Echocardiographic ejection fraction in patients with acute heart failure: correlations with hemodynamic, clinical, and neurohormonal measures and short-term outcome.

BACKGROUND: Although echocardiographic ejection fraction (EF) is frequently used for the estimation of left ventricular contractility in patients with acute heart failure, its exact role and correlations with clinical, hemodynamic, and neurohormonal variables of cardiac contractility is not known. METHODS: Patients (343) with acute heart failure, enrolled into two prospective placebo-controlled hemodynamic studies of tezosentan, and in whom EF was available at baseline, were included. Outcome was evaluated in a subset of 94 patients who were enrolled in the placebo arms of the studies. RESULTS: Higher echocardiographic EF was correlated with older age, increased incidence of hypertension and atrial fibrillation, and female gender. We observed weak correlation between EF and cardiac output or cardiac power and no correlation with wedge pressure, and the change in hemodynamic variables over time. Higher EF was correlated with more baseline leukocytosis and higher plasma levels of endothelin-1 and blood urea nitrogen, while lower EF was related to higher baseline B-type natriuretic peptide (BNP). We observed no overall correlations between EF and outcome. CONCLUSIONS: In patients with acute heart failure, echocardiographic EF is weakly correlated with hemodynamic measures of left ventricular contractility and outcome; hence, it should be interpreted cautiously when evaluating patients admitted due to acute heart failure.

The hemodynamic and neurohormonal effects of low doses of tezosentan (an endothelin A/B receptor antagonist) in patients with acute heart failure.

BACKGROUND: In previous studies (the RITZ project), tezosentan, an intravenous (i.v.)-balanced dual endothelin (ET-A/B) antagonist, in doses of 50 and 100 mg/h, improved the hemodynamics but not the clinical outcome of patients with acute heart failure (AHF). OBJECTIVE: To evaluate the effect of lower doses of tezosentan in patients with AHF. SUBJECTS AND METHODS: Included were 130 patients hospitalized due to AHF with dyspnea at rest, despite initial treatment, and were in need of hemodynamic monitoring with cardiac index (CI)<2.5 l/min/m(2) and wedge pressure > or = 20 mm Hg. Patients were randomized in a double-blind fashion to receive placebo or tezosentan: 0.2, 1, 5, or 25 mg/h for 24 h. RESULTS: The primary endpoint of the study, CI increase at 6 h of treatment, was significant in the 5 and 25 mg/h groups. Tezosentan induced a dose-dependent increase in CI and a decrease in wedge pressure, peaking after 3 h in the 5 and 25 mg/h groups. In the 1 mg/h group, this effect was smaller during the first 6 h and increased gradually, becoming significant at 24 h and beyond treatment discontinuation. There was no hemodynamic effect in the 0.2 mg/h arm. Type-B natriuretic peptide (BNP) decreased in the 1, 5, and 25 mg/h groups but not on placebo. Endothelin levels were significantly increased by the 5 and 25 mg/h groups but not in the lower (< or = 1 mg/h) tezosentan doses. Urine output decreased on the 25 mg/h dose. There was a trend towards improvement in patients' subjective dyspnea score and worsening heart failure events, mainly in the 1 mg/h group. CONCLUSIONS: In patients admitted with AHF, tezosentan doses of 1-25 mg/h are efficacious in improving the hemodynamics and reducing BNP. Tezosentan doses beyond 1 mg/h increased plasma endothelin levels and reduced urine output, probably limiting their clinical efficacy, as compared to tezosentan 1 mg/h.

RITZ-5: randomized intravenous TeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study.

OBJECTIVES: The objective of this study was to evaluate the addition of intravenous (IV) tezosentan to standard therapy for patients with pulmonary edema. BACKGROUND: Tezosentan is an IV nonselective endothelin (ET)-1 antagonist that yields favorable hemodynamic effects in patients with acute congestive heart failure (CHF). METHODS: Pulmonary edema was defined as acute CHF leading to respiratory failure, as evidenced by an oxygen saturation (SO(2)) <90% by pulse oxymeter despite oxygen treatment. All patients received oxygen 8 l/min through a face mask, 3 mg of IV morphine, 80 mg of furosemide, and 1 to 3 mg/h continuous drip isosorbide-dinitrate according to their blood pressure level and were randomized to receive a placebo or tezosentan (50 or 100 mg/h) for up to 24 h. RESULTS: Eighty-four patients were randomized. The primary end point, the change in SO(2) from baseline to 1 h, was 9.1 +/- 6.3% in the placebo arm versus 7.6 +/- 10% in the tezosentan group (p = NS). The incidence of death, recurrent pulmonary edema, mechanical ventilation, and myocardial infarction during the first 24 h of treatment was 19% in both groups. Reduced baseline SO(2), lower echocardiographic ejection fraction, high baseline mean arterial blood pressure (MAP), and inappropriate vasodilation (MAP reduction at 30 min of <5% or >30%) correlated with worse outcomes. A post-hoc analysis revealed that the outcome of patients who received only 50 mg/h tezosentan was better than patients in the placebo group whereas patients receiving 100 mg/h had the worst outcomes. CONCLUSIONS: In the present study, tezosentan (an ET-1 antagonist) did not affect the outcome of pulmonary edema, possibly because of the high dose used.