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.” |