 3
7/82
(4
5.1%
)
Hep
arin
: 21/
78 (2
6.9%
) R
R 0
.60
(0.3
9-0.
92)
Uro
kina
se: 6
/82
(7.3
%)
Hep
arin
: 7/7
8 (8
.9%
) R
R 1
.23
(0.4
3-3.
49)
All:
hep
arin
for
a m
inim
um
of 5
d.
The
maj
or b
leed
ing
repo
rted
in
clud
es m
oder
ate
1
seve
re b
leed
ing.
A
ngio
grap
hic
follo
w-u
p da
ta
avai
labl
e up
to 1
2 m
o.
Mar
ini e
t al 14
7 /198
8H
igh
dose
: uro
kina
se
3,30
0,00
0 un
its o
ver
12 h
Hig
h-do
se
urok
inas
e: 1
0/10
7 d
Hig
h-do
se u
roki
nase
: 0/
10H
igh-
dose
uro
kina
se:
0/10
Hig
h-do
se u
roki
nase
: 0/
10Pr
imar
y ou
tcom
e w
as lu
ng
scan
per
fusi
on.
L
ow d
ose:
uro
kina
se 8
00,0
00
units
ove
r 12
h d
aily
for
3 d
Low
-dos
e ur
okin
ase:
10/
10L
ow-d
ose
urok
inas
e:
0/10
Low
-dos
e ur
okin
ase:
0/
10L
ow-d
ose
urok
inas
e:
0/10
Thr
ombo
lysi
s ar
ms
did
not
rece
ive
hepa
rin.
Hep
arin
30,
000
units
/d fo
r 7
d fo
llow
ed b
y O
AC
Hep
arin
: 10/
10H
epar
in: 0
/10
Hep
arin
: 0/1
0H
epar
in: 0
/10
All
patie
nts:
OA
Cs
cont
inue
d fo
r 1
y.
rt-P
A (a
ltepl
ase)
1 h
epar
in v
s he
pari
n
Dal
la-V
olta
et a
l 142 /1
992
rt-P
A 1
0 m
g fo
llow
ed b
y 90
mg
over
2 h
rt-P
A a
ltepl
ase:
20
/20
30 d
rt-P
A a
ltepl
ase:
1/2
0 (5
.0%
)rt
-PA
alte
plas
e: 3
/20
(15.
0%)
rt-P
A a
ltepl
ase:
2/2
0 (1
0.0%
)Pr
imar
y ou
tcom
e w
as
angi
ogra
phic
rep
erfu
sion
.
Hep
arin
10,
000
units
follo
wed
by
1,7
50 u
nits
/h fo
r 7-
10 d
Hep
arin
: 16/
16H
epar
in: 0
/16
RR
2.4
3 (0
.11-
55.8
9)H
epar
in: 2
/16
(12.
5%)
RR
1.2
0 (0
.23-
6.34
)H
epar
in: 0
/16
RR
4.0
5 (0
.21-
78.7
6)
Gol
dhab
er e
t al 15
8 /199
3rt
-PA
alte
plas
e 10
0 m
g ov
er
2 h
follo
wed
by
hepa
rin
1,00
0 un
its/h
rt-P
A: 4
6/46
In h
ospi
tal
14-2
1 d
rt-P
A: 0
/46
rt-P
A: 3
/46
(6.5
%)
rt-P
A: 0
/46
Prim
ary
outc
ome
was
ec
hoca
rdio
grap
hic
righ
t ve
ntri
cula
r fu
nctio
n.
H
epar
in 5
,000
uni
ts fo
llow
ed
by 1
,000
uni
ts/h
Hep
arin
: 55/
55H
epar
in: 5
/55
(9.1
%)
RR
0.1
1 (0
.01-
1.91
)H
epar
in: 1
/55
(1.8
%) R
R 3
.59
(0.3
9-33
.33)
Hep
arin
: 2/5
5 (3
.6%
) R
R 0
.24
(0.0
1-4.
84)
Kon
stan
tinid
es
et a
l 159 /2
002
Alte
plas
e 10
0 m
g fo
llow
ed
by a
ltepl
ase
90 m
g ov
er
2 h
1 h
epar
in 1
,000
un
its/h
Alte
plas
e: 1
18/1
1830
dA
ltepl
ase:
4/1
18 (3
.4%
)A
ltepl
ase:
1/1
18
(0.8
%)
Alte
plas
e: 4
/118
(3.4
%)
Prim
ary
outc
ome
was
dea
th
or n
eed
for
esca
latio
n of
th
erap
y (la
ter
deci
sion
co
uld
be m
ade
afte
r un
blin
ding
).
Hep
arin
5,0
00 u
nits
follo
wed
by
1,0
00 u
nits
/h 1
pla
cebo
Hep
arin
1 p
lace
bo:
138/
138
Hep
arin
1 p
lace
bo:
4/13
8 (2
.9%
) R
R 1
.17
(0.3
0-4.
57)
Hep
arin
1 p
lace
bo:
5/13
8 (3
.6%
) R
R 0
.23
(0.0
3-1.
97)
Hep
arin
1 p
lace
bo:
3/13
8 (2
.2%
) R
R 1
.56
(0.3
6-6.
83)
Tabl
e S4
1—C
onti
nued
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
67© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Aut
hor/
Year
Inte
rven
tions
No.
Pat
ient
s A
naly
zed
Len
gth
of
Fol
low
-up
Rec
urre
nt D
VT
and
PE
(%) R
R (9
5% C
I)M
ajor
Ble
edin
g (%
) R
R (9
5% C
I)To
tal M
orta
lity
(%)
RR
(95%
CI)
Com
men
ts
Lev
ine
et a
l 160 /1
990
rt-P
A 0
.6m
g/kg
ove
r 2
min
rt-P
A: 3
3/33
10 d
rt-P
A: 0
/33
rt-P
A: 0
/33
rt-P
A: 1
/33
(3.0
%)
Prim
ary
outc
ome
was
lung
sc
an r
eper
fusi
on
Pl
aceb
o pl
us h
epar
in
5,00
0 un
its fo
llow
ed
by 3
0,00
0/d
Plac
ebo:
25/
25Pl
aceb
o: 0
/25
Plac
ebo:
0/2
5Pl
aceb
o: 0
/25
RR
2.2
9 (0
.10-
54.0
6)
PIO
PED
In
vest
igat
ors 14
4 /199
0rt
-PA
40-
80 m
g at
1 m
g/m
inrt
-PA
: 9/9
7 d
rt-P
A: 0
/9rt
-PA
: 1/9
(11.
1%)
rt-P
A: 0
/9Pr
imar
y ou
tcom
e no
t sta
ted
(ser
ial a
ngio
grap
hic
and
lung
sca
ns w
ere
asse
ssed
).
Plac
ebo
1 h
epar
in
(dos
es d
eter
min
ed
by p
hysi
cian
)
Plac
ebo:
4/4
Plac
ebo:
0/4
Plac
ebo:
0/4
RR
1.5
0 (0
.07-
30.5
9)Pl
aceb
o: 0
/4H
epar
in d
oses
det
erm
ined
by
att
endi
ng p
hysi
cian
in
both
gro
ups
O
ne d
eath
occ
urre
d 19
d
afte
r tr
eatm
ent
Fas
ullo
et a
l 154 /2
011
Alte
plas
e 10
0 m
g ov
er 2
hA
ltepl
ase:
37/
3710
dA
ltepl
ase:
0/3
7A
ltepl
ase:
2/3
7 (5
.4%
)A
ltepl
ase:
0/3
7A
ll ha
d ri
ght v
entr
icul
ar
dysf
unct
ion.
Pri
mar
y ou
tcom
e w
as
echo
card
iogr
aphi
c ch
ange
s.
Pl
aceb
o 1
hep
arin
5,
000
units
fo
llow
ed b
y 1,
000
units
/h
Plac
ebo:
35/
35Pl
aceb
o: 3
/35
(8.5
%)
Plac
ebo:
1/3
5 (2
.9%
)Pl
aceb
o: 5
/35
(14.
2%)
Thr
ee r
ecur
rent
PE
wer
e fa
tal.
One
add
ition
al fa
tal
and
nonf
atal
PE
in
hepa
rin
arm
by
180
d.
N
o fa
tal o
r in
trac
rani
al
blee
ds.
Tene
ctap
lase
1 h
epar
in v
s he
pari
n
Bec
attin
i et a
l 153 /2
010
Tene
ctap
lase
: � 2
mg/
kg
bolu
sTe
nect
apla
se: 2
8/28
30 d
Tene
ctap
lase
: 2/2
8Te
nect
apla
se: 2
/28
Tene
ctap
lase
: 0/2
8A
ll ha
d ri
ght v
entr
icul
ar
dysf
unct
ion.
Pri
mar
y ou
tcom
e w
as
echo
card
iogr
aphi
c ch
ange
s.
Pl
aceb
o 1
hep
arin
(8
0 In
tern
atio
nal U
nits
/kg
and
18 I
nter
natio
nal
Uni
ts/k
g pe
r h)
Plac
ebo:
32/
32Pl
aceb
o: 1
/32
Plac
ebo:
1/3
2Pl
aceb
o: 1
/32
No
fata
l PE
or
maj
or
blee
ding
; one
intr
acra
nial
bl
eed
(ten
ecta
plas
e).
CTA
5 C
omm
ittee
on
Thr
ombo
lytic
Age
nts;
OA
C 5
ora
l ant
icoa
gula
nt; P
IOPE
D 5
Pro
spec
tive
Inve
stig
atio
n of
Pul
mon
ary
Em
bolis
m D
iagn
osis
; UPE
T 5
Uro
kina
se P
ulm
onar
y E
mbo
lism
Tri
al. S
ee T
able
S1
, S2,
and
S11
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
.
Tabl
e S4
1—C
onti
nued
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Tabl
e S4
2 —[S
ecti
on 5
.6.1
] Sy
stem
ic T
hrom
bol
ytic
The
rapy
vs
Ant
icoa
gula
tion
Alo
ne i
n P
atie
nts
Wit
h A
cute
PE
: Met
hodo
logi
c Q
ual
ity
Aut
hor/
Year
Inte
rven
tion
Stud
y D
esig
nR
ando
miz
e C
once
aled
Blin
ding
Los
t to
Fol
low
-up
Ana
lysi
sC
omm
ents
SK 1
hep
arin
vs
hepa
rin
Tibb
utt e
t al 14
8 /197
4SK
600
,000
uni
ts in
trap
ulm
onar
y fo
llow
ed b
y 10
0,00
0 un
its fo
r 72
hR
CT
PYPa
tient
s: P
Y C
areg
iver
s: P
N
Dat
a C
olle
ctor
s: P
N
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
SK: 0
/11
(0%
)Pe
r pr
otoc
olA
ll hy
droc
ortis
one
100
mg
and
at 6
0 h
of tr
eatm
ent,
war
fari
n in
itial
dos
e 25
mg
for
6 m
o.
H
epar
in 5
,000
uni
ts in
trap
ulm
onar
y fo
llow
ed b
y 2,
500
units
for
72 h
Hep
arin
: 0/1
2 (0
%)
Seve
n pa
tient
s w
ho fa
iled
to
com
plet
e th
e tr
eatm
ent
regi
men
wer
e ex
clud
ed
from
the
anal
ysis
.
Lye
t al 14
6 /197
8SK
250
,000
uni
ts fo
llow
ed b
y 10
0,00
0 un
its/h
for
72 h
RC
TC
YPa
tient
s: P
Y C
areg
iver
s: P
N
Dat
a C
olle
ctor
s: P
N
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
SK: 0
/14
(0%
)A
s tr
eate
d In
clud
ed 5
non
rand
omiz
ed
patie
nts,
and
unc
erta
in if
de
aths
occ
urre
d in
thos
e w
ho w
ere
rand
omiz
ed o
r no
t ran
dom
ized
.
H
epar
in 1
5,00
0 U
follo
wed
by
1250
U/h
for
7day
sH
epar
in: 0
/11
(0%
)
Dot
ter
et a
l 143 /1
979
SK 2
50,0
00 u
nits
follo
wed
by
100,
000
units
/h fo
r 18
-72
hR
CT
PYPa
tient
s: P
Y C
areg
iver
s: P
N
Dat
a C
olle
ctor
s: P
N
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
SK p
lus
hepa
rin:
0/1
5 (0
%)
ITT
H
epar
in 1
,500
uni
ts p
er k
g fo
r 2-
7 d
Hep
arin
: 0/1
6 (0
%)
Jerj
es-S
anch
ez e
t al 14
5 /199
5SK
1,5
00,0
00 u
nits
ove
r 1
h fo
llow
ed
by a
bol
us o
f hep
arin
10,
000
units
1
con
stan
t inf
usio
n of
1,
000
units
/h
RC
TC
YPa
tient
s: P
Y C
areg
iver
s: P
N
Dat
a C
olle
ctor
s: P
N
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
SK 1
hep
arin
: 0/4
(0%
)IT
T
H
epar
in 1
0,00
0 un
its fo
llow
ed
by 1
,000
uni
ts/h
Hep
arin
: 0/4
(0%
)
Uro
kina
se v
s he
pari
n
UPE
T S
tudy
G
roup
141,
149 /1
970
Uro
kina
se: i
nfus
ion
of 2
,000
C
TA u
nits
/lb fo
llow
ed b
y 2,
000
CTA
uni
ts/lb
per
h H
epar
in:
infu
sion
of 7
5 un
its/lb
follo
wed
by
10
units
/lb p
er h
RC
TC
YPa
tient
s: C
Y C
areg
iver
s: C
N
Dat
a C
olle
ctor
s: C
Y A
djud
icat
ors:
CY
Dat
a A
naly
sts:
CY
Uro
kina
se: 0
/82
(0%
) H
epar
in: 0
/78
(0%
)
As
trea
ted
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Mar
ini e
t al 14
7 /198
8H
igh
dose
: uro
kina
se 3
,300
,000
uni
ts
over
12
hR
CT
PYPa
tient
s: P
N
Car
egiv
ers:
CN
D
ata
Col
lect
ors:
PN
A
djud
icat
ors:
PN
D
ata
Ana
lyst
s: P
N
Hig
h-do
se u
roki
nase
: 0/
10 (0
%)
ITT
L
ow d
ose:
uro
kina
se 8
00,0
00 u
nits
ov
er 1
2 h
daily
for
3 d
Low
-dos
e ur
okin
ase:
0/
10 (0
%)
H
epar
in 3
0,00
0 un
its/d
for
7 d
follo
wed
by
OA
CH
epar
in: 0
/10
(0%
)
rt-P
A (a
ltepl
ase)
1 h
epar
in v
s he
pari
n
Dal
la-V
olta
et a
l 142 /1
992
rt-P
A (a
ltepl
ase)
10
mg
follo
wed
by
90
mg
over
2 h
RC
TPY
Patie
nts:
PN
C
areg
iver
s: C
N
Dat
a C
olle
ctor
s: P
N
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
rt-P
A: 0
/20
(0%
)IT
T
H
epar
in 1
0,00
0 un
its fo
llow
ed
by 1
,750
uni
ts/h
for
7-10
dH
epar
in: 0
/16
(0%
)
Gol
dhab
er e
t al 15
8 /199
3rt
-PA
100
mg
over
2 h
follo
wed
by
hep
arin
1,0
00 u
nits
/hR
CT
CY
Patie
nts:
PN
C
areg
iver
s: C
N
Dat
a C
olle
ctor
s: P
N
Adj
udic
ator
s: P
N
Dat
a A
naly
sts:
PN
rt-P
A: 0
/46
(0%
)IT
T
H
epar
in 5
,000
uni
ts fo
llow
ed b
y 1,
000
units
/hH
epar
in: 0
/55
(0%
)
Kon
stan
tinid
es e
t al 15
9 /200
2rt
-PA
(alte
plas
e) 1
00 m
g fo
llow
ed
by a
ltepl
ase
90 m
g ov
er
2 h
1 h
epar
in 1
,000
uni
ts/h
RC
TC
YPa
tient
s: P
Y C
areg
iver
s: C
N
Dat
a C
olle
ctor
s: P
Y A
djud
icat
ors:
PN
D
ata
Ana
lyst
s: P
Y
rt-P
A: 0
/118
(0%
)IT
TA
ll: U
FH
5,0
00 u
nits
.
H
epar
in 5
,000
uni
ts fo
llow
ed
by 1
,000
uni
ts/h
UF
H: 0
/138
(0%
)
Lev
ine
et a
l 160 /1
990
rt-P
A 0
.6 m
g/kg
ove
r 2
min
RC
TPY
Patie
nts:
CY
Car
egiv
ers:
CY
Dat
a C
olle
ctor
s: C
Y A
djud
icat
ors:
CY
Dat
a A
naly
sts:
CY
rt-P
A: 0
/33(
0%)
ITT
All:
UF
H in
itial
bol
us o
f 5,
000
units
follo
wed
by
cont
inuo
us in
fusi
on a
t st
artin
g do
se o
f 30,
000
for
the
fi rst
24
h.
Pl
aceb
o 1
hep
arin
5,0
00 u
nits
fo
llow
ed b
y 30
,000
/dH
epar
in: 0
/25(
0%)
(Con
tinu
ed)
Aut
hor/
Year
Inte
rven
tion
Stud
y D
esig
nR
ando
miz
e C
once
aled
Blin
ding
Los
t to
Fol
low
-up
Ana
lysi
sC
omm
ents
Tabl
e S4
2—C
onti
nued
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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PIO
PED
In
vest
igat
ors 14
4 /199
0rt
-PA
40-
80m
g at
1 m
g/m
inR
CT
PYPa
tient
s: C
Y C
areg
iver
s: C
Y D
ata
Col
lect
ors:
PY
Adj
udic
ator
s: P
Y D
ata
Ana
lyst
s: P
Y
rt-P
A: 0
/9(0
%)
ITT
All:
hep
arin
dos
es d
eter
min
ed
by a
tten
ding
phy
sici
an.
Pl
aceb
o pl
us h
epar
in (d
oses
de
term
ined
by
phys
icia
n)H
epar
in: 0
/4(0
%)
Fas
ullo
et a
l 154 /2
011
Alte
plas
e 10
0 m
g ov
er 2
hR
CT
CY
Patie
nts:
CY
Car
egiv
ers:
CY
Dat
a C
olle
ctor
s: P
Y A
djud
icat
ors:
CY
Dat
a A
naly
sts:
PY
rt-P
A: 0
/37
ITT
Prim
ary
outc
ome
was
ec
hoca
rdio
grap
hic
chan
ges.
Pl
aceb
o 1
hep
arin
5,0
00 u
nits
fo
llow
ed b
y 1,
000
units
/hH
epar
in: 0
/35
rt-P
A (a
ltepl
ase)
1 h
epar
in v
s he
pari
n
Bec
attin
i et a
l 153 /2
010
Tene
ctap
lase
: � 2
mg/
kg b
olus
RC
TC
YPa
tient
s: C
Y C
areg
iver
s: C
Y D
ata
Col
lect
ors:
CY
Adj
udic
ator
s: C
Y D
ata
Ana
lyst
s: P
Y
Tene
ctap
lase
: 0/2
8(0%
)IT
TPr
imar
y ou
tcom
e w
as
echo
card
iogr
aphi
c ch
ange
s.
Pl
aceb
o 1
hep
arin
(80
Inte
rnat
iona
l U
nits
/kg
and
18 I
nter
natio
nal
Uni
ts/k
g pe
r h)
Hep
arin
: 0/3
0(0%
)
See
Tabl
e S1
, S2,
S5,
S11
, and
S41
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
.
Aut
hor/
Year
Inte
rven
tion
Stud
y D
esig
nR
ando
miz
e C
once
aled
Blin
ding
Los
t to
Fol
low
-up
Ana
lysi
sC
omm
ents
Tabl
e S4
2—C
onti
nued
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
71© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Tabl
e S4
3 —[S
ecti
on 8
.1]
Evi
denc
e P
rofi l
e: F
onda
pari
nux
vs P
lace
bo
for
Acu
te S
VT
a-c
Qua
lity
Ass
essm
ent
Sum
mar
y of
Fin
ding
s
St
udy
Eve
nt R
ates
(%)
Ant
icip
ated
Abs
olut
e E
ffec
ts
Part
icip
ants
(S
tudi
es),
Fol
low
-up
Ris
k of
Bia
sIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Publ
icat
ion
Bia
sO
vera
ll Q
ualit
y of
Evi
denc
eW
ith N
o F
onda
pari
nux
With
F
onda
parin
uxR
elat
ive
Eff
ect
(95%
CI)
Ris
k W
ith N
o F
onda
parin
ux
Ris
k D
iffer
ence
W
ith F
onda
parin
ux
(95%
CI)
Mor
talit
y (im
port
ant o
utco
me)
3,00
2 (1
stu
dy),
3 m
oN
o se
riou
s ri
sk o
f bia
s d N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous e,
f U
ndet
ecte
dM
oder
ate d-
g due
to
impr
ecis
ion
1/1,
500
(0.1
)2/
1,50
2 (0
.1)
RR
1.9
9 (0
.18-
21.8
7)4
per
1,00
0 h 4
mor
e pe
r 1,
000
(fro
m 3
few
er
to 8
3 m
ore)
VT
E (c
ritic
al o
utco
me)
3,00
2 (1
stu
dy),
3 m
oN
o se
riou
s ri
sk o
f bia
s d N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
No
seri
ous
impr
ecis
ion
Und
etec
ted
Hig
h d 22
/1,5
00 (1
.5)
4/1,
502
(0.3
)R
R 0
.18
(0.0
6-0.
53)
33 p
er 1
,000
h 27
few
er p
er
1,00
0 (f
rom
16
few
er to
31
few
er)
SVT
rec
urre
nce
(impo
rtan
t out
com
e)
3,00
2 (1
stu
dy),
3 m
oN
o se
riou
s ri
sk o
f bia
s d N
o se
riou
s in
cons
iste
ncy
No
seri
ous
indi
rect
ness
Seri
ous f,g
U
ndet
ecte
dH
igh d d
ue to
im
prec
isio
n26
/1,5
00 (1
.7)
8/1,
502
(0.5
)R
R 0
.31
(0.1
4-0.
68)
19 p
er 1
,000
h 13
few
er p
er
1,00
0 (f
rom
6
few
er to
16
few
er)
Maj
or b
leed
ing
(cri
tical
out
com
e)
2,98
7 (1
stu
dy),
47 d
No
seri
ous
risk
of b
ias d
No
seri
ous
inco
nsis
tenc
yN
o se
riou
s in
dire
ctne
ssSe
riou
s e,i
Und
etec
ted
Mod
erat
e d,e,
i due
to
impr
ecis
ion
1/1,
488
(0.1
)1/
1,49
9 (0
.1)
RR
0.9
9 (0
.06-
15.8
6) e
1 pe
r 1,
000
0 fe
wer
per
1,0
00
(fro
m 1
few
er
to 1
0 m
ore)
Qua
lity
of li
fe n
ot m
easu
red
……
……
……
……
……
…
Bib
liogr
aphy
: CA
LIS
TO
stu
dy b
y D
ecou
sus
et a
l. 161 C
AL
IST
O 5
Com
pari
son
of A
RIX
TR
A™
in lo
wer
LIm
b Su
perfi
cia
l Thr
ombo
phle
bitis
with
pla
cebo
; SV
T 5
supe
rfi c
ial v
ein
thro
mbo
sis.
See
Tab
le S
1 an
d S5
lege
nds
for
expa
nsio
n of
oth
er a
bbre
viat
ions
. a F
onda
pari
nux
2.5
mg
for
45 d
. b P
atie
nts
in th
e tw
o tr
eatm
ent g
roup
s be
nefi t
ed fr
om c
lose
clin
ical
mon
itori
ng w
ith a
dequ
ate
diag
nost
ic p
roce
dure
s in
the
even
t of n
ew a
nd p
ersi
sten
t sym
ptom
s.
c Pat
ient
s w
ith in
fusi
on-r
elat
ed S
VT
wer
e ex
clud
ed if
from
CA
LIS
TO
. d A
lloca
tion
conc
eale
d. O
utco
me
adju
dica
tors
, st
eeri
ng c
omm
ittee
, pa
tient
s, p
rovi
ders
, an
d da
ta c
olle
ctor
s bl
inde
d. F
ollo
w-u
p ra
te w
as 9
8%.
ITT
ana
lysi
s fo
r ef
fi cac
y ou
tcom
es.
Not
sto
pped
ear
ly f
or
bene
fi t.
e CI
incl
udes
val
ues
sugg
estin
g la
rge
bene
fi t a
nd v
alue
s su
gges
ting
larg
e ha
rm.
f We
rate
d do
wn
by o
nly
one
leve
l bec
ause
the
low
eve
nt r
ate
and
larg
e sa
mpl
e si
ze.
g Sm
all n
umbe
r of
eve
nts.
h B
asel
ine
risk
der
ived
from
a la
rge
pros
pect
ive
coho
rt s
tudy
. 162
i The
upp
er li
mit
of th
e C
I fo
r ab
solu
te e
ffec
t (10
mor
e bl
eeds
) is
not l
ow e
noug
h to
sug
gest
a c
lear
bal
ance
of b
enefi
ts v
s ha
rms.
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
72© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
(Con
tinu
ed)
Tabl
e S4
4 —[S
ecti
on 8
.1]
Supe
rfi c
ial
Vei
n T
hrom
bos
is T
reat
men
t: C
lini
cal
Des
crip
tion
and
Res
ult
s (R
ando
miz
ed T
rial
s C
ompa
ring
Tre
atm
ents
)
Aut
hor/
Year
Type
of
Publ
icat
ion a
Part
icip
ants
Inte
rven
tion b
Out
com
es c
Fol
low
-up
Res
ults
STE
NO
X S
tudy
163
Gro
up/2
003
Para
llel R
CT,
m
ultic
ente
r43
6 pa
tient
s w
ith
ultr
asou
nd-c
onfi r
med
ac
ute
sym
ptom
atic
SV
T ( �
5 c
m le
ngth
) of
the
low
er e
xtre
mity
Eno
xapa
rin
40 m
g SC
dai
lyE
noxa
pari
n 1.
5 m
g/kg
SC
dai
lyTe
noxi
cam
, 20
mg
po d
aily
Plac
ebo
once
dai
lyA
ll gi
ven
for
8-12
dA
ll pa
tient
s pr
escr
ibed
ela
stic
ba
ndag
es o
r co
mpr
essi
on
stoc
king
s fo
r at
leas
t 15
d
Day
12
(end
of t
reat
men
t):
Scre
enin
g ul
tras
ound
or
sym
ptom
atic
rec
urre
nce:
VT
E
SVT
rec
urre
nce/
exte
nsio
n to
sa
phen
ofem
oral
junc
tion
3-m
o V
TE
SV
T r
ecur
renc
e/ex
tens
ion
Maj
or b
leed
ing
Dea
th
3 m
oV
TE
day
12:
Pla
cebo
: 4/1
12 (3
.6%
) (PE
0)
Eno
xapa
rin
40 m
g: 1
/110
(0.9
%) (
PE 0
); R
R 0
.25
(95%
CI,
0.0
3-2.
24)
Eno
xapa
rin
1.5
mg/
kg: 1
/106
(0.9
%)
(PE
0);
RR
0.2
6 (9
5% C
I, 0
.03-
2.33
) Te
noxi
cam
: 2/9
9 (2
.0%
) (PE
1);
RR
0.5
7 (9
5% C
I, 0
.11-
3.02
) P
5 n
s fo
r al
l com
pari
sons
of a
ctiv
e tr
eatm
ent v
s pl
aceb
o SV
T r
ecur
renc
e/ex
tens
ion
day
12:
Plac
ebo:
33/
112
(29.
5%)
Eno
xapa
rin
40 m
g: 9
/110
(8.3
%);
RR
0.2
8 (9
5% C
I, 0
.14-
0.55
) E
noxa
pari
n 1.
5 m
g/kg
: 6/1
06 (5
.7%
); R
R 0
.19
(95%
CI,
0.0
8-0.
44)
Teno
xica
m: 1
3/99
(13.
1%);
RR
0.4
5 (9
5% C
I, 0
.25-
0.80
) V
TE
3 m
o:
Plac
ebo:
5/1
12 (4
.5%
) (PE
0)
Eno
xapa
rin
40 m
g: 6
/110
(5.7
%);
(PE
2);
RR
1.2
2 (9
5% C
I, 0
.38-
3.89
) E
noxa
pari
n 1.
5mg/
kg: 4
/106
(3.9
%)
(PE
0);
RR
0.8
5 (9
5% C
I, 0
.23-
3.06
) Te
noxi
cam
: 4/9
9 (4
.3%
) (PE
1);
RR
0.9
1 (9
5% C
I, 0
.25-
3.28
) P
5 n
s fo
r al
l com
pari
sons
of a
ctiv
e tr
eatm
ent v
s pl
aceb
o SV
T r
ecur
renc
e/ex
tens
ion
3 m
o: P
lace
bo:
37/1
12 (3
3.0%
) E
noxa
pari
n 40
mg:
16/
110
(14.
5%);
RR
0.4
4 (9
5% C
I, 0
.26-
0.74
)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
73© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Aut
hor/
Year
Type
of
Publ
icat
ion a
Part
icip
ants
Inte
rven
tion b
Out
com
es c
Fol
low
-up
Res
ults
E
noxa
pari
n 1.
5 m
g/kg
: 16/
106
(15.
1%);
RR
0.4
6 (9
5% C
I, 0
.27-
0.77
)
Te
noxi
cam
: 15/
99 (1
5.2%
); R
R 0
.46
(95%
CI,
0.2
7-0.
78)
M
ajor
ble
edin
g: 0
Dea
th: 0
Tito
n et
al 16
4 /19
94Pa
ralle
l RC
T,
mul
ticen
ter
117
patie
nts
with
ul
tras
ound
-con
fi rm
ed
SVT
of t
he lo
wer
ex
trem
ities
Nad
ropa
rin
fi xed
dos
e, 6
,150
an
ti-X
a In
tern
atio
nal
Uni
ts d
aily
Ech
ocar
diog
raph
ic e
xten
sion
of
thro
mbu
s at
day
7 a
nd a
t 8 w
k8
wk
Day
7 e
xten
sion
of t
hrom
bus:
Fix
ed-d
ose
nadr
opar
in: 1
/38
(2.6
%)
N
adro
pari
n 31
.5 a
nti-X
a In
tern
atio
nal U
nits
/kg
SC d
aily
Cha
nges
in s
ympt
oms
and
clin
ical
si
gns
(war
mth
, fl u
shin
g, e
dem
a,
pain
on
palp
atio
n)
Wei
ght-
base
d na
drop
arin
: 2/4
0 (5
%);
RR
1.9
0 (9
5% C
I, 0
.18-
20.1
)
N
apro
xen
500
mg
po d
aily
DV
TN
apro
xen:
1/3
9 (2
.6%
); R
R 0
.97
(95%
CI,
0.0
6-15
.02)
Trea
tmen
ts g
iven
for
6 d
PE P
5 n
s
All
patie
nts
wor
e co
mpr
essi
on
stoc
king
s fo
r 7
dM
ajor
ble
edin
g8-
wk
exte
nsio
n of
thro
mbu
s or
new
SV
T:
Fix
ed-d
ose
nadr
opar
in: 2
/36
(5.6
%)
W
eigh
t-ba
sed
nadr
opar
in: 0
/40
(0%
); R
R 0
.18
(95%
CI,
0.0
1-3.
64)
N
apro
xen:
0/3
9 (0
%);
RR
(95%
CI)
0.
19 (0
.01-
3.73
)
No
DV
T, P
E, o
r m
ajor
ble
edin
g in
any
gro
up
In
tens
ity o
f sym
ptom
s/si
gns:
Ove
rall
impr
ovem
ent i
n sc
ore
from
day
0 to
day
7:
Fix
ed-d
ose
nadr
opar
in: 7
9.1%
impr
oved
Wei
ght-
base
d na
drop
arin
: 63.
0% im
prov
ed
N
apro
xen:
46.
4% im
prov
ed
P �
.01
in fa
vor
of n
adro
pari
n vs
nap
roxe
n;
this
diff
eren
ce w
as m
aint
aine
d at
8 w
k
Pran
doni
for
Vesa
lio
Inve
stig
ator
s G
roup
165 /2
005
Para
llel R
CT,
m
ultic
ente
r16
4 pa
tient
s w
ith
ultr
asou
nd-c
onfi r
med
ac
ute
SVT
of t
he
grea
ter
saph
enou
s ve
in
Hig
h-do
se w
eigh
t-ad
just
ed
nadr
opar
in (1
90 a
nti-X
a In
tern
atio
nal U
nits
/kg
for
10 d
follo
wed
by
95 a
nti-X
a In
tern
atio
nal U
nits
/kg
for
20 d
)
Com
posi
te o
utco
me
of
asym
ptom
atic
or
sym
ptom
atic
SV
T e
xten
sion
, asy
mpt
omat
ic
or s
ympt
omat
ic D
VT,
sy
mpt
omat
ic P
E a
t 3 m
o
3 m
o3
mo
follo
w-u
p:
Tabl
e S4
4—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
74© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Aut
hor/
Year
Type
of
Publ
icat
ion a
Part
icip
ants
Inte
rven
tion b
Out
com
es c
Fol
low
-up
Res
ults
Im
prov
emen
t in
clin
ical
sy
mpt
oms
and
sign
s at
1 m
o
L
ow-d
ose
nadr
opar
in
(2,8
50 a
nti-X
a In
tern
atio
nal
Uni
ts fo
r 30
d)
Maj
or b
leed
ing
SVT
Hig
h do
se: 2
/83
(2.4
%) (
1 oc
curr
ed
whi
le o
n tr
eatm
ent)
Low
dos
e: 5
/81
(6.2
%)
(all
occu
rred
whi
le o
n tr
eatm
ent)
RR
2.5
6 (9
5% C
I, 0
.51-
12.8
3)
D
eath
No
plac
ebo
grou
p N
SAID
S an
d as
piri
n us
e di
scou
rage
dV
TE
Hig
h do
se: 4
/83
(4.8
%)
(3 s
ympt
omat
ic e
vent
s; 1
[PE
] occ
urre
d w
hile
on
trea
tmen
t)
Low
dos
e: 2
/81
(2.5
%) (
both
sy
mpt
omat
ic D
VT
) RR
0.5
1 (9
5% C
I,
0.10
-2.7
2)
R
ate
of im
prov
emen
t in
clin
ical
sy
mpt
oms
and
sign
s si
mila
r bo
th g
roup
s M
ajor
ble
edin
g: 0
D
eath
: 0
Mar
chio
ri e
t al 16
6 /200
2Pa
ralle
l RC
T,
sing
le c
ente
r60
pat
ient
s w
ith
ultr
asou
nd-c
onfi r
med
fi r
st a
cute
SV
T o
f gr
eate
r sa
phen
ous
vein
Low
-dos
e U
FH
(5,0
00
Inte
rnat
iona
l Uni
ts b
id
SC fo
r 4
wk)
VT
E6
mo
VT
E d
urin
g tr
eatm
ent p
erio
d: L
ow d
ose:
4/
30 (1
3.3%
) (3
asym
ptom
atic
DV
T, 1
PE
) E
xten
sion
/Rec
urre
nce
of th
rom
bosi
s
Hig
h-do
se U
FH
(12,
500
Inte
rnat
iona
l Uni
ts fo
r 1
wk
then
10,
000
Inte
rnat
iona
l U
nits
for
3 w
k)
Maj
or b
leed
ing
Hig
h do
se: 0
/30
(0%
); R
R 0
.11
(95%
CI,
0.0
1-1.
98; P
5 n
s)
HIT
D
eath
Ext
ensi
on/r
ecur
renc
e SV
T d
urin
g tr
eatm
ent p
erio
d:
Low
dos
e: 7
/30
(23.
3%)
Hig
h do
se: 3
/30
(10%
); R
R 0
.40
(95%
CI,
0.1
1-1.
40; P
5 n
s)
Use
of c
onco
mita
nt s
yste
mic
or
loca
l ant
iinfl a
mm
ator
y dr
ugs
perm
itted
but
use
no
t des
crib
ed
Ove
rall
VT
E d
urin
g fo
llow
-up
peri
od:
Low
dos
e: 6
/30
(20%
) H
igh
dose
: 1/3
0 (3
.3%
); R
R 0
.17
(95%
CI,
0.0
2-1.
30; P
5 n
s)
O
vera
ll ex
tens
ion/
recu
rren
ce S
VT
dur
ing
follo
w-u
p pe
riod
: Low
dos
e: 1
1/30
(36.
7%)
Hig
h do
se: 8
/30
(26.
7%);
RR
0.7
3 (9
5% C
I, 0
.34,
1.5
5; P
5 n
s)
Tabl
e S4
4—C
onti
nued
(Con
tinu
ed)
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
75© 2012 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml). DOI: 10.1378/chest.11-2301
Aut
hor/
Year
Type
of
Publ
icat
ion a
Part
icip
ants
Inte
rven
tion b
Out
com
es c
Fol
low
-up
Res
ults
N
o m
ajor
ble
edin
g, H
IT, o
r de
ath
in
any
grou
p
Bel
caro
et a
l 167 /1
999
Para
llel R
CT,
m
ultic
ente
r56
2 pa
tient
s w
ith
ultr
asou
nd-c
onfi r
med
SV
T a
nd la
rge
vari
cose
vei
ns o
r ve
nous
inco
mpe
tenc
e
A. E
last
ic c
ompr
essi
on s
tock
ings
al
one
Ext
ensi
on o
f SV
T a
t 3 m
o6
mo
Ext
ensi
on o
f thr
ombu
s at
3 m
o:
A: 3
2/78
(41%
) B: 1
1/78
(14.
1%);
RR
0.3
4 (9
5% C
I, 0
.19-
0.63
) C: 0
/70;
R
R 0
.02
(95%
CI,
0.0
0-0.
27) D
: 4/7
1 (5
.6%
); R
R 0
.14
(95%
CI,
0.0
5-0.
37)
E: 4
/76
(5.2
%);
RR
0.1
3 (9
5% C
I,
0.05
-0.3
5) F
: 5/7
1 (7
.0%
); R
R 0
.17
(95%
CI,
0.0
7-0.
42)
Ext
ensi
on o
f SV
T a
t 6 m
o
B. E
last
ic c
ompr
essi
on s
tock
ings
an
d si
mpl
e fl u
sh li
gatio
nN
ew D
VT
at 3
mo
C
. Ela
stic
com
pres
sion
sto
ckin
gs
and
com
plet
e st
ripp
ing
and
perf
orat
or li
gatio
n
P ,
.05
for
grou
ps C
, D, E
, F v
s A
or
B
D
. Ela
stic
com
pres
sion
sto
ckin
gs
and
low
-dos
e SC
hep
arin
Ext
ensi
on a
t 6 m
o: A
: 13/
78 (1
6.7%
) B
: 6/7
8 (7
.7%
); R
R 0
.46
(95%
CI,
0.
18-1
.15)
C: 1
/70
(1.4
%);
RR
0.0
9 (9
5% C
I, 0
.01-
0.64
) D: 2
/71
(2.8
%);
RR
0.1
7 (9
5% C
I, 0
.04-
0.72
) E: 1
/76
(1.3
%);
RR
0.0
8 (9
5% C
I, 0
.01-
0.59
) F
: 5/7
1 (7
%);
RR
0.4
2 (9
5% C
I, 0
.16-
1.13
)
E. E
last
ic c
ompr
essi
on s
tock
ings
an
d L
MW
HF.
Ela
stic
com
pres
sion
sto
ckin
gs
and
VK
A
D
oses
and
dur
atio
n of
an
ticoa
gula
nts
not s
peci
fi ed
P
not s
tate
d
N
ew D
VT
at 3
mo:
A: 6
/78
(7.7
%)
B: 2
/78
(2.5
%);
RR
0.3
3 (9
5% C
I,
0.07
-1.6
0) C
: 2/7
0 (2
.8%
); R
R 0
.37
(95%
CI,
0.0
8-1.
78) D
: 0/7
1 (0
%);
RR
0.0
8 (9
5% C
I, 0
.0-1
.47)
E: 0
/76
(0%
); R
R 0
.08
(95%
CI,
0.0
-1.3
8) F
: 0/7
1 (0
%);
RR
0.0
8 (9
5% C
I, 0
.0-1
.47)
P
5 n
s
Loz
ano
et a
l 168 /2
003
Para
llel R
CT,
si
ngle
cen
ter
60 p
atie
nts
with
ul
tras
ound
-con
fi rm
ed
abov
e-kn
ee in
tern
al
saph
enou
s SV
T
Saph
enof
emor
al d
isco
nnec
tion
unde
r lo
cal a
nest
hesi
a w
ith
shor
t-te
rm u
se o
f a
com
pres
sion
ban
dage
Rec
urre
nce/
exte
nsio
n of
SV
T6
mo
Rec
urre
nt S
VT
Sur
gica
l gro
up: 1
/30
(3.3
%)
Eno
xapa
rin
grou
p: 3
/30
(10%
); R
R 3
.0 (9
5% C
I, 0
.33-
27.2
4)
VT
E
C
ompl
icat
ions
of s
urge
ry
Tabl
e S4
4—C
onti
nued
(Con
tinu
ed)
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Aut
hor/
Year
Type
of
Publ
icat
ion a
Part
icip
ants
Inte
rven
tion b
Out
com
es c
Fol
low
-up
Res
ults
O
utpa
tient
eno
xapa
rin
1 m
g/kg
bi
d fo
r 1
wk
then
onc
e da
ily
for
3 w
k
VT
E S
urgi
cal g
roup
: 2/3
0 (6
.7%
) (bo
th
sym
ptom
atic
PE
) Eno
xapa
rin
grou
p:
0/30
(0%
); R
R 0
.20
(95%
CI,
0.0
1-4.
0)
Maj
or b
leed
ing
Dea
th
No
plac
ebo/
cont
rol g
roup
Wou
nd in
fect
ions
: Sur
gica
l gro
up:
2/30
(6.7
%)
Cos
ts
All
patie
nts
wer
e in
stru
cted
to
wea
r el
astic
com
pres
sion
st
ocki
ngs
and
used
ac
etam
inop
hen
for
pain
Maj
or b
leed
ing:
0
D
eath
: 0
C
ost o
f tre
atm
ent:
Surg
ical
gro
up: $
1,4
00/
patie
nt; m
ean,
1.6
d in
hos
pita
l E
noxa
pari
n gr
oup:
$ 3
00/p
atie
nt;
0 d
in h
ospi
tal
Sulli
van
et a
l 169 /2
001
Syst
emat
ic r
evie
w
of 6
stu
dies
(in
clud
es B
elca
ro
(14
patie
nts)
and
5
smal
l cas
e se
ries
)
Patie
nts
with
obj
ectiv
ely
confi
rm
ed a
bove
-kne
e SV
T
Lig
atio
n of
gre
ater
sap
heno
us
vein
at s
aphe
nofe
mor
al
junc
tion
with
or
with
out
vein
str
ippi
ng (n
5 2
46)
SVT
pro
gres
sion
Surg
ical
gr
oup:
4-
6 m
o
SVT
pro
gres
sion
: Sur
gica
l gro
up:
18/1
48 (1
2%) M
edic
al g
roup
: 10/
71 (1
4%);
RR
1.1
6 (9
5% C
I, 0
.56-
2.38
) D
VT:
Sur
gica
l gro
up: 7
/204
(3.4
%) M
edic
al
grou
p: 2
/88
(2.2
%) R
R 0
.66
(95%
CI,
0.
14-3
.13)
PE
: Sur
gica
l gro
up: 2
/98
(2.0
%) M
edic
al
grou
p: 0
/17
(0%
); R
R 1
.10
(95%
CI,
0.
06-2
1.98
) Su
rgic
al c
ompl
icat
ions
: 6/7
8 (7
.7%
) (h
emat
oma,
ser
oma,
infe
ctio
n)
Ble
edin
g co
mpl
icat
ions
: 0/1
7 (0
%)
DV
T
PEM
edic
al
grou
p: 6
d
to 1
4 m
o
A
ntic
oagu
latio
n (I
V h
epar
in
follo
wed
by
VK
A fo
r 6
wks
-6 m
o) (n
5 8
8)Su
rgic
al c
ompl
icat
ions
Ble
edin
g co
mpl
icat
ions
Tabl
e S4
4—C
onti
nued
(Con
tinu
ed)
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Aut
hor/
Year
Type
of
Publ
icat
ion a
Part
icip
ants
Inte
rven
tion b
Out
com
es c
Fol
low
-up
Res
ults
Gór
ski e
t al 17
0 /200
5Pa
ralle
l RC
T,
mul
ticen
ter
46 p
atie
nts
with
ul
tras
ound
-con
fi rm
ed
SVT
Topi
cal l
ipos
omal
hep
arin
sp
ray
gel (
4 sp
rays
of
458
Inte
rnat
iona
l Uni
ts ti
d)
Pain
by
visu
al a
nalo
g sc
ale
(0-1
0)21
dD
ata
extr
apol
ated
from
gra
phs
and
fi gur
es
in a
rtic
le b
y re
view
er
A
rea
of e
ryth
ema
Eno
xapa
rin
40 m
g SC
onc
e da
ilySu
bjec
tive
effi c
acy
asse
ssm
ent
by in
vest
igat
or a
nd p
atie
ntPa
in b
y vi
sual
ana
log
scal
e, d
ay 2
1: T
opic
al
hepa
rin:
0 L
MW
H: 0
Trea
tmen
t giv
en fo
r 7-
14 d
Dup
lex
asse
ssm
ent f
or th
rom
bus
regr
essi
on d
ay 2
1Im
prov
emen
t not
ed a
t eac
h tim
e po
int;
no p
ain
at 2
1 d,
no
sign
ifi ca
nt d
iffer
ence
be
twee
n gr
oups
DV
TA
rea
of e
ryth
ema:
Im
prov
emen
t not
ed a
t ea
ch ti
me
poin
t; no
ery
them
a at
21
d,
no s
igni
fi can
t diff
eren
ce b
etw
een
grou
ps
A
dver
se e
vent
s
D
eath
Subj
ectiv
e ef
fi cac
y as
sess
men
t: M
ajor
ity o
f pa
tient
s ( .
75%
) rep
orte
d go
od o
r ve
ry
good
trea
tmen
t effi
cacy
, no
sign
ifi ca
nt
diff
eren
ce b
etw
een
grou
ps
T
hrom
bus
regr
essi
on: T
opic
al h
epar
in:
10/2
1 (4
7.6%
) LM
WH
: 9/2
3 (3
9.1%
); R
R 0
.82
(95%
CI,
0.4
2-1.
62)
D
VT:
Top
ical
hep
arin
: 3/2
1 (1
4.3%
) LM
WH
: 1/
23 (4
.3%
); R
R 0
.30
(95%
CI,
0.0
3-2.
70)
A
dver
se e
vent
s: A
llerg
ic r
eact
ion
in 1
pat
ient
in
eno
xapa
rin
grou
p
Dea
th: 0
And
reoz
zi
et a
l 171 /1
996
Para
llel R
CT,
m
ultic
ente
r56
pat
ient
s w
ith S
VT
of
the
low
er li
mbs
A: D
erm
atan
sul
fate
100
mg
SC o
nce
daily
Pain
30 d
Dat
a ex
trap
olat
ed fr
om g
raph
s an
d fi g
ures
in
artic
le b
y re
view
er
In
crea
se in
func
tiona
l abi
lity
B: D
erm
atan
sul
fate
100
mg
SC b
idL
ocal
ede
ma
Res
olut
ion
of p
ain,
day
30:
Gro
up A
: 47
% G
roup
B: 8
3% G
roup
C: 7
9%
C
: Der
mat
an s
ulfa
te 2
00 m
g in
tram
uscu
lar
once
dai
ly P
not s
tate
d
(Con
tinu
ed)
Tabl
e S4
4—C
onti
nued
© 2012 American College of Chest Physicians at Washington University on March 5, 2012chestjournal.chestpubs.orgDownloaded from
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Aut
hor/
Year
Type
of
Publ
icat
ion a
Part
icip
ants
Inte
rven
tion b
Out
com
es c
Fol
low
-up
Res
ults
Tr
eatm
ent g
iven
for
30 d
Incr
ease
in a
bilit
y to
per
form
nor
mal
dai
ly
activ
ities
, day
30:
Gro
up A
: 44%
Gro
up B
: 67
% G
roup
C: 8
4%
P
, .0
5 gr
oups
B a
nd C
vs
grou
p A
Loc
al e
dem
a, d
ay 3
0: P
rogr
essi
ve
impr
ovem
ent i
n al
l 3 g
roup
s; n
o si
gnifi
cant
di
ffer
ence
s be
twee
n gr
oups
The
CA
LIS
TO
stu
dy th
at c
ompa
red
fond
apar
inux
with
no
fond
apar
inux
is d
escr
ibed
in T
able
28
and
Tabl
e S4
2. H
IT 5
hep
arin
-indu
ced
thro
mbo
cyto
peni
a; N
SAID
5 n
onst
eroi
dal a
ntiin
fl am
mat
ory
drug
; ST
EN
OX
5 S
uper
fi cia
l Thr
ombo
phle
bitis
Tre
ated
by
Eno
xapa
rin.
See
Tab
le S
1, S
2, S
5, S
21, a
nd S
43 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Stu
dy d
esig
n: R
CT,
coh
ort.
b Dru
gs: V
KA
, UF
H, L
MW
H, N
SAID
s, a
spir
in, t
opic
al tr
eatm
ents
, sur
gery
vs
plac
ebo,
no
trea
tmen
t, ea
ch o
ther
or
diff
eren
t dur
atio
ns o
r re
gim
ens
of th
e sa
me
agen
t. c O
utco
mes
: ext
ensi
on o
f thr
ombu
s, s
ympt
omat
ic r
elie
f, D
VT
and
PE
, maj
or b
leed
ing,
sur
gica
l com
plic
atio
ns, a
nd d
eath
.
Tabl
e S4
4—C
onti
nued
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Table S45 —[Section 8.1] SVT Treatment: Methodologic Quality
Author/Year Randomization Allocation Concealment Blinding Loss to Follow-up/ ITT
STENOX Study Group 163 /2003
Central randomization Visually identical drugs and packaging; triple dummy design
Investigators, patients, and assessors blinded
9 lost to follow-up/ ITT
Titon et al 164 /1994 Randomized to one of three treatment groups; method of randomization not specifi ed
Open label Not blinded 8 lost to follow-up/ not specifi ed
Prandoni for Vesalio group et al 165 /2005
Computer-generated random number sequence assigned to each patient to determine treatment group
Double dummy Patients and adjudicators of outcome events blind
0 lost to follow-up/ ITT
Marchiori et al 166 /2002 Randomized to treatment group by computer-generated list
Not specifi ed Assessors blinded 0 lost to follow-up/ not specifi ed
Belcaro et al 167 /1999 Not specifi ed Not blinded Not blinded 118 lost to follow-up/not specifi ed
Lozano et al 168 /2003 Method not specifi ed Not blinded Not blinded 3 lost to follow-up/not specifi ed
Sullivan et al 169 /2001 Review of six studies; includes one RCT (Belcaro [14 patients]) and fi ve small case series
N/A N/A N/A
Andreozzi et al 170 /1996 Patients randomly assigned to one of three therapeutic groups (method not specifi ed)
Open label Not blinded Not specifi ed/not specifi ed
Górski et al 171 /2005 Performed according to a prespecifi ed randomization list; treatment allocated according to next number on list; no stratifi cation was performed
Open trial Not blinded 6 lost to follow-up/ITT
See Table S5, S12, S43, and S44 legends for expansion of abbreviations.
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Tabl
e S4
6 —[S
ecti
on 9
.1]
Init
ial
Tre
atm
ent
of A
cute
UE
DV
T W
ith
Ant
icoa
gula
nt T
hera
py: C
lini
cal
Des
crip
tion
and
Res
ult
s (R
ando
miz
ed T
rial
s [N
one
Per
form
ed]
and
Pro
spec
tive
Ob
serv
atio
nal
Stu
dies
of
at L
east
20
Pat
ient
s)
Aut
hor/
Year
Type
of P
ublic
atio
n a Pa
rtic
ipan
tsIn
terv
entio
n b O
utco
mes
c F
ollo
w-u
pR
esul
ts
Sava
ge e
t al 17
2 /199
9
Pros
pect
ive
coho
rt,
two
cent
er46
out
patie
nts
with
UE
DV
T
(incl
udes
16
with
CV
C)
Dal
tepa
rin
daily
for
5-7
d (2
00 I
nter
natio
nal U
nits
/kg)
an
d V
KA
with
targ
et I
NR
of
2.0-
3.0
Dur
atio
n of
VK
A n
ot p
rovi
ded
Sym
ptom
atic
re
curr
ence
/ext
ensio
n of
DV
TPE M
ajor
ble
edin
gD
eath
3 m
oR
ecur
renc
e/ex
tens
ion
DV
T: 1
/46
(2%
) PE
: 0/4
6 M
ajor
ble
edin
g: 1
/46
(2%
) (on
VK
A)
Dea
th: 7
/46
(15%
) (no
ne fr
om P
E o
r bl
eedi
ng)
Kar
abay
et a
l 173 /2
003
Pros
pect
ive
coho
rt,
sing
le c
ente
r36
inpa
tient
s w
ith U
ED
VT
(in
clud
es 1
3 w
ith C
VC
)N
adro
pari
n SC
bid
, 86
anti-
Xa
Inte
rnat
iona
l Uni
ts/k
g fo
r up
to 7
d, t
hen
VK
A (s
tart
ed
on d
ay 3
; tar
get I
NR
2-2
.5)
for
mea
n of
4.7
mo
Sym
ptom
rel
ief
Lys
is o
f thr
ombu
s on
ul
tras
ound
Rec
urre
nt D
VT
PE Dea
th
1 y
Sign
ifi ca
nt s
ympt
om r
elie
f, da
y 7:
32
/36
(89%
) L
ysis
, day
10:
� 3
5%: 1
6/36
(45%
) ,
35%
: 17/
36 (4
7%) N
one:
3/3
6 (8
%)
Rec
urre
nt D
VT:
0/3
6 PE
: 0/3
6 D
eath
: 9/3
6 (2
5%) (
none
due
to P
E
or b
leed
ing)
Pran
doni
et a
l 120 /2
004
Pros
pect
ive
coho
rt,
num
ber
of c
ente
rs
not s
tate
d
53 p
atie
nts
with
fi rs
t UE
DV
T
(incl
uded
6 w
ith C
VC
)T
hera
peut
ic-d
ose
hepa
rin
(81%
rec
eive
d U
FH
, 19%
re
ceiv
ed L
MW
H) t
hen
VK
A
(med
ian,
3 m
o)
Rec
urre
nt V
TE
Dea
thM
edia
n of
48
mo
Res
ults
not
pre
sent
ed a
ccor
ding
to in
itial
tr
eatm
ent w
ith U
FH
vs
LM
WH
R
ecur
rent
VT
E: 3
/53
(5.7
%)
(2 a
rm, 1
leg)
C
umul
ativ
e in
cide
nce
1, 2
, and
5 y
: 2.
0%, 4
.2%
, 7.7
%
Dea
th: 1
1/53
(20.
8%) (
due
to c
ance
r, PE
, con
gest
ive
hear
t fai
lure
[num
bers
no
t pro
vide
d])
(Con
tinu
ed)
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Aut
hor/
Year
Type
of P
ublic
atio
n a Pa
rtic
ipan
tsIn
terv
entio
n b O
utco
mes
c F
ollo
w-u
pR
esul
ts
Kov
acs
et a
l 174 /2
007
Pros
pect
ive
coho
rt,
mul
ticen
ter
74 c
ance
r pa
tient
s w
ith
confi
rm
ed U
ED
VT
(all
had
CV
C)
Dal
tepa
rin
daily
for
5-7
d (2
00 I
nter
natio
nal U
nits
/kg)
an
d V
KA
to a
chie
ve ta
rget
IN
R o
f 2.0
-3.0
Rec
urre
nt V
TE
PE Maj
or b
leed
ing
Dea
thC
athe
ter
failu
re d
ue
to D
VT
or
inab
ility
to in
fuse
3 m
oR
ecur
rent
VT
E: 0
/74
PE: 0
/74
Maj
or b
leed
ing:
3/7
4 (4
%)
Dea
th: 7
/74
(6 c
ance
r, 1
maj
or b
leed
) C
athe
ter
failu
re d
ue to
DV
T o
r in
abili
ty
to in
fuse
: 0/7
4
CV
C 5
cent
ral v
enou
s ca
thet
er; U
ED
VT
5 u
pper
-ext
rem
ity D
VT.
See
Tab
le S
2, S
7, a
nd S
41 le
gend
s fo
r ex
pans
ion
of o
ther
abb
revi
atio
ns.
a Stu
dy d
esig
n: p
rosp
ectiv
e co
hort
stu
dies
. b D
rugs
: IV
UF
H o
r L
MW
H fo
llow
ed b
y O
AC
s.
c Out
com
es: r
ecur
rent
DV
T a
nd P
E, m
ajor
ble
edin
g, to
tal m
orta
lity,
and
ear
ly s
ympt
om r
elie
f.
Tabl
e S4
6—C
onti
nued
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Table S49 —[Section 9.2] Initial Treatment of Acute UEDVT With Thrombolytic Therapy: Methodologic Quality
Author/Year Randomization Allocation Concealment Blinding Loss to Follow-up
Horne et al 175 /2000 No N/A N/A Not specifi ed
Lee et al 176 /2006 No N/A N/A 0 lost to follow-up
See Table S12 legend for expansion of abbreviation.
Table S48 —[Section 9.2] Initial Treatment of Acute UEDVT With Thrombolytic Therapy: Clinical Description and Results (Randomized Trials [None Performed] and Prospective Observational Studies of at Least 10 Patients)
Author/Year Type of Publication a Participants Intervention b Outcomes c Follow-up Results
Horne et al 175 /2000 Prospective cohort, single center
18 patients with axillary or subclavian DVT
Catheter-directed rt-PA (2 mg/cm of thrombus to maximum of 20 mg) then VKA for 3 mo
Immediate patency 6 mo Immediate patency: 10/18 (56%)
Establishment of antegrade fl ow
Antegrade fl ow: 11/18 (61%)
Bleeding events Bleeds (all minor): 5/18 (28%)
Lee et al 176 /2006 Prospective case series, single center
35 patients with primary UEDVT who had complete resolution of acute symptoms with CDT (n 5 29) or IV heparin (n 5 6)
Oral VKA for mean of 5.2 mo
Recurrent DVT 54 mo Ipsilateral recurrent DVT: 8/35 (23%)
Early prospective observational studies with , 10 patients and retrospective studies are described in Table 3 of the eighth edition of these guide-lines. 46 See Table S2, S10, S11, and S46 legends for expansion of abbreviations. a Study design: retrospective and prospective cohort studies. b Drugs: thrombolytic therapy compared with different types of lytic therapy or with anticoagulants. c Outcomes: recurrent DVT and PE, vein patency, major bleeding, total mortality, and PTS of the arm.
Table S47 —[Section 9.1] Initial Treatment of Acute UEDVT With Anticoagulant Therapy: Methodologic Quality
Author/Year Randomization Allocation Concealment Blinding Loss to Follow-up/ ITT
Savage et al 172 /1999 N/A N/A N/A 1 lost to follow-up/N/A
Karabay et al 173 /2003 N/A N/A N/A 0 lost to follow-up/N/A
Prandoni et al 120 /2004 N/A N/A N/A 2 lost to follow-up/N/A
Kovacs et al 174 /2006 N/A N/A N/A 0 lost to follow-up/N/A
See Table S12 and S46 legends for expansion of abbreviations.
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(Con
tinu
ed)
Tabl
e S5
0 —[S
ecti
on 9
.3]
Lon
g-te
rm T
reat
men
t of
Acu
te U
ED
VT
: Cli
nica
l D
escr
ipti
on a
nd R
esu
lts
Aut
hor/
Year
Type
of P
ublic
atio
nPa
rtic
ipan
tsIn
terv
entio
n a O
utco
mes
b F
ollo
w-u
pR
esul
ts
Sava
ge e
t al 17
2 /199
9
Pros
pect
ive
coho
rt,
two
cent
er46
out
patie
nts
with
co
nfi r
med
UE
DV
T
(incl
udes
16
with
CV
C)
Dal
tepa
rin
200
Inte
rnat
iona
l U
nits
/kg
daily
for
5-7
d an
d V
KA
to a
chie
ve ta
rget
IN
R o
f 2.0
-3.0
for
3 m
oD
urat
ion
of V
KA
no
t pro
vide
d
Sym
ptom
atic
rec
urre
nce/
exte
nsio
n of
DV
TPE M
ajor
ble
edin
gD
eath
3 m
oR
ecur
renc
e/ex
tens
ion:
1/4
6 (2
%)
PE: 0
M
ajor
ble
edin
g: 1
/46
(2%
) (o
n V
KA
) D
eath
: 7/4
6 (1
5%) (
none
from
PE
or
ble
edin
g)
Kar
abay
et a
l 173 /2
003
Pros
pect
ive
coho
rt,
sing
le c
ente
r36
inpa
tient
s w
ith
confi
rm
ed U
ED
VT
(in
clud
es 1
3 w
ith C
VC
)
Nad
ropa
rin
SC b
id, 8
6 an
ti-X
a In
tern
atio
nal
Uni
ts/k
g fo
r up
to 7
d,
then
VK
A (s
tart
ed o
n da
y 3;
targ
et I
NR
2-2
.5)
for
mea
n of
4.7
mo
Sym
ptom
rel
ief
Lys
is o
f thr
ombu
s on
ul
tras
ound
Rec
urre
nt D
VT
PE Dea
thPT
S
1 y
Sign
ifi ca
nt s
ympt
om r
elie
f, da
y 7:
32
/36
(89%
) L
ysis
, day
10:
� 3
5%: 1
6/36
(45%
) ,
35%
: 17/
36 (4
7%)
Non
e: 3
/36
(8%
) R
ecur
rent
DV
T: 0
PE
: 0
Dea
th: 9
/36
(25%
) (no
ne d
ue to
PE
or
blee
ding
) PT
S: 0
Mar
tinel
li et
al 17
7 /200
4
Cas
e-co
ntro
l stu
dy w
ith
pros
pect
ive
follo
w-u
p of
cas
es, s
ingl
e ce
nter
98 p
atie
nts
with
pr
imar
y U
ED
VT
(n
one
with
CV
C)
VK
A fo
r m
ean
6 m
o (7
7 pa
tient
s), h
epar
in
SC (1
4 pa
tient
s), o
r an
tipla
tele
t age
nts
(7 p
atie
nts)
for
� 3
mo
Rec
urre
nt V
TE
aft
er
antic
oagu
lant
s st
oppe
dM
edia
n of
5.1
yR
ecur
rent
VT
E: 1
2/98
(12%
) ov
eral
l (al
l UE
DV
T)
Ann
ual i
ncid
ence
rec
urre
nt V
TE
: 2.
4% (9
5% C
I, 1
.2%
-4.0
%)
(res
ults
not
pro
vide
d by
tr
eatm
ent g
roup
)
Pran
doni
et a
l 178 /2
004
Pros
pect
ive
coho
rt,
num
ber
of c
ente
rs
not s
tate
d
53 p
atie
nts
with
con
fi rm
ed
fi rst
UE
DV
T (i
nclu
ded
6 w
ith C
VC
)
The
rape
utic
-dos
e he
pari
n (8
1% r
ecei
ved
UF
H, 1
9%
rece
ived
LM
WH
) the
n V
KA
(med
ian,
3 m
o)
Rec
urre
nt V
TE
Med
ian
of 4
8 m
oR
esul
ts n
ot p
rese
nted
acc
ordi
ng
to in
itial
trea
tmen
t with
UF
H v
s L
MW
H
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Aut
hor/
Year
Type
of P
ublic
atio
nPa
rtic
ipan
tsIn
terv
entio
n a O
utco
mes
b F
ollo
w-u
pR
esul
ts
Dea
thPT
SR
ecur
rent
VT
E: 3
/53
(5.7
%)
(2 a
rm, 1
leg)
C
umul
ativ
e in
cide
nce
1, 2
, and
5 y
: 2.
0%, 4
.2%
, 7.7
%
Dea
th: 1
1/53
(20.
8%) (
due
to c
ance
r, PE
, con
gest
ive
hear
t fai
lure
[b
reak
dow
n no
t pro
vide
d])
PTS:
13/
53 (2
4.5%
); 2
y C
umul
ativ
e in
cide
nce:
27.
3%
Kov
acs
et a
l 174 /2
007
Pros
pect
ive
coho
rt,
mul
ticen
ter
74 c
ance
r pa
tient
s w
ith
confi
rm
ed U
ED
VT
(a
ll ha
d C
VC
)
Dal
tepa
rin
200
Inte
rnat
iona
l U
nits
/kg
daily
for
5-7
d an
d V
KA
to a
chie
ve ta
rget
IN
R o
f 2.0
-3.0
Rec
urre
nt V
TE
PE Maj
or b
leed
ing
Dea
thC
athe
ter
failu
re d
ue to
D
VT
or
inab
ility
to
infu
se
3 m
oR
ecur
rent
VT
E: 0
PE
: 0
Maj
or b
leed
ing:
3 (4
%)
Dea
th: 7
(6 c
ance
r, 1
maj
or b
leed
) C
athe
ter
failu
re d
ue to
DV
T o
r in
abili
ty to
infu
se: 0
Ear
ly p
rosp
ectiv
e ob
serv
atio
nal s
tudi
es w
ith ,
20
patie
nts,
and
ret
rosp
ectiv
e st
udie
s, a
re d
escr
ibed
in T
able
3 o
f the
Eig
ht e
ditio
n of
thes
e gu
idel
ines
46 S
ee T
able
S2,
S7,
S10
, and
S46
lege
nds
for
expa
nsio
n of
abb
revi
atio
ns.
a Dru
gs: V
KA
, UF
H, L
MW
H v
s pl
aceb
o, c
ontr
ol o
r ea
ch o
ther
. b O
utco
mes
: rec
urre
nt D
VT
and
PE
, maj
or b
leed
ing,
tota
l mor
talit
y, a
nd P
TS
of th
e ar
m. Ta
ble
S50—
Con
tinu
ed
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Table S51 —[Section 9.3] Long-term Treatment of Acute UEDVT: Methodologic Quality
Author/Year Randomization Allocation Concealment Blinding Loss to Follow-up
Savage et al 172 /1999 N/A N/A N/A 1 lost to follow-up
Karabay et al 173 /2003 N/A N/A N/A 0 lost to follow-up
Martinelli et al 177 /2004 N/A N/A N/A Not specifi ed
Prandoni et al 178 /2004 N/A N/A N/A 2 patients lost to follow-up
Kovacs et al 174 /2007 N/A N/A N/A 0 lost to follow-up
See Table S12 and S46 legends for expansion of abbreviations.
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