Dual antiplatelet therapy (DAPT) immediately after minor ischemic stroke or high-risk TIA may reduce risk of stroke but may increase nonfatal non-intracranial hemorrhage compared to aspirin alone

EBM Focus - Volume 13, Issue 37

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Reference: N Engl J Med 2018 Jul 19;379(3):215 (level 2 [mid-level] evidence)

Initiation of DAPT after minor ischemic stroke or high-risk TIA was shown to reduce risk of stroke without increasing hemorrhage in Chinese patients in the CHANCE trial. Questions about the generalizability of these data lead investigators of the POINT trial to conduct a similar study in an international population. They randomized 4,881 patients to receive either clopidogrel (600 mg loading dose followed by 75 mg daily) plus aspirin 50 mg-325 mg daily or aspirin 50 mg-325 mg alone over a 90 day period. The aspirin doses were selected by the individual treating physicians, though a dose of 162 mg daily for 5 days followed by 81 mg daily was recommended. Participants were identified and randomized 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%) of patients in the clopidogrel plus aspirin group and 160 (6.5%) in the aspirin group. This finding was driven primarily by stroke; the two individual outcomes that were independently significant were ischemic stroke (4.6% vs 6.3%, p=0.01) and ischemic or hemorrhagic stroke (4.8% vs 6.4%, p=0.01). The primary safety outcome of major hemorrhage (defined as symptomatic intracranial hemorrhage, intraocular bleeding causing vision loss, transfusion of 2 or more units of red cells, hospitalization or prolongation of an existing hospitalization, or death due to 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=0.04). The estimated number needed to treat (NNT) for DAPT over 90 days was 67 and the number needed to harm (NNH) 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=0.04) and in the first 30 days (p=0.02) than at 90 days and the risk of major hemorrhage was significant only after 8 days (p=0.04). These data are in contrast to the findings of the CHANCE trial which found reduction in ischemic stroke of 3.5% without increased risk of hemorrhage.

Focus point: 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.

For more information, see the topic Antiplatelet therapy for secondary prevention of stroke in DynaMed Plus. DynaMed users click here.

DynaMed Plus EBM Focus Editorial Team

This EBM Focus was written by Sarah Dalrymple, MD, Faculty Development and Information Mastery Fellow and Clinical Instructor at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed Plus and Associate Professor in Family Medicine at the University of Massachusetts Medical School and Katharine DeGeorge, MD, MS, Assistant Professor in Family Medicine at the University of Virginia and Clinical Editor at DynaMed Plus.