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Experimental Biology and Medicine 231:696-699 (2006)
© 2006 Society for Experimental Biology and Medicine

MINIREVIEW

Clinical Trials of Endothelin Antagonists in Heart Failure: A Question of Dose?

Nicholas F. Kelland and David J. Webb1

Clinical Pharmacology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, UK

To whom requests for reprints should be addressed at 1 Clinical Pharmacology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen’s Medical Research Institute, 3rd Floor East Room E3.22, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK. E-mail: d.j.webb{at}ed.ac.uk

Circulating plasma endothelin (ET)-1 concentrations are substantially elevated, and correlate with the hemodynamic severity and New York Heart Association (NYHA) class, in patients with chronic heart failure (CHF). In early preclinical studies involving different models of experimental heart failure, ET antagonists reduced cardiac pressures, increased cardiac output, and prolonged survival. ET receptor antagonists also impressively improved systemic and pulmonary hemodynamics in patients with CHF, without causing neurohormonal activation. However, recent clinical trials, including the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) and EARTH (Endothelin A Receptor Antagonist Trial in Heart Failure) studies, have shown neutral effects in terms of mortality and symptoms. This paper describes the possible reasons why benefit was not seen in these clinical studies, and suggests what lessons can be learnt from the way the studies were undertaken to apply to future studies.

Key Words: endothelin antagonists • heart failure • clinical trials




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