Tenecteplase is a triple combination mutant variant of alteplase with high fibrin specificity and resistance to plasminogen activator inhibitor-1. The reduced rate of systemic clearance of the drug relative to alteplase allows tenecteplase to be given by rapid bolus injection to patients with acute myocardial infarction (AMI) with ST segment elevation. The efficacy of tenecteplase in AMI has been demonstrated in a phase I dose-ranging trial [Thrombolysis in Myocardial Infarction (TIMI) 10A], a nonblind phase II comparison with alteplase (TIMI 10B), and a randomized double-blind phase III comparison with alteplase in 16 949 patients [the second Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) trial]. Patients also received aspirin and intravenous heparin in all trials. In TIMI 10A and 10B, TIMI grade 3 coronary flow was achieved after 90 minutes in 54.3 to 65.8% of patients receiving tenecteplase 30, 40 or 50mg; in TIMI 10B, grade 3 flow was reported in 62.7% patients receiving alteplase (≤100mg by front-loaded infusion over 90 minutes). Thirty-day mortality was similar with bodyweight-adjusted intravenous bolus doses of tenecteplase 30 to 50mg and front-loaded 90-minute infusion of alteplase in ASSENT-2 (approximately 6.2%). Rates of reinfarction and cardiogenic shock were also similar between groups, although mortality was reduced with tenecteplase in patients receiving treatment more than 4 hours after onset of symptoms (7 vs 9.2%; p = 0.018). Preliminary data show maintenance of the similarity between groups over 1 year (approximate 10.2% mortality in both groups), with loss of statistical significance between groups in patients treated late. ASSENT-2 showed the risks of intracranial hemorrhage (0.93%) and stroke (all causes) [1.78%] with tenecteplase to be similar to those with alteplase (0.94 and 1.66%, respectively). The rate of noncerebral bleeding was lower with tenecteplase than with alteplase (26.43 vs 28.95%; p = 0.0003). No causal link has been demonstrated between tenecteplase and allergic reactions in patients. Conclusions: Bolus tenecteplase is an effective thrombolytic agent, suitable for first-line use in patients with AMI with ST segment elevation. Results to date show overall efficacy and tolerability profiles similar to those of alteplase, with comparable mortality after 1 year's follow-up. The apparent advantages of tenecteplase (reduced mortality in patients receiving late treatment and reduced incidence of noncerebral bleeding complications) in ASSENT-2 are of interest and merit further attention. The full implications of the availability of bolus administration and its potential clinical advantages over the currently widely used infusion regimens, together with the effect on outcomes of addition of tenecteplase to platelet glycoprotein IIb/IIIa inhibition, are currently under investigation. Tenecteplase acts on the physiologic fibrinolytic system in a manner similar to tissue plasminogen activator (t-PA). Studies in animals have shown earlier and more sustained fe ral artery recanalization with tenecteplase than with alteplase (the recombinant form of natural t-PA) after artificially induced thrombus formation. Studies in a rabbit model showed tenecteplase to induce 50% lysis of whole blood clots 3 times faster than natural t-PA (mean 35 vs 120 minutes) when either drug was given at the same dose (0.18 mg/kg). Tenecteplase was also shown to have fibrinolytic activity and fibrin binding capacity similar to those of natural t-PA in plasma-based clots, but with fibrin specificity and resistance to plasminogen activator inhibitor-1 enhanced 14- and 80-fold, respectively. The fibrin specificity and plasminogen-conserving properties relative to alteplase of tenecteplase in circulating blood in humans have been shown in a phase II comparison of intravenous bolus doses of 30, 40 or 50mg with a front-loaded 90-minute infusion of alteplase of up to 100mg. Median levels of circulating plasminogen were reduced from baseline by 10 to 15% in tenecteplase recipients, and by 50% in patients receiving alteplase, over the first 6 hours. Consumption of α2-antiplasmin and increases in median levels of plasmin/α2-antiplasmin complex in plasma in alteplase recipients were 4 to 5 times greater than those seen with any dose of tenecteplase. Over the first 6 hours, circulating levels of fibrinogen were reduced from baseline by a median 5 to 10% in patients receiving tenecteplase and by 40% in those receiving alteplase. Available data indicate that tenecteplase lacks the procoagulant properties seen with other thrombolytic drugs such as streptokinase or (to a lesser extent) alteplase. Tenecteplase has an initial volume of distribution similar to that of plasma. Extravascular distribution is suggested by an increased volume of distribution at steady state relative to the initial volume of distribution: data obtained in rats indicate the liver to be the organ chiefly involved. Tenecteplase is eliminated from plasma in a biphasic fashion, with a mean initial half-life (t1/2) of approximately 22 minutes and a mean terminal elimination t1/2 of 1.5 to 2.2 hours (approximately 90 to 130 minutes). The initial (α) phase is dominant, accounting for a mean 66 to 75% of the total area under the plasma drug concentration versus time curve across the dose range of 30 to 50mg. Plasma clearance is independent of dose, and is approximately 4 times slower than with alteplase. © Adis International Limited. All rights reserved.
