The dual endothelin receptor antagonist tezosentan acutely improves hemodynamic parameters in patients with advanced heart failure

Background Endothelin-1, a potent vasoconstrictor, is elevated in congestiv e heart failure and is postulated to play a major role in the pathogenesis of the disease. Endothelin receptor antagonism may be a specific therapeuti c approach. This study was designed to determine the effective dosage range , hemodynamic effects, and tolerability of tezosentan, an intravenous dual endothelin receptor antagonist, in patients with advanced heart failure. Methods This randomized, double-blind, placebo-controlled multicenter trial enrolled 38 patients with symptomatic stable heart failure (New York Heart Association class III, left ventricular ejection fraction <35%) undergoing right heart catheterization. Patients were equally randomized to a 4-hour intravenous infusion of placebo or tezosentan in ascending doses (5, 20, 50 , and 100 mg over I hour each). Angiotensin-converting enzyme inhibitors an d diuretics were withheld 24-hours before the study. Hemodynamics were meas ured during and for 4 hours after the infusion. Results Compared with Placebo, tezosentan treatment produced a significant increase in cardiac index (treatment difference 0.59 L/min/m(2), P=.0001) a nd decreases in pulmonary and systemic vascular resistances (P<less than or equal to>.01) without changes in heart rate. Consistently greater decrease s in pulmonary capillary wedge pressure, mean right atrial pressure, and pu lmonary and arterial pressures with tezosentan did not reach statistical si gnificance. Hemodynamic changes were dose dependent with maximal effects at 20 and 50 mg per hour. Tezosentan was well tolerated. Despite increased en dothelin-1 concentrations, hemodynamic rebound was not observed. Conclusion Tezosentan rapidly and dose dependently improved hemodynamics. T he favorable effects on cardiac index and pulmonary and systemic vascular r esistances without changes in heart rate may be beneficial in the treatment of acute heart failure.