MOST
Adjunctive Intravenous Argatroban or Eptifibatide for 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?
Study Overview
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
- Adjunctive treatment with IV argatroban or eptifibatide did not improve outcomes.
- Argatroban was associated with higher mortality (24% vs. 8%) and more any-ICH within 36h (37% vs. 24%).
- Eptifibatide showed no functional benefit; symptomatic ICH, any ICH, and major systemic hemorrhage were similar to placebo.
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).
Patients per Arm
Argatroban: 59, Eptifibatide: 227, Placebo: 228 (randomized); safety sample: Argatroban 54, Eptifibatide 212, Placebo 217
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
Design
Study Type: Phase 3, adaptive, response-adaptive randomized, single-blind, placebo-controlled trial
Randomization: 1
Blinding: Single-blind (patients/LARs blinded; investigators aware of assignment; centralized video-adjudication of 90-day mRS)
Enrollment Period: October 15, 2019 – July 1, 2023
Follow-up Duration: 90 days
Centers: 57
Countries: United States
Sample Size: 514
Analysis: Bayesian intention-to-treat analysis using a normal dynamic linear model with vague prior; efficacy threshold posterior probability ≥0.985; per-protocol sensitivity, subgroup, and multiple-imputation analyses
Inclusion Criteria
- Acute ischemic stroke within 3 hours of symptom onset
- Received IV thrombolysis (alteplase 0.9 mg/kg or tenecteplase 0.25 mg/kg)
- Age ≥18 years
- Baseline NIHSS ≥6
- Able to receive adjunctive investigational product within 75 minutes of thrombolysis initiation
Exclusion Criteria
- Detailed eligibility criteria are provided in the trial protocol (Supplementary Appendix); the primary publication does not enumerate exclusion criteria.
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Median Age | 66 (IQR 58–78) | 68 (IQR 60–79 argatroban; 58–79 eptifibatide) |
| Male Sex | 52% (118/228) | 53% (31/59) argatroban; 48% (109/227) eptifibatide |
| Race — White | 75% (170/228) | |
| Race — Black | 23% (53/228) | |
| Hispanic/Latino | 6% (14/228) | |
| Alteplase | 66% (151/228) | 88% (52/59) argatroban; 69% (157/227) eptifibatide |
| Tenecteplase | 34% (77/228) | 12% (7/59) argatroban; 31% (70/227) eptifibatide |
| Time onset→thrombolysis (min, mean±SD) | 101±36 | |
| Time thrombolysis→bolus (min, mean±SD) | 63±18 | 62±14 argatroban; 65±20 eptifibatide |
| Median NIHSS (IQR) | 11 (7–17) | 12 (8–18) argatroban; 12 (8–17) eptifibatide |
| Prior aspirin use | 36% (81/228) | |
| Atrial fibrillation | 18% (42/228) | 31% (18/59) argatroban; 16% (37/227) eptifibatide |
| Hypertension | 75% (171/228) | 76% (45/59) argatroban; 73% (166/227) eptifibatide |
| Diabetes | 31% (71/228) | 24% (14/59) argatroban; 26% (59/227) eptifibatide |
| Prior stroke | 18% (40/228) | 14% (8/59) argatroban; 22% (50/227) eptifibatide |
| Prestroke mRS 0–2 | 91% (208/228) | 95% (56/59) argatroban; 90% (205/227) eptifibatide |
| Large-vessel occlusion (centrally read) | 48% (110/228) | 61% (36/59) argatroban; 52% (118/227) eptifibatide |
| EVT planned at randomization | 48% (110/228) | 53% (31/59) argatroban; 50% (113/227) 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 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. | Primary | 6.8 ± 3.0 | 5.2 ± 3.7 (argatroban), 6.3 ± 3.2 (eptifibatide) | ||
| 90-day modified Rankin scale score of 0 to 2 or return to prestroke score | Secondary | 61% (139/228) | 44% (26/59) argatroban; 56% (126/227) eptifibatide | OR 0.50 (95% CI 0.28–0.90) argatroban; OR 0.80 (95% CI 0.55–1.16) eptifibatide | |
| 90-day modified Rankin scale score of 0 or 1 or return to prestroke score | Secondary | 40% (92/228) | 24% (14/59) argatroban; 36% (82/227) eptifibatide | OR 0.46 (95% CI 0.24–0.89) argatroban; OR 0.84 (95% CI 0.57–1.22) eptifibatide | |
| Median 90-day modified Rankin scale (IQR) | Secondary | 2 (1–3) | 3 (2–5) argatroban; 2 (1–3) eptifibatide | ||
| Post-thrombectomy mTICI 2b or 3 (of patients who underwent EVT) | Secondary | 94% (93/99) | 81% (22/27) argatroban; 93% (92/99) eptifibatide | OR 0.28 (95% CI 0.08–1.02) argatroban; OR 0.85 (95% CI 0.27–2.62) eptifibatide | |
| _Safety sample denominators | Adverse | Placebo N=217, Argatroban N=54, Eptifibatide N=212 — only patients who received any amount of investigational product were included in Table 3 safety analyses (2 deaths in patients who never received IP were excluded). | |||
| Symptomatic ICH within 36h (primary safety) | Adverse | 2% (4/217) | 4% (2/54) argatroban; 3% (7/212) eptifibatide | ||
| Parenchymal hemorrhage type 1 or 2 within 36h | Adverse | 5% (11/217) | 6% (3/54) argatroban; 8% (18/212) eptifibatide | ||
| Any ICH within 36h (centrally read) | Adverse | 24% (51/217) | 37% (20/54) argatroban; 24% (51/212) eptifibatide | ||
| Other major hemorrhage (non-ICH) within 7 days | Adverse | 1% (3/217) | 2% (1/54) argatroban; 1% (2/212) eptifibatide | ||
| Death from any cause within 90 days | Adverse | 8% (17/217) | 24% (13/54) argatroban; 12% (25/212) eptifibatide | ||
| Serious adverse events (randomized sample) | Adverse | 34% (78/228) | 44% (26/59) argatroban; 37% (85/227) eptifibatide | ||
Subgroup Analysis
No subgroup demonstrated benefit with either agent; in all subgroups, the upper limit of the 95% CI for the mean difference in utility-weighted mRS crossed 0. Futility threshold met at interim analysis after 500 patients.
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)
Funding
National Institute of Neurological Disorders and Stroke (NINDS), grant 1U01NS100699-01A1
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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