Tenecteplase vs. Alteplase for Patients With Acute Ischemic Stroke - ORIGINAL

Sep 25, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Anthony A. Bavry, MD,MPH,FACC
Trial Sponsor:
Boehringer Ingelheim
Date Published:
09/12/2024
Original Posted Date:
09/25/2024
References

Contribution To Literature:

The ORIGINAL trial demonstrated that in patients of Chinese descent with symptoms consistent with acute ischemic stroke, thrombolytic therapy with tenecteplase was noninferior to alteplase with respect to neurologic function at 90 days.

Description:

The goal of the trial was to test the noninferiority of tenecteplase, a bioengineered tissue plasminogen activator, to alteplase in a Chinese cohort of acute ischemic stroke qualifying for intravenous thrombolytic therapy.

Study Design

  • Multicenter
  • Active-controlled
  • Randomized
  • Open-label
  • Noninferiority

Patients with suspected acute ischemic stroke were randomized in a 1:1 fashion to receive an intravenous bolus of tenecteplase 0.25 mg/kg (maximum dose 25 mg, n = 732) or alteplase 0.9 mg/kg (maximum dose 90 mg, n = 733) with 10% administered as a bolus followed by a 1-hour infusion.

  • Total number of enrollees: 1,465
  • Duration of follow-up: 90 days
  • Mean patient age: 66 years
  • Percentage female: 30%

Inclusion criteria:

  • Age ≥18 years
  • National Institutes of Health Stroke Scale (NIHSS) score 1-25 (≤4 must have motor deficit score ≥1)
  • Symptom duration >30 minutes but <4.5 hours from onset to thrombolysis

Exclusion criteria:

  • Intracranial hemorrhage on computed tomography scan or prior history
  • Platelet count <100,000/mm3 or other bleeding diathesis
  • Significant trauma or major surgery <3 months prior
  • Systolic or diastolic blood pressure >185 or >110 mm Hg, respectively
  • Seizure at stroke onset

Other salient features/characteristics:

  • Median NIHSS score: 6
  • Thrombolysis ≤3 hours of symptom onset: 53%
  • Endovascular thrombectomy performed: 8%

Principal Findings:

The primary outcome, proportion of patients with a modified Rankin scale (mRS) score ≤1 at 90 days, for tenecteplase vs. alteplase, was: 72.7% vs. 70.3% (relative risk [RR] 1.03, 95% confidence interval [CI] 0.97-1.09, p for noninferiority = 0.003, p for superiority = 0.37).

Secondary outcomes for tenecteplase vs. alteplase:

  • NIHSS score 0 or improvement ≥4 points from baseline at 24 hours: 48.0% vs. 45.0% (RR 1.07, 95% CI 0.96-1.19)
  • mRS ≤2 at 90 days: 80.9% vs. 79.9% (RR 1.01, 95% CI 0.96-1.06)
  • Barthel Index score ≥95 at 90 days: 75.7% vs. 73.9% (RR 1.02, 95% CI 0.96-1.08)

Safety outcomes for tenecteplase vs. alteplase:

  • Symptomatic intracerebral hemorrhage at 36 hours: 1.2% vs. 1.2% (RR 1.01, 95% CI 0.37-2.70)
  • All-cause mortality at 90 days: 4.6% vs. 5.8% (RR 0.80, 95% CI 0.51-1.23)
  • mRS ≥5 at 90 days 6.8% vs. 7.8% (RR 0.92, 95% CI 0.66-1.29)

Interpretation:

Several randomized trials have established the noninferiority of tenecteplase to alteplase for thrombolytic treatment of acute ischemic stroke in various populations. The current data complement the preceding TRACE-2 study, which similarly demonstrated noninferiority in a Chinese cohort but excluded patients undergoing endovascular thrombectomy. Baseline intracranial imaging and thrombectomy were performed in only a minority of patients, which may reflect resource limitations at participating sites. Both TRACE-2 and ORIGINAL trials demonstrated an outsize effect size favoring tenecteplase in patients >80 years of age, but these findings remain exploratory in this relatively small group. Future cohorts enriched for thrombectomy candidates or older patients may provide novel insight into the efficacy of tenecteplase in special patient populations.

References:

Meng X, Li S, Dai H, et al. Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke: The ORIGINAL Randomized Clinical Trial. JAMA 2024;Sep 12:[Epub ahead of print].

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Vascular Medicine, Lipid Metabolism, Novel Agents

Keywords: Ischemic Stroke, Tenecteplase, Thrombolytic Therapy, Tissue Plasminogen Activator


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