Perioperative Bridging of Warfarin with Low Molecular Weight Heparin in Atrial Fibrillation:

If everyone else jumped off the BRIDGE, would you?

Chelsea Minor, Pharm.D. PGY1 Pharmacy Resident

South Texas Veterans Health Care System The University of Texas at Austin College of Pharmacy

The University of Texas Health Science Center at San Antonio January 22, 2016

Objectives

1. Describe the pathophysiology and risk factors for thromboembolism (TE) associated withatrial fibrillation (AFib)

2. Review the pharmacology and kinetic properties of various anticoagulation agents3. Classify the severity of and identify the risk factors for bleeding4. Review the evidence supporting current guideline bridging recommendations5. Formulate a recommendation regarding the use of perioperative bridging of warfarin with

low molecular weight heparin (LMWH) in patients with AFib

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Background

I. Epidemiology 1. Prevalence of AFib in the United States is expected to reach 12.1 million cases by 2030 1

Figure 1. Projected prevalence of AFib cases in U.S 1

2. Patients with AFib have five times the risk of stroke as their age matched controls 2

3. Each year, 69,165 Americans will have a stroke attributed to AFib 3-5

4. Approximately 41-65% of patients with moderate to high stroke risk are prescribed

oral anticoagulation therapy 3

5. Approximately one in six warfarin treated patients with AFib undergo an electiveprocedure requiring temporary interruption of anticoagulation per year 6-7

Atrial Fibrillation

I. Definition 1. AFib is a supraventricular tachycardia arising from disorganized atrial depolarization2. AFib is characterized by:

a. Extremely rapid atrial rate (400 to 600 beats/min)b. Disorganized atrial activation

Table 1. Classification of AFib 8 Classification Description Paroxysmal AFib that terminates spontaneously or with intervention within

seven days of onset but episodes may recur with variable frequency Persistent Continuous AFib that is sustained > seven days Long-standing persistent Continuous AFib > 12 months duration Permanent Joint decision between patient and clinician to stop further attempts

to restore or maintain sinus rhythm Non-valvular AFib (NVAF) AFib in the absence of rheumatic mitral stenosis, a mechanical or

bioprosthetic heart valve, or mitral valve repair

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II. Etiology 8

1. Multifactorial mechanisms of AFib development2. Risk factors contribute to electrical remodeling, structural, and neurohormonal changes

Table 2. Risk factors for AFib 8 Atrial Distension High Adrenergic Tone Chronic hypertension Sepsis Mitral valve disease Hyperthyroidism Cardiomyopathy Binge drinking Congenital defects Alcohol withdrawal Pulmonary embolism (PE) Excessive caffeine Pulmonary hypertension Sympathomimetics Myocardial ischemia Surgery Sleep apnea Emphysema or other lung disease

III. Pathophysiology1. Mechanism 8

a. Histopathological changes, such as atrial fibrosis or loss of atrial muscle mass,lead to electrical remodeling

b. Electrical remodeling results in multiple reentry circuits, rapidly firing atrialfoci, decreased atrial refractoriness, and shortening of action potentials

2. Stroke risk 9-11

a. Ischemic strokes occur commonly due to a cardiac embolus in the left atriumb. Stagnant blood flow in the dysfunctional atria can lead to clot formation in the

atria or atrial appendage, subsequent embolization, and cerebral occlusion

Figure 2. Mechanisms contributing to AFib related stroke 12

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IV. Estimating stroke risk1. Epidemiology

a. Ischemic strokes associated with AFib demonstrate greater disability and

mortality compared to other ischemic strokes 13(UTD-S)

b. Strokes associated with AFib have been shown to increase composite risk of

death, disability, and handicap by ~50% at three months 14

2. Validated risk stratification tools are used to predict stroke risk:a. CHADS2 score

Table 3. CHADS2 Score 15 Risk Factor Point Value Score Annual Stroke Rate

Congestive heart failure 1 0 1.9% Hypertension 1 1 2.8% Age > 75 years 1 2 4.0%

Diabetes 1 3 5.9% Previous stroke/TIA 2 4 8.5%

5 12.5% 6 18.2%

TIA: transient ischemic attack

b. CHA2DS2- VASc score

Table 4. CHA2DS2- VASc Score 16 Risk Factor Point Value Score Annual Stroke Rate

Congestive heart failure 1 0 0% Hypertension 1 1 1.3%

Age > 75 2 2 2.2% Diabetes 1 3 3.2%

Previous stroke/TIA 2 4 4.0% Vascular disease 1 5 6.7%

Age 65-74 1 6 9.8% Female gender 1 7 9.6%

8 6.7% 9 15.2%

Vascular disease: myocardial infarction (MI), peripheral arterial disease (PAD), aortic plaque

Figure 3. Rates of death, stroke, and systemic embolism (SSE) in CHADS2 vs. CHA2DS2-VASc 17

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c. Limited data validating scoring tools in perioperative setting

Table 5. Proposed stroke risk according to CHADS2 in perioperative setting 18 Score 30 Day Postoperative Stroke Rate (95% CI)

0 1.01 (0.83-1.21) 1 1.62 (1.46-1.79) 2 2.05 (1.87-2.24) 3 2.63 (2.26-3.04) 4 3.62 (2.66-4.80) 5 3.65 (1.83-6.45) 6 7.35 (2.42-16.3)

V. Pharmacologic management of AFib 19 1. Rate control2. Rhythm control3. Stroke prophylaxis

a. Recommendations for antithrombotic therapy are determined by stroke riskb. American College of Chest Physicians (ACCP)

Table 6. CHEST Guidelines 9th Edition (2012) 20 Risk CHADS2 score Prophylaxis Regimen Grade Low 0 No therapy

Aspirin 81-325 mg daily Aspirin 81-325 mg daily + clopidogrel 75 mg daily

IIB

Moderate 1 Oral anticoagulation (IB) If unsuitable consider:

Aspirin 81-325 mg daily Aspirin 81 mg daily + clopidogrel 75 mg daily

IIB

High > 2 Oral anticoagulation a If unsuitable consider:

Aspirin 81-325 mg daily (IB) Aspirin 81 mg daily + clopidogrel 75 mg daily (IB)

IA

aCHEST 2012 recommends dabigatran 150 mg twice daily over VKA therapy in patients with paroxysmal AFib (IIB)

c. American College of Cardiology (ACC)/American Heart Association (AHA)Task Force on Practice Guidelines and the Heart Rhythm Society (HRS)

Table 7. AHA/ASA/HRS Guideline Recommendations (2014) 8 Risk CHA2DS2-VASc score Prophylaxis Regimen Class Low 0 No therapy IIA

Moderate 1 No therapy IIB

High > 2 Oral anticoagulation Warfarin (IA) Dabigatran (IB) Apixaban (IB) Rivaroxaban (IB)

I

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Anticoagulation I. Vitamin K antagonists (VKAs)

1. Pharmacology of warfarin 21-22 a. VKAs interfere with the cyclic conversion of vitamin K and vitamin K epoxide by

modulating gamma carboxylation of glutamate residues on the N-terminal regions of vitamin K dependent coagulation factors

b. Inhibits production of vitamin K dependent clotting factors II, VII, IX, and X along with anticoagulant proteins C and S, which require gamma carboxylation for their coagulation activity

Figure 4. Mechanism of action of warfarin 23

2. Pharmacokinetics of warfarin 24

a. Half-life(t1/2) i. R-warfarin: 45 hours

ii. S-warfarin: 29 hours b. Highly protein bound: 99% c. Metabolism

i. R-warfarin: CYP1A2, CYP3A4 ii. S-warfarin: CYP2C9

d. Coagulation factors’ half-lives

Table 8. Half-life of clotting factors Clotting factors t1/2 (h)

Factor VII 4-6

Protein C 8-10 Factor IX 20-30 Factor X 24-40 Protein S 40-60 Factor II 60-100

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II. LMWH 25 1. Pharmacology of LMWH

a. Heparin is pentasaccharide, which binds to antithrombin, causes a conformational change, and interacts with thrombin and factor Xa (FXa)

b. Unfractionated heparin (UFH) has equivalent activity against thrombin and FXa c. LMWHs are approximately one-third the molecular weight range of UFH d. LMWH has greater activity against FXa, as it cannot bind to both antithrombin

and thrombin

Figure 5. Mechanism of action of heparin products 25

2. Pharmacokinetics of LMWH

a. Elimination is primarily renal b. Better bioavailability and longer half-life than UFH c. Dose independent clearance

Table 9. Comparison of current LMWH agents 26-29 LMWH (SQ) BA (%) Time to Cmax (h) t1/2 (h) Dalteparin 87 4 3-5 Enoxaparin 100 3-5 7 Nadroparin 89 3-6 2-11.2 Tinzaparin 86.7 4-5 3-4 SQ: subcutaneous; BA: bioavailability; Cmax: concentration max; t1/2: half-life

III. Direct oral anticoagulants (DOACs)

Table 10. Comparison of current DOACs 30-33 DOAC BA (%) Time to Cmax (h) Protein binding (%) t1/2 (h) Renal elimination (%) Dabigatran 3-7 1-2 35 12-17 7 Rivaroxaban 80-100 2-4 92-95 5-9 66 Apixaban 50 3-4 87 12 27 Edoxaban 62 1-2 55 10-14 50

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Bleeding Risk I. Classification of bleeding

Table 11. International Society of Thrombosis and Hemostasis bleeding definitions34 Classification Criteria Major bleed (MB) A fall in hemoglobin of > 2.0 g/dL or requiring > two units of blood

transfusions; symptomatic bleeding in a critical organ/region; a fatal bleed

Clinically relevant non-major bleed (CRNM)

Does not meet criteria for MB but prompts a clinical response including: hospital admission, physician guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy

Minor bleed All other non-major bleeds

II. Estimating risk of bleeding 1. ATRIA 35

a. Risk factors for bleeding retrospectively identified in patients with NVAF b. Score > five indicates high bleeding risk

Table 12. ATRIA 35

Risk Factor Points Score Annual hemorrhage rate (%) Anemia 3 0-3 0.76

Severe renal disease 3 4 2.62 Age > 75 years 2 5-10 5.76

Any prior hemorrhage diagnosis 1 Hypertension history 1

Severe renal disease: Defined as eGFR < 30 mL/min or dialysis-dependent

2. HEMORR2HAGES 36 a. Quantified bleeding risk in 3791 Medicare beneficiaries with AFib b. Score ≥ four considered high bleeding risk

Table 13. HEMORR2HAGES 36

Risk Factor Points Score Bleeds per 100 patient-years on warfarin (95% CI)

Hepatic or renal disease 1 (each) 0 1.9 (0.6-4.4) Ethanol use 1 1 2.5 (1.3-4.3) Malignancy 1 2 5.3 (3.4-8.1)

Older age (> 75 years) 1 3 8.4 (4.9-13.6) Reduced platelet count or function 1 (each) 4 10.4 (5.1-18.9)

Re-bleeding 2 ≥ 5 12.3 (5.8-23.1) Hypertension, uncontrolled 1

Anemia 1

Genetic factors 1

Elevated risk of fall 1

Stroke 1 Hepatic disease: cirrhosis, two-fold or greater elevation of AST or ALT, or albumin < 3.6 g/dL; Renal insufficiency: CrCl < 30 ml/min; History of alcohol abuse, recent hospitalization for alcohol-related illness, and worsening liver disease; Recent metastatic cancer; Platelets < 75k; Scheduled use of antiplatelet therapy, NSAID therapy, or blood dyscrasia; Prior hospitalization bleeding; Most recent hematocrit < 30 or hemoglobin < 10 g/dL; CYP2C9*2 and/or CYP2C9*3; Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls; Prior ischemic stroke or brain infarct detected by brain imaging

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3. HAS-BLED 37 a. Validated with warfarin, not DOACs b. Score > three indicates high bleeding risk

Table 14. HAS-BLED 37

Risk Factor Points Score Annual Bleeding Risk (%)

Bleeding rate (%/year)

Hypertension 1 0 0.9 1.13 Abnormal renal/hepatic function 1 (each) 1 3.4 1.02

Stroke 1 2 4.1 1.88 Bleeding 1 3 5.8 3.74

Labile INRs 1 4 8.9 8.70 Elderly (≥ 65 years) 1 5 9.1 12.50 Drugs or alcohol use 1 (each) 6-9 Insufficient data Insufficient data

Hypertension: SBP > 160 mmHg; Abnormal renal function: chronic dialysis, renal transplantation, or serum creatinine > 2.3 mg/dL; Abnormal liver function: chronic hepatic disease (i.e. cirrhosis), evidence of significant hepatic derangement (i.e. bilirubin > 2 x ULN, AST/ALT > 3 x ULN); Bleeding: prior bleed history and/or predisposition to bleeding (i.e. bleeding diathesis, anemia, etc); Labile INR: unstable/high INR or < 60% time spent in therapeutic range; Drugs/alcohol: concomitant drugs that may increase bleed risk (i.e. antiplatelet agents, NSAIDS, etc) or alcohol abuse

Perioperative Bridging Recommendations

I. Rationale for bridging

1. Patients undergoing an elective procedure may require an interruption of VKA therapy 2. The antithrombotic effect of VKAs takes four to five days to recede after it is stopped

and to establish on re-initiation 3. Patients with AFib are at an increased risk for perioperative TE, such as stroke and

require additional anticoagulation during this period of sub-therapeutic VKA therapy 4. Bridging anticoagulation, typically with a LMWH, can provide adequate anticoagulation

during this perioperative period

Figure 6. Perioperative management of VKA 38

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II. Perioperative management of bridging anticoagulation 39

1. Stop warfarin approximately five days before surgery 2. Resume warfarin 12-24 hours after surgery 3. In patients receiving therapeutic subcutaneous LMWH, stop LMWH approximately 24

hours before surgery 4. In patients receiving intravenous UFH, stop UFH 4-6 hours before surgery 5. In patients undergoing a high bleed risk surgery, resume LMWH or UFH 48-72 hours

after surgery

III. ACC/AHA/HRS Guidelines 2014 8 1. Decisions about bridging therapy should balance the risks of stroke, bleeding, and the

duration of time anticoagulation will be interrupted 2. In the following high risk patients, consider bridging with UFH or LMWH:

a. Mechanical valves b. Prior stroke or TIA c. CHA2DS2-VASc score > two

3. Low risk patients, without above risk factors, undergoing procedure with bleed risk: a. Stop warfarin up to one week prior to procedure b. Do not bridge c. Resume warfarin after adequate hemostasis is achieved

4. Consider continuing oral anticoagulation for the following procedures: a. Pacemaker or implantable cardioverter defibrillation (ICD) implantation b. Catheter ablation c. Coronary angiography

Table 15. Summary of evidence from ACC/AHA/HRS 2014 Guidelines 40-42 Trial Objective Study Design Results Birnie, et al Compare the incidence of

device-pocket hematomas in patients continuing warfarin therapy vs. undergoing heparin bridging during pacemaker or ICD implantation

Multicenter, single-blinded, RCT (n=668)

Reduced incidence of device-pocket hematoma in continuation group. No difference in bleeding or TE between groups

Hakalahti, et al Evaluate the safety of therapeutic vs. subtherapeutic oral anticoagulation during ablation

Observational, single center, prospective (n=193)

No significant difference in major or minor bleeding, or thromboembolic events

Lahtela, et al Evaluate the safety and efficacy of uninterrupted anticoagulation compared to bridging therapy in patients with AFib undergoing cardiac stenting

Observational, multicenter, prospective (n=451)

No difference in rates of bleeding complications or major adverse cardiac and cerebral events between groups

RCT, randomized control trial

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IV. CHEST Guidelines 2012 39 1. Recommendation to bridge is based on CHADS2 risk score

Table 16. CHEST Guidelines Risk Stratification (2012) 39

Risk Group CHADS2 Score Recommendation Low 0-2a Do not bridge

Moderate 3-4 Recommendation to bridge based on assessment of

individual patient and surgical factors High

5-6b Bridge anticoagulation

a Assumes no prior stroke or TIA; b Stroke or TIA in prior 3 months, or rheumatic valvular heart disease

2. Consider continuing oral anticoagulation for the following procedures:

a. Dental b. Dermatologic c. Cataract surgery

Table 17. Summary of evidence from the CHEST 2012 Guidelines 43-45 Trial Objective Study Design Results Nematullah, et al Evaluate the risk of

bleeding in patients continuing warfarin while undergoing elective dental procedures

Meta-analysis of five RCTs

No difference in clinically significant non-major or minor bleeding

Nelms, et al Evaluate the safety of continuing warfarin in patients, undergoing soft tissue surgery

Retrospective chart review (n=26)

Only one case of postoperative bleeding managed with gentle pressure, intraoperative bleeding well controlled in all cases

Jamula, et al Determine the efficacy and safety of continuing warfarin treatment before and after cataract surgery

Meta-analysis of eleven studies

Pooled incidence of bleeding was not clinically significant

V. Perioperative management of DOACs Table 18. Recommendations for perioperative management of DOACs 30-33

Drug Recommendation Bridging Apixaban Low bleeding risk surgery:

Stop 24 hours prior Mod-high bleeding risk surgery: Stop 48 hours prior

Do NOT bridge

Rivaroxaban Stop at least 24 hours prior N/A Edoxaban Stop at least 24 hours prior N/A Dabigatran CrCl < 50 mL/min:

Stop 3-5 days prior CrCl ≥ 50mL/min: Stop 1-2 days prior

N/A

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Literature Review

Malato A, Saccullo G, Lo Coco L, et al. Patients requiring interruption of long-term oral anticoagulant therapy: the use of fixed sub-therapeutic doses of low-molecular-weight heparin. J Thromb Haemost. 2010;81:107-13. 46

Objective To evaluate the efficacy and safety of bridging therapy with fixed dose subcutaneous LMWH in patients on long term VKA therapy undergoing an invasive procedure

Methods Study Design Single center, prospective, intention-to-treat, cohort study Population Inclusion Criteria Exclusion Criteria

Adult outpatients on chronic VKA for mechanical heart valves, AFib, stroke with embolic source, VTE, or other indications

Due to have major surgery or invasive procedure requiring temporary interruption of VKA

Minor surgery or dental procedure Renal insufficiency Previous MB Chronic anemia (Hgb ≤ 10 g/L) Platelets (< 100k/ mm3) Severe comorbidities Receiving other anticoagulants Body weight ≤ 40 kg or ≥ 100 kg

Interventions Preoperatively: In all patients, VKA was discontinued 5 ± 1 days prior to procedure High risk group: When INR < 1.5, LMWH was initiated twice daily at a fixed sub-

therapeutic dose (3800 or 4000 IU of anti-FXa for nadroparin or enoxaparin, respectively) and continued until the night before procedure

Low risk group: INR of ≤ 1.2 was required before surgery. LMWH was initiated once daily at a prophylactic dosage (3800 or 4000 IU of anti-FXa for nadroparin or enoxaparin, respectively) the night before procedure

Postoperatively: LMWH was resumed 12 hours post-op (twice daily in high risk group; once daily

in low risk group) and continued until INR in therapeutic range. Usual dose of VKA resumed one day post-op, unless inadequate hemostasis

Assessments Patients were followed up to one month after surgery (30 ± 2 days) CBC measured every 1-2 days while patients were on LMWH INR measured every 1-2 days for one week post-op

Endpoints Primary efficacy endpoint: perioperative arterial or venous TE Primary safety endpoint: MB Secondary safety endpoint: minor bleeding

Statistical Analyses

Intention-to-treat : all patients who received > one dose of LMWH Primary outcome rates expressed as a proportion with a 95% CI Fisher’s exact test was used for the frequency analysis Expected incidence of perioperative MB of 3%, required a sample size of ≥ 300

patients Results

Enrollment University Hospital of Palermo, in Palermo, Italy Between 2003-2008, 486 patients on chronic anticoagulation were considered 134 were excluded 352 patient were included

24 did not receive study medication 328 received at least one dose of LMWH

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Baseline Characteristics

Table 19. Baseline characteristics (n=328) Characteristic Findings Mean age, range (years) 62.3 (25-89) Weight, mean ± SD (kg) 76.3 ± 17.4 AFib without previous stroke, n (%) 122 (37.1) AFib with previous stroke, n (%) 58 (17.6)

Low risk group, n (%) 182 (55.4) High risk group, n (%) 146 (44.6) Non-major invasive procedure, n (%) 225 (69) Major surgery, n (%) 103 (31)

Results

Table 20. Results (n=328)

Endpoint Total

Low risk (n=182)

High risk (n=146)

P-value

TE, n (%) 95% CI

6 (1.8) 0.4 – 3.2

1 (0.54) -0.54 – 1.6

5 (3.4) 0.5 – 6.3

0.092

MB, n (%) 95% CI

7 (2.1) 0.6 – 3.6

1 (2.8) -2.6 – 8.2

6 (8.8) 2.1 – 15.5

0.417

Minor bleeding, n (%) 95% CI

15 (4.6) 6 (3.3) 2.7 – 3.9

9 (6.1) 2.3 – 9.9

Discussion Critique Strengths Limitations

Thirty day follow up Standardized dosing of LMWH

Not randomized Single center Various indications for anticoagulation Did not report CHADS2 scores Excluded patients >100 kg

Implications A standardized bridging anticoagulation regimen with fixed doses of LMWH was associated with a low risk of TE and MB

MB occurred more frequently in the group that underwent major surgery

Douketis JD, Healey JS, Brueckmann M, et al. Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery of procedure: substudy of the RE-LY trial. J Throm Haemost. 2015;113:625-32. 6 Objective Compare perioperative clinical outcomes in patients treated with dabigatran or

warfarin requiring an elective procedure while enrolled in RE-LY Methods

Study Design Pre-specified, retrospective, sub-analysis of RE-LY trial Population Inclusion Criteria Exclusion Criteria

Age > 18 years CHADS2 score > 1 NVAF First interruption of anticoagulation

Urgent surgery or procedure Unspecified surgery or procedure MB or TE 30 days prior

Interventions Perioperative management of warfarin was left to physician discretion Bridging with LMWH or UFH vs. no bridging therapy

Assessments Observed seven days before the procedure and 30 days afterwards

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Endpoints MB: Non-life threatening MB, life threatening MB, fatal bleed SSE Any TE: SSE, MI, PE, or vascular death

Statistical Analyses

Fisher’s exact test for categorical data Student’s T test for continuous data Multivariable logistic regression analysis to adjust for covariates

Results Enrollment December 2005 to March 2009

4133 patients included in analysis Baseline Characteristics

Table 21. Baseline characteristics of warfarin-treated patients (n=1424) Characteristic Bridged (n=391) Not bridged (n=1033) Age, mean (years) 71.5 73.1 CHADS2 score, mean 2.1 2.1 CHA2DS2-VASc score, mean 3.6 3.6 HAS-BLED score , mean 1.4 1.3 Prior stroke or TIA, n (%) 81 (20.7) 170 (16.5)

Results

Table 22. Results of warfarin treated patients (n=1424)

Endpoint Bridged (n=383)

Not bridged (n=1032)

OR (95% CI)

P-value

MB, n (%) 26 (6.8) 16 (1.6) 4.62 (2.45 – 8.72) <0.001 SSE, n (%) 2 (0.5) 2 (0.2) 2.70 (0.38 – 19.3) 0.321 TE, n (%) 7 (1.8) 3 (0.3) 6.39 (1.64 – 24.8) 0.007

Discussion Critique Strengths Limitations

Multivariable logistic regression analysis to control for confounders

Balanced baseline characteristics Strong external validity

Not randomized No standardized bridging Small sample size Under powered

Implications MB rates were significantly higher in patients who were bridged arm SSE rates did not differ in patients who were bridged or not bridged Rates of TE were significantly higher in patients who were bridged

Steinberg BA, Peterson ED, Sunghee K, et al. Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: findings from the outcomes registry for better informed treatment of atrial fibrillation (ORBIT-AF). Circ. 2015;131:488-94. 47

Objective Compare the incidence of interruption of oral anticoagulation for procedures, causes for interruption, patterns of bridging agents, and outcomes for patients in the ORBIT-AF registry who were bridged to those who were not bridged

Methods Study Design Retrospective review of prospective, multicenter, outpatient, ORBIT-AF registry data Population Inclusion Criteria Exclusion Criteria

Age ≥ 18 years ECG documented AFib At least 1 follow-up visit

Life expectancy < six months Transient AFib from reversible condition Not on oral anticoagulation at baseline

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Interventions Bridging with LMWH, UFH, fondaparinux, or no bridging Procedures included cardiac catheterization, catheter ablation, endoscopy, cardiac

surgery, non-cardiac surgery, device implantation, dental procedure Assessments Interruptions in anticoagulation therapy for procedures were recorded

Observed for 30 days post-surgery or procedure Endpoints Safety: Any bleeding events, MB

Cardiovascular (CV) events: SSE, MI, or CV hospitalization Composite of MI, SSE, MB causing hospitalization, and death within 30 days

Statistical Analyses

Chi squared test for categorical data Wilcoxon rank-sum test for continuous data

Results Enrollment Patients in ORBIT-AF: 10,132

7372 patients included in cohort Baseline Characteristics

Table 23. Baseline characteristics (n=2200) Characteristic Not bridged

(n=1608) Bridged (n=592)

P value

Age, mean (years) 75 74 0.009 CHADS2 score, mean 2.34 2.53 0.004 CHA2DS2-VASc score, mean 4.03 4.25 0.01 ATRIA score, mean 2.74 2.72 0.9 Prior CVA (%) 15 22 0.0003 Congestive heart failure (%) 34 44 <0.0001 Significant valvular disease (%) 27 34 0.0006 Moderate/severe mitral stenosis (%) 1.1 2.5 0.01 Prior mechanical valve replacement (%) 2.4 9.6 <0.0001 Warfarin (%) 93 96 Dabigatran (%) 6.8 3.7 INR prior to procedure, mean 2.34 2.28 0.3

Results Table 24. Results Unadjusted, n (%) Adjusted Endpoint Not bridged

(n=1724) Bridged (n=503)

P-value OR (95% CI) P value

CV events 43 (2.5) 23 (4.6) 0.02 1.62 (0.95-2.78) 0.07

Bleeding events

22 (1.3) 25 (5.0) <0.0001 3.84 (2.07-7.14) <0.0001

Overall composite

108 (6.3) 64 (13.0) <0.0001 1.94 (1.38-2.71) 0.0001

Discussion Critique Strengths Limitations

Large cohort Strong external validity Adjusted for covariates

Observational study Used ATRIA score No standardized bridging procedure

Implications Bridging anticoagulation was associated with an increased risk of bleeding and CV events

Composite outcome driven by rate of hospitalization in bridged group

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Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med. 2015;373:823-33. 48 Objective To evaluate whether forgoing bridging therapy with LMWH is non-inferior to bridging

with LMWH for the prevention of perioperative arterial TE and superior in regard to MB

Methods Study Design Multicenter, randomized, double bind, placebo-controlled, intention-to-treat analysis Population Inclusion Criteria Exclusion Criteria

> 18 years of age Chronic (permanent or paroxysmal)

AFib/flutter Warfarin therapy for > 3 months Undergoing elective operation or

invasive procedure requiring interruption of warfarin therapy

CHADS2 score ≥ 1

Mechanical heart valve SSE, or TIA within previous 12 weeks MB within the previous 6 weeks CrCl < 30 mL/min Platelets (< 100k/mm3) Planned cardiac, intracranial, or

intraspinal surgery

Interventions Preoperatively: Dalteparin sodium 100 IU/kg SQ BID or placebo Postoperatively: Warfarin restarted evening of or day after procedure LMWH or placebo resumed:

12-24 hours after low bleeding risk procedure 48-72 hours after high bleeding risk procedure

Assessments Final follow-up was 30-37 days post procedure Endpoints MB: non-life-threatening MB, life-threatening MB, and fatal bleed

SSE Any TE: SSE, MI, PE, and any vascular death

Statistical Analyses

Primary efficacy outcome: non-inferiority analysis, one sided test at 0.025 95% CI calculated using Barnard’s test Expected event rate 1.0% for both groups; non-inferiority margin 1.0% Primary safety outcome: two sided test at 0.05; p-value calculated with Fisher’s

mid-P test; expected event rates were 1.0% with no bridging and 3.0% with bridging

90% power for two primary endpoints required sample size of 1882 Results

Enrollment From July 2009 to December 2014 at 108 sites in the U.S. and Canada 1884 patients recruited

Baseline Characteristics

Table 25. Baseline characteristics (n=1884) Characteristic Not bridged

(n=950) Bridged (n=934)

Age, year ± SD 71.8 ± 8.74 71.6 ± 8.88 Caucasian, n (%) 860 (90.5) 849 (90.9) Male, n (%) 696 (73.3) 686(73.4) Mean CHADS2 score, ± SD 2.3 ± 1.03 2.4 ± 1.07 Aspirin, n (%) 324 (34.1) 329 (35.2) Clopidogrel, n (%) 30 (3.2) 21 (2.2) Prior stroke, n (%) 79 (8.3) 99 (10.6)

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Results

Table 26. Results

Endpoint Not bridged (n=918)

Bridged (n=895)

P-value

Arterial TE, n (%) 4 (0.4) 3 (0.3) 0.01*, 0.73 MB, n (%) 12 (1.3) 29 (3.2) 0.005 Death, n (%) 5 (0.5) 4 (0.4) 0.88 Minor bleeding, n (%) 110 (12.0) 187 (20.9) <0.001 *Non-inferiority

Discussion Critique Strengths Limitations

Large sample Randomized controlled trial Common procedures well represented

Low event rate Selected non-inferiority margin was

too wide so sample size and power re-calculated during study

Excluded high risk patients Time in therapeutic range not

reported Implications Provided little data for patients with CHADS2 score > 5

Patients with mechanical heart valves, patients undergoing major surgical procedures associated with high rates of arterial TE or bleeding, and CrCl < 30mL/min were excluded, limiting external validity

Forgoing bridging did not increase the risk of TE, but did decrease the risk of bleeding

Conclusions I. Summary

1. Forgoing bridging in low to moderate risk patients does not increase the risk of TE, but decreases the risk of bleeding

2. Data limited to observational studies with only one randomized trial 3. Majority of patients studied had a low to moderate risk of TE

a. Current randomized control trial underway with higher risk patients b. PERIOP2 (NCT00432796): LMWH bridging therapy vs. placebo bridging

therapy for patients on long term warfarin requiring temporary interruption

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II. Recommendations 1. Gaps in current literature include patients with the following risk factors:

a. CHADS2 > 5 b. Mechanical valves c. Stroke or TIA within the prior three months

2. Do not bridge patients in the absence of the above risk factors 3. Recommend bridging patients with any of the above risk factors 4. Continue oral anticoagulation in patients undergoing a very low bleeding risk procedure

(see appendix A) Table 27. Criteria for perioperative bridging Criteria Points Very low bleeding risk procedure

-4

CHADS2 > 5

1

Mechanical valve or Stroke or TIA within the prior three months

2

Very low bleeding risk procedures defined in appendix A.

Table 28. Perioperative bridging recommendations Score Recommendation ≤ -1 Recommend continuing oral anticoagulation, without bridging

0 Recommend against perioperative bridging with LMWH, unless significant

clinical factors suggest otherwise ≥ 1 Recommend perioperative bridging with LMWH

The above scoring system has not been prospectively validated and was developed for the purposes of

this lecture. It should not replace clinical judgement.

III. Additional considerations

1. Patients at an increased risk of TE

a. High procedural risk of TE (see appendix B)

b. Prior TE when anticoagulation withheld

c. Secondary indication for anticoagulation

2. Patients at an increased risk for hemorrhage

a. High procedural bleed risk (see appendix A)

b. Patients with high bleeding risk

c. Patients with an increased fall risk

3. Alternative strategies

a. Decreased duration of LMWH pre-operatively

b. Increased time till restarting LMWH post-operatively

c. Unconventional LMWH dosing

1. Fixed sub-therapeutic dosing (i.e. enoxaparin 40mg twice daily)

2. Prophylactic dosing (i.e. enoxaparin 40mg once daily)

Minor |18

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Appendices Appendix A. Associated bleeding risk of surgeries or procedures during perioperative antithrombotic drug administration 8,20,39,49,50 Very Low Low Moderate High Pacemaker or ICD implantation

Colonoscopy ± biopsy Invasive dental procedures

Aortic aneurysm repair

Catheter ablation Endodontics Invasive ophthalmic procedure

Bladder

Coronary angiography Endoscopy ± biopsy Major intraabdominal Bowel polypectomy Dental procedures Restorations Major intrathoracic Coronary artery bypass

grafting Dermatologic procedures

Laparoscopic cholecystectomy

Resection of colon polyps

Heart valve replacement

Cataract surgery Simple extractions Renal biopsy Intracranial Prosthetics Prostate biopsy Major cancer Hernia repair Peripheral artery

bypass or major vascular surgery

Major orthopedic Prostate Reconstructive plastic Spinal surgery/

epidural procedure Appendix B. Incidence of perioperative stroke by surgery type (%) 51-62

Surgery type Stroke risk (%) References General surgery 0.08-1.0 Bateman, 2009 Orthopedic surgery 0.2-0.9 Bateman, 2009 Non-carotid major vascular surgery 0.6 Sharifpour, 2013 Head and neck surgery 0.2-4.8 Nosan, 1993; Thompson, 2004 Carotid endarterectomy 1.4 Gupta, 2011 Coronary artery bypass grafting 1.2-2.3 Sezai, 2015 Valve surgery 1.4-6.5 O'Brien, 2009; Biancari, 2013 Thoracic endovascular aortic surgery 3.8 Ullery, 2012 Open thoracic surgery 5.4-5.8 Quintana, 2014; Higgins, 2014