Alteplase is the only approved agent for intravenous thrombolysis in patients with ischemic stroke within 4.5 hours of symptom onset.1 Nevertheless, continuous infusion is required to administer aletplase due to its short half-life.1 At the International Stroke Conference (ISC) 2018, the EXTEND-IA TNK trial has revealed that tenecteplase might be an attractive alternative to alteplase for stroke thrombolysis.2,3
Tenecteplase is a variant of alteplase, genetically modified to acquire higher fibrin specificity and longer half-life.1,4 In contrast to alteplase, tenecteplase is currently approved by the US Food and Drug Administration (FDA) only for the treatment of myocardial infarction, but not for the treatment of acute ischemic stroke.1-3
“While some previous studies showed trends toward improved clinical outcomes with tenecteplase compared with alteplase, results were not statistically significant,” said Dr. Bruce C. Campbell of the Royal Melbourne Hospital in Australia.5
The EXTEND-IA TNK was an investigator-initiated, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) study that enrolled patients with large vessel occlusion (internal carotid, basilar or middle cerebral artery) ischemic stroke patients.2,3 Inclusion criteria were ischemic stroke within 4.5 hours of symptom onset, pre-stroke modified Rankin Scale (mRS) ≤3, and no contraindication to intravenous (i.v.) thrombolysis.2,3
A total of 202 eligible patients were randomized to receive i.v. tenecteplase (0.25mg/kg, max 25mg) or alteplase (0.9mg/kg, max 90mg) before thrombectomy.2,3 The primary outcome was substantial reperfusion on the initial catheter angiogram, assessed by blinded core laboratory as modified Treatment In Cerebral Infarction (mTICI) 2b/3 or the absence of retrievable thrombus.2,3
The design included sequential testing of noninferiority (a margin of 2.3%), followed by test of superiority if noninferiority was demonstrated.2,3 “Ours was a noninferiority hypothesis because we felt that if you could show that tenecteplase is at least as good as alteplase, then the convenience and cost would justify a switch,” said Dr. Campbell.5
Surprisingly, the results of the trial, presented in ISC 2018, have shown that tenecteplase was not just noninferior, but superior to alteplase in terms of reperfusion.2,3
In the study, twice more patients achieved substantial reperfusion on the initial angiogram with tenecteplase, as compared to alteplase (22% vs. 10%, adjusted OR=2.6, p=0.002 for non-inferiority and p=0.02 for superiority).2,3
Functional outcomes on the 90-day mRS score also favored tenecteplase, since it was significantly shifted toward less disability after adjustment for age and initial stroke severity (ordinal cOR 1.7; 95% CI: 1.0-2.8, p=0.037).2,3
Besides, only 1% rate of symptomatic intracerebral hemorrhage (SICH) was reported for both groups.2,3 Dr. Campbell noted that the trend for mortality “was in the right direction” (10% for tenecteplase vs. 18% in the alteplase group; p=0.08).2,3,5
Of note, tenecteplase is around 34% cheaper per case than alteplase and can be given as a single bolus.5 “With alteplase, if you need to put patients in an ambulance, you have to take the infusion pump with you. Sometimes you can’t transport them at all while they’re having the infusion, depending on the system,” said Dr. Campbell.5
“The fact that the design was to show noninferiority but the study actually showed superiority was very, very impressive,” concluded Prof. Bruce Oviagele of the Medical School of South Carolina (MUSC). “With this study and maybe at least one of these other ones [referring to the other two ongoing trials of tenecteplase: ATTEST-2 and TASTE], I think we’re going to see a change.”5
1. Logallo N, Novotny V, Assmus J, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial. Lancet Neurol. 2017;16(10):781-788.
2. Campbell BC, Mitchell PJ, Churilov L, et al. Tenecteplase versus alteplase before endovascular thrombectomy (EXTEND-IA TNK): A multicenter, randomized, controlled study. ISC 2018. 24 January 2018; United States. LB2.
3. Presentation Slides for Campbell. Science News. International Stroke Conference 2018. Professional Heart Daily. 2018. (Accessed February 6, 2018, at https://professional.heart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_498715.pdf).
4. Logallo N, Kvistad CE, Thomassen L. Therapeutic Potential of Tenecteplase in the Management of Acute Ischemic Stroke. CNS Drugs. 2015;29(10):811-8.
5. Tenecteplase Superior to Alteplase for Stroke Thrombolysis. Medscape. 2018 (Accessed February 6, 2018, at https://www.medscape.com/viewarticle/891838#vp_2).