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

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/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.

• Authors: 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
• Journal: European journal of heart failure (Eur J Heart Fail) Vol. 6 Issue 5 Pg. 601-9 (Aug 2004) ISSN: 1388-9842 [Print] England
• PMID: 15302008 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin Receptor Antagonists
• Endothelins
• Pyridines
• Tetrazoles
• Natriuretic Peptide, Brain
• tezosentan

Topics

• Aged
• Double-Blind Method
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin Receptor Antagonists
• Endothelins (blood)
• Female
• Heart Failure (drug therapy, physiopathology)
• Hemodynamics (drug effects)
• Humans
• Male
• Middle Aged
• Natriuretic Peptide, Brain (blood)
• Prospective Studies
• Pyridines (administration & dosage, pharmacology)
• Tetrazoles (administration & dosage, pharmacology)