Clopidogrel and Aspirin for Mild Ischemic Stroke - In-depth Notes

Importance of Study

  • Previous trials indicate dual antiplatelet therapy (DAPT) reduces early stroke risk in acute mild ischemic stroke or TIA within 24 hours of onset.
  • Need to assess if DAPT continues to be effective when started later (24-72 hours post-symptom onset).

Objective

  • Assess efficacy and safety of clopidogrel + aspirin versus aspirin alone when initiated at:
  • Within 24 hours
  • More than 24 to 48 hours
  • More than 48 to 72 hours.

Study Design and Setting

  • Trial: INSPIRES trial (Intensive Statin and Antiplatelet Therapy for Acute High-Risk Intracranial or Extracranial Atherosclerosis).
  • Type: Double-blind, placebo-controlled, multicenter.
  • Location: 222 hospitals in China.
  • Duration: September 17, 2018, to October 15, 2022.
  • Follow-up duration for 90 days.

Participants

  • Total: 6100 patients (3050 in clopidogrel-aspirin group, 3050 in aspirin-alone group).
  • Age median: 65 years (IQR, 57-71).
  • 64.2% male, 35.8% female.

Interventions

  • Patients received:
  • Clopidogrel + Aspirin: 300 mg loading dose on day 1, 75 mg daily for 90 days (clopidogrel); 100-300 mg on day 1, then 100 mg daily for 90 days (aspirin).
  • Aspirin Alone: 100-300 mg on day 1, then 100 mg daily for 90 days.

Outcomes

  • Primary Efficacy Outcome: New stroke (ischemic or hemorrhagic) within 90 days.
  • Primary Safety Outcome: Moderate-to-severe bleeding.

Results Overview

  • Percentage of patients with strokes:
  • ≤24 hours: 97 of 783 (12.4%)
  • >24 to ≤48 hours: 211 of 2552 (8.3%)
  • >48 to 72 hours: 193 of 2765 (7.0%).

Stroke Risks Comparison

  • Clopidogrel + Aspirin vs. Aspirin Alone:
  • >48 to 72 hours: 5.8% vs 8.2% (HR 0.70)
  • >24 to 48 hours: 7.6% vs 8.9% (HR 0.85)
  • ≤24 hours: 11.5% vs 13.4% (HR 0.83)
  • P = 0.38 for interaction.

Bleeding Risks Comparison

  • Moderate-to-severe bleeding:
  • >48 to 72 hours: 0.9% in clopidogrel-aspirin vs 0.4% aspirin (HR 2.00)
  • >24 to 48 hours: 0.7% vs 0.3% (HR 2.25)
  • ≤24 hours: 1.5% vs 0.8% (HR 1.57)
  • P = 0.92 for interaction.

Conclusions

  • DAPT with clopidogrel + aspirin shows consistent efficacy and safety across all time-to-randomization groups.
  • Supports initiation of DAPT within a 72-hour window post-symptom onset without significant excess risk for moderate-to-severe bleeding.

Key Takeaway

  • Patients with mild ischemic stroke or TIA should have access to DAPT within 72 hours after symptom onset for optimal secondary prevention of subsequent strokes without significantly increased risk of bleeding.