Preventing recurrent ischemic stroke: A 3-step plan
To prevent recurrent stroke, address the patient’s risk factors, clear stenosis, and thin the blood
Aspirin is the most commonly prescribed drug for prevention of secondary stroke. Yet, despite 21 randomized clinical trials involving more than 18,000 participants, consensus is lacking on many aspects of using aspirin for stroke prevention. In a meta-analysis of trials enrolling patients with previous TIA or stroke, treatment with antiplatelet agents compared with control reduced the rate of subsequent non-fatal stroke from 10.8% to 8.3%.42
Aspirin has significant gastrointestinal (GI) toxicity and causes GI bleeding.43 The relative risk of developing peptic ulcer is 1.3, and symptoms of upper gastrotoxicity may cause withdrawal from aspirin treatment.43 Hemorrhagic stroke increases with aspirin use, but for patients at risk for secondary ischemic stroke, aspirin’s antithrombotic benefit outweighs the increased risk of hemorrhagic stroke (or GI toxicity).44
Aspirin dosing is controversial despite a large number of randomized, controlled trials. Faced with the same published papers and involvement in many of the same studies worldwide, experts fail to reach consensus on an optimal dose between 30 mg and 1500 mg. When aspirin is the antiplatelet drug of choice, absent data to show that higher dosing provides greater benefit, it is reasonable to use daily doses between 50 mg and 325 mg.
Ticlopidine. Ticlopidine is a thienopyridine derivative that irreversibly inhibits platelet aggregation by blocking the adenosine diphosphate (ADP) receptor, and it requires metabolism in the liver for this activity to take place. Ticlopidine, given 250 mg twice a day, inhibits platelet function within 24 to 48 hours of administration, peaks at 3 to 7 days, and lasts for the lifespan of the platelet.45 Bleeding time is doubled and remains prolonged for 4 to 10 days after the last dose.
The Ticlopidine Aspirin Stroke Study (TASS) examined the effects of ticlopidine 500 mg versus aspirin 1300 mg on the risk of stroke or death in 3069 patients with recent ischemic events. Ticlopidine was more effective than aspirin in reducing the risk of death from any cause or nonfatal stroke.46 The risk of fatal or nonfatal stroke was reduced by 21% compared with aspirin.46
Subgroup analysis of TASS suggested a more favorable benefit-to-risk ratio for nonwhite patients compared with white patients.47 In an attempt to validate this subgroup analysis, a second study, the African American Antiplatelet Stroke Prevention Study (AAASPS), randomized 1809 black patients with recent noncar-dioembolic stroke to receive ticlopidine 500 mg/d or aspirin 650 mg/d, and followed them for 2 years. The researchers reported no difference between the agents in the prevention of recurrent stroke, MI, or vascular death.48
Unfortunately, the clinical usefulness of this compound is limited by side effects. Diarrhea and skin rash, the most common side effects, were usually relieved by a temporary reduction in dose. However, severe reversible neutropenia occurred in nearly 1% of patients.46 Potentially life threatening thrombotic thrombocytopenic purpura has also been associated with ticlopidine. The potential for a serious adverse event requires that patients be carefully monitored during the first 3 months of treatment.46 This side effect profile makes ticlopidine a poor choice as a first line drug for secondary stroke prevention.
Clopidogrel. Like ticlopidine, clopidogrel is a thienopyridine derivative and blocks the ADP receptor. Clopidogrel’s antiplatelet effect is dose-related, with 75 mg causing prolongation of bleeding time roughly equivalent to 500 mg of ticlopidine. After a loading dose of 300 mg, the onset of action is about 2 to 5 hours, and peak platelet inhibition occurs between 3 and 7 days. Like ticlopidine, bleeding time remains prolonged for 4 to 10 days after the last dose.
The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial evaluated clopidogrel (75 mg once daily) versus aspirin (325 mg once daily) in reducing the risk of the combined outcome of ischemic stroke, MI, or vascular death in more than 19,000 patients who entered the trial with recent ischemic stroke, recent MI, or symptomatic peripheral vascular disease.49 A modest but statistically significant relative risk reduction of 8.7% was found for clopidogrel over aspirin (95% CI, 0.3–16.5; P=.043). For the subgroup of patients entering the trial with stroke, there was a risk reduction of 7.3% favoring clopidogrel, but this did not reach statistical significance (95% CI, –5.7 to 18.7; P=.26).
The main adverse events experienced by patients taking clopidogrel were diarrhea and rash. Patients taking aspirin experienced gastrointestinal discomfort and, more seriously, a small but statistically significant increase in gastrointestinal hemorrhage.49
The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial examined the effects of clopidogrel plus aspirin compared with aspirin alone on the combined end point of: (1) cardiovascular death, MI, or stroke; and (2) cardiovascular death, MI, stroke, or refractory ischemia in 12,562 patients with an acute coronary syndrome without ST segment elevation.50 Combination antiplatelet therapy demonstrated a relative risk reduction of 20% (95% CI, 0.72–0.90; P<.001; absolute risk reduction [ARR]=2.1%) and 16% (95% CI, 0.79–0.94; P<.001; ARR=2.3%) for the 2 primary endpoints compared with aspirin alone. Major bleeding was significantly more common in the clopidogrel plus aspirin group (relative risk increase of 38%; 95% CI, 1.13–1.67; P=.001; absolute risk increase =1%).
