Tenecteplase 0.4 mg/kg in moderate and severe acute ischemic stroke: A pooled analysis of NOR-TEST & NOR-TEST 2A

Background The optimal dose of tenecteplase in acute ischaemic stroke remains to be defined. We present a pooled analysis of the two NOR-TEST trials exploring the efficacy and safety of tenecteplase 0.4 mg/kg in acute ischemic stroke. Methods We retrospectively reviewed two multi-center PROBE trials, NOR-TEST and NOR-TEST 2A, conducted in Norway. The patients were randomized to either 0.4 mg/kg single bolus tenecteplase or standard 0.9 mg/kg alteplase. The primary endpoint was favorable functional outcome at three months (mRS 0-1) or return to baseline if pre-stroke mRS was 2. The secondary endpoints included favorable functional outcome at three months (Modified Rankin Scale 0-2), major neurological improvement and safety data. The pooling project includes a pooled analysis of patients with moderate to severe stroke (NIHSS ≥6) from both trials and an additional post-hoc analysis of patients with mild stroke (NIHSS ≤5) from NOR-TEST. Results The per-protocol analysis contains 483 patients, of which 235 were assigned to tenecteplase and 248 to alteplase. In per-protocol analysis, functional outcome was better in the alteplase arm with cut-off mRS 2 (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=0.014). 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. High age was not associated with either higher mortality or intracranial hemorrhage rates. 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. Trial Registration [ClinicalTrials.gov][1] Identifiers: [NCT01949948][2], [NCT03854500][3] ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT01949948, [NCT03854500][3] ### Funding Statement The funding company had no role in study design, data analysis, interpretation or writing of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the regional Committee for Medical and Health Research Ethics and the Norwegian Medicines Agency. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable Anonymized data supporting our findings in the presented article may be provided by Vojtech Novotny or Christopher Elnan Kvistad upon reasonable request. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01949948&atom=%2Fmedrxiv%2Fearly%2F2023%2F05%2F05%2F2023.05.04.23289542.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03854500&atom=%2Fmedrxiv%2Fearly%2F2023%2F05%2F05%2F2023.05.04.23289542.atom