medwireNews: Combining intravenous argatroban or eptifibatide with thrombolysis for acute ischemic stroke patients may not reduce poststroke disability and could be associated with increased mortality, suggests a study published in The New England Journal of Medicine.
The MOST trial investigators conducted the single-blind phase 3 trial following “a favorable direction of effect” in three phase 2 trials of the anticoagulant argatroban when administered adjunctively with thrombolysis for acute ischemic stroke and “equivocal effects” with adjunctive platelet inhibition with eptifibatide.
They randomly assigned 514 patients, from 57 sites in the USA, who had undergone thrombolysis (70% alteplase, 30% tenecteplase) within 3 hours of stroke onset, to receive either of the two drugs or placebo no more than 75 minutes after thrombolysis.
Argatroban was given as a bolus of 100 µg/kg followed by an infusion of 3 µg/kg per minute over a 12-hour period (n=59), eptifibatide was given as a bolus of 135 µg/kg followed by an infusion of 0.75 µg over 2 hours and then 10 hours of saline (n=227), while placebo was given as a bolus followed by 12-hour infusion (n=228).
The patients had a median age of 67 years, 50% were men, 25% were Black, and 8% were Hispanic or Latino. They had a score of at least 6 points on the 42-point National Institutes of Health Stroke Scale, where higher scores indicate worse neurological deficit. Around half of patients in each of the groups had endovascular thrombectomies planned at the time of randomization.
The investigators point out that “the trial groups were similar in terms of predictive variables that affect ischemic stroke outcomes.” The only exceptions were that patients in the argatroban group were more likely than those in the eptifibatide and placebo groups to have a history of atrial fibrillation (31 vs 16 and 18%, respectively) or to have received alteplase thrombolysis (88 vs 69 and 66%), and they were less likely to have a previous stroke (14 vs 22 and 18%).
Opeolu Adeoye (Washington University, St Louis, Missouri, USA) and colleagues explain that trial enrollment was stopped in July 2023 on the recommendation of the data and safety monitoring board after an interim analysis at 30 days of follow-up for the first 500 patients enrolled. This showed that both drugs had less than a 0.1% chance of achieving a significant benefit in terms of improvement on the modified Rankin Scale (mRS) at 90 days, which was below the prespecified probability threshold for futility of 20% or above.
They report that at the 90-day follow-up, mean scores on the 0–10-point mRS, with higher scores reflecting better functional outcomes, were 5.2 points among patients in the argatroban arm, 6.3 points for those in the eptifibatide arm, and 6.8 points for those given placebo. This translated to probabilities that argatroban and eptifibatide were better than thrombolysis alone of 0.2% and 4.1%, respectively.
Mortality rates at 90 days were 24% with argatroban, 12% with eptifibatide, and 8% with placebo. None of the 13 deaths in the argatroban group were attributed to treatment, but six of the 26 in the eptifibatide group and three of 18 in the placebo group were possibly treatment related.
The researchers report that the incidence of symptomatic intracranial hemorrhage at 36 hours was similar, at 4%, 3%, and 2% among those given argatroban, eptifibatide, and placebo, respectively, as was the incidence of parenchymal hemorrhage type 1 or 2 within 36 hours, and that of other major systemic hemorrhages within 7 days.
However, the incidence of any intracranial hemorrhage within 36 hours was numerically higher in the argatroban group, at 37%, compared with rates of 24% in both the eptifibatide and placebo arms. At least one serious adverse event occurred in 44% of patients in the argatroban group and in 37% and 34% of those in the eptifibatide and placebo groups, respectively.
In summary, Adeoye and team say that the findings “raise the question of whether the addition of any anticoagulant or antiplatelet therapy to current standard of thrombolysis followed by thrombectomy in patients with ischemic stroke is a viable approach.”
They note, however, that their trial did not “address the potential effect of adjunctive ‘intra-arterial’ antithrombotic medications in patients undergoing thrombectomy, which may offer more directly targeted effects on cerebral microperfusion than systematically administered intravenous medications.”
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