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Tenecteplase is a modified form of human tissue plasminogen activator (tPA) that binds to fibrin and converts plasminogen to plasmin. In the presence of fibrin, in vitro studies demonstrate that Tenecteplase conversion of plasminogen to plasmin is increased relative to its conversion in the absence of fibrin. This fibrin specificity decreases systemic activation of plasminogen and the resulting degradation of circulating fibrinogen as compared to a molecule lacking this property. Following administration of 30, 40, or 50 mg of TNKase (tenecteplase) , there are decreases in circulating fibrinogen (4%–15%) and plasminogen (11%–24%). The clinical significance of fibrin-specificity on safety (e.g.,bleeding) or efficacy has not been established.Biological potency is determined by an in vitro clot lysis assay and is expressed in Tenecteplase-specific units. The specific activity of Tenecteplase has been defined as 200 units/mg.
In patients with acute myocardial infarction (AMI), TNKase (tenecteplase) administered as a single bolus exhibits a biphasic disposition from the plasma. Tenecteplase was cleared from the plasma with an initial half-life of 20 to 24 minutes. The terminal phase half-life of Tenecteplase was 90 to 130 minutes. In 99 of 104 patients treated with Tenecteplase, mean plasma clearance ranged from 99 to 119 mL/min.
The initial volume of distribution is weight related and approximates plasma volume. Liver metabolism is the major clearance mechanism for Tenecteplase.
ASSENT-2 was an international,randomized,double-blind trial that compared 30-day mortality rates in 16,949 patients assigned to receive an IV bolus dose of TNKase (tenecteplase) or an accelerated infusion of Activase® (Alteplase).1 Eligibility criteria included onset of chest pain within 6 hours of randomization and ST-segment elevation or left bundle branch block on electrocardiogram (ECG). Patients were to be excluded from the trial if they received GP IIb/IIIa inhibitors within the previous 12 hours.TNKase (tenecteplase) was dosed using actual or estimated weight in a weight-tiered fashion as described in DOSAGE AND ADMINISTRATION. All patients were to receive 150–325 mg of aspirin administered as soon as possible, followed by 150–325 mg daily. Intravenous heparin was to be administered as soon as possible: for patients weighing ≤ 67 kg, heparin was administered as a 4000 unit IV bolus followed by infusion at 800 U/hr; for patients weighing > 67 kg,heparin was administered as a 5000 unit IV bolus followed by infusion at 1000 U/hr. Heparin was continued for 48 to 72 hours with infusion adjusted to maintain aPTT at 50–75 seconds. The use of GP IIb/IIIa inhibitors was discouraged for the first 24 hours following randomization. The results of the primary endpoint (30-day mortality rates with non-parametric adjustment for the covariates of age, Killip class, heart rate, systolic blood pressure and infarct location) along with selected other 30-day endpoints are shown in Table 1.
Table 1: ASSENT-2 Mortality, Stroke, and Combined Outcome
of Death or Stroke
Measured at Thirty Days
|Relative Risk TNKase/Activase
|Intracranial Hemorrhage (ICH)||0.9%||0.9%||0.99
|Death or Nonfatal Stroke||7.1%||7.0%||1.01
Rates of mortality and the combined endpoint of death or stroke among pre-specified subgroups, including age, gender, time to treatment, infarct location, and history of previous myocardial infarction, demonstrate consistent relative risks across these subgroups. There was insufficient enrollment of non-Caucasian patients to draw any conclusions regarding relative efficacy in racial subsets.
Rates of in-hospital procedures, including percutaneous transluminal coronary angioplasty (PTCA), stent placement, intra-aortic balloon pump (IABP) use, and coronary artery bypass graft (CABG) surgery, were similar between the TNKase (tenecteplase) and Activase® (Alteplase) groups.
TIMI 10B was an open-label,controlled,randomized,dose-ranging,angiography study which utilized a blinded core laboratory for review of coronary arteriograms.2 Patients (n=837) presenting within 12 hours of symptom onset were treated with fixed doses of 30, 40, or 50 mg of TNKase (tenecteplase) or the accelerated infusion of Activase and underwent coronary arteriography at 90 minutes. The results showed that the 40 mg and 50 mg doses were similar to accelerated infusion of Activase in restoring patency. TIMI Grade 3 flow and TIMI Grade 2/3 flow at 90 minutes are shown in Table 2. The exact relationship between coronary artery patency and clinical activity has not been established.
Table 2: TIMI 10B Patency Rates
TIMI Grade Flow at 90 Minutes
≤ 100 mg
|TIMI Grade 3 Flow||63%||54%||63%||66%|
|TIMI Grade 2/3 Flow||82%||77%||79%||88%|
|95% CI (TIMI 2/3 Flow)||(77%,86%)||(72%,81%)||(72%,85%)||(79%,94%)|
The angiographic results from TIMI 10B and the safety data from ASSENT-1, an additional uncontrolled safety study of 3,235 TNKase (tenecteplase) -treated patients, provided the framework to develop a weight-tiered TNKase (tenecteplase) dose regimen.3 Exploratory analyses suggested that a weight-adjusted dose of 0.5 mg/kg to 0.6 mg/kg of TNKase (tenecteplase) resulted in a better patency to bleeding relationship than fixed doses of TNKase (tenecteplase) across a broad range of patient weights.
The Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention (ASSENT 4 PCI) was a Phase IIIb/IV study designed to assess the safety and effectiveness of a strategy of administering full dose TNKase (tenecteplase) with a single bolus of 4000 U of unfractionated heparin in patients with ST segment elevation AMI, in whom primary percutaneous coronary intervention (PCI) was planned, but in whom a delay of 1–3 hours was anticipated before PCI.The trial was prematurely terminated with 1667 randomized patients (75 of whom were treated in the United States) due to a numerically higher mortality in the patients receiving TNKase (tenecteplase) prior to primary PCI versus PCI without TNKase (tenecteplase) (median time from randomization to balloon of 115 minutes).The incidence of the 90-day primary endpoint,a composite of death or cardiogenic shock or congestive heart failure (CHF) within 90 days, was 18.6% in patients treated with TNKase (tenecteplase) plus PCI versus 13.4% in those treated with PCI alone (p=0.0055; OR 1.39 (95% C.I.1.11–1.74)).
There were trends toward worse outcomes in the individual components of the primary endpoint between TNKase (tenecteplase) plus PCI versus PCI alone (mortality 6.7% vs. 5.0%, respectively; cardiogenic shock 6.1% vs. 4.8%, respectively; and CHF 12.1% vs. 9.4%, respectively). In addition, there were trends towards worse outcomes in recurrent MI (6.1% vs. 3.5%, respectively; p=0.03) and repeat target vessel revascularization (6.6% vs.3.6%,respectively; p=0.005) in patients receiving TNKase (tenecteplase) plus PCI versus PCI alone.
There was no difference in in-hospital major bleeding between the two groups (5.6% vs.4.4% for TNKase (tenecteplase) plus PCI vs.PCI alone, respectively).For patients treated with TNKase (tenecteplase) plus PCI, in-hospital rates of intracranial hemorrhage and total stroke were similar to those observed in previous trials (0.97% and 1.8%, respectively); however, none of the patients treated with PCI alone experienced a stroke (ischemic, hemorrhagic or other).
1. ASSENT-2 Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet. 1999;354:716–22.
2. Cannon CP,Gibson CM,McCabe CH,Adgey AAJ,Schweiger MJ,Sequeira RF, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction. Results of the TIMI 10B trial.Circulation. 1998;98:2805–14.
3. Van de Werf F, Cannon CP, Luyten A, Houbracken K, McCabe CH, Berioli S, et al. Safety assessment of a single bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. Am Heart J. 1999;137:786–91.
Last reviewed on RxList: 11/6/2008
This monograph has been modified to include the generic and brand name in many instances.
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