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CLINICAL RESEARCH: HEART FAILURE/TRANSPLANTATION

Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure

Guillermo Torre-Amione, MD^*,*, James B. Young, MD, Wilson S. Colucci, MD, Basil S. Lewis, MD, Craig Pratt, MD^*, Gad Cotter, MD^||, Karl Stangl, MD^¶, Uri Elkayam, MD^#, John R. Teerlink, MD^**, Aline Frey, PharmD, Maurizio Rainisio, PhD and Isaac Kobrin, MD

^* Methodist DeBakey Heart Center and Baylor College of Medicine, Houston, Texas, USA
Section on Heart Failure and Cardiac Transplant Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
Cardiovascular Section, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA
Cardiology Department, Lady Davis Carmel Medical Center, Haifa, Israel
^|| Cardiology Institute, Assaf-Harofeh Medical Center, Zerifin, Israel
^¶ Department of Cardiology, Charite Hospital, Humboldt University, Berlin, Germany
^# Division of Cardiology, University of Southern California School of Medicine, Los Angeles, California, USA
^** Cardiology, San Francisco Veterans Affairs Medical Center/University of California at San Francisco, San Francisco, California, USA
Actelion Pharmaceuticals Ltd., Allschwil, Switzerland

Manuscript received August 30, 2002; revised manuscript received December 14, 2002, accepted January 30, 2003.

^* Reprint requests and correspondence: Dr. Guillermo Torre-Amione, Baylor College of Medicine Section of Cardiology, Texas Medical Center, One Baylor Plaza, Houston, Texas 77030, USA.
gtorre{at}bcm.tmc.edu

OBJECTIVES: We sought to investigate the efficacy and safety of tezosentan, a dual endothelin receptor antagonist, in patients hospitalized for acute heart failure (HF).

BACKGROUND: Tezosentan has been previously shown to improve hemodynamics in patients with stable chronic HF.

METHODS: In a double-blind fashion, 292 patients (cardiac index 2.5 l/min per m² and pulmonary capillary wedge pressure (PCWP) 15 mm Hg) who were admitted to the hospital and in need of intravenous treatment for acute HF and central hemodynamic monitoring were randomized to 24-h intravenous treatment with tezosentan (50 or 100 mg/h) or placebo. Central hemodynamic variables, the dyspnea score, and safety variables were measured.

RESULTS: After 6 h of treatment, significantly greater increases in the cardiac index and decreases in PCWP were observed with both tezosentan dosages than with placebo (mean treatment effects at 0.38 and 0.37 l/min per m² with 50 and 100 mg/h and –3.9 mm Hg for each dose, respectively; p < 0.0001). This effect was maintained during the remaining infusion and for 6 h after treatment cessation. A tendency for an improved dyspnea score and a decreased risk of clinical worsening was observed after 24 h of treatment with each tezosentan dose. Adverse events, more frequent with tezosentan than with placebo (headache, asymptomatic hypotension, early worsening of renal function, nausea, vomiting), were dose-related.

CONCLUSIONS: Intravenous tezosentan rapidly and effectively improved hemodynamics in these patients. The similar beneficial effects of the two dosages and the increased dose-related adverse events with the higher dosage suggest that the optimal dosing regimen is <50 mg/h.

Abbreviations and Acronyms   BP   blood pressure   CL   confidence limit   ECG   electrocardiogram/electrocardiographic   ET   endothelin   HF   heart failure   PAP   pulmonary artery pressure   PCWP   pulmonary capillary wedge pressure   PVR   pulmonary vascular resistance   RAP   right atrial pressure   SVR   systemic vascular resistance

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