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Connolly SJ, et al. "Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation". The New England Journal of Medicine. 2009. 360(20):2066-78.
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Clinical Question

Among patients with atrial fibrillation who are not suitable candidates for vitamin K antagonists, does the addition of clopidogrel to aspirin reduce the risk of vascular events compared to aspirin alone?

Bottom Line

Compared with aspirin alone, clopidogrel plus aspirin reduces major vascular events but increases the risk of major bleeding among patients with atrial fibrillation (AF) who are not suitable candidates for vitamin K antagonists (VKAs).

Major Points

AF was first identified as a risk factor for stroke in a 1978 Framingham study publication.[1][2] The 1991 SPAF study[3] demonstrated the superiority of warfarin over aspirin in stroke prevention in AF. Despite the benefits of anticoagulation, many patients with AF do not receive such therapy because of a known or perceived risk of bleeding or another factor that renders VKAs unsuitable. For years, such patients had been prescribed aspirin or combination aspirin/clopidogrel, although the comparative efficacy of these strategies had not yet been rigorously studied until ACTIVE A.

The 2009 Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE A) randomized 7,554 patients with AF who were deemed unsuitable candidates for VKA therapy to aspirin/clopidogrel or aspirin alone. At a mean follow-up of 3.6 years, aspirin/clopidogrel was associated with an 11% relative risk reduction in the composite outcome of stroke, non-CNS embolism, MI, or vascular death, primarily driven by stroke reduction. This benefit came at the cost of increased rates of major bleeding (2.0% vs. 1.3%). Importantly, there was no difference in the combined outcome of vascular events plus major bleeding, suggesting that any gains in stroke reduction were offset by increases in major bleeding.

A post hoc subgroup analysis found that the greatest benefits were seen among patients aged 65-74 years old and those with a CHADS2 score of one. These results indicate that combination aspirin/clopidogrel does not confer benefit over aspirin alone in AF, and provides a useful data point when individualizing therapy for AF, particularly among those deemed poor candidates for traditional anticoagulant therapy with a VKA.

ACTIVE A was one of the first atrial fibrillation trials to study alternative anticoagulant or antithrombotic agents in patients deemed poor candidates for VKA therapy. While ACTIVE A established that aspirin/clopidogrel should probably not be used as an alternative to warfarin in this patient population, the results of AVERROES (2011)[4] suggest that apixaban may be a suitable selection because of its superior efficacy without increasing bleeding.

The related ACTIVE W (2006) was carried out by the same investigators but compared aspirin/clopidogrel to a VKA such as warfarin, and showed that aspirin/clopidogrel was inferior in efficacy without reducing major bleeding.


AHA/ACC/HRS AF (April 2014, adapted)[5]

  • In patients with nonvalvular AF with prior stroke, TIA, or CHA2DS2-VASc score ≥2, recommend oral anticoagulation with:
    • Warfarin, goal INR 2-3 (class I, level A)
    • Dabigatran (class I, level B)
    • Rivaroxaban (class I, level B)
    • Apixaban (class I, level B)
  • In patients with nonvalvular AF unable to maintain INR 2-3 with warfarin, recommend dabigatran, rivaroxaban, or apixaban (class I, level C)
  • In patients with nonvalvular AF with moderate or severe CKD with CHA2DS2-VASc score ≥2, consider treatment with reduced doses of dabigatran, rivaroxaban, or apixaban, although safety has not yet been clearly delineated (class IIb, level C)
  • In patients with ESRD, dabigatran and rivaroxaban are untested and are not recommended (class III, level C)
  • In patients with a mechanical heart valve, do not use dabigatran (class III, level B)


  • Multicenter, double-blind, parallel-group, industry-sponsored, randomized, controlled trial
  • N=7,554
    • Aspirin/clopidogrel (n=3,772)
    • Aspirin (n=3,782)
  • Setting: 580 centers in 33 countries
  • Enrollment: 2003-2006
  • Analysis: Intention-to-treat
  • Follow-up: 3.6 years
  • Primary outcome: Composite of stroke, non-CNS embolism, MI, or CV death


Inclusion Criteria

  • AF at enrollment or ≥2 episodes within prior 6 months
  • ≥1 additional stroke risk factor:
    • Age ≥75 years or age 55-74 years with T2DM or CAD
    • HTN
    • Prior stroke, TIA, or non-CNS systemic embolism
    • LVEF <45%
    • PAD

Exclusion Criteria

  • Known indication for VKA or clopidogrel
  • ≥1 risk factor for hemorrhage:
    • Documented PUD within prior 6 months
    • HIstory of intracerebral hemorrhage
    • Platelets <50k
    • Alcohol abuse

Baseline Characteristics

  • Mean age: 71 years
  • Male: 58%
  • AF type
    • Permanent: 64%
    • Paroxysmal: 22%
    • Persistent: 14%
  • Mean CHADS2 score: 2
  • Baseline drug use:
    • Aspirin: 83%
    • VKA: 9%
  • Reason for enrollment:
    • Risk of bleeding: 23%
    • Physician deemed VKA inappropriate: 50%
    • Patient preference: 26%


  • Randomized to clopidogrel 75mg or matching placebo daily
  • All patients also received aspirin 75-100mg daily
  • Patients undergoing cardioversion received open-label VKA 4 weeks before and after cardioversion and then resumed assigned study treatment
  • Follow-up at 1 month, 3 months, 6 months, 9 months, and 12 months, and then q 6 months until trial end


Comparisons are clopidogrel plus aspirin vs. aspirin alone.

Primary Outcomes

Major vascular event (stroke, non-CNS embolism, MI, or vascular death)
6.8% vs. 7.6% per year (RR 0.89; 95% CI 0.81-0.98; P=0.01)

Secondary Outcomes

2.4% vs. 3.3% per year (RR 0.72; 95% CI 0.62-0.83; P<0.001)
0.7% vs. 0.9% per year (RR 0.78; 95% CI 0.59-1.03; P=0.08)
Major hemorrhage
2.0% vs. 1.3% per year (RR 1.57; 95% CI 1.29-1.92; P<0.001)
Major vascular event plus major hemorrhage
968 vs. 996 events (RR 0.97; 95% CI 0.89-1.06; P=0.54)

Subgroup Analysis

Outcomes appeared to favor combined therapy among patients aged 65-74 years and those with CHADS2 score of one. There were no interactions evident with other variables studied.


  • The authors did not provide an explanation of why physicians deemed VKAs inappropriate in a large subset of patients.[6]


Funding by Sanofi-Aventis and Bristol-Myers Squibb.

Further Reading