RCT: Tenecteplase Noninferior to Alteplase in Acute Ischemic Stroke

Background: Acute ischemic stroke (AIS) is a leading cause of morbidity and mortality globally, with a particularly high burden in China. Intravenous thrombolysis with alteplase, administered within 4.5 hours of symptom onset, is the current standard of care. Tenecteplase, a genetically modified variant of alteplase with greater fibrin specificity and a longer half-life, allows for single-bolus administration, potentially simplifying and expediting treatment. Prior studies suggest tenecteplase may be as effective as alteplase in AIS, but data specific to Chinese patients are limited.

Objective: To determine whether tenecteplase is noninferior to alteplase in achieving excellent functional outcomes in Chinese patients with AIS treated within 4.5 hours of symptom onset.

Methods:

• Design: Multicenter, randomized, open-label, blinded-endpoint, noninferiority trial conducted at 55 centers in China between July 2021 and July 2023.
• Participants: 1,489 Chinese adults aged ≥18 years with AIS, National Institutes of Health Stroke Scale (NIHSS) scores of 1–25, measurable neurological deficits, and symptom onset within 4.5 hours.
• Interventions: Patients were randomized 1:1 to receive either:
  • Tenecteplase: 0.25 mg/kg intravenous single bolus (maximum 25 mg).
  • Alteplase: 0.9 mg/kg intravenous (maximum 90 mg), with 10% as an initial bolus and the remainder infused over 1 hour.
• Outcomes:
  • Primary Outcome: Proportion of patients achieving a modified Rankin Scale (mRS) score of 0 or 1 at 90 days (indicating no symptoms or no significant disability).
  • Secondary Outcomes: Major neurological improvement at 24 hours, mRS scores of 0–2 at 90 days, change in NIHSS score at 90 days, Barthel Index score ≥95 at 90 days.
  • Safety Outcomes: Symptomatic intracerebral hemorrhage (sICH) per ECASS III definition and all-cause mortality at 90 days.

Results:

• Participants: 1,465 patients were included in the full analysis set (732 tenecteplase; 733 alteplase). Median age was 66 years, median NIHSS score was 6, and 30.4% were female.
• Primary Outcome:
  • 72.7% in the tenecteplase group achieved mRS 0 or 1 at 90 days compared to 70.3% in the alteplase group.
  • Adjusted risk ratio (RR): 1.03 (95% CI, 0.97–1.09), meeting the predefined noninferiority margin (RR ≥0.937).
• Secondary Outcomes:
  • Major Neurological Improvement at 24 Hours: 48.0% (tenecteplase) vs. 45.0% (alteplase); RR, 1.07 (95% CI, 0.96–1.19).
  • mRS 0–2 at 90 Days: 80.9% (tenecteplase) vs. 79.9% (alteplase); RR, 1.01 (95% CI, 0.96–1.06).
  • Change in NIHSS Score at 90 Days: Mean change of –3.70 (tenecteplase) vs. –3.02 (alteplase); adjusted difference, –0.45 (95% CI, –1.40 to 0.50).
  • Barthel Index ≥95 at 90 Days: 75.7% (tenecteplase) vs. 73.9% (alteplase); RR, 1.02 (95% CI, 0.96–1.08).
• Safety Outcomes:
  • sICH: Occurred in 1.2% of patients in both groups; RR, 1.01 (95% CI, 0.37–2.70).
  • 90-Day Mortality: 4.6% (tenecteplase) vs. 5.8% (alteplase); RR, 0.80 (95% CI, 0.51–1.23).

Conclusions: Tenecteplase was noninferior to alteplase in achieving excellent functional outcomes (mRS 0 or 1) at 90 days in Chinese patients with AIS treated within 4.5 hours of symptom onset. Safety profiles, including rates of sICH and mortality, were similar between the two treatments. These findings support tenecteplase as a suitable alternative to alteplase for intravenous thrombolysis in AIS.

Implications for Practice:

• Administration Advantage: Tenecteplase’s single-bolus administration could streamline treatment workflows and reduce door-to-needle times.
• Efficacy and Safety: Comparable efficacy and safety profiles suggest tenecteplase can be confidently used in place of alteplase.
• Patient Selection: Results are applicable to a broad range of AIS patients, including those with varying stroke severities and ages.

Study Strengths and Limitations:

• Strengths: Large sample size, multicenter design, and inclusion of a real-world patient population enhance the generalizability of findings.
• Limitations: Open-label design may introduce bias despite blinded endpoint assessments. The relatively low proportion of patients undergoing thrombectomy limits conclusions about combined therapy.

Future Research:

• Further studies could explore the effectiveness of tenecteplase in specific subgroups, such as patients with large vessel occlusions or those requiring endovascular interventions.
• Investigations into long-term outcomes beyond 90 days and real-world implementation strategies may provide additional insights.

Reference: Meng, X., et al. (2024). Tenecteplase vs alteplase for patients with acute ischemic stroke: The ORIGINAL randomized clinical trial. JAMA. DOI: https://doi.org/10.1001/jama.2024.14721