Trail Toward Tenecteplase

The authors have done an Indian study on tenecteplase (TNK) and alteplase for thrombolysis of acute ischemic stroke within 4.5 hours.[1] The previous Indian studies on TNK included patients within 3 hours of stroke onset, but this study extended the time to thrombolysis to 4.5 hours. This study showed a comparable efficacy and safety profile of TNK and alteplase in thrombolysis of AIS throughout the 4.5-hour window period while the majority of western literature focused on higher doses of TNK (0.25–0.4 mg/kg), a lower dose of 0.20 mg/kg has been approved in India for AIS.[2] In this study, ASPECTS varied from 2 to 10 and it needs to find out whether the patient cohort with low ASPECTS who were given thrombolytics had reperfusion or not within a 3–4.5-hour window. It will give better ideas for patient selection and risk profile.

TNK has advantages over alteplase as it has greater fibrin sensitivity leading to reduction in hemorrhagic complications, greater resistance to plasminogen activator inhibitor that leads to higher efficacy of clot lysis and longer serum half-life which allows for single bolus administration.[3] The few trials have been performed comparing the efficacy and safety of TNK and alteplase for thrombolysis of acute ischemic stroke within 4.5 hours. In 2015, Huang et al.[4] published the results from a randomized trial that compared TNK 0.25 mg/kg to alteplase for patients with acute ischemic stroke within 4.5 hours of symptom onset. A total of 104 patients were enrolled, with 52 assigned to each group. There was no difference between groups with regards to the primary outcome of “percentage penumbra salvaged,” 68% in each group. There were also no statistically significant differences in secondary outcomes between groups, but for the TNK group, there were trends toward more early neurologic improvement at 24 hours (40% vs. 24%) and a higher percentage of the good neurologic outcome at 90 days (28% vs. 20%).[4] In 2017, NOR-TEST which was a phase 3 randomized open label study published the results from a block-randomized study comparing TNK 0.4 mg/kg and standard-dose alteplase for patients with suspected acute ischemic stroke with 4.5 hours or less of symptoms or within 4.5 hours of awakening with symptoms. A total of 549 patients were randomized to the TNK group and 551 were randomized to the alteplase group. There was no difference between groups in the primary outcome of the good neurologic outcome at 90 days (64% TNK vs. 63% alteplase).[5] In 2018, EXTEND-IA TNK, a multicenter randomized, controlled study published the results comparing TNK 0.25 mg/kg to standard dose alteplase for patients with symptoms of acute ischemic stroke for less than 4.5 hours prior to thrombectomy. There were 101 patients in each group. There was a statistically significant difference between groups with regards to the primary outcome of reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. This primary outcome was found in 22% of patients in the TNK group as compared to 10% of those with alteplase. Patients in the TNK also had superior functional neurologic outcomes at 90 days as compared to the alteplase group.[6] In TASTE-A which is a prehospital phase2, a randomized open-label trial at Melbourne mobile stroke units (MSU) patients were randomly allocated to receive standard of care alteplase (0.9 mg/kg body weight) or TNK 0.25 mg/kg body weight.[7] The primary outcome was the volume of perfusion lesion on arrival at the hospital assessed by CT-perfusion imaging. Treatment with TNK on MSU resulted in superior rates of early reperfusion compared with alteplase and no safety concerns were noted.

This study published in this issue of Annals of Indian Academy of Neurology has its own strengths that include Indian data on TNK between 3 and 4.5 hours; no significant difference in efficacy in comparison to alteplase and research compared the safety signals as in Caucasian population.[1] The limitations of the study include sample size in a 3 to 4.5-hour window, single-center study, investigator discretion about which thrombolytic agent to be given which may lead to bias, and lack of clarity on whether any of the study patients underwent thrombectomy or not which may influence the interpretation of the results.

To conclude, TNK is at least as effective as alteplase with regards to neurologic improvement after treatment of acute ischemic stroke within 4.5 hours. In addition, TNK is less expensive and easier to administer. TNK is better than alteplase in some of the cases with regard to the outcomes of post thrombolytic bleeding, the functional outcome at 90 days as measured by the mRs, and recanalization/reperfusion rates following thrombectomy.[8] However, larger studies with a prospective design may be requested to further clarify 3 to 4.5-hour time window.