Principal Findings:

Baseline cardiac index was 1.9 L/min/m² across all 3 groups. At 6 hours, the index for the T-50 group was increased by 0.42 L/min/m² and for the T-100 arm there was an increase of 0.41 L/min/m². This demonstrated a highly significant treatment effect of 38% and 37% respectively versus placebo (p<0.0001). 75% of the drug effect was achieved in the first hour of treatment at the 25 mg dosage. This effect in cardiac index was sustained over the 24-hour treatment period and maintained for at least 6 hours after termination of the drug. Another significant change was seen in PCWP, which was ~25 mm Hg across all groups at baseline. At 6 hours, treatment reduced PCWP by 4.5 and 4.6 in the T-50 and T-100 arms respectively, with virtually no change for the placebo group (p<0.0001). Both tezosentan groups showed decreased systolic, diastolic, and mean pulmonary pressures. On a 7-point dyspnea scale, a significant number of patients on the study drug improved dyspnea scores and fewer patients worsened on tezosentan (p=0.048). Additionally, tezosentan patients were free of more events in terms of death or time to worsening HF, although the results were not significant. (Because the study was not powered to detect these endpoints, investigators combined the 2 active arms to obtain these measurements.) In reviewing safety data, researchers found a dose-dependent reduction in systolic and diastolic blood pressures at 24 hours, which was expected given that tezosentan is a vasodilator. However, this reduction in blood pressure did not translate into an increased heart rate. Headache occurred more frequently in the treatment arms, and overall there were more adverse events (symptomatic hypotension, renal impairment, nausea, vomiting) in the T-100 cohort than the T-50 group. Adverse events in the T-50 group were similar to those in the placebo arm. At 28 days of follow-up, the number of patients with renal impairment was similar across all arms (placebo, 8; T-50, 7; T-100, 9). The need for hemodialysis was present in 3, 4, and 5 patients respectively. Analysis of time to death, cardiac failure, pulmonary edema, or cardiogenic shock at 28 days from treatment start showed virtually identical curves between placebo and the T-100 group, indicating that T-100 was a safe dose at 28 days. However, there were even fewer events in the T-50 group. No changes were detected suggesting a pro-arrhythmic effect or change in electrocardiographic parameters associated with active therapy.