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Original Investigation
April 29, 2019

Risk for Major Hemorrhages in Patients Receiving Clopidogrel and Aspirin Compared With Aspirin Alone After Transient Ischemic Attack or Minor Ischemic Stroke: A Secondary Analysis of the POINT Randomized Clinical Trial

Author Affiliations
  • 1Data Coordination Unit, Department of Public Health Sciences, Medical University of South Carolina, Charleston
  • 2Dean’s Office, Dell Medical School, University of Texas at Austin, Austin
  • 3Department of Neurology, University of California, San Francisco, San Francisco
  • 4Department of Emergency Medicine, University of Michigan, Ann Arbor
  • 5The Emmes Corporation, Rockville, Maryland
JAMA Neurol. 2019;76(7):774-782. doi:10.1001/jamaneurol.2019.0932
Key Points

Question  What is the bleeding profile of clopidogrel plus aspirin vs aspirin alone when used to prevent strokes in patients with acute transient ischemic attack or minor ischemic stroke?

Findings  In this secondary analysis of a multinational randomized clinical trial of 4881 patients who received clopidogrel plus aspirin vs placebo plus aspirin, the risk of major hemorrhage was low and most were extracranial and treatable. Intracranial hemorrhages were rare.

Meaning  Short-term treatment with clopidogrel plus aspirin after acute transient ischemic attack or minor ischemic stroke has a low major hemorrhage complication rate and reduces the risk of ischemic stroke.

Abstract

Importance  Results show the short-term risk of hemorrhage in treating patients with acute transient ischemic attack (TIA) or minor acute ischemic stroke (AIS) with clopidogrel plus aspirin or aspirin alone.

Objective  To characterize the frequency and kinds of major hemorrhages in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial.

Design, Setting, and Participants  This secondary analysis of the POINT randomized, double-blind clinical trial conducted in 10 countries in North America, Europe, and Australasia included patients with high-risk TIA or minor AIS who were randomized within 12 hours of symptom onset and followed up for 90 days. The total enrollment, which occurred from May 28, 2010, through December 17, 2017, was 4881 and constituted the intention-to-treat group; 4819 (98.7%) were included in the as-treated analysis group. The primary safety analyses were as-treated, classifying patients based on study drug actually received. Intention-to-treat analyses were performed as secondary analyses. Data were analyzed in April 2018.

Interventions  Patients were assigned to receive clopidogrel (600 mg loading dose on day 1 followed by 75 mg daily for days 2-90) or placebo; all patients also received open-label aspirin, 50 to 325 mg/d.

Main Outcomes and Measures  The primary safety outcome was all major hemorrhages. Other safety outcomes included minor hemorrhages.

Results  A total of 269 sites worldwide randomized 4881 patients (median age, 65.0 years [interquartile range, 55-74 years]; 2195 women [45.0%]); the primary results have been published previously. In the as-treated analyses, major hemorrhage occurred in 21 patients (0.9%) receiving clopidogrel plus aspirin and 6 (0.2%) in the aspirin alone group (hazard ratio, 3.57; 95% CI, 1.44-8.85; P = .003; number needed to harm, 159). There were 4 fatal hemorrhages (0.1%; 3 in the clopidogrel plus aspirin group and 1 in the aspirin alone group); 3 of the 4 were intracranial. There were 7 intracranial hemorrhages (0.1%); 5 were in the clopidogrel plus aspirin group and 2 in the aspirin plus placebo group. The most common location of major hemorrhages was in the gastrointestinal tract.

Conclusions and Relevance  The risk for major hemorrhages in patients receiving either clopidogrel plus aspirin or aspirin alone after TIA or minor AIS was low. Nevertheless, treatment with clopidogrel plus aspirin increased the risk of major hemorrhages over aspirin alone from 0.2% to 0.9%.

Trial Registration  ClinicalTrials.gov identifier: NCT00991029

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