Burton J. Tabaac, MD
This topical review takes a deep dive analysis into the literature as it pertains to Tenecteplase (tNK), a type of IV thrombolysis, in the treatment of acute ischemic stroke. A qualitative synthesis of published stroke trials is presented. Most interestingly is the argument, using meta-analysis, that tNK is superior in recanalizing large vessel occlusions (LVO) compared to Alteplase (tPA). This resonates with the vascular neurology world because the original prospective studies were unable to demonstrate superiority or non-inferiority of tNK on clinical outcome. As detailed, the current body of clinical trial evidence evaluating tNK relative to tPA points in the direction of superior early recanalization in LVO and non-inferior disability-free outcome at 3 months in favor of tNK.
In regards to dosing, current clinical practice guidelines for stroke include IV tNK 0.25mg/kg recommended for LVO, based on phase 2 trial data with improved 3-month outcome relative to tPA. We have known, at least since 2012, that reperfusion and clinical outcomes with the use of tNK appear improved, and intracranial hemorrhage risk is not increased, as compared to alteplase.1 The paper cites a network meta-analysis of five randomized trials on tNK versus tPA that found better efficacy on clinical and imaging endpoints. The authors elaborate, there has been no evidence to support an advantage of the 0.4mg/kg dose relative to 0.25mg/kg in the treatment of ischemic stroke, adding, “Trials that directly compared the two doses tended to favor the 0.25mg/kg dose.” The National Institute of Neurological Disorders and Stroke Tenecteplase trial has since eliminated the 0.4mg/kg as being inferior, and EXTEND-IA-TNK (part 2) reported a higher number of symptomatic intracranial hemorrhage events in the 0.4mg/kg group relative to the 0.25mg/kg dosed patients.2 The ongoing NOR-TEST 2 trial may confirm whether there is any disadvantage of the 0.4mg/kg dose relative to standard dose tPA. Current randomized phase 3 trials are ongoing in an aim to answer the question of if tNK has decreased hemorrhagic risk, and if tNK can establish efficacy beyond the 4.5 hour time window.
When assessing the implementation of thrombolytic therapy in system coordinated care, one must consider the capability of each medical facility, and primary vs. comprehensive stroke center, while mitigating interfacility transfer(s). What is the best way to manage “drip and ships,” and how does the medication administration play a role? This article underscores several practical advantages of the rapid single bolus Tenecteplase administration, whereas Alteplase requires an infusion immediately following the initial bolus dosage.
There are currently five authoritative clinical practice guidelines that have been issued since the publication of all of the completed randomized trials of tNK vs. tPA, but no two are in agreement with regards to a recommendation to use tNK in stroke, or on the strength of that recommendation. The most recent AHA/ASA Guidelines for the Early Management of Patients With Acute Ischemic Stroke recommend tNK as an alternative that may be considered for large vessel occlusion (at 0.25mg/kg) or minor, non-LVO (at 0.4mg/kg), class IIB recommendations.3 Note, the randomized EXTEND-IA TNK (part 2) comparison was published after the guidelines writing committee’s literature search closed, and so is not accounted for in the current guideline. Ongoing randomized phase 3 trials are testing the superiority or non-inferiority of tNK relative to tPA within the 4.5 hour window. Further, there are other studies that are keen on testing tNK in wake-up stroke, with additional trials assessing the combination of tPA with endovascular thrombectomy.
1. Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, O’Brien B, Bladin C, McElduff P, Allen C, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366:1099-107.
2. Kheiri B, Osman M, Abdalla A, Haykal T, Ahmed S, Hassan M, Bachuwa G, Al Qasmi M, Bhatt DL. 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.
3. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2019;50:e344-e418.