by Judy George, Senior Staff Writer, MedPage Today

August 20, 2019

Dual antiplatelet therapy should be started within 24 to 48 hours of high-risk transient ischemic attack (TIA) or minor ischemic stroke and continued for 21 days, a pooled analysis of the CHANCE and POINTtrials found.

Clopidogrel-aspirin treatment started quickly reduced the risk of major ischemic events over 90 days compared with aspirin alone (6.5% vs 9.1%), but the effect was mainly within the first 21 days, reported S. Claiborne Johnston, MD, PhD, of Dell Medical School at the University of Texas at Austin, Yongjun Wang, MD, of Capital Medical University in Beijing, and colleagues in JAMA Neurology.

“This study provides precise estimates of efficacy and risk of dual antiplatelet therapy after minor ischemic stroke or TIA using pooled individual patient-level data from two large-scale randomized trials, CHANCE and POINT, that evaluated clopidogrel-aspirin as a treatment to prevent stroke after a minor ischemic stroke or high-risk TIA,” Wang told MedPage Today.

“It suggests 21 days may be optimal based on risk reduction for new strokes and risks of hemorrhage,” Johnston added. “While this is a secondary analysis of randomized trials, it is likely to be the best evidence we’ll have about optimal duration of treatment; a new trial testing only duration of treatment would be expensive and unlikely to gain funding support,” he told MedPage Today.

The analysis incorporated data from CHANCE, a trial conducted at 114 sites in China from 2009 to 2012, and POINT, a study at 269 international sites from 2010 to 2017. Both were double-blind randomized trials of minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] of ≤3) or high-risk TIA (ABCD2 — age, blood pressure, clinical features, duration of symptoms, and presence of diabetes — score of ≥4) patients.

The median age in the study was 63 and 61% were men; most participants (65%) had a minor stroke as the qualifying event. In total, 5,016 patients were assigned clopidogrel and aspirin and 5,035 were assigned aspirin alone.

Patients were randomized to treatment groups within 12 hours (POINT) or 24 hours (CHANCE) of symptom onset. In the clopidogrel-aspirin arm, CHANCE used 21 days of dual antiplatelet therapy followed by clopidogrel alone from day 22 to 90, while POINT used 90 days of dual antiplatelet therapy.

Both trials followed patients for 90 days. The primary efficacy outcome was a major ischemic event — ischemic stroke, myocardial infarction, or death from ischemic vascular causes. The primary safety outcome was major hemorrhage.

In the pooled analysis, clopidogrel-aspirin treatment reduced the risk of major ischemic events at 90 days compared with aspirin alone (6.5% vs 9.1%, HR 0.70, 95% CI 0.61-0.81, P<0.001). This occurred mainly within the first 21 days (5.2% vs 7.8%, HR 0.66, 95% CI 0.56-0.77, P<0.001), but not from day 22 to day 90.

Major hemorrhages were more frequent in the clopidogrel-aspirin group, but the difference was not significant.

This analysis clarifies the optimal duration of dual antiplatelet therapy minor stroke or high-risk TIA in patients who do not have a cardioembolic source requiring anticoagulation, observed James Grotta, MD, of Memorial Hermann Hospital in Houston, who was not involved with the study.

“But it is important to remember that the majority of acute stroke patients were not included in these trials — those with NIHSS over 3, those treated with thrombolytics, and those requiring endarterectomy,” Grotta told MedPage Today. “For those patients, the benefits of dual antiplatelet therapy remain uncertain.”

“Furthermore, previous analyses of CHANCE suggest that dual antiplatelet therapy may not be beneficial in all subgroups of TIA or minor stroke patients: those with documented atherosclerotic lesions, multiple infarcts, or elevated neutrophil counts were the groups that appeared to benefit,” he added. “Unfortunately, this pooled analysis does not provide further information about such subgroups of TIA and minor stroke patients that may or may not benefit from dual antiplatelet therapy.”

The analysis had several limitations, the researchers noted. Bias may exist because of differences in trial design. The 21-day time course of clopidogrel-aspirin in CHANCE limited the use of that data to draw conclusions about combined antiplatelet therapy after 21 days. In addition, patients with different causative subtypes of ischemic stroke and TIA may respond differently to dual antiplatelet therapy, and this analysis did not address this.

Primary Source

JAMA Neurology

Source Reference: Pan Y, et al “Outcomes Associated With Clopidogrel-Aspirin Use in Minor Stroke or Transient Ischemic Attack: A Pooled Analysis of Clopidogrel in High-Risk Patients With Acute Non-Disabling Cerebrovascular Events (CHANCE) and Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) Trials” JAMA Neurology 2019; DOI: 10.1001/jamaneurol.2019.2531.