TL;DR: 🟢 Positive (noninferiority) — tenecteplase was noninferior to alteplase for standard-window acute ischemic stroke, adding to a rapidly consolidating multinational evidence base (TRACE-2, AcT, EXTEND-IA TNK).
1. Publication
- Title: Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke: The ORIGINAL Randomized Clinical Trial
- Acronym: ORIGINAL
- Year & Journal: JAMA, published September 12, 2024 (332(17):1437-1445)
- Citation: Meng X, Li S, Dai H, et al. JAMA. 2024;332(17):1437-1445. doi:10.1001/jama.2024.14721
2. Context & Rationale
Background: Tenecteplase (single IV bolus) offers practical advantages over alteplase (infusion) for acute ischemic stroke thrombolysis. Prior trials (TRACE-2, EXTEND-IA TNK) supported tenecteplase's non-inferiority, but confirmatory data in diverse populations remained valuable.
Research Question/Hypothesis: In Chinese patients with acute ischemic stroke eligible for IV thrombolysis within 4.5h, is tenecteplase non-inferior to alteplase for excellent functional outcome (mRS 0-1) at 90 days?
3. Design & Methods
- Study Type: Phase III, multicenter, prospective, randomized, open-label, blinded endpoint (PROBE), active-controlled, non-inferiority trial
- Population: Chinese patients with acute ischemic stroke eligible for IV thrombolysis within 4.5h
- Intervention: Tenecteplase (single bolus)
- Comparator: Alteplase (standard infusion)
- Statistical Power & Follow-Up: Primary: excellent functional outcome (mRS 0-1) at 90 days.
4. Key Results
Outcome | Tenecteplase | Alteplase | Notes |
mRS 0-1 at 90 days (primary) | Non-inferior | — | Non-inferiority criterion met |
Safety profile | Similar | Similar | No excess bleeding or other safety signal |
5. Internal Validity Assessment
PROBE design (blinded endpoint assessment despite open-label treatment) with a prespecified non-inferiority margin. Overall: Strong — consistent with and confirmatory of multiple prior tenecteplase-vs-alteplase non-inferiority trials (TRACE-2, AcT, EXTEND-IA TNK, TASTE), collectively supporting tenecteplase as a robust alternative.
6. External Validity Assessment
Chinese, multicenter acute ischemic stroke population eligible for standard-window IV thrombolysis — adds important non-Western population data to the tenecteplase evidence base (complementing TRACE-2's similarly Chinese population and AcT's Canadian population).
7. Strengths & Limitations
Strengths: PROBE design with blinded endpoint assessment; confirms non-inferiority in a large, distinct population; single-bolus administration offers clear logistical advantages (especially relevant in resource-limited or transfer settings).
Limitations: Open-label treatment delivery; single-country (China) population, though this complements (rather than duplicates) other national tenecteplase trials.
8. Interpretation & Practice Impact
Supports tenecteplase as a suitable, practical alternative to alteplase for standard-window acute ischemic stroke thrombolysis — reinforcing a rapidly consolidating global evidence base (TRACE-2, AcT, EXTEND-IA TNK, ORIGINAL, TASTE, ATTEST-2) that has since led to regulatory approval (FDA approved tenecteplase for AIS in March 2025, based on the AcT trial).
9. Controversies & Subsequent Evidence
Multiple subsequent meta-analyses (e.g., European Journal of Medical Research 2025; Journal of Stroke and Cerebrovascular Diseases 2024) have pooled ORIGINAL with TRACE-2, AcT, TASTE, and ATTEST-2, consistently confirming tenecteplase's non-inferiority (and in some pooled analyses, favoring tenecteplase's point estimate) with similar safety profiles — reflecting a genuinely consolidating, high-confidence evidence base across multiple countries and populations.
10. Summary & Executive Takeaway
Summary: ORIGINAL, a PROBE-design non-inferiority trial, randomized Chinese acute ischemic stroke patients eligible for standard-window IV thrombolysis to tenecteplase or alteplase. Tenecteplase was non-inferior for excellent functional outcome (mRS 0-1) at 90 days, with a similar safety profile.
Overall Takeaway: ORIGINAL adds further confirmatory evidence that tenecteplase is a safe, effective, and logistically simpler alternative to alteplase for standard-window acute ischemic stroke thrombolysis — part of a rapidly consolidating multinational evidence base that has already influenced regulatory approval and guideline recommendations.
11. Bibliography
- Wang Y, Li S, Pan Y, et al. TRACE-2. Lancet. 2023;401(10377):645-654.
- Menon BK, et al. AcT trial. Lancet. 2022;400:161-169.
- Parsons MW, et al. TASTE. Lancet Neurol. 2024;23(8):775-786.