Evaluation of a Weight-Adjusted Single-Bolus Plasminogen Activator in Patients With Myocardial Infarction

Abstract

Background —Lanoteplase (nPA) is a rationally designed variant of tissue plasminogen activator with greater fibrinolytic potency and slower plasma clearance than alteplase. Methods and Results —InTIME (Intravenous nPA for Treatment of Infarcting Myocardium Early), a multicenter, double-blind, randomized, double-placebo angiographic trial, evaluated the dose-response relationship and safety of single-bolus, weight-adjusted lanoteplase. Patients (n=602) presenting within 6 hours of acute myocardial infarction were randomized and treated with either a single-bolus injection of lanoteplase (15, 30, 60, or 120 kU/kg) or accelerated alteplase. The primary objective was to determine TIMI grade flow at 60 minutes. Angiographic assessments were also performed at 90 minutes and on days 3 to 5. Follow-up was continued for 30 days. Lanoteplase achieved its primary objective, demonstrating a dose-response in TIMI grade 3 flow at 60 minutes (23.6% to 47.1% of subjects, P <0.001). Similar results were observed at 90 minutes (26.1% to 57.1%, P <0.001). At 90 minutes, coronary patency (TIMI 2 or 3) increased across the dose range up to 83% of subjects at 120 kU/kg lanoteplase compared with 71.4% with alteplase. Thus, at this dose, lanoteplase was superior to alteplase in restoring coronary patency (difference, 12%; 95% CI, 1% to 23%). The early safety experience in this study suggests that lanoteplase was well tolerated at all doses with safety comparable to that of alteplase. Conclusions —Lanoteplase, a single-bolus, weight-adjusted agent, increased coronary patency at 60 and 90 minutes in a dose-dependent fashion. Coronary patency at 90 minutes was achieved more frequently with 120 kU/kg lanoteplase than alteplase. In this study, safety with lanoteplase and alteplase was comparable. InTIME-II, a worldwide mortality trial, will evaluate efficacy and safety with this promising new agent.

Fibrinolysis for Acute Myocardial Infarction

“…Deletion of the fingerlike domain contributes to lesser fibrin specificity. 1,43 A phase 2 study of nPA, Intravenous nPA for Infarcting Myocardium Early (InTIME), evaluated nPA administered as a split, single bolus over 2 to 4 minutes in doses varying between 15 and 120 kU/kg compared with accelerated rt-PA. 43 Although a clear dose response on 60-minute TIMI 3 patency was evident over the first 3 doses, no incremental patency advantage was evident between 60 and 120 kU/kg, and neither of the 2 top doses exceeded that achieved with rt-PA. The 120-kU/kg dose was subsequently chosen for a large phase 3 comparative study (InTIME-2) with a 2-to-1 randomization of nPA compared with accelerated rt-PA. 44 Although the 30-day mortality rates for nPA (6.77%) and rt-PA (6.60%) were similar, there was an unacceptable excess of intracranial hemorrhage with nPA (1.13% versus 0.62%, Pϭ0.003) and an increase in the composite of mild and moderate bleeding with nPA (22% versus 17%, Pϭ0.0001).…”

Angiographic and clinical outcomes after rescue coronary stenting

“…Current 1 thrombolytic agents fail to restore coronary artery patency in 17-45% of patients with acute myocardial infarction, and the mortality rate of patients whose arteries remain occluded is high [1][2][3][4]. The only randomized trial of rescue angioplasty vs. conservative therapy for treatment of thrombolytic failure showed a trend toward reducing 30 day mortality and severe heart failure with rescue angioplasty [5].…”

Pharmacotherapy During Percutaneous Coronary Interventions

“…Lanoteplase (n-PA) is another genetically engineered mutant of wild-type t-PA, however, it is not currently approved for use due to an increase in hemorrhagic stroke (154)(155). Anistreplase (APSAC) is another fibrinolytic agent that has a significantly longer half-life compared to streptokinase (90 to 100 minutes versus 18-23 minutes).…”