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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.

Thrombolysis has become an accepted form of therapy for acute myocardial infarction. As demonstrated in the Global Utilization of Streptokinase and t-PA for Occluded Arteries trial, early, complete and sustained patency of the infarct-related coronary artery is correlated with reduced mortality. However, current thrombolytic regimens are able to achieve such patency within 90 min in only 81% of cases. To improve the risk/benefit ratio of thrombolytic therapy, newer agents such as reteplase have been developed to establish more rapid, more complete and more stable coronary artery patency, thus reducing mortality. This report summarizes the pharmacological properties of reteplase. It also summarizes the findings from various animal and clinical studies in which reteplase was compared with alteplase and streptokinase and the findings from animal and clinical studies evaluating infusion, single-bolus, double-bolus, doses of reteplase.

Background: The therapeutic benefit of thrombolytic therapy has been shown to correlate directly with completeness (TIMI grade 3 flow) and speed of reperfusion of the infarct-related coronary artery. The purpose of the RAPID II study was to determine whether a double-bolus regimen of reteplase, a recently developed deletion mutant of wild-type tissue plasminogen activator, could improve 90-minute coronary artery patency rates achieved with the most successful standard regimen, an "accelerated" front-loaded infusion of alteplase., Methods and Results: Three hundred twenty-four patients with acute myocardial infarction were randomized to receive (along with intravenous heparin and aspirin) either a 10 plus 10 megaunits double bolus of reteplase or front-loaded alteplase. The primary end point of "patency at 90 minutes, graded according to the TIMI classification" was centrally assessed in a blinded fashion. Infarctrelated coronary artery patency (TIMI grade 2 or 3) and complete patency (TIMI grade 3) at 90 minutes after the start of thrombolytic therapy were significantly higher in the reteplase-treated patients (TIMI grade 2 or 3: 83.4% versus 73.3% for front-loaded alteplase-treated patients, P = .03; TIMI grade 3: 59.9% versus 45.2%, P = .01). At 60 minutes, the incidence of both, patency and complete patency, was also significantly higher in reteplase-treated patients (reteplase versus alteplase, TIMI grade 2 or 3: 81.8% versus 66.1%, P = .01; TIMI grade 3: 51.2% versus 37.4%, P < .03). Reteplase-treated patients required fewer acute additional coronary interventions (13.6% versus 26.5%, P < .01), and 35-day mortality was 4.1% for reteplase and 8.4% for alteplase (P = NS). There were no significant differences between reteplase and alteplase in bleedings requiring a transfusion (12.4% versus 9.7%) or hemorrhagic stroke (1.2% versus 1.9%)., Conclusions: Reteplase, when given as a double bolus of 10 plus 10 megaunits to patients with acute myocardial infarction, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and requires significantly fewer acute coronary interventions than front-loaded alteplase without an apparent increased risk of complications.

The ability of thrombolytic therapy to lower mortality in patients with acute myocardial infarction was first demonstrated in 1986 by the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico. In the ensuing 10 years, large efforts have been undertaken to develop more effective and safer thrombolytic agents. In addition, the value of adjunctive agents influencing thrombotic and thrombolytic processes was demonstrated, and newer agents are under active investigation. This review focuses on theoretical and practical aspects of optimizing thrombolytic therapy and on genetically engineered third generation plasminogen activators. Optimized thrombolytic therapy may make this form of therapy available to patients who are currently considered ineligible, and it will lead to earlier, more complete reperfusion of infarct-related coronary arteries. The benefits and risks of optimized thrombolytic regimens relative to those of mechanical reperfusion strategies will require constant reassessment while both forms of treatment develop.

Background: Early restoration and maintenance of normal (TIMI 3) blood flow during acute myocardial infarction is critical for optimal preservation of left ventricular function and survival. Recombinant plasminogen activator (r-PA, reteplase) is a nonglycosylated deletion mutant of wild-type tissue-type plasminogen activator (TPA) that has been shown to achieve more rapid and complete thrombolysis compared with other plasminogen activators in animal models., Methods and Results: The RAPID Trial was designed to test the hypothesis that bolus administration of one or more dosage regimens of r-PA was superior to standard-dose alteplase (TPA) in achieving infarct-related artery patency 90 minutes after initiation of treatment. Six hundred six patients with acute myocardial infarction were randomized to one of four treatment arms: (1) TPA 100 mg i.v. over 3 hours, (2) r-PA as a 15-MU single bolus, (3) r-PA as a 10-MU bolus followed by 5 MU 30 minutes later, or (4) r-PA as a 10-MU bolus followed by 10 MU 30 minutes later. Coronary arteriography was performed at 30, 60, and 90 minutes after initiation of treatment and at hospital discharge. The 10 + 10-MU r-PA group achieved better 90-minute and 5- to 14-day TIMI 3 flow (63% [CI, 55% to 71%] versus 49% [41% to 57%], P = .019, and 88% [82% to 94%] versus 71% [63% to 79%], P < .001, respectively) than the TPA group. The TIMI 3 flow in the 10 + 10-MU r-PA group at 60 minutes was equivalent to that in the TPA group at 90 minutes (51 versus 49%). Global ejection fraction and regional wall motion in the 10 + 10-MU r-PA group were superior to those of the TPA group at hospital discharge (53 +/- 1.3% versus 49 +/- 1.3%, P = .034; -2.19 +/- 0.12 versus -2.61 +/- 0.13 SD per chord, P = .02, respectively). The 15-MU and 10 + 5-MU r-PA patency and left ventricular function results were similar to those of the TPA and inferior to those of the 10 + 10-MU r-PA group. Bleeding complications were similar between the groups., Conclusions: r-PA given as a double bolus of 10 + 10 MU achieves more rapid, complete, and sustained thrombolysis of the infarct-related artery than standard-dose TPA, without an apparent increased risk of complications. This was associated with improved global and regional left ventricular function at hospital discharge.

To determine whether a weight-adjusted high dose (2 mg/kg body weight over 3 h) rapid infusion of recombinant tissue-type plasminogen activator (rt-PA) was more efficacious than a weight-adjusted standard dose (1.25 mg/kg over 3 h) in achieving reperfusion in the setting of acute myocardial infarction, 175 patients were entered into a randomized multicenter trial. Eighty-four patients were entered into the high dose group, receiving 1.2 mg/kg (10% given as a bolus injection) over 1 h, followed by 0.8 mg/kg over the next 2 h. Ninety-one patients were given 0.75 mg/kg (10% given as a bolus injection) in 1 h, followed by 0.5 mg/kg administered over the next 2 h. The median dose in the group that received 2 mg/kg dose was 145 mg, compared with 100 mg in the group that received 1.25 mg/kg. The 90 min patency rate in the group that received 2 mg/kg was 84% compared with 70% in the group that received 1.25 mg/kg (p = 0.003). Sixty-four percent of the patients in each group underwent coronary angioplasty at the time of cardiac catheterization. The infarct-related artery patency rate at the end of catheterization was 91% in the group that received 2 mg/kg compared with 83% in the group that received 1.25 mg/kg (p = 0.08). Among patients with a patent infarct-related coronary artery after catheterization, the 6 month mortality rate in the group that received 2 mg/kg was 2.9% compared with 9.8% in the group that received 1.25 mg/kg (p = 0.15). The bleeding complication rate in the two groups was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

A new, predominantly single chain preparation of recombinant tissue-type plasminogen activator was evaluated to determine coronary thrombolytic efficacy in 100 patients with acute myocardial infarction. At 3.6 +/- 1.2 hours (mean +/- SD) from symptom onset, patients received either intravenous tissue plasminogen activator (1.25 mg/kg body weight over 3 hours) or placebo on a 3:1 randomized, double-blind basis. Coronary angiography, performed 68 +/- 13 minutes after initiation of the study drug infusion, demonstrated patency of the infarct-related artery in 40 (57%) of 70 patients in the tissue plasminogen activator group compared with 3 (13%) of 23 patients in the placebo group (p less than 0.001). Patients in the placebo group were then eligible to receive intracoronary streptokinase. At 90 minutes the patency was observed in 49 (69%) of 71 tissue plasminogen activator patients compared with 5 (24%) of 21 placebo patients (p less than 0.001). At 120 minutes patency was observed in 59 (79%) of 75 patients of the tissue plasminogen activator group and in 10 (40%) of 25 in the intracoronary streptokinase/placebo group. A nadir value of less than 100 mg/dl fibrinogen occurred in 8 (11%) of 73 patients receiving tissue plasminogen activator versus 8 (40%) of 20 patients treated with intracoronary streptokinase (p = 0.002). Moderate or severe bleeding episodes occurred in 39% of patients treated with tissue plasminogen activator compared with 32% of patients who received placebo/intracoronary streptokinase (p = NS). Thus, this tissue plasminogen activator preparation achieves a high rate of recanalization and, at the doses employed, exhibits increased fibrinogen sparing compared with intracoronary streptokinase.