Level 2 [mid-level] evidence

Initiation of dual antiplatelet therapy (DAPT) after minor ischemic stroke or high-risk transient ischemic attack (TIA) was shown to reduce the risk of stroke without increasing hemorrhage in Chinese patients in the CHANCE1 trial. Questions about the generalizability of these data lead investigators of the POINT trial to conduct a similar study in an international population.2 They randomly assigned 4881 patients to receive either clopidogrel (600-mg loading dose followed by 75 mg daily) plus aspirin 50 mg to 325 mg daily or aspirin 50 mg to 325 mg alone over a 90-day period. The aspirin doses were selected by the individual treating physicians, although a dosage of 162 mg/d for 5 days followed by 81 mg/d was recommended. Participants were identified and randomization occurred within 12 hours of the initial event. In both studies, minor ischemic stroke was defined as an acute ischemic stroke with a score of 3 or less on the National Institutes of Health Stroke Scale (NIHSS). High-risk TIA is defined as one with a score of 4 or more on the ABCD2 scale, which estimates the risk of recurrent stroke.

The trial was stopped early when a safety signal of major hemorrhage was exceeded. After review, it was determined that at the time the trial was stopped, a treatment effect had also been reached. The primary efficacy outcome, a composite of ischemic stroke, myocardial infarction, or death from ischemic vascular causes, occurred in 121 (5.0%) patients in the clopidogrel-plus-aspirin group and 160 (6.5%) in the aspirin group. This finding was driven primarily by stroke; the 2 individual outcomes that were independently significant, both favoring the combination therapy, were ischemic stroke (4.6% vs 6.3%, P =.01) and ischemic or hemorrhagic stroke (4.8% vs 6.4%, P =.01). The primary safety outcome of major hemorrhage was seen in 0.9% of patients receiving clopidogrel plus aspirin and 0.4% of patients receiving aspirin alone, driven primarily by nonfatal non-intracranial hemorrhage (P =.04). The estimated number needed to treat for DAPT over 90 days was 67 and the number needed to harm was 200. A secondary analysis of the primary efficacy and safety outcomes was performed by time period and found that the benefit of clopidogrel plus aspirin was greater in the first 7 days (P =.04) and in the first 30 days (P =.02) than at 90 days, and the risk of major hemorrhage was significant only after 8 days (P =.04). These data contrast with the findings of the CHANCE trial, which found reduction in ischemic stroke of 3.5% without increased risk of hemorrhage.

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The POINT trial adds to the evidence supporting DAPT therapy for 90 days to prevent stroke in patients with a high-risk TIA or minor stroke, albeit with a smaller benefit and an increased risk of nonfatal non-intracranial hemorrhage than was seen before. This is a good opportunity for shared decision-making. There is no reason to continue DAPT beyond 90 days unless a subsequent trial establishes benefit, especially given that the benefits seen here were only significant in the first 30 days.

Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Massachusetts, and assistant clinical professor in family medicine, University of Massachusetts Medical School, Worcester.

DynaMed is a database that provides evidence-based information on more than 3000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.

References

  1. Wang Y, Wang Y, Zhao X, et al; for the CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11-19.
  2. Johnston SC, Easton JD, Farrant M, et al; for the Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379(3):215-225.