Determination of a weight-adjusted dose of TNK-tissue plasminogen activator.

BACKGROUND: TNK-tissue plasminogen activator (TNK-tPA) is a potent new thrombolytic agent for treatment of acute myocardial infarction. TNK-tPA was evaluated in 4214 patients in two dose-ranging trials (Thrombolysis in Myocardial Infarction [TIMI] 10B and Assessment of the Safety and Efficacy of a New Thrombolytic Agent [ASSENT] I). This article describes the rationale for the weight-adjusted dosing regimen of TNK-tPA that was selected for evaluation in the large phase III clinical trial ASSENT II. METHODS: Weight-based analyses were conducted with data from both the angiographic TIMI 10B trial, which compared TNK-tPA in doses of 30 mg, 40 mg, and 50 mg with the accelerated regimen of tPA in 889 patients, and the ASSENT I trial, which evaluated the safety of TNK-tPA in doses of 30 mg, 40 mg, and 50 mg in 3301 patients. Graphic and statistical analytic methods were used to assess relationships between weight and efficacy or safety measurements. RESULTS: The plasma clearance, initial plasma concentrations, and plasma steady-state volume of distribution all increased with decreasing body weight (all P<.001). The corrected TIMI frame count decreased (flow was faster) (P =.001) and the TIMI grade 3 flow increased with an increasing weight-standardized dose of TNK-tPA (P<.008). Mortality was inversely related to dose, but this relationship was not statistically significant. There was no clear relationship between intracranial hemorrhage and dose and weight. Serious bleeding events increased with increasing weight-standardized dose (P<.02). CONCLUSIONS: On the basis of these analyses, a weight-adjusted dosing regimen was devised for TNK-tPA that included five dosing increments and was based on a target weight-standardized dose of 0.53 mg/kg.

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

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).

A simulation study of estimators for rates of change in longitudinal studies with attrition.

Many longitudinal studies and clinical trials are designed to compare rates of change over time in one or more outcome variables in several groups. Most such studies have incomplete data because some patients drop out before completing the study. The missing data may induce bias and inefficiency in naive estimates of important parameters. This paper uses Monte Carlo methods to compare the bias and efficiency of several two-stage estimators of the effect of treatment on the mean rate of change when the missing data arise from one of four processes. We also study the validity of confidence intervals and the power of hypothesis tests based on these estimates and their standard errors. In general, the weighted least squares estimator does relatively well, as does an analysis of covariance type estimator proposed by Wu et al. The best estimates of variance components are based on complete cases or maximum likelihood.