London, UK - Results of the Endothelin Antagonist Receptor Trial in Heart Failure (EARTH), showing no effect of darusentan on remodeling in CHF patients, should spell the end of the endothelin-antagonist strategy in CHF, experts say. Appearing in the July 24, 2004 issue of the Lancet, results from EARTH were first presented at the European Society of Cardiology Congress in 2002, as reported by heartwire.1

EARTH enrolled 642 patients with class 2 through 4 heart failure, all of whom had LVEFs <35%. Patients were randomized to placebo or one of five doses of darusentan for 24 weeks. Only 485 patients completed the trial; the primary end point of the study was LV end-systolic volume (LVESV) measured by MRI.

At six months, the EARTH investigators, led by Dr Inder Anand (University of Minnesota, Minneapolis), found the changes in LVESV from baseline were no different between the placebo and treatment groups at any dose. Heart failure appeared to worsen in more than 10% of the trial participants, while an additional 5% died during the study, but in both instances, patient numbers were not significantly different between the darusentan- and placebo-treated patients. Changes in neurohormone concentrations and in clinical parameters were not significantly different between the placebo and darusentan groups.

As Inder and colleagues point out, trials of endothelin-receptor blockade in heart failure, including REACH-I and ENABLE, have proved disappointing, despite promising preclinical studies. The authors speculate that while the strategy may have the potential to attenuate cardiac remodeling or improve symptoms, endothelin antagonists may not be able to add anything to ACE inhibitors, beta blockers, and spironolactone.

"Although this was not a mortality trial, and long-term benefits of the drug cannot be excluded, endothelin-receptor antagonists are unlikely to have an important role in the management of patients with chronic heart failure who are receiving effective doses of ACE inhibitor and beta blocker," Inder et al write.

Trial validates LV end-systolic volume as primary end point

On a more positive note, the authors point out that an important contribution to the field from EARTH was the use of change in LVESV as a primary end point.

Endothelin-receptor antagonists are unlikely to have an important role in the management of patients with chronic heart failure who are receiving effective doses of ACE inhibitor and beta blocker.

"We argued that a mortality trial with endothelin blockade could be justified only if the drug had a significant effect on LV remodeling at six months. Darusentan did not improve any variable of left ventricular remodeling. However, we believe that this drug development strategy was useful and could be applied in future chronic-heart-failure trials," they write. "An important conclusion of our study is that cardiac MRI is a feasible and accurate measuring technique in multicenter dose-ranging studies."

Commenting on the study for heartwire, Dr Jay Cohn (University of Minnesota, Minneapolis), one of the investigators for the EARTH trial, says that the results from EARTH are in keeping with other recent morbidity/mortality trials in CHF patients.

"Drugs that do not favorably affect LV structural remodeling do not have a favorable long-term effect on outcome in heart failure. EARTH was the first trial that utilized the remodeling assessment to make a decision about the prudence of a long-term trial," Cohn said. "I believe the data should discourage future development of a drug of this specific pharmacologic effect to reduce long-term morbidity and mortality."