TEMPO-2
(2024)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
• 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)
Inclusion Criteria
Adults ≥18 years, functionally independent (pre-stroke mRS 0-2), minor stroke (NIHSS ≤5), intracranial occlusion or focal perfusion lesion, within 12 hours of onset, ASPECTS ≥7
Study Design
Arms: Tenecteplase vs Non-thrombolytic standard of care
Patients per Arm: Tenecteplase: 432; Control: 452
Outcome
• SICH: Tenecteplase 1.9% vs Control 0.4% (RR 4.2, p=0.059)
• Death at 90 days: Tenecteplase 4.6% vs Control 1.1% (adjHR 3.8, p=0.009)
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
Study Design
- Study Type
- Randomised, open-label with blinded endpoint assessment (PROBE), parallel group, phase 3 superiority trial
- Randomization
- Yes
- Blinding
- Open-label treatment allocation with blinded outcome assessment at 90 days by certified raters
- Sample Size
- 884
- Follow-up
- 90 days (median 92 days, IQR 85-99)
- Centers
- 48
- Countries
- Canada, Australia, United Kingdom, Singapore, Brazil, New Zealand, Finland, Austria, Spain, Ireland
Primary Outcome
Definition: 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
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 338/452 (74.8%) | 309/432 (71.5%) | - (0.88-1.04) | 0.2882 |
Limitations & 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
Citation
Lancet 2024; 401(10444): 2597-2605