Tenecteplase in Ischemic Stroke: Challenge and Opportunity

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Tenecteplase in Ischemic Stroke: Challenge and Opportunity

Authors Li G, Wang C, Wang S , Xiong Y, Zhao X 

Received 3 February 2022

Accepted for publication 15 April 2022

Published 11 May 2022 Volume 2022:18 Pages 1013—1026

DOI https://doi.org/10.2147/NDT.S360967

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Taro Kishi

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Guangshuo Li,¹ Chuanying Wang,¹ Shang Wang,^1,2 Yunyun Xiong,^{1– 3,*} Xingquan Zhao<sup>1,2,*

1</sup>Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; ²China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China; ³Chinese Institute of Brain Research, Beijing, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xingquan Zhao, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, West Nansihuan Road 119, Beijing, People’s Republic of China, Email zxq@vip.163.com Yunyun Xiong, China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China, Email xiongyunyun@bjtth.org

Purpose of Review: Intravenous thrombolysis is the first-line therapy for ischemic stroke, and alteplase has been used as an intravenous thrombolysis drug for over 20 years. However, considering its low rate of recanalization and risk of intracerebral hemorrhage, alteplase may not be the optimal thrombolytic drug of choice for ischemic stroke. Tenecteplase (TNK) is a genetically engineered, mutant, tissue plasminogen activator that is a potential substitute to alteplase in ischemic stroke. The pharmacokinetic advantages of TNK include greater fibrin selectivity than alteplase and prolonged half-life time. In this review, we have summarized the clinical trials of TNK in ischemic stroke.
Recent Findings: Clinical trials showed a higher recanalization rate of TNK over alteplase without increasing the rate of intracerebral hemorrhage. However, not all clinical trials showed superiority of TNK over alteplase in functional outcomes and early neurological improvement. TNK was superior to alteplase in terms of recanalization in patients who fulfilled the imaging mismatch criteria and in those planning to undergo mechanical thrombectomy.
Summary: TNK has the potential to substitute alteplase for ischemic stroke therapy. Future TNK clinical trials that target functional outcomes are warranted.

Keywords: stroke, thrombolysis, TNK-tissue plasminogen activator, tenecteplase, clinical trial

Introduction

In the global burden of disease study 2019, stroke ranked third among the main causes of disability-adjusted life-years.¹ Of all strokes, >80% are ischemic strokes due to intracranial or extracranial vessel occlusion.² Recanalization of occluded vessels in the ultra-early period is crucial to improving functional outcomes of patients with ischemic stroke. Hence, reperfusion therapy, especially intravenous thrombolysis, has been recommended as the first-line therapy of ischemic stroke in the current guidelines.³

Clinical trials^4–6 on recombinant tissue plasminogen activator (rtPA) have demonstrated its efficacy in ischemic stroke 20 years ago. In the very beginning, the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study, also known as the NINDS trial,⁴ proved the efficacy and safety of intravenous thrombolysis alteplase in the 3-h time window of ischemic stroke onset in 1995. The European Cooperative Acute Stroke Study III trial, also known as the ECASS III trial,⁷ extended the time window of alteplase to 4.5 h. The Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial⁶ and the EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial⁸ showed that alteplase can be used in wake-up stroke, un-witnessed stroke, and unknown-onset stroke.

Tenecteplase (TNK) is a genetically engineered, mutant, tissue plasminogen activator that has shown a greater recanalization rate than alteplase in acute myocardial infarction as well as a lower risk of hemorrhagic events.⁹ Several clinical trials^10–19 were conducted to test the efficacy and safety of TNK in reperfusion therapy for ischemic stroke. The 2019 American Heart Association/American Stroke Association Guidelines²⁰ recommended 0.4 mg/kg TNK as an alternative to alteplase in patients with mild neurological impairment and no major intracranial occlusion. Moreover, 0.25 mg/kg TNK was recommended in the 2019 American Heart Association/American Stroke Association Guidelines²⁰ in patients without contraindications for intravenous (IV) fibrinolysis who were also eligible to undergo mechanical thrombectomy. Considering the limited clinical trials on TNK, the class of recommendation and level of evidence are low (IIb, B-R). The 2021 European Stroke Organisation Guidelines²¹ recommended 0.25 mg/kg TNK over 0.9 mg/kg alteplase before mechanical thrombectomy within 4.5 h from stroke onset. However, the recommendation of TNK over alteplase was based on expert consensus recommendation with a weak strength of recommendation and low quality of evidence. In the real-world clinic, TNK is still used cautiously to treat ischemic stroke, and more clinical trials on TNK in ischemic stroke are needed. In this review, we summarize the clinical trials on TNK in ischemic stroke (Table 1).

Table 1 Clinical Trials on TNK in Ischemic Stroke

Pharmacokinetic Comparison

Because fibrin molecules bind to each other and form the skeleton of a thrombus^22,23 (Figure 1), it can be lysed through fibrinolysis. Tissue plasminogen activator (tPA) is generated in endothelial cells to convert plasminogen into plasmin. Plasmin breaks down the fibrin skeleton by converting fibrin into fibrinogen degradation products, and the thrombus is eventually dissolved to achieve recanalization of the occluded vessel.

Figure 1 Mechanism of thrombosis.

Similar to alteplase, TNK is also a 527-amino acid-modified human tissue plasminogen activator that contains the fibronectin finger, epidermal growth factor, kringle 1, kringle 2, and serine protease domains. However, three amino acids are substituted in TNK compared to alteplase: the substitution of threonine 103 with asparagine and glutamine 117 with asparagine has increased the half-life of TNK; the amino acid replacement in positions 296–299 has enhanced its resistance to plasminogen activator inhibitor-1 (PAI-1) and potentiated fibrin specificity.²⁴ The different biomolecular structure of TNK has given it more pharmacological advantages over alteplase²⁵ (Table 2). The prolonged half-life enables TNK to be administered as a single intravenous bolus rather than a bolus and continuous infusion. The single bolus of TNK is more convenient for “drip and ship” cases. Moreover, poor fibrin selectivity of alteplase results in excessive systematic bleeding events and disintegration of the blood–brain barrier leading to post-stroke cerebral edema and hemorrhagic transformation.²⁶ Alteplase also causes more damage to the fibrinolytic system than TNK and increases the risk of intracerebral hemorrhage.^26,27 Further, alteplase inhibits platelet aggregation and influences the coagulation process with an elevated risk of hemorrhagic events.^28,29 Therefore, theoretically, TNK is a better thrombolytic agent than alteplase with lower risk of side-effects when administrated intravenously in ischemic stroke patients.²⁵

Table 2 Pharmacokinetic Comparison Between Alteplase and TNK

Optimal Dose in Ischemic Stroke

A pilot dose-escalation safety study was conducted to investigate the safety and efficacy of TNK in ischemic stroke patients (n=88) at four doses (0.1 mg/kg, 0.2 mg/kg, 0.4 mg/kg, 0.5 mg/kg).¹⁰ The occurrence of symptomatic intracranial hemorrhage (sICH) at TNK doses of 0.1 mg/kg, 0.2 mg/kg, and 0.4 mg/kg were lower than that of alteplase (0% vs 0% vs 0% vs 15%, respectively). A phase IIb, randomized, double-blind trial was conducted in 2010 to compare the three doses of TNK (0.1 mg/kg, 0.25 mg/kg, and 0.4 mg/kg) with alteplase.¹² The trial was terminated prematurely because patient enrolment was very slow, with only 112 patients being finally enrolled. The dose of 0.4 mg/kg TNK was prematurely terminated considering its poor performance in both efficacy and safety; in terms of good outcome (combining major neurological improvement and symptomatic ICH), the 0.25 mg/kg TNK group had the highest proportion (15/31, 48.4%), followed closely by the 0.1 mg/kg TNK group (14/31, 45.2%). By comparison, the rt-PA group had 41.9% (13/31) good outcomes. The difference between the 0.25 mg/kg and 0.1 mg/kg groups was not statistically significant because of the insufficient sample size after patient enrolment was terminated (n=112). Moreover, the study did not show conclusive results for an optimal dose of TNK in ischemic stroke.

The Tenecteplase VERSUS Alteplase for Acute Ischemic Stroke (TAAIS) trial enrolled patients with middle cerebral artery (MCA) occlusion on CTA and reversible penumbra on CTP (n=75) and showed the superiority of 0.25 mg/kg TNK over 0.1 mg/kg TNK among all the efficacy endpoints (mean rates of reperfusion at 24 h: 88.8% vs. 69.3%, P=0.006; complete recanalization at 24 h: 80% vs. 35%, P=0.002; median improvement in National Institutes of Health Stroke Scale score at 24 h: 11 vs. 7, P=0.0059; and mRS 0–1: 72% vs. 36%, P=0.011). However, no significant difference was detected in safety endpoints between the two doses of TNK (sICH: 4% vs. 4%, P=1.000).¹³ The TAAIS trial¹³ and another meta-analysis³⁰ both implied that the optimal dosage of TNK in ischemic stroke may be 0.25 mg/kg, and this dosage was utilized in subsequent Phase II and Phase III trials including ATTEST (Alteplase vs. tenecteplase for thrombolysis after ischaemic stroke),¹⁵ TEMPO-1 (Tenecteplase–Tissue-Type Plasminogen Activator Evaluation for Minor Ischemic Stroke With Proven Occlusion),¹⁴ and EXTEND-IA TNK (Tenecteplase vs. Alteplase before Endovascular Therapy for Ischemic Stroke trial).¹⁷ The TEMPO-1 study also found that there were no serious drug-related adverse events in the 0.1 mg/kg TNK group. In the 0.25 mg/kg TNK group, there was one sICH (4%). Comparable risks of sICH were found between the 0.1 mg/kg TNK and 0.25 mg/kg TNK groups. Owing to a small sample size (n=100) and non-randomized study design, it was served as a safety and feasibility trial. The Norwegian tenecteplase stroke trial (NOR-TEST trial),¹⁶ a phase III trial with over 1000 enrolled patients, utilized 0.4 mg/kg TNK and failed to prove the superiority of TNK over alteplase on functional outcomes (mRS score 0–1 at 3 months: 64% vs. 63%, P=0.52). Safety outcomes were also similar between the TNK and alteplase groups (sICH: 3% vs. 2%, P=0.49; death within 3 months: 5% vs. 4%, P=0.49). The limitations of the NOR-TEST trial¹⁶ included a large proportion of TIA and stroke mimics (25%) and mild neurological impairment (median NIHSS score=4) that decreased its external validation. The EXTEND-IA TNK 2 trial failed to prove the superiority of 0.4 mg/kg TNK compared with 0.25 mg/kg TNK. Per another study,¹⁸ 0.25 mg/kg was the optimal dosage for patients undergoing bridge therapy. (intravenous thrombolysis [IVT]+mechanical thrombectomy [MT])

Recanalization and Reperfusion

The TAAIS trial demonstrated that TNK was superior to alteplase in reperfusion at 24 h (79.3% vs 55.4%, P=0.004).¹³ The ATTEST trial failed to demonstrate the superiority of TNK over alteplase in reperfusion.¹⁵ The TAAIS trial¹³ only enrolled patients with a reversible penumbra on CTP and limited the percentage of hypoperfusion area volume (at least 20% greater than the infarct core lesion), whereas the ATTEST trial¹⁵ did not. While MR-DWI was used in most trials, the infarction core volume was measured via non-contrast CT in the ATTEST trial,¹⁵ which likely led to bias. The TEMPO-1 study,¹⁴ a prospective multicenter cohort study, showed that patients treated with 0.25 mg/kg TNK had a greater recanalization rate than those treated with 0.1 mg/kg TNK (52.17% vs 39.13%). TEMPO-1¹⁴ enrolled patients with minor stroke (initial NIHSS score ≤5) owing to intracranial vessel occlusion and assessed the recanalization rate at 4–8 h from the administration of TNK, a timepoint earlier than those used in the TAAIS trial¹³ and ATTEST trial.¹⁵ Hence, the results from the TEMPO-1 study¹⁴ were more representative of patients with minor stroke. Although the ATTEST trial¹⁵ enrolled 104 patients, only 71 were included in the penumbra salvage analysis and 67 in the recanalization analysis, less than the sample size estimated to produce significant results on reperfusion and recanalization. A pooled analysis³¹ of the data from the TAAIS¹³ and the ATTEST¹⁵ trials showed that the recanalization rate of patients treated with TNK is greater than that of patients treated with alteplase, including the rate of complete (71% vs 42%, P<0.001) and partial (80% vs 57%, P<0.001) recanalization, indicating the superiority of TNK over alteplase in recanalization rate.

The EXTEND-IA TNK trial¹⁷ showed that more patients in the 0.25 mg/kg TNK group achieved substantial reperfusion (ie, restoration of blood flow to >50% of the involved territory or an absence of retrievable thrombus in the target vessel at the time of the initial angiographic assessment) than those in the alteplase group before thrombectomy, within 4.5 h after the onset of ischemic stroke (22% vs 10%, P=0.002); this indicated the superiority of TNK to alteplase in reperfusion and recanalization rate in ischemic stroke. TNK has demonstrated its superiority over alteplase in terms of recanalization rate and reperfusion in previously conducted clinical trials.^13,14,17 Other imaging endpoints including infarct core volume and salvage tissue volume may warrant further investigations in future trials.

The reperfusion/recanalization rates among the TAAIS,¹³ ATTEST,¹⁵ and EXTEND-IA TNK¹⁷ trials were measured at different time points, and the trials also had different inclusion criteria. The reperfusion and recanalization rates were measured at 24 h after treatment in the TAAIS trial.¹³ The percentage of penumbra salvage and recanalization were measured at 24–48 h post treatment in the ATTEST trial.¹⁵ In the EXTEND-IA TNK trial,¹⁷ the reperfusion and recanalization rates were measured at the initial angiography or 1–2 h post thrombolysis, earlier than the measurement time in the former two trials. The TAAIS trial enrolled patients with an NIHSS score≥4 and intracranial arterial occlusion in the anterior, middle, and posterior cerebral artery, within 6 h.¹³ The ATTEST trial enrolled all the patients within 4.5 h after the onset of ischemia.¹⁵ In the EXTEND-IA TNK trial, the patients were enrolled if they had cerebral vascular occlusion within 4.5 h after the onset of stroke and were eligible for mechanical thrombectomy within 6 h.¹⁷ Different time points of reperfusion/recanalization rates and number of enrolled patients may have led to bias in the results of the three trials.^13,15,17

^{More at link.}