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EXtending the time for Thrombolysis in Emergency Neurological Deficits

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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: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1813046

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

Content summarized and formatted by NeuroTrials.ai.

EXTEND

(2019)

Objective

To investigate whether intravenous alteplase between 4.5 and 9.0 hours after stroke onset or on awakening with stroke symptoms results in better outcomes in patients with salvageable brain tissue on perfusion imaging.

Study Summary

• Alteplase resulted in higher percentage of patients with excellent outcome (mRS 0-1): 35.4% vs 29.5% (RR 1.44, P=0.04)
• Increased symptomatic ICH: 6.2% vs 0.9% (RR 7.22, P=0.05)
• Secondary ordinal analysis did not show significant functional improvement
• Trial stopped early after 225/310 patients due to loss of equipoise

Intervention

Randomized 1:1 to intravenous alteplase (0.9 mg/kg, max 90mg) or matching placebo between 4.5-9.0 hours after stroke onset or on awakening with stroke symptoms. Patients selected based on perfusion-diffusion mismatch on automated imaging.

Inclusion Criteria

Age ≥18 years, excellent functional status (mRS <2), NIHSS 4-26, hypoperfused but salvageable brain regions on automated perfusion imaging, perfusion-core mismatch ratio >1.2 with absolute difference >10ml and core <70ml

Study Design

Arms: Alteplase 0.9 mg/kg (max 90mg) vs matching placebo

Patients per Arm: Alteplase: 113 patients, Placebo: 112 patients

Outcome

• Primary (mRS 0-1): 35.4% alteplase vs 29.5% placebo (adjusted RR 1.44)
• Symptomatic ICH: 6.2% alteplase vs 0.9% placebo
• 90-day mortality: 11.5% alteplase vs 8.9% placebo (NS)

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)

Study Design

Study Type: Phase 3, investigator-initiated, multicenter, randomized, placebo-controlled trial
Randomization: Yes
Blinding: Double-blind (patients and investigators)
Sample Size: 225
Follow-up: 90 days
Centers: 28
Countries: Australia, New Zealand, Taiwan, Finland

Primary Outcome

Definition: Score of 0 or 1 on modified Rankin scale at 90 days (excellent functional outcome)

Control	Intervention	HR/OR	P-value
33/112 (29.5%)	40/113 (35.4%)	- (Adjusted RR 1.44 (1.01-2.06))	0.04

Limitations & 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

Citation

N Engl J Med 2019;380:1795-803. DOI: 10.1056/NEJMoa1813046

View Original Publication →

EXTEND

EXtending the time for Thrombolysis in Emergency Neurological Deficits

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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