Combination treatment with aspirin and warfarin

• a meta-analysis of randomised trials, published between 1960 and July 1999, which included patients with established coronary heart disease and used oral anticoagulants (OAs) for >= 3m months, was undertaken (1)
  
  
• this study (1) concluded that:
  • in patients with coronary artery disease, high intensity OAs (INR > 2.8) reduce total mortality, stroke and fatal and non-fatal myocardial infarction; however patients treated with high intensity OAs had an increase in episodes of major bleeding
  • treatment with moderate intensity OAs (INR 2 to 3) reduced fatal and non-fatal myocardial infarction, and stroke; however there was an associated increase in incidence of major bleeding
  • high or moderate intensity OAs do not reduce end points more than aspirin but increases bleeding
  • aspirin plus low density OAs (INR <2) does not differ in effect from aspirin therapy alone

A more recent systematic review and meta-analysis has been undertaken (2,3):

• review included ten randomised controlled trials (n=4,180) with at least three months of follow up that compared aspirin plus warfarin with warfarin alone, with the same intensity of anticoagulation in each of the treatment arms (i.e. warfarin was administered to achieve the same target international normalised ratio or was given at the same fixed dose in each group)
  • five of the studies (n=990) were of patients with mechanical heart valves, two were of patients with atrial fibrillation (n=495), two were of patients with coronary artery disease (n=150), and one was a primary prevention study of patients at high risk of cardiovascular (CV) disease (n=2,545)
• aspirin was used at a dose of 75 to 300mg daily in eight of the studies, with the other studies (both in patients with mechanical heart valves) using 500mg and 1000mg daily
• results:
  • a significant reduction in the risk of arterial thromboembolism (defined as myocardial infarction, unstable angina requiring hospitalisation, stroke, transient ischaemic attack, or systemic embolism) for the combined therapy compared with warfarin alone (6.3% vs. 8.8%; OR 0.66, 95%CI 0.52 to 0.84; NNT=40), but not for all-cause mortality (both 6.7%; OR 0.98, 95%CI 0.77 to 1.25)
  • a greater incidence of major bleeding with warfarin plus aspirin compared with warfarin alone (3.8% vs. 2.8%; OR 1.43, 95%CI 1.00 to 2.02, P=0.05)
• secondary analysis only identified a significant advantage for combination therapy in reducing arterial thromboembolism in the subgroup of patients with mechanical heart valves. (OR 0.27, 95%CI 0.15 to 0.49)

Reference:

1. Anand SS, Yusuf S (1999). Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA, 282, 2058-67.
2. Dentali F et al.. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease. Arch Intern Med 2007;167:117–24.
3. MeReC Extra 2007.When should aspirin be added to warfarin?