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Connolly SJ, et al. "Dabigatran versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine. 2009. 361(12):1139-51.
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Clinical Question

Among individuals with chronic atrial fibrillation, how does dabigatran compare to warfarin in terms of stroke risk and the risk of major bleeding?

Bottom Line

The RE-LY study demonstrated that compared to warfarin, high-dose dabigatran reduces stroke risk without increasing the risk of major bleeding among patients with atrial fibrillation.

Major Points

Prior to RE-LY, warfarin was the primary anticoagulant used in the prevention of thromboembolic stroke among patients with atrial fibrillation (AF). Warfarin's advantages included its inexpensive cost and once daily dosing. Warfarin is less than ideal, however, because of the variable amount of vitamin K in food, its steep dose-response relationship, interactions with other drugs, and the fact that only 60% of patients are maintained within an INR of 2.0 to 3.0. Dabigatran is a new direct thrombin inhibitor marketed under the name Pradaxa. It use in prevention of stroke in atrial fibrillation was not known.

Published in 2009, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial was a non-inferiority study randomizing 18,000 patients with nonvalvular AF and a moderate-to-high risk of thromboembolic stroke to either high- or low-dose dabigatran or to warfarin. At a median follow-up of 2 years, high-dose dabigatran reduced the incidence of stroke (1.11% vs. 1.69%) without a concomitant rise in major bleeding events (3.11% vs. 3.36%). Although the study was designed to test the non-inferiority of either dose compared to warfarin, the final analysis ultimately demonstrated superiority of high-dose dabigatran over warfarin. Of note, both high and low doses of dabigatran were associated with a statistically significant increase in MI (0.74% and 0.72%, respectively, vs. 0.53% for placebo).

The FDA subsequently only approved the higher dose (150 mg) for use in non-valvular AF based upon its risk/benefit profile.[1] Additionally, a lower dose was approved for use in individuals with renal impairment that was not studied in a clinical trial (75 mg).[2] Given the anecdotal reports of increased bleeding in the early clinical use of the medication, the FDA performed a mini-sentinel study in 2013[3] that did not demonstrate an increased risk of bleeding with dabigatran when compared to warfarin. There is some anecdotal evidence that obese patients and those with elevated GFRs may not attain therapeutic levels of the drug.[4]


AHA/ACC/HRS AF (April 2014, adapted)[5]

  • In patients with nonvalvular AF with prior stroke, TIA, or CHA2DS2-VASc score ≥2, recommend oral anticoagulation with:
    • Warfarin, goal INR 2-3 (class I, level A)
    • Dabigatran (class I, level B)
    • Rivaroxaban (class I, level B)
    • Apixaban (class I, level B)
  • In patients with nonvalvular AF unable to maintain INR 2-3 with warfarin, recommend dabigatran, rivaroxaban, or apixaban (class I, level C)
  • In patients with nonvalvular AF with moderate or severe CKD with CHA2DS2-VASc score ≥2, consider treatment with reduced doses of dabigatran, rivaroxaban, or apixaban, although safety has not yet been clearly delineated (class IIb, level C)
  • In patients with ESRD, dabigatran and rivaroxaban are untested and are not recommended (class III, level C)
  • In patients with a mechanical heart valve, do not use dabigatran (class III, level B)


  • Multicenter, parallel-group, randomized controlled trial
  • N=18,113
    • Low-dose dabigatran (n=6,015)
    • High-dose dabigatran (n=6,076)
    • Warfarin (n=6,022)
  • Setting: 951 centers in 44 countries
  • Enrollment: 2005-2007
  • Follow-up: median 2 years
  • Analysis: Intention-to-treat, non-inferiority


Inclusion Criteria

  • Age ≥75 years or 65-74 years with T2DM, HTN, or CAD
  • AF documented on EKG within 6 months of screening
  • One of the following:
    • Prior stroke or TIA
    • LVEF <40%
    • NYHA class II-IV within 6 months of screening

Exclusion Criteria

  • Severe valvular disease
  • Stroke within 14 days
  • Severe stroke within 6 months of screening
  • Condition conveying an increased risk of hemorrhage
  • Creatinine clearance <30 ml/min
  • Active liver disease
  • Pregnancy

Baseline Characteristics

From the low-dose dabigatran group.

  • Demographics: Age 71 years, male 64%
  • Baseline health data: Weight 83 kg, BP 131/77
  • Type of AF: Persistent 32%, paroxysmal 32%, permanent 35%
  • CHADS2 score:
    • 0 or 1: 33%
    • 2: 35%
    • 3 to 6: 33%
  • PMH: stroke/TIA 20%, MI 17%, HF 32%, DM 23%, HTN 79%
  • Medications: Aspirin 40%, ARB/ACE-inhibitor 66%, beta-blocker 63%, amiodarone 10%, statin 45%, PPI 14%, H2-antagonist 4%, long-term vitamin K antagonist therapy 50%


  • Randomly assigned to one of two doses of dabigatran or warfarin
    • Low-dose dabigatran (110mg BID)
    • High-dose dabigatran (150mg BID)
    • Warfarin adjusted to INR 2.0-3.0
  • Quinidine use permitted until 2 years after trial initiation, once it became known that quinidine interacts with dabigatran
  • Post-randomization follow-up visits at 14 days, 1 month, 3 months, every 3 months for 1 year, then every 4 months until study completion
  • LFTs monthly during first year


Primary Outcomes

Stroke or systemic embolism
Low-dose dabigatran vs. warfarin:
1.53% vs. 1.69% (RR 0.91, 95% CI 0.74-1.11, P<0.001 for noninferiority)
High-dose dabigatran vs. warfarin:
1.11% vs. 1.69% (RR 0.66, 95% CI 0.53-0.82, P<0.001 for superiority)

Secondary Outcomes

Low-dose dabigatran vs. warfarin

1.4% vs. 1.6% (P=0.41)
0.72% vs. 0.53% (HR 1.35; 95% CI 0.98-1.87; P=0.07)
0.12% vs. 0.09% (P=0.56)
19.4% vs. 20.8% (P=0.003)
Vascular death
2.43% vs. 2.69% (P=0.21)
All-cause mortality
3.75% vs. 4.13% (P=0.13)
Major hemorrhage
2.71% vs. 3.36% (P=0.003)

High-dose dabigatran vs. warfarin

1.0% vs. 1.6% (P<0.001)
0.74% vs. 0.53% (HR 1.38; 95% CI 1.00-1.91; P=0.048)
0.09% vs. 0.09% (P=0.21)
20.2% vs. 20.8% (P=0.34)
Vascular death
2.28% vs. 2.69% (P=0.04)
All-cause mortality
3.64% vs. 4.13% (P=0.051)
Major hemorrhage
3.11% vs. 3.36% (P=0.31)


  • RE-LY reported a higher rate of major bleeding in warfarin-treated patients compared to other studies of warfarin in AF
  • Therapeutic INR reached only 64% of the time, dabigatran may only be better than poorly controlled anticoagulation with warfarin
  • Guiding dosing by serum levels of the medication may improve outcomes[6]
  • Increased rates of MI is concerning for a platelet-activating effect of the medication and necessitates further studying[6]
  • Expensive therapy[6]


Supported by a grant from Boehringer Ingelheim, with authors disclosing support from multiple sources within pharmaceutical industry.

Further Reading

  1. Nhi Beasley B et al. "Perspective: Anticoagulant options -- Why the FDA approved a higher but not a lower dose of dabigatran." The New England Journal of Medicine. 2011;364:1788-1790.
  2. Reiffel JA. "Letter by Reiffel regarding article, "Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial"." Circulation. 2012;125(3):e292.
  3. Southworth MR, et al. "Dabigatran and Postmarketing Reports of Bleeding." The New England Journal of Medicine. 2013;368:1272-1274.
  4. Breuer L, et al. "Correspondence: Ischemic Stroke in an Obese Patient Receiving Dabigatran." The New England Journal of Medicine. 2013;368:2440-2442.
  5. January CT, et al. "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary." Circulation. 2014:epub April.
  6. 6.0 6.1 6.2 Multiple authors. "Correspondence: Dabigatran versus warfarin in patients with atrial fibrillaiton." The New England Journal of Medicine. 2009;361:2671-2675.