New England Journal of Medicine MAY 14, 2009

Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation

The ACTIVE Investigators (Stuart J. Connolly et al.)

Bottom Line

In patients with atrial fibrillation deemed unsuitable for vitamin K antagonist therapy, the addition of clopidogrel to aspirin reduced the risk of major vascular events but significantly increased the risk of major hemorrhage compared to aspirin alone.

Key Findings

1. The primary outcome (composite of stroke, myocardial infarction, non-CNS systemic embolism, or vascular death) occurred at an annual rate of 6.8% in the clopidogrel plus aspirin group compared to 7.6% in the aspirin plus placebo group (hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.01).

2. The reduction in the primary outcome was primarily driven by a decrease in the rate of stroke (2.4% per year in the combination group vs. 3.3% per year in the aspirin alone group).

3. Major bleeding occurred at an annual rate of 2.0% in the combination therapy group compared to 1.3% in the aspirin alone group (hazard ratio, 1.57; 95% CI, 1.29 to 1.92; P<0.001).

4. The rate of intracranial hemorrhage was significantly higher in the combination therapy group (0.4% per year) than in the aspirin alone group (0.2% per year; P=0.006).

Study Design

Design

RCT

Double-Blind

Sample

7,554

Patients

Duration

3.6 yr

Median

Setting

Multicenter, international

Population Patients with atrial fibrillation and at least one risk factor for stroke who were deemed unsuitable for vitamin K antagonist therapy.

Intervention Clopidogrel (75 mg daily) plus aspirin (75-100 mg daily).

Comparator Placebo plus aspirin (75-100 mg daily).

Outcome Composite of stroke, non-CNS systemic embolism, myocardial infarction, or vascular death.

Study Limitations

• The study population was restricted to patients deemed unsuitable for oral anticoagulation, which may limit the generalizability to patients who could potentially tolerate warfarin or direct oral anticoagulants.

• The observed increase in major bleeding risk offsets much of the absolute benefit derived from the reduction in ischemic events.

• The trial was open-label regarding the clinical choice of unsuitability, introducing potential selection bias for patients enrolled based on physician preference.

• The results do not support the use of dual antiplatelet therapy as a standard of care for stroke prevention in atrial fibrillation, as oral anticoagulants remain superior.

Clinical Significance

The trial establishes that while clopidogrel added to aspirin is superior to aspirin alone for preventing major vascular events in patients with atrial fibrillation who cannot take oral anticoagulants, it carries a significant bleeding penalty. It is generally regarded as a second-line or fallback strategy when superior oral anticoagulation therapy is strictly contraindicated or impossible to manage.

Historical Context

The ACTIVE-A trial was conducted during a period when vitamin K antagonists (like warfarin) were the standard of care for stroke prevention in atrial fibrillation, despite significant monitoring burdens and bleeding risks. ACTIVE-A followed the ACTIVE-W trial, which demonstrated that warfarin was superior to dual antiplatelet therapy, and it served to clarify the role of antiplatelet combinations in patients who were not candidates for oral anticoagulation.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological basis for using anti-thrombotic therapy in patients with atrial fibrillation, and why does this study examine clopidogrel and aspirin specifically for stroke prevention?

Key Response

Atrial fibrillation leads to blood stasis in the left atrium, particularly the left atrial appendage, facilitating thrombus formation. While Vitamin K Antagonists (VKAs) target the coagulation cascade (more effective for stasis-induced red thrombi), antiplatelets like aspirin and clopidogrel target platelet aggregation. The study investigates if dual antiplatelet therapy (DAPT) provides a synergistic effect over aspirin alone in patients who cannot tolerate the superior efficacy of anticoagulants.

Resident

In the ACTIVE-A trial, the addition of clopidogrel to aspirin reduced the risk of major vascular events but increased major bleeding. How should a clinician use the 'Number Needed to Treat' (NNT) versus the 'Number Needed to Harm' (NNH) from this study to guide therapy for a patient unsuitable for warfarin?

Key Response

In ACTIVE-A, the NNT to prevent one major vascular event over one year was approximately 125, while the NNH for a major hemorrhage was approximately 143. Residents must recognize that the benefit is primarily driven by a 28% reduction in stroke, but this must be balanced against the significant increase in major extracranial bleeding, requiring a personalized risk-benefit assessment using scores like CHA2DS2-VASc and HAS-BLED.

Fellow

Considering the results of ACTIVE-A alongside the later development of Direct Oral Anticoagulants (DOACs), which patients, if any, should still be considered for the aspirin-plus-clopidogrel regimen in modern practice?

Key Response

With the advent of DOACs (Apixaban, Rivaroxaban, etc.), many patients once deemed 'unsuitable' for VKA due to monitoring difficulties or dietary interactions are now candidates for anticoagulation. DAPT in AF is now largely relegated to patients who refuse all forms of oral anticoagulation or those with a very specific, absolute contraindication to both VKA and DOACs who are also not candidates for Left Atrial Appendage Occlusion (LAAO).

Attending

The ACTIVE-A trial defined 'unsuitability' for VKA therapy based on physician judgment or patient preference. How does this subjective inclusion criterion impact our interpretation of the trial's 'real-world' applicability compared to modern trials with stricter objective exclusion criteria?

Key Response

The 'physician discretion' for VKA unsuitability in ACTIVE-A (often citing 'low risk of stroke' or 'patient preference') created a heterogeneous population. This highlights a practice-changing point: many patients in the trial might have actually tolerated VKA or DOAC therapy. It teaches that the efficacy of DAPT is only 'superior' to aspirin in a context where the gold standard (anticoagulation) is truly unavailable, rather than just inconvenient.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Analyze the potential for 'competing risk' bias in the ACTIVE-A study design, specifically regarding how the increase in major hemorrhage might influence the observed rate of vascular death within the composite primary endpoint.

Key Response

Since the primary endpoint included vascular death, and major hemorrhage can lead to fatal outcomes, there is a complex interplay. If clopidogrel increases fatal bleeds, it could theoretically offset the reduction in ischemic stroke deaths within the 'vascular death' category. Researchers must use specific statistical models (like Fine-Gray) to ensure that the reduction in ischemic events is not being masked or confounded by the mortality associated with the treatment's primary side effect.

Journal Editor

A major critique of ACTIVE-A during peer review would be the lack of a 'clopidogrel-only' arm. Why was the comparison limited to aspirin vs. aspirin plus clopidogrel, and how does this affect the editorial significance of the trial's findings?

Key Response

The trial sought to build on the established (though weak) standard of care for VKA-unsuitable patients, which was aspirin. However, by not having a clopidogrel monotherapy arm, the study cannot determine if the observed bleeding risk was due to the synergy of DAPT or if clopidogrel alone would have provided a better net clinical benefit. This limitation forces the editor to frame the results strictly as an 'add-on' therapy study rather than a comparison of antiplatelet strategies.

Guideline Committee

Current AHA/ACC/HRS guidelines have downgraded the recommendation for aspirin plus clopidogrel (Class IIb) in AF. How do the findings of ACTIVE-A justify this lower-tier recommendation compared to the Class I recommendation for DOACs?

Key Response

While ACTIVE-A showed DAPT is better than aspirin (which is now Class III/No Benefit for AF stroke prevention), the magnitude of benefit is significantly less than that of anticoagulants (as shown in ACTIVE-W and DOAC trials). Guideline committees emphasize that DAPT's bleeding profile is nearly identical to VKA therapy but with significantly less protection against ischemic stroke, making it an unfavorable choice in the presence of safer, more effective DOAC options.

Clinical Landscape

Noteworthy Related Trials

2009

RE-LY Trial

n = 18,113 · NEJM

Tested

Dabigatran (110mg or 150mg BID)

Population

Patients with atrial fibrillation at risk for stroke

Comparator

Warfarin

Endpoint

Stroke or systemic embolism

Key result: Dabigatran 150 mg was superior to warfarin in preventing stroke or systemic embolism, with lower rates of hemorrhagic stroke.

2011

ARISTOTLE Trial

n = 18,201 · NEJM

Tested

Apixaban (5mg BID)

Population

Patients with atrial fibrillation with at least one additional risk factor for stroke

Comparator

Warfarin

Endpoint

Stroke or systemic embolism

Key result: Apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality.

2011

ROCKET AF Trial

n = 14,264 · NEJM

Tested

Rivaroxaban (20mg daily)

Population

Patients with nonvalvular atrial fibrillation at increased risk of stroke

Comparator

Warfarin

Endpoint

Stroke or systemic embolism

Key result: Rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation.

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