ARISTOTLE

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Granger CB, et al. "Apixaban versus warfarin in patients with atrial fibrillation". The New England Journal of Medicine. 2011. 365(11):981-982.
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Clinical Question

Among patients with nonvalvular atrial fibrillation and ≥1 stroke risk factor, does apixaban reduce rates of stroke or systemic embolism in comparison to warfarin without increasing bleeding risks?

Bottom Line

In patients with nonvalvular atrial fibrillation and at ≥1 risk factor, apixaban is associated with a greater reduction in rates of stroke or systemic embolism while having a lower rate of lower bleeding than warfarin.

Major Points

VKA therapy is the standard of care for prevention of stroke and systemic embolism in AF, but it has multiple drawbacks including drug-drug interactions, need for frequent monitoring, and dietary modification. Several drugs, including dabigatran in RE-LY (2009) and rivaroxaban in ROCKET AF (2011) (and later edoxaban in ENGAGE AF-TIMI 48)[1] have proven efficacious as alternatives to VKA therapy in AF. Like these other drugs, apixaban, an oral factor Xa inhibitor, does not require monitoring, has fewer drug-drug interactions, and may therefore be advantageous clinically. Its efficacy had not yet been established in a large clinical trial, however.

The 2011 Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial randomized 18,201 patients with nonvalvular AF and ≥1 stroke risk factor to apixaban or warfarin. With a median follow-up of 1.8 years, apixaban was superior to warfarin in rates of stroke or systemic embolism (annual incidence 1.27% vs. 1.60%). It was also associated with less major bleeding (annual incidence 2.13% vs. 3.09%). The trial was criticized for having patients in a therapeutic INR range for only 66% of the time, although this is generally the target achieved in most clinical trials of warfarin.[2] The related AVERROES trial (2011)[3] showed that apixaban decreased stroke incidence without increasing major bleeding when compared to aspirin, among AF patients who were poor candidates for VKA therapy.

Guidelines

AHA/ACC/HRS AF (April 2014, adapted)[4]

  • 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, comparative trial
  • N=18,201
    • Apixaban (n=9,120)
    • Warfarin (n=9,081)
  • Setting: 1,034 centers in 39 countries
  • Enrollment: 2006-2010
  • Median follow-up: 1.8 years
  • Analysis: Intention-to-treat and non-inferiority
  • Primary outcomes:
    • Effectiveness: Stroke or systemic embolism
    • Safety: Major bleeding

Population

Inclusion Criteria

  • Atrial fibrillation or atrial flutter on 2 EKGs at least 2 weeks apart in the prior year and ≥1 stroke risk factor:
    • Age ≥75 years
    • Prior stroke, TIA, or embolism
    • Symptomatic HF in prior 3 months or LVEF <40%
    • DM
    • HTN requiring medications

Exclusion Criteria

  • AF from reversible cause
  • Moderate or severe mitral stenosis
  • Need for anticoagulation other than AF
  • Stroke in prior week
  • Need for ASA ≥165 mg/d or ASA and clopidogrel
  • Creatinine >2.5 mg/dL or creatinine clearance <25 mL/min

Baseline Characteristics

From the Apixaban group.

  • Demographics: Age 70 years, female 35.5%
  • Region: 24.7% N. America, 19.1% Latin America, 40.3% Europe, 16.0% Asian Pacific
  • CHADS2 score: 2.1
    • 1: 34.0%
    • 2: 25.8%
    • ≥3: 30.2%
  • Stroke risk factors:
    • Age ≥75 years: 31.2%
    • Stroke, TIA, embolism: 19.2%
    • HF including reduced LVEF: 35.5%
    • DM: 25.0%
    • HTN requiring medications: 87.3%
  • Other PMH: MI 14.5%, Bleeding 16.7%, fall in prior 12 months 4.2%
  • Baseline health data: SBP 130 mmHg, weight 82 kg
  • Creatinine clearance:
    • >80 mL/min: 41.2%
    • >50-80 mL/min: 41.9%
    • >30-50 mL/min: 15.0%
    • ≤30 mL/min: 1.5%
  • AF-specific: paroxysmal 15.1%, persistent/permanent 84.9%
  • VKA for >30 prior days: 57.1%
  • Medications: ACE-inhibitor or ARB 70.9%, amiodarone 11.1%, beta-blocker 63.6%, ASA 31.3%, clopidogrel 1.9%, digoxin 32.0%, CCB 30.1, statin 45.0%, NSAID 8.2%, antacids 18.5%

Interventions

  • Randomization to a group:
    • Apixaban - treatment with apixaban 5 mg BID or 2.5 BID if ≥2 of the following:
      • Age ≥80 years
      • Weight <60 kg
      • Creatinine ≥1.5 mg/dL
    • Warfarin - warfarin 2 mg daily with adjustment for a goal INR of 2-3
  • Discontinuation of any VKA 3 days before group randomization with treatment initiation when INR reached <2
  • Both groups received placebo forms of the alternative therapy

Of note, investigators encouraged >40% enrollment of patients without prior VKA treatment.

Outcomes

Presented as apixaban vs. warfarin. Analyses are for superiority except where specified.

Primary Outcomes

Stroke or systemic embolism
1.27%/yr vs. 1.60%/yr (HR 0.79; 95% CI 0.66-0.95; P=0.01 for superiority, P<0.001 for noninferiority)
Major/severe bleeding

Bleeding by ISTH criteria was the predefined primary outcome, others included for completeness.

ISTH criteria: 2.13%/yr vs. 3.09%/yr (HR 0.69; 95% CI 0.60-0.80; P<0.001)
GUSTO criteria: 0.52%/yr vs. 1.13%/yr (HR 0.46; 95% CI 0.35-0.60; P<0.001)
TIMI criteria: 0.96%/yr vs. 1.69%/yr (HR 0.57; 95% CI 0.46-0.70; P<0.001)

Secondary Outcomes

Components of the primary outcome
Stroke: 1.19%/yr vs. 1.51%/yr (HR 0.79; 95% CI 0.65-0.95; P=0.01)
Ischemic or unknown stroke type: 0.97%/yr vs. 1.05%/yr (HR 0.92; 95% CI 0.74-1.13; P=0.42)
Hemorrhagic transformation: 12 vs. 20 patients (no statistics given)
Hemorrhagic stroke: 0.24%/yr vs. 0.47%/yr (HR 0.51; 95% CI 0.35-0.75; P<0.001)
Systemic embolism: 0.09%/yr vs. 0.10%/yr (HR 0.87; 95% CI 0.44-1.75; P=0.70)
Fatal or disabling stroke
0.50%/yr vs. 0.71%/yr (HR 0.71; 95% CI 0.54-0.94; P not given)
Fatal stroke: 42 vs. 67 patients (no statistics given)
All-cause mortality
3.52%/yr vs. 3.94%/yr (HR 0.89; 95% CI 0.80-0.99; P=0.047)
CV mortality

Including hemorrhagic stroke

1.80%/yr vs. 2.02%/yr (HR 0.89; 95% CI 0.76-1.04; P not given)
Non-CV mortality

Including non-hemorrhagic stroke bleeding

1.14% vs. 1.22% (HR 0.93; 95% CI 0.77-1.13; P not given)

Additional Analysis

Coumadin group, time in therapeutic INR range

Excluding the first week and during treatment interruptions

66.0%

Subgroup Analysis

For the primary outcome, there was no significant interaction for multiple groups including age, sex, weight, AF type, prior stroke/TIA, DM, HF, CHADS2 score, renal imparement, dose, region, or aspirin use.

Adverse Events

Study drug discontinuation
25.3% vs. 27.5% (P=0.001)
Death as reason: 3.6% vs. 3.8% (no statistics given)

Criticisms

  • Therapeutic INR reached only 62% of the time (which is consistent with RE-LY 64% and ROCKET AF 55%) [2]
  • No reversal agent[2][5]

Funding

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

Further Reading

  1. Giugliano RP, et al. "Edoxaban versus warfarin in patients with atrial fibrillation." The New England Journal of Medicine. 2013;369(22):2093-2104.
  2. 2.0 2.1 2.2 Multiple authors. "Correspondence: Apixaban versus warfarin in atrial fibrillation." The New England Journal of Medicine. 2012;366:88-90.
  3. Connolly SJ, et al. "Apixaban in patients with atrial fibrillation." The New England Journal of Medicine. 2011;364(9):806-817.
  4. January CT, et al. "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary." Circulation. 2014:epub April.
  5. Mega JL. "Editorial: A new era for anticoagulation in atrial fibrillation." The New England Journal of Medicine. 2011;365;1052-1054.