Antiplatelet Agents for Stroke Prevention

Many clinical trials of secondary prevention have evaluated the benefit of long-term use of anti-platelet drugs in reducing the risk of stroke. The Antiplatelet Trialists’ Collaboration (1994), in a meta-analysis of 142 trials, showed that anti-platelet drugs (aspirin, dipyridamole, sulfinpyrazone, suloctidil and ticlopidine) reduced the incidence of a composite outcome of ischemic stroke, myocardial infarction, and vascular death [1]. The calculated risk reduction of vascular events provided by anti-platelet-aggregating drugs is approximately 27% both among patients with all types of vascular disease and in patients who have had a recent transient ischemic attack (TIA) or minor stroke. In the analyses of 17 trials among persons with a past history of stroke or TIA, the Antiplatelet Trialists’ Collaboration Group reported an odds reduction of 22% for nonfatal stroke, nonfatal myocardial infarction or vascular death with a 2-year risk of 18% for those treated with anti-platelets and 22% for controls. In this meta-analysis, aspirin was the most widely used agent [1, 2].In 1953 a general practitioner, Craven [3], found that ingestion of 12 aspirin tablets daily resulted in spontaneous nose bleeding. After this observation, several studies dealt with the action of aspirin on platelet aggregation [4, 5, 6, 7, 8].Aspirin blocks the active site of cyclooxygenase, the enzyme that produces the cyclic endoperoxidase precursor of thromboxane A2. This action of aspirin on platelet cyclooxygenase is permanent and persists for the life span of the platelet [9, 10]. To maintain suppression of the cyclooxygenase activity, daily doses of 30–50 mg aspirin are sufficient to acetylate the new platelets that are released each day [10, 11].In 1971 and 1972 anecdotal observations found a positive effect of aspirin in patients with amaurosis fugax [12, 13]and in 1978 in the first large controlled clinical trial, the Canadian Cooperative Study Group showed 1,300 mg of aspirin to be protective against vascular events in patients with TIA or minor stroke [14]. After these results, several clinical trials followed. Meta-analyses of these trials in which aspirin has been tested against placebo in patients with recent TIA or minor ischemic stroke have shown aspirin to reduce the risk of future vascular events by 20–25%. Aspirin, given to TIA or ischemic stroke patients, in doses above 75 mg daily reduces the relative risk of stroke and other important vascular events by about 13% [15].What Is the Optimum Dose of Aspirin? The optimum dose of aspirin in stroke prevention is not known. No adequate trials have been conducted with direct dose comparisons [16]. In a meta-analysis, the overall reduction in the relative risk associated with high-dose aspirin was 11% for stroke and 9% for stroke or vascular death. The overall reduction in the relative risk associated with low-dose aspirin was 15% for stroke and 13% for stroke or vascular death [17]. There is an international discussion in different areas of stroke prevention regarding the optimal dose of aspirin. Whereas European experts only exceptionally (2%) prescribe aspirin doses >500 mg, 36% of the American clinicians prefer a dose of >500 mg. In contrast, doses < 200 mg daily are used by 57% European clinicians but only 2% of their American colleagues [18]. At present there is no compelling evidence that higher or lower doses are more efficacious [19].When to Start the Treatment with Aspirin? A meta-analysis of the results of IST (International Stroke Trial) [20], CAST (Chinese Acute Stroke Trial) [21]and MAST-I (Multicenter Acute Stroke Trial-Italy) [22]showed a statistically significant effect of early aspirin treatment and suggests that aspirin should be started as soon as possible after the onset of ischemic stroke [23]. Ticlopidine is a thienopyridine that inhibits ADP-dependent activation of the glycoprotein (GP)IIb/IIIa platelet receptor for fibrinogen binding platelet aggregation [24]without direct effects on arachidonic acid metabolism [25]. Because ADP is widely involved in the early phase in most pathways of activation that enable platelets to bind fibrinogen, ticlopidine has much broader inhibitory effects on platelet function than aspirin [26, 27].Several clinical trials have shown that ticlopidine has a place in secondary prevention of stroke. In the Canadian-American Ticlopidine Study, CATS [28], a randomized, placebo-controlled trial that compared the benefit of 500 mg ticlopidine to placebo, for the primary end points (nonfatal stroke, myocardial infarction, or vascular death), the event rate per year was 15.3% in the placebo group and 10.8% in the ticlopidine group (relative risk reduction 30.2%; 95% confidence interval, CI, 7.5–48.3, p = 0.006). For the secondary end points (fatal and nonfatal stroke) the on-treatment risk reduction of ticlopidine was 33.5%. An adverse experience at any time was reported in 54% of patients in the ticlopidine group and 34% in the placebo group, and severe events were reported in 8.2 and 2.8%, respectively. The most important side effects were diarrhea, rashes, and neutropenia. In the Ticlopidine-Aspirin Stroke Study, TASS [29], designed to test the beneficial and adverse effects of ticlopidine (250 mg twice daily) compared to aspirin (650 mg twice daily), considering an intention-to-treat analysis, the 3-year event rate for primary end points (death or non-fatal stroke) was 17% for ticlopidine and 19% for aspirin (risk reduction of ticlopidine compared to aspirin 12%; 95% CI 2–26%). In an on-treatment analysis of the data which included eligible patients who received at least one dose of the drug, ticlopidine produced a 47.6% risk reduction compared with aspirin for fatal or non-fatal stroke during the 1st year of treatment [30]. In the ticlopidine group, the incidence of neutropenia was 2.4%, and 0.8% of patients experienced severe neutropenia (absolute neutrophil count ≤450 cells/mm3).Ticlopidine is effective for the prevention of recurrent TIA and stroke but there were potentially serious adverse effects which have clearly limited the development of this drug in the clinical setting. These considerations certainly justify the development of new anti-platelet agents.Clopidogrel is a new anti-platelet drug chemically related to ticlopidine with a greater activity in animal models of thrombosis [31]. Like ticlopidine, clopidogrel inhibits platelet activation and aggregation by antagonizing the platelet ADP receptor [32]. CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events [33]) was a randomized, blinded, international trial designed to assess the relative efficacy of clopidogrel and aspirin in reducing the risk of the outcome cluster of ischemic stroke, myocardial infarction, or vascular death, as well as to assess their relative safety. The intention-to-treat analysis showed that the relative risk reduction was 8.7% (95% CI 0.3–16.5, p = 0.043) in favor of clopidogrel from an overall annual event rate of ischemic stroke, myocardial infarction, or vascular death, ranging from 5.83% in the aspirin group to 5.33% in the clopidogrel group. In terms of ‘number needed to treat’, 11 patients would have to be treated with clopidogrel instead of aspirin, for 3 years, to prevent one major vascular event [34]. Although CAPRIE was not powered to demonstrate risk reduction in specific qualifying condition, it is interesting to emphasize that in patients randomized for stroke, the average event rate per year in the clopidogrel group was 7.15% compared with 7.71% in the aspirin group, with a relative risk reduction of 7.3% (95% CI 5.7–18.7) in favor of clopidogrel [34, 35]. The percentage of adverse events (upper gastrointestinal discomfort, abnormal liver function, intracranial hemorrhage, gastrointestinal hemorrhage, skin rash, and diarrhea) reported was higher in the aspirin group for all categories except for rash and diarrhea. There were 0.10% of patients in the clopidogrel group with significant neutropenia and 0.17% in the aspirin group. Among these patients, the neutrophil count fell below 0.45 × 109/l for 5 patients in the clopidogrel group (0.05%) and 4 patients in the aspirin group (0.04%). There are no studies which directly compare the clinical efficacy and safety of ticlopidine and clopidogrel, but TASS and CAPRIE suggest that both anti-platelet agents are slightly more effective than aspirin in secondary stroke prevention [36]. CAPRIE shows that clopidogrel is devoid of the hematological toxicity of ticlopidine, and other side effects of ticlopidine (rash and diarrhea) were less frequent with clopidogrel. From the medical point of view, the conclusion that clopidogrel is either as good as or better than aspirin may justify its use as a suitable therapy in stroke prevention, but the daily cost of clopidogrel in the United States is $2.40 in comparison with a cost of $0.17 for aspirin, and for many physicians this difference will be critical in making a decision [37].Dipyridamole interferes with platelet function by inhibiting the phosphodiesterase enzyme that degrades cyclic adenosine monophosphate (AMP) to 5′-AMP [38]. The European Stroke Prevention Study 2, ESPS-2 [39], comparing aspirin 25 mg and dipyridamole 200 mg twice per day with aspirin alone showed better results for the combination (18% relative risk reduction for stroke in the aspirin group, 16% in the dipyridamole group, and 37% in the aspirin plus dipyridamole group). For many clinicians, the superiority of the combination of dipyridamole and aspirin over aspirin alone must be confirmed by other studies, because the dose of aspirin used in ESPS-2 was much lower than doses they currently use, and all previous trials with the combination of aspirin and dipyridamole versus aspirin showed no benefit of adding dipyridamole to aspirin [35]. Moreover, the encouraging news in the ESPS-2 results was soured by data problems discovered during the study [40]. When the ESPS-2 data are aggregated in a meta-analysis with the previous trials of dipyridamole combined with aspirin alone, the combination reduces the risk of stroke by 23% over aspirin alone. Excluding ESPS-2 results, the combination reduces the risk by 12%. The authors of this meta-analysis conclude that another randomized clinical trial showing a significant benefit of the combination of dipyridamole plus aspirin over aspirin alone may be needed before the addition of dipyridamole to aspirin is widely accepted for prevention of stroke [41].GP IIb/IIIa serves as a receptor on platelets that binds plasma-borne adhesive proteins, such as fibrinogen and von Willebrand factor, to permit platelet aggregation [42, 43]. Agents that block this final common pathway by blocking the binding of adhesive proteins to GP IIb/IIIa, termed GP IIb/IIIa antagonists (abciximab, tirofiban, eptifibatide, lamifiban, lotrafiban, xemilofiban), are currently considered the most powerful specific inhibitors of platelet participation in acute thrombosis [43, 44]. Abciximab, eptifibatide, and tirofiban have received US Food and Drug Administration approval for use in patients with unstable angina pectoris undergoing percutaneous coronary intervention [45, 46]. In stroke prevention there are no final data. BRAVO (Blockage of the GP IIb/IIIa Receptor to Avoid Vascular Occlusion) is an ongoing trial with lotrafiban per os.Aspirin is usually the first choice in secondary stroke prevention. The optimal dose is not known: we prefer 100–325 mg daily. Aspirin should be started as soon as possible after the onset of ischemic stroke. The first alternative in patients who are either intolerant of aspirin therapy or who are considered as a treatment failure will be clopidogrel because its safety profile is better than that of ticlopidine. Before the addition of dipyridamole to aspirin we need another randomized clinical trial showing a significant benefit of the combination of dipyridamole plus aspirin versus aspirin alone. New approaches with oral GP IIb/IIIa antagonists, and new combinations of anti-platelet agents with different mechanisms of action may also be promising and should be evaluated in clinical trials.

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