AcT
Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial
Clinical Question
Is intravenous tenecteplase (0.25 mg/kg) non-inferior to alteplase (0.9 mg/kg) in patients with acute ischaemic stroke presenting within 4.5 h of symptom onset?
Study Overview
Objective
To determine whether intravenous tenecteplase (0.25 mg/kg) is non-inferior to alteplase (0.9 mg/kg) in patients with acute ischaemic stroke eligible for intravenous thrombolysis within 4.5 h of symptom onset.
Study Summary
- Tenecteplase met non-inferiority vs alteplase for 90–120 day mRS 0–1: 36.9% (296/802) vs 34.8% (266/765); unadjusted risk difference 2.1% (95% CI –2.6 to 6.9), exceeding the prespecified –5% non-inferiority threshold
- Symptomatic intracerebral haemorrhage at 24 h was similar: 3.4% (27/800) tenecteplase vs 3.2% (24/763) alteplase
- 90-day mortality was similar: 15.3% (122/796) tenecteplase vs 15.4% (117/763) alteplase
Intervention
Single intravenous bolus of tenecteplase 0.25 mg/kg (max 25 mg) compared with intravenous alteplase 0.9 mg/kg (max 90 mg; 0.09 mg/kg bolus followed by 60 min infusion of remaining 0.81 mg/kg).
Patients per Arm
Tenecteplase n=806; Alteplase n=771 (ITT)
Bottom Line
Intravenous tenecteplase 0.25 mg/kg given as a single bolus is non-inferior to alteplase 0.9 mg/kg (bolus + infusion) for 90–120 day functional outcome (mRS 0–1) in acute ischaemic stroke patients eligible for thrombolysis within 4.5 h, with similar safety. Tenecteplase is a reasonable alternative to alteplase as standard-of-care thrombolytic.
Major Points
- First phase 3 RCT to demonstrate non-inferiority of tenecteplase 0.25 mg/kg vs alteplase 0.9 mg/kg for 90–120 day mRS 0–1 in acute ischaemic stroke within 4.5 h.
- Primary outcome (mRS 0–1 at 90–120 days): 36.9% tenecteplase vs 34.8% alteplase; unadjusted risk difference 2.1% (95% CI –2.6 to 6.9), meeting the prespecified –5% non-inferiority threshold.
- Safety profile comparable: 24 h symptomatic intracerebral haemorrhage 3.4% vs 3.2%; 90-day mortality 15.3% vs 15.4%.
- Pragmatic, registry-linked, multicentre design across 22 Canadian primary and comprehensive stroke centres enhances generalisability.
- Single-bolus administration of tenecteplase offers workflow advantages, especially for drip-and-ship and endovascular thrombectomy candidates.
Design
Study Type: Pragmatic, multicentre, open-label, parallel-group, registry-linked, randomised, controlled, non-inferiority trial with blinded outcome assessment
Randomization: 1
Blinding: Open-label treatment allocation; blinded (central, masked) outcome assessment via standardised telephone interviews
Allocation: 1:1 using a previously validated minimal sufficient balance algorithm to balance allocation by site; fully concealed via secure real-time web-based server
Enrollment Period: Dec 10, 2019 to Jan 25, 2022
Follow-up Duration: Up to 120 days after randomisation (primary outcome at 90–120 days)
Centers: 22
Countries: Canada
Sample Size: 1600
Analyzed: 1577
Analysis: Intention-to-treat (ITT) for primary outcome (all randomised who did not withdraw consent); per-protocol as secondary exploratory; safety in all treated patients
Power Calculation: Assuming 35% mRS 0–1 in alteplase and 38% in tenecteplase, one-sided non-inferiority margin of 5% and one-sided α of 0.025, total sample of 1600 ensured ≥90% power with up to 5% loss to follow-up
Registration: ClinicalTrials.gov NCT03889249
Inclusion Criteria
- Age ≥18 years
- Diagnosis of ischaemic stroke causing disabling neurological deficit
- Presentation within 4.5 h of symptom onset
- Eligible for intravenous thrombolysis per Canadian Stroke Best Practice Recommendations (CSBPR 2018)
- Patients also eligible for endovascular thrombectomy were eligible for enrolment
Exclusion Criteria
- Standard contraindications to intravenous thrombolysis per CSBPR (e.g., active haemorrhage or condition increasing risk of major haemorrhage after alteplase)
- Pregnancy (per medical history/exam) without consultation with an expert stroke physician
Arms
| Field | Tenecteplase | Control |
|---|---|---|
| N | 806 | 771 |
| Intervention | Intravenous tenecteplase as a one-time decile-weight-tiered bolus of 0.25 mg/kg (maximum 25 mg) | Intravenous alteplase total dose 0.9 mg/kg (maximum 90 mg), given as 0.09 mg/kg bolus followed by 60 min infusion of remaining 0.81 mg/kg |
| Duration | Single bolus | Bolus + 60 min infusion |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Proportion of patients with a modified Rankin Scale (mRS) score of 0–1 (intention-to-treat) | Primary | 34.8% (266/765) alteplase | 36.9% (296/802) tenecteplase | Unadjusted risk difference 2.1% (favoring tenecteplase); non-inferiority met (lower 95% CI > –5%) | |
| 90–120 day mRS score of 0–2 | Secondary | ||||
| Actual 90–120 day mRS score (ordinal) | Secondary | ||||
| Return to baseline function at 90 days | Secondary | ||||
| 90–120 day EQ-VAS and EQ-5D-5L | Secondary | ||||
| Door-to-needle time | Secondary | ||||
| Proportion of patients given endovascular therapy | Secondary | ||||
| Recanalisation status at first angiographic acquisition (extended TICI and revised AOL) in patients taken for endovascular therapy | Secondary | ||||
| Baseline CT to arterial puncture time in patients undergoing endovascular therapy | Secondary | ||||
| Cognition via brief online cognitive assessment (to be reported separately) | Secondary | ||||
| Length of hospital stay (post-hoc) | Secondary | ||||
| Discharge destination | Secondary | ||||
| 24 h symptomatic intracerebral haemorrhage: 3.4% (27/800) tenecteplase vs 3.2% (24/763) alteplase | Safety | ||||
| 90-day all-cause mortality: 15.3% (122/796) tenecteplase vs 15.4% (117/763) alteplase | Safety | ||||
| Orolingual angio-oedema within 24 h of thrombolysis (data not detailed in abstract) | Safety | ||||
| Extracranial bleeding requiring blood transfusion within 24 h (data not detailed in abstract) | Safety | ||||
| 24h Symptomatic ICH - Tenecteplase | Adverse | 27/800 (3.4%) | |||
| 24h Symptomatic ICH - Alteplase | Adverse | 24/763 (3.2%) | |||
| 90-day Mortality - Tenecteplase | Adverse | 122/796 (15.3%) | |||
| 90-day Mortality - Alteplase | Adverse | 117/763 (15.4%) | |||
Subgroup Analysis
Prespecified subgroups assessed for heterogeneity of treatment effect: age (<80 vs ≥80), sex, baseline NIHSS (<8 vs 8–15 vs >15), symptom onset-to-needle time (≤180 vs >180 min), large vessel occlusion (yes/no including ICA, M1 MCA, or functional M1 MCA on CTA), type of enrolling centre (comprehensive vs primary stroke centre), and source registry (OPTIMISE vs QuiCR). All exploratory; per the trial, results were consistent across subgroups.
Criticisms
- Open-label design (treatment allocation not masked to clinicians or patients), although outcome assessment was blinded
- Single-country (Canada) enrolment may limit generalisability to other health systems
- Race and ethnicity data not collected
- Non-inferiority margin of 5% on absolute risk difference is generous and could mask a clinically meaningful inferiority
Funding
Canadian Institutes of Health Research; Alberta Strategy for Patient Oriented Research Support Unit. Funders had no role in study design, data collection, analysis, interpretation, or report writing.
Based on: AcT (The Lancet, 2022)
Authors: Menon BK, Buck BH, Singh N, ..., Field TS
Citation: Lancet. 2022 Jul 16-22;400(10347):161-169.
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