EXPECTS
Alteplase for Posterior Circulation Ischemic Stroke at 4.5 to 24 Hours
Year of Publication: 2025
Authors: Shenqiang Yan, M.D., Ying Zhou, ..., and Min Lou
Journal: The New England Journal of Medicine
Citation: N Engl J Med 2025;392:1288-96.
Link: https://www.nejm.org/doi/10.1056/NEJMoa2413344
PDF: https://bookcafe.yuntsg.com/ueditor/jsp/...12651007782.pdf
PDF: Clinical Question
Does intravenous thrombolysis with alteplase, administered 4.5 to 24 hours after onset, improve functional outcomes in patients with posterior circulation ischemic stroke who do not have extensive early hypodensity on CT and do not undergo planned thrombectomy?
Bottom Line
In Chinese patients with mainly mild posterior circulation ischemic stroke who did not receive thrombectomy, alteplase administered 4.5 to 24 hours after stroke onset resulted in a higher frequency of functional independence at 90 days compared to standard medical care, with similar rates of symptomatic intracranial hemorrhage and lower mortality.
Major Points
- 234 patients were enrolled (117 alteplase, 117 standard treatment).
- A higher percentage of patients in the alteplase group achieved functional independence (mRS 0-2) at 90 days compared to the standard treatment group (89.6% vs. 72.6%; adjusted risk ratio, 1.16; 95% CI, 1.03 to 1.30; P=0.01).
- The median NIHSS score at randomization was 3 (IQR 2-6), indicating mostly mild strokes.
- The incidence of symptomatic intracranial hemorrhage within 36 hours was 1.7% in the alteplase group and 0.9% in the standard treatment group (unadjusted risk ratio, 1.98; 95% CI, 0.18 to 21.56).
- At 90 days, 5.2% of alteplase patients and 8.5% of standard treatment patients had died (unadjusted risk ratio, 0.61; 95% CI, 0.23 to 1.62).
- An ordinal analysis of mRS distribution showed functional improvement with an adjusted common odds ratio of 2.12 (95% CI, 1.31 to 3.43) favoring alteplase.
- Patients with planned thrombectomy were excluded, limiting generalizability to more severe strokes.
Design
Study Type: Prospective, multicenter, open-label, randomized trial with blinded outcome assessment
Randomization: 1
Blinding: Blinded outcome assessment by trained third-party personnel.
Enrollment Period: August 2022 through May 2024
Follow-up Duration: 90 days
Centers: 30
Countries: China
Sample Size: 234
Analysis: Primary analysis was intention-to-treat; effects reported as risk ratios with 95% CIs, adjusted for age, NIHSS score, and time from stroke onset to randomization. Ordinal logistic regression for mRS distribution. Two-sided P-value <0.05 considered significant. Multiple imputation for missing primary outcome data.
Inclusion Criteria
- Patients 18 years of age or older.
- Clinical signs of posterior circulation ischemic stroke.
- Symptom onset 4.5 to 24 hours before randomization.
- Posterior circulation Acute Stroke Prognosis Early CT Score (PC-ASPECTS) of 7 or higher.
- NIHSS score of 1 or higher.
- Prestroke modified Rankin scale score of 0 or 1.
Exclusion Criteria
- Extensive early hypodensity on CT.
- Planned endovascular treatment at the time of randomization.
- Guideline-based contraindications for alteplase other than the time window.
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Median age (IQR) - yr | 63 (55-74) | 64 (57-76) |
| Male sex no. (%) | 78 (66.7) | 75 (64.1) |
| Hypertension - no. (%) | 73 (62.4) | 83 (70.9) |
| Diabetes mellitus - no. (%) | 38 (32.5) | 40 (34.2) |
| Atrial fibrillation - no. (%) | 14 (12.0) | 9 (7.7) |
| Previous ischemic stroke - no. (%) | 12 (10.3) | 18 (15.4) |
| Score on the modified Rankin scale before stroke - 0 no. (%) | 114 (97.4) | 114 (97.4) |
| Score on the modified Rankin scale before stroke - 1 no. (%) | 3 (2.6) | 3 (2.6) |
| Median NIHSS score at randomization (IQR) | 3 (1-6) | 3 (2-6) |
| Median PC-ASPECTS at randomization (IQR) | 9 (8-10) | 9 (8-10) |
| Time from stroke onset to randomization - >4.5 to <9 hr no. (%) | 30 (25.6) | 26 (22.2) |
| Time from stroke onset to randomization - 9 to 24 hr no. (%) | 42 (35.9) | 41 (35.0) |
| Time from stroke onset to randomization - Unknown onset time no. (%) | 45 (38.5) | 50 (42.7) |
Arms
| Field | Alteplase Group | Control |
|---|---|---|
| Intervention | Intravenous alteplase (0.9 mg per kilogram of body weight; maximum dose, 90 mg), with 10% as bolus and remainder infused over 60 minutes). | Antiplatelet therapy and other treatments in accordance with the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke. |
| Duration | 60 minutes infusion (followed by 90-day follow-up) | Ongoing (followed by 90-day follow-up) |
| N | 117 | 117 |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Functional independence, defined as a score of 0 to 2 on the modified Rankin scale, at 90 days. | Primary | 85 of 117 patients (72.6%) | 103 of 115 patients (89.6%) | 1.16 | 0.01 |
| Ordinal distribution of the scores on the modified Rankin scale at 90 days | Secondary | Median 3 (IQR 1-6); distribution: mRS 0: 25.6%, mRS 1: 35.0%, mRS 2: 12.0%, mRS 3: 12.0%, mRS 4: 3.4%, mRS 5: 3.4%, mRS 6: 8.5% | Median 2 (IQR 1-4); distribution: mRS 0: 39.1%, mRS 1: 34.8%, mRS 2: 15.7%, mRS 3: 2.6%, mRS 4: 1.7%, mRS 5: 0.9%, mRS 6: 5.2% | 2.12 | |
| Absence of disability (mRS 0 or 1) at 90 days | Secondary | 71 of 117 patients (60.7%) | 85 of 115 patients (73.9%) | 1.16 | |
| Major neurologic improvement at 24 hr (reduction from baseline of ≥8 points on NIHSS or NIHSS score ≤1) | Secondary | 42 of 117 patients (35.9%) | 42 of 116 patients (36.2%) | 0.97 | |
| Major neurologic improvement at 7 days | Secondary | 55 of 113 patients (48.7%) | 65 of 116 patients (56.0%) | 1.11 | |
| Total score on EQ-5D at 90 days | Secondary | 0.5±0.4 | 0.5±0.4 | ||
| Score on visual analog scale on EQ-5D at 90 days | Secondary | 50±37.1 | 52.1±37.5 | ||
| Median infarct volume at 22-36 hr (IQR) - ml | Secondary | ||||
| Death within 90 days | Adverse | 10 of 117 patients (8.5%) | 6 of 115 patients (5.2%) | 0.61 | |
| Symptomatic intracranial hemorrhage within 36 hr after randomization (SITS-MOST definition) | Adverse | 1 of 115 patients (0.9%) | 2 of 116 patients (1.7%) | 1.98 | |
| Parenchymal hematoma within 36 hr after randomization | Adverse | 1 of 115 patients (0.9%) | 3 of 116 patients (2.6%) | 2.97 | |
| Any intracranial hemorrhage within 36 hr after randomization | Adverse | 5 of 115 patients (4.3%) | 11 of 116 patients (9.5%) | 2.18 | |
Criticisms
- The trial excluded patients with planned thrombectomy, limiting generalizability to patients presenting directly to thrombectomy-capable centers or with more severe strokes.
- The trial population primarily included patients with mild strokes, which may limit the generalizability to patients with more severe posterior circulation strokes.
- The use of alteplase was based on established efficacy at trial initiation, but future studies should explore tenecteplase for simplified administration and potential benefits.
Subgroup Analysis
No evidence of heterogeneity of treatment effect was detected in prespecified subgroups of age (<65 or ≥65 years), sex, NIHSS score at randomization (<10 or ≥10), time from stroke onset to randomization (>4.5 to <9 hours, 9 to 24 hours, or unknown onset time), PC-ASPECTS at randomization (<9 or ≥9), type of imaging evaluation before randomization, and stroke classification. Post hoc analyses of functional outcomes adjusted for age, NIHSS score at randomization, and time from stroke onset to randomization are provided in Supplementary Table S3.
Funding
National Natural Science Foundation of China
Based on: EXPECTS (The New England Journal of Medicine, 2025)
Authors: Shenqiang Yan, M.D., Ying Zhou, ..., and Min Lou
Citation: N Engl J Med 2025;392:1288-96.
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