Expert Analysis: Tenecteplase Yet to Prove Itself vs Alteplase

The Lancet Neurology recently published results from the Tenecteplase Versus Alteplase for Thrombolysis (Clot Dissolving) in Acute Ischemic Stroke (NOR-TEST) clinical trial (ClinicalTrials.gov Identifier: NCT01949948), which provided randomized controlled trial data for the use of a novel antifibrinolytic in the treatment of acute ischemic stroke.¹ Despite negative trial results, there is still reason to be enthusiastic about the future of tenecteplase.

Alteplase was approved in 1996 and to date remains the only medical therapy approved by the US Food and Drug Administration and supported by American Heart Association guidelines for the treatment of acute ischemic stroke.^2,3 Even in the era of interventional neurology, alteplase remains the most widely available medication proven to improve outcomes in acute ischemic stroke, particularly early in presentation.⁴ Alteplase is not without risk, carrying a 2% risk for fatal hemorrhage⁵ and low rates of efficacy in large vessel occlusion.²

Enter tenecteplase, a bioengineered variant that has shown promise in phase 1 and 3 trials as a safe, more effective, and easier-to-administer alternative to alteplase.^2,6-8

Tenecteplase was made to have a high specificity for fibrin and resistance to natural brakes on alteplase.^1,7 A pooled analysis of 2 randomized controlled trials and a meta-analysis of 6 studies with 81 patients showed tenecteplase to be superior in terms of recanalizing large vessel occlusions.^6,9 In terms of safety, a meta-analysis in patients with acute coronary syndrome showed tenecteplase to have fewer systemic bleeding complications than alteplase at a higher dose than used in NOR-TEST. In a phase 2 study in patients with stroke, a dose of 0.4 mg/kg was shown to have increased incidence of intracranial hemorrhage, albeit in a small sample.⁷

In this setting, Logallo et al sought to investigate the safety and efficacy of tenecteplase. This well-designed and well-executed randomized controlled trial enrolled 1100 acute patients from 13 stroke centers in Norway. Patients were randomly assigned to intravenous tenecteplase or standard dose alteplase according to Norwegian guidelines. Despite this, the trial did not meet its primary outcome, failing to show a difference in rate of excellent outcomes or secondary safety endpoints, including symptomatic intracranial hemorrhage and death at 3 months.

Although tenecteplase has yet to prove itself as an equivalent therapy, there still may be hope. In an accompanying editorial,¹⁰ Professor Craig Anderson, principal investigator of the ENCHANTED trial, which explored the role of reduced dose alteplase, pointed out that the patients enrolled in NOR-TEST were mostly categorized as having mild stroke (National Institutes of Health Stroke Scale 0-7), a group expected to have excellent outcomes anyway and at lowest risk for complications from antifibrinolytic therapy. He also commented that his experience with ENCHANTED and analysis of NOR-TEST highlights that any new therapies in stroke are unlikely to be hugely more effective and will require large enough cohorts to prove any efficacy. Noninferiority designs may be more practical in the ability to show statistical proof that we should be changing our practice.

As the NOR-TEST investigators pointed out, this study does add value to current literature by demonstrating safety in a large cohort at a dose previously thought to have higher complication rates. This knowledge can greatly inform future trial design.

Ultimately, tenecteplase is still promising as an alternative to alteplase. A large retrospective analysis of more than 60,000 patients in a national registry suggests that up to 20% of patients eligible for alteplase don’t receive it, with many being higher-risk groups such as the elderly, who are likely being undertreated.¹¹ A safer alternative may be a catalyst to improve compliance with guidelines. Even if data suggesting tenecteplase is better and safer at opening large vessel occlusions does not pan out in phase 3 trials, the ability to give tenecteplase as a single push dose is an attractive property. We will have to wait for a larger superiority trial or a noninferiority design with sicker stroke patients before we decide whether tenecteplase will make it into our armamentarium in the treatment of acute ischemic stroke.

References

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 [published online August 2, 2017]. Lancet Neurol. doi: 10.1016/S1474-4422(17)30253-3
2. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.
3. Drug Approval Package: Alteplase. https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/alteplase_toc.cfm. Updated July 5, 2017. Accessed August 23, 2017. 
4. Emberson J, Lees KR, Lyden P, et al. 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(9958):1929-1935.
5. Whiteley WN, Emberson J, Lees KR, et al. Risk of intracerebral haemorrhage with alteplase after acute ischaemic stroke: a secondary analysis of an individual patient data meta-analysis. Lancet Neurol. 2016;15(9):925-933.
6. Bivard A, Huang X, Levi CR, et al. Tenecteplase in ischemic stroke offers improved recanalization: Analysis of 2 trials. Neurology. 2017;89(1):62-67.
7. Huang X, MacIsaac R, Thompson JL, et al. Tenecteplase versus alteplase in stroke thrombolysis: An individual patient data meta-analysis of randomized controlled trials. Int J Stroke. 2016;11(5):534-543.
8. Zerna C, Hegedus J, Hill MD. Evolving treatments for acute ischemic stroke. Circ Res. 2016;118(9):1425-1442.
9. Zang Y, Hou J, Wang L-Y. Therapeutic effect of tenecteplase on treatment of cerebral arterial thrombosis: a meta-analysis. Eur Rev Med Pharmacol Sci. 2016;20(20):4369-4379.
10. Anderson CS. NOR-TEST-ing tenecteplase in acute ischemic stroke [published online August 8, 2017]. Lancet Neurol. doi: 10.1016/S1474-4422(17)30277-6
11. Messe SR, Khatri P, Reeves MJ, et al. Why are acute ischemic stroke patients not receiving IV tPA? Results from a national registry. Neurology. 2016;87(15):1565-1574.