Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure

Objectives We sought to investigate the efficacy and safety of tezosentan, a dual endothelin receptor antagonist, in patients hospitalized for acute heart failure (HF). Background Tezosentan has been previously shown to improve hemodynamics in patients with stable chronic HF. Methods In a double-blind fashion, 292 patients (cardiac index ≤2.5 l/min per m2 and pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg) who were admitted to the hospital and in need of intravenous treatment for acute HF and central hemodynamic monitoring were randomized to 24-h intravenous treatment with tezosentan (50 or 100 mg/h) or placebo. Central hemodynamic variables, the dyspnea score, and safety variables were measured. Results After 6 h of treatment, significantly greater increases in the cardiac index and decreases in PCWP were observed with both tezosentan dosages than with placebo (mean treatment effects at 0.38 and 0.37 l/min per m2 with 50 and 100 mg/h and −3.9 mm Hg for each dose, respectively; p < 0.0001). This effect was maintained during the remaining infusion and for ≥6 h after treatment cessation. A tendency for an improved dyspnea score and a decreased risk of clinical worsening was observed after 24 h of treatment with each tezosentan dose. Adverse events, more frequent with tezosentan than with placebo (headache, asymptomatic hypotension, early worsening of renal function, nausea, vomiting), were dose-related. Conclusions Intravenous tezosentan rapidly and effectively improved hemodynamics in these patients. The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is <50 mg/h.