© 2004 European Society of Cardiology
The hemodynamic and neurohormonal effects of low doses of tezosentan (an endothelin A/B receptor antagonist) in patients with acute heart failure
a The Cardiology Department, Assaf-Harofeh Medical Center 70300 Zerifin, Israel
b Charité Campus Berlin, Germany
c AKH University of Vienna Austria
d Actelion Pharmaceuticals Ltd. Switzerland
e Baylor College of Medicine Houston, TX, USA
* Corresponding author. Present address: Duke University Medical Center, Durham, NC, 27710. USA Tel.: +1-919-6816195; Fax: +1-919-6817755. E-mail address: cotterg{at}hotmail.com
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Abstract |
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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.
Key Words: Heart failure • Endothelin • Vasodilation
Received April 7, 2004; Revised May 12, 2004; Accepted May 18, 2004
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