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ACTIVE A: reducing stroke risk in patients with atrial fibrillation

Peter Burrill
BPharm(Hons) MRPharmS DipPresSci FCPP FFPMM
Specialist Pharmaceutical Adviser for Public Health
Derbyshire County Primary Care Trust

ACTIVE W previously compared aspirin plus clopidogrel with oral anticoagulation.1 Oral anticoagulation was shown to be superior to aspirin plus clopidogrel. ACTIVE A compared aspirin plus clopidogrel with aspirin alone in patients with atrial fibrillation who were at increased risk for stroke and for whom therapy with a vitamin K antagonist was considered unsuitable.2

Method
ACTIVE A was a randomised, double-blind, multicentre trial performed at 580 centres in 33 countries. Patients were eligible for ACTIVE (either ACTIVE A or ACTIVE W) if they had atrial fibrillation at enrolment or had had at least two episodes of intermittent atrial fibrillation in the previous six months. In addition, patients were required to have at least one of the following risk factors for stroke:

  • An age of 75 years or more.
  • Systemic hypertension during treatment.
  • Previous stroke, transient ischemic attack, or noncentral nervous system systemic embolism.
  • A left ventricular ejection fraction of less than 45%.
  • Peripheral vascular disease.
  • An age of 55 to 74 years and diabetes mellitus or coronary artery disease.

Patients were excluded if they required a vitamin K antagonist or clopidogrel or had any of the following risk factors for haemorrhage:

  • Documented peptic ulcer disease within the
  • previous six months.
  • A history of intracerebral haemorrhage.
  • Significant thrombocytopenia (platelet count
  • Ongoing alcohol abuse.

Patients who were considered to be candidates for vitamin K antagonist therapy were enrolled in ACTIVE W, and those for whom such therapy was considered to be unsuitable were enrolled in ACTIVE A.

By means of an interactive telephone system, patients in ACTIVE A were randomly assigned in equal numbers, in blocks of varying sizes, to receive clopidogrel at a dose of 75 mg or matching placebo once daily, in a double-blind fashion. All patients also received aspirin (recommended dose, 75 to 100 mg per day).

The primary study outcome was any major vascular event (stroke, non-central nervous system systemic embolism, myocardial infarction, or death from vascular causes).

The most important secondary outcome was stroke. Other secondary outcomes were the other individual components of the primary outcome (noncentral nervous system systemic embolism, myocardial infarction, and death from vascular causes) and the composite of the primary outcome and major haemorrhage.

Major haemorrhage was defined as any overt bleeding requiring transfusion of at least two units of blood or any overt bleeding meeting the criteria for severe haemorrhage, which included any of the following:

  • Fatal haemorrhage.
  • A drop in the haemoglobin level of 5 g per decilitre or more.
  • Hypotension requiring inotropic agents.
  • Intraocular bleeding leading to substantial loss of vision.
  • Requirement for surgical intervention.
  • Symptomatic intracranial haemorrhage.
  • Requirement for transfusion of four units or more of blood.

Minor bleeding was defined as any nonmajor bleeding associated with modification of the study drug regimen.
The trial appears to have been allocation concealed and adequately powered. All analyses were based on the intention-to-treat principle. The trial was sponsored by Sanofi-Aventis and Bristol-Myers Squibb.

Results
A total of 7,554 patients were enrolled and were randomly assigned to receive clopidogrel (3,772) or placebo (3,782) in addition to aspirin. The median duration of follow-up for both groups was 3.6 years.

The mean age was 71 years; 58.2% were men. Atrial fibrillation was permanent in 63.7%, persistent in 14.0%, and paroxysmal in 22.1%. The mean CHADS2 score was 2.0.
Rates of discontinuation of the study medication were 16.3% and 15.2% for clopidogrel and placebo, respectively, at 1 year, increasing to 39.4% and 37.1% at 4 years. All patients were receiving aspirin at the time of randomisation, with use decreasing in both groups to 92.9% at 1 year and 81.1% at 4 years.

The primary endpoint occurred in 832 patients receiving clopidogrel (22.1%) as compared with 924 patients receiving placebo (24.4%) (relative risk [RR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.01). This is a number needed to treat (NNT) of 43.

The reduction in the risk of major vascular events in the clopidogrel group was primarily due to a reduction in the incidence of stroke. Stroke occurred in 296 patients receiving clopidogrel (7.8%) and 408 patients receiving placebo (10.8%) relative risk, 0.72; 95% CI, 0.62 to 0.83; P

There was no reduction in myocardial infarction (MI) (RR 0.78 [0.59–1.03]), noncentral nervous system systemic embolism (RR 0.96 [0.66–1.40]), death from vascular causes (RR 1.00 [0.89–1.12]), or death from any cause (RR 0.98 [0.89–1.08]).
Major bleeding occurred in 251 patients receiving clopidogrel as compared with 162 patients receiving placebo (6.7% vs 4.3%; RR 1.57; 95% CI, 1.29 to 1.92; P

Minor bleeding occurred in 10.8% and 4.6%, respectively; RR 2.42 (2.03–2.89), P With the combination of major vascular events (the primary outcome) and major haemorrhage, there was no significant difference between the overall event rate with aspirin plus clopidogrel and the rate with aspirin alone (968 vs 996 events; RR 0.97; 95% CI, 0.89–1.06; P=0.54).

Discussion
The paper reports the results as "the addition of clopidogrel to aspirin reduced the rate of major vascular events from 7.6% per year to 6.8%. This was primarily due to a reduction in the rate of stroke. The rate of major haemorrhage increased with the addition of clopidogrel, from 1.3 to 2.0% per year."2

However, when the NNTs and NNHs are compared, they are similar and appear to cancel each other out. ACTIVE A does not provide strong enough evidence to recommend clopidogrel plus aspirin instead of aspirin alone for patients with atrial fibrillation unsuitable for oral anticoagulation.

References
1. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J et al. 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; 367:1903-12
2. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360(20):2066–78.