Edema and/or fluid retention was reported in 20 (25 percent), 26 (32 percent), 21 (25 percent) and 19 (14 percent) patients in the darusentan 50 mg, 100 mg, 300 mg and placebo groups, respectively. Four patients (2 percent) in the combined darusentan group discontinued the study due to fluid retention or edema. Almost all reports of clinical fluid retention occurred during the first six weeks of treatment. In approximately 70 percent of cases where diuretic therapy was altered, investigators subsequently reported that the edema or fluid retention prompting this additional diuretic therapy had resolved. Liver function test results were comparable between the groups and small mean decreases in hemoglobin (0.9-1.1g/dL), suggestive of hemodilution, were observed with darusentan.

Six patients had cardiac events during the trial that were reported as serious adverse events. There was one sudden death in a patient in the placebo group. Two darusentan patients had non-ST segment elevation myocardial infarctions, one in the darusentan 50 mg group and the other in the 100 mg group (but while receiving 50 mg during dose titration). Both of these events occurred in patients with prior coronary heart disease, and were associated with fluid retention and heart failure. There was one case of atrial fibrillation associated with symptoms of heart failure. This patient was receiving darusentan 100 mg and had prior left ventricular dysfunction, an exclusion criterion for the trial and thus was discontinued from further therapy following this incident. Lastly, there were two instances of fluid retention and heart failure, both randomized to the darusentan 300 mg group (one patient had two episodes: one on 100 mg and one on 300 mg). All episodes of fluid retention and heart failure responded promptly to diuretic therapy and with the exception of the patient with previous heart failure, the other four patients had left ventricular hypertrophy and left ventricular ejection fractions (measurements of heart pumping capacity) greater than 0.60.

Darusentan is an investigational compound and has not yet been determined safe or efficacious in humans.

gilead/