Published online before print November 4, 2002, doi: 10.1161/01.CIR.0000038497.80095.E1
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(Circulation. 2002;106:2666.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Hemodynamic and Neurohumoral Effects of Selective Endothelin A (ETA) Receptor Blockade in Chronic Heart Failure
The Heart Failure ETA Receptor Blockade Trial (HEAT)
From the Cardiovascular Center, Cardiology, University Hospital, Zürich, Switzerland (T.F.L., F.E., D.H., G.N., F.R.); Allgemeines Krankenhaus, Wien, Austria (R.P.); Kerckhoff Clinic, Bad Nauheim, Germany (V.M.); Herz- und Kreislaufzentrum, Department of Cardiology, Dresden, Germany (M.R.S.); Franz Volhard Clinic, Berlin, Germany (R.W., R.D., S.P.); the Department of Biostatistics, University of Zürich, Switzerland (V.R.); Abbott, Ludwigshafen, Germany (T.N.); and the Clinical Research Center, InterCorNet (T.F.L.), Zurich, Switzerland.
Correspondence to Thomas F. Lüscher, MD, FRCP, Professor and Head of Cardiology, University Hospital, Rämistrasse 100, CH-8091 Zürich, Switzerland. E-mail cardiotfl{at}gmx.ch
Background— The endothelin (ET-1) system is activated in chronic heart failure (CHF). Whether, what type, and what degree of selective ET blockade is clinically beneficial is unknown. We investigated hemodynamic and neurohumoral effects of 3 weeks of treatment with various dosages of the orally available ETA antagonist darusentan in addition to modern standard therapy in patients with CHF.
Methods and Results— A total of 157 patients with CHF (present or recent NYHA class III of at least 3 months duration), pulmonary capillary wedge pressure 
12 mm Hg, and a cardiac index 
2.6 L · min-1 · m-2 were randomly assigned to double-blind treatment with placebo or darusentan (30, 100, or 300 mg/d) in addition to standard therapy. Short-term administration of darusentan increased the cardiac index, but this did not reach statistical significance compared with placebo. The increase in cardiac index was significantly more pronounced after 3 weeks of treatment (P<0.0001 versus placebo). Pulmonary capillary wedge pressure, pulmonary arterial pressure, pulmonary vascular resistance, and right atrial pressure remained unchanged. Heart rate, mean artery pressure, and plasma catecholamines remained unaltered, but systemic vascular resistance decreased significantly (P=0.0001). Higher dosages were associated with a trend to more adverse events (including death), particularly early exacerbation of CHF without further benefit on hemodynamics compared with moderate dosages.
Conclusions— This study demonstrates for the first time in a large patient population that 3 weeks of selective ETA receptor blockade improves cardiac index in patients with CHF. However, long-term studies are needed to determine whether ETA blockade is beneficial in CHF.
Key Words: endothelin • heart failure • hemodynamics
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