Victor J. Del Brutto, MD
@vdelbrutto
Since the National Institute of Neurological Disorders and Stroke trial results were published in 1995, recombinant tissue plasminogen activator (rtPA) alteplase has been the mainstay of thrombolytic therapy for acute ischemic stroke. Nevertheless, alteplase has a non-negligible risk of symptomatic intracranial hemorrhage, as well as limited efficacy in regards to the rate of vessel recanalization, especially in the setting of large vessel occlusion. For this reason, several studies have aimed to find an alternative thrombolytic agent with superior efficacy, safer profile, and simpler mode of administration. Tenecteplase, a genetically engineered mutant tPA, has several pharmacological advantages over alteplase, including higher fibrin specificity, less disruption of hemostasis, and longer half-life. This suggests that tenecteplase is a potentially better agent with higher rate of recanalization and lesser hemorrhagic complications. In addition, tenecteplase has a more practical way of administration (single bolus) in comparison to alteplase (bolus plus one-hour infusion).
In light of two recent large randomized controlled trials, tenecteplase has made its way into the American Heart Association guidelines. Initially, in the 2018 decree, tenecteplase debuted as a weak recommendation indicating that a 0.4 mg/kg single intravenous bolus might be considered as an alternative to alteplase in patients with minor deficits and no large vessel occlusion. The caveats of the aforementioned recommendation strictly adhered, in terms of dosing and selection criteria, to the NOR-TEST trial. This large (N=1100) phase III, randomized, open-label, double blind, superiority study compared tenecteplase to alteplase within 4.5 hours of symptoms onset using only CT for imaging selection. The authors reported no difference in functional outcome at 3 months and similar rate of hemorrhagic complications in both treatment groups. However, results were significantly affected by a high percentage of minor strokes and stroke mimics.
More recently, the EXTEND-IA trial demonstrated that patients with large vessel occlusion who were eligible for mechanical thrombectomy have more than double the chances of achieving reperfusion before thrombectomy when treated with tenecteplase 0.25 mg/kg compared to standard dose of alteplase. In addition, tenecteplase resulted in better functional outcomes at 90 days and similar rate of symptomatic intracranial bleeding. These findings resulted in a new recommendation endorsed by the AHA Stroke Council in the latest guidelines published in October 2019. The expert panel concluded that there is moderate-quality evidence to recommend that tenecteplase may be reasonable to choose over tenecteplase (dose 0.25 mg/kg) in patients eligible to undergo mechanical thrombectomy.
Despite the big step that implies including a novel thrombolytic agent as part of our therapeutic options for the management of acute stroke, the wording utilized in the latest guidelines is particularly conservative. This is the result of the systematic way literature is analyzed and the use of a predefined language based on the available evidence. Nevertheless, there is much more published information about the use of tenecteplase in acute stroke beyond the two isolated studies referenced above. At least a handful of trials [1-5] and a meta-analysis [6] have consistently shown similar efficacy of tenecteplase when compared to alteplase in acute ischemic stroke, and an inclination to better outcomes in the subset of patients presenting with large vessel occlusion or those with perfusion/core mismatch on advanced imaging techniques. Complementary to this, evidence from the cardiology literature provides supplementary evidence on the safety and efficacy of tenecteplase. On the other hand, the current recommendations leave some room for hesitation. For example, in a patient with minor deficits and large vessel occlusion, which is the appropriate dose, 0.25 mg/kg or 0.4 mg/kg? Or should we wait for vessel imaging diagnosis of large vessel occlusion to favor tenecteplase over alteplase?
Future trials should evaluate the efficacy and safety of tenecteplase in patients who are ineligible for alteplase, such as those beyond 4.5 hours of symptoms onset or those with disruption of hemostasis either due to an underlying coagulopathy or use of anticoagulants.
References:
[1] Huang X, Cheripelli BK, Lloyd SM, Kalladka D, Moreton FC, Siddiqui A, et al. Alteplase versus tenecteplase for thrombolysis after ischaemic stroke (ATTEST): a phase 2, randomised, open-label, blinded endpoint study. Lancet Neurol. 2015;14:368-76.
[2] Parsons M, Spratt N, Bivard A, Campbell B, Chung K, Miteff F, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366:1099-107.
[3] Haley EC Jr, Lyden PD, Johnston KC, Hemmen TM; TNK in Stroke Investigators. A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke. Stroke. 2005;36:607-12.
[4] Parsons MW, Miteff F, Bateman GA, Spratt N, Loiselle A, Attia J, et al. Acute ischemic stroke: imaging-guided tenecteplase treatment in an extended time window. Neurology. 2009;72:915-21.
[5] Haley EC Jr, Thompson JL, Grotta JC, Lyden PD, Hemmen TG, Brown DL, et al. Phase IIB/III trial of tenecteplase in acute ischemic stroke: results of a prematurely terminated randomized clinical trial. Stroke. 2010;41:707-11.
[6] Zang Y, Hou J, Wang LY. Therapeutic effect of tenecteplase on treatment of cerebral arterial thrombosis: a meta-analysis. Eur Rev Med Pharmacol Sci. 2016;20:4369-4379.
