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Results revealed that adjunctive treatment with intravenous argatroban or eptifibatide was associated with increased mortality in acute ischemic stroke treated with intravenous thrombolysis.
Opeolu Adeoye, MD, MS
(Credit: Washington University in St. Louis)
Findings newly published in The New England Journal of Medicine from the phase 3 Multi-Arm Optimization of Stroke Thrombolysis (MOST) trial (NCT03735979) showed that adjunctive treatment with intravenous argatroban, an anticoagulant agent, or eptifibatide (Integrillin; Millennium Pharmaceuticals), an antiplatelet agent, failed to reach efficacy in reducing poststroke disability among patients with acute ischemic stroke (AIS) who were treated with intravenous thrombolysis within 3 hours after symptom onset.1,2
Among 514 patients with AIS who had received intravenous thrombolysis within 3 hours following symptom onset, the mean utility-weighted modified Rankin scale (mRS) scores were 5.2 (±3.7) for argatroban (n = 59), 6.3 (±3.2) with eptifibatide (n = 227), and 6.8 (±3.0) with placebo (n = 228) at 90 days. Overall, the posterior probability was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51 ± 0.51) that argatroban was better compared with the placebo and 0.041 (posterior mean difference, -0.50 ± 0.29) that eptifibatide was better in comparison with the placebo.
“We’re a little disappointed in the results. But it’s meaningful to optimal patient care that we’ve answered the question definitively. Neither of the drugs helps prevent further clots. Even with those treatments, over half of patients still have a significant disability three months after their stroke,” lead author Opeolu Adeoye, MD, MS, professor of emergency medicine at the Washington University in St. Louis, said in a statement.2 “After you give the thrombolysis, the clot can re-form, which contributes to the stroke worsening or persisting. When we looked at the data, it was readily apparent that neither drug was going to come anywhere close to our threshold.”
In this 3-group, adaptive, single-blind, randomized, controlled phase 3 study, investigators enrolled patients from 57 sites in the United States. Researchers assigned participants to receive intravenous argatroban, eptifibatide, or placebo in 75 minutes after the initiation of thrombolysis. Authors assessed the primary efficacy outcome, the utility-weighted 90-day mRS score (range from 0 to 10, with higher scores representing improved outcomes), by means of centralized adjudication. In addition, the researchers evaluated the primary safety outcome, symptomatic intracranial hemorrhage, in 36 hours after randomization.
Of all the patients who received intravenous thrombolysis, 70% received alteplase, 30% received tenecteplase, and 225 patients underwent endovascular thrombectomy (44%). In the 3 groups, authors observed that the incidence of symptomatic intracranial hemorrhage was 4% with argatroban, 3% with eptifibatide, and 2% with placebo. Additional findings showed that mortality was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%) at 90 days.
“Without negative trials, we would not know how to design new trials. Future success is built upon the hard work of previous research effort,” coauthor Peter Panagos, MD, professor of emergency medicine at Washington University in St. Louis, said in a statement.2 “Because we are involved in and lead most of the key basic science and clinical research for stroke and cerebrovascular patients nationally and internationally, we can bring the latest interventions to our patients in St. Louis and help advance treatment and prevention strategies. Our involvement in clinical trials helps bring the highest quality, most innovative treatments to our community.”
These results were previously presented at the 2024 International Stroke Conference (ISC), held February 7-9, in Phoenix, Arizona, by Adeoye, who treats patients at Barnes-Jewish Hospital and Missouri Baptist Medical Center, and senior author Andrew Barerrto, MD, MS, associate professor of neurosurgery, McGovern Medical School at UTHealth Houston.3 During the meeting, the duo sat down with NeurologyLive® to provide an overview of the methods of the trial and further discuss the findings.
Adeoye spoke about the reasons behind the unexpected negative impact of the adjunctive therapies in poststroke patients while Barerrto talked about how the trial’s prespecified design contributes to the understanding of the medications' efficacy. Both experts also shared their thoughts on the trial's limitations and their reactions to any surprising results uncovered in the analysis. In addition, Adeoye and Barerrto talked about the next steps for researchers in exploring alternative approaches to enhance thrombolysis performance.
