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TNK-Tissue Plasminogen Activator in Acute Myocardial Infarction Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A Dose-Ranging Trial

BACKGROUND TNK-tissue plasminogen activator (TNK-TPA) is a genetically engineered variant of TPA, which in experimental models has a slower plasma clearance and greater fibrin specificity and is 80-fold more resistant to plasminogen activator inhibitor-1 than alteplase TPA. METHODS AND RESULTS The thrombolysis in Myocardial Infarction (TIMI) 10A trial was a Phase 1, dose-ranging pilot trial designed to evaluate the pharmacokinetics, safety, and efficacy of TNK-TPA in patients with acute myocardial infarction. One hundred thirteen patients with acute ST-segment elevation myocardial infarction presenting within 12 hours and without contraindications to thrombolysis were enrolled and treated with a single bolus of TNK-TPA over 5 to 10 seconds with doses ranging from 5 to 50 mg. TNK-TPA demonstrated a plasma clearance of 151 +/- 55 mL/min and a half-life of 17 +/- 7 minutes. Comparable values for wild-type TPA are 572 +/- 132 mL/min and 3.5 +/- 1.4 minutes, respectively. Systemic fibrinogen and plasminogen levels fell by only 3% and 13%, respectively, at 1 hour after TNK-TPA administration. TIMI grade 3 flow at 90 minutes was achieved in 57% to 64% of patients at the 30- to 50-mg doses. Seven patients (6.2%) experienced a major hemorrhage, which occurred at a vascular access site in six patients. CONCLUSIONS TNK-TPA has a prolonged half-life so it can be administered as a single bolus. TNK-TPA appears to be very fibrin specific, and the initial patency and safety profiles are encouraging. Further study of this new thrombolytic agent is ongoing.

Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: The ASSENT-1 trial☆☆☆★★★

BACKGROUND To evaluate the safety of several doses of a new thrombolytic, TNK tissue-plasminogen activator (tPA), given as a single bolus to patients with acute myocardial infarction. METHODS AND RESULTS A total of 3235 patients were given TNK-tPA: 1705 received 30 mg, 1457 received 40 mg, and 73 received 50 mg. The 50-mg dose was discontinued and replaced by 40 mg because of increased bleeding observed in the Thrombolysis In Myocardial Infarction (TIMI)-10B study, the phase II angiographic efficacy trial conducted in parallel with this study. The total stroke rate at 30 days in the trial was 1.5%. An intracranial hemorrhage was observed in 25 patients (0.77%): 16 in the 30-mg group (0.94%) and 9 in the 40-mg group (0.62%). No strokes occurred in the 73 patients treated with 50 mg TNK-tPA. In patients treated within 6 hours after symptom onset the rates of intracranial hemorrhage were 0.56% (30 mg TNK-tPA) and 0.58 (40 mg TNK-tPA). Death, death or nonfatal stroke, or severe bleeding complications occurred in a low proportion of patients: 6.4%, 7.4%, and 2.8%, respectively, without significant differences among the treatment groups. CONCLUSIONS The overall safety profile of a single bolus of 30 to 50 mg TNK-tPA is comparable to that of accelerated r-tPA observed in other large trials. The safety data from this trial and the patency data of TIMI-10B were the basis for a decision to conduct a large phase III mortality trial comparing weight-adjusted single-bolus TNK-tPA with accelerated r-tPA (ASSENT-2).

Pharmacokinetics and Pharmacodynamics of Tenecteplase: Results from a Phase II Study in Patients with Acute Myocardial Infarction

Tenecteplase is a site‐specific engineered tissue plasminogen activator (t‐PA) variant that can be administered as a single intravenous bolus injection because of its slower plasma clearance. The objective of this study was to investigate the dose‐ranging pharmacokinetics and pharmacodynamics of intravenous bolus tenecteplase compared with intravenous alteplase recombinant t‐PA in patients with acute myocardial infarction. A total of 103 patients received intravenous bolus doses of 30, 40, or 50 mg tenecteplase, and 56 patients received 100 mg rt‐PA as the accelerated 90‐minute infusion regimen in this randomized, open‐label study. Tenecteplase and r‐tPA plasma concentrations were measured for 6 hours. Tenecteplase exhibited biphasic elimination from the plasma with a mean initial half‐life of 22 minutes and a mean terminal half‐life of 115 minutes. The mean plasma clearance was 105 mL/min and did not depend on tenecteplase dose over the dose range studied. In comparison, rt‐PA has a fourfold faster plasma clearance. Pharmacokinetic‐pharmacodynamic evaluation showed that a dose of approximately 0.5 mg/kg results in a plasma AUC value that provides a TIMI 3 flow at 90 minutes that is comparable to that reported with accelerated r‐tPA. In conclusion, tenecteplase has a fourfold slower plasma clearance compared with rt‐PA, allowing dosing as an W bolus injection. Weight‐adjusted dosing of tenecteplase may optimize the therapeutic regimen of tenecteplase.

Weight-adjusted dosing of TNK-tissue plasminogen activator and its relation to angiographic outcomes in the thrombolysis in myocardial infarction 10B trial

Fixed doses of thrombolytic agents are generally administered to patients of varying body weights, and the dose-response relation may be confounded by the variability in patient weight. We hypothesized that higher doses of TNK-tissue plasminogen activator (tPA) per unit body weight would be related to improved flow at 90 minutes after thrombolytic administration. A total of 886 patients with acute myocardial infarction were randomized to receive either a single bolus of 30, 40, or 50 mg of TNK-tPA or front-loaded tPA in the Thrombolysis In Myocardial Infarction (TIMI) 10B trial. The dose of TNK-tPA administered was divided by the patients weight to arrive at the TNK-tPA dose (mg) per unit body weight (kg), and patients were stratified into tertiles based on mg/kg of TNK-tPA: low dose, 0.2 to 0.39 mg/kg; mid-dose, 0.40 to 0.51 mg/kg; high dose, 0.52 to 1.24 mg/kg. Flow in the culprit and nonculprit arteries was analyzed using the TIMI flow grades and the corrected TIMI frame count (CTFC). The median CTFC in culprit arteries differed between the tertiles (3-way p = 0.007), with the CTFC being 7.2 frames faster in high-dose than in low-dose patients (43.1 +/- 30.1, median 31.2, n = 171 vs 54.6 +/- 34.8, median 38.4, n = 166, 2-way p = 0.002). Patients in the mid- and high-dose tertiles achieved patency more frequently (TIMI grade 2 or 3 flow) by 60 minutes (p = 0.02), and the 90-minute percent diameter stenosis was less severe in patients in the high- versus low-dose tertile (p = 0.03). In nonculprit arteries, the CTFC was faster in high- than in low-dose tertiles (29.6 +/- 13.4, median 26.9, n = 130 vs 34.7 +/- 16.3, median 32.8, n = 108, 3-way p = 0.03, 2-way p = 0.008). In patients who underwent percutaneous transluminal coronary angioplasty (PTCA), the CTFC in culprit arteries after PTCA was fastest in the high- and mid-dose tertiles than in those receiving low doses (2-way p = 0.05). Thus, higher doses per unit body weight of TNK-tPA result in not only faster culprit artery flow, but also faster nonculprit, global, and post-PTCA flow, which may reflect earlier opening, reduced stunning, or improved microvascular function. The greater effectiveness of thrombolysis must be weighed against any increase in risk.

Comparison of left ventricular function and infarct size in patients with and without persistently positive technetium-99m pyrophosphate myocardial scintigrams after myocardial infarction: Analysis of 357 patients☆

One hundred nine patients with persistently positive technetium-99m pyrophosphate (Tc-99m-PPi) myocardial scintigrams 6 months after acute myocardial infarction (MI) (Group A) and 185 patients without such persistently positive scintigrams (Group B) were compared with regard to enzymatically determined infarct size, early and late measurements of left ventricular (LV) function determined by radionuclide ventriculography, and preceding clinical course during the 6 months after MI. The CK-MB-determined infarct size index in Group A (17.4 +/- 10.6 g-Eq/m2) did not differ significantly from that in Group B (16.0 +/- 14.6 g-Eq/m2). Similarly, myocardial infarct areas in the 2 groups, determined by planimetry of acute Tc-99m-PPi scintigrams in those patients with well-localized 3+ or 4+ anterior pyrophosphate uptake, were not significantly different (35.7 +/- 13.4 vs 34.4 +/- 13.1 cm2, respectively). However, patients in Group A had significantly lower LV ejection fractions than those in Group B, both within 18 hours of the onset of MI (0.42 +/- 0.14 vs 0.49 +/- 0.14, p less than 0.01) and at 3 months after MI, both at rest (0.42 +/- 0.14 vs 0.51 +/- 0.14, p less than 0.01) and at maximal symptom-limited supine bicycle exercise (0.44 +/- 0.17 vs 0.51 +/- 0.17, p less than 0.01). Peak exercise levels achieved in the 2 groups were not significantly different. Furthermore, patients in Group A demonstrated a greater incidence of congestive heart failure during the initial hospital admission (41 vs 24%; p less than 0.01) and a greater requirement for digoxin (p less than 0.05) and furosemide (p less than 0.01) after discharge.(ABSTRACT TRUNCATED AT 250 WORDS)