Isaac Kobrin

Bio: Isaac Kobrin is an academic researcher from Actelion. The author has contributed to research in topics: Mibefradil & Heart failure. The author has an hindex of 31, co-authored 84 publications receiving 3462 citations. Previous affiliations of Isaac Kobrin include Hoffmann-La Roche & University of Arizona.

Effects of Tezosentan on Symptoms and Clinical Outcomes in Patients With Acute Heart Failure: The VERITAS Randomized Controlled Trials

Abstract: ContextPlasma concentrations of the vasoconstrictor peptide endothelin-1 are increased in patients with heart failure, and higher concentrations are associated with worse outcomes. Tezosentan is an intravenous short-acting endothelin receptor antagonist that has favorable hemodynamic actions in heart failure.ObjectiveTo determine if tezosentan improves outcomes in patients with acute heart failure.Design, Setting, and ParticipantsThe Value of Endothelin Receptor Inhibition With Tezosentan in Acute Heart Failure Studies, 2 independent, identical, and concurrent randomized, double-blind, placebo-controlled, parallel-group trials conducted from April 2003 through January 2005 at sites in Australia, Europe, Israel, and North America. Patients admitted within the previous 24 hours with persisting dyspnea and a respiratory rate of 24/min or greater were eligible provided they fulfilled 2 of 4 criteria: (1) elevated plasma concentrations of B-type or N-terminal pro–B-type natriuretic peptide, (2) clinical pulmonary edema, (3) radiologic pulmonary congestion or edema, or (4) left ventricular systolic dysfunction.InterventionInfusion of tezosentan (5 mg/h for 30 minutes, followed by 1 mg/h for 24 to 72 hours [n = 730]) or placebo (n = 718).Main Outcome MeasuresThe coprimary end points were change in dyspnea (measured at 3, 6, and 24 hours using a visual analog scale from 0-100) over 24 hours (as area under the curve) in the individual trials and incidence of death or worsening heart failure at 7 days in both trials combined.ResultsOf the 1435 patients who received treatment as assigned, 855 (60%) were men; mean age was 70 years. Mean left ventricular ejection fraction (measured in 779 patients [54%]) was 29% (SD, 11%). Baseline dyspnea scores were similar in the 2 treatment groups. Tezosentan did not improve dyspnea more than placebo in either trial, with a mean treatment difference of −12 (95% confidence interval [CI], −105 to 81) mm · h (P = .80) in the first trial and −25 (95% CI, −119 to 69) mm · h (P = .60) in the second. The incidence of death or worsening heart failure at 7 days in the combined trials was 26% in each treatment group (odds ratio, 0.99; 95% confidence interval, 0.82-1.21; P = .95).ConclusionThe endothelin receptor antagonist tezosentan did not improve symptoms or clinical outcomes in patients with acute heart failure.Trial Registrationclinicaltrials.gov Identifiers: NCT00525707 (VERITAS-1) and NCT00524433 (VERITAS-2).

Enalapril improves systemic and renal hemodynamics and allows regression of left ventricular mass in essential hypertension

Abstract: Enalapril, a new angiotensin-converting enzyme inhibitor, is an effective antihypertensive agent for both renovascular and essential hypertension. It is structurally different from captopril in that it does not possess a sulfhydryl group. The systemic and renal hemodynamic, biochemical and cardiac adaptive changes induced by enalapril were studied in 8 patients with essential hypertension before and after 12 weeks of therapy. Mean arterial pressure decreased from 110 to 90 mm Hg (p < 0.01), and this was mediated through a decrease in total peripheral resistance from 42 ± 3 to 32 ± 3 U (p < 0.01). Cardiac index and heart rate did not change. Renal plasma flow was increased in 6 of 8 patients and renal vascular resistance decreased from 123 ± 6 to 91 ± 7 U (p < 0.001). Left ventricular mass index decreased from a mean of 166 ± 29 to 117 ± 8 g/m2 (p < 0.05) without impaired myocardial contractility. Thus, enalapril lowers arterial pressure by reducing total peripheral resistance without reflexive cardiac effects. It also has favorable hemodynamic effects on the kidney. This is the first report of regression of LV mass with this agent in man.

Diurnal Variation of Blood Pressure in Elderly Patients with Essential Hypertension

Abstract: Twenty-one elderly patients with essential hypertension, all over 65 years of age, were subjected to automated noninvasive 24-hour blood pressure measurement. Readings were obtained every 7.5 minutes throughout the day. The data were analyzed with respect to: correlation between office and ambulatory pressure measurements; possible differences in the circadian blood pressure pattern; and the existence of hypertensive or atherosclerotic cardiovascular complications. In all patients, the office systolic pressures were significantly higher than the ambulatory daytime pressures; diastolic pressures were similar. At night, two patterns of blood pressure emerged. In one there was a further fall in both systolic and diastolic pressures to normotensive levels, whereas the other pattern revealed no change in diastolic pressure, although systolic pressure increased significantly to similar levels as measured in the office. The prevalence of hypertensive or atherosclerotic cardiovascular complications in the patients with the first pattern was significantly less than in the group of patients with the second pattern (chi square, P less than 0.025). The data reported herein indicate that ambulatory blood pressure monitoring may help in the overall clinical evaluation of elderly patients with hypertension.

Immediate and short-term hemodynamic effects of diltiazem in patients with hypertension

Abstract: The immediate effects of intravenous diltiazem effects and short-term (4 weeks) of the oral drug on systemic and regional hemodynamics, cardiac structure, and humoral responses were evaluated by previously reported methods in nine patients with mild-to-moderate essential hypertension and in one patient with primary aldosteronism. Diltiazem was first administered in three intravenous doses of 0.06, 0.06, and 0.12 mg/kg, respectively; patients were then treated for 4 weeks with daily doses ranging from 240 to 360 mg (average 300 mg). Intravenous diltiazem immediately reduced mean arterial pressure (from 115 +/- 3 to 96 +/- 3 mm Hg; p less than .01) through a fall in total peripheral resistance index (from 37 +/- 3 to 23 +/- 2 U/m2; p less than .01) that was associated with an increase in heart rate (from 66 +/- 2 to 77 +/- 3 beats/min; p less than .01) and cardiac index (from 3.3 +/- 0.3 to 4.3 +/- 0.4 liters/min/m2; p less than .01). These changes were not associated with changes in plasma levels of catecholamines or aldosterone or in plasma renin activity. After 4 weeks the significant decrease in mean arterial pressure persisted (104 +/- 3 mm Hg; p less than .01) and there were still no changes in the humoral substances or plasma volume. Renal blood flow index increased (from 368 +/- 52 to 462 +/- 57 ml/min/m2; p less than .01) and renal vascular resistance index decreased (from 0.37 +/- 0.06 to 0.26 +/- 0.04 U/m2; p less than .01), while splanchnic hemodynamics did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic Implications of Echocardiographically Determined Left Ventricular Mass in the Framingham Heart Study

Abstract: A pattern of left ventricular hypertrophy evident on the electrocardiogram is a harbinger of morbidity and mortality from cardiovascular disease. Echocardiography permits the noninvasive determination of left ventricular mass and the examination of its role as a precursor of morbidity and mortality. We examined the relation of left ventricular mass to the incidence of cardiovascular disease, mortality from cardiovascular disease, and mortality from all causes in 3220 subjects enrolled in the Framingham Heart Study who were 40 years of age or older and free of clinically apparent cardiovascular disease, in whom left ventricular mass was determined echocardiographically. During a four-year follow-up period, there were 208 incident cardiovascular events, 37 deaths from cardiovascular disease, and 124 deaths from all causes. Left ventricular mass, determined echocardiographically, was associated with all outcome events. This relation persisted after we adjusted for age, diastolic blood pressure, pulse pressure, treatment for hypertension, cigarette smoking, diabetes, obesity, the ratio of total cholesterol to high-density lipoprotein cholesterol, and electrocardiographic evidence of left ventricular hypertrophy. In men, the risk factor-adjusted relative risk of cardiovascular disease was 1.49 for each increment of 50 g per meter in left ventricular mass corrected for the subject's height (95 percent confidence interval, 1.20 to 1.85); in women, it was 1.57 (95 percent confidence interval, 1.20 to 2.04). Left ventricular mass (corrected for height) was also associated with the incidence of death from cardiovascular disease (relative risk, 1.73 [95 percent confidence interval, 1.19 to 2.52] in men and 2.12 [95 percent confidence interval, 1.28 to 3.49] in women). Left ventricular mass (corrected for height) was associated with death from all causes (relative risk, 1.49 [95 percent confidence interval, 1.14 to 1.94] in men and 2.01 [95 percent confidence interval, 1.44 to 2.81] in women). We conclude that the estimation of left ventricular mass by echocardiography offers prognostic information beyond that provided by the evaluation of traditional cardiovascular risk factors. An increase in left ventricular mass predicts a higher incidence of clinical events, including death, attributable to cardiovascular disease.

A Systematic Review and Meta-analysis

Abstract: Methods: We conducted a systematic review of studies published from January 1, 1950, through November 31, 2008, using PubMed, EMBASE, Web of Knowledge, CINAHL, and all Evidence-Based Medicine Reviews. Randomized clinical trials and prospective studies of RRTs that reported data on changes in the primary outcome of hospital mortality or the secondary outcome of cardiopulmonary arrest cases were included.

Users' Guides to the Medical Literature: III. How to Use an Article About a Diagnostic Test: B. What Are the Results and Will They Help Me In Caring for My Patients?

Abstract: CLINICAL SCENARIO You are back where we put you in the previous article1on diagnostic tests in this series on how to use the medical literature: in the library studying an article that will guide you in interpreting ventilation-perfusion (V/Q) lung scans. Using the criteria in Table 1, you have decided that the Prospective Investigation of Pulmonary Diagnosis (PIOPED) study2will provide you with valid information. Just then, another physician comes looking for an article to help with the interpretation of V/Q scanning. Her patient is a 28-year-old man whose acute onset of shortness of breath and vague chest pain began shortly after completing a 10-hour auto trip. He experienced several episodes of similar discomfort in the past, but none this severe, and is very apprehensive about his symptoms. After a normal physical examination, electrocardiogram and chest radiograph, and blood gas measurements that show a Pco2of

Use and Misuse of the Receiver Operating Characteristic Curve in Risk Prediction

Abstract: The c statistic, or area under the receiver operating characteristic (ROC) curve, achieved popularity in diagnostic testing, in which the test characteristics of sensitivity and specificity are relevant to discriminating diseased versus nondiseased patients. The c statistic, however, may not be optimal in assessing models that predict future risk or stratify individuals into risk categories. In this setting, calibration is as important to the accurate assessment of risk. For example, a biomarker with an odds ratio of 3 may have little effect on the c statistic, yet an increased level could shift estimated 10-year cardiovascular risk for an individual patient from 8% to 24%, which would lead to different treatment recommendations under current Adult Treatment Panel III guidelines. Accepted risk factors such as lipids, hypertension, and smoking have only marginal impact on the c statistic individually yet lead to more accurate reclassification of large proportions of patients into higher-risk or lower-risk categories. Perfectly calibrated models for complex disease can, in fact, only achieve values for the c statistic well below the theoretical maximum of 1. Use of the c statistic for model selection could thus naively eliminate established risk factors from cardiovascular risk prediction scores. As novel risk factors are discovered, sole reliance on the c statistic to evaluate their utility as risk predictors thus seems ill-advised.