Transient ischemic attack (TIA) and acute minor ischemic stroke are common and often lead to disabling events. In China, there are approximately 3 million new strokes every year, and approximately 30% of them are minor ischemic strokes.1,2 The incidence of TIA in China has not been determined, but on the basis of the incidence in other countries, there are probably more than 2 million TIAs annually in China.3-5 The risk of another stroke occurring after a TIA or minor stroke is high, with approximately 10 to 20% of patients having a stroke within 3 months after the index event; most of these strokes occur within the first 2 days.5-8
The role of antiplatelet therapy for secondary stroke prevention has been well established. However, aspirin is the only antiplatelet agent that has been studied in the acute phase of stroke, during which its benefit is modest.9,10 Aspirin and clopidogrel synergistically inhibit platelet aggregation,11,12 and such dual therapy reduces the risk of recurrent ischemic events in patients with the acute coronary syndrome.13,14 Large-scale trials of secondary prevention of ischemic events after stroke have not shown a benefit of the combination of clopidogrel and aspirin.15-17 However, these trials did not study the early, high-risk period after stroke, they included some patients with strokes of moderate severity, and they included few if any patients with TIA. Three small pilot trials have shown trends toward a benefit of the combination therapy and minimal safety concerns in patients with minor stroke or TIA.18-20
We conducted the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial to test the hypothesis that 3 months of treatment with a combination of clopidogrel and aspirin would reduce the risk of recurrent stroke, as compared with aspirin alone, among patients with acute high-risk TIA or minor ischemic stroke.
In this large-scale trial involving patients with high-risk TIA or minor ischemic stroke, we found that the addition of clopidogrel to aspirin within 24 hours after symptom onset reduced the risk of subsequent stroke by 32.0%, as compared with aspirin alone. Event rates during this early period were very high, and clopidogrel was associated with an absolute risk reduction of 3.5 percentage points, equivalent to a number needed to treat of 29 patients to prevent one stroke over a period of 90 days. Combination therapy with clopidogrel and aspirin, as compared with aspirin alone, was not associated with an increased incidence of hemorrhage, although there was a worrisome trend in overall bleeding toward more events with the combination therapy.
The results of our trial differ from those of other trials of combination therapy with clopidogrel and aspirin after cerebral ischemic events.7,8,17 One possible explanation is that, unlike previous trials, our trial targeted a population at particularly high risk for recurrent ischemia and at low risk for hemorrhage. Previous trials included patients with more severe strokes than our trial did, and they did not enroll patients in the first hours after an index minor stroke or TIA, during which the risk of recurrent ischemia is particularly high. This may explain why other trials did not show a reduction in the risk of ischemic events but did show an increased risk of hemorrhage.
In our study, the curves for survival free of stroke were particularly steep in the first few days, during which the curves representing the treatment groups diverged dramatically. Subsequently, the rates of stroke were similar. This suggests that the requirement for randomization within 24 hours after the onset of symptoms, with nearly half the patients enrolled within 12 hours (and treated shortly thereafter), was important. Although we did not see a relative difference in the efficacy outcome between patients randomly assigned to a study group within 12 hours and those assigned after a longer interval, absolute event rates were higher among those who were enrolled within 12 hours. In clinical practice, treatment with clopidogrel and aspirin as soon as possible after symptom onset is likely to produce the greatest absolute benefit, since ischemic event rates are highest in the initial hours after symptoms appear.
Our trial was conducted entirely in China, a country with approximately 150 to 250 deaths from stroke per 100,000 persons per year, which is five times as high as the rate in the United States.23Although diagnostic tools and therapies commonly used in the United States and Europe are available in most hospitals in China, some patients cannot afford this level of care.24,25 Secondary prevention practices are also less rigorous in China, where rates of treatment of hypertension, diabetes, and hyperlipidemia are low, as shown in our study population (Table S3 in theSupplementary Appendix). Furthermore, the distribution of stroke subtypes in China differs from that in more developed countries; China has a higher incidence of large-artery intracranial atherosclerosis25 and a higher prevalence of genetic polymorphisms that affect the metabolism of clopidogrel.26 The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial (ClinicalTrials.gov number, NCT00991029), sponsored by the National Institutes of Health, which is similar to our trial, is now enrolling patients at sites primarily in the United States.27 The POINT trial is assessing a higher loading dose of clopidogrel (600 mg) and a narrower time window (treatment within 12 hours after symptom onset) than were used in our study.
Several common clinical conditions mimic TIA, including seizures, migraine, peripheral vertigo, syncope, and anxiety.28 To minimize the risk of enrolling patients with TIA mimics, we excluded all patients with isolated sensory symptoms, isolated visual changes, or isolated dizziness or vertigo without evidence of acute infarction on baseline CT or MRI of the head. In addition, enrollment of patients with TIA was limited to those with a high ABCD2 score (≥4) to increase the likelihood that spells were due to true TIAs and to ensure that we were enrolling patients who were at high risk for subsequent ischemic events.29 The risk of subsequent stroke in the trial was high for this patient population, suggesting that our strategy was successful. Our findings may not apply to other populations of patients with ischemic events.
In conclusion, our study shows that among patients with high-risk TIA or minor ischemic stroke who are initially seen within 24 hours after symptom onset, treatment with clopidogrel plus aspirin for 21 days, followed by clopidogrel alone for a total of 90 days, is superior to aspirin alone in reducing the risk of subsequent stroke events. The combination of clopidogrel with aspirin did not cause more hemorrhagic events in this patient population than aspirin alone.