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A new trial has found the thrombolytic reteplase to be superior to alteplase in patients with acute ischemic stroke presenting within 4.5 hours of symptom onset, with an excellent functional outcome at 90 days.

The Chinese RAISE trial also showed a higher rate of intracranial hemorrhage with reteplase than with alteplase, although the incidence of symptomatic intracranial hemorrhage and death were similar in the two groups.

Reteplase, a recombinant plasminogen activator given as two bolus doses 30 minutes apart, had previously been used in the treatment of acute myocardial infarction (MI) but, until now, has not been pursued for a stroke indication, lead investigator Shuya Li, MD, Beijing Tiantan Hospital, Beijing, China, and collaborators wrote.

While the demand for intravenous thrombolysis in acute ischemic stroke has increased substantially with the continuous improvement in the quality of stroke care, "the development of diverse, effective, and affordable thrombolytic agents is still needed," they added.

The findings were published online on June 14 in The New England Journal of Medicine.

Reteplase vs Alteplase?

Double-bolus administration of reteplase has been shown to increase the incidence of successful reperfusion and reduce the incidence of early re-thrombosis compared with single-bolus administration, and the safety profile of single-bolus and double-bolus administration regimens remains consistent.

A previous phase 2 trial suggested better outcomes with two 18-mg doses of reteplase than with two 12-mg doses or with alteplase at a dose of 0.9 mg/kg in patients with acute ischemic stroke. The higher dose of reteplase was not associated with an increased risk for fatal bleeding.

For the phase 3 RAISE trial, 1412 patients with ischemic stroke within 4.5 hours of symptom onset received intravenous reteplase (a bolus of 18 mg followed 30 minutes later by a second bolus of 18 mg) or intravenous alteplase (0.9 mg/kg of body weight; maximum dose, 90 mg).

The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin scale at 90 days. This occurred in 79.5% of the patients in the reteplase group vs 70.4% of those in the alteplase group (risk ratio [RR], 1.13; P < .001 for noninferiority and P = .002 for superiority).

A good functional outcome (modified Rankin scale score of 0-2 at 90 days) was reported in 85.3% of the patients in the reteplase group and 79.8% of those in the alteplase group (RR, 1.07; 95% CI, 1.02-1.12).

The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after symptom onset. This was observed in 17 of 700 patients (2.4%) in the reteplase group and 14 of 699 of those (2.0%) in the alteplase group (RR, 1.21; 95% CI, 0.54-2.75).

The incidence of any intracranial hemorrhage at 90 days was higher with reteplase than with alteplase (7.7% vs 4.9%; RR, 1.59; 95% CI, 1.00-2.51), as was the incidence of adverse events (91.6% vs 82.4%; RR, 1.11; 95% CI, 1.03-1.20).

The researchers also noted that the percentage of patients who had an early dramatic recovery (defined as a decrease of at least four points in the NIHSS score or a score of no more than one point) at 24 hours was higher 58% with reteplase vs 48% with alteplase, which they suggested may indicate a higher incidence of recanalization with reteplase.

Tenecteplase Becoming Agent of Choice

Reteplase is mainly used in China for the treatment of acute MI, Professor Bruce Campbell, MBBS, head of neurology and stroke at The Royal Melbourne Hospital, Australia, told Medscape Medical News.

The RAISE trial was a well-conducted study, but tenecteplase is now becoming the thrombolytic of choice for acute ischemic stroke in many Western countries, he said.

"Given that tenecteplase has now been demonstrated to be superior to alteplase in meta-analysis and single bolus is easier than double bolus, I'd want to see head-to-head superiority against tenecteplase before considering using reteplase — which would require a large trial with uncertain prospects for success, which may not be feasible," said Campbell, who was not part of the study.

"However, if reteplase were substantially cheaper, there may be a role in some countries," he added.

Also commenting on the RAISE trial, Marc Fisher, MD, professor of neurology at Harvard Medical School, Boston, noted that while the findings suggest that "reteplase may be better than alteplase in a Chinese population, but we do not how they compare in a more heterogeneous population with more severe strokes," Fisher said. "We do not know how it compares to tenecteplase, and a head-to-head study will be required to assess that comparison."

Campbell and Fisher are both coauthors of the TRACE-III trial of tenecteplase in the late time window, which was presented at the recent European Stroke Organisation Conference and has now also been published online in The New England Journal of Medicine.

The RAISE trial was supported by China Resources Angde Biotech Pharma, the National Key Research and Development Program of China, the National Natural Science Foundation of China, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and the Beijing Municipal Science and Technology Commission. Li, Campbell, and Fisher reported no commercial disclosures.