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ARISTOTLE

Apixaban versus Warfarin in Patients with Atrial Fibrillation

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Year of Publication: 2011

Authors: Granger CB, Alexander JH, McMurray JJV, ..., Hylek EM

Journal: The New England Journal of Medicine

Citation: Granger CB, et al. N Engl J Med. 2011;365(11):981–992.

Link: https://doi.org/10.1056/NEJMoa1107039

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1107039

Clinical Question

Does apixaban reduce the risk of stroke or systemic embolism compared to warfarin in patients with atrial fibrillation?

Bottom Line

Apixaban was superior to warfarin in preventing stroke/systemic embolism, caused less bleeding, and reduced mortality.

        Major Points
        Largest DOAC vs warfarin trial: 18,201 patients with AF and ≥1 stroke risk factor randomized at 1,034 clinical sites in 39 countries.
Triple benefit: apixaban was superior for efficacy (stroke/SE: 1.27% vs 1.60%/yr, HR 0.79, 95% CI 0.66–0.95, P=0.01), superior for safety (major bleeding: 2.13% vs 3.09%/yr, HR 0.69, 95% CI 0.60–0.80, P<0.001), and reduced all-cause mortality (3.52% vs 3.94%/yr, HR 0.89, 95% CI 0.80–0.998, P=0.047).
Hemorrhagic stroke reduced by 49% (0.24% vs 0.47%/yr, HR 0.51, 95% CI 0.35–0.75, P<0.001). Ischemic or uncertain type of stroke rates were similar (0.97% vs 1.05%/yr, HR 0.92, 95% CI 0.74–1.13, P=0.42).
Dose reduction criteria: apixaban 2.5 mg BID if ≥2 of: age ≥80, weight ≤60 kg, creatinine ≥1.5 mg/dL (~4.7% of patients received the reduced dose).
Double-dummy design: patients received either apixaban + warfarin-placebo or warfarin + apixaban-placebo, with sham INR monitoring to maintain blinding.
Mean CHADS2 score was 2.1; ~19% had prior stroke/TIA/SE. Median TTR for warfarin arm was 66.0% (mean 62.2%).
Paper conclusion: in patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.

      

Design

Study Type: Randomized, double-blind, double-dummy, controlled trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: December 2006 – April 2010

Follow-up Duration: Median 1.8 years

Centers: 1034

Number of Countries: 39

Countries: North America, Latin America, Europe, Asian Pacific

Sample Size: 18201

Analysis: Intention-to-treat for efficacy; safety population (received ≥1 dose) for bleeding

Inclusion Criteria

Atrial fibrillation or flutter at enrollment, or two or more episodes of atrial fibrillation/flutter documented by electrocardiography at least 2 weeks apart in the 12 months before enrollment.
At least one additional risk factor for stroke: age ≥75 years; previous stroke, transient ischemic attack, or systemic embolism; symptomatic heart failure within the previous 3 months or left ventricular ejection fraction ≤40%; diabetes mellitus; or hypertension requiring pharmacologic treatment.
No specific CHADS2 score required, but effectively enrolled patients with CHADS2 ≥1.

Exclusion Criteria

Atrial fibrillation due to a reversible cause
Moderate or severe mitral stenosis
Conditions other than atrial fibrillation that required anticoagulation (e.g., a prosthetic heart valve)
Stroke within the previous 7 days
Need for aspirin at a dose of >165 mg/day or for both aspirin and clopidogrel
Severe renal insufficiency (serum creatinine >2.5 mg/dL or calculated CrCl <25 mL/min)

Baseline Characteristics

Characteristic	Control	Active
N	9081	9120
Median Age (yr)	70 (IQR 63–76)	70 (IQR 63–76)
Female (%)	35.0%	35.5%
Mean CHADS2 Score	2.1 ± 1.1	2.1 ± 1.1
CHADS2 = 1 (%)	34.0%	34.0%
CHADS2 = 2 (%)	35.8%	35.8%
CHADS2 ≥3 (%)	30.2%	30.2%
Prior Stroke/TIA/SE (%)	19.7%	19.2%
Heart Failure or LVEF ≤40% (%)	35.4%	35.5%
Hypertension Requiring Treatment (%)	87.6%	87.3%
Diabetes (%)	24.9%	25.0%
AF Type - Paroxysmal (%)	15.5%	15.1%
AF Type - Persistent or Permanent (%)	84.4%	84.9%
Prior VKA Use >30 consecutive days (%)	57.2%	57.1%
Median SBP (mmHg)	130 (IQR 120–140)	130 (IQR 120–140)
Median Weight (kg)	82 (IQR 70–95)	82 (IQR 70–96)
Aspirin Use at Baseline (%)	30.5%	31.3%

Arms

Field	Apixaban	Control
Intervention	Apixaban 5 mg twice daily. Reduced dose of 2.5 mg twice daily if ≥2 of: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (~4.7% received reduced dose). Administered with matched warfarin-placebo and sham INR values to maintain blinding (double-dummy design). Concomitant aspirin ≤165 mg/day was permitted.	Adjusted-dose warfarin targeting INR 2.0–3.0, with dose titration managed by site investigators using a blinded encrypted point-of-care INR device. Median time in therapeutic range (TTR) was 66.0% (mean 62.2%). Administered with matched apixaban-placebo to maintain double-dummy blinding. Concomitant aspirin ≤165 mg/day was permitted.
Duration	Median 1.8 years	Median 1.8 years

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Stroke (ischemic or hemorrhagic) or systemic embolism	Primary	1.60%/year (265 events)	1.27%/year (212 events)	0.79	0.01 for superiority; <0.001 for noninferiority
Death from any cause (key secondary)	Secondary	3.94%/year (669 events)	3.52%/year (603 events)	0.89	0.047
Stroke, systemic embolism, or death from any cause	Secondary	5.04%/year (837 events)	4.49%/year (752 events)	0.89	0.02
Myocardial infarction	Secondary	0.61%/year (102 events)	0.53%/year (90 events)	0.88	0.37
Stroke, systemic embolism, MI, or death from any cause	Secondary	5.49%/year (906 events)	4.85%/year (810 events)	0.88	0.01
Pulmonary embolism or deep-vein thrombosis	Secondary	0.05%/year (9 events)	0.04%/year (7 events)	0.78	0.63
Hemorrhagic stroke	Secondary	0.47%/year (78 events)	0.24%/year (40 events)	0.51	<0.001
Ischemic or uncertain type of stroke	Secondary	1.05%/year (175 events)	0.97%/year (162 events)	0.92	0.42
Safety Population	Adverse	Apixaban N: 9088 · Warfarin N: 9052
Major Bleeding (ISTH)	Adverse	3.09%/year (462 events)	2.13%/year (327 events)	0.69	<0.001
Intracranial Hemorrhage	Adverse	0.80%/year (122 events)	0.33%/year (52 events)	0.42	<0.001
Major or Clinically Relevant Nonmajor Bleeding	Adverse	6.01%/year (877 events)	4.07%/year (613 events)	0.68	<0.001
Any Bleeding	Adverse	25.8%/year (3060 events)	18.1%/year (2356 events)	0.71	<0.001

Subgroup Analysis

Benefits of apixaban consistent across prespecified subgroups: age (<65, 65–74, ≥75), sex, CHADS2 score (1, 2, ≥3), prior stroke/TIA (yes vs no), prior warfarin experience (yes vs no), AF type (paroxysmal vs persistent/permanent), renal function (normal, mild, moderate/severe impairment), region (North America, Latin America, Europe, Asian Pacific), and concomitant aspirin use. For major bleeding, interaction was significant for diabetes status (P=0.003) and renal impairment (P=0.03), with greater bleeding reduction among patients without diabetes and among those with moderate/severe renal impairment.

Criticisms

Median follow-up 1.8 years — limited data on very long-term safety and efficacy.
Excluded recent stroke (within 7 days) — acute-phase efficacy not directly tested.
Excluded severe renal impairment (CrCl <25 mL/min or creatinine >2.5 mg/dL) — safety in dialysis patients unknown.
Warfarin arm median TTR was 66% (mean 62%) — reasonable but not optimal. Sites with excellent TTR may see smaller advantage for apixaban.
No reversal agent was available during the trial (andexanet alfa approved later in 2018).
~31% of patients used concomitant aspirin — may confound bleeding comparisons.
Industry-funded (Bristol-Myers Squibb and Pfizer) — sponsors of apixaban.
Ischemic or uncertain type of stroke rates were similar between groups (HR 0.92, P=0.42) — superiority was primarily driven by hemorrhagic stroke reduction.
Risk stratification used CHADS2 (range 1–6), not the more contemporary CHA2DS2-VASc score; limited data on patients with very low CHADS2 (score of 1, ~34% of cohort) where treatment benefit may not outweigh bleeding risk.

Funding

Bristol-Myers Squibb and Pfizer

Based on: ARISTOTLE (The New England Journal of Medicine, 2011)