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

Gad Cotter, Edo Kaluski, Karl Stangl, Richard Pacher, Christoph Richter, Olga Milo-Cotter, Loïc Perchenet, Isaac Kobrin, Shoshana Kaplan, Maurizio Rainisio, Aline Frey, Eric Neuhart, Zvi Vered, Jasper Dingemanse, Guillermo Torre-Amione

Research output: Contribution to journalArticle

55 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)601-609
Number of pages9
JournalEuropean Journal of Heart Failure
Volume6
Issue number5
DOIs
StatePublished - Aug 2004

Keywords

  • Endothelin
  • Heart failure
  • Vasodilation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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