Ticlopidine. Dipyridamole. Clopidogrel

Ticlopidine

The other antiplatelet agent that has proven efficacy in stroke prevention is ticlopidine. In the Canadian American Ticlopidine Study, ticlopidine was compared to placebo after a completed non-cardioembolic stroke among 1053 patients. Ticlopidine resulted in a 23% risk reduction in an intention-to-treat analysis and a 30% reduction in the efficacy analysis. The risk reduction for nonfatal or fatal recurrent stroke was 33%. In the Ticlopidine Aspirin Stroke Study, ticlopidine was compared to aspirin (1300 mg/day) among 3069 patients with TIA or minor stroke. Overall, there was a 12% reduction in stroke or death at 3-years, but a 47% risk reduction in fatal or non-fatal stroke was observed during the first year for those treated with ticlopidine compared to aspirin. Benefits were found both among men and women and the effect was observed in the subgroup with minor stroke.

Dipyridamole

Trials using other antiplatelet agents, such as sulfinpyrazone and suloctidil, have not been as effective as aspirin or have not demonstrated any added benefit to aspirin alone. Dipyridamole was not thought to have any added benefit to aspirin based on the French AICLA trial, however results from the European Stroke Prevention Stroke Study II have indicated that 200 mg BID of modified-release Dipyridamole was more effective than Aspirin (25 mg BID) in the prevention of stroke, myocardial infarction and vascular death after TIA or minor stroke. In this trial 6602 patients were randomized in a factorial design, 76% with stroke and 24% with TIAs. Primary endpoints were stroke, death, and stroke or death together. Patients were followed for 2 years. The relative risk reduction of stroke was 18% for aspirin, 16% for dipyridamole, and 37% for the combination of the two. The relative risk reduction of stroke or death was 13% for aspirin, 15% for dipyridamole, and 24% for the combination of the two. Factorial analysis also demonstrated a highly significant effect of ASA and dipyridamole for preventing TIA. Headache was the most common adverse event and occurred more frequently in the dipyridamole group. Bleeding and GI hemorrhage was more common in patients taking ASA compared to placebo or dipyridamole. The combined long-acting formulation is not yet available or approved in the U.S.

Clopidogrel

Clopidogrel, a thienopyridine derivative similar to ticlopidine, is a new antiplatelet agent which is an inhibitor of platelet aggregation induced by adenosine diphosphate. This agent at a dose of 75 mg BID was recently compared to aspirin (325 mg per day) in reducing the risk of ischemic stroke, myocardial infarction, or vascular death among patients with atherosclerotic vascular disease. Nearly 20,000 patients with stroke, MI, or peripheral vascular disease were recruited over 3 years with a mean follow-up of 1.9 years. Patients treated with clopidogrel had a 5.32% risk of stroke, MI, or vascular death compared to 5.83% with ASA (p=.043). Among the stroke subgroup, there was a nonsignificant reduction from 7.71% to 7.15% in outcome events, however the number of non-fatal strokes were reduced from 322 to 298 with clopidogrel. The most significant effects were observed for the subgroup with PAD. Among patients with PAD or stroke with a prior history of MI, the event rate reduced from 10.74% to 8.35% with clopidogrel (relative risk reduction of 22.7%). The medicine was safe and was not associated with an increased risk of neutropenia. The drug is now FDA approved.

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