Farah Aleisa, MD
Tenecteplase (TNK) is a tissue-type plasminogen activator modified by 3 amino acids from alteplase, and it has the potential to reperfuse brain tissue in case of blocked brain vessels. It has greater fibrin specificity resulting in lower bleeding risks,1 and it has initial serum half-life of 20 minutes and a mean terminal half-life of 100 minutes, such that it can be given as a bolus dose on a weight-adjusted basis,2 being given even in the pre-hospital setting, which allows faster time to reperfusion and less delay for endovascular therapy if needed.
There are 5 independent randomized trials that have studied the efficacy of TNK in comparison to altelplase (ALT) in acute ischemic stroke.3-7 These trials enrolled a total of 1585 patients (828 TNK, 757 ALT), mean National Institutes of Health Stroke Scale (NIHSS) at baseline was 7, and mean time from last known well to treatment start was 148 minutes. All patients with ALT received standard 0.9 mg/kg dosing; TNK dosing was one-time bolus only, at doses of 0.1 mg/kg in 6.8% of patients, 0.25 mg/kg in 24.6%, and 0.4 mg/kg in 68.6%.
For the primary endpoint of freedom from disability (mRS=0–1) at 3 months, data were available from all 5 trials, on 1585 patients. Crude cumulative rates of disability-free outcome were TNK 57.9% versus ALT 55.4%. The lower 95% CI bound of −1% fell within the lead non-inferiority margin of −6.5%. TNK in both the 0.25 mg/kg dose alone and the 0.4 mg/kg dose alone met the lead non-inferiority level.
For the secondary efficacy analyses of functional independence (mRS=0–2) at 3 months, data were available from 4 trials on 1473 patients. Crude cumulative rates of independence were TNK 71.9% versus ALT 70.5%.
For the safety endpoint of symptomatic intracranial hemorrhage (sICH), data were available for 1585 patients from all 5 trials. Crude summary: sICH rates were TNK 3% versus ALT 3%, risk difference 0% (95% CI, –1% to 2%).
There is a potential drawback to TNK’s all-at-once administration in that, with ALT, the longer infusion may be stopped after only a partial dose if the patient exhibits signs of potential hemorrhage; in addition, serum half-life of ALT is shorter than TNK, allowing hemostasis to return more quickly. However, these possible advantages of ALT in uncommon patients with early bleeding complications have not been shown to importantly alter clinical outcome, and seem unlikely to outweigh the substantial functional improvements achieved with faster transfer to thrombectomy centers.
These studies included milder presenting stroke deficits severity of mean NIHSS 7 versus NIHSS 12 in the 2 pivotal National Institute of Neurological Disorders and Stroke r-tPA trials.8-9 Therefore, findings of non-inferiority are more secure for patients with milder (e.g., NIHSS, 1–14) deficits than patients with more severe (e.g., NIHSS =15) deficits.
With regard to different doses of TNK, for the lead efficacy outcome of freedom from disability (mRS, 0–1), there was no evidence of heterogeneity of treatment effect across the 3 studied TNK concentrations.
We can conclude that the results of these studies have direct implications for clinical practice and treatment guidelines; TNK has been widely recognized as offering highly desirable feasibility advantages over ALT in the era of endovascular thrombectomy.
The TASTE study (Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation) is a global trial following on from Parsons’ pilot trial. It compares TNK with standard dose ALT and plans for a maximum sample size of 1024 subjects. ATTEST-2 in the UK is similarly examining TNK and ALT, aiming for 1870 subjects. Finally, the TWIST study (Tenecteplase in Wake-Up Ischemic Stroke Trial) from Norway is proposing a trial of TNK versus best standard treatment in patients with stroke on awakening; basic computed tomographic imaging will be used for selecting the 500 planned patients. All of these trials use TNK 0.25 mg/kg dosage.
We expect that advantages in patient care from a thrombolytic agent with a much simpler administration schedule will be most widely realized if backed by regulatory approval in the process, and starting large randomized controlled trials should remain the highest priority.
References:
1. Huang X, MacIsaac R, Thompson JL, Levin B, Buchsbaum R, Haley EC, Levi C, Campbell B, Bladin C, Parsons M, et al. Tenecteplase versus alteplase in stroke thrombolysis: an individual patient data meta-analysis of randomized controlled trials. Int J Stroke. 2016; 11:534–543.
2. Campbell BCV, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Dowling RJ, Yan B, Bush SJ, Dewey HM, Thijs V, et al.; EXTEND-IA TNK Investigators. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. 2018; 378:1573–1582.
3. Huang X, MacIsaac R, Thompson JL, Levin B, Buchsbaum R, Haley EC Jr, et al. Tenecteplase versus alteplase in stroke thrombolysis: an individual patient data meta-analysis of randomized controlled trials. Int J Stroke. 2016.
4. Thelengana A, Radhakrishnan DM, Prasad M, Kumar A, Prasad K. Tenecteplase versus alteplase in acute ischemic stroke: systematic review and meta-analysis [published online May 4, 2018, Acta Neurol Belg. doi: 10.1007/s13760-018-0933-9].
5. Xu N, Chen Z, Zhao C, Xue T, Wu X, Sun X, et al. Different doses of tenecteplase vs alteplase in thrombolysis therapy of acute ischemic stroke: evidence from randomized controlled trials. Drug Des Devel Ther. 2018;12:2071–2084.
6. Kheiri B, Osman M, Abdalla A, Haykal T, Ahmed S, Hassan M, et al. Tenecteplase versus alteplase for management of acute ischemic stroke: a pairwise and network meta-analysis of randomized clinical trials. J Thromb Thrombolysis. 2018;46:440–450.
7. Piaggio G, Elbourne DR, Altman DG, Pocock SJ, Evans SJ; CONSORT Group. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement. JAMA. 2006;296:1152–1160.
8. Emberson J, Lees KR, Lyden P, Blackwell L, Albers G, Bluhmki E, et al; Stroke Thrombolysis Trialists’ Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014. 384:1929.
9. Kim JT, Fonarow GC, Smith EE, Reeves MJ, Navalkele DD, Grotta JC, et al. Treatment with tissue plasminogen activator in the golden hour and the shape of the 4.5-hour time-benefit curve in the national United States Get With The Guidelines-Stroke population. Circulation. 2017;135:128–139.
