Tenecteplase

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Abstract
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 femoral 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 (t½) of approximately 22 minutes and a mean terminal elimination t½ 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. The therapeutic efficacy of tenecteplase in AMI has been assessed in 3 major studies. The first (TIMI 10A) was a phase I dose-ranging trial, the second (TIMI 10B) was a nonblind phase II comparison of fixed doses of intravenous bolus tenecteplase with a front-loaded infusion of alteplase, and the third (ASSENT-2) was a phase III comparison of bodyweight-adjusted bolus tenecteplase with infused alteplase. Patients underwent thrombolysis within 12 hours of onset of symptoms in TIMI 10A and 10B, and within 6 hours in ASSENT-2. TIMI 10A and 10B. These studies focused on re-establishment of coronary blood flow as reflected by TIMI gradings and frame counts, whereas 30-day mortality was the primary end-point in ASSENT-2. Patients in all trials received aspirin 150 to 325mg daily, with intravenous heparin for 48 to 72 hours. In TIMI 10A, 113 patients received single bolus doses of tenecteplase ranging from 5 to 50mg; TIMI grade 3 flow was achieved after 90 minutes by 57 to 64% of patients receiving tenecteplase 30 to 50mg (p = 0.032 vs lower doses). In TIMI 10B, which involved an evaluable cohort of 837 patients, TIMI grade 3 flow was reported after 90 minutes in 54.3 to 65.8% of patients receiving tenecteplase 30, 40 or 50mg, and in 62.7% of alteplase recipients (15mg intravenous bolus, then infusion of 0.75 mg/kg to a maximum dose of 50mg over 30 minutes, and a subsequent infusion of 0.5 mg/kg to a maximum of 35mg over the next 60 minutes). TIMI frame counts were concordant with flow gradings in both studies. The 30-day mortality rate in TIMI 10A was 3.5% across all treatment groups, with reinfarction reported in 4.4% of patients. In TIMI 10B, overall rates of mortality and reinfarction at 30 days were 4.9 and 5.4%, respectively, with no significant differences between any of the treatment groups. ASSENT-2. This was a large, randomized double-blind study carried out in 29 countries in an intention- to-treat population of 16 949 patients. Tenecteplase was given on a bodyweight-adjusted basis as intravenous bolus doses ranging from 30 to 50mg (n = 8461), whereas alteplase was given as a front-loaded infusion as in TIMI 10B. Heparin was given as a 4000U bolus plus infusion of 800 U/h for patients ≤67kg, and as a 5000U bolus plus 1000 U/h in patients >67kg, with a target activated partial thromboplastin time of 50 to 75 seconds for 48 to 72 hours. Kaplan-Meier survival curves for tenecteplase and alteplase were superimposable, and 30-day mortality rates were similar in both groups (6.179% with tenecteplase and 6.151% with alteplase). This similarity persisted in analyses carried out in prespecified patient subgroups, although the mortality rate at 30 days was reduced with tenecteplase in patients receiving treatment more than 4 hours after AMI (7 vs 9.2%; p = 0.018). Thirty-day reinfarction rates were 4.1 and 3.8% with tenecteplase and alteplase, respectively; corresponding rates of cardiogenic shock were 3.9 and 4%. Preliminary 1-year follow-up data from 14 203 patients, 12 311 of whom remained alive, show mortality rates of 10.15 and 10.23% in patients receiving tenecteplase and alteplase, respectively (p = 0.87 between groups). Corresponding rates of mortality of 12.1 and 14.4% were reported in patients receiving treatment more than 4 hours after onset of symptoms; the statistical significance between groups noted after 30 days was not apparent after 1 year, however (p = 0.069). The risks of intracranial hemorrhage and stroke from all causes (the major adverse events of concern in patients receiving thrombolytic agents) with tenecteplase appear similar on the basis of current data to those with alteplase. In the ASSENT-2 study, there were no significant differences between bodyweight-adjusted bolus doses of tenecteplase and front-loaded infusion of alteplase in incidences of intracranial hemorrhage (0.93 vs 0.94%), stroke (all causes; 1.78 vs 1.66%), ischemic stroke (0.72 vs 0.64%) and hemorrhagic conversion (0.07 vs 0.09%). However, the rate of noncerebral bleeding complications was significantly lower in the tenecteplase group (26.43 vs 28.95%; p = 0.0003). The phase II first Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-1) trial, which was set up to assess the tolerability of tenecteplase in 3235 patients with AMI, showed severe bleeding in 1.6% of patients across bolus doses of 30 to 50mg. The overall rate of stroke at 30 days was 1.5%. The incidence of intracranial hemorrhage was 0.77%. Allergic reactions have been reported only rarely (<1% of patients) in recipients of tenecteplase, although no causal link between the drug and these effects has been shown. As arrhythmia associated with reperfusion is sometimes reported in patients receiving thrombolytic therapy, it is recommended that appropriate counter-measures be available in centers in which tenecteplase is in use. Tenecteplase should be administered as a single bodyweight-adjusted intravenous bolus injection of 30 to 50mg over 5 seconds as soon as possible after the onset of symptoms of AMI. The drug is presented in 50mg vials as a lyophilized powder for dissolution in water for injections and immediate use. The syringe supplied is designed primarily for use with needleless intravenous systems, although attachment to a needle is possible if necessary. Tenecteplase should not be given to patients with any of the following: active internal bleeding; a history of cerebrovascular accident; a history of intracranial or intraspinal surgery within the preceding 2 months; intracranial neoplasm, arteriovenous malformation or aneurysm; known bleeding diathesis; severe uncontrolled hypertension. Although sustained antibody formation has not been reported in patients receiving a single dose of tenecteplase, readministration should be undertaken with caution. Studies of the use of tenecteplase in pregnant or nursing women have not been carried out, and careful risk-benefit assessment is therefore required when contemplating the use of the drug in these patients.