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- Title
The hemodynamic and neurohormonal effects of low doses of tezosentan (an endothelin A/B receptor antagonist) in patients with acute heart failure
- Authors
Cotter, Gad; Kaluski, Edo; Stangl, Karl; Pacher, Richard; Richter, Christoph; Milo-Cotter, Olga; Perchenet, Loïc; Kobrin, Isaac; Kaplan, Shoshana; Rainisio, Maurizio; Frey, Aline; Neuhart, Eric; Vered, Zvi; Dingemanse, Jasper; Torre-Amione, Guillermo
- Abstract
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/m2 and wedge pressure≥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 (≤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.
- Subjects
HEMODYNAMICS; ENDOTHELINS; PATIENT monitoring; HEART failure; CARDIAC patients
- Publication
European Journal of Heart Failure, 2004, Vol 6, Issue 5, p601
- ISSN
1388-9842
- Publication type
Article
- DOI
10.1016/j.ejheart.2004.05.004