cardiovascular-agents and tezosentan

Hospitalization for heart failure (HF) is a clinical entity associated with high postdischarge morbidity and mortality, yet few therapies are available to improve outcomes in patients with this condition. In the past decade, large phase III studies of HF treatments have failed to demonstrate drug efficacy, safety, or both, despite encouraging results from preceding phase II trials. This Review is focused on this disconnect between the results of phase II and phase III trials of drugs for HF and discusses findings from five drug-development programs (for levosimendan, tezosentan, tolvaptan, rolofylline, and nesiritide) to shed light on common themes in clinical trials conducted in patients hospitalized for HF. In particular, the importance of selecting the 'right' patient population, drug, and clinical end points to optimize the trial design is discussed. Areas that require further investigation are highlighted and we suggest possible directions that will help to guide future clinical trials in these patients. Large, expensive phase III trials should not be initiated without adequate phase II evidence or on the basis of overly optimistic interpretation of phase II data. Additionally, drug development programs should be targeted not only to change short-term symptoms, but also to improve the postdischarge event rate.

Topics: Animals; Benzazepines; Cardiovascular Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Evidence-Based Medicine; Heart Failure; Humans; Hydrazones; Natriuretic Peptide, Brain; Patient Readmission; Patient Selection; Pyridazines; Pyridines; Risk Assessment; Risk Factors; Simendan; Tetrazoles; Time Factors; Tolvaptan; Treatment Outcome; Xanthines

The treatment of acute heart failure is gaining importance, specifically in the perioperative setting. Increasing evidence shows that established forms of therapy using beta-adrenergic inotropic drugs have no effect on long-term survival; thus, anesthetists and intensive care specialists are focusing on new strategies. This review examines, with respect to the literature of the past year, whether these strategies will gain significance in the perioperative setting.. Owing to its unique efficacy profile, levosimendan, a calcium sensitizer, improves long-term survival in patients with acute heart failure and has been incorporated into the European Society of Cardiology guidelines. Improved heart function without increased oxygen consumption, anti-ischemic effects, no arrhythmogenic effect and positive effects on intestinal perfusion have been described. Despite the positive effects on hemodynamics and symptoms, tezosentan, an endothelin antagonist, did not improve outcome, perhaps due to too high dosages of the drug. Nesiritide, a recombinant brain natriuretic peptide, may represent an alternative to nitroglycerin and dobutamine and possibly have a benefit for survival. No final conclusions can yet be drawn, however. L-NAME, a nitric oxide synthase antagonist, represents a promising new approach for the treatment of cardiogenic shock. The results must be confirmed in large, randomized studies.. For perioperative treatment of acute heart failure, levosimendan, nesiritide and L-NAME constitute promising alternatives to conventional inotropic and vasodilatory drugs. The strongest evidence for improving outcome is given for levosimendan. According to the present literature, tezosentan does not currently have any significance for treatment of perioperative heart failure.

Topics: Calcium Signaling; Cardiotonic Agents; Cardiovascular Agents; Endothelins; Enzyme Inhibitors; Heart Failure; Humans; Hydrazones; Natriuretic Peptide, Brain; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pyridazines; Pyridines; Simendan; Tetrazoles

Mixed ET(A/B) and selective ET(A) receptor antagonists showed promising hemodynamic and symptomatic improvements in patients with heart failure. Randomized, clinical trials to investigate the effects of ET receptor antagonists on survival in patients with heart failure still need to be conducted. Also, the effects of selective ET(A) and mixed ET(A/B) receptor antagonists on the clinical outcome of patients with CHF will have to be assessed.

Topics: Animals; Bosentan; Cardiovascular Agents; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelins; Heart Failure; Humans; Isoxazoles; Oligopeptides; Peptides, Cyclic; Phenylpropionates; Piperidines; Pyridines; Pyrimidines; Sulfonamides; Tetrazoles; Thiophenes; Treatment Outcome

Myocardial depression in sepsis is frequently encountered clinically and contributes to morbidity and mortality. Increased plasma levels of endothelin-1 (ET-1) have been described in septic shock, and previous reports have shown beneficial effects on cardiovascular performance and survival in septic models using ET receptor antagonists. The aim of the current study was to investigate specific cardiac effects of ET receptor antagonism in endotoxicosis. Sixteen domestic pigs were anesthetized and subjected to endotoxin for 5 h. Eight of these pigs were given tezosentan (dual ET receptor antagonist) after 3 h. Cardiac effects were evaluated using the left ventricular (LV) pressure-volume relationship. Endotoxin was not associated with any effects on parameters of LV contractile function [end-systolic elastance (Ees), preload recruitable stroke work (PRSW), power(max)/end-diastolic volume (PWR(max)/EDV) and dP/dt(max)/end-diastolic volume (dP/dt(max)/EDV)] but with impairments in isovolumic relaxation (time constant for pressure decay, tau) and mechanical efficiency. Tezosentan administration decreased Ees, PWR(max)/EDV, and dP/dt(max)/EDV, while improving tau and LV stiffness. Thus, dual ET receptor antagonism was associated with a decline in contractile function but, in contrast, improved diastolic function. Positive hemodynamic effects from ET receptor antagonism in acute endotoxemia may be due to changes in cardiac load and enhanced diastolic function rather than improved contractile function.

Topics: Animals; Blood Pressure; Cardiovascular Agents; Coronary Circulation; Disease Models, Animal; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endotoxemia; Endotoxins; Female; Heart Rate; Myocardial Contraction; Oxygen Consumption; Pyridines; Receptor, Endothelin A; Receptor, Endothelin B; Sus scrofa; Tetrazoles; Time Factors; Ventricular Function, Left; Ventricular Pressure