MOST
Adjunctive Antithrombotic Therapy After Thrombolysis for Acute Ischemic Stroke
Year of Publication: 2024
Authors: Opeolu Adeoye, Joseph Broderick, Colin P. Derdeyn, ..., Andrew D. Barreto
Journal: New England Journal of Medicine
Citation: N Engl J Med 2024;391(9):810–820
PDF: Clinical Question
Does adjunctive antithrombotic therapy with argatroban or eptifibatide improve outcomes after IV thrombolysis for acute ischemic stroke?
Bottom Line
Adjunctive treatment with argatroban or eptifibatide following IV thrombolysis did not improve functional outcomes and was associated with higher mortality than 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)
- Posterior probability of benefit vs. placebo: 0.002 (argatroban), 0.041 (eptifibatide)
- Mortality: 24% (argatroban), 12% (eptifibatide), 8% (placebo); ICH rates similar
- Trial stopped early for futility; no subgroup showed benefit
Design
Study Type: Phase 3, adaptive, randomized, single-blind, controlled trial
Randomization: 1
Blinding: Single-blind (participants blinded, investigators not)
Enrollment Period: October 2019 – July 2023
Follow-up Duration: 90 days
Centers: 57
Countries: United States
Sample Size: 514
Analysis: Bayesian intention-to-treat analysis with posterior probability estimation, sensitivity per-protocol analyses, subgroup analysis, and multiple imputation for missing data
Inclusion Criteria
- Acute ischemic stroke within 3 hours of symptom onset
- Received IV thrombolysis (alteplase or tenecteplase)
- Age ≥18 years
- NIHSS ≥6
- Able to receive adjunctive treatment within 75 minutes of thrombolysis initiation
Exclusion Criteria
- Contraindications to antithrombotics
- High bleeding risk
- Severe comorbidities (not fully detailed)
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Median Age | 66 (IQR 58–78) | 68 (IQR 58–79) |
| Male Sex | 52% | 50% (avg) |
| Alteplase | 66% | 88% (argatroban), 69% (eptifibatide) |
| Tenecteplase | 34% | 12% (argatroban), 31% (eptifibatide) |
| NIHSS (median) | 11 | 12 |
| Atrial fibrillation | 18% | 31% (argatroban), 16% (eptifibatide) |
| Hypertension | 75% | 76% (argatroban), 73% (eptifibatide) |
| Diabetes | 31% | 24% (argatroban), 26% (eptifibatide) |
| Prior stroke | 18% | 14% (argatroban), 22% (eptifibatide) |
| Large-vessel occlusion | 48% | 61% (argatroban), 52% (eptifibatide) |
| EVT planned | 48% | 53% (argatroban), 50% (eptifibatide) |
| Prestroke mRS 0–2 | 91% | 95% (argatroban), 90% (eptifibatide) |
Arms
| Field | Argatroban | Eptifibatide | Control |
|---|---|---|---|
| Intervention | IV bolus (100 µg/kg) + 12h infusion (3 µg/kg/min) of argatroban started within 75 min of thrombolysis | IV bolus (135 µg/kg) + 2h infusion (0.75 µg/kg/min) eptifibatide + 10h saline infusion to maintain blinding | IV saline bolus + 12h infusion post-thrombolysis |
| Duration | Single treatment with 90-day follow-up | Single treatment with 90-day follow-up | Single treatment with 90-day follow-up |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Utility-weighted mRS score at 90 days | Primary | 6.8 ± 3.0 | 5.2 ± 3.7 (argatroban), 6.3 ± 3.2 (eptifibatide) | ||
| 90-day mRS 0–2 | Secondary | 61% | 44% (argatroban), 56% (eptifibatide) | 0.50 (argatroban), 0.80 (eptifibatide) | |
| Mortality at 90 days | Secondary | 8% | 24% (argatroban), 12% (eptifibatide) | ||
| Symptomatic ICH | Secondary | 2% | 4% (argatroban), 3% (eptifibatide) | ||
| Symptomatic ICH | Adverse | 2% | 4% (argatroban), 3% (eptifibatide) | ||
| Death | Adverse | 8% | 24% (argatroban), 12% (eptifibatide) | ||
| Any ICH within 36h | Adverse | 24% | 37% (argatroban), 24% (eptifibatide) |
Subgroup Analysis
No subgroup demonstrated benefit with either agent; futility threshold met at interim analysis
Criticisms
- Trial stopped early for futility, leading to smaller sample size in argatroban group
- Single-blind design (investigators unblinded)
- Higher baseline atrial fibrillation in argatroban group
- No formal hypothesis testing; Bayesian analysis only
Funding
National Institute of Neurological Disorders and Stroke (NINDS)
Based on: MOST (New England Journal of Medicine, 2024)
Authors: Opeolu Adeoye, Joseph Broderick, Colin P. Derdeyn, ..., Andrew D. Barreto
Citation: N Engl J Med 2024;391(9):810–820
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