Clopidogrel Plus Aspirin After Transient Ischemic Attack
Abstract & Commentary
Source: Wang Y, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013;369:11-19.
Transient ischemic attacks (TIAs) and minor strokes are often the harbingers of a large, debilitating stroke. Approximately 10% of patients experiencing a TIA will go on to have a large stroke within the next 3 months, with most of these events occurring early. Aspirin reduces the early risk of recurrent stroke in such patients. Clopidogrel, on the other hand, has been tested in patients with large stroke and does not reduce the risk of recurrent stroke, but actually increases bleeding. However, clopidogrel in addition to aspirin has not been tested in TIA and minor stroke, a population of patients who are at high risk for major stroke over a short period of time, but are at lower risk of intracerebral hemorrhage. Accordingly, Wang and colleagues performed a multicenter, randomized, controlled trial of aspirin plus placebo vs aspirin plus clopidogrel in patients presenting with TIA or minor stroke. Their primary endpoint was the rate of stroke at 90 days.
The Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study was sponsored by the Chinese government and was performed in 114 centers in China. After screening more than 41,000 patients, 5170 patients presenting with TIA symptoms of less than 24 hours duration were enrolled. Using the NIH stroke scale and the ABCD scale, they included only those with minor deficits, but at high risk for future large stroke. They excluded patients with hemorrhage or other intracranial pathology on initial CT or MRI scan, those with only sensory symptoms (to avoid enrolling patients with other potential causes such as migraine), those with a clear need for anticoagulation (such as atrial fibrillation or prosthetic valve), patients at high risk for bleeding (such as recent gastrointestinal bleed), and those undergoing surgery or angioplasty. All patients received open-label aspirin on admission 75-300 mg, with the dose left to the discretion of the treating physician. Patients were randomized to the aspirin group (n = 2586; aspirin 75 mg daily from days 2-90) or to the aspirin plus clopidogrel group (n = 2584; clopidogrel loading dose 300 mg followed by 75 mg daily from days 2-90, plus aspirin 75 mg daily on days 2-21 followed by placebo aspirin from days 22-90). The groups were well matched in their baseline characteristics.
The primary outcome, stroke, was less frequent in the clopidogrel plus aspirin group compared to the aspirin alone group (8.2% vs 11.7%; hazard ratio [HR] 0.68; P < 0.001). The difference between groups was driven by a reduction in ischemic strokes, and there was no difference in the rate of hemorrhagic stroke (eight patients [0.3%] in each group; P = NS). Importantly, the benefit was seen within the first few days and the curves remained separated thereafter. The number needed to treat to prevent one stroke was 29. The benefits were consistent across all major subgroups. Analysis of secondary endpoints showed no difference in the rate of death (0.4% in each group), vascular death (0.2%), or recurrent TIA (1.2% vs 1.8%, P = NS). There was no difference between groups in moderate or severe hemorrhage (0.3%), but there was a trend toward a higher rate of any bleeding event in the clopidogrel plus aspirin group (2.3% vs 1.6%, P = 0.09). The authors conclude that among patients with TIA or minor stroke who can be treated within 24 hours after the onset of symptoms, the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first 90 days and does not increase the risk of hemorrhage.
Commentary
This interesting study shows that clopidogrel in addition to aspirin early after the onset of TIA or minor stroke reduces the risk of subsequent stroke. This is not consistent with the lack of benefit of clopidogrel that is seen in trials enrolling patients with larger stroke. Most likely, the disparity between the current study and prior trials is because the patients in this trial had smaller areas of brain infarction and were, therefore, less likely to develop hemorrhagic transformation. In addition, patients were enrolled very early after symptom onset in this study (median 13 hours). The study is strengthened by its rigorous design, independent blinded clinical events committee, and lack of industry involvement. However, there are several limitations that should be acknowledged. First, this was conducted solely in China. Chinese patients have higher rates of polymorphisms of the cytochrome P450 system that metabolizes clopidogrel. Therefore, their response to this drug may be different than those of other ethnicities. Second, these data should not be extrapolated to those suffering major stroke, as they have been shown to fare worse with clopidogrel. Third, those with less specific symptoms, such as vertigo or sensory symptoms, and those with lower risk of recurrence based on the ABCD scale may not benefit to the same extent. Fourth, the loading dose of clopidogrel was 300 mg; perhaps a 600 mg loading dose may result in more pronounced early benefit. In the light of the CHANCE trial data, it is reasonable to treat patients of Chinese origin presenting with high-risk TIA with a combination of aspirin and clopidogrel for 90 days. There are ongoing large, randomized trials of dual antiplatelet therapy in patients with TIA that should help refine which populations stand to benefit most from the addition of clopidogrel to aspirin, and whether higher loading doses add incremental benefit, in patients with TIA and minor stroke.
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