Clinical Question

Does adding clopidogrel (Plavix) to aspirin following a transient ischemic attack (TIA) or minor stroke safely improve outcomes?

Bottom Line

This study provides support for a strategy of adding clopidogrel to aspirin for the first week or so after a minor ischemic stroke or TIA because this is when the greatest benefit occurs. Harms were spread fairly evenly throughout the study period. (Level of Evidence = 1b)

Synopsis

The CHANCE trial was a Chinese study that found improved outcomes with no increase in bleeding risk for patients with minor ischemic stroke or TIA who were given aspirin plus clopidogrel for three weeks. This current study broadens the population to include non-Chinese patients, uses a higher loading dose of clopidogrel (600 mg instead of 300 mg), and continues the combined clopidogrel plus aspirin for 90 days. The investigators identified patients with a minor stroke (National Institutes of Health Stroke Scale score of 1 to 3 points) or high-risk TIA (ABCD2 score of at least 4 points) and randomized them to receive either aspirin alone or a 600-mg loading dose of clopidogrel, then 75 mg clopidogrel daily plus aspirin. The aspirin dose varied by site from 50 mg to 325 mg per day based on physician preference, but the recommended dosage was 162 mg daily for five days, followed by 81 mg daily. All patients were recruited within 12 hours of symptom onset. The primary outcome was a composite of ischemic stroke, myocardial infarction, or vascular death, and the secondary outcome was recurrent ischemic stroke within 90 days. A total of 4,881 patients were recruited and randomized, but the trial was stopped early because it reached a prespecified level of increased intracranial hemorrhage. Rates of loss to follow-up were similar between groups (6% to 7%) and more than one-fourth of patients in each group stopped taking the study medication prematurely. The mean age of participants was 65 years, 45% were women, 20% were black, 43% had a TIA, and 57% had a minor stroke. At the end of the 90-day study period, there was no difference in the likelihood of vascular death, myocardial infarction, or all-cause mortality between groups. Although the composite outcome was less common with clopidogrel, this was due to a reduction in ischemic stroke only. Patients who received both clopidogrel and aspirin were less likely to have an ischemic stroke (4.6% vs. 6.3%; P = .01; number needed to treat [NNT] = 59) but were more likely to experience a major hemorrhage (0.9% vs. 0.4%; P = .01; NNT = 200); most of the difference in the latter outcome was due to noncerebral hemorrhages. The excess strokes in the aspirin-only group largely occurred in the first week, whereas hemorrhagic events occurred throughout the study period.

Study design: Randomized controlled trial (double-blinded)

Funding source: Government

Allocation: Concealed

Setting: Outpatient (any)

Reference: Johnston SC, Easton JD, Farrant M, et al.; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379(3):215–225.

Editor's Note: Dr. Ebell is Deputy Editor for Evidence-Based Medicine for AFP and cofounder and Editor-in-Chief of Essential Evidence Plus, published by Wiley-Blackwell.