Incidence and predictors of bleeding events after fibrinolytic therapy with fibrin-specific agents: a comparison of TNK-tPA and rt-PA.

BACKGROUND: Fibrinolytic therapy increases the risk of bleeding events. TNK-tPA (tenecteplase) is a variant of rt-PA with greater fibrin specificity and reduced plasma clearance that can be given as a single bolus. We compared the incidence and predictors of bleeding events after treatment with TNK-tPA and rt-PA. METHODS AND RESULTS: In the Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT)-2 trial, 16 949 patients with acute myocardial infarction were randomly assigned a single weight-adjusted bolus of TNK-tPA or a 90-min infusion of rt-PA. A total of 4.66% of patients in the TNK-tPA group experienced major non-cerebral bleeding, in comparison with 5.94% in the rt-PA group (P=0.0002). This lower rate was associated with a significant reduction in the need for blood transfusion (4.25% vs 5.49%, P=0.0003) and was consistent across subgroups. Independent risk factors for major bleeding were older age, female gender, lower body weight, enrolment in the U.S.A. and a diastolic blood pressure <70 mmHg. Females at high risk (age >75 years and body weight <67 kg) were less likely to have major bleeding when treated with TNK-tPA even after other risk factors were taken into account. A total of 0.93% of patients in the TNK-tPA and 0.94% of patients in the rt-PA group experienced an intracranial haemorrhage. Female patients >75 years of age who weighed <67 kg tended to have lower rates of intracranial haemorrhage when treated with TNK-tPA (3/264, 1.14% vs 8/265, 3.02%). CONCLUSIONS: The increased fibrin specificity and single bolus administration of TNK-tPA do not increase the risk of intracranial haemorrhage but are associated with less non-cerebral bleeding, especially amongst high-risk patients.

Aims and methods. LUTS suggestive of BPH.

OBJECTIVE: Few epidemiological studies are available on Italian patients with lower urinary tract symptoms and their QoL. QUIBUS (QUality of life Investigated in BPH patients with Urinary Symptoms) is an observational longitudinal study aimed at evaluating symptoms and QoL in a large sample of Italian patients and investigating their correlation with demographic, social and clinical characteristics of BPH. PATIENTS AND METHODS: Patients with lower urinary tract symptoms and prostate enlargement suggestive of BPH (both old and new diagnosis) were enrolled between November 1998 and May 1999 in 31 Italian centers of urology. This longitudinal investigation consists of an enrollment visit, in which demographic, social and clinical aspects are recorded as baseline data, and a follow-up visit after 1 year of treatment freely assigned by the investigators. Symptoms and QoL are assessed by means of IPSS, ICS-BPH (at both visits) and SF-36 (only at the follow-up visit) questionnaires. RESULTS: 1,033 patients were enrolled. The follow-up visit is still under evaluation. In this series of papers the baseline results are presented and discussed in terms of (i) medical management, (ii) life-style, (iii) symptoms, bothersomeness and QoL, (iv) sexual function of a large and representative sample of Italian patients and (v) uroflowmetry.

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.

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

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 patient's 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.

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).

Verapamil 240 SR versus verapamil 120 SR in arterial hypertension. A randomized double-blind, placebo-controlled study with 24-hour ambulatory blood pressure monitoring.

Fifteen patients (6 males, 9 females), age range 36-70 years, were enrolled in a randomized, double-blind, placebo-controlled study according to a Latin-square design, with the aim of comparing 24-hour blood pressure profiles after three 15-day treatment periods with placebo, verapamil SR 120 mg (V120 SR) given twice daily (bid), and verapamil SR 240 mg (V240 SR) given once daily (od). All of the patients were diagnosed as mild or moderate essential hypertensives on the basis of standard casual recordings. Noninvasive 24-hour ambulatory blood pressure (BP) monitoring was performed with an ICR Spacelab 5200 automatic device. In comparison with placebo, a clinically and statistically significant reduction in both systolic and diastolic BP over 24 hours was obtained with both active treatments. Comparison of the two active treatments shows that V240 SR led to a greater reduction in systolic and diastolic BP than V120 SR. No changes in heart rate were observed. Both treatments were well tolerated. In conclusion, both verapamil regimens proved to be effective and safe in treating essential hypertensives, with V240 SR giving better 24-hour BP control.

[Simvastatin versus gemfibrozil in the treatment of primary hypercholesterolemia in hypertensive patients treated with hydrochlorothiazide]. / Simvastatina versus gemfibrozil nel trattamento dell'ipercolesterolemia primaria in pazienti ipertesi in trattamento con idroclorotiazide.

Recent pharmacological studies confirmed the role of hypercholesterolemia in the pathogenesis of coronary atherosclerosis. A 10% reduction in cholesterol levels can reduce the risk of coronary heart disease by 15%. However many hypercholesterolemic patients often suffer from arterial hypertension and drugs such as thiazide diuretics cause an imbalance in lipid metabolism. The efficacy and the tolerability of simvastatin (a inhibitor of HGM-CoA reductase) with that of gemfibrozil (a fibric acid derivative, which can reduce the VLDL level) were compared in a placebo-controlled study in 2 groups of patients with primary hypercholesterolemia and mild-to-moderate essential hypertension treated with hydrochlorothiazide. After 10 weeks standard hypolipidemic diet and hydrochlorothiazide (25 mg od) therapy, 30 patients whose cholesterol levels were still greater than or equal to 250 mg/100 ml and whose diastolic blood pressure was less than 95 mmHg were randomized to one of the following treatments: simvastatin, 20 mg od, gemfibrozil, 600 mg bid or placebo, while continuing dietetic and diuretic treatment. After 24 weeks treatment, simvastatin induced a 37% reduction in cholesterol plasma levels, a 9% increase of HDL and a 16% reduction of LDL. APO-A1 showed a 4% increase, while APO-B showed a 3% reduction. Gemfibrozil induced a 20% reduction in plasma triglycerides and a 13% decrease in plasma cholesterol, with a significant 19% increase in HDL and a 11% reduction in LDL. No significant variations in any of the lipid parameters monitored were observed in the placebo group. Treatment with simvastatin or gemfibrozil in hypertensive patients in hydrochlorothiazide monotherapy can reduce total cholesterol and LDL-cholesterol plasma levels, while significantly increasing HDL plasma levels compared to placebo. Simvastatin, however, resulted more efficient than gemfibrozil on total cholesterol or cholesterol fractions.

Non-invasive cardiovascular monitoring in Shy-Drager syndrome.

The pattern of arterial blood pressure and heart rate were investigated in a patient with progressive autonomic dysfunction and nineteen healthy age-matched controls. A marked postprandial reduction of blood pressure was observed in the patient; this phenomenon was not noted in the control group; besides, the rhythmicity of blood pressure and heart rate were altered with peak values shifted approximately eight hours later with respect to the controls.

High prevalence of septal thickness overestimation in hypertensive subjects and controls.

The aim of our study was to assess the frequency of important problems in the ultrasonic estimate of septal thickness as a consequence of multiple endocardial lines inside the septum in echocardiographic tracings of otherwise good technical quality. We performed an echocardiographic study in a population composed of 311 subjects (131 essential hypertensive subjects and 180 normotensive healthy controls) by using M-mode echocardiography under two-dimensional control, according to the recommendations of the American Society of Echocardiography. We observed the presence of one or more continuous lines inside the septum, each of them simulating an endocardial border and thus producing the appearance of two or more superimposed septal thicknesses differing by 2 mm or more in greater than 50% of the subjects (54% normotensive and 56% hypertensive). Furthermore, within the group of subjects with multiple septal lines, we found the disappearance of at least one of the farthest linear echoes, with resulting septal thinning of almost 2 mm in 58% of the normotensive and 61% of the hypertensive subjects. These findings suggest the need for caution when interpreting echocardiographic measurements of left ventricular septal thickness. We suggest that in the presence of multiple lines inside the septum, the echocardiographic examination should be continued up to the appearance of the thinnest septal image, possibly devoid of multiple lines inside the septum.