Clopidogrel/aspirin combo reduces risk for ischemic stroke, but increases risk of major hemorrhage

In patients with minor ischemic stroke or high-risk transient ischemic attack (TIA), treatment with clopidogrel plus aspirin reduced their risk for ischemic stroke, myocardial infarction, or death from ischemic vascular causes, but conferred a higher risk for major hemorrhage compared with aspirin alone, according to results from the international, multicenter Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) study, presented May 2018 at the 4th European Stroke Organization Conference, Gothenburg, Sweden, and simultaneously published in the New England Journal of Medicine.

“These findings are likely to have a global effect on clinical practice, as these drugs are easily available in many hospitals and clinics,” said Walter Koroshetz, MD, director of the National Institutes of Health’s National Institute of Neurological Disorders and Stroke (NINDS). “As the benefit of the combination was concentrated in the first 2 weeks while risk of bleeding was constant over 90 days, it may be especially valuable in acute management of a minor ischemic stroke or TIA.”

Previous results from the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial showed that patients treated 24 hours after a minor ischemic stroke or TIA with clopidogrel plus aspirin had a 32% lower risk for stroke recurrence compared with those treated with aspirin alone. The CHANCE patient population, however, was restricted to those of Chinese descent. Researchers of the POINT study sought to expand these results to a more ethnically diverse group of patients and for a period of 3 months.

The randomized, double-blind, placebo-controlled POINT was led by S. Claiborne Johnston, MD, PhD, dean and professor of neurology, Dell Medical School, University of Texas, Austin, TX, and included 4,881 patients from 269 international sites with minor ischemic stroke or high-risk TIA who had been randomized 1:1 to treatment with clopidogrel (loading dose: 600 mg day 1 followed by 75 mg/d) plus aspirin (ranging from 50-325 mg/d as selected by site investigators) or aspirin plus placebo at the same doses.

They included only patients who could undergo randomization within 12 hours of an acute ischemic stroke ( ≤ 3 on the National Institutes of Health Stroke Scale) or with a high-risk TIA ( > 4 on ABCD scale). All patients underwent computed tomography or magnetic resonance imaging to rule out intracranial bleeding and other conditions that may have caused their neurologic symptoms.

After 84% of targeted enrollment was reached, the trial was stopped by the safety monitoring board after finding that treatment with the clopidogrel/aspirin combination was associated with a lower risk for major ischemic events (HR: 0.74; 95% CI: 0.58-0.94; P=0.01) and a higher risk for major hemorrhage compared with aspirin alone at 90 days.

In patients treated with the clopidogrel/aspirin combination, 5.0% had major ischemic events, compared with 6.5% of patients treated with aspirin alone (HR: 0.75; 95% CI: 0.59-0.95; P=0.02). Major hemorrhages occurred in 0.9% and 0.4% among these two groups of patients, respectively (HR: 2.32; 95% CI: 1.10-4.87; P=0.02).

Most major hemorrhages were nonfatal and nonintracranial (16 in clopidogrel/aspirin group vs 7 with aspirin alone). Minor hemorrhages occurred in 1.6% vs 0.5%, respectively (HR: 3.12; 95% CI: 1.67-5.83; P=0.002).

In a secondary analysis, Dr. Johnston and colleagues found that the benefits of clopidogrel/aspirin were greater during the first 7 days and in the first 30 days, compared with 90 days (P=0.04 for days 0 to 7; P=0.02 for days 0-30). Conversely, the risk of hemorrhage with the clopidogrel/aspirin combination were greater from 8-90 days than for the first 7 days (P=0.04 for days 8-90; P=0.34 for days 0-7).

“We saw a real benefit with the combination therapy, but that treatment does come with a risk. Overall, the risk of severe bleeding was very small, but it was not zero,” said Dr. Johnston. “Each year, strokes cause millions of disabilities around the world and preventing many of those would lead to not only tremendous health savings, but improved quality of life for many individuals and their families.”

In an accompanying editorial, James C. Grotta, MD, director, Stroke Research Program, and director, Mobile Stroke Unit Consortium, Memorial Hermann Hospital, Houston, TX, stressed several aspects of the POINT trial that are necessary to fully grasp the picture painted by these results.

“First, most of the prevented events were ischemic strokes—the most common and arguably most important of the outcomes after a TIA or minor stroke. Second, most of the bleeding complications were systemic, nonfatal, nonintracranial hemorrhages and not the most feared event of intracranial bleeding. Third, and most salient, is the timing of these outcomes. Most of the benefit regarding stroke prevention occurred in the first week of treatment with the combination, whereas most of the bleeding occurred later. In a secondary analysis, the benefit of aspirin plus clopidogrel in preventing ischemic outcomes was significant throughout the first 7 to 30 days of treatment, whereas the risk of major hemorrhage became greater only during the period from 8 to 90 days,” he wrote.

In conclusion, he added: “The POINT trial has provided useful data to help us further personalize our efforts in preventing recurrent stroke.”

This study was funded by the NINDS.