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ENABLE Results Show Pitfalls of Endothelin Antagonists in Treating CHF
March 21, 2002

ATLANTA, Georgia (ACC) -- Although the initial results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) trial were discouraging, they provide possible support for the potential use of endothelin antagonists as a treatment for moderate-to-severe heart failure, reported Milton Packer, MD, of Columbia Presbyterian Medical Center in New York City.

The ENABLE trial “represents the definitive trial of endothelin antagonism, a novel neurohormonal approach to the treatment of congestive heart failure,” said Dr. Packer, who spoke at a news conference Monday, March 18, 2002 and at a Late-Breaking Clinical Trial session Tuesday, March 19, 2002.

“Our primary endpoint was all-cause mortality and hospitalization for heart failure,” he said. “In this trial, there was no favorable effect on this primary endpoint.”

In the trial, patients on conventional medications for chronic heart failure were randomly assigned to receive either a placebo or bosentan, an oral endothelin-receptor antagonist. Endothelin, which is produced in excess in the blood vessels and other tissues of patients with heart failure, is the most potent vasoconstrictor known and has other renal and cardiac actions thought to be harmful in heart failure.

“A number of earlier studies had linked increased levels of endothelin to the progression of heart failure, and we found that if one blocked the effects of endothelin in animal models, the animals got better or didn’t develop heart failure at all,” Dr. Packer said. “The results were very striking.”

Bosentan blocks both endothelin receptors A and B, he noted, and results of early studies in experimental models of heart failure were very promising.

In clinical settings, however, one early finding was “extremely disappointing,” Dr. Packer said. “When patients were given bosentan, in the short term, they tended to develop worsening heart disease. But, surprisingly, after time, they began to improve.”

So, the investigators’ goal was to develop a way to minimize the early adverse effects of bosentan so that patients could benefit from the long-term effects, he said.

“The strategy we used was to reduce the dosage of the drug from the original target dose of 500 milligrams twice a day to 125 milligrams twice a day,” Dr. Packer reported. “ENABLE was launched in order to evaluate the effects of this lower dose of bosentan.”

More than 1,600 patients with severe heart failure already on optimal medical therapy with conventional drugs were enrolled in the study. Participants had an ejection fraction of less than 35 percent in the previous six months, New York Heart Association class IIIb or IV in the previous two months, hospitalization for heart failure within the previous 12 months, or decreased exercise tolerance. They were randomized to either placebo or bosentan, which was added on top of conventional treatment, and they were followed for an average of one and a half years.

The earlier problem of short-term worsening heart failure was seen again, he said. Patients treated with the drug developed immediate and sustained fluid retention.

“Our findings suggest this early fluid retention had an adverse prognostic effect,” Dr. Packer said. “So, we have looked at the data again and are now considering that the dose of 125 milligrams twice a day may be too high and will need to be reduced even further to minimize these adverse effects.”

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