Dabigatran an Alternative to Warfarin for Stroke Prevention in A-Fib Patients

BARCELONA, Spain—In patients with atrial fibrillation, 2 doses of the reversible, direct thrombin inhibitor dabigatran show similar or better effectiveness than warfarin in preventing stroke and systemic embolism, with equal or lower risk of major bleeding, according to late breaking trial results presented August 30 at the European Society of Cardiology (ESC) Congress 2009. The findings were simultaneously published online in the New England Journal of Medicine.

For the noninferiority RE-LY (Randomized Evaluation of Long-term anticoagulant therapY) trial, researchers led by Stuart J. Connolly, MD, of McMaster University (Hamilton, Canada), compared 2 doses of dabigatran (110 or 150 mg twice daily) with warfarin (adjusted dose) in 18,113 patients at 951 centers who were at risk of stroke from atrial fibrillation. Aspirin was used continuously by about one fifth of patients in all 3 arms.

Dabigatran etexilate (Pradaxa, Boehringer-Ingelhiem Pharmaceuticals, Ridgfield, CT) is approved in Europe for the prevention of venous thromboembolism.

Dose Makes a Difference

After a median follow-up of 2 years, both doses of dabigatran proved noninferior to warfarin with regard to the primary endpoint of stroke or systemic embolism. However, the 150-mg dose of dabigatran was superior to warfarin (P < 0.001), whereas the 110-mg dose was not (P = 0.34). Rates of hemorrhagic stroke were lower with both doses of dabigatran, but MI rates were higher with each dose, reaching significance at 150 mg. Dabigatran was comparable with warfarin with regard to mortality, although there was a trend toward improved survival with 150-mg dabigatran (tables 1 and 2).

Table 1. Efficacy Outcomes (Per Year) for Lower-Dose Dabigatran vs. Warfarin

 

 

Dabigatran, 110 mg
(n = 6,015)

Warfarin
(n = 6,022)

RR (95% CI)

P Value

Stroke or Systemic Embolism

1.53%

1.69%

0.91 (0.74-1.11)

< 0.001 for noninferiority

Hemorrhagic Stroke

0.12%

0.38%

0.31 (0.17-0.56)

< 0.001

MI

0.72%

0.53%

1.35 (0.98-1.87)

0.07

All-Cause Death

3.75%

4.13%

0.91 (0.80-1.03)

0.33


Table 2. Efficacy Outcomes (Per Year) for Higher-Dose Dabigatran vs. Warfarin

 

 

Dabigatran, 150 mg
(n = 6,076)

Warfarin
(n = 6,022) 

RR (95% CI)

P Value

Stroke or Systemic Embolism

1.11%

1.69%

0.66 (0.53-0.82)

< 0.001 for noninferiority

Hemorrhagic Stroke

0.10%

0.38%

0.26 (0.14-0.49)

< 0.001

MI

0.74%

0.53%

1.38 (1.00-1.9)

0.048

All-Cause Death

3.64%

4.13%

0.88 (0.77-1.00)

0.051


By most measures dabigatran was associated with less bleeding than warfarin, with both doses significantly reducing the risk of life-threatening and intracranial bleeding. However, some differences between the lower and higher doses did emerge. For example, the risk of major bleeding was significantly lower vs. warfarin at the 110-mg dose of dabigatran but not at the 150-mg dose. In addition, a significantly higher rate of gastrointestinal bleeding appeared with the 150-mg dose (tables 3 and 4).

Table 3. Safety Outcomes (Per Year) for Lower-Dose Dabigatran vs. Warfarin

 

 

Dabigatran, 110 mg

Warfarin

RR (95% CI)

P Value

Major Bleeding

2.71%

3.36%

0.80 (0.69-0.93)

0.003

Life-Threatening Bleeding

1.22%

1.80%

0.68 (0.55-0.83)

< 0.001

Intracranial Bleeding

0.23%

0.74%

0.31 (0.20-0.47)

< 0.001

Gastrointestinal Bleeding

1.12%

1.02%

1.10 (0.86-1.41)

0.43


Table 4. Safety Outcomes (Per Year) for Higher-Dose Dabigatran vs. Warfarin

 

 

Dabigatran, 150 mg

Warfarin

RR (95% CI)

P Value

Major Bleeding

3.11%

3.36%

0.93 (0.81-1.07)

0.31

Life-Threatening Bleeding

1.45%

1.80%

0.81 (0.66-0.99)

0.04

Intracranial Bleeding

0.30%

0.74%

0.40 (0.27-0.60)

< 0.001

Gastrointestinal Bleeding

1.51%

1.02%

1.50 (1.19-1.89)

< 0.001


The only adverse event associated with dabigatran was dyspnea, which occurred significantly more often in patients at both doses (11.8% with the lower dose and 11.3% with the higher dose) compared with warfarin (5.8%; P < 0.001 for both comparisons). Dr. Connolly noted that careful monitoring turned up no signal of hepatotoxicity.

Overall, the net clinical benefit outcome, which combines major vascular events, major bleeding, and death, favored dabigatran over warfarin and was similar for the 2 doses.

Success Raises Questions

A.J. Camm, MD, of St. George’s Hospital Medical School (London, United Kingdom), said that the dabigatran results raised a number of questions, such as:

  • Which of the 2 doses should be chosen and how should the dose be tailored to individual patients?
  • Should patients who are currently satisfactorily managed on warfarin be changed to dabigatran?
  • Will elderly patients fare as well with dabigatran as the general study population?
  • Does it matter that there is no antidote to dabigatran?
  • Will physicians or patients feel comfortable if the degree of anticoagulation is no longer monitored?

Dr. Camm recommended that dabigatran be considered a “stimulant to a paradigm change in the development of anticoagulant medications,” but that the study results should “not be allowed to derail trials of other agents.”

Study Details

All 3 treatment groups were well balanced with regard to baseline characteristics. Their mean CHADS2 score was 2.1. About half had received long-term therapy with a vitamin K antagonist. 

Sources
  • Connolly SJ. The RE-LY Study: Randomized Evaluation of Long-term anticoagulation therapY. Dabigatran compared to warfarin in 18,113 patients with atrial fibrillation at risk of stroke. Presented at: ESC Congress 2009; August 30, 2009; Barcelona, Spain.

  • Connolly SJ, Ezekowitz MD, Yusuf F, et al. Dabigatran versus warfarin. N Engl J Med 2009;Epub ahead of print.

Disclosures
  • The study was supported by a grant from Boehringer-Ingelheim.
  • The study was supported by a grant from Boehringer-Ingelheim. Dr. Connolly reports receiving consulting fees, lecture fees, and grants from Boehringer-Ingelheim
  • Information regarding any potential conflicts of interest for Dr. Camm was not available.

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