Argatroban Improves Early Neurological Deterioration Following Ischemic Stroke

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Good functional outcome at 90 days was more prevalent among patients on argatroban plus antiplatelet therapy vs antiplatelet alone.

Findings from the EASE clinical trial (NCT04275180) showed that treatment with argatroban and antiplatelet therapy resulted in significantly greater likelihood of good functional outcome at 90 days in poststroke patients. Overall, the results provided evidence to support the use of argatroban in patients with early neurological deterioration (END).1

Published in Jama Neurology, the open-label trial featured 628 adults with acute ischemic stroke (AIS) who experienced END, defined as an increase of 2 or more points on the National Institutes of Health Stroke Scale (NIHSS) within 48 hours from symptom onset. Patients were randomized to argatroban (n = 314), a direct thrombin inhibitor, or control (n = 314), on top of receiving standard therapy based on guidelines. Argatroban was given intravenously for 7 days, with continuous infusion at a dose of 60 mg per day for 2 days, followed by 20 mg per day for 5 days.

Led by Xuting Zhang, MD, Department of Neurology, Zhejang University School of medicine, the trial’s primary end point was good functional outcome at 90 days, defined as modified Rankin Scale (mRS) scores of 0 to 3. The full analysis set population included 601 patients after accounting for withdrawals (n = 18), duplicate randomization (n = 1) and lost follow-up (n = 8).

At 90 days, the percentage of patients with mRS scores of 0 to 3 was 80.5% in the argatroban group and 73.3% in the control group. In the full analysis set population, the risk of having a good outcome showed was significantly different between the argatroban and control groups (unadjusted risk difference, 7.2 [95% CI, 0.6%-14.0%] RR, 1.10 [95% CI, 1.01-1.20] P = .04). The occurrence of adverse events (AEs) was similar across the 2 groups, including symptomatic intracranial hemorrhage, parenchymal hematoma, other bleeding events, and other common AEs.

READ MORE: Addition of Factor XIa Inhibitor Milvexian Fails to Reduce Stroke Risk

"Many questions remain. Combining antiplatelet therapy with low-dose anticoagulation has demonstrated efficacy for reducing vascular events, particularly stroke, in patients with chronic atherosclerotic disease,” Brett Cucchiara, MD, professor of neurology at the University of Pennsylvania, wrote in a related editorial.2 "Given the EASE trial results, should this same strategy be tested more extensively in acute stroke? If low-dose acute anticoagulation combined with antiplatelet therapy is effective in patients with early deterioration, would it be even more effective if targeted at patients at high risk of deterioration before they worsen? Currently available risk scores can effectively identify such patients."

Between the argatroban and control groups, there was no significant differences on secondary outcomes of mRS score 0-2, NIHSS score at 90 days, Barthel scale score at 90 days, and stroke or other vascular events within 90 days in the both the unadjusted and adjusted analysis. Notably, a subgroup analysis identified a potentially stronger effect of argatroban among female participants (argatroban vs control: female, 81.7% vs 65.5%; male, 79.9% vs 77.7%; P = .046).

Characteristics such as age, NIHSS score at randomization, reperfusion therapy, and time from the onset of symptom to randomization, did not have a significant impact on the effectiveness of argatroban in reducing the risks of the primary outcome. When comparing patients on dual vs mono antiplatelet therapy, investigators found no significant interaction beween subgroups receiving argatroban and different antiplatelet therapies.

Cucchiara added, “How do we reconcile the results of the EASE trial with results of trials of adjunctive parenteral anticoagulation in patients with large vessel occlusion undergoing mechanical thrombectomy, which show significantly more bleeding and no improvement in outcomes? Are these differences due to the specific type of anticoagulant, the dose, the underlying volume of infarcted tissue, or the presence or absence of residual thrombus? While (hopefully) more work is done to answer these important questions, in the meantime, these new data will undoubtedly fan the flames of the age-old controversy over if and when patients with acute stroke should be treated with parenteral anticoagulation."2

REFERENCES
1. Zhang X, Zhong W, Xue R, et al. Argatroban in patients with acute ischemic stroke with early neurological deterioration: a randomized clinical trial. JAMA Neurol. Published online January 8, 2024. doi:10.1001/jamaneurol.2023.5093.
2. Cucchiara B, Majersik JJ. The case of anticoagulation for progressing stroke: have we come full circle? JAMA Neurol. Published online January 8, 2024. doi:10.1001/jamaneurol.2023.5086
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