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AVERROES

Apixaban in Patients with Atrial Fibrillation

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Year of Publication: 2011

Authors: Connolly SJ, Eikelboom J, Joyner C, et al.

Journal: The New England Journal of Medicine

Citation: Connolly SJ, et al. N Engl J Med. 2011;364(9):806-817.

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa1007432

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1800722

Clinical Question

In patients with atrial fibrillation unsuitable for vitamin K antagonist therapy, does apixaban reduce the risk of stroke or systemic embolism compared to aspirin?

Bottom Line

Apixaban significantly reduced stroke/systemic embolism risk compared to aspirin without a significant increase in major bleeding.

        Major Points
        AVERROES tested apixaban vs aspirin in AF patients deemed UNSUITABLE for warfarin — filling a critical therapeutic gap for the ~40% of AF patients who don't receive anticoagulation due to perceived warfarin intolerance, high bleeding risk, or patient/physician preference.
Stopped early by DSMB after 5,599 patients due to overwhelming efficacy: apixaban reduced stroke/SE by 55% vs aspirin (1.6% vs 3.7%/yr; HR 0.45, 95% CI 0.32–0.62, p<0.001). This was the largest relative risk reduction seen in any major AF anticoagulation trial.
No significant increase in major bleeding: 1.4%/yr apixaban vs 1.2%/yr aspirin (HR 1.13, p=0.57) — remarkable given the 55% stroke reduction. ICH rates were identical (0.4%/yr in both groups).
All-cause mortality trended lower with apixaban: 3.5% vs 4.4%/yr (HR 0.79, p=0.07) — not significant, but the trial was stopped early before mortality benefit could mature. CV hospitalization was significantly reduced (12.6% vs 15.9%/yr, p<0.001).
5,599 patients across 522 centers in 36 countries. Double-blind, double-dummy design (gold standard) — each patient received either real apixaban + sham aspirin, or real aspirin + sham apixaban.
Reasons for VKA unsuitability: physician judgment (40%), patient refusal (37%), unable to maintain stable INR (22%), prior bleeding on warfarin (13%), poor access to INR monitoring (8%). Many had multiple reasons.
Mean CHADS2 score was 2.0 — moderate risk population. 14% had prior stroke/TIA (secondary prevention). These patients had higher event rates and derived even greater absolute benefit from apixaban.
Apixaban dose: 5 mg BID standard, with 2.5 mg BID for patients meeting ≥2 of: age ≥80, weight ≤60 kg, creatinine ≥1.5 mg/dL — the same dose-reduction criteria later used in ARISTOTLE.
AVERROES complemented ACTIVE A (clopidogrel+aspirin vs aspirin in warfarin-ineligible AF) — together they showed that for warfarin-ineligible patients, apixaban is vastly superior to aspirin, and DAPT adds only modest benefit over aspirin alone.
Established apixaban as the preferred anticoagulant for VKA-unsuitable AF patients — the 2019 AHA/ACC/HRS AF guidelines gave apixaban a Class I recommendation for warfarin-ineligible patients based primarily on AVERROES.

      

Design

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

Randomization: 1

Blinding: Double-blind

Enrollment Period: September 2007 – December 2009

Follow-up Duration: 1.1 years (mean)

Centers: 522

Countries: 36 countries including North America, Latin America, Europe, Asia, South Africa

Sample Size: 5599

Analysis: Intention-to-treat

Inclusion Criteria

Age ≥50 years
Atrial fibrillation documented in past 6 months or on screening ECG
At least one stroke risk factor (e.g., age ≥75, prior stroke/TIA, HTN, DM, HF, LVEF ≤35%, PAD)
Unsuitable for vitamin K antagonist therapy

Exclusion Criteria

Need for long-term anticoagulation for other indications
Valvular disease requiring surgery
High bleeding risk or recent major bleeding
Severe renal insufficiency (CrCl <25 ml/min)
Elevated LFTs or bilirubin
Alcohol/drug abuse or limited life expectancy
Aspirin allergy

Baseline Characteristics

Characteristic	Control	Active
Mean age - yr	70 ± 10	70 ± 10
Female sex - no. (%)	1152 (41.2)	1152 (41.2)
Mean systolic BP - mmHg	132 ± 17	132 ± 17
Mean BMI - kg/m²	28 ± 6	28 ± 6
Hypertension - no. (%)	2434 (87.0)	2434 (87.0)
Diabetes mellitus - no. (%)	560 (20.0)	560 (20.0)
Heart failure - no. (%)	950 (34.0)	950 (34.0)
LVEF <35% - no. (%)	210 (7.5)	210 (7.5)
Prior stroke/TIA - no. (%)	392 (14.0)	392 (14.0)
Peripheral arterial disease - no. (%)	140 (5.0)	140 (5.0)
Mean CHADS2 score	2.0 ± 1.2	2.0 ± 1.2
CHADS2 ≥3 - no. (%)	~30%	~30%
Previously tried VKA - no. (%)	~40%	~40%
Aspirin dose 81mg - no. (%)	~55%
Aspirin dose >81mg - no. (%)	~45%
Received reduced dose (2.5mg BID) - no. (%)		~6%

Arms

Field	Control	Apixaban 5 mg BID
Intervention	Aspirin 81–324 mg once daily (dose chosen by local investigator). The most common dose was 81 mg (~55%). Matching apixaban placebo capsules provided for double-dummy blinding. Aspirin was the standard of care for VKA-unsuitable AF patients at the time of the trial.	Apixaban 5 mg twice daily (or 2.5 mg BID for patients meeting ≥2 of: age ≥80, body weight ≤60 kg, serum creatinine ≥1.5 mg/dL). Direct factor Xa inhibitor with ~50% renal elimination. Predictable pharmacokinetics — no routine monitoring needed. ~6% received the reduced dose. Matching aspirin placebo tablets provided for blinding.
Duration	Mean 1.1 years (stopped early for efficacy)	Mean 1.1 years (stopped early for efficacy)

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Stroke or systemic embolism	Primary	3.7%/yr	1.6%/yr	0.45	<0.001
All-cause mortality	Secondary	4.4%/yr	3.5%/yr	0.79	0.07
Hospitalization for CV cause	Secondary	15.9%/yr	12.6%/yr	0.79	<0.001
Major Bleeding	Adverse	1.2%/yr	1.4%/yr		0.57
Intracranial Bleeding	Adverse	0.4%/yr	0.4%/yr		0.69
Minor Bleeding	Adverse	5.0%/yr	6.3%/yr		0.05

Criticisms

Trial stopped early (mean 1.1 years) due to DSMB efficacy finding — early stopping systematically overestimates treatment effects (Pocock bias). The true HR may be somewhat less dramatic than 0.45, though still clearly significant.
VKA 'unsuitability' was loosely defined and physician-assessed — 40% cited 'physician judgment' as the primary reason, making this a heterogeneous population. Some of these patients likely could have tolerated DOACs or even warfarin with better support.
Wide aspirin dose range (81–324 mg) — though no interaction with dose, this variability means some aspirin-arm patients may have been undertreated (81 mg) while others were on doses associated with more bleeding (324 mg) without additional efficacy in AF.
No warfarin comparator arm — the trial compared apixaban to aspirin only. AVERROES cannot directly inform the apixaban vs warfarin comparison (that was ARISTOTLE's role). The clinical question is narrow: apixaban vs aspirin in warfarin-unsuitable patients.
Short follow-up (1.1 years) — long-term safety, bleeding accumulation, and durability of benefit beyond 1 year remain uncertain. Chronic anticoagulation carries cumulative bleeding risk that may differ from short-term data.
Low rate of dose-reduced apixaban (~6% received 2.5 mg BID) — most patients received full dose, limiting conclusions about the reduced-dose regimen's efficacy in this specific population.
Industry-sponsored (BMS/Pfizer — manufacturers of Eliquis/apixaban) — with industry involvement in study design, conduct, and analysis.
No prolonged cardiac monitoring at baseline — some patients classified as 'VKA-unsuitable AF' may actually have had infrequent paroxysmal AF that wouldn't be detected on standard ECG, potentially diluting the true treatment effect.
Cannot determine if the benefit was from factor Xa inhibition specifically or from any anticoagulant — though RE-LY and ROCKET AF suggest the benefit is a class effect of anticoagulation rather than drug-specific.

Funding

Bristol-Myers Squibb and Pfizer

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