Apixaban Versus Acetylsalicylic Acid to Prevent Strokes - AVERROES

Feb 10, 2011
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bristol-Myers Squibb, Pfizer
Date Presented:
01/01/2010
Date Published:
01/01/2011
Date Updated:
02/10/2011
Original Posted Date:
02/10/2011
References

Description:

The goal of the trial was to evaluate treatment with the oral direct factor Xa inhibitor apixaban compared with acetylsalicylic acid (aspirin) among patients with atrial fibrillation who were unsuitable for warfarin therapy.

Hypothesis:

Apixaban will be more effective in preventing stroke.

Study Design

  • Blinded
  • Parallel
  • Randomized

Patient Populations:

  • Patients with atrial fibrillation and at least one high-risk factor
  • Unsuitability for warfarin therapy due to inability to control INR, increased risk for bleeding, patient refusal, or intermediate risk for stroke

    Number of enrollees: 5,599
    Duration of follow-up: mean 1.1 years
    Mean patient age: 70 years
    Percentage female: 41%

Primary Endpoints:

  • Stroke or systemic embolism

Drug/Procedures Used:

Patients with atrial fibrillation who were unsuitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n = 2,808) versus aspirin 81-324 mg daily (n = 2,791).

Concomitant Medications:

At baseline, in the apixaban group, the use of aspirin was 76%, the use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker was 64%, beta-blocker was 56%, digoxin 29%, and amiodarone 11%.

Principal Findings:

Overall, 5,599 patients were randomized. In the apixaban group, the mean age was 70 years, 41% were women, mean CHADS2 score was 2.0, 27% had a CHADS2 score ≥3, 14% had a prior stroke or transient ischemic attack, 19% were diabetics, and 40% had congestive heart failure. In the aspirin group, 91% of patients received a dose of 81-162 mg daily.

The primary outcome, stroke or systemic embolism, occurred at a rate of 1.6% per year in the apixaban group compared with 3.7% per year in the aspirin group (relative risk [RR] 0.45, p < 0.001). Stroke was 1.6% per year versus 3.4% per year (p < 0.001), respectively. Apixaban reduced disabling or fatal strokes (modified Rankin score 3-6; p < 0.001).

The rate of stroke, systemic embolism, myocardial infarction (MI), or vascular death was 4.2% per year in the apixaban group versus 6.4% per year in the aspirin group (p < 0.001). MI was 0.8% per year versus 0.9% per year (p = 0.57), vascular death was 2.7% per year versus 3.1% per year (p = 0.37), cardiovascular hospitalization was 12.6% per year versus 15.9% per year (p < 0.001), and all-cause mortality was 3.5% per year versus 4.4 events per year (p = 0.07), respectively.

Major bleeding was similar between the groups (RR 1.13, p = 0.57). The rate of clinically relevant nonmajor bleeding was 3.1% per year in the apixaban group versus 2.7% per year in the aspirin group (p = 0.35). Fatal bleeding was 0.1% per year versus 0.2% per year (p = 0.53), and intracranial hemorrhage was 0.4% per year versus 0.4% per year (p = 0.69), respectively.

Termination of study drug was lower in the apixaban group (RR 0.88, p = 0.03). Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3x upper limit of normal occurred in 0.7% versus 1% (p = 0.12), respectively.

Interpretation:

Among patients with atrial fibrillation with elevated risk for stroke and not suitable for warfarin therapy, apixaban was beneficial and well tolerated. This therapy reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin. Apixaban did not increase the risk for major bleeding. This represents an important new agent in stroke prophylaxis among atrial fibrillation patients that does not require international normalized ratio (INR) monitoring. The need for twice daily dosing may represent a challenge for some patients.

The ongoing ARISTOTLE trial will compare apixaban against warfarin in patients with atrial fibrillation.

References:

Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17.

Presented by Dr. Stuart Connolly at the European Society of Cardiology Congress, Stockholm, Sweden, August 2010.

Keywords: Myocardial Infarction, Stroke, Follow-Up Studies, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Warfarin, Risk Factors, Pyrazoles, International Normalized Ratio, Intracranial Hemorrhages, Heart Failure, Embolism, Factor Xa, Pyridones, Diabetes Mellitus


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