The use of clopidogrel with aspirin in short-term treatments of acute transient ischemic attack (TIA) or minor acute ischemic stroke (AIS) has a low rate of complication due to major hemorrhage. Further, the combined treatment reduces risk for ischemic stroke, according to the findings of a clinical trial published in JAMA Neurology.
This study was a secondary analysis of the Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT) trial, which was a randomized, double-blinded, placebo controlled trial featuring participants in 10 countries with high-risk TIA or minor AIS. Enrollment for the primary study was conducted between May 2010 to December 2017, during which participants were randomly assigned to receive either clopidogrel (600 mg loading dose followed by 75 mg from day 2 to 90) plus aspirin (50 to 325 mg per day) or aspirin plus placebo within 12 hours of symptom onset, and followed for 90 days. Of those enrolled, 4881 individuals were assigned to the intention-to-treat subgroup and 4819 (98.7%) were assigned to the as-treated analysis subgroup.
The primary focus of the analysis was major hemorrhagic events. Investigators aimed to describe the bleeding profiles of clopidogrel plus aspirin and aspirin plus placebo to characterize the major hemorrhages and identify factors that predict major hemorrhages.
As-treated subgroup was chosen by study authors for primary analysis due to high study drug discontinuation rate. They also believed this subgroup represented the worst-case scenario for safety of the 2 treatments. For completeness and comparison, authors included secondary analyses on the intention-to-treat subgroup.
Analysis of the as-treated group revealed major hemorrhage in 21 individuals (0.9%) receiving clopidogrel plus aspirin and 6 (0.2%) in the aspirin plus placebo group (hazard ratio 3.57; 95% CI, 1.44-8.85; P =.003; number needed to harm, 159). Fatal hemorrhages was found in 4 individuals (0.1%; 3 in the clopidogrel plus aspirin group and 1 in the aspirin alone group), 3 of which were intracranial. Total number of intracranial hemorrhages was 7 (0.1%); 5 were in the clopidogrel plus aspirin group and 2 in the aspirin alone group. Major hemorrhages were most commonly found in the gastrointestinal tract.
A limitation of this study reported by study authors was the small number of major bleeds present to assess the bleed risk factor, presumably caused by the limited 90-day follow-up period. They do, however, find it reassuring that the overall number of major bleeds was low in this high risk population.
Investigators concluded that for every 1000 individuals treated, adding clopidogrel might prevent 15 major ischemic events, mostly strokes, and cause 5 more major hemorrhages, mostly gastrointestinal. They warn that risk for hemorrhage when using clopidogrel plus aspirin must be balanced against the benefit of dual antiplatelet treatment.
Multiple authors declare affiliations with the pharmaceutical industry. Please refer to reference for a complete list of authors’ disclosures.
Tillman H, Johnston SC, Farrant M, et al. 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 [published online April 29, 2019]. JAMA Neurol. doi: 10.1001/jamaneurol.2019.0932