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ACTIVE A

Aspirin plus clopidogrel versus aspirin alone for prevention of vascular events in patients with atrial fibrillation (ACTIVE A): a randomised controlled trial

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Year of Publication: 2009

Authors: Connolly SJ, et al.

Journal: The Lancet

Citation: Connolly SJ, et al. Lancet. 2009;373(9671):1903–1912.

Link: https://www.thelancet.com/journals/lance...0507-1/fulltext

Clinical Question

Does adding clopidogrel to aspirin reduce vascular events in atrial fibrillation (AF) patients unsuitable for vitamin K antagonists?

Bottom Line

Clopidogrel plus aspirin modestly reduced major vascular events compared to aspirin alone, but increased major bleeding.

        Major Points
        Part of the ACTIVE program (ACTIVE W proved OAC superior to DAPT; ACTIVE A tested DAPT when OAC was unsuitable) — complementary trials establishing the AF treatment hierarchy.
Largest trial of dual antiplatelet therapy (DAPT) in AF: 7,554 patients across 580 centers in 33 countries with median 3.6-year follow-up.
DAPT reduced major vascular events by 11% vs aspirin alone (6.8% vs 7.6% per year, HR 0.89, 95% CI 0.81–0.98, P=0.01).
Stroke specifically reduced by 28% (2.1% vs 2.8% per year, RR 0.72, P=0.001) — benefit driven primarily by ischemic stroke reduction.
Major bleeding significantly increased (2.0% vs 1.3% per year, RR 1.57, P<0.001), offsetting much of the stroke reduction and resulting in marginal net clinical benefit.
No significant reduction in all-cause mortality or MI — the benefit was stroke-specific, suggesting clopidogrel adds antithrombotic rather than broad cardiovascular protection in AF.
Absolute benefit was small (NNT ~143 per year for stroke alone) while bleeding NNH was ~143 per year — near-equivalent absolute trade-off between stroke prevented and major bleeding caused.
Established DAPT as a reasonable but suboptimal alternative in AF patients truly unable to take OAC, now largely superseded by DOACs which provide better risk-benefit ratio.
The 'unsuitable for OAC' criterion was physician-determined and heterogeneous — reasons included perceived bleeding risk (50%), patient refusal (26%), and anticipated non-compliance (15%).
Together with ACTIVE W, defined the treatment ladder for AF stroke prevention: OAC > DAPT > aspirin alone, a hierarchy that guided practice until DOACs transformed the field.

      

Design

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

Randomization: 1

Blinding: Double-blind

Enrollment Period: June 2003 – May 2006

Follow-up Duration: Median 3.6 years

Centers: 580

Countries: 33 countries

Sample Size: 7554

Analysis: Intention-to-treat

Inclusion Criteria

Atrial fibrillation (AF)
Unsuitable for vitamin K antagonists
≥1 risk factor for stroke (e.g., age ≥75, hypertension, prior stroke, etc.)

Exclusion Criteria

Indication for or ability to take oral anticoagulant therapy
Indication for dual antiplatelet therapy (e.g., recent coronary stent)
Recent major bleeding or high bleeding risk
Known contraindication to clopidogrel or aspirin
Mechanical prosthetic heart valve requiring anticoagulation
Severe mitral stenosis (rheumatic valvular disease)
Active peptic ulcer disease or GI bleeding within past 12 months
Planned cardioversion or catheter ablation for AF

Arms

Field	Control	Aspirin + Clopidogrel
Intervention	Aspirin 75–100 mg daily + placebo clopidogrel	Aspirin 75–100 mg daily + clopidogrel 75 mg daily
Duration	Median 3.6 years	Median 3.6 years

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Major vascular events (stroke, MI, systemic embolism, or vascular death)	Primary	7.6% per year	6.8% per year	0.89	0.01
Stroke	Secondary	2.8% per year	2.1% per year	0.75	0.001
Major bleeding	Secondary	1.3% per year	2.0% per year	1.57	<0.001
Major Bleeding	Adverse	1.3% per year	2.0% per year		<0.001

Criticisms

Increased major bleeding (RR 1.57) nearly offset the stroke reduction — the net clinical benefit was marginal, with similar numbers of strokes prevented and major bleeds caused.
Participants selected as 'unsuitable for OAC' represent a heterogeneous and poorly defined population — reasons ranged from perceived bleeding risk to patient refusal, limiting generalizability.
Absolute benefit small (NNT ~143 per year for stroke alone) — the clinical significance of this modest benefit is debatable given the bleeding trade-off.
Now largely superseded by DOACs (RE-LY, ROCKET AF, ARISTOTLE, ENGAGE AF) which provide superior stroke prevention with better safety profiles, making DAPT in AF an outdated strategy for most patients.
No comparison with reduced-dose warfarin or other OAC alternatives — the trial only compared DAPT to aspirin, not to any anticoagulant.
The definition of 'unsuitable for OAC' was physician-determined and varied across 33 countries — what constitutes unsuitability differs dramatically by practice setting.
Industry-sponsored by Sanofi-Aventis and Bristol-Myers Squibb (clopidogrel manufacturers) — potential bias in study design and framing of results.
Clopidogrel resistance (CYP2C19 polymorphism) was not assessed — variable antiplatelet response may have diluted the treatment effect in some patients.
Aspirin dose variability (75–100 mg) across the trial may have introduced heterogeneity in the control arm's antiplatelet effect.

Funding

Sanofi-Aventis and Bristol-Myers Squibb

Based on: ACTIVE A (The Lancet, 2009)