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RAISE

Reteplase versus Alteplase for Acute Ischemic Stroke

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Year of Publication: 2024

Authors: Shuya Li, M.D., Hong-Qiu Gu, ..., for the RAISE Investigators

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2024;390:2264-73. DOI: 10.1056/NEJMoa2400314

Link: https://doi.org/10.1056/NEJMoa2400314

Clinical Question

Is reteplase (double 18-mg bolus) noninferior — and, if noninferior, superior — to alteplase for excellent 90-day functional outcome in patients with acute ischemic stroke treated within 4.5 hours after symptom onset?

Study Overview

Objective

To determine if reteplase is noninferior or superior to alteplase in patients with acute ischemic stroke treated within 4.5 hours.

Study Summary

Reteplase was superior to alteplase for excellent 90-day functional outcome.
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.

Patients per Arm

684 reteplase, 679 alteplase

Bottom Line

Among patients with acute ischemic stroke treated within 4.5 hours after symptom onset in China, intravenous reteplase (double 18-mg bolus, 30 minutes apart) was superior to standard alteplase for an excellent functional outcome at 90 days (mRS 0–1: 79.5% vs 70.4%; RR 1.13, 95% CI 1.05–1.21; P<0.001 for noninferiority and P=0.002 for superiority in a hierarchical test). Rates of symptomatic intracranial hemorrhage and 90-day mortality were similar between groups, but reteplase was associated with a higher incidence of any intracranial hemorrhage (7.7% vs 4.9%), clinically relevant nonmassive hemorrhage (5.4% vs 2.4%), and overall adverse events. Findings may not generalize outside the Asian, ≤80-year-old population studied; patients eligible for or planned to undergo endovascular thrombectomy were excluded (though 45 patients ultimately received rescue thrombectomy).

        Major Points
        1412 patients with acute ischemic stroke within 4.5 hours after symptom onset were randomized 1:1 at 62 sites in China (707 to reteplase, 705 to alteplase; ITT population).
Primary outcome (mRS 0–1 at 90 days): 79.5% (562/707) reteplase vs 70.4% (496/705) alteplase; risk ratio 1.13 (95% CI 1.05–1.21); risk difference 9.4 percentage points (95% CI 3.3–15.4); P<0.001 for noninferiority and P=0.002 for superiority.
Secondary efficacy outcomes all favored reteplase: mRS 0–2 at 90 days 85.3% vs 79.8% (RR 1.07); ordinal mRS common OR 0.61 (0.27–0.95); early dramatic recovery at 24 hr 58.1% vs 48.2%; Barthel ≥95 at 90 days 82.0% vs 76.2%.
Primary safety outcome — symptomatic ICH within 36 hr (ECASS III definition): 17/700 (2.4%) reteplase vs 14/699 (2.0%) alteplase; RR 1.21 (0.54–2.75); P=0.64.
Any intracranial hemorrhage within 90 days was higher with reteplase: 54 (7.7%) vs 34 (4.9%); RR 1.59 (1.00–2.51). Clinically relevant nonmassive hemorrhage was also higher: 5.4% vs 2.4%; RR 2.23 (1.03–4.84).
90-day mortality was similar: 30 (4.3%) reteplase vs 24 (3.4%) alteplase; RR 1.25 (0.66–2.35).
Median NIHSS at admission was 6 (IQR 5–8) in both groups; median time from symptom onset to bolus was 180 min (reteplase) vs 183 min (alteplase); median door-to-needle 59 vs 60 minutes.
Trial was NOT terminated early — reached the prespecified target of 1412 patients. Testing for superiority was prespecified as nested after noninferiority.
Patients with prior or planned endovascular thrombectomy were excluded; 45 patients (20 reteplase, 25 alteplase) received rescue thrombectomy during the trial.

      

Design

Study Type: Phase 3, multicenter, prospective, open-label, blinded-endpoint, randomized noninferiority trial with prespecified hierarchical superiority testing

Randomization: 1

Blinding: Open-label treatment. Outcomes assessed at 30 and 90 days by trained/certified neurologists unaware of trial-group assignments; 90-day mRS obtained by face-to-face or telephone interview. Independent clinical event committee (unaware of assignments) adjudicated intracranial and other clinically significant hemorrhage events and death.

Enrollment Period: March 21, 2022, to June 22, 2023

Follow-up Duration: 90 days

Centers: 62

Countries: China

Sample Size: 1412

Analysis: Intention-to-treat for efficacy outcomes (per Journal policy, replacing the mITT specified in the SAP); safety analyses in the safety population (randomized patients who received either drug and had ≥1 post-treatment safety evaluation; N=700 reteplase, 699 alteplase). Missing 90-day mRS data (3.0%; 22 reteplase, 20 alteplase) handled by multiple imputation (100 replicates; Rubin's rules). Noninferiority tested via Farrington–Manning score test with margin of RR ≥0.93 (preserving ≥50% of alteplase-vs-placebo effect); superiority tested hierarchically (established if lower 95% CI bound of RR >1). Risk ratios estimated with robust Poisson regression, trial center as random effect; risk differences via binomial regression with identity link; ordinal mRS via ordinal logistic regression (proportional-odds assumption assessed with chi-square score test). Prespecified sensitivity analyses included tipping-point analysis, per-protocol population, mITT analyses with alternative intercurrent-event strategies. Analyses conducted in SAS 9.4. All analyses beyond the primary were not adjusted for multiplicity.

Inclusion Criteria

Age 18 to 80 years
Disabling ischemic stroke with NIHSS score of 4 to 25 at admission
Able to receive intravenous thrombolysis within 4.5 hours after last known well
Excellent pre-stroke functional status (modified Rankin scale score ≤1)
No intracranial hemorrhage on brain imaging (noncontrast CT or MRI)
Eligible for intravenous thrombolysis under Chinese Stroke Association guidelines (consistent with US AHA/ASA and ESO guidelines)

Exclusion Criteria

Previously undergone or planned to undergo endovascular thrombectomy (based on EVT eligibility/planning, not LVO diagnosis per se; 45 patients received rescue thrombectomy during the trial)
(Age >80 years excluded via inclusion criterion)
Additional standard thrombolysis contraindications per Supplementary Appendix and protocol

Arms

Field	Reteplase Group	Control
Intervention	Reteplase 18 mg intravenous bolus × 2, each administered over 2 minutes; first bolus immediately after randomization and the second 30 minutes later. Standard stroke care per guidelines.	Alteplase 0.9 mg/kg IV (maximum 90 mg); 10% delivered as a bolus over 1 minute and the remainder infused over 60 minutes. Standard stroke care per guidelines.
Duration	Two boluses 30 minutes apart, then 90-day follow-up	60-minute infusion, then 90-day follow-up

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Excellent functional outcome — modified Rankin scale score of 0 or 1 at 90 days (ITT, with multiple imputation for missing data).	Primary	70.4% (496 of 705 patients)	79.5% (562 of 707 patients)	11	<0.001 for noninferiority (Farrington–Manning); 0.002 for superiority (hierarchical)
Good functional outcome — mRS 0–2 at 90 days	Secondary	79.8% (563 of 705)	85.3% (603 of 707)
Ordinal distribution of mRS at 90 days (common OR for a higher mRS, reteplase vs alteplase)	Secondary	Median mRS 1 (IQR 0–2)	Median mRS 0 (IQR 0–1)	Common OR 0.61 (0.27–0.95)
Early dramatic recovery at 24 hr (NIHSS decrease ≥4 points or NIHSS ≤1)	Secondary	48.2% (340 of 705)	58.1% (411 of 707)
Early dramatic recovery at 7 days (NIHSS decrease ≥4 points or NIHSS ≤1)	Secondary	66.5% (469 of 705)	73.5% (519 of 707)
Barthel Index score ≥95 at 90 days	Secondary	76.2% (537 of 705)	82.0% (580 of 707)
Symptomatic intracranial hemorrhage within 36 hr (ECASS III)	Adverse	2.0% (14 of 699)	2.4% (17 of 700)		0.64
Symptomatic intracranial hemorrhage within 7 days (ECASS III)	Adverse	2.1% (15 of 699)	2.4% (17 of 700)
Parenchymal hemorrhage type 2 within 36 hr (SITS-MOST)	Adverse	1.4% (10 of 699)	1.7% (12 of 700)
Any intracranial hemorrhage within 90 days	Adverse	4.9% (34 of 699)	7.7% (54 of 700)
Major hemorrhage within 90 days (ISTH)	Adverse	3.0% (21 of 699)	3.3% (23 of 700)
Clinically relevant nonmassive hemorrhage within 90 days (ISTH)	Adverse	2.4% (17 of 699)	5.4% (38 of 700)
Death within 90 days	Adverse	3.4% (24 of 699)	4.3% (30 of 700)
Death within 7 days	Adverse	1.6% (11 of 699)	1.6% (11 of 700)
Any adverse event	Adverse	82.4% (576 of 699)	91.6% (641 of 700)
Serious adverse event	Adverse	11.9% (83 of 699)	15.0% (105 of 700)

Criticisms

Open-label design (patients and treating clinicians aware of treatment assignment) — potential for performance/ascertainment bias despite blinded endpoint assessment.
Superiority was tested hierarchically after noninferiority rather than as a primary superiority trial; the Journal notes this yields less robust statistical support for the superiority finding.
Primary outcome data were missing for ~3% of patients (42 patients) and required multiple imputation.
Conducted entirely at Chinese sites in an Asian population — high atherothrombotic burden and higher excellent-outcome (mRS 0–1) rates than in TRACE-2 (62% tenecteplase / 58% alteplase) or AcT (37% tenecteplase / 35% alteplase) limit generalizability to non-Asian populations.
Excluded patients with prior or planned endovascular thrombectomy (based on EVT eligibility, not LVO diagnosis) — findings may not apply to patients selected for EVT; 45 patients (20 reteplase, 25 alteplase) received rescue thrombectomy during the trial.
Excluded patients >80 years old.
Women were underrepresented (~29–31% of each arm), further limiting generalizability.
Baseline strokes were mostly mild-to-moderate (median NIHSS 6); results may not extend to severe strokes.
Funded by the drug manufacturer (China Resources Angde Biotech Pharma), which also supplied both trial drugs free of charge.

Subgroup Analysis

No significant heterogeneity was observed across prespecified subgroups for the primary outcome (Figure 1). Prespecified subgroups were: age (18–60 vs >60 yr), sex (female vs male), NIHSS at admission (4–7 vs >7), pre-stroke mRS (0 vs 1–2), and time from symptom onset to administration (<3 h vs ≥3 h). Point estimates were numerically larger among patients aged >60 years (RR 1.20, 1.10–1.29) and those with NIHSS >7 (RR 1.29, 1.07–1.51).

Funding

China Resources Angde Biotech Pharma (manufacturer, provided both trial drugs free of charge and funded the trial but had no role in data analysis or interpretation); National Key Research and Development Program of China (grants 2022YFC2502400 and 2022YFC2502404); National Natural Science Foundation of China (grant U20A20358); Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant 2019-I2M-5-029); Beijing Municipal Science and Technology Commission (grant Z221100007422050).

Based on: RAISE (The New England Journal of Medicine, 2024)