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MOST

Adjunctive Antithrombotic Therapy After Thrombolysis for Acute Ischemic Stroke

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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

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa2314779

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa2314779

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
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

Content summarized and formatted by NeuroTrials.ai.

MOST

(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

• Adjunctive treatment with IV argatroban or eptifibatide did not improve outcomes. • Argatroban was associated with higher mortality (24% vs. 8%). • Eptifibatide also showed no functional benefit, and was associated with more major bleeding.

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

Outcome

• Utility-weighted mRS at 90d: Argatroban 5.2, Eptifibatide 6.3, Placebo 6.8.
• • Posterior probability of benefit: Argatroban 0.002, Eptifibatide 0.041.
• • Symptomatic ICH: Argatroban 4%, Eptifibatide 3%, Placebo 2%.
• • 90d mortality: Argatroban 24%, Eptifibatide 12%, Placebo 8%.
• • Any ICH: Argatroban 37%, Eptifibatide 24%, Placebo 24%.
• • Serious adverse events: Argatroban 44%, Eptifibatide 37%, Placebo 34%.

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

Study Design

Study Type: Phase 3, adaptive, randomized, single-blind, controlled trial
Randomization: Yes
Blinding: Single-blind (participants blinded, investigators not)
Sample Size: 514
Follow-up: 90 days
Centers: 57
Countries: United States

Primary Outcome

Definition: Utility-weighted mRS score at 90 days

Control	Intervention	HR/OR	P-value
6.8 ± 3.0	5.2 ± 3.7 (argatroban), 6.3 ± 3.2 (eptifibatide)	- (−1.51±0.51 (argatroban), −0.50±0.29 (eptifibatide))	-

Limitations & 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

Citation

N Engl J Med 2024;391(9):810–820

View Original Publication →

MOST

Adjunctive Antithrombotic Therapy After Thrombolysis for Acute Ischemic Stroke

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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