Tenecteplase: A Review of Its Pharmacology and Uses.

Abstract

Tenecteplase is a tissue plasminogen activator produced by recombinant DNA technology. It binds to fibrin and catalyzes the conversion of plasminogen to plasmin, which leads to rapid lysis of clots. Thrombolytic therapy with alteplase or tenecteplase is used in the treatment of myocardial infarction, ischemic stroke, and pulmonary embolism (PE). Alteplase is approved by the US Food and Drug Administration (FDA) for all 3 indications; tenecteplase is FDA approved only for the treatment of myocardial infarction.1,2Many hospital systems are adding tenecteplase to the formulary or switching to tenecteplase as the thrombolytic of choice despite its lack of FDA approval for indications other than myocardial infarction.3-5 Institutions cite workflow advantages and potential cost savings with tenecteplase (the wholesale acquisition cost is $8071.39 per 50-mg vial of tenecteplase, as compared with $10 560.43 per 100-mg vial of alteplase).1,2 Therefore, it is imperative for all clinicians involved with the treatment of patients with myocardial infarction, ischemic stroke, or PE to understand the pharmacology, uses, and clinical evidence regarding tenecteplase.Tenecteplase promotes the initiation of fibrinolysis by binding to fibrin and converting plasminogen to plasmin (Figure).2 Due to 3 different sequence variations, tenecteplase has a 6-fold longer half-life, a 15-fold higher fibrin specificity, and an 80-fold increased resistance to plasminogen activator inhibitor 1 when compared with alteplase.6 These characteristics offer several advantages. A longer half-life permits a single bolus administration. A single bolus dose offers ease of administration, a potential reduction in medication errors, and a reduction in medication preparation and administration time, which is critical when treating time-sensitive conditions such as stroke. Higher fibrin specificity decreases the systemic activation of plasminogen and the resulting degradation of circulating fibrinogen, potentially reducing systemic bleeding. Increased resistance to plasminogen activator inhibitor 1 (which helps ensure that clots remain intact) potentially increases the potency and efficacy of tenecteplase compared with alteplase. Tenecteplase is biphasically eliminated via the liver, with an initial half-life of 20 to 24 minutes and a terminal-phase half-life of 90 to 130 minutes.2 Table 1 includes additional information on the pharmacokinetic and pharmacodynamic properties of tenecteplase and alteplase.Tenecteplase, like alteplase, is contraindicated in patients with active internal bleeding, a history of cerebrovascular accident, intracranial or intraspinal surgery within the last 2 months, intracranial neoplasm, arteriovenous malformation or aneurysm, known bleeding diathesis, or severe uncontrolled hypertension. Societal guidelines may have additional contraindications or precautions not listed in the package insert. For example, the American Heart Association/American Stroke Association guidelines include coagulopathy, gastrointestinal bleed within 21 days or malignancy, infective endocarditis, aortic arch dissection, concomitant abciximab or intravenous aspirin use, and use of low-molecular-weight heparin, thrombin inhibitors, or factor Xa inhibitors as additional contraindications to the use of alteplase, with no specific comment on contraindications to tenecteplase.7 Bleeding is the most common adverse effect, followed by hypersensitivity reactions (anaphylaxis and angioedema are rare). Less common adverse effects include cardiogenic shock, arrhythmias, atrioventricular block, pulmonary edema, heart failure, cardiac arrest, recurrent myocardial ischemia, myocardial reinfarction, myocardial rupture, cardiac tamponade, pericarditis, pericardial effusion, mitral regurgitation, and thrombosis.2Tenecteplase has indication-specific dosing. Tenecteplase’s FDA-approved packaging contains dosing information for myocardial infarction only, so it is important to ensure that the dose used in practice is correct for the indication. It is supplied as a lyophilized powder and requires reconstitution with sterile water. Patients who receive tenecteplase should be monitored for adverse reactions. Vital signs should be assessed per institutional protocol. In general, antiplatelet and anticoagulant medications should be withheld for at least 24 hours after administration of tenecteplase due to the increased risk of bleeding when used in combination.2 Table 2 includes information for indication-specific dosing, administration, and monitoring.The body of literature assessing the role of tenecteplase in the treatment of ischemic stroke, PE, and myocardial infarction is expanding. The following sections summarize the literature currently available.Thrombolytic therapy in acute ischemic stroke is aimed at restoring perfusion by salvaging the ischemic penumbra and improving neurologic outcomes. Thrombolytics are indicated within 4.5 hours of symptom onset.7 Patients with large-vessel occlusions and those who present after 4.5 hours may also be candidates for mechanical thrombectomy.7Six major randomized controlled trials have compared tenecteplase with alteplase for the treatment of acute ischemic stroke. In the TNK-S2b (Study of Tenecteplase in Acute Ischemic Stroke Phase 2b) trial,8 published in 2010, eligible patients were randomized within 3 hours of symptom onset to receive tenecteplase in different dosing tiers: 0.1 mg/kg, 0.25 mg/kg, or 0.4 mg/kg (n = 25 per group). The investigators compared outcomes in these patients with outcomes of historical control patients who had received standard-dose alteplase.8 The median National Institutes of Health Stroke Scale (NIHSS) scores of patients in the different tenecteplase groups ranged from 8 to 10 and in the alteplase group was 13. Slow enrollment led to early study termination. The percentages of patients with good neurologic outcomes, as measured by modified Rankin Scale scores, were nonsignificantly higher in the groups receiving tenecteplase 0.1 mg/kg and 0.25 mg/kg than in the alteplase group. The group receiving tenecteplase 0.4 mg/kg had the highest rate of symptomatic intracranial hemorrhage at 15%. In comparison, the alteplase group had a 3.2% rate of symptomatic intra-cranial hemorrhage.8An Australian trial9 published in 2012 randomized 75 patients with suspected ischemic stroke within 6 hours of symptom onset to receive tenecteplase 0.1 mg/kg, tenecteplase 0.25 mg/kg, or standard-dose alteplase (n = 25 per group). Included patients had a mean NIHSS score of 14.4 and a mean time to treatment of 2.9 hours. Patients receiving tenecteplase had a significantly greater percentage of reperfusion on imaging studies than did those receiving alteplase (79.3% vs 55.4%; P = .004) and superior neurologic outcomes based on improvement in NIHSS score from baseline to 24 hours (8.0 vs 3.0; P < .001). The outcomes for tenecteplase compared with alteplase were reported in aggregate, but the authors did include a small dose-tier analysis. Tenecteplase at the higher dose (0.25 mg/kg) was associated with superior imaging efficacy outcomes compared with alteplase. Seventy-two percent of patients in the higher-dose tenecteplase group had excellent recovery (defined as no clinically significant disability), as compared with 40% of patients receiving alteplase (P = .02). When compared with the lower dose of tenecteplase (0.1 mg/kg), the higher dose yielded better reperfusion and recanalization rates, which resulted in greater clinical improvement at 24 hours and an increase in the number of patients with excellent recovery at 3 months (P = .01). Adverse events were similar in the 2 tenecteplase groups and the alteplase group.9The ATTEST (Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis) study,10 published in 2015, assessed the efficacy and safety of tenecteplase 0.25 mg/kg (n = 47) versus standard-dose alteplase (n = 49) administered within 4.5 hours of symptom onset in patients with suspected acute ischemic stroke. The median NIHSS score was 12 in the tenecteplase group and 11 in the alteplase group. The percentage of penumbra salvaged was 68% in both groups (P = .81). Safety outcomes were not significantly different. However, the tenecteplase group had a nonsignificantly higher percentage of patients with early neurologic improvement (40% vs 24%; P = .10) and a nonsignificantly higher percentage of patients with a good neurologic outcome at 90 days (28% vs 20%; P = .28).10The NOR-TEST (Norwegian Tenecteplase Stroke Trial),11 published in 2017, randomized patients with suspected ischemic stroke admitted within 4.5 hours of symptom onset or within 4.5 hours of awakening with symptoms to receive tenecteplase 0.4 mg/kg (n = 549) or standard-dose alteplase (n = 551). Excellent functional outcome, defined as a modified Rankin Scale score of 0 to 1, was achieved in 354 patients (64%) in the tenecteplase group and 345 patients (63%) in the alteplase group (odds ratio [OR], 1.08; 95% CI, 0.84-1.38; P = .52). The frequency of adverse events was similar. The mean NIHSS scores were 5.6 and 6.8 in the tenecteplase and alteplase groups, respectively; these scores were lower than those found in previous studies.11The EXTEND-IA TNK (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke) investigators published 2 trials.12,13 The EXTEND-IA TNK part 1 trial,12 published in 2018, randomized patients with acute ischemic stroke who were eligible to undergo thrombectomy to receive tenecteplase 0.25 mg/kg (n = 101) or standard-dose alteplase (n = 101) within 4.5 hours of symptom onset. Reperfusion of greater than 50% of the ischemic area or no evidence of retrievable thrombus at the time of initial angiography occurred in 22% of patients receiving tenecteplase and 10% of patients receiving alteplase (P = .03 for superiority; P = .002 for noninferiority). Tenecteplase also resulted in significantly improved 90-day functional outcomes compared with alteplase, with median modified Rankin Scale scores of 2 and 3, respectively (P = .04). Adverse events were similar.12 The EXTEND-IA TNK part 2 trial,13 published in 2020, was designed to define the optimal dose of tenecteplase, either 0.25 mg/kg or 0.4 mg/kg.13 Reperfusion and functional outcomes were similar in the 2 groups. The incidence of symptomatic intracranial hemorrhage was nonsignificantly higher in the group receiving 0.4 mg/kg than in the group receiving 0.25 mg/kg (4.7% and 1.3%, respectively; P = .12).13Part A of NOR-TEST 2 was published in 2022.14 The investigators conducted a phase 3 trial to evaluate the noninferiority of tenecteplase 0.4 mg/kg to alteplase 0.9 mg/kg in patients with moderate or severe ischemic stroke.14 However, the trial was terminated early because the rates of symptomatic intracranial hemorrhage exceeded a prespecified safety threshold. At the time of trial termination, 21% of patients in the tenecteplase group and 7% of patients in the alteplase group had developed an intracranial hemorrhage. Favorable functional outcome, defined as a modified Rankin Scale score of 0 to 1, was significantly higher in the alteplase group. However, outcomes must be interpreted with caution due to low trial enrollment and subsequent inability to meet power to evaluate the outcomes.14 The results of this trial, in combination with concerns of previous trials, should raise serious caution about the higher 0.4-mg/kg dose of tenecteplase.Several meta-analyses have concluded that tenecteplase is a safe and effective alternative to alteplase in the treatment of acute ischemic stroke.15-17 One meta-analysis also concluded that tenecteplase is potentially associated with improved functional outcomes.16 These meta-analyses did not include NOR-TEST 2,14 but including this trial would not be likely to change the outcome because previous trials showed similar safety outcomes with alteplase and a lower dose of tenecteplase at 0.25 mg/kg. Based on results of studies completed before its publication, the 2019 edition of the American Heart Association/American Stroke Association guidelines states, “It may be reasonable to choose tenecteplase (single IV [intravenous] bolus of 0.25 mg/kg, maximum 25 mg) over IV alteplase in patients without contraindications for IV fibrinolysis who are also eligible to undergo mechanical thrombectomy.”7(pe371)Overall, tenecteplase is shown to be at least as effective and safe as alteplase in patients with acute ischemic stroke when dosed at 0.25 mg/kg. Ongoing studies at the time of the writing of this article, including NOR-TEST 2 Part B (NCT03854500), ATTEST-2 (NCT02814409), and TASTEa (NCT04071613), will further inform the choice between alteplase and tenecteplase.Patients with a PE can be classified into 3 different categories based on hemodynamic stability. Patients with hemodynamic instability are considered to have a massive or high-risk PE. Patients who are hemodynamically stable have a submassive or intermediate-risk PE if they have evidence of right ventricular (RV) strain or elevated troponin levels; these patients have a low-risk PE in the absence of RV strain. Patients with high-risk or massive PEs present with hypotension (systolic blood pressure < 90 mm Hg or a decrease of > 40 mm Hg not explained by another cause, sustained for at least 15 minutes) and RV dysfunction (RV hypokinesis, dilation, or overload or elevated B-type natriuretic peptide level) or myocardial injury (elevated troponin level).18 Thrombolytics are indicated in patients with massive PE and low bleeding risk, according to the 2021 American College of Chest Physicians guidelines.18 Two meta-analyses have concluded that tenecteplase is safe and effective in the treatment of patients with massive or high-risk PE.19,20 However, thrombolytics are controversial for submassive or intermediate-risk PE and are not indicated for low-risk PE.The PEITHO (Pulmonary Embolism Thrombolysis) trial is the largest trial to date of tenecteplase in patients with submassive PE, defined as having RV dysfunction and an elevated troponin level.21 The international, multicenter, double-blinded trial evaluated clinical and safety outcomes in 1006 patients randomized to receive either weight-based tenecteplase with heparin or placebo with heparin. Patients in the tenecteplase group had significantly lower rates of death or hemodynamic compromise within 7 days than did those who received placebo (2.6% vs 5.6%; OR, 0.44; 95% CI, 0.23-0.87; P = .02; number needed to treat, 34).21 However, patients receiving tenecteplase had significantly higher rates of extracranial bleeding (6.3% vs 1.2%; OR, 5.55; 95% CI, 2.3-13.39; P < .001; number needed to harm, 20) and stroke (2.4% vs 0.2%; OR, 12.10; 95% CI, 1.57-93.39; P = .003; number needed to harm, 46).21 In a 24-month outcome evaluation, long-term survival was not significantly different between the tenecteplase and placebo groups, with rates of 20.3% and 18%, respectively.22 There were also no differences in functional limitations, dyspnea, residual pulmonary hypertension, RV dysfunction, or chronic pulmonary hypertension.2 In patients with submassive PE, the risk of bleeding and lack of long-term benefits when compared with anticoagulation alone must be weighed against any short-term benefit.No trials have compared alteplase and tenecteplase in patients with PE, and the American College of Chest Physicians guidelines make no comment on the choice between the thrombolytic agents.18 Tenecteplase may have a theoretical advantage due to a shorter infusion time, but this possibility has yet to be studied. Current American College of Chest Physicians guidelines recommend thrombolytic therapy in patients with massive PE or in select patients with acute PE who decompensate after starting anticoagulant therapy but have yet to develop hypotension and have an acceptable bleeding risk. This decompensation can include an increase in heart rate, a decrease in systolic blood pressure that remains greater than 90 mm Hg, worsening gas exchange, signs of shock, worsening right heart dysfunction noted on echocardiography, or an increase in cardiac biomarkers.18 In the PEITHO trial, tenecteplase dosing was similar to dosing used to treat myocardial infarction.21 The guidelines also suggest systemic thrombolytic therapy over catheter-directed thrombolysis, although this recommendation is weak and based on low-quality evidence.18Overall, the decision to administer thrombolytic therapy must balance the benefits with the risk of bleeding. Patients with suspected PE and hemodynamic instability on presentation receive the most benefit with thrombolytics. Those at high risk for clinical deterioration must be monitored closely and considered for thrombolytic therapy if deterioration occurs.Thrombolytic therapy is indicated in patients with ST-segment elevation myocardial infarction (STEMI) when a delay of greater than 120 minutes in performing primary percutaneous coronary intervention (PCI) is anticipated.23 This a class I recommendation by the American College of Cardiology Foundation and the American Heart Association for patients with STEMI presenting within 12 hours of the onset of ischemic symptoms. Thrombolytic therapy may also be reasonable “if there is clinical and/or ECG [electrocardiographic] evidence of ongoing ischemia within 12 to 24 hours of symptom onset and a large area of myocardium at risk or hemodynamic instability” (class IIa recommendation).23(pe95) Concomitant antiplatelet and anticoagulant therapy should be administered, and patients should be transported to a PCI-capable hospital following thrombolytic therapy.23Tenecteplase was approved by the FDA in 2000 “for the lysis of thrombi in the coronary vasculature to restore perfusion and reduce mortality” in the management of STEMI.2 Dosing information is listed in Table 2. Investigators in the STREAM (Strategic Reperfusion Early After Myocardial Infarction) trial,24 which compared primary PCI and tenecteplase in patients with STEMI who presented within 3 hours of symptom onset, found a nonsignificantly higher risk of intracranial bleeding in the tenecteplase group among patients aged 75 years or older.24 The ongoing STREAM-2 trial (NCT02777580) is comparing half-dose tenecteplase with primary PCI in patients aged 60 years or older with STEMI and symptom onset within 3 hours.Practically, primary PCI is the preferred therapy to restore perfusion in patients with STEMI. However, when PCI is not feasible within 120 minutes of medical contact, tenecteplase may be used.Tenecteplase use for various indications is increasing. Its attractive properties include greater fibrin specificity, longer half-life, and increased resistance to plasminogen activator inhibitor 1 when compared with alteplase. These qualities permit ease of administration and potential workflow and efficiency advantages. Although FDA approved only for the treatment of myocardial infarction, increasing evidence suggests that tenecteplase is at least as effective and safe as alteplase for acute ischemic stroke and can be used in patients with massive PE. As the use of tenecteplase expands, clinicians must know its pharmacokinetic and pharmacodynamic properties and continue to follow emerging evidence regarding its safety and efficacy in practice.