RESCUE BT2
Tirofiban for Stroke without Large or Medium-Sized Vessel Occlusion
Clinical Question
In patients with acute ischemic stroke who have no occlusion of large or medium-sized vessels, is intravenous tirofiban more effective than oral aspirin for improving functional outcomes?
Study Overview
Objective
To evaluate the efficacy and safety of intravenous tirofiban compared to aspirin in patients with acute ischemic stroke without large or medium-sized vessel occlusion.
Study Summary
- Tirofiban led to a significantly higher rate of excellent outcome at 90 days compared to aspirin.
- No difference in overall disability or functional independence.
- Symptomatic intracranial hemorrhage occurred only in the tirofiban group.
Intervention
Multicenter, double-blind, double-dummy, randomized trial in China. Patients were assigned to receive either intravenous tirofiban (0.4 µg/kg/min bolus, then 0.1 µg/kg/min infusion for up to 48 hours) or oral aspirin (100 mg daily for 2 days), followed by open-label aspirin for all through 90 days.
Patients per Arm
Tirofiban: 606; Aspirin: 571
Bottom Line
In patients with acute ischemic stroke without large or medium-sized vessel occlusion, intravenous tirofiban was associated with a greater likelihood of excellent functional outcome at 90 days compared to oral aspirin, with a slightly higher incidence of symptomatic intracranial hemorrhage and no significant difference in mortality.
Major Points
- RESCUE BT2 was a multicenter, randomized, double-blind, double-dummy trial in China comparing intravenous tirofiban to oral aspirin in patients with acute ischemic stroke without large or medium-sized vessel occlusion.
- The primary endpoint was an excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 or 1.
- Tirofiban significantly improved the rate of excellent outcome versus aspirin (29.1% vs. 22.2%; adjusted risk ratio 1.26; P=0.02).
- The global outcome at 90 days was also improved with tirofiban (adjusted common odds ratio 1.38; P=0.01), but subsequent secondary outcomes were not statistically significant under hierarchical gatekeeping.
- Symptomatic intracranial hemorrhage was more frequent in the tirofiban group (1.0% [6/606] vs. 0% [0/571], P=0.03); mortality was similar (3.8% vs 2.6%, adjusted RR 1.62, P=0.12).
Design
Study Type: Multicenter, double-blind, double-dummy, randomized clinical trial.
Randomization: 1
Blinding: Double-blind, double-dummy.
Enrollment Period: October 20, 2020, through June 30, 2022.
Follow-up Duration: 90 days.
Centers: 117
Countries: China
Sample Size: 1177
Analysis: Modified intention-to-treat; risk ratios estimated using modified Poisson regression with adjustment for age, baseline NIHSS, thrombolysis status, and time to randomization. Secondary endpoints assessed with sequential gatekeeping.
Inclusion Criteria
- Age ≥18 years, able to complete usual activities of daily life without support before the stroke
- Acute ischemic stroke with NIHSS score ≥5 and at least one limb with an NIHSS motor item score of 2–4
- No visible large or medium-sized intracranial vessel occlusion on CTA, MRA, or DSA (nonocclusive stenoses and small penetrating-artery ischemia allowed)
- Presentation matched one of four scenarios: (1) within 24 h after last-known-well AND ineligible for IVT (e.g., arrival >4.5 h or contraindication) or ineligible for EVT (no large/medium vessel occlusion); (2) >24 h and <96 h after last-known-well but within 24 h after progression of ischemic stroke symptoms defined as NIHSS increase ≥2 points; (3) treated with IVT followed by early neurologic deterioration (NIHSS increase ≥4 within first 24 h); or (4) treated with IVT followed by no neurologic improvement (NIHSS decrease <2 points between 4 and 24 h after thrombolytic therapy)
Exclusion Criteria
- Imaging-confirmed intracranial hemorrhage
- Any definite source of cardiac embolism
- Prestroke modified Rankin Scale score ≥2
- History of intracranial hemorrhage
- History of major systemic hemorrhage
- Receipt of oral anticoagulants plus dual antiplatelet therapy within 1 week
- Uncontrolled hypertension
- Severe renal insufficiency
- Laboratory exclusion criteria met (per protocol thresholds)
- Intracranial tumor
- Preexisting neurologic or psychiatric disease
Arms
| Field | Control | Tirofiban |
|---|---|---|
| Intervention | Oral aspirin (100 mg per day) + intravenous placebo for 2 days, followed by open-label aspirin 100 mg daily to day 90. | Intravenous tirofiban (0.4 µg/kg/min for 30 min, then 0.1 µg/kg/min for up to 48 h) + oral placebo for 2 days, followed by open-label aspirin 100 mg daily to day 90. |
| Duration | 90 days | 90 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Excellent outcome (mRS 0–1) at 90 days. | Primary | 22.2% (126/567) | 29.1% (176/604) | 1.26 | 0.02 |
| Global outcome at 90 days (composite of mRS 0–1, NIHSS 0–1, Barthel Index 95–100, Glasgow Outcome Scale 5) | Secondary | — | — | 1.38 (95% CI, 1.07–1.78) | 0.01 |
| Shift in mRS distribution at 90 days | Secondary | Median mRS 2 (IQR 2–3) | Median mRS 2 (IQR 1–3) | 1.23 (95% CI, 1.00–1.51) | 0.06 |
| Functional independence (mRS 0–2) at 90 days | Secondary | 56.4% (320/567) | 62.1% (375/604) | 1.07 (95% CI, 0.98–1.16) | Not reported (hierarchical gatekeeping) |
| EQ-5D-5L score at 90 days (median, IQR) | Secondary | 0.78 (0.56–0.84) | 0.83 (0.64–0.93) | 1.40 (95% CI, 1.23–1.62) | Not reported (hierarchical gatekeeping) |
| Excellent outcome (mRS 0–1) at 30 days | Secondary | 16.9% (96/568) | 23.0% (139/605) | 1.29 (95% CI, 1.03–1.62) | Not reported (hierarchical gatekeeping) |
| Functional independence (mRS 0–2) at 30 days | Secondary | 46.3% (263/568) | 50.7% (307/605) | 1.06 (95% CI, 0.95–1.18) | Not reported (hierarchical gatekeeping) |
| Death at 90 days | Adverse | 2.6% (15/567) | 3.8% (23/604) | 1.62 (95% CI, 0.88–2.95) | 0.12 |
| Symptomatic intracranial hemorrhage within 48 hours (Heidelberg criteria) | Adverse | 0% (0/571) | 1.0% (6/606) | 0.03 | |
| Intracranial hemorrhage on any imaging | Adverse | 0% (0/571) | 1.0% (6/606) | 0.03 | |
| Serious adverse event | Adverse | 13.0% (74/571) | 16.0% (97/606) | 0.14 | |
| Any adverse event | Adverse | 61.1% (349/571) | 62.7% (380/606) | 0.58 | |
| Bleeding events - severe | Adverse | 0.2% (1/571) | 1.5% (9/606) | ||
| Bleeding events - moderate | Adverse | 0% (0/571) | 0.3% (2/606) | ||
| Bleeding events - mild | Adverse | 5.6% (32/571) | 9.7% (59/606) |
Subgroup Analysis
Subgroup analyses did not reveal any significant treatment effect heterogeneity. See Supplementary Appendix for details.
Criticisms
- Heterogeneous population spanning four different clinical presentations (limits generalizability to any single scenario).
- Only a small subset of patients received IV thrombolysis before enrollment.
- Lower than expected rate of excellent outcomes in both arms may reflect care quality or population differences.
- Follow-up imaging was not mandated unless neurologic deterioration occurred, limiting detection of asymptomatic hemorrhagic transformation.
- Conducted entirely in China (predominantly Han Chinese, ~95%) — limits generalizability to other populations.
- Presumed atherothrombotic mechanism in most patients; limited generalizability to cardioembolic strokes.
Funding
National Natural Science Foundation of China (Major Program, project number 82090040)
Based on: RESCUE BT2 (The New England Journal of Medicine, 2023)
Authors: W. Zi, J. Song, W. Kong, ..., and Q. Yang
Citation: N Engl J Med 2023;388:2025-36.
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