Trial Favors Reteplase Over Alteplase in Improving Functional Outcomes in Patients with Ischemic Stroke

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Data from the Phase III RAISE trial (NCT05295173) show treatment with reteplase has a greater likelihood of producing an excellent functional outcome compared to alteplase in patients with ischemic stroke within 4.5 hours after symptom onset.^1,2 While alteplase is the current internationally approved standard thrombolytic agent for acute ischemic stroke, alternative thrombolytic agents are needed, according to the authors of the study, published in The New England Journal of Medicine.¹

“The demand for intravenous thrombolysis in acute ischemic stroke has increased substantially with the continuous improvement in the quality of stroke care,” the study authors wrote. “From 2015 to 2019, the use of intravenous thrombolysis grew by 60.3%, reaching 22.9% among patients treated within 4.5 hours after symptom onset. The development of diverse, effective, and affordable thrombolytic agents is still needed.”¹

Alteplase is a tissue plasminogen activator indicated for the treatment of acute myocardial infarction to lower mortality and incidence of heart failure, pulmonary embolism associated with low blood pressure, and blocked central venous catheter, as well as for acute ischemic stroke.³

Reteplase, a recombinant plasminogen activator that utilizes a double-bolus approach with a fixed dose regimen, has been approved for acute myocardial infarction across several geographic regions. The investigators noted that a meta-analysis showed no significant differences between reteplase and alteplase in mortality or incidence of disabling stroke in patients with acute myocardial infarction.¹

The multicenter, prospective, open-label, noninferiority, randomized RAISE trial was conducted at 62 sites in China with a blinded end-point assessment. Patients between 18 and 80 years of age who had an ischemic stroke within 4.5 hours after symptom onset were randomly assigned in a 1:1 ratio to receive intravenous (IV) reteplase with a bolus of 18 mg followed 30 minutes later by a second bolus of 18 mg to compare with IV alteplase at a dose of 0.9 mg per kilogram of body weight with a maximum dose of 90 mg.

The trial’s primary efficacy outcome was excellent functional outcome defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]) at 90 days, with a primary safety outcome of symptomatic intracranial hemorrhage within 36 hours after symptom onset. In total, 707 patients were randomly assigned to the reteplase cohort and 705 were randomly assigned to the alteplase cohort.

Investigators observed an excellent functional outcome in 79.5% of the patients in the reteplase cohort compared to 70.4% of those in the alteplase cohort (risk ratio, 1.13; 95% confidence interval [CI], 1.05 to 1.21; P<0.001 for noninferiority and P=0.002 for superiority). Symptomatic intracranial hemorrhage within 36 hours following disease onset occurred in 2.4% of patients in the reteplase cohort compared to 2.0% in the alteplase cohort (risk ratio, 1.21; 95% CI, 0.54 to 2.75).

Incidence of any intracranial hemorrhage at 90 days was 7.7% in the reteplase cohort compared to 4.9% in the alteplase cohort (risk ratio, 1.59; 95% CI, 1.00 to 2.51). In terms of safety, 91.6% of patients in the reteplase cohort experienced an adverse event compared to 82.4% in the alteplase cohort (risk ratio, 1.11; 95% CI, 1.03 to 1.20). Investigators stated reteplase shows a favorable trade-off between efficacy and the risk of fatal bleeding compared to alteplase.

“Our trial showed that reteplase was superior to alteplase in improving patients’ functional outcomes without increasing the incidence of symptomatic intracranial hemorrhage and death among eligible patients with acute ischemic stroke,” the study authors wrote. “In addition, the percentage of patients who had an early dramatic recovery with respect to the NIHSS score at 24 hours was higher by 10 percentage points with reteplase than with alteplase. This finding suggests that the mechanism underlying the benefits of reteplase may involve a higher incidence of recanalization. There were safety concerns for reteplase in terms of any intracranial hemorrhage, clinically relevant nonmassive hemorrhage, and overall adverse events.”¹

References

1. Li, S, et al. Reteplase versus Alteplase for Acute Ischemic Stroke. N Engl J Med 2024;390:2264-2273. DOI: 10.1056/NEJMoa2400314. Vol. 390 No. 24

2. A Study of r-PA Treating Patients With Acute Ischemic Stroke (RAISE). ClinicalTrials.gov. March 4, 2024. https://clinicaltrials.gov/study/NCT05295173

3. Label for ACTIVASE [Supplement 5203, Action Date 02/13/2015]. fda.gov. Accessed July 15, 2024.