NOR-TEST 2 – What’s the Right Dose of Tenecteplase for Stroke?

July 25, 2022

Written by Carmen Wolfe

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Tenecteplase, at a dose of 0.4 mg/kg, is not safe for patients with moderate to severe ischemic stroke.

Why does this matter?
Many institutions are considering a switch from alteplase to tenecteplase for treatment of acute ischemic stroke, citing benefits such as cost savings, ease of administration, and positive signal in the literature pointing to better efficacy. Should the results of this randomized trial give us pause before we all jump onto the tenecteplase boat?  

“The dose makes the poison”
Tenecteplase has enjoyed a place in the sun over the past few years, as study after study shows support for its use in acute ischemic stroke^1,2,3,4. The NOR-TEST 2, part A results may come as a surprise to those who were all aboard the tenecteplase boat, though we shouldn’t abandon ship despite the concerning headline.

The original NOR-TEST trial was a phase 3 trial that randomized 1,100 patients to tenecteplase (0.4 mg/kg) or alteplase (0.9 mg/kg), and results pointed to equivalent safety and efficacy. However, these patients had mild strokes, and nearly 20% of patient didn’t have a stroke at all. Hence…NOR-TEST 2 to look at patients with moderate to severe ischemic stroke.

NOR-TEST 2 took place across 11 hospitals in Norway and randomized patients presenting with an NIHSS score of 6 or more who presented with 4.5 hours of symptoms onset and were otherwise eligible for thrombolysis. The trial was terminated prematurely after a per protocol safety review revealed increased rates of ICH in the tenecteplase group. Results from this prematurely terminated study showed that when compared to standard dosing of alteplase (0.9 mg/kg), tenecteplase at the dose of 0.4 mg/kg led to higher rates of intracranial hemorrhage, higher mortality at three months, and worse functional outcomes. The NOR-TEST 2 trial is continuing in a Part B format with a lower dose of tenecteplase (0.25 mg/kg).

This trial provides important data that a dose of tenecteplase at 0.4 mg/kg is harmful in patients with moderate to severe ischemic strokes and guides future stroke trials toward utilization of a lower dose. Tenecteplase may still be the correct medication in acute ischemic stroke, but 0.4 mg/kg is certainly the wrong dose.

Source
Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial. Lancet Neurol. 2022 Jun;21(6):511-519. doi: 10.1016/S1474-4422(22)00124-7. Epub 2022 May 4.

In the same issue of Lancet Neurology, TASTE A, given by EMS, showed benefit for tenecteplase at a 0.25 mg/kg dose.
Comparison of tenecteplase with alteplase for the early treatment of ischaemic stroke in the Melbourne Mobile Stroke Unit (TASTE-A): a phase 2, randomised, open-label trial. Lancet Neurol. 2022 Jun;21(6):520-527. doi: 10.1016/S1474-4422(22)00171-5. Epub 2022 May 4.

Works Cited

1. Katsanos AH, Safouris A, Sarraj A, et al. Intravenous Thrombolysis With Tenecteplase in Patients With Large Vessel Occlusions: Systematic Review and Meta-Analysis. Stroke. 2021;52(1):308-312.
2. Gerschenfeld G, Smadja D, Turc G, et al. Functional Outcome, Recanalization, and Hemorrhage Rates After Large Vessel Occlusion Stroke Treated With Tenecteplase Before Thrombectomy. Neurology. 2021;97(22):e2173-e2184.
3. Potla N, Ganti L. Tenecteplase vs. alteplase for acute ischemic stroke: a systematic review. Int J Emerg Med. 2022;15(1):1. Published 2022 Jan 4.
4. Bivard A, Zhao H, Churilov L, et al. Comparison of tenecteplase with alteplase for the early treatment of ischaemic stroke in the Melbourne Mobile Stroke Unit (TASTE-A): a phase 2, randomised, open-label trial. Lancet Neurol. 2022;21(6):520-527.