RE-COVER

Published

Schulman S, et al. "Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism". New England Journal of Medicine. 2009. 361(24):2342-52.
PubMed • Full text • PDF

Clinical Question

Among patients with acute VTE, how does dabigatran compare to warfarin with respect to VTE recurrence and bleeding risk?

Bottom Line

Among patients with acute VTE, the oral direct thrombin inhibitor dabigatran is as effective as warfarin at reducing recurrence risk, and is associated with less bleeding.

Major Points

The vitamin K antagonist warfarin has long been the standard of care for outpatient therapy of VTE. However, its use requires frequent lab draws for monitoring and dose adjustment, and as a result, a therapeutic INR is achieved only about 60% of the time. Alternative therapies to warfarin include dabigatran, an oral direct thrombin inhibitor, and rivaroxaban, an oral factor Xa inhibitor, both of which theoretically require no monitoring. The RE-COVER trial is part of an industry-supported series of trials investigating the role of dabigatran as an alternative to warfarin therapy. It was published in 2009, the same year as the RE-LY trial, which demonstrated the noninferiority of dabigatran to warfarin in non-valvular atrial fibrillation.

RE-COVER randomized 2,500 patients with acute VTE to either dabigatran 150mg orally twice daily or dose-adjusted warfarin to achieve an INR of 2-3. At approximately 6 months of follow up, there were similar rates of the primary outcome of VTE or VTE-related death in each arm (2.5-2.7%). Safety outcomes favored dabigatran: while there was no difference in major bleeding risk (1.6-1.9%), the risk of any bleeding was reduced by 26% with dabigatran (16% vs. 22%). In contrast to the results of RE-LY, there was no increased risk of MI with dabigatran.

This trial adds considerable weight to the notion that dabigatran 150mg twice daily is an acceptable alternative to warfarin dose-adjusted to achieve an INR between 2-3. In the US, dabigatran is FDA-approved for reducing stroke risk in non-valvular atrial fibrillation, not for the treatment of acute VTE, though it has been used off label for this disease. In Europe, dabigatran is approved for both non-valvular atrial fibrillation and for VTE prophylaxis following orthopedic surgery. Some of the hesitance of FDA approval appears to be from cost-benefit analysis, which estimates the cost of dabigatran 150mg twice daily to be $5,000-$6,000 per patient-year. The oral factor Xa inhibitor rivaroxaban, however, received this indication following the results of EINSTEIN-PE (2012).

Guidelines

CHEST Antithrombotic Therapy for VTE Disease (2016, adapted):

• In patients with proximal DVT or pulmonary embolism (PE), recommended long-term (3 months) anticoagulant therapy over no such therapy (Grade 1B).
  • For patients with DVT of the leg or PE and no cancer who are not treated with dabigatran, rivaroxaban, apixaban, or edoxaban, VKA therapy is recommended over low-molecular weight heparin (LMWH) (Grade 2C)
• In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy, dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over vitamin K antagonist (VKA) therapy (all Grade 2B)
• In patients with DVT of the leg or PE and cancer (“cancer-associated thrombosis”), as long-term (first 3 months) anticoagulant therapy, LMWH is recommended over other agents (Grade 2C)
• In patients with DVT of the leg or PE who receive extended therapy, recommend no need to change the choice of anticoagulant after the first 3 months (Grade 2C)
• In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), recommend switching to treatment with LMWH at least temporarily (Grade 2C).

ESC Guidelines on the diagnosis and management of acute pulmonary embolism (2014, adapted):

• LMWH or fondaparinux is the recommended form of acute phase parenteral anticoagulation for most patients (class I, level A).
• In parallel to parenteral anticoagulation, treatment with a VKA is recommended, targeting an INR of 2-3 (class I, level B).
• As an alternative to the combination of parenteral anticoagulation with a VKA, one of the following methods of anticoagulation are recommended (class I, level B):
  • Rivaroxaban 15 mg BID for 3 weeks, then 20 mg daily
  • Apixaban 10 mg BID for 7 days, then 5 mg twice daily
  • Dabigatran 150 mg BID (with dose adjustments for some patients)
  • Edoxaban (after acute phase parenteral anticoagulation)
• New oral anticoagulants are not recommended in patients with severe renal impairment (class III, level A).

Design

• Randomized, double-blind, double-dummy, noninferiority trial
• N=2,564 patients with acute VTE (25 excluded)
  • Dabigatran (n=1,274)
  • Warfarin (n=1,265)
• Setting: 228 centers in 29 countries (mostly Europe and North America)
• Enrollment: 2006-2008
• Follow-up: ~6 months
• Analysis: Modified intention-to-treat
• Primary outcome: VTE or VTE-related death (composite)

Population

Inclusion Criteria

• Age ≥18 years
• Acute symptomatic proximal DVT of the legs or PE diagnosed by:
  • Compression ultrasonography
  • Venography of legs
  • V/Q scanning
  • Angiography
  • CT angiography
• Appropriate and eligible for 6 months of anticoagulation

Exclusion Criteria

• Symptom duration >14 days
• PE with hemodynamic instability
• PE requiring thrombolysis
• Other indication for warfarin therapy
• Recent unstable CV disease
• High risk of bleeding
• Liver disease with AST >2x ULN
• eGFR <30cc/min
• Life expectancy <6 months
• Contraindiction to heparin or contrast material
• Pregnancy or risk of pregnancy
• Requirement for long-term antiplatelet therapy (although low-dose aspirin was allowed)

Baseline Characteristics

• Age: 55 years
• Male: 58%
• Race:
  • White: 95%
  • Black: 2.8%
  • Asian 2%
• Weight: 84kg
• BMI: 29
• eGFR: 106cc/min
• Index event
  • DVT: 69%
  • PE: 21%
  • DVT and PE: 9.5%
  • Neither DVT nor PE: 0.2%
• Cancer: 5%
• Prior VTE: 25.7%
• Parenteral anticoagulation
  • Treatment before randomization: 3 days
  • Treatment after randomization: 6 days
  • UFH: 11%
  • LMWH: 89%
  • Fondaparinux: 3.9%
• Exposure to study drug: 163 days
• Adherence to study drug: 98%
• INR in therapeutic range: 60% (only valid for warfarin group)

Interventions

• Randomized to dabigatran 150mg bid or warfarin with goal INR 2-3; both groups received sham medication identical to other therapy arm
• Those randomized to dabigatran underwent lab monitoring as well, with sham INR
• Both groups received initial parenteral anticoagulation (UFH or LMWH) for at least 5 days and true INR or sham INR ≥2 for 2 consecutive days
• Patients assessed for recurrence or bleeding at day 7 and then monthly for 6 months, with additional follow up 30 days after study completion
• Major bleeding defined as clinically overt and 1) associated with hemoglobin 20g/L, 2) resulted in transfusion of 2 or more PRBC units, 3) involved critical site, or 4) was fatal

Outcomes

Outcomes are dabigatran vs. warfarin.

Primary Outcomes

VTE or related death

2.7% vs. 2.5% (HR 1.05; 95% CI 0.65-1.70)

Secondary Outcomes

Symptomatic DVT

1.3% vs. 1.4% (HR 0.87; 95% CI 0.44-1.71)

Symptomatic nonfatal PE

1.0% vs. 0.6% (HR 1.85; 95% CI 0.74-4.64)

VTE-related death

0.1% vs. 0.2% (HR 0.33; 95% CI 0.03-3.15)

Death

1.6% vs. 1.7% (HR 0.98; 95% CI 0.53-1.79)

Major bleeding

1.6% vs. 1.9% (HR 0.82; 95% CI 0.45-1.48)

Major or clinically relevant nonmajor bleeding

5.6% vs. 8.8% (HR 0.63; 95% CI 0.47-0.84)

Any bleeding

16.1% vs. 21.9% (HR 0.71; 95% CI 0.59-0.85)

Adverse Events

Any event

66% vs. 68% (P=0.51)

Serious event

13% vs. 12% (P=0.43)

Event leading to study discontinuation

9% vs. 6.5% (P=0.05)

Events with incidence ≥3%

Headache: 6.2% vs. 7% (P=0.50)

Extremity pain: 5% vs. 5.6% (P=0.57)

Nausea: 3.8% vs. 4.6% (P=0.41)

Diarrhea: 4.5% vs. 3.0% (P=0.06)

Nasopharyngitis: 3.9% vs. 4.3% (P=0.74)

Dyspnea: 3.2% vs. 4.2% (P=0.24)

Back pain: 3.6% vs. 3.9% (P=0.73)

Arthralgia: 3.8% vs. 2.6% (P=0.12)

Peripheral edema: 3.4% vs. 3.8% (P=0.65)

Dyspepsia: 3.1% vs. 0.7% (P<0.001)

Acute coronary syndrome

0.4% vs. 0.2% (P=0.73)

Myocardial infarction

0.3% vs. 0.2% (P=0.69)

AST >3x ULN

3.1% vs. 2.1% (P=0.14)

ALT >3x ULN

3.4% vs. 3.8% (P=0.68)

ALT >3x ULN plus bilirubin >2x ULN

0.2% vs. 0.4% (P=0.69)

Criticisms

• Study was funded, designed, carried out, and analyzed by Boehringer Ingelheim, the makers of dabigatran (Pradaxa)

Funding

Funding from Boehringer Ingelheim, with multiple author disclosures.