Thrombolysis in Imaging-Eligible, Late-Window Patients to Assess the Efficacy and Safety of Tenecteplase - TIMELESS

Feb 20, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Anthony A. Bavry, MD, MPH, FACC
Trial Sponsor:
Genentech, Inc.
Date Published:
02/08/2024
Date Updated:
02/20/2024
Original Posted Date:
02/20/2024
References

Contribution To Literature:

The TIMELESS trial showed that in patients with ischemic stroke due to large artery occlusion and favorable perfusion imaging, tenecteplase administration beyond 4.5 hours of symptom onset did not improve neurologic outcomes and carried similar risk of hemorrhagic conversion compared with placebo.

Description:

The goal of the trial was to determine the efficacy and safety of tenecteplase administered between 4.5 and 24 hours after last known well (LKW) time in patients with acute ischemic stroke and salvageable tissue on perfusion imaging.

Study Design

  • Multicenter
  • Double-blinded
  • Placebo-controlled

Patients with acute ischemic stroke due to internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion and a LKW time of 4.5-24 hours were randomized in 1:1 fashion to receive an intravenous push of tenecteplase 0.25 mg/kg (maximum dose 25 mg, n = 228) or matching placebo (n = 230).

  • Total number of enrollees: 458
  • Duration of follow-up: 90 days
  • Median patient age: 73 years
  • Percentage female: 54%

Inclusion criteria:

  • Age ≥18 years
  • Pre-stroke modified Rankin scale (mRS) score ≤2
  • National Institutes of Health Stroke Scale (NIHSS) score ≥5
  • Ischemic stroke due to occlusion of ICA or the first (M1) or second (M2) segments of the middle cerebral artery
  • Salvageable cerebral tissue, defined as ischemic core volume <70 mL, ratio of ischemic tissue to initial infarct volume ≥1.8, and penumbra volume ≥15 mL on computed tomography or magnetic resonance imaging perfusion imaging

Exclusion criteria:

  • Active internal bleeding
  • Inherited or acquired bleeding diathesis, including use of direct oral anticoagulant therapy ≤48 hours prior or vitamin K antagonist with international normalized ratio >1.7
  • Intracranial neoplasm, acute intracranial hemorrhage, or vascular malformation or aneurysm
  • Systolic or diastolic blood pressure >180 or >110 mm Hg, respectively
  • Stroke ≤90 days prior
  • Intracranial or intraspinal surgery or trauma ≤2 months prior
  • Thrombolytic administration ≤3 months prior

Other salient features/characteristics:

  • Median NIHSS score: 12
  • Median time from LKW to tenecteplase/placebo: 13 hours
  • Occlusion site: ICA 8%, M1 50%, M2 38%
  • Endovascular thrombectomy (EVT) performed: 77%
  • Median time from tenecteplase/placebo to arterial puncture for EVT: 16 minutes

Principal Findings:

Primary efficacy outcome, median mRS at 90 days, for tenecteplase vs. placebo, was: 3 (interquartile range [IQR] 1-5) vs. 3 (IQR 1-4), adjusted odds ratio (aOR) 1.13 (95% confidence interval [CI] 0.82-1.57), p = 0.45.

Secondary efficacy outcomes for tenecteplase vs. placebo:

  • Functional independence (mRs ≤2) at 90 days: 46.0% vs. 42.4%, aOR 1.18 (95% CI 0.80-1.74)
  • Reperfusion (≥90% reduction in penumbra volume) at 24 hours: 56.9% vs. 57.7%, aOR 1.04 (95% CI 0.69-1.57)

Safety outcomes for tenecteplase vs. placebo:

  • All-cause death at 90 days: 19.7% vs. 18.2%
  • Symptomatic (NIHSS increase ≥4) intracranial hemorrhage at 36 hours: 3.2% vs. 2.3%

Exploratory subgroup analyses (not adjusted for multiplicity):

  • EVT performed, yes vs. no: aOR 1.18 (95% CI 0.81-1.70) vs. 1.04 (95% CI 0.52-2.06)
  • Randomized at EVT-capable site, yes vs. no: aOR 1.05 (95% CI 0.78-1.52) vs. 2.53 (95% CI 0.42-15.16)

Interpretation:

The TIMELESS trial failed to show a benefit to tenecteplase compared with placebo outside the conventional 4.5-hour window after LKW for thrombolytic therapy in large-vessel ischemic strokes. Prior data have suggested benefit to perfusion imaging-guided use of alteplase beyond this window, although the corresponding TWIST trial for tenecteplase was negative. However, such trials preceded or excluded EVT, which has become increasingly available and demonstrates greater benefit when combined with thrombolytic therapy within 4.5 hours of symptom onset. This change in practice is reflected in the current trial, wherein 77% of patients underwent EVT at a median of 16 minutes after treatment with tenecteplase or placebo. Tenecteplase administration beyond 4.5 hours was not associated with either clinical benefit or improvement in perfusion imaging in this setting. Although exploratory, subgroup analysis showed a similar lack of treatment effect in the minority of patients who did not undergo EVT. The authors note that only 3.5% of patients underwent randomization and study drug administration prior to transfer to a comprehensive stroke center with EVT capability. Given the longer delay to potential EVT, it is unclear whether tenecteplase would yield a treatment benefit in this specific population if sufficiently powered.

References:

Albers GW, Jumaa M, Purdon B, et al. Tenecteplase for Stroke at 4.5 to 24 Hours With Perfusion-Imaging Selection. N Engl J Med 2024;390:701-11.

Editorial: Leifer D. Tenecteplase for Stroke — Opening the Window? N Engl J Med 2024;390:760-1.

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

Keywords: Tenecteplase, Ischemic Stroke, Perfusion Imaging


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