Dual Antiplatelet Treatment up to 72 Hours after Ischemic Stroke

N Engl J Med. 2023 Dec 28;389(26):2413-2424. doi: 10.1056/NEJMoa2309137.


Background: Dual antiplatelet treatment has been shown to lower the risk of recurrent stroke as compared with aspirin alone when treatment is initiated early (≤24 hours) after an acute mild stroke. The effect of clopidogrel plus aspirin as compared with aspirin alone administered within 72 hours after the onset of acute cerebral ischemia from atherosclerosis has not been well studied.

Methods: In 222 hospitals in China, we conducted a double-blind, randomized, placebo-controlled, two-by-two factorial trial involving patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) of presumed atherosclerotic cause who had not undergone thrombolysis or thrombectomy. Patients were randomly assigned, in a 1:1 ratio, within 72 hours after symptom onset to receive clopidogrel (300 mg on day 1 and 75 mg daily on days 2 to 90) plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 21) or matching clopidogrel placebo plus aspirin (100 to 300 mg on day 1 and 100 mg daily on days 2 to 90). There was no interaction between this component of the factorial trial design and a second part that compared immediate with delayed statin treatment (not reported here). The primary efficacy outcome was new stroke, and the primary safety outcome was moderate-to-severe bleeding - both assessed within 90 days.

Results: A total of 6100 patients were enrolled, with 3050 assigned to each trial group. TIA was the qualifying event for enrollment in 13.1% of the patients. A total of 12.8% of the patients were assigned to a treatment group no more than 24 hours after stroke onset, and 87.2% were assigned after 24 hours and no more than 72 hours after stroke onset. A new stroke occurred in 222 patients (7.3%) in the clopidogrel-aspirin group and in 279 (9.2%) in the aspirin group (hazard ratio, 0.79; 95% confidence interval [CI], 0.66 to 0.94; P = 0.008). Moderate-to-severe bleeding occurred in 27 patients (0.9%) in the clopidogrel-aspirin group and in 13 (0.4%) in the aspirin group (hazard ratio, 2.08; 95% CI, 1.07 to 4.04; P = 0.03).

Conclusions: Among patients with mild ischemic stroke or high-risk TIA of presumed atherosclerotic cause, combined clopidogrel-aspirin therapy initiated within 72 hours after stroke onset led to a lower risk of new stroke at 90 days than aspirin therapy alone but was associated with a low but higher risk of moderate-to-severe bleeding. (Funded by the National Natural Science Foundation of China and others; INSPIRES ClinicalTrials.gov number, NCT03635749.).

Publication types

  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Aspirin* / administration & dosage
  • Aspirin* / adverse effects
  • Aspirin* / therapeutic use
  • Atherosclerosis / complications
  • Atherosclerosis / drug therapy
  • Clopidogrel* / administration & dosage
  • Clopidogrel* / adverse effects
  • Clopidogrel* / therapeutic use
  • Double-Blind Method
  • Drug Therapy, Combination
  • Hemorrhage / chemically induced
  • Humans
  • Ischemic Attack, Transient / drug therapy
  • Ischemic Attack, Transient / etiology
  • Ischemic Stroke* / drug therapy
  • Ischemic Stroke* / etiology
  • Platelet Aggregation Inhibitors* / administration & dosage
  • Platelet Aggregation Inhibitors* / adverse effects
  • Platelet Aggregation Inhibitors* / therapeutic use
  • Secondary Prevention
  • Stroke / drug therapy
  • Stroke / etiology
  • Treatment Outcome


  • Aspirin
  • Clopidogrel
  • Platelet Aggregation Inhibitors

Associated data

  • ClinicalTrials.gov/NCT03635749