Reteplase Versus Alteplase for Acute Ischemic Stroke - RAISE

Contribution To Literature:

The RAISE trial showed that in patients with acute ischemic stroke presenting within 4.5 hours of symptom onset, intravenous thrombolytic therapy with reteplase was associated with better functional outcomes but may carry slightly higher bleeding risk than alteplase.


The goal of the trial was to assess the efficacy and safety of reteplase compared with alteplase in the treatment of acute ischemic stroke.

Study Design

  • Randomized
  • Multicenter
  • Open-label
  • Noninferiority

Patients with acute ischemic stroke and symptom onset ≤4.5 hours were randomized in a 1:1 fashion to receive thrombolytic reperfusion therapy with intravenous reteplase (n = 707) or alteplase (n = 705). Reteplase was administered as a bolus of 18 mg over 2 minutes and repeated at 30 minutes. Alteplase was administered at 0.9 mg/kg (maximum dose 90 mg), with 10% of the dose administered as a bolus over 1 minute followed by a 60-minute infusion.

  • Total number of enrollees: 1,412
  • Duration of follow-up: 90 days
  • Median patient age: 63 years
  • Percentage female: 29%

Inclusion criteria:

  • Age 18-80 years
  • Acute ischemic stroke diagnosed based on symptoms and intracranial imaging
  • Last known well time ≤4.5 hours
  • Pre-stroke modified Rankin scale (mRS) score ≤1
  • National Institutes of Health Stroke Scale (NIHSS) score 4-25

Exclusion criteria:

  • Prior or current intracranial hemorrhage or other intracranial anatomic abnormality
  • NIHSS score 1a (level of consciousness) ≥2
  • Intracranial or intraspinal surgery, cerebral or other severe trauma, or stroke ≤3 months prior
  • Planned or prior endovascular recanalization therapy (ERT)
  • Bleeding diathesis, including platelet count <100,000/µL, therapeutic anticoagulation ≤24-48 hours prior, or high-risk gastrointestinal pathology ≤3 months prior
  • Uncontrolled hypertension despite therapy >185/110 mm Hg

Other salient features/characteristics:

  • Median NIHSS score: 6
  • Median time from symptom onset to reperfusion: 180 minutes
  • Percentage receiving rescue ERT: 3%

Principal Findings:

The primary efficacy outcome, mRS score ≤1 at 90 days, for reteplase vs. alteplase, was: 79.5% vs. 70.4% (relative risk [RR] 1.13, 95% confidence interval [CI] 1.05-1.21, pnoninferiority < 0.001, psuperiority = 0.002).

Secondary efficacy outcomes for reteplase vs. alteplase:

  • Median mRS at 90 days: 0 vs. 1 (odds ratio 0.61, 95% CI 0.27-0.95)
  • Decrease from baseline NIHSS score ≥4 points or score ≤1 at 7 days: 73.5% vs. 66.5% (RR 1.10, 95% CI 1.02-1.19)
  • Barthel Index score ≥95 at 90 days: 82.0% vs. 76.2% (RR 1.08, 95% CI 1.02-1.13)

Primary safety outcome, symptomatic intracranial hemorrhage at 36 hours, for reteplase vs. alteplase: 2.4% vs. 2.0% (RR 1.21, 95% CI 0.54-2.75, p = 0.64)

Secondary safety outcomes for reteplase vs. alteplase:

  • Any intracranial hemorrhage at 90 days: 7.7% vs. 4.9% (RR 1.59, 95% CI 1.00-2.51)
  • Clinically relevant nonmassive hemorrhage at 90 days: 5.4% vs. 2.4% (RR 2.23, 95% CI 1.03-4.84)
  • All-cause death at 90 days: 4.3% vs. 3.4% (RR 1.25, 95% CI 0.66-2.35)


The RAISE trial demonstrated that reteplase was superior to alteplase with respect to 90-day functional status after acute ischemic stroke treated primarily with intravenous thrombolytics. Although the incidence of symptomatic intracranial hemorrhage and death was not significantly different, exploratory secondary outcomes suggested that this increased efficacy may be associated with slightly higher overall bleeding risk. The authors note an overall higher incidence of excellent functional outcome even in the alteplase arm compared to prior data, which may be due to the relatively low median NIHSS score as well as differences in acute stroke pathology unique to this exclusively Asian study population. The study also excluded patients who were planned for ERT, which was performed in only a small number of patients. The current superiority data would support future investigations of reteplase in other populations, for whom the balance of increased efficacy versus potential bleeding risk may differ.


Li S, Gu HQ, Li H, et al., on behalf of the RAISE Investigators. Reteplase Versus Alteplase for Acute Ischemic Stroke. N Engl J Med 2024;Jun 14:[Epub ahead of print].

Clinical Topics: Vascular Medicine

Keywords: Ischemic Stroke, Thrombolytic Therapy

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