EXTEND
EXtending the time for Thrombolysis in Emergency Neurological Deficits
Year of Publication: 2019
Authors: H. Ma, B.C.V. Campbell, M.W. Parsons, ..., G.A. Donnan
Journal: New England Journal of Medicine
Citation: N Engl J Med 2019;380:1795-803. DOI: 10.1056/NEJMoa1813046
Link: https://nejm.org
PDF: Clinical Question
Does intravenous thrombolysis with alteplase initiated between 4.5 and 9.0 hours after stroke onset or on awakening with stroke symptoms provide benefit in patients with salvageable brain tissue?
Bottom Line
Among patients with ischemic stroke and salvageable brain tissue, alteplase between 4.5-9.0 hours resulted in higher percentage with excellent outcome but increased symptomatic hemorrhage risk.
Major Points
- Phase 3 multicenter randomized placebo-controlled trial stopped early at 225/310 patients
- Patients selected based on perfusion-diffusion mismatch on automated imaging
- Primary outcome (mRS 0-1) achieved in 35.4% alteplase vs 29.5% placebo (adjusted RR 1.44, P=0.04)
- Symptomatic ICH significantly higher: 6.2% vs 0.9% (RR 7.22, P=0.05)
- Secondary ordinal analysis did not show significant functional improvement
- 65% of patients awoke with stroke symptoms (unknown onset time)
- Trial terminated due to loss of equipoise after WAKE-UP trial publication
- Door-to-needle time approximately 2 hours (longer than guideline recommendations)
Design
Study Type: Phase 3, investigator-initiated, multicenter, randomized, placebo-controlled trial
Randomization: 1
Blinding: Double-blind (patients and investigators)
Enrollment Period: August 2010 to June 2018
Follow-up Duration: 90 days
Centers: 28
Countries: Australia, New Zealand, Taiwan, Finland
Sample Size: 225
Analysis: Intention-to-treat analysis using covariate-adjusted modified Poisson regression with robust error estimation, adjusted for age and NIHSS score. Ordinal logistic regression for mRS distribution. Stata software version 13
Inclusion Criteria
- Age ≥18 years
- Excellent functional status before enrollment (mRS <2)
- NIHSS score 4-26 at presentation
- Hypoperfused but salvageable brain regions on automated perfusion imaging
- Perfusion lesion-ischemic core mismatch ratio >1.2
- Absolute difference in volume >10ml
- Ischemic core volume <70ml
- Treatment within 4.5-9.0 hours after stroke onset or on awakening with stroke symptoms
Exclusion Criteria
- Investigator considering endovascular thrombectomy at time of enrollment
- Standard contraindications to thrombolysis
- Large vessel occlusion not a prerequisite for inclusion
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age - mean (SD) | 71.0±12.7 years | 73.7±11.7 years |
| Male | 58.9% | 52.2% |
| NIHSS score - median | 10.0 (6.0-16.5) | 12.0 (8.0-17.0) |
| Atrial fibrillation history | 32.1% | 40.7% |
| Geographic region - Australia/NZ/Finland | 78.6% | 79.6% |
| Geographic region - Taiwan | 21.4% | 20.4% |
| Time >4.5-6.0 hours | 9.8% | 10.6% |
| Time >6.0-9.0 hours | 25.0% | 24.8% |
| Awoke with stroke | 65.2% | 64.6% |
| Large vessel occlusion | 72.3% | 69.0% |
| Ischemic core volume - median | 2.4 (0-19.5) ml | 4.6 (0-23.2) ml |
| Perfusion lesion volume - median | 78 (47.7-111.8) ml | 74.3 (40.1-134.0) ml |
Arms
| Field | Alteplase | Control |
|---|---|---|
| Intervention | Intravenous alteplase 0.9 mg/kg (maximum 90mg) administered as 10% bolus and 90% infusion over 1 hour | Matching placebo administered in same manner as alteplase |
| Duration | Single dose over 1 hour | Single dose over 1 hour |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Score of 0 or 1 on modified Rankin scale at 90 days (excellent functional outcome) | Primary | 33/112 (29.5%) | 40/113 (35.4%) | 17 | 0.04 |
| Functional independence (mRS 0-2) at 90 days | Secondary | 48/112 (42.9%) | 56/113 (49.6%) | 1.36 | Not reported for secondary outcomes |
| Ordinal analysis of mRS distribution (functional improvement) | Secondary | Not specified | Not specified | Common OR 1.55 (0.96-2.49) | Not significant (CI crosses 1.0) |
| Reperfusion ≥50% at 24 hours | Secondary | 57/109 (52.3%) | 76/106 (71.7%) | 1.35 | Not adjusted for multiple comparisons |
| Symptomatic intracranial hemorrhage | Adverse | 1/112 (0.9%) | 7/113 (6.2%) | 7.22 | 0.053 |
| Death within 90 days | Adverse | 10/112 (8.9%) | 13/113 (11.5%) | 1.17 | 0.67 |
Subgroup Analysis
No significant interactions observed between trial group and subgroups including large-vessel occlusion status, time to intervention, age, or stroke severity.
Criticisms
- Trial terminated early at 73% of planned sample size due to loss of equipoise
- Secondary ordinal analysis did not show significant functional improvement
- Unadjusted analyses did not show significant differences for primary outcome
- Imbalances in baseline covariates (age, stroke severity) favored placebo group
- Door-to-needle time of ~2 hours longer than guideline recommendations
- Majority had large-vessel occlusion but endovascular therapy not widely available during study period
- No adjustment for multiple comparisons in secondary outcomes
- Limited power due to early termination
Funding
Australian National Health and Medical Research Council and Commonwealth Scientific and Industrial Research Organization Flagship Program. Taiwan sites supported by Ministry of Health and Welfare and Ministry of Science and Technology
Based on: EXTEND (New England Journal of Medicine, 2019)
Authors: H. Ma, B.C.V. Campbell, M.W. Parsons, ..., G.A. Donnan
Citation: N Engl J Med 2019;380:1795-803. DOI: 10.1056/NEJMoa1813046
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