Adding clopidogrel (Plavix) to aspirin therapy in the immediate days following a minor stroke prevented more ischemic events, but at the cost of increased bleeding risk, a randomized trial suggested.
After minor ischemic stroke or high-risk transient ischemic attack (TIA), dual antiplatelet therapy (DAPT) with clopidogrel and aspirin had a 5.0% rate of major ischemic events at 90 days, combining ischemic strokes, MIs, and deaths from ischemic vascular events.
This was significantly less than the 6.5% rate on aspirin and placebo (HR 0.75, 95% CI 0.59 to 0.95), with the difference driven by ischemic stroke, according to a group led by S. Claiborne Johnston, MD, PhD, of the University of Texas at Austin.
Findings from their Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial were presented at the European Stroke Organisation Conference in Gothenburg, Sweden, and simultaneously published online in the New England Journal of Medicine.
Major ischemic events that did occur tended to manifest during the first week after the initial stroke or TIA. Major hemorrhage, on the other hand, was a greater risk with DAPT throughout 90-day follow-up (0.9% versus 0.4% for aspirin alone, HR 2.32, 95% CI 1.10 to 4.87).
“It is not possible to make direct comparisons between clinical and safety outcomes because disability due to each of the outcomes cannot be ascertained, but we estimate that for every 1,000 patients who are treated with clopidogrel plus aspirin during a period of 90 days, such treatment would prevent approximately 15 ischemic events and would cause five major hemorrhages,” Johnston and colleagues said.
POINT reinforces the finding from CHANCE, a Chinese study, that clopidogrel plus aspirin is associated with lower ischemic risk than aspirin alone. However, CHANCE did not find a higher rate of bleeding with the combination.
“The CHANCE trial used a lower loading dose of clopidogrel, but this is an unlikely explanation for the difference, since most bleeding events in the POINT trial occurred long after the loading dose,” James Grotta, MD, of Memorial Hermann Hospital in Houston, noted in an accompanying editorial.
“More likely, the difference was due to a shorter duration of combined treatment (only 21 days in the CHANCE trial versus 90 days in the POINT trial) and differences in the metabolism of clopidogrel in Asian versus non-Asian persons,” he suggested.
Based on the literature, Grotta suggested that it is reasonable to give DAPT in the first 3 weeks after a TIA or minor stroke and then transition patients to monotherapy — that is, if patients can adhere to therapy and are not at increased risk of bleeding.
POINT investigators randomized adults to aspirin plus either placebo or clopidogrel, the latter at a loading dose of 600 mg on the first day and 75 mg daily thereafter. In total, 4,881 people were enrolled from 269 international sites before the study was stopped early for efficacy. The data and safety monitoring board decided that the population was large enough to show that DAPT was associated with both fewer major ischemic events and a higher risk of major hemorrhage than aspirin alone.
Enrollment required randomization within 12 hours of acute ischemic stroke (a score of 3 or less on the NIH Stroke Scale) or TIA (scoring 4 or higher on the ABCD scale), CT or MRI to rule out intracranial bleeding, and no contraindications to the medications.
Johnston and colleagues noted that POINT is not necessarily generalizable to excluded groups, including patients with moderate-to-severe stroke, cardioembolic stroke, or those who are candidates for thrombolysis or thrombectomy.
Another caveat was the discontinuation of assigned medication by 29.6% of DAPT and 27.5% of aspirin-only group patients.
But because the results were similar in both intention-to-treat and as-treated analyses and with only 4% of patients being lost to follow-up, the POINT study still seems generally valid and generalizable, according to Grotta.
