The New England Journal of Medicine SEPTEMBER 17, 2009

Dabigatran versus Warfarin in Patients with Atrial Fibrillation

Stuart J. Connolly, Michael D. Ezekowitz, Salim Yusuf et al.

Bottom Line

In patients with atrial fibrillation, dabigatran 150 mg twice daily reduced the risk of stroke or systemic embolism compared to warfarin with similar major bleeding, while dabigatran 110 mg twice daily showed similar efficacy but significantly reduced major bleeding.

Key Findings

1. The primary outcome of stroke or systemic embolism occurred at a rate of 1.69% per year in the warfarin group, 1.53% per year with 110 mg of dabigatran (RR 0.91; 95% CI, 0.74-1.11; P<0.001 for noninferiority), and 1.11% per year with 150 mg of dabigatran (RR 0.66; 95% CI, 0.53-0.82; P<0.001 for superiority).

2. Major bleeding occurred at a rate of 3.36% per year with warfarin, compared to 2.71% per year with 110 mg of dabigatran (P=0.003) and 3.11% per year with 150 mg of dabigatran (P=0.31).

3. Hemorrhagic stroke rates were significantly lower in both dabigatran groups (0.12% per year for 110 mg, 0.10% for 150 mg) compared to the warfarin group (0.38% per year, P<0.001 for both comparisons).

4. Myocardial infarction occurred at a higher rate with dabigatran (0.72% per year for 110 mg [P=0.07]; 0.74% for 150 mg [P=0.048]) compared to warfarin (0.53% per year).

5. Rates of death from any cause were 4.13% per year with warfarin, 3.75% per year with 110 mg of dabigatran (P=0.13), and 3.64% per year with 150 mg of dabigatran (P=0.051).

Study Design

Design

RCT

PROBE (Open-Label, Blinded Endpoint)

Sample

18,113

Patients

Duration

2.0 yr

Median

Setting

44 countries

Population Patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke.

Intervention Dabigatran etexilate, 110 mg or 150 mg twice daily (doses blinded to each other).

Comparator Dose-adjusted warfarin targeting an INR of 2.0 to 3.0 (administered open-label).

Outcome Stroke or systemic embolism.

Study Limitations

• The trial used an open-label design for warfarin administration, which could introduce bias in clinical management or reporting, although endpoints were blindly adjudicated (PROBE design).

• The mean time in therapeutic range (TTR) for the warfarin group was 64%, which is standard for global trials but may underrepresent the efficacy and safety of expertly managed, highly controlled warfarin therapy.

• Dabigatran was associated with a higher rate of dyspepsia, potentially affecting patient adherence.

• The slight numerical increase in myocardial infarction with dabigatran raised clinical questions that required subsequent analyses.

• At the time of the trial, there was no specific reversal agent available for dabigatran in the event of life-threatening bleeding (idarucizumab was developed and approved years later).

Clinical Significance

The RE-LY trial was a paradigm-shifting study that demonstrated a direct oral anticoagulant (DOAC) could effectively and safely replace warfarin for stroke prevention in nonvalvular atrial fibrillation. It offered patients a highly effective treatment without the burden of routine INR monitoring or severe food/drug interactions, sparking the widespread global adoption of DOACs in clinical practice.

Historical Context

For over fifty years, vitamin K antagonists such as warfarin were the only oral anticoagulants available for preventing stroke in patients with atrial fibrillation. Despite their efficacy, their narrow therapeutic window and need for constant monitoring made them cumbersome. RE-LY introduced dabigatran (a direct thrombin inhibitor) as the first landmark alternative, paving the way for the era of direct oral anticoagulants (DOACs).

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of dabigatran differ from that of warfarin, and why does this explain the rapid onset of action seen with dabigatran without the need for bridging therapy?

Key Response

Dabigatran directly and reversibly inhibits thrombin (Factor IIa). Warfarin inhibits VKORC1, depleting functional vitamin K-dependent factors (II, VII, IX, X). Warfarin takes days to deplete existing factors, requiring bridging for acute settings, while dabigatran acts immediately on active thrombin.

Resident

A patient on dabigatran 150 mg BID for atrial fibrillation presents with a massive gastrointestinal bleed. How does the management of this life-threatening bleed differ from reversing a supratherapeutic INR in a patient on warfarin?

Key Response

Warfarin reversal typically involves 4-factor prothrombin complex concentrate (PCC) and Vitamin K. Dabigatran has a specific reversal agent, idarucizumab (a monoclonal antibody fragment). If unavailable, activated PCC (FEIBA) can be used, and dabigatran can be dialyzed unlike highly protein-bound warfarin.

Fellow

The RE-LY trial showed a statistically non-significant but numerically increased rate of myocardial infarction in the dabigatran groups compared to warfarin. What are the proposed mechanisms for this signal, and how does it influence your choice of anticoagulant in an AFib patient with severe CAD?

Key Response

The numerical increase in MI with dabigatran might be due to the absence of warfarin's broader protective effects against coronary thrombosis (Factor VII/IX inhibition) or potentially a direct platelet activation effect by dabigatran. Fellows must weigh this signal against the robust stroke reduction, perhaps favoring a factor Xa inhibitor in severe CAD.

Attending

In RE-LY, dabigatran 110 mg BID was non-inferior for stroke prevention with less bleeding, while 150 mg BID was superior for stroke prevention with similar bleeding. Since the FDA did not approve the 110 mg dose, how do we reconcile the trial's safety findings with the clinical reality of dosing dabigatran in elderly patients?

Key Response

The FDA's decision forces clinicians to either use 150 mg BID (risking bleeding in frail patients) or the 75 mg BID dose (which was based on pharmacokinetics, not clinical efficacy in RE-LY). This highlights a disconnect between trial design and regulatory approval, requiring careful patient selection or pivoting to other DOACs.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The RE-LY trial utilized a PROBE (Prospective Randomized Open-label Blinded Endpoint) design rather than a double-blind, double-dummy design for the warfarin arm. What are the methodological advantages and threats to internal validity associated with this design?

Key Response

A PROBE design is pragmatic and avoids the complex, potentially risky process of sham INR monitoring which can artificially alter standard warfarin management. However, the open-label nature introduces performance and detection biases, potentially influencing the reporting of subjective adverse events or minor bleeds.

Journal Editor

The time in therapeutic range (TTR) for the warfarin arm in RE-LY was approximately 64 percent. As an editor evaluating comparator validity, how does this TTR influence the interpretation of dabigatran's superiority, particularly for health systems with highly optimized anticoagulation clinics?

Key Response

A TTR of 64 percent is adequate but inferior to highly controlled clinics where TTRs exceed 75 percent. Sub-analyses showed that in centers with excellent TTR, the superiority of dabigatran 150 mg over warfarin was attenuated. A critical reviewer would flag that the comparator's performance might artificially inflate the novel drug's relative efficacy.

Guideline Committee

Based on RE-LY and subsequent DOAC data, current ACC/AHA/HRS guidelines strongly prefer DOACs over warfarin for non-valvular AFib. What specific patient populations evaluated or excluded in early DOAC trials require strict adherence to warfarin, and what is the class of recommendation?

Key Response

Current guidelines (Class I) state that patients with moderate-to-severe mitral stenosis or mechanical heart valves must be managed with warfarin. RE-LY excluded hemodynamically significant valve disease, and the RE-ALIGN trial specifically showed harm with dabigatran in mechanical valves, cementing warfarin's ongoing role.

Clinical Landscape

Noteworthy Related Trials

2011

ROCKET AF

n = 14,264 · NEJM

Tested

Rivaroxaban 20mg daily

Population

Patients with nonvalvular atrial fibrillation at moderate-to-high risk for stroke

Comparator

Warfarin (target INR 2.0-3.0)

Endpoint

Stroke or systemic embolism

Key result: Rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism, with no significant difference in the risk of major bleeding.

2011

ARISTOTLE

n = 18,201 · NEJM

Tested

Apixaban 5mg twice daily

Population

Patients with nonvalvular atrial fibrillation and at least one risk factor for stroke

Comparator

Warfarin (target INR 2.0-3.0)

Endpoint

Stroke or systemic embolism

Key result: Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.

2013

ENGAGE AF-TIMI 48

n = 21,105 · NEJM

Tested

Edoxaban 60mg or 30mg daily

Population

Patients with nonvalvular atrial fibrillation and a CHADS2 score of 2 or higher

Comparator

Warfarin (target INR 2.0-3.0)

Endpoint

Stroke or systemic embolism

Key result: Both dose regimens of edoxaban were noninferior to warfarin regarding stroke or systemic embolism prevention, with significantly lower bleeding rates.

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