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(2024)Objective
To assess whether adjunctive intravenous argatroban or eptifibatide improves 90-day outcomes in patients with acute ischemic stroke treated with thrombolysis within 3 hours.
Study Summary
Intervention
IV argatroban (100 µg/kg bolus + 12h infusion) or IV eptifibatide (135 µg/kg bolus + 2h infusion) vs. placebo, initiated within 75 minutes after IV thrombolysis (alteplase or tenecteplase).
Inclusion Criteria
Adults ≥18 with NIHSS ≥6, received IV thrombolysis within 3 hours of symptom onset, able to receive adjunctive drug within 75 minutes of thrombolysis.
Study Design
Arms: Argatroban vs. Eptifibatide vs. Placebo (all post-IV thrombolysis)
Patients per Arm: Argatroban: 59, Eptifibatide: 227, Placebo: 228 (randomized); safety sample: Argatroban 54, Eptifibatide 212, Placebo 217
Outcome
• • Bayesian posterior probability of superiority vs placebo: Argatroban 0.002, Eptifibatide 0.041 (not frequentist p-values).
• • Symptomatic ICH within 36h (safety sample): Argatroban 4% (2/54), Eptifibatide 3% (7/212), Placebo 2% (4/217).
• • 90d mortality (safety sample): Argatroban 24% (13/54), Eptifibatide 12% (25/212), Placebo 8% (17/217).
• • Any ICH within 36h (safety sample): Argatroban 37% (20/54), Eptifibatide 24% (51/212), Placebo 24% (51/217).
• • Serious adverse events: Argatroban 44% (26/59), Eptifibatide 37% (85/227), Placebo 34% (78/228).
Bottom Line
Adjunctive treatment with argatroban or eptifibatide following IV thrombolysis did not improve 90-day functional outcomes; argatroban was additionally associated with higher mortality (24% vs 8% placebo), while eptifibatide mortality (12%) was similar to placebo.
Major Points
- Phase 3 randomized trial comparing adjunctive IV argatroban, eptifibatide, or placebo after thrombolysis for acute ischemic stroke
- 514 patients enrolled; 70% received alteplase, 30% tenecteplase; 44% also received thrombectomy
- Primary outcome: utility-weighted mRS at 90 days was lower in both active arms (5.2 argatroban, 6.3 eptifibatide) vs. placebo (6.8)
- Bayesian posterior probability of superiority vs. placebo: 0.002 (argatroban), 0.041 (eptifibatide) — well below the 0.985 efficacy threshold; not frequentist p-values
- Mortality (safety sample): 24% (13/54 argatroban), 12% (25/212 eptifibatide), 8% (17/217 placebo); symptomatic ICH similar (4%/3%/2%); any ICH within 36h 37% argatroban vs 24% placebo and eptifibatide
- Trial stopped early for futility; no subgroup showed benefit
Study Design
- Study Type
- Phase 3, adaptive, response-adaptive randomized, single-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Single-blind (patients/LARs blinded; investigators aware of assignment; centralized video-adjudication of 90-day mRS)
- Sample Size
- 514
- Follow-up
- 90 days
- Centers
- 57
- Countries
- United States
Primary Outcome
Definition: Utility-weighted 90-day modified Rankin scale score (range 0–10, higher = better; utility weights 10.0/9.1/7.6/6.5/3.3/0.0/0.0 for mRS 0–6). Posterior mean difference vs placebo: −1.51±0.51 (argatroban), −0.50±0.29 (eptifibatide). Analyzed with a Bayesian normal dynamic linear model.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 6.8 ± 3.0 | 5.2 ± 3.7 (argatroban), 6.3 ± 3.2 (eptifibatide) | - | - |
Limitations & Criticisms
- Trial stopped early for futility, leading to smaller sample size in argatroban group (n=59) via response-adaptive randomization
- Single-blind design (local investigators unblinded, mitigated by centralized video-adjudication of 90-day mRS)
- Higher baseline atrial fibrillation and prior alteplase use in the argatroban group; imbalance in previous stroke and thrombolysis type
- Bayesian framework only; no frequentist hypothesis testing or p-values
- Exclusion criteria not enumerated in the primary publication (detailed only in the protocol/Supplementary Appendix)
Citation
N Engl J Med 2024;391(9):810–820