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 Agnes Y. Y. Lee and Erica A. Peterson Treatment of cancer-associated thrombosis

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Review Series

CANCER-ASSOCIATED THROMBOTIC DISEASE

Treatment of cancer-associated thrombosisAgnes Y. Y. Lee and Erica A. Peterson

Division of Hematology, Department of Medicine, University of British Columbia, British Columbia Cancer Agency, Vancouver, BC, Canada

Therapeutic options for the management

of venous thromboembolism (VTE) in

patients with cancer remain very limited.

Although low-molecular-weight heparin

monotherapy has been identified as a

simple and efficacious regimen compared

with an initial parenteral anticoagulant

followed by long-term therapy with a vita-

min K antagonist, many clinical questions

remain unanswered. These include optimal

duration of anticoagulant therapy, treatment

of recurrent VTE, and the treatment of

patients with concurrent bleeding or those

with a high risk of bleeding. Treatment rec-

ommendations from consensus clinical

guidelines are largely based on retrospec-

tive reports or extrapolated data from the

noncancer population with VTE, as ran-

domized controlled trials focused on

cancer-associated thrombosis are sorely

lacking. Furthermore, with improvements

in imaging technology and extended

survival duration of patients with cancer,

we are encountering more unique chal-

lenges, such as the management of in-

cidental VTE. Clinicians should be aware

of the limitations of the novel oral anti-

coagulants and avoid the use of these

agents because of the paucity of evidence

in the treatment of cancer-associated

thrombosis. (Blood. 2013;122(14):2310-

2317)

Introduction

Venous thromboembolism (VTE) is a significant cause of morbidityand mortality in patients with cancer.1 Although deep vein thrombosis(DVT) and pulmonary embolism (PE) are the most commonlyencountered venous thrombotic complications, other vascularterritories, such as the splanchnic veins and upper extremityvenous system, can also be involved. With the increasing ageand cancer prevalence of our population, enhanced detection ofincidental thrombosis and greater thrombogenicity of multiagentchemotherapeutic regimens, we have observed a steady increase inthe incidence of cancer-associated thrombosis during the past 2decades.2,3 A leading cause of death in patients with cancer,4

thrombosis is associated with higher mortality risk, irrespectiveof cancer stage.5,6

Unfortunately, despite the burden of VTE in oncology patients,there has been limited advancement in the management of cancer-associated thrombosis since the introduction of low-molecular-weight heparin (LMWH) for long-term therapy. Anticoagulanttherapy in malignancy remains burdensome and is viewed as havinga negative impact on patient quality of life. It is also associatedwith a high risk of bleeding and may limit the therapeutic optionsto treat the underlying cancer.7

In this review, we outline the current evidence and consensusguideline recommendations for the initial and long-term manage-ment of the first and recurrent episodes of VTE in patients withcancer. We also discuss the management of commonly encounteredthrombotic complications, recognizing the lack of rigorous evidencein these areas, such as incidentally detected VTE, splanchnic veinthrombosis, catheter-related thrombosis, and VTE treatment in patientswith a high risk of bleeding. We close with a critical look at the use

of the novel oral anticoagulants (NOACs) in the treatment ofcancer-associated thrombosis.

Initial management of a first episode ofcancer-associated VTE

Choice of anticoagulant

Options for the initial treatment of cancer-associated thrombosisinclude LMWH, unfractionated heparin (UFH), and fondaparinux.Although studies directly comparing these agents are lacking inoncology patients, data extrapolated from subgroup analysis oftrials in unselected patients showed no difference in efficacy betweenLMWH and UFH in patients with cancer.8 However, a statisticallysignificant reduction in mortality risk with LMWH at 3 months offollow-up has been noted. The reason for this survival benefit isunknown, but research exploring the antineoplastic properties ofLMWH is ongoing. In addition to better efficacy, LMWH providesother advantages vs UFH, including lower cost (because hospitalizationand laboratorymonitoring are not required) and simple dosing (becausethe total daily dose is based on body weight). LMWH is also asso-ciated with a lower risk for heparin-induced thrombocytopenia (HIT).9

Data on the use of fondaparinux for the initial management ofDVT and PE in patients with cancer are also derived from post hocsubgroup analysis. In the Matisse trials, the 3-month rate for symp-tomatic, recurrent VTE was higher for fondaparinux vs enoxaparin inDVT treatment (12.7% vs 5.4%) but was lower for fondaparinux vsUFH in PE treatment (8.9% vs 17.2%).10 Like LMWH, fondaparinuxis administered as a once-daily, weight-based subcutaneous injec-tion. Fondaparinux is rarely associated with the development of

Submitted April 3, 2013; accepted June 20, 2013. Prepublished online as

Blood First Edition paper, July 10, 2013; DOI 10.1182/blood-2013-04-460162.

© 2013 by The American Society of Hematology

2310 BLOOD, 3 OCTOBER 2013 x VOLUME 122, NUMBER 14

drug-induced thrombocytopenia and has been used off label for themanagement of HIT.11 Barriers to its use in oncology patients includea relatively long half-life of 17 to 21 hours, the lack of a reversalagent, and 100% dependence on renal clearance.12

On the basis of currently available evidence, LMWH is the rec-ommended anticoagulant for the initial therapy of VTE in mostpatients with cancer (Table 1).13-16 However, UFH can be used inthose with severe renal impairment (creatinine clearance [CrCl],30 mL/min) given its shorter half-life, reversibility with protaminesulfate, and dependence on hepatic clearance. Fondaparinux is areasonable choice in patients with a history of HIT.

Use of thrombolysis in cancer-associated VTE

As most trials of thrombolytic therapy exclude patients with cancerbecause of a perceived higher risk of bleeding, evidence for throm-bolysis in patients with malignancy is limited to small single-center,retrospective series. These studies compared the degree of clot lysisand short-term complications between patients with vs those withoutcancer who had presented with extensive DVT or PE.17-19 Althoughcomparable results between cancer and noncancer patient groupswere observed, these studies provide a low level of evidence becauseof insufficient statistical power and patient selection bias. Nonethe-less, there is no strong evidence to routinely exclude patients forconsideration of thrombolysis on the basis of the presence ofmalignancy alone. Because the safety, cost-effectiveness, and long-term benefit of thrombolysis remain uncertain,20 it is prudent toreview each patient carefully and exclude patients with centralnervous system lesions or other risk factors for bleeding.

Long-term management of a first episode ofcancer-associated VTE

Choice of anticoagulant

Although vitamin K antagonists (VKAs) have been the mainstayagents for long-term management and secondary prophylaxis of

acute VTE in patients without cancer,21 their use is problematic inoncology patients. VKAs are less effective in patients with cancer,with rates of recurrent VTE threefold higher than in patientswithout cancer despite maintenance of the international normalizedratio (INR) within the therapeutic range.22,23

Several open-label, randomized controlled trials have comparedLMWH with VKA therapy for long-term management of cancer-associated PE or proximal DVT (Figure 1).24-27 Three differentLMWH preparations, enoxaparin, tinzaparin, and dalteparin, wereinvestigated for 3 to 6 months in similarly designed studies. Overall,the results from these trials provide consistent evidence of improvedefficacy of LMWH vs VKA in the prevention of recurrent VTE inpatients with cancer-associated VTE. A meta-analysis of 7 studiesconfirms this finding, reporting a relative risk reduction of 53%.28

In addition to improved efficacy vs VKA therapy, LMWH alsooffers other advantages including (a) no need for laboratory moni-toring of its anticoagulant activity; (b) a shorter half-life that facili-tates temporary interruption for procedures or thrombocytopenia; (c)limited drug interactions; and (d) no food interactions or reliance onoral intake or gastrointestinal tract absorption. As a result, LMWHis recommended for both initial and long-term anticoagulationin cancer-associated thrombosis by major consensus guidelines(Table 1).13-15,21 The high cost associated with LMWH therapyand the requirement for daily subcutaneous injections are the majorbarriers to its use. Yet, qualitative studies have reported that patientacceptance of daily injections is quite favorable.29 In fact, in thosewho had used warfarin and LMWH therapy, most prefer the conve-nience and “empowerment” with LMWH. If LMWH is unavailable,the American Society of Clinical Oncology (ASCO) 2013 VTEPrevention and Treatment Guideline recommends the use of VKAwith a target INR of 2 to 3 as an acceptable alternative.14

Anticoagulation in patients with renal impairment

Renal impairment is not uncommon among patients with malig-nancy. Because LMWH is partially cleared by renal excretion andmetabolism, drug accumulation is expected with long-term use in

Table 1. Consensus guidelines on treatment of deep vein thrombosis or pulmonary embolism in patients with cancer

ACCP 201221 NCCN 201113 ASCO 201314

Initial/acute

treatment

Not addressed in cancer patients. LMWH LMWH is preferred for initial 5-10 d of

treatment in patients with a CrCl .30 mL/min.Dalteparin 200 U/kg OD

Enoxaparin 1 mg/kg BID

Tinzaparin 175 U/kg OD

Fondaparinux 5 mg (,50 kg), 7.5 mg (50-100 kg),

or 10 mg (.100 kg) OD

APTT-adjusted UFH infusion

Long-term

treatment

LMWH preferred to VKA [2B].* LMWH is preferred for first 6 mo as monotherapy

without warfarin in patients with proximal DVT

or PE and metastatic or advanced cancer.

LMWH is preferred for long-term therapy.

In patients not treated with LMWH, VKA

therapy is preferred to dabigatran or

rivaroxaban [2C].* Patients receiving

extended therapy should continue with the

same agent used for the first 3 mo of

treatment [2C].*

Warfarin 2.5-5 mg every day initially with

subsequent dosing based on INR value

targeted at 2-3.

VKAs (target INR, 2-3) are acceptable for

long-term therapy if LMWH is not available.

Duration of

treatment

Extended anticoagulant therapy is

preferred to 3 mo of treatment [2B].*

Minimum 3 mo. At least 6 mo duration.

Indefinite anticoagulant if active cancer or

persistent risk factors.

Extended anticoagulation with LMWH or VKA may

be considered beyond 6 mo for patients with

metastatic disease or patients who are

receiving chemotherapy.

ACCP, American College of Chest Physicians; BID, twice-daily dosing; NCCN, National Comprehensive Cancer Network; OD, once-daily dosing.

*ACCP adaptation of the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group evidence-based recommendations: 2B,

weak recommendation, moderate-quality evidence; 2C, weak recommendation, low- or very-low-quality evidence.16

BLOOD, 3 OCTOBER 2013 x VOLUME 122, NUMBER 14 TREATMENT OF CANCER-ASSOCIATED THROMBOSIS 2311

those with significant renal insufficiency (CrCl ,30 mL/min). Ofthe major LMWH preparations, tinzaparin appears to have the lowestpotential to accumulate, whereas enoxaparin shows significant ac-cumulation in renal insufficiency.30 This property reflects the chainlength of the LMWH, with the longer-chain tinzaparin beingpartially cleared by the reticuloendothelial system.30,31

Limited data are available on the use of LMWH in patientswith significant renal dysfunction, but they do indicate that the riskof bleeding is higher in patients with renal impairment.32,33

Manufacturer-recommended dose reduction in renal impairmentexists for enoxaparin but not for other LMWH preparations.34

Most experts and guidelines recommend dose adjustment basedon anti-factor Xa activity in patients with a CrCl ,30 mL/min.13,21

If anti-factor Xa monitoring is not readily available, VKA therapy islikely a safer option for long-term anticoagulation in these patients.A warning against the use of tinzaparin in elderly patients with

renal impairment has been issued by the US Food and DrugAdministration after the results of an interim analysis of a random-ized trial comparing tinzaparin with UFH for initial VTE therapyin this vulnerable population.35 Only 33 patients with a history ofongoing malignancy were enrolled in this study; 20 of them werein the tinzaparin group.36

Duration of anticoagulation and anticoagulant options for

extended therapy

The decision regarding the continuation of anticoagulation beyondthe first 3 to 6 months is largely based on weighing the risk forrecurrent thrombosis against the risk of major bleeding. Thisevaluative process is best developed in patients with unprovokedVTE, in whom studies have been done to determine whether bio-markers, radiologic imaging, and clinical prediction models canidentify patients with a sufficiently high risk for recurrent thrombosisto benefit from extended anticoagulation, or an acceptably low riskto allow discontinuation of anticoagulation.37-39 A clinical model topredict the risk for recurrent VTE during anticoagulation therapyin cancer-associated thrombosis has been proposed but not yetvalidated.40 In addition, studies regarding the optimal durationof anticoagulant therapy are lacking in oncology patients.

Given that the risk for recurrent thrombosis in patients withactive cancer is high even while they are receiving anticoagulation,it is generally recommended that extended anticoagulation be con-sidered in this population.14,21 It has not been established whetherrisk factors for a first episode of VTE, such as metastatic or pro-gressive disease and ongoing chemotherapy, will also increase therisk for recurrent VTE, but it has been generally accepted thatcontinuing anticoagulation in patients with these ongoing riskfactors is warranted.13-15 Patients given extended anticoagulationrequire frequent reassessment to review the risk-benefit balance ofcontinuing anticoagulant therapy. Factors that need to be taken intoaccount, aside from the risk for recurrent VTE and the risk ofbleeding, include the status of the malignancy, type of cancertreatment (if any), quality of life, and patient preference.

The choice of anticoagulant for extended anticoagulant therapy(beyond 6 months) also has not been investigated. A randomizedtrial is currently addressing this question.41 Patient preference andtolerance of previous therapy play significant roles in this decision.Thus far, long-term toxicity associated with VKA or LMWH hasnot been a concern, although it remains controversial whether pro-longed exposure to LMWH accelerates clinically significant boneloss.42 As with duration of therapy, the anticoagulant of choice needsto be discussed with each patient and individualized.

Inferior vena cava (IVC) filters

Patients with cancer are frequent recipients of IVC filters. Yet, dataon the efficacy and safety in this population are limited to retrospectivesingle-center series or anecdotal reports.43,44 Rates of recurrent VTEup to 32% have been reported in patients with cancer treated with IVCfilters, and fatal PE after filter insertion has been well documented.45

Evidence on the safety and efficacy of IVC filters in the generalpopulation is also sparse. Only 1 randomized trial has been done toevaluate filter placement in patients with proximal DVT who are athigh risk for PE. In the PREPIC (Prevention du Risque d’EmboliePulmonaire par Interruption Cave) trial, the use of permanent IVCfilters in conjunction with anticoagulation resulted in a decreasedincidence of PE at the expense of an increase risk for recurrent DVTand without any reduction in overall mortality rate during 8 yearsof follow-up.46,47 Results for the included 56 patients with cancer

Figure 1. Comparison of randomized controlled trials of different preparations

of LMWH vs VKA for the long-term management of cancer-associated thrombosis.

Recurrent VTE (A), major bleeding episodes (B), and mortality (C) during the anti-

coagulant treatment period are shown for the CLOT24 (6 months of dalteparin or

VKA), LITE25 (3 months of tinzaparin or warfarin), and CANTHANOX27 (3 months of

enoxaparin or warfarin) trials. NS, not statistically significant.

2312 LEE and PETERSON BLOOD, 3 OCTOBER 2013 x VOLUME 122, NUMBER 14

have not been published. Most importantly, the value of an IVC filterin patients who cannot receive anticoagulation, the major indicationfor filter insertion, has not been examined in prospective studies.

Complications associated with IVC filters raise further concernabout the appropriateness of their use. Insertion problems occur in4% to 11% of patients, and long-term adverse effects such as throm-bosis of the IVC or lower extremity veins occur in 4% to 32%.48 Ahigh incidence of mechanical or device failures associated withretrievable filter models led the US Food and Drug Administrationto issue a Safety Alert in 2010.49 These problems include filtermigration, strut fracture with embolization, and caval perforation.50,51

Given the high rates of complications and the absence of data tosupport their efficacy, IVC filters should be restricted to patientswith acute VTE and contraindications to anticoagulation. Their usein patients with recurrent thrombotic events despite standard anti-coagulant therapy goes against biological rationale because filtersdo not treat the underlying thrombotic condition, and the presenceof an intravascular foreign body is likely to promote thrombusformation, which can occur proximally or distally to the filter. Inaddition, the use of IVC filters may provide a sense of false securityregarding the risk for recurrent PE, causing delays or discontinuationof anticoagulant therapy. If retrievable filters are placed, effortsshould be made to remove the device and reinitiate anticoagulationas soon as the high-risk period for bleeding has passed.

Treatment of recurrent VTE duringanticoagulant therapy

Failure of anticoagulation in cancer-associated thrombosis is common,but there is a paucity of data to help guide treatment. An empiricapproach for the treatment of recurrent VTE during anticoagulanttherapy is outlined in Figure 2. Once recurrent VTE is confirmed, itis essential that HIT be excluded in patients who were first exposedto LMWH or UFH within the past 10 to 14 days. Complianceshould also be reviewed. In patients who experience a recurrentevent while receiving VKA therapy and have a subtherapeuticINR, options include continuation of VKA after a bridging periodwith LMWH (or UFH) or switching to LMWH monotherapy. Thelatter is likely a better option, especially in patients who had unstableINR values and the time-in-therapeutic range was low. For patientswho experienced warfarin failure while the INR values had beentherapeutic, transition to LMWH is recommended given its greaterefficacy vs warfarin.24,25,27,52 Recurrent VTE events during LMWHtherapy can be treated with a dose escalation of LMWH. Aretrospective study of 70 patients with cancer with recurrent VTEdemonstrated that transition to LMWH (in patients receiving VKAtherapy at the time of recurrence) or LMWH dose escalation by20% to 25% (in patients receiving LMWH at recurrence) preventedadditional VTE in 91% of patients during a minimum of 3 monthsof follow-up.53 Only 1 patient had a major bleeding event. If anotherrecurrent VTE episode occurs after the first dose escalation, furtherdose increase or twice-daily dosing of LMWH are reasonable options.The use of anti-factor Xa levels may help to further tailor LMWHescalation (Figure 2), although published evidence to support thisstrategy is lacking.

Treatment of incidental VTE

Incidental or unsuspected VTE is defined as evidence of thrombosisdetected on imaging studies performed for other indications such

as cancer staging.54 Retrospective studies in unselected oncologypatients have demonstrated incidental VTE rates of up to 6%,55,56

with thrombotic events evenly distributed between PE and/or DVTand intra-abdominal thrombosis.55 A prevalence of incidental PEof 3.1% was reported in a meta-analysis that included data frommore than 6000 oncology patients.57 Incidental VTE also representsa significant proportion of thrombotic complications in patients withcancer, comprising up to 60% in large series.58

Studies have suggested that, like suspected or symptomaticVTE, the occurrence of incidental VTE can have a negative impacton both patient quality of life and clinical outcomes. Patients withincidental PE often have symptoms such as fatigue and shortnessof breath.59 In a retrospective case-control study comparing 51unselected oncology patients with incidental PE and 144 patientswith symptomatic PE, the 12-month rates of recurrent VTE, bleeding,and mortality were similar between the groups.60 A retrospectivecohort of 135 consecutive patients with pancreatic cancer reportedsimilar findings.61 In another study, a comparison of cancer patientswith and without incidental PE matched for age, cancer diagnosis,and stage of disease at the time of a restaging computed tomographyscan of the chest found that patients with incidental PE had a highermortality rate than those without PE.62

Whether anticoagulation is indicated or beneficial in patientswith incidental VTE remains controversial. Evidence is limited to 2retrospective studies in patients with lung and pancreatic cancer. Ina cohort of 113 patients with lung cancer and incidental PE, the 62patients who did not receive anticoagulation had higher mortality

Figure 2. Management algorithm of recurrent VTE in patients with cancer. BID,

twice-daily dosing; INR, international normalized ratio; OD, once-daily dosing.

BLOOD, 3 OCTOBER 2013 x VOLUME 122, NUMBER 14 TREATMENT OF CANCER-ASSOCIATED THROMBOSIS 2313

rates compared with patients who were treated.63 Similarly, inpatients with pancreatic cancer with incidental VTE, the use ofanticoagulant therapy was associated with a 70% reduction inmortality rate.61 However, these studies are potentially biased tofavor anticoagulation because anticoagulant therapy is likely tobe withheld in those with a short life expectancy.

Nonetheless, based on published literature to date, it is recom-mended that patients with incidental DVT and PE receive therapeuticanticoagulation if there are no contraindications.14,21 However,caution should be exercised in cases where the diagnosis of PEor DVT is questionable, especially for isolated subsegmental PE.Confirming the diagnosis with the appropriate testing (ie, computedtomographic pulmonary angiography or compression venousultrasonography) is strongly encouraged in such cases.

Treatment of cancer-associated thrombosis inpatients with a high risk of bleeding

Bleeding is frequently associated with anticoagulant use in patientswith cancer. In a prospective study including 181 oncology patientsreceiving VKA for the treatment of DVT, the 1-year cumulativeincidence of major bleeding was 12.4%, with one third of thebleeding events occurring during the initial phase of anticoagula-tion.23 Although subtherapeutic INR values are associated withrecurrent VTE, there appears to be no correlation between the INRlevel and bleeding in patients with cancer.22,64 Bleeding compli-cations are not restricted to VKA therapy, as prospective randomizedcontrolled trials comparing LMWH and VKA therapy for cancer-associated VTE have reported similar bleeding rates.24-26 Featuresspecific to oncology patients that contribute to bleeding include theextent, location, and histologic features of the cancer, need forinvasive diagnostic or treatment procedures, and the developmentof thrombocytopenia from chemotherapy or from the underlyingmalignancy. Other comorbidities such as renal impairment andcoagulopathy from liver dysfunction, disseminated intravascularcoagulopathy, or sepsis further predispose them to bleeding.

Because of potentially serious and life-threatening bleedingcomplications, all patients require an individualized assessment oftheir bleeding risk before the initiation of anticoagulation. Currentand potential bleeding sources should be identified and managed,and the risk of serious bleeding should be weighed against theseverity of the thrombotic event and risk for recurrent VTE. Inpatients with minor bleeding, anticoagulation may be continuedas long as close follow-up is available. In patients with absolutecontraindications to anticoagulation, the risk of bleeding likelyoutweighs the benefit of treatment, and anticoagulants should bewithheld.14 In these patients, follow-up imaging should be performedto assess for thrombus progression, and IVC filter insertion can beconsidered. If severe cancer- or chemotherapy-induced thrombo-cytopenia is present, platelet transfusions may be used to allowanticoagulation. Most experts agree that therapeutic anticoagula-tion with LMWH may be administered if the platelet count can bemaintained above 50 3 109/L.65 For platelet counts between 20and 50 3 109/L, half-dose LMWH can be administered with closefollow-up for possible bleeding. If platelet count is ,20 3 109/L,therapeutic doses of anticoagulation should be held. Limited evidencefrom case series suggests that the use of prophylactic doses ofLMWH can be tolerated in patients with platelet counts,203 109/Lwith associated resolution of thrombotic symptoms.66 VKA therapyshould be avoided in patients with severe thrombocytopenia from

the prolonged anticoagulant effect and unpredictable dose response.Figure 3 illustrates a reasonable approach to the treatment of cancer-associated thrombosis in patients with thrombocytopenia.65

Management of VTE in patients with intracranial malignanciesis particularly challenging because of the fear of intracranialhemorrhage. No randomized controlled data exist for managementof patients with primary or metastatic intracranial tumors and VTE;however, small retrospective studies indicate that anticoagulationcan be safely used. Anticoagulation with intravenous UFH followedby VKA or subcutaneous UFH has been associated with rates ofsymptomatic intracranial hemorrhage between 0% and 7%.67-70

Similar results have been reported with LMWH in patients withglioma or metastatic brain tumors with a trend toward improvedsurvival duration.71-73 The ASCO 2013 VTE Guideline recommendstreating patients with intracranial malignancies with standardanticoagulation.14

Treatment of catheter-related thrombosis

Treatment of catheter-related thrombosis is largely inferred fromtreatment of DVT because randomized controlled trials evaluatingmanagement strategies have not been performed. Whether lineremoval is necessary (to eliminate the thrombotic source), harmful(because it can trigger PE), or beneficial (in shortening or avoidinganticoagulation therapy) has not been studied in clinical trials. Asmall prospective study evaluating the use of anticoagulation alonereported that in 74 patients with active cancer, LMWH for 5 to7 days followed by warfarin with a target INR of 2.0 to 3.0 for3 months resulted in no recurrent VTE at the expense of 3 episodesof major bleeding, including 1 fatal hemorrhage.74 After 3 monthsof treatment, 57% of patients had functional catheters in situ, whereasthe remainder had catheter removal for reasons other than progressivethrombosis or device failure. A small patient series observed that a

Figure 3. Management algorithm of VTE in patients with cancer and thrombo-

cytopenia. Management of acute VTE (,1 month) and subacute or chronic VTE ($1

month) are outlined in panels A and B, respectively.

2314 LEE and PETERSON BLOOD, 3 OCTOBER 2013 x VOLUME 122, NUMBER 14

short course of low-dose LMWH is effective and safe in treatingcatheter-related thrombosis in patients with severe thrombocytopenia.75

To date, published data and clinical experience suggest thatcatheter-related thrombosis is associated with a low risk forthrombosis recurrence and postthrombotic syndrome.76,77 There-fore, conservative treatment is recommended. A sensible approachis to remove the catheter only if (1) central venous access is nolonger required; (2) the device is nonfunctional or defective; or (3)line-related sepsis is suspected or documented. Unless contraindicated,therapeutic anticoagulation should be given using either LMWHalone or LMWH followed by warfarin therapy. A short period ofanticoagulation (3-5 days of LMWH) may even salvage somethrombosed catheters and obviate the need to remove and replacethe line. Anticoagulation is recommended for a minimum of 3 monthsand while the catheter remains in place.

Treatment of splanchnic vein thrombosis inpatients with cancer

Splanchnic vein thromboses, involving the portal, splenic, mesen-teric, or hepatic veins, are uncommon in the general population, butsignificant rates have been reported in patients with intraabdominalmalignancies.78 In a retrospective single-institution study of 135consecutive patients with pancreatic adenocarcinoma, incidentalsplanchnic vein thrombosis was present in 23%.60

Management of splanchnic vein thrombosis has not been wellstudied. Limited experience is available from studies that includedboth patients with and without cancer. In a retrospective cohort of832 patients with splanchnic vein thrombosis, of which 27% hadunderlying cancer, warfarin therapy and gastrointestinal tract variceswere independent predictors of bleeding.79 Furthermore, VTErecurrence was not reduced after anticoagulant therapy. An inter-national registry of 613 patients with splanchnic vein thrombosisreported that most patients are treated with anticoagulation and thatthe risk of major bleeding is low.80 Whether such results apply tocancer-related splanchnic vein thrombosis is not known.

In patients with acute, symptomatic splanchnic vein thrombosiswithout contraindications to anticoagulation, guidelines recommend

the use of anticoagulant therapy.21 For patients with incidentallydetected splanchnic vein thrombosis, there is no specific guidanceon treatment. It is reasonable to withhold anticoagulation if the patientis truly asymptomatic, especially if radiologic evidence indicates thatthe thrombus is chronic in nature. Repeated imaging is prudent todetect thrombus progression if anticoagulation is not given.

Use of NOACs in cancer-associatedthrombosis

The development of NOACs that directly inhibit factor Xa orthrombin is a milestone achievement in the prevention and treatmentof VTE. These agents are more attractive to patients and cliniciansbecause they are taken by mouth in fixed doses once or twice daily,have few drug and food interactions, and do not require laboratorymonitoring. Dabigatran, a direct thrombin inhibitor, and rivarox-aban and apixaban, 2 direct factor Xa inhibitors, are the forerunnersin this class of agents. These drugs have been shown to be effectivein VTE prophylaxis after major hip and knee arthroplasty and instroke prevention in patients with nonvalvular atrial fibrillation.81

They are also noninferior to warfarin for the prevention of recurrentVTE without an increased risk of bleeding, and rivaroxaban hasreceived regulatory approval as monotherapy in the treatment ofDVT.82-87 All 3 agents are effective and safe for long-termsecondary VTE prophylaxis in patients who have already received6 to 12 months of anticoagulation.82,85,87 Unfortunately, very smallnumbers of patients with cancer were included in these trials, andthe results of this patient subgroup have not been published. A smallphase 2 study evaluating the safety and tolerability of apixabanfound a low risk of major bleeding (2.2%) during 12 weeks oftherapy in 125 patients with metastatic or advanced cancer withoutthrombosis.88 No studies have specifically addressed the treatmentof cancer-associated VTE using these direct inhibitors.

Despite the undeniable practical advantages of these agents vsVKA and LMWH therapy for the prevention and treatment of cancer-associated thrombosis, important and clinically relevant concernsprevail regarding the extrapolation of published results to the cancerpopulation. These include the small number of highly selectedpatients with cancer (approximately 5%) enrolled in each studyand the use of warfarin or placebo rather than LMWH in the controlgroup. In addition, although these anticoagulants have fewer druginteractions than VKAs, interactions do exist with some chemo-therapeutic agents (Table 2). Whether these interactions are clinicallysignificant is not known. Finally, gastrointestinal tract problems inpatients with cancer can potentially alter drug delivery and absorption,and higher rates of gastrointestinal tract bleeding have been reportedwith dabigatran compared with warfarin.81 These shortcomings arecompounded by the lack of reversal agents to rapidly normalizehemostasis and the lack of widely available laboratory assays tomeasure the anticoagulant activity. Clinicians need to discuss theselimitations to fully inform their patients with cancer and know thatthe current ASCO Guideline does not recommend the use of thesenew agents.14 Clinical trials are strongly encouraged to address thisand the many other unmet clinical needs in patients with cancer-associated thrombosis.

Authorship

Contribution: A.Y.Y.L. and E.A.P. wrote the manuscript.

Table 2. Interactions between chemotherapeutic agents andimmunosuppressants with NOACs based on known metabolicpathway activity

Dabigatran Rivaroxaban Apixaban

Interactioneffect* P-glycoprotein

P-glycoproteinCYP3A4

P-glycoproteinCYP3A4

Increases NOAC

plasma levels†

Cyclosporine Cyclosporine Cyclosporine

Tacrolimus Tacrolimus Tacrolimus

Tamoxifen Tamoxifen Tamoxifen

Lapatinib Lapatinib Lapatinib

Nilotinib Nilotinib Nilotinib

Sunitinib Sunitinib Sunitinib

Imatinib Imatinib

Reduces NOAC

plasma levels‡

Dexamethasone Dexamethasone Dexamethasone

Doxorubicin Doxorubicin Doxorubicin

Vinblastine Vinblastine Vinblastine

CYP3A4, cytochrome P450 3A4.

*Clinicians should consult with the pharmacist to determine if these and other

drug interactions exist when NOACs are being considered.

†Drugs that inhibit P-glycoprotein transport or CYP3A4 pathway can increase

NOAC levels.

‡Drugs that induce P-glycoprotein transport or CYP3A4 pathway can lower

NOAC levels.

BLOOD, 3 OCTOBER 2013 x VOLUME 122, NUMBER 14 TREATMENT OF CANCER-ASSOCIATED THROMBOSIS 2315

Conflict-of-interest disclosure: A.Y.Y.L. reports receiving researchfunding from LEO Pharma and honoraria from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, LEO Pharma, Pfizer, and SanofiAventis. The remaining author declares no competing financial interests.

Correspondence: Agnes Y. Y. Lee, University of British Columbiaand Vancouver Coastal Health Diamond Health Care Centre, 2775Laurel St, 10th Floor, Vancouver, BC, Canada; email: alee14@bccancer.bc.ca.

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