The ACTIVE Trial (Atrial Fibrillation Clopidogrel Trial with Irbesartan for the Prevention of Vascular Events) was designed to assess the role of clopidogrel and aspirin in the prevention of stroke and other vascular events in patients with atrial fibrillation (AF). ACTIVE W has already reported and compared clopidogrel + aspirin with a vitamin K antagonist. The ACTIVE A trial, the results of which are discussed here, compared combination therapy with clopidogrel and aspirin versus aspirin alone in patients with AF who were considered unsuitable for a Vitamin K antagonist.
This was a randomised, double-blind multi-centre trial involving 7554 patients from 580 centres in 33 countries. Patients were eligible for ACTIVE (either A or W) if they had AF at the time of enrolment or had had 2 episodes of AF in the preceding 6 months. Additionally, patients were required to have at least one of the following risk factors: age > 75 years, systemic hypertension, previous stroke or TIA, LVEF <45%, peripheral vascular disease or age 55-74 years and diabetes mellitus or coronary artery disease. Patients considered to be candidates for vitamin K antagonists were enrolled in ACTIVE W and those not considered suitable in ACTIVE A. Patients in both trials could also be randomised to ACTIVE I which involved factorial randomisation to either irbesartan or placebo – this study is ongoing.
Patients in ACTIVE A were randomised to either aspirin and clopidogrel (n=3772) or aspirin (n=3782). Follow up visits to assess compliance and clinical outcome were held at 1 month and then 3 monthly for the first year and 6 monthly until the end of the trial. The primary outcome was any major vascular event (stroke, non central nervous system systemic embolism, myocardial infarction or death from vascular causes). The main secondary outcome measures were the other individual components of the primary outcome and the composite of the primary outcome and major haemorrhage.
At a median of 3.6 years follow up, major vascular events had occurred in 832 patients receiving clopidogrel (6.8%/year) and 924 patients receiving placebo (7.6%/year), (relative risk with clopidogrel 0.89, 95%CI 0.81-0.98, p = 0.01). The difference was predominantly due to a reduction in the rate of stroke with clopidogrel – stroke occurred in 296 patients in the dual anti-platelet therapy arm (2.4%/year) versus 408 placebo patients (3.3%/year), (RR 0.72, 95%CI 0.62-0.83, p < 0.001). Myocardial infarction occurred in 90 patients receiving clopidogrel (0.7%/year) and 115 receiving placebo (0.9%/year, RR 0.78, 95%CI 0.59-1.03, p = 0.08). Major bleeding occurred in 251 patients receiving clopidogrel (2%/year) and 162 patients receiving placebo (1.3%/year) (RR1.57, 95%CI 1.29-1.92, p<0.001). Rates of discontinuation of the study medication were 16.3% and 15.2% for clopidogrel and placebo respectively at 1 year, rising to 39.4% and 37.1% at 4years. All patients were receiving aspirin at the time of randomisation and this decreased to 92.9% at 1 year and 81.1% at 4 years in both groups. A total of 777 patients (10.3%) received a vitamin K antagonist following discontinuation of the trial medication.
For patients unable to take vitamin K antagonists, the addition of clopidogrel to aspirin therapy significantly reduced the rate of major vascular events, primarily driven by a reduction in strokes. However, one extra major bleeding episode would occur for ever 143 patients treated for one year with this combination.
· ACTIVE Investigators et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. The New England Journal of Medicine (2009) vol. 360 (20) pp. 2066-78