By Dr Giuseppe Reale,

Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore – Roma, ESO-YSPR Committee

Alteplase is the cornerstone of acute ischemic stroke pharmacological treatment, either alone or prior to mechanical thrombectomy.1

Considering that approximately 20% of all strokes are due to large vessel occlusion (LVO)2, the majority of stroke patients will receive pharmacological treatment alone. However, alteplase has an early recanalization rate of less than 50%3, which is even lower in case of LVO. Considering that early reperfusion is a strong predictor of good outcome4, the quest of an “heir” for alteplase with a more favorable pharmacological profile seems justified, as clearly described in a recently published review from Coutts et al5. Tenecteplase might be one of them.

Tenecteplase is essentially a molecule of alteplase genetically engineered in three points. Compared to alteplase, it has higher fibrin affinity, greater resistance to PAI-1 (plasminogen activator inhibitor-1) and longer half-life (allowing for a single IV bolus instead of 1-hour infusion), with low effects on general hemostasis6.

Looking at the pharmacological features of tenecteplase, three possible strength points are claimed: 1) higher efficacy in clot lysis; 2) lower hemorrhagic complications; 3) faster administration. The first two points might contribute to the achievement of higher recanalization rate with better outcomes, while the last point might accelerate the stroke-network processes (as an example, door-in-door-out in a drip and ship model) and the door-to-groin time.

At the moment, tenecteplase is the drug of choice in systemic fibrinolysis for myocardial infarction, where it has been shown to be safer and simpler to use than alteplase7.

Regarding stroke, the 2017 large multicenter randomized controlled trial NOR-TEST (n=1100) failed to show differences in terms of safety or efficacy between the 0.4 mg/kg tenecteplase and the standard alteplase groups8. The 2018 EXTEND-IA TNK trial showed higher rates of >50% recanalization of the ischemic territory before planned thrombectomy in the 0.25 mg/kg tenecteplase group (22% vs 10% of the alteplase group). Although not tailored for clinical outcomes, the trial showed 90-days mRS favoring the tenecteplase group (mRS 0-2: 63%/10% tenecteplase + thrombectomy vs 50% alteplase + thrombectomy; death: 10% vs 18%)9.

Finally, a recent meta-analysis pointed out that tenecteplase is not inferior to alteplase in reducing 90 days disability among stroke patients10.

As we usually conclude, further trials are needed, but, in this case, there are plenty of choices…

EXTEND-IA TNK II (NCT03340493) is comparing tenecteplase 0.25 mg/Kg vs 0.4 mg/Kg before thrombectomy, with the same outcome of the first trial. ATTEST-2 (NCT02814409) is assessing superiority of tenecteplase 0.25 mg/Kg vs standard alteplase in a large sample size (n=1870), with the primary outcome being 90-days mRS. TASTE (ACTRN12613000243718) is a non-inferiority trial comparing tenecteplase 0.25 mg/kg vs standard alteplase among patients eligible for intravenous thrombolysis with radiologically confirmed mismatch and a core <70 mL. The outcome is no disability at 90 days (mRS 0-1). TWIST (NCT03181360) is evaluating the efficacy of 0.25 mg/Kg tenecteplase vs no thrombolysis standard of care among wake-up stroke patients. The outcome is 90 days mRS. TEMPO-2 (NCT02398656) is a large trial (n=1274) assessing the efficacy of tenecteplase 0.25 mg/Kg among patients who have a low NIHSS (0-5) in presence of a documented intracranial artery occlusion.

Finally, NOR-TEST2 (NCT03854500), planned to start this year, is going to recruit 1342 patients in order to compare the efficacy and safety of 0.4 mg/Kg tenecteplase vs standard alteplase in <4.5 h stroke, in wake-up stroke and before thrombectomy. Another trial, AcTQuICR (NCT03889249), will test the non-inferiority of 0.25 mg/Kg tenecteplase vs alteplase in a pragmatic set, while the TIMELESS trial (NCT03785678) will test tenecteplase 0.25 mg/Kg in LVO stroke patients between 4.5 and 24 hours.

Name Sample (estim.) Patients Treatment vs control Outcome
EXTEND-IA TNK II

(NCT03340493)

188 acute ischemic stroke with planned EVT tenecteplase 0.4 mg/Kg vs 0.25 mg/Kg before EVT

(superiority)

>50% recanalization of the ischemic territory before planned EVT
ATTEST-2 (NCT02814409) 1870 < 4.5 h acute ischemic stroke suitable for IVT tenecteplase 0.25 mg/kg vs standard alteplase

(superiority)

90 days mRS
TASTE (ACTRN12613000243718) 1024 acute ischemic stroke, eligible for IVT with mismatch and core <70 mL tenecteplase 0.25 mg/kg vs standard alteplase (non-inferiority) mRS 0-1 at 90 days
TWIST (NCT03181360) 500 Wake-up stroke 0.25 mg/Kg tenecteplase vs no IVT standard of care 90 days mRS
TEMPO-2 (NCT02398656) 1274 Acute ischemic stroke with low NIHSS (0-5) and LVO, no planned EVT/IVT tenecteplase 0.25 mg/Kg

vs standard of care

90 days mRS
NOR-TEST2 (NCT03854500) 1342 <4.5 hours stroke or wake-up stroke, with or without planned EVT 0.4 mg/Kg tenecteplase vs standard alteplase (superiority) 90 days 0-1 mRS
AcTQuICR (NCT03889249) 1600 acute ischemic stroke eligible for IVT alone or before EVT 0.25 mg/Kg tenecteplase vs alteplase (non-inferiority) 90 and 120 days mRS
TIMELESS (NCT03785678) 456 LVO acute ischemic stroke between 4.5 and 24 hours tenecteplase 0.25 mg/Kg vs placebo 90 days mRS

Table abbreviations: EVT: endovascular treatment, IVT: intravenous thrombolysis, LVO: large vessel occlusion.

 

The struggle to improve stroke care and outcomes never ends, as the above-mentioned trials demonstrate. Let us keep an eye on them, waiting for a worthy heir of alteplase.

 

Author’s conflict of interest: none.

 

References

  1. AHA/ASA Acute ischemic stroke treatment Guidelines 2018.
  2. Rai AT, Seldon AE, Boo S, et al. A population-based incidence of acute large vessel occlusions and thrombectomy eligible patients indicates significant potential for growth of endovascular stroke therapy in the USA. J Neurointerv Surg 2017;9:722–726.
  3. Bhatia R, Hill MD, Shobha N, et al. Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. Stroke 2010;41:2254–2258.
  4. Rha JH and Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007;38:967–973.
  5. Coutts SB, Berge E, Campbell BC, Muir KW, Parsons MW. Tenecteplase for the treatment of acute ischemic stroke: A review of completed and ongoing randomized controlled trials. Int J Stroke 2018;13:885-892.
  6. Keyt BA, Paoni NF, Refino CJ, et al. A faster-acting and more potent form of tissue plasminogen activator. Proc Natl Acad Sci USA 1994; 91:3670–3674.
  7. Van De Werf F, Adgey J, Ardissino D et al. Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999;354:716-722.
  8. 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;16:781–788.
  9. Campbell BCV, Mitchell PJ, Churilov L, et al. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med 2018;78:1573–1582.
  10. Burgos AM, Saver JL. Evidence that Tenecteplase Is Noninferior to Alteplase for Acute Ischemic Stroke. Stroke. 2019;50:2156-2162.