In 1988, we undertook a randomized, placebo-controlled, double-blind trial to investigate the safety and efficacy of low-dose
acetylsalicylic acid (ASA), modified-release
dipyridamole, and the two agents in combination for
secondary prevention of
ischemic stroke. Patients with prior
stroke or
transient ischemic attack (TIA) were randomized to treatment with ASA alone (50 mg daily), modified-release
dipyridamole alone (400 mg daily), the two agents in a combined formulation, or placebo. Primary endpoints were
stroke, death, and
stroke or death together. TIA and other vascular events were secondary endpoints. Patients were followed on treatment for two years. Data from 6,602 patients were analysed. Factorial analysis demonstrated a highly significant effect for ASA and for
dipyridamole in reducing the risk of
stroke (p < or = 0.001) and
stroke or death combined (p < 0.01). In pairwise comparisons,
stroke risk in comparison to placebo was reduced by 18% with ASA alone (p = 0.013); 16% with
dipyridamole alone (p = 0.039); and 37% with combination
therapy (p < 0.001). Risk of
stroke or death was reduced by 13% with ASA alone (p = 0.016); 15% with
dipyridamole alone (p = 0.015); and 24% with the combination (p < 0.001). The treatment had no statistically significant effect on the death rate alone. Factorial analysis also demonstrated a highly significant effect of ASA (p < 0.001) and
dipyridamole (p < 0.01) for preventing TIA. The risk reduction for the combination was 36% (p < 0.001) in comparison with placebo.
Headache was the most common adverse event, occurring more frequently in
dipyridamole-treated patients. All-site
bleeding and gastrointestinal
bleeding were significantly more common in patients who received ASA in comparison to placebo or
dipyridamole. We conclude that (1) ASA 25 mg twice daily and
dipyridamole, in a modified-release form, at a dose of 200 mg twice daily have each been shown to be equally effective for the
secondary prevention of
ischemic stroke and TIA; (2) when co-prescribed the protective effects are additive, the combination being significantly more effective than either agent prescribed singly; (3) low-dose ASA does not eliminate the propensity for induced
bleeding.