Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure?

The last two decades have seen major advances in the treatment of chronic heart failure, primarily as a result of therapeutic manipulation of activated neurohormonal systems. Despite this progress, many patients still suffer significant morbidity and premature death. Antagonism of the biological effects of endothelin, a potent vasoconstrictor, represents a further potential target. To date, positive results from animal models of heart failure have not been translated into clinical practice, perhaps as a consequence of the high doses of drug used. The ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study evaluated the effects of low dose bosentan, a non-selective endothelin receptor antagonist, in patients with severe heart failure (left ventricular ejection fraction <35%, New York Heart Association class IIIb–IV). A total of 1613 patients were randomized to receive either bosentan (125 mg twice a day) or placebo. The preliminary results were presented at the 51st Annual Scientific Session of the American College of Cardiology (17–20 March 2002, Atlanta, GA, USA). The primary endpoint of all-cause mortality or hospitalization for heart failure was reached in 321/808 patients on placebo and 312/805 receiving bosentan. Treatment with bosentan appeared to confer an early risk of worsening heart failure necessitating hospitalization, as a consequence of fluid retention. It has been suggested that further studies using even lower doses of bosentan or more aggressive concomitant diuretic therapy may avoid this adverse effect. The results from the ENABLE study have, however, thrown further doubt on the potential benefits of non-specific endothelin receptor blockade in heart failure.