Thrombolysis Alone vs With Argatroban or Eptifibatide: A Prespecified Subgroup Analysis of the MOST Trial.

IV thrombolysis only (IVT-O) is the primary reperfusion therapy for most stroke patients. At least 50% of IVT-O patients remain disabled. We assessed 2 therapies added to IVT-O aimed at increasing clot lysis or preventing arterial reocclusion. This 3-arm, adaptive, single-blinded, randomized controlled phase III clinical trial was conducted at 57 US sites. Patients with acute ischemic stroke (AIS) within 3 hours of onset receiving IV tissue plasminogen activator or tenecteplase were randomized to argatroban (100 μg/kg bolus and 12-hour infusion at 3 μg/kg/min), eptifibatide (135 μg/kg bolus and 2-hour infusion at 0.75 μg/kg/min), or placebo (bolus and 12-hour infusion). The primary end point was utility-weighted 90-day modified Rankin Scale score (uwmRS score; worst = 0, best = 10). This prespecified secondary analysis was conducted on the intent-to-treat population in the IVT-O cohort using a Bayesian normal dynamic linear model. Of 514 patients enrolled into Multi-arm Optimization of Stroke Thrombolysis (MOST) before the study was stopped for futility, 260 were in the IVT-O cohort (118 treated with placebo, 114 with eptifibatide, and 28 with argatroban; mean age 66 years, 46.9% female). Baseline variables were similar across groups (median NIH Stroke Scale score 8, mean time from symptom onset to IVT 105 minutes, mean time from IVT bolus to study drug start 62 minutes). A clot was visible in 30.8% of patients. There was only a 1% or 2.5% chance that argatroban or eptifibatide, respectively, was superior to placebo for the primary outcome (mean uwmRS scores SD of 5.5 3.6, 6.6 3.2, and 7.4 2.6 for argatroban, eptifibatide, and placebo, respectively). No secondary outcomes favored either treatment group. The risk difference for symptomatic hemorrhage between the argatroban and eptifibatide arms vs placebo was -0.8% (p = 0.82) and 1.8% (p = 0.36). Mortality was 3.4% with placebo, 14.3% for argatroban (p = 0.03), and 11.4% for eptifibatide (p = 0.02). There was no benefit in any subgroup. Outcomes in patients treated with IVT-O were not improved by adding either argatroban or eptifibatide. Increased bleeding was not observed, but mortality was higher in both investigational arms. Limitations included small sample size in the argatroban subgroup. This study was registered on ClinicalTrials.gov (registration number: NCT03735979) on November 8, 2018. The first patient was enrolled on October 15, 2019. This study provides Class II evidence that in patients with AIS treated with IVT within 3 hours of onset, argatroban or eptifibatide does not improve outcomes vs thrombolysis alone but does increase mortality.