Elsevier

The Lancet

Volume 367, Issue 9526, 10–16 June 2006, Pages 1903-1912
The Lancet

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Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial

https://doi.org/10.1016/S0140-6736(06)68845-4Get rights and content

Summary

Background

Oral anticoagulation therapy reduces risk of vascular events in patients with atrial fibrillation. However, long-term monitoring is necessary and many patients cannot achieve optimum anticoagulation. We assessed whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events.

Methods

Patients were enrolled if they had atrial fibrillation plus one or more risk factor for stroke, and were randomly allocated to receive oral anticoagulation therapy (target international normalised ratio of 2·0–3·0; n=3371) or clopidogrel (75 mg per day) plus aspirin (75–100 mg per day recommended; n=3335). Outcome events were adjudicated by a blinded committee. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Analyses were by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00243178.

Results

The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. There were 165 primary events in patients on oral anticoagulation therapy (annual risk 3·93%) and 234 in those on clopidogrel plus aspirin (annual risk 5·60%; relative risk 1·44 (1·18–1.76; p=0.0003). Patients on oral anticoagulation therapy who were already receiving this treatment at study entry had a trend towards a greater reduction in vascular events (relative risk 1·50, 95% CI 1·19–1·89) and a significantly (p=0·03 for interaction) lower risk of major bleeding with oral anticoagulation therapy (1.30; 0.94–1.79) than patients not on this treatment at study entry (1·27, 0·85–1·89 and 0·59, 0·32–1·08, respectively).

Conclusion

Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy.

Introduction

Atrial fibrillation is a common cardiac arrhythmia, especially in the elderly, and affects over 1% of the population. It increases the risk of stroke and other vascular events.1, 2 Oral anticoagulation therapy such as warfarin reduces stroke by two-thirds compared with no treatment.3, 4 Compared with aspirin, oral anticoagulation therapy reduces the risk of stroke by 45% and reduces cardiovascular events by 29%.5 However, it increases the risk of major bleeding by about 70%5 compared with aspirin. Oral anticoagulation therapy is currently the treatment of choice for patients at high risk of stroke.6

The response to oral anticoagulation therapy is affected by gut flora, variations in hepatic function, interactions with several drugs, and diet,7 requiring regular monitoring of the level of anticoagulation. Therefore, only about half of potentially eligible patients receive oral anticoagulation therapy.8 An effective, simple and safe alternative to this treatment could be of great clinical value.

Both aspirin and clopidogrel are antiplatelet agents that act through different mechanisms and are effective in preventing vascular events in patients at high risk.9 Aspirin reduces risk of stroke in patients with atrial fibrillation by 22%.3, 4 The additive benefits of combining a thienopyridine with aspirin have been clearly shown in patients undergoing percutaneous coronary intervention, in those with acute coronary syndrome or acute myocardial infarction.10, 11, 12, 13 Since aspirin has a documented protective effect in atrial fibrillation, it is reasonable to expect that the addition of clopidogrel to aspirin will provide incremental benefits so that this combination would be non-inferior to oral anticoagulation therapy alone in preventing vascular events. We aimed to assess whether clopidogrel plus aspirin was statistically non-inferior to oral anticoagulation therapy for prevention of vascular events in patients with atrial fibrillation at high risk of stroke and eligible for oral anticoagulation therapy.

Section snippets

Participants

Three separate inter-related trials comprise the ACTIVE programme. Patients eligible for and willing to take oral anticoagulation therapy were enrolled into ACTIVE W, in which clopidogrel plus aspirin was compared to oral anticoagulation therapy Patients ineligible for or unwilling to take oral anticoagulation therapy were enrolled into ACTIVE A, in which clopidogrel was compared with placebo in patients receiving aspirin. ACTIVE I was a randomised placebo-controlled trial of irbesartan for

Results

Patients were enrolled between June, 2003, and December, 2004. Patient enrolment was briefly re-opened in July, 2005, because overall event rates were lower than expected. On August 25, 2005, the data and safety monitoring board recommended that the study be stopped due to clear evidence of superiority of oral anticoagulation over clopidogrel plus aspirin. Investigators were notified to discontinue study medication and to treat study patients according to current guidelines. The data and safety

Discussion

We have shown that oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients with atrial fibrillation at high risk of stroke who do not have contraindications to oral anticoagulation therapy. This finding was driven largely by higher rates of stroke and non-CNS systemic embolus with clopidogrel plus aspirin. Stroke and non-CNS systemic embolus are thought to result predominantly from cardiac thrombus formation in patients with atrial

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