TEMPO-2
Tenecteplase Versus Standard of Care for Minor Ischaemic Stroke With Proven Occlusion (TEMPO-2): a randomised, open label, phase 3 superiority trial
Year of Publication: 2024
Authors: Shelagh B. Coutts, Sandeep Ankolekar, Ramana Appireddy, ..., Michael D. Hill
Journal: Lancet
Citation: Lancet 2024; 401(10444): 2597-2605
PDF: Clinical Question
Is intravenous tenecteplase (0.25mg/kg) superior to non-thrombolytic standard of care in preventing disability at 90 days in patients with minor ischaemic stroke (NIHSS ≤5) and intracranial occlusion presenting within 12 hours of onset?
Study Overview
Objective
To determine if intravenous tenecteplase (0.25mg/kg) is superior to non-thrombolytic standard of care for preventing disability in minor ischaemic stroke patients with intracranial occlusion within 12 hours of onset
Study Summary
- Tenecteplase did not improve return to baseline function compared to standard care (71.5% vs 74.8%, RR 0.96)
- More deaths occurred in the tenecteplase group (4.6% vs 1.1%, adjHR 3.8)
- Trial stopped early for futility; minor stroke with occlusion should not be routinely treated with IV thrombolysis
Intervention
Tenecteplase 0.25mg/kg IV bolus (max 50mg) vs non-thrombolytic standard of care (principally dual antiplatelet therapy)
Patients per Arm
Tenecteplase: 432; Control: 452
Bottom Line
Tenecteplase did not improve functional outcomes compared to standard care in minor stroke patients with intracranial occlusion, and was associated with increased mortality. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis.
Major Points
- Trial stopped early for futility after planned interim analysis (conditional power <1%)
- No difference in primary outcome: return to baseline mRS 71.5% tenecteplase vs 74.8% control (RR 0.96, 95% CI 0.88-1.04)
- Higher 90-day mortality in tenecteplase group: 4.6% vs 1.1% (adjHR 3.8, 95% CI 1.4-10.2, p=0.009)
- Trend toward more symptomatic ICH with tenecteplase: 1.9% vs 0.4% (RR 4.2, p=0.059)
- Higher early recanalization with tenecteplase (47.7% vs 21.6%) but no functional benefit
- More patients achieved NIHSS 0 at discharge with tenecteplase (57.8% vs 50%), but no 90-day benefit
- Control group predominantly received dual antiplatelet therapy (57.3%)
- Subgroup analyses suggested women and patients >80 years may fare worse with tenecteplase
Design
Study Type: Randomised, open-label with blinded endpoint assessment (PROBE), parallel group, phase 3 superiority trial
Randomization: 1
Blinding: Open-label treatment allocation with blinded outcome assessment at 90 days by certified raters
Enrollment Period: April 27, 2015 to January 19, 2024
Follow-up Duration: 90 days (median 92 days, IQR 85-99)
Centers: 48
Countries: Canada, Australia, United Kingdom, Singapore, Brazil, New Zealand, Finland, Austria, Spain, Ireland
Sample Size: 884
Analysis: Intention-to-treat analysis. Generalized linear modelling with Poisson distribution and log link function to generate risk ratios. Robust (Huber-Sandwich) standard error estimation. Cox proportional hazards model for mortality. Minimal sufficient balance randomisation algorithm.
Inclusion Criteria
- Age ≥18 years
- Functionally independent before stroke (baseline pre-stroke mRS 0-2)
- Minor stroke with NIHSS score ≤5
- Presented within 12 hours of last seen normal
- Direct imaging evidence of intracranial occlusion or indirect evidence with focal perfusion lesion relevant to presenting symptoms
- No region of well-evolved infarction concordant with acute presenting syndrome
- ASPECTS score ≥7
- Patient and physician judged that routine IV thrombolysis was not warranted
Exclusion Criteria
- Standard contraindications to intravenous thrombolysis
Baseline Characteristics
| Characteristic | Control | Tenecteplase |
|---|---|---|
| N | 452 | 432 |
| Age - median (IQR) | 72 (61-79) years | 72 (62-80) years |
| Female sex | 180 (39.8%) | 188 (43.5%) |
| Race - Caucasian | 382 (84.5%) | 371 (85.9%) |
| Race - Asian | 42 (9.3%) | 40 (9.3%) |
| Race - Black | 7 (1.5%) | 6 (1.4%) |
| Ethnicity - Hispanic | 9 (2.0%) | 5 (1.2%) |
| Hypertension | 261 (57.7%) | 265 (61.3%) |
| Past smoking | 176 (38.9%) | 172 (39.8%) |
| Hyperlipidemia | 172 (38.1%) | 180 (41.7%) |
| Diabetes mellitus | 86 (19.0%) | 82 (19.0%) |
| Past stroke | 85 (18.8%) | 72 (16.7%) |
| Atrial fibrillation | 78 (17.3%) | 91 (21.1%) |
| Ischaemic heart disease | 73 (16.2%) | 69 (16.0%) |
| Congestive heart failure | 18 (4.0%) | 16 (3.7%) |
| Chronic renal failure | 17 (3.8%) | 22 (5.1%) |
| Peripheral vascular disease | 15 (3.3%) | 13 (3.0%) |
| Past ICH | 1 (0.2%) | 3 (0.7%) |
| NIHSS - median (IQR) | 2 (1-3) | 2 (1-3) |
| Haemoglobin - median (IQR) | 141 (131-152) g/L | 140 (129-150) g/L |
| Glucose - median (IQR) | 6 (6-7) mM | 6 (6-7) mM |
| Creatinine - median (IQR) | 84 (70-97) µM | 82 (70-98) µM |
| ASPECTS - median (IQR) | 10 (9-10) | 10 (9-10) |
| Onset to randomization - median (IQR) | 273 (162-448) min | 286 (161-440) min |
| Onset to hospital arrival - median (IQR) | 151 (72-337) min | 148 (76-332) min |
| Onset to treatment - median (IQR) | 311 (184-495) min | 293 (165-453) min |
| Occlusion - LVO (ICA, M1) | 50 (11.1%) | 53 (12.3%) |
| Occlusion - MeVO (M2, A2 or distal) | 245 (54.4%) | 235 (54.5%) |
| Occlusion - Vertebrobasilar | 25 (5.6%) | 20 (4.6%) |
| Focal perfusion lesion only | 127 (28.2%) | 118 (27.4%) |
| No occlusion detected | 3 (0.7%) | 5 (1.2%) |
Arms
| Field | Tenecteplase | Control |
|---|---|---|
| Intervention | Tenecteplase 0.25mg/kg (maximum dose 50mg) as a single intravenous bolus administered over 5-10 seconds immediately after randomisation | Standard of care non-thrombolytic treatment; at minimum single agent antiplatelet therapy. Guideline-based care recommended with local investigator choice of antithrombotic regimen. Majority received dual antiplatelet therapy with aspirin and clopidogrel (57.3%) or aspirin monotherapy (23.5%) |
| Duration | Single bolus | Per clinical judgment |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Return to baseline neurological functioning measured by mRS using sliding dichotomy approach. Responder defined as: If pre-morbid mRS 0-1, then mRS 0-1 at 90 days; if pre-morbid mRS 2, then mRS 0-2 at 90 days | Primary | 338/452 (74.8%) | 309/432 (71.5%) | 0.2882 | |
| mRS 0-1 at 90 days | Secondary | 321/450 (71.3%) | 298/432 (69.0%) | RR 0.97 | |
| mRS 0-2 at 90 days (functional independence) | Secondary | 391/450 (86.9%) | 352/432 (81.5%) | RR 0.94 | |
| NIHSS = 0 at 5 days or discharge | Secondary | 226/452 (50.0%) | 247/427 (57.8%) | RR 1.16 | |
| Return to pre-morbid mRS | Secondary | 222/452 (49.1%) | 212/432 (49.1%) | RR 1.00 | |
| Mean mRS score at 90 days | Secondary | 1.11 | 1.27 | Difference 0.16 | |
| Median mRS at 90 days | Secondary | 1 (IQR 0-2) | 1 (IQR 0-2) | ||
| Lawton IADL percent functioning | Secondary | 90.8% | 86.4% | Difference -4.5 | |
| EQ5D-5L index | Secondary | 0.84 | 0.81 | Difference -0.03 | |
| EQ5D-5L VAS | Secondary | 0.76 | 0.73 | Difference -3.4 | |
| Recanalization at 4-8 hours (subset n=515) | Secondary | 21.6% | 47.7% | <0.001 | |
| Death at 90 days | Adverse | 5/452 (1.1%) | 20/432 (4.6%) | adjHR 3.8 | 0.0085 |
| Death within 5 days | Adverse | 1/452 (0.2%) | 8/432 (1.9%) | 0.0184 | |
| Symptomatic ICH | Adverse | 2/452 (0.4%) | 8/432 (1.9%) | RR 4.2 | 0.0588 |
| Death after symptomatic ICH | Adverse | 1/452 (0.2%) | 6/432 (1.4%) | 1.0000 | |
| Any hemorrhage on follow-up imaging | Adverse | 40/435 (9.2%) | 62/432 (14.4%) | 0.0202 | |
| SAE occurred | Adverse | 80/452 (17.7%) | 100/432 (23.1%) | 0.0454 | |
| Stroke progression | Adverse | 33/452 (7.3%) | 35/432 (8.1%) | 0.7056 | |
| Stroke recurrence | Adverse | 15/452 (3.3%) | 16/432 (3.7%) | 0.8554 | |
| Rescue EVT for index stroke | Adverse | 10/452 (2.2%) | 15/432 (3.5%) | 0.3120 | |
| Aspiration pneumonia | Adverse | 2/452 (0.4%) | 6/432 (1.4%) | 0.1688 | |
| Atrial fibrillation | Adverse | 3/452 (0.7%) | 4/432 (0.9%) | 0.7198 | |
| Congestive Heart Failure | Adverse | 1/452 (0.2%) | 5/432 (1.2%) | 0.1159 | |
| Seizure | Adverse | 3/452 (0.7%) | 3/432 (0.7%) | 1.0000 | |
| Urinary Tract Infection | Adverse | 4/452 (0.9%) | 2/432 (0.5%) | 0.6869 |
Subgroup Analysis
Heterogeneity of treatment effect suggested by sex (p_int=0.043): women more likely to do better with control (risk difference 10.1%) vs men (no effect). Age interaction (p_int=0.038): patients >80 years more likely to do better with control (risk difference 14.9%) vs younger patients (no effect). No heterogeneity by onset to treatment time (≤4.5h vs >4.5h), symptom status, occlusion type (LVO vs MeVO vs VB vs perfusion lesion), or baseline NIHSS.
Criticisms
- Open-label treatment allocation (though outcome assessment was blinded)
- Trial took nearly 9 years to complete due to pandemic and drug supply issues, with potential for selection bias and secular changes in care
- Control group treatment was heterogeneous (not one single comparator), though this may improve generalizability
- Patients with focal perfusion lesion (without overt occlusion) may be qualitatively different from those with visible arterial occlusion
- Excess late deaths in tenecteplase group remain unexplained and may be chance finding given low absolute numbers
- No parallel registry collected to confirm that enrolled patients did not have disabling symptoms
- 149/884 (17%) had complete symptom resolution at randomization
- Higher recanalization rate (47.7%) may not have been sufficient to influence outcomes
Funding
Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, British Heart Foundation. Tenecteplase was standard off-the-shelf drug paid for by Boehringer Ingelheim (no role in trial design, conduct, data analysis, or manuscript preparation)
Based on: TEMPO-2 (Lancet, 2024)
Authors: Shelagh B. Coutts, Sandeep Ankolekar, Ramana Appireddy, ..., Michael D. Hill
Citation: Lancet 2024; 401(10444): 2597-2605
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