The New England Journal of Medicine March 03, 2011

Apixaban in Patients with Atrial Fibrillation

Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, et al.

Bottom Line

In patients with atrial fibrillation who were deemed unsuitable for vitamin K antagonist therapy, apixaban significantly reduced the risk of stroke or systemic embolism compared to aspirin, without increasing the risk of major bleeding.

Key Findings

1. Theprimaryoutcome(strokeorsystemicembolism)occurredatarateof1.6%peryearintheapixabangroupversus3.7%peryearintheaspiringroup(HR0.45;95%CI0.32to0.62;P<0.001)[2.1].

2. Major bleeding occurred at similar rates in both groups: 1.4% per year with apixaban versus 1.2% per year with aspirin (HR 1.13; 95% CI 0.74 to 1.75; P=0.57).

3. Intracranial hemorrhage was rare and comparable between arms, with 11 cases in the apixaban group and 13 cases in the aspirin group.

4. The risk of a first hospitalization for cardiovascular causes was significantly reduced with apixaban compared with aspirin (12.6% vs. 15.9% per year; P<0.001).

5. The rates of death from any cause were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group, trending toward a reduction with apixaban but not reaching statistical significance (HR 0.79; 95% CI 0.62 to 1.02; P=0.07).

Study Design

Design

Double-Blind RCT

Double-Blind

Sample

5,599

Patients

Duration

1.1 yr

Median

Setting

Multicenter, 36 countries

Population Patients aged 50 years or older with atrial fibrillation (documented within 6 months) who were at increased risk for stroke (having at least one additional risk factor such as prior stroke/TIA, age ≥85, hypertension, diabetes, or heart failure) and for whom vitamin K antagonist therapy was deemed unsuitable by the investigator.

Intervention Apixaban 5 mg twice daily (reduced to 2.5 mg twice daily in select patients with specific criteria: age ≥80, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL).

Comparator Aspirin at a dose of 81 to 324 mg daily.

Outcome The composite occurrence of stroke (ischemic or hemorrhagic) or systemic embolism.

Study Limitations

• The trial was terminated prematurely (mean follow-up of 1.1 years) by the data and safety monitoring board due to overwhelming efficacy, which limited the evaluation of long-term safety and efficacy and may slightly overestimate the treatment effect.

• The criteria for determining a patient as 'unsuitable' for vitamin K antagonist therapy were largely left to the clinical judgment of the investigators, potentially creating heterogeneity in the study population.

• Early study termination reduced the statistical power to definitively evaluate differences in all-cause mortality, which trended toward benefit but narrowly missed significance.

Clinical Significance

The AVERROES trial fundamentally changed the management of atrial fibrillation by proving that a direct oral factor Xa inhibitor (apixaban) provides massively superior stroke protection compared to aspirin—cutting stroke risk by more than half—without a significant increase in major bleeding or intracranial hemorrhage. This effectively established DOACs as the preferred alternative for patients unable or unwilling to tolerate warfarin, displacing aspirin from its traditional role in this patient subgroup.

Historical Context

Prior to the advent of direct oral anticoagulants (DOACs), the cornerstone of stroke prevention in atrial fibrillation was warfarin, a vitamin K antagonist (VKA) that required stringent monitoring and carried substantial bleeding risks. As a result, 30% to 50% of high-risk patients were deemed unsuitable for or refused VKAs. For these patients, aspirin was the default alternative, providing only a modest ~20% relative reduction in stroke risk compared to placebo. AVERROES was the first and only trial to compare a DOAC directly to aspirin in VKA-unsuitable patients, decisively demonstrating apixaban's superiority and marking the beginning of the end for aspirin monotherapy in atrial fibrillation stroke prophylaxis.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Based on the mechanisms of action of apixaban and aspirin, why is targeting the coagulation cascade via Factor Xa more effective than targeting platelet aggregation via COX-1 for preventing stroke in atrial fibrillation?

Key Response

Atrial fibrillation causes blood stasis in the left atrial appendage, leading to the formation of fibrin-rich 'red' thrombi, which are most effectively prevented by anticoagulants like apixaban. Aspirin targets platelet-rich 'white' thrombi, which are more relevant in arterial high-shear stress conditions like acute coronary syndrome, making it inadequate for AFib stroke prevention.

Resident

A patient with a history of poor INR control on warfarin is considered unsuitable for VKA therapy. Based on the AVERROES trial, what are the clinical advantages of switching this patient to apixaban rather than daily aspirin regarding the balance of efficacy and bleeding risk?

Key Response

AVERROES demonstrated that apixaban significantly reduces stroke and systemic embolism compared to aspirin (a 55 percent relative risk reduction) without a significant increase in major bleeding, establishing apixaban as a vastly superior choice for VKA-unsuitable patients over aspirin.

Fellow

The AVERROES trial was stopped early due to clear evidence of apixaban's superiority over aspirin. How does the early termination of a clinical trial affect the estimation of treatment effect size, and how should a fellow interpret the bleeding risk data given the truncated follow-up period?

Key Response

Early termination can sometimes exaggerate the treatment effect size due to capturing a 'random high' in data trends, and it limits the collection of long-term safety data. Fellows must recognize that while the efficacy boundary was definitively crossed, rare or long-term bleeding events might be underrepresented, requiring reliance on subsequent post-marketing surveillance.

Attending

Prior to AVERROES, aspirin was widely prescribed for AFib patients deemed unsuitable for warfarin due to perceived frailty or bleeding risk. How does this trial fundamentally shift our teaching regarding the risk-benefit paradigm of antiplatelets versus anticoagulants in frail populations?

Key Response

The trial dispelled the pervasive myth that aspirin is a 'safer' alternative to anticoagulation in frail patients. It taught us that the bleeding risk of aspirin is comparable to apixaban in this population, but its efficacy is vastly inferior, decisively shifting clinical practice and teaching away from using aspirin for AFib stroke prevention.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In the AVERROES trial, criteria for deeming a patient unsuitable for VKA therapy were largely based on investigator discretion. How might this subjective inclusion criterion affect the internal validity and external generalizability of the study, and what statistical methods evaluate treatment effect homogeneity across these varied reasons?

Key Response

Subjective criteria can lead to selection bias and a highly heterogeneous study population. Researchers must use formal interaction tests and subgroup analyses based on specific reasons for VKA unsuitability (e.g., poor INR control versus patient refusal) to determine if the treatment effect remains consistent across these distinct clinical phenotypes.

Journal Editor

As a peer reviewer, what concerns might you raise regarding the choice of the variable aspirin dose (81 to 324 mg daily, at investigator discretion) and how could this variability introduce confounding regarding both bleeding and efficacy outcomes?

Key Response

The variable aspirin dose could confound the results, as higher doses might drive up bleeding events without proportionately increasing efficacy, artificially making apixaban look safer by comparison. An editor would flag this to ensure the authors conducted appropriate adjusted analyses or sensitivity checks accounting for dose-dependent effects.

Guideline Committee

How did the findings of the AVERROES trial influence the ACC/AHA/HRS guidelines regarding the use of aspirin for stroke prevention in atrial fibrillation, and what specific paradigm shift did this create compared to prior historical recommendations?

Key Response

AVERROES provided pivotal Level of Evidence B-R that directly led to guidelines downgrading and eventually removing aspirin as an acceptable monotherapy for stroke prevention in AFib. It established a Class I recommendation that DOACs should be used over aspirin even in patients who cannot tolerate or refuse warfarin, effectively eliminating the historical practice of using aspirin as a fallback therapy.

Clinical Landscape

Noteworthy Related Trials

2009

RE-LY Trial

n = 18,113 · NEJM

Tested

Dabigatran 110 mg or 150 mg twice daily

Population

Patients with atrial fibrillation and a risk of stroke

Comparator

Warfarin

Endpoint

Stroke or systemic embolism

Key result: Dabigatran 150 mg was superior to warfarin for stroke prevention with similar major bleeding, while 110 mg was non-inferior for stroke with less bleeding.

2011

ARISTOTLE Trial

n = 18,201 · NEJM

Tested

Apixaban 5 mg twice daily

Population

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

Comparator

Warfarin

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.

2011

ROCKET AF Trial

n = 14,264 · NEJM

Tested

Rivaroxaban 20 mg once daily

Population

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

Comparator

Warfarin

Endpoint

Stroke or systemic embolism

Key result: Rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolism, with less intracranial hemorrhage.

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