ACTIVE W (clopidogrel plus aspirin versus anticoagulation in atrial fibrillation)

Atrial fibrillation is a common cardiac arrhythmia, especially in the elderly, and affects over 1% of the population.

• atrial fibrillation increases the risk of stroke and other vascular events
  • oral anticoagulation therapy such as warfarin reduces stroke by two-thirds compared with no treatment and compared with aspirin, oral anticoagulation therapy reduces the risk of stroke by 45% and reduces cardiovascular events by 29% (1)
• the ACTIVE W trial was designed to assess whether clopidogrel plus aspirin was non-inferior to oral anticoagulation therapy for prevention of vascular events
  • 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 eligible for the study:
    • patients had electrocardiographic evidence of atrial fibrillation and at least one of the following:
      • age 75 years or older
      • on treatment for systemic hypertension;
      • previous stroke, transient ischaemic attack, or non-CNS systemic embolus
      • left ventricular dysfunction with left ventricular ejection fraction less than 45%
      • peripheral arterial disease
    • if patients were aged 55-74 years and did not have one of the other inclusion criteria they were required to have either diabetes mellitus requiring drug therapy or previous coronary artery disease
    • patients were excluded if they had any of the following: contraindication for clopidogrel or for oral anticoagulant (such as prosthetic mechanical heart valve); documented peptic ulcer disease within the previous 6 months; previous intracerebral haemorrhage; significant thrombocytopenia (platelet count <50×109/L); or mitral stenosis
  • study protocol:
    • patients 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)
    • primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. Analyses were by intention-to-treat.
  • results:
    • study was stopped early because of clear evidence of superiority of oral anticoagulation therapy
      • 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).
  • the study authors concluded 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, especially in those already taking oral anticoagulation therapy
  • a follow-up analysis concluded that:
    • in patients with atrial fibrillation for whom vitamin K-antagonist therapy was unsuitable, the addition of clopidogrel to aspirin reduced the risk of major vascular events, especially stroke, and increased the risk of major hemorrhage
      • stroke occurred in 296 patients receiving clopidogrel (2.4% per year) and 408 patients receiving placebo (3.3% per year) (relative risk, 0.72; 95% CI, 0.62 to 0.83; P<0.001)
      • myocardial infarction occurred in 90 patients receiving clopidogrel (0.7% per year) and in 115 receiving placebo (0.9% per year) (relative risk, 0.78; 95% CI, 0.59 to 1.03; P=0.08)
      • major bleeding occurred in 251 patients receiving clopidogrel (2.0% per year) and in 162 patients receiving placebo (1.3% per year) (relative risk, 1.57; 95% CI, 1.29 to 1.92; P<0.001)

Reference:

1. ACTIVE Writing Group on behalf of the ACTIVE Investigators. 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. Lancet. 2006 Jun 10;367(9526):1903-12
2. ACTIVE Investigators, Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, Chrolavicius S, Yusuf S.Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009 May 14;360(20):2066-78.