Tenecteplase, 0.4 mg/kg, in Moderate and Severe Acute Ischemic Stroke: A Pooled Analysis of NOR-TEST and NOR-TEST 2A

Abstract

Background The optimal dose of tenecteplase in acute ischemic stroke remains to be defined. We present a pooled analysis of the 2 NOR-TESTs (Norwegian Tenecteplase Stroke Trials) exploring the efficacy and safety of tenecteplase, 0.4 mg/kg. Methods and Results We retrospectively reviewed 2 PROBE (Prospective Randomized Open, Blinded End-point) trials, NOR-TEST and NOR-TEST 2A. Patients were randomized to either tenecteplase, 0.4 mg/kg, or alteplase, 0.9 mg/kg. The primary end point was favorable functional outcome at 3 months (modified Rankin Scale score, 0-1) or return to baseline if prestroke modified Rankin Scale score was 2. Secondary end points included favorable functional and clinical outcome and safety data. The pooled analysis includes patients with National Institutes of Health Stroke Scale score ≥6 from both trials and an additional post hoc analysis of patients with National Institutes of Health Stroke Scale score ≤5 from NOR-TEST. The per-protocol analysis contains 483 patients, of whom 235 were assigned to tenecteplase and 248 were assigned to alteplase. In per-protocol analysis, functional outcome was better in the alteplase arm with cutoff modified Rankin Scale score of 2 (odds ratio [OR], 0.52 [95% CI, 0.33-0.80]; P=0.003) and expressed by ordinal shift analysis (OR, 1.64 [95% CI, 1.17-2.28]; P=0.004). Mortality at 3 months was higher in the tenecteplase arm (OR, 2.48 [95% CI, 1.20-5.10]; P=0.01). Mortality and intracranial hemorrhage rates were higher in the severe stroke group randomized to tenecteplase, whereas these rates were similar for alteplase and tenecteplase in moderate and mild stroke. Conclusions Tenecteplase, 0.4 mg/kg, is unsafe in moderate and severe stroke, and the risk of death and intracranial hemorrhage probably increases with stroke severity. A lower tenecteplase dose should be tested in future trials. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01949948, NCT03854500.

Keywords: clinical trial; ischemic stroke; tenecteplase; thrombolytic therapy; tissue plasminogen activator.

Figure 1. Distribution of modified Rankin Scale scores at 3 months in the per‐protocol analysis.

ALT indicates alteplase; and TNK, tenecteplase.

Figure 2. Distribution of outcome and hemorrhage based on age groups in the per‐protocol analysis.

ALT indicates alteplase; ICH, intracranial hemorrhage; mRS, modified Rankin Scale; OR, odds ratio; sICH, symptomatic ICH; and TNK, tenecteplase.

Figure 3. Distribution of outcome and hemorrhage based on severity of stroke on admission in the per‐protocol analysis.

ALT indicates alteplase; ICH, intracranial hemorrhage; mild stroke, National Institutes of Health Stroke Scale (NIHSS) score ≤5; moderate stroke, NIHSS score 6 to 14; mRS, modified Rankin Scale; OR, odds ratio; severe stroke, NIHSS score ≥15; sICH, symptomatic ICH; and TNK, tenecteplase.