AVERROES

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Connolly SJ, et al. "Apixaban in patients with atrial fibrillation". The New England Journal of Medicine. 2011. 364(9):806-817.
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Clinical Question

In patients with atrial fibrillation thought to be unsuitable for anticoagulation with a vitamin K antagonist, does apixaban reduce risk for stroke or systemic embolism when compared to aspirin? Also, how does apixaban compare to aspirin rates of major bleeding?

Bottom Line

In patients with atrial fibrillation thought to be unsuitable candidates for anticoagulation with a vitamin K antagonist, apixaban signficantly reduced the risk of stroke and systemic embolism without increasing the risk of major bleeding or intracranial hemorrhage when compared to aspirin.

Major Points

The 1991 SPAF study[1] demonstrated the superiority of Vitamin K antagonist (VKA, i.e. warfarin) therapy over aspirin in prevention of stroke in patients with AF. While prophylaxis with aspirin 81-325 mg is recommended as an alternative for low risk patients, VKA therapy is the standard of care for those with a >1 moderate risk factor and no contraindications to the therapy.[2] VKA therapy presents multiple challenges including increased rate of bleeding, drug-drug interactions, and need for frequent monitoring. ACTIVE A (2009) compared the alternative regimen of aspirin plus clopidogrel to aspirin alone in patients with AF thought to be unsuitable for VKA therapy. Dual therapy decreased rates of major vascular events at cost of increased major bleeding.

Apixaban is a novel oral anticoagulant that inhibits factor Xa. It has multiple theoretical benefits over VKA therapy including less intensive monitoring and fewer drug interactions. Its role in prevention of stroke in patients unsuitable for VKA therapy, but maintained on aspirin therapy, was unknown.

The 2011 Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial randomized 5,599 patients with AF thought to be unsuitable candidates for VKA therapy to apixaban or aspirin. The trial was terminated early given a treatment benefit with apixaban. With a mean follow-up of 1.1 years, the apixaban group had lower rates of stroke or systemic embolism than the aspirin group (1.6%/yr vs. 3.7%/yr) without an increase in rates of major bleeding (1.4%/yr vs. 1.2%/yr).

Also published in 2011, ARISTOTLE demonstrated the superiority of apixaban over VKA in prevention of stroke or systemic embolism while having a lower rate of bleeding than warfarin.

Guidelines

AHA/ACC/HRS AF (April 2014, adapted)[3]

  • 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)

Design

  • Multicenter, double-blind, randomized, placebo controlled trial
  • N=5,599
    • Apixaban (n=2,808)
    • Aspirin (n=2,791)
  • Setting: 522 centers in 36 countries
  • Enrollment: 2007-2009
  • Mean follow-up: 1.1 years (stopped early)
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • Effectiveness: Stroke or systemic embolism
    • Safety: Major bleeding

Population

Inclusion Criteria

  • Age ≥50 years
  • Documented AF within prior 6 months
  • ≥1 one of the following:
    • Prior stroke or TIA
    • Age ≥75 years
    • HTN on therapy
    • DM on therapy
    • Heart failure ≥ NYHA class II
    • LVEF ≤35%
    • PAD
  • Unsuitable to receive VKA therapy (specific reasons detailed in baseline characteristics section below)

Exclusion Criteria

  • Other conditions necessitating long-term anticoagulation
  • Valvular disease necessitating surgery
  • Serious bleeding in prior 6 months
  • High risk for bleeding (active PUD, Plt <100,000/mm3, Hgb <10 g/dL, stroke in prior 10 days, hemorrhagic tendencies, or blood dyscrasias)
  • Current EtOH abuse, drug abuse, or "psychosocial issues"
  • Life expectancy <1 year
  • Creatinine >2.5 mg/dL or CrCl <25 mL/min
  • AST/ALT >2x ULN
  • Total bilirubin >1.5x ULN
  • Aspirin allergy
  • Clopidogrel use

Baseline Characteristics

From the apixaban group.

  • Demographics: Age 70 years, male 59%, at least high school education 58%
    • Location:
      • N. America: 15%
      • Latin America: 21%
      • W. Europe: 22%
      • E. Europe: 23%
      • Asia or S. Africa: 19%
  • Baseline health data: BMI 28 kg/m2, HR 74 BPM, SBP 132 mmHg
  • Type of AF: Paroxysmal 27%, persistent 21%, permanent 52%
  • CHADS2 score:
    • Mean: 2.0
    • 0 or 1: 36%
    • 2: 37%
    • ≥3: 27%
  • Baseline medications: VKA (in prior 30 days) 14%, ASA (in prior 30 days) 76%, ACE-inhibitor or ARB 64%, verapamil or diltiazem 9%, beta blocker 56%, digoxin 29%, amiodarone 11%, statin 31%
  • Stroke risk factors:
    • Prior TIA or stroke: 14%
    • HTN (ont treatment): 86%
    • HF:
      • NYHA I/II: 32%
      • NYHA III/IV: 7%
    • LVEF ≤35%: 5%
    • PAD: 2%
    • DM (on treatment): 19%
    • Mitral stenosis: 2%
  • EKG findings: AF 68%, A-flutter 1%, sinus rhythm 25%, other rhythm or paced 5%, LVH 17%
  • Reason for therapy unsuitability:
    • INR not maintained in therapeutic range: 17%
    • Serious bleeding on VKA: 3%
    • Non-bleeding adverse events on VKA: 3%
    • INR couldn't or unlikely to be measured at regular intervals: 43%
    • Expected difficulty in contacting patient for VKA dose change: 11%
    • Uncertain ability for VKA adherence: 16%
    • Concurrent VKA activity altering medications: 2%
    • Concurrent VKA metabolism altering medications: 1%
    • Liver disease: <1%
    • MCI: 3%
    • HF or cardiomyopathy: 6%
    • Other factors increasing risk for VKA use: 3%
    • CHADS2 risk of 1: 11%
    • Patient refusing VKA: 15%
    • Multiple reasons: 51%

Interventions

  • Randomized to a treatment arm:
    • Apixaban 5.0 mg PO BID plus placebo
      • Apixaban 2.5 mg po BID was substituted if age ≥80 years, weight ≤60 kg, or creatinine ≥1.5 mg/dL
    • Aspirin 81-325 mg daily plus placebo
  • Investigators were encouraged to stop non-study aspirin
  • Clinicians could start clopidogrel therapy if indicated

Outcomes

Presented as apixaban vs. aspirin. Statistics presented where given by the authors. %/yr indicates percent per year per 100 patient years. Analyses are to time of first event.

Primary Outcomes

Stroke or systemic embolism
1.6%/yr vs. 3.7%/yr (HR 0.45; 95% CI 0.32-0.62; P<0.001)
Major bleeding
Defined as overt bleeding plus ≥1 of the following: Drop in hemoglobin ≥2 gm/dL in 24h, transfusion of ≥2 units pRBC, bleeding in critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramusclar, or retroperitoneal), or fatal bleeding.
1.4%/yr vs. 1.2%/yr (HR 1.13; 95% CI 0.74-1.75; P=0.57)
The following were not primary outcomes but are included here for completeness:
Intracranial: 0.4%/yr vs. 0.4%/yr (HR 0.85; 95% CI 0.38-1.90; P=0.69)
Subdural: 0.1%/yr vs. 0.1%/yr
Non-subdural, non-hemorrhagic stroke: <0.1%/yr vs. 0.1%/yr
Extracranial or unclassified: 1.1%/yr vs. 0.9%/yr (HR 1.23; 95% CI 0.74-2.05; P=0.42)
GI: 0.4%/yr vs. 0.4%/yr (HR 0.85; 95% CI 0.38-1.90; P=0.69)
Non-GI: 0.6%/yr vs. 0.4%/yr (HR 1.55; 95% CI 0.77-3.12; P=0.22)
Fatal: 0.1%/yr vs. 0.2%/yr (HR 0.67; 95% CI 0.19-2.37; P=0.53)

Secondary Outcomes

Stroke, systemic embolism, or death
4.6%/yr vs. 7.2%/yr (HR 0.64; 95% CI 0.51-0.78; P<0.001)
Stroke, systemic embolism, MI, or vascular mortality
4.2%/yr vs. 6.4%/yr (HR 0.66; 95% CI 0.53-0.83; P<0.001)
Stroke, systemic embolism, MI, vascular mortality, or major bleeding
5.3%/yr vs. 7.2%/yr (HR 0.74; 95% CI 0.60-0.90; P=0.003)
Stroke
1.6% vs. 3.4% (HR 0.46; 95% CI 0.33-0.65; P<0.001)
Ischemic: 1.1%/yr vs. 3.0%/yr (HR 0.37; 95% CI, 0.25-0.55; P<0.001)
Hemorrhagic: 0.2%/yr vs. 0.3%/yr (HR 0.67; 95% CI 0.24-1.88; P=0.45)
Unspecified: 0.3%/yr vs. 0.1%/yr (HR 2.24; 95% CI 0.69-7.27; P=0.18)
Disabiling or fatal: 1.0%/yr vs. 2.3%/yr (HR 0.43; 95% CI 0.28-0.65; P<0.001)
Systemic embolism
0.1%/yr vs. 0.4%/yr (HR 0.15; 95% CI 0.03-0.68; P=0.01)
MI
0.8%/yr vs. 0.9%/yr (HR 0.86; 95% CI 0.50-1.48; P=0.59)
All-cause mortality
3.5%/yr vs. 4.4%/yr (HR 0.79; 95% CI 0.62-1.02; P=0.07)
Vascular mortality
2.7%/yr vs. 3.1%/yr (HR 0.87; 95% CI 0.65-1.17; P=0.37)
CV hospitalization
12.6%/yr vs 15.9%/yr (HR 0.79; 95% CI 0.69-0.91; P<0.001)
Other bleeding
Clinically-relevant non-major: 3.1%/yr vs. 2.7%/yr (HR 1.15; 95% CI 0.86-1.54; P=0.35)
Minor bleeding: 6.3%/yr vs. 5.0%/yr (HR 1.24; 95% CI 1.00-1.53; P=0.05)

Additional Analysis

Permanent discontinuation of study medication
17.9%/yr vs. 20.5%/yr (HR 0.88; 95% CI 0.78-0.99; P=0.03)
Dose of aspirin or its placebo
81 mg: 65% vs. 64%
162 mg: 26% vs. 27%
243 mg: 3% vs. 2%
324 mg: 7% vs. 7%
Unknown: <1% vs. <1%
Apixaban 2.5 mg po BID or its placebo
6% vs. 7%

Subgroup Analysis

There was no difference for either primary endpoints for patients by age group, sex, GFR, CHADS2 score, prior stroke or TIA, ASA dose, prior VKA use, refusal of VKA, or HF.

CHADS2 score

For stroke or systemic embolism:

P-value for interaction: 0.23
0-1: 1.6%/yr vs. 0.9%/yr
2: 3.7%/yr vs. 2.1%/yr
≥3: 6.3%/yr vs. 1.9%/yr

For major bleeding:

P-value for interaction: 0.70
0-1: 0.5%/yr vs. 0.5%/yr
2: 1.3%/yr vs. 1.2%/yr
≥3: 2.1%/yr vs. 2.9%/yr
Prior stroke or TIA

For stroke or systemic embolism:

P-value for interaction: 0.18
No: 3.0%/yr vs. 1.5%/yr
Yes: 8.3%/yr vs. 2.5%/yr

For major bleeding:

P-value for interaction: 0.73
No: 1.0%/yr vs. 1.1%/yr
Yes: 2.7%/yr vs. 3.5%/yr

Adverse Events

Any serious
22.2% vs. 27.2% (HR and 95% CI not given; P<0.001)
The authors note that this was attributable to the lower rate of vascular-related CNS disorders in the apixaban group.
AST/ALT > 3x ULN
1% vs. 2% (HR and 95% CI not given; P=0.31)

Criticisms

  • Early termination of study could have inflated benefit
  • Given that 91% of the patients were prescribed aspirin at ≤162 mg, it's unclear if the benefit would remain with aspirin 325 mg[4]
  • Unclear if the use of NSAID use would change outcomes (the authors report that it does not)[4]

Funding

  • Bristol-Myers Squibb and Pfizer, the manufacturers of Eliquis, the brand name of apixaban
  • Authors with multiple financial disclosures

Further Reading

  1. McBride R, et al. "Stroke Prevention in Atrial Fibrillation Study. Final results." Circulation 1991;84:527-539.
  2. Fuster V, et al. "ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary." Journal of the American College of Cardiology. 2006;48(4):854-906.
  3. January CT, et al. "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary." Circulation. 2014:epub April.
  4. 4.0 4.1 Multiple authors. "Correspondence: Apixaban in patients with atrial fibrillation." The New England Journal of Medicine. 2011;364(24):2362-2364