Adding either argatroban or eptifibatide to thrombolytic therapy doesn’t improve function following an ischemic stroke, results of new research show.
“Ultimately, we found no benefit for either medication added to standard-of-care thrombolysis in terms of improving stroke outcomes,” lead study author Opeolu M. Adeoye, MD, professor of emergency medicine and department chair, Washington University School of Medicine, St Louis, Missouri, told Medscape Medical News.
The results were surprising and disappointing for Adeoye. “W e went into the trial hopeful and thinking we would be able to benefit patients in reducing disability from stroke,” he said.
The Multi-arm Optimization of Stroke Thrombolysis (MOST) trial was stopped early due to futility following recommendations from the data and safety monitoring board. The findings were presented at the International Stroke Conference (ISC) 2024, being held in Phoenix.
A thrombolytic drug alone doesn’t help all patients, particularly those with larger clots. “Clots can open; they can reform; they can re-occlude, etc.,” said another author, Andrew D. Barreto, MD, associate professor, Department of Neurology, University of Texas Health Science Center, Houston. “The thought was that adding additional medications that thin the blood, like argatroban or eptifibatide, would amplify the effects of the clot-busting drug.”
Indeed, this approach has had success in cardiology in terms of blood vessel opening, said Adeoye, adding that some preclinical data suggest that antithrombotic drugs may be neuroprotective.
And six phase 2 studies going back over a dozen years suggested that these drugs are safe in stroke patients. Although these studies weren’t powered for efficacy, “we did see a signal that adding them would be better than just the clot-busting drug alone,” findings that prompted the current phase 3 trial, said Barreto.
The three-arm, single-blind MOST trial included 514 adult patients with acute ischemic stroke and a National Institutes of Health Stroke Scale (NIHSS) score of 6 or greater at 57 US centers, mean age about 68 years, 70% White/25% Black, and with about equal numbers of female and male patients.
All received standard stroke care including thrombolysis within 3 hours of symptom onset. Initially, researchers used intravenous alteplase (0.9 mg/kg), but as the standard of care changed over time, they began using tenecteplase (0.25 mg/kg).
Study patients were also randomly assigned to receive placebo or either argatroban (100 µg/kg bolus followed by 3 µg/kg per minute for 12 hours) or eptifibatide (135 µg/kg bolus followed by 0.75 µg/kg/min infusion for 2 hours). These treatments were initiated within 75 minutes of thrombolysis.
Two Different Mechanisms
The drugs have different mechanisms of action. Argatroban is an anticoagulant, a direct inhibitor of thrombin, while the antiplatelet eptifibatide blocks the glycoprotein IIb/IIIa receptor and was specifically developed to ensure rapid inhibition of platelet aggregation.
Patients could also receive endovascular thrombectomy as part of their usual care. In this study, about 44% of patients received this treatment.
The primary endpoint was 90-day utility weighted modified Rankin Scale (uw-mRS) scores, where the worst outcome is 0 and the best outcome is 10.
The study used a response-adaptive randomization design, where the randomization switches from a drug that doesn’t appear to have a chance of working to the arm more likely to be beneficial.
Of the 514 patients, the analysis included 228 in the placebo, 59 in the argatroban, and 227 in eptifibatide groups. Of the total, 421 completed the study.
The mean 90-day uw-mRS was 6.8 in the placebo group, 5.2 in the argatroban group, and 6.3 in the eptifibatide group.
The probability of argatroban being better than placebo was 0.2%; the probability of eptifibatide being better than placebo was 0.9%. The futility threshold was enrollment of 500 and less than a 20% chance of benefit, thus the decision to stop the trial.
In all subgroup analyses, which looked at age, stroke severity, the two thrombolytic drugs, and use of endovascular therapy, “we didn’t really see much of a signal that would suggest that’s the group we would need to be testing further,” said Barreto.
No Increased ICH Risk
The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours of randomization. The researchers found no significant increase in rates of this outcome.
The argatroban cohort had significantly lower odds of favorable outcomes compared with placebo, noted Adeoye. For example, it had more all-cause deaths, although none were related to the study drug.
Speculating on why the intervention didn’t work, Barreto pointed to changes in standard of care between the earlier trials and the current one, including the incorporation of endovascular therapy and switch to tenecteplase.
Although the results were disappointing, Adeoye sees a bright side. “What we’re very proud of, and excited about, is the fact that we have a definitive answer on these two drugs, and we did it in one trial as opposed to sequential, separate ongoing trials.”
But he stressed that more work needs to be done, especially given that even with endovascular therapy, half of stroke patients don’t achieve independence.
“In this trial, we established that argatroban and eptifibatide added to thrombolysis did not work, but that doesn’t address the fact that we need to continue to see what we can do to improve the total proportion of stroke patients who, after our treatments, are functionally independent 90 days after the stroke.”
Down the Rabbit Hole
Commenting on the research, Larry B. Goldstein, MD, professor and chair, Department of Neurology, University of Kentucky, praised the study’s adaptive design, noted that the hypothesis the study was based on was “reasonable” given the concern about additional thromboses, and found the results useful.
“The goal is not only to see what works but also what doesn’t work so we don’t go down that rabbit hole.”
He also pointed out that because the two blood-thinning drugs studied have very different mechanisms of action, it’s unlikely that another antithrombotic would add benefit to thrombolysis, “but you never say never.”
Adeoye and Barreto report research funding from the National Institutes of Health/National Institute of Neurological Disorders and Stroke. Adeoye also reports an executive role, receiving royalties/being a patent beneficiary, Sense Diagnostics, Inc. Goldstein has no relevant conflicts of interest.
Source link : https://www.medscape.com/viewarticle/adding-antithrombotic-tpa-does-not-improve-stroke-outcome-2024a10002us?src=rss
Publish date : 2024-02-08 16:16:24
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