PDF: RAISE
(2024)Objective
To determine if reteplase is noninferior or superior to alteplase in patients with acute ischemic stroke treated within 4.5 hours.
Study Summary
• Similar rates of symptomatic ICH and mortality.
• Trial conducted in a Chinese population.
Intervention
Reteplase (18 mg bolus ×2) versus Alteplase (0.9 mg/kg IV over 60 minutes) within 4.5 hours of stroke onset.
Inclusion Criteria
Adults with acute ischemic stroke, NIHSS 4–24, mRS 0–1, within 4.5 hours of onset, no intracranial hemorrhage.
Study Design
Arms: Reteplase vs. Alteplase
Patients per Arm: 684 reteplase, 679 alteplase
Outcome
• Symptomatic ICH: 2.4% vs 2.0%
• Any ICH: higher with reteplase (7.7% vs 4.9%)
Bottom Line
Reteplase was noninferior to alteplase for improving functional outcomes and had a similar safety profile in patients with acute ischemic stroke treated within 4.5 hours after symptom onset. Reteplase offers a practical advantage of single-bolus administration. However, the trial was terminated early for futility.
Major Points
- 1363 patients with acute ischemic stroke were randomized (684 to reteplase, 679 to alteplase) within 4.5 hours after symptom onset.
- The trial was terminated early because the prespecified futility criterion for noninferiority was met during the first interim analysis.
- A modified Rankin scale score of 0 to 1 at 90 days occurred in 48.7% of the reteplase group and 47.9% of the alteplase group (risk difference, 0.9 percentage points; 95% CI, -4.7 to 6.6; P for noninferiority <0.001; P for superiority = 0.77).
- Mortality at 90 days was 10.1% in the reteplase group and 10.5% in the alteplase group (risk difference, -0.4 percentage points; 95% CI, -4.0 to 3.3).
- Symptomatic intracranial hemorrhage occurred in 1.9% in the reteplase group and 1.8% in the alteplase group (risk difference, 0.1 percentage points; 95% CI, -1.2 to 1.5).
- The median time from onset to randomization was 175 minutes in the reteplase group and 172 minutes in the alteplase group.
- The median NIHSS score was 7 in both groups.
Study Design
- Study Type
- Multicenter, prospective, randomized, open-label, blinded-endpoint, noninferiority trial (Phase 3)
- Randomization
- Yes
- Blinding
- Blinded-endpoint evaluation by trained assessors unaware of treatment assignments. Central imaging review and adjudication of symptomatic intracranial hemorrhage by blinded committees.
- Sample Size
- 1363
- Follow-up
- 90 days
- Centers
- 122
- Countries
- China
Primary Outcome
Definition: Score of 0 to 1 on the modified Rankin scale (no or minimal disability) at 90 days.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 47.9% (325 of 679 patients) | 48.7% (333 of 684 patients) | - (-4.7 to 6.6 (difference)) | <0.001 (for noninferiority); 0.77 (for superiority) |
Limitations & Criticisms
- The trial was terminated early because the prespecified futility criterion for noninferiority was met, meaning it did not achieve its full planned sample size (1363 patients enrolled vs. 2700 planned). This limits its statistical power and may affect the robustness of the findings for superiority claims.
- The noninferiority margin of 6 percentage points used for the primary outcome was relatively large, potentially allowing for clinically meaningful differences within the noninferiority range.
- The study was open-label, meaning patients and investigators were aware of the treatment assignment, which could introduce bias, though outcome assessment was blinded.
- The study population was primarily Chinese, which may limit generalizability to other ethnic groups.
- The trial focused on patients without clear indication for endovascular thrombectomy, limiting generalizability to patients with large vessel occlusions who might benefit from thrombectomy.
- The median baseline NIHSS score was 7, indicating a relatively mild to moderate stroke severity, which might not be representative of all acute ischemic stroke patients.
Citation
N Engl J Med 2023;389:1270-81. DOI: 10.1056/NEJMoa2307895