Clopidogrel-Aspirin in Minor Stroke/TIA of Maximum Benefit in First 21 Days

For patients presenting with acute minor stroke or high-risk TIA, the risk-benefit balance when using clopidogrel plus aspirin appears to be greatest in the first 21 days, according to a secondary analysis of the POINT trial.

Compared with aspirin alone, the combination significantly reduces major ischemic events in those initial weeks (HR 0.65; 95% CI 0.50-0.85), with no additional benefit of treatment from 22 to 90 days. Risk of major hemorrhage, though more than doubled with clopidogrel plus aspirin, remained low overall.

These results, published online ahead of print recently in Circulation, align nicely with those from the earlier CHANCE trial, which was conducted in China and treated patients for a shorter time period, lead author S. Claiborne Johnston, MD, PhD (Dell Medical School, University of Texas at Austin), told TCTMD.

Based on the CHANCE findings, the American Heart Association/American Stroke Association added a class IIa recommendation to the 2018 guidelines on the early management of acute ischemic stroke stating that treatment for 21 days with aspirin plus clopidogrel started within 24 hours can be beneficial for early secondary stroke prevention in patients with minor stroke.

But confirmatory results from POINT were not yet available when the guidelines were written, and clinically, Johnston said, duration of treatment has varied. “There’s been a big range of use, and I think this [new analysis] gives more definitive data around this 21 days,” he said. “That’s what we’re using clinically here and . . . it’ll be interesting to see what the guidelines do with this. It is a secondary analysis, but it certainly makes a lot of sense given the time frames for safety and for efficacy.”

The findings might strengthen the recommendation around treatment for 21 days, Johnston said. “I don’t think anyone could be faulted for treating for 90 days given the results of POINT. I don’t think anyone could be faulted for treating for 21 days given the results of CHANCE. But I think this pushes a little toward that shorter time window: that 3-week time window.”

POINT enrolled 4,881 patients with acute minor ischemic stroke or high-risk TIA who presented within 12 hours of symptom onset at 269 centers in North America, Europe, Australia, and New Zealand. The main results, published last year in the New England Journal of Medicine, showed that those treated with clopidogrel plus aspirin versus aspirin alone for 90 days had a lower risk of major ischemic events (ischemic stroke, MI, or ischemic vascular death), but at a cost of increased major hemorrhage.

Similar to a time-course analysis conducted by the CHANCE investigators, this new POINT analysis was meant to explore how the benefits and risks of treatment varied over time. Through the entire 90-day treatment period, the rate of major ischemic events was lower in patients who received clopidogrel plus aspirin (6.5% vs 5.0%) and the major hemorrhage rate was higher (0.9% vs 0.4%; HR 2.32; 95% CI 1.10-4.87).

Although the hemorrhage rate remained relatively constant over time, ischemic events were clustered early on. In the first 21 days, the rate was 3.6% in those who received clopidogrel plus aspirin and 5.6% in those who received aspirin alone. Rates of major hemorrhage early on were 0.4% and 0.2%, respectively, representing a smaller absolute difference than was seen over the entire 90-day treatment period.

It’s pretty clear from the time courses of ischemia and hemorrhage that treating sooner is better, that you’re not going to be able to prevent ischemic events unless you treat before them. S. Claiborne Johnston

The risk-benefit balance therefore was more favorable for the combination in the first 21 days. For every 1,000 patients treated for 3 weeks with clopidogrel plus aspirin instead of aspirin alone, 20 major ischemic events would be prevented at a cost of two major hemorrhages, the researchers calculated. That compares with 16 ischemic events prevented at a cost of five major hemorrhages with longer treatment.

Johnston et al also used modeling to determine whether later initiation of treatment could be useful, finding that there could be a benefit to starting clopidogrel plus aspirin as long as 3 days after symptom onset. It makes sense based on what is known about the mechanisms and time courses of events that the drugs would continue to work even when started later, but that shouldn’t take away from the message to treat as early as possible, Johnston said.

“It’s pretty clear from the time courses of ischemia and hemorrhage that treating sooner is better, that you’re not going to be able to prevent ischemic events unless you treat before them,” he said. “You really do need to initiate treatment as soon as possible . . . so there should still be a continued emphasis on emergent treatment.”