Dual Antiplatelet Therapy for Prevention of Recurrent Ischemic Events

Jean Nappi, PharmD, Fccp, Bcps; Robert Talbert, PharmD, Fccp, Bcps

Disclosures

Am J Health Syst Pharm. 2002;59(18) 

In This Article

Efficacy of Antiplatelet Monotherapy In The Prevention of Recurrent MI and Stroke

The efficacy of aspirin in the secondary prevention of MI and stroke has been demonstrated in the Antiplatelet Trialists' Collaboration (ATC) metaanalysis[44] and several large-scale clinical trials including the International Stroke Trial (IST),[45] the Chinese Acute Stroke Trial (CAST),[46] and the Second International Study of Infarct Survival (ISIS-2).[47] The ATC analysis examined the effect of prolonged (more than one month) antiplatelet therapy (mostly with aspirin) on patients versus controls among 70,000 high-risk patients in 145 randomized trials.[44] High-risk patients were defined as those with vascular disease or another condition implying an increased risk of occlusive vascular disease. MI, stroke, or vascular death occurred in 11.4% of patients receiving antiplatelet therapy and 14.7% of controls (27% odds reduction, 2p < 0.00001). When aspirin therapy was analyzed separately, the odds reduction was 25% more than the control group. Similar odds reductions were seen in ISIS-2 in which a 30% reduction of vascular mortality, nonfatal reinfarction, and nonfatal stroke occurred in patients with a suspected acute MI receiving aspirin for five weeks.[47] Data from IST showed that early initiation of aspirin (median time to randomization, 19 hours) in 19,435 patients with acute stroke reduced both the risk of stroke recurrence and mortality.[45] In CAST, 21,106 patients with acute ischemic stroke were randomized to either aspirin therapy (160 mg/day) or placebo for up to four weeks.[46] Results showed a 14% reduction in mortality (2p = 0.04) during the treatment period and significantly fewer recurrent ischemic strokes in the aspirin group (2p = 0.01).

Other trials, including the Swedish Aspirin Low-Dose Trial (SALT),[48] the United Kingdom Transient Ischemic Attack (UK-TIA) trial,[49] and the Dutch TIA trial[50] have provided support for the efficacy of aspirin in reducing recurrent vascular events in patients with a history of stroke or TIA. Equally important was the wide range of aspirin dosages used in these trials. SALT showed an 18% reduction in stroke or death with aspirin 75 mg/day versus placebo.[48] UK-TIA found a 15% reduction in the risk of major stroke, MI, or vascular death in 2435 patients treated with 300 or 600 mg/day of aspirin or placebo.[49] Although high doses of aspirin might adversely affect prostacyclin production, there was no significant difference in efficacy between the two aspirin doses, but there was a direct relationship between gastrointestinal (GI) hemorrhage and the higher dose of aspirin. The Dutch TIA trial found no significant difference in efficacy between 30 and 283 mg/day of aspirin in reducing the number of deaths from vascular causes, nonfatal stroke, or nonfatal MI in 3131 patients with a recent TIA or minor stroke.[50] As in the UK-TIA trial, the higher dose of aspirin was associated with more GI bleeding and discomfort.

Dipyridamole

When dipyridamole was used as monotherapy in 1474 patients in 10 trials included in the ATC, it was not associated with a greater odds reduction in the development of MI, stroke, or vascular death than aspirin (dipyridamole, 23% versus aspirin, 25%).[44] Although dipyridamole has not been recommended as monotherapy in the secondary prevention of ischemic events,[43] it is currently indicated in package labeling as an adjunct to anticoagulation in the prevention of postoperative thromboembolic complications after cardiac valve replacement[51] and in its extended-release form in combination with aspirin for recurrent stroke prevention.[5,52] However, this formulation did not decrease the frequency of MI as seen in the second European Stroke Prevention Study (ESPS-2).[53]

The ADP receptor antagonists ticlopidine and clopidogrel are a relatively new class of antiplatelet agents. When these agents were compared with aspirin in a systematic review of four randomized controlled trials (n = 22,656) involving patients with a history of recent ischemic stroke or TIA, recent MI, or symptomatic PAD, a modest but significant reduction (9%) in the odds of developing acute MI, stroke, or vascular death was shown with the ADP receptor antagonists.[54] Ticlopidine was associated with a higher rate of neutropenia than aspirin. The investigators concluded that clopidogrel is an appropriate alternative to aspirin since it is at least as safe as aspirin and safer than ticlopidine. This preference for clopidogrel over ticlopidine in the management of recent MI, stroke, and TIA is consistent with the recommendations from the American College of Chest Physicians and the American Heart Association Stroke Council.[5,55]

Clinical trials of ticlopidine in patients with recent stroke or TIA found a significant reduction in the frequency of recurrent vascular complications. In two trials involving patients with cerebrovascular disease (Canadian American Ticlopidine Study [CATS][56] and Ticlopidine Aspirin Stroke Study [TASS][57] ), relative-risk reductions of 10.8% (p = 0.006) and 12% (p = 0.048), respectively, were noted for the combined outcome of first recurrent atherothrombotic event (MI or stroke in CATS; nonfatal stroke in TASS) and vascular death versus placebo or aspirin, respectively. Significant reductions (46.3%) (p = 0.009) in vascular death and nonfatal MI were seen in 652 patients with unstable angina treated with ticlopidine and conventional therapy.[58]

The Study of Ticlopidine versus Aspirin after Myocardial Infarction (STAMI) trial showed no difference between ticlopidine (500 mg/day) and aspirin (160 mg/day) in the combined primary endpoints of death, recurrent AMI, stroke, and angina in 1470 post-AMI patients.[59]

The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial found an 8.7% relative-risk reduction (5.32% versus 5.83%) in the composite endpoint of ischemic stroke, MI, and vascular death in favor of clopidogrel versus aspirin (p = 0.043) in patients with a recent ischemic stroke, recent MI, or established PAD.[60] An additional analysis across all patient subgroups found a 19.2% reduction (p = 0.008) in the relative risk of MI alone in patients using clopidogrel.[61] Although not powered to detect the effect of treatment in specific subgroups, patients with established PAD were most likely to benefit from clopidogrel therapy.[60] Overall, adverse events were similar in both groups. Clopidogrel was associated more often with severe rash (0.26% versus 0.10%) (p = 0.017) and severe diarrhea (0.23% versus 0.11%) (p = 0.080) compared with aspirin therapy. Severe upper GI hemorrhage was more frequent with aspirin (0.71%) than with clopidogrel (0.49%) (p = 0.05).

Table 1 and Table 2 summarize the trials discussed above and additional studies evaluating the efficacy of antiplatelet agents for secondary prevention of ischemic events in patients with stroke or MI.

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