ACTIVE A
(2009)Objective
Clopidogrel in addition to aspirin to reduce the risk of major vascular events in patients with atrial fibrillation who are unsuitable for vitamin K antagonist therapy.
Study Summary
• The ACTIVE A trial showed that in atrial fibrillation patients for whom vitamin K antagonists were unsuitable, dual therapy with clopidogrel and aspirin significantly reduced the risk of stroke compared to aspirin alone, but at the cost of an increased risk of major bleeding..
Intervention
Clopidogrel 75 mg once daily plus aspirin 75–100 mg once daily vs. aspirin 75–100 mg alone. Patients were followed for a median of 3.6 years.
Inclusion Criteria
Patients with atrial fibrillation and at least one risk factor for stroke (age ≥75, hypertension, prior stroke/TIA, heart failure, diabetes, CAD, PAD), and in whom vitamin K antagonist therapy was deemed unsuitable due to bleeding risk, physician judgment, or patient preference.
Study Design
Arms: Clopidogrel + Aspirin vs. Aspirin alone
Patients per Arm: Clopidogrel + ASA: 3772, ASA alone: 3782
Outcome
• Primary outcome (stroke, MI, systemic embolism, or vascular death): 6.8%/yr in the clopidogrel + ASA group vs 7.6%/yr in ASA alone (RR 0.89; 95% CI 0.81–0.98; P=0.01). <br>• Stroke: 2.4%/yr vs. 3.3%/yr (RR 0.72; 95% CI 0.62–0.83; P<0.001). <br>• Ischemic stroke: 1.9%/yr vs. 2.8%/yr. <br>• Myocardial infarction: 0.7%/yr vs. 0.9%/yr (P=0.08). <br>• Major bleeding: 2.0%/yr vs. 1.3%/yr (RR 1.57; 95% CI 1.29–1.92; P<0.001). <br>• Intracranial hemorrhage: 0.4%/yr vs. 0.2%/yr (RR 1.87; P=0.006)..
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.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 7554
- Follow-up
- Median 3.6 years
- Centers
- 580
- Countries
- 33 countries
Primary Outcome
Definition: Major vascular events (stroke, MI, systemic embolism, or vascular death)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 7.6% per year | 6.8% per year | 0.89 (0.81–0.98) | 0.01 |
Limitations & 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.
Citation
Connolly SJ, et al. Lancet. 2009;373(9671):1903–1912.