RITZ-5: randomized intravenous TeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema: a prospective, multicenter, double-blind, placebo-controlled study.

Author(s): Kaluski E, Kobrin I, Zimlichman R, Marmor A, Krakov O, Milo O, Frey A, Kaplan S, Krakover R, Caspi A, Vered Z, Cotter G

Affiliation(s): Cardiology Division, Assaf-Harofeh Medical Center, Zerifin, Israel. ekaluski@asaf.health.gov.il

Publication date & source: 2003-01-15, J Am Coll Cardiol., 41(2):204-10.

Publication type: Clinical Trial; Multicenter Study; Randomized Controlled Trial

OBJECTIVES: The objective of this study was to evaluate the addition of intravenous (IV) tezosentan to standard therapy for patients with pulmonary edema. BACKGROUND: Tezosentan is an IV nonselective endothelin (ET)-1 antagonist that yields favorable hemodynamic effects in patients with acute congestive heart failure (CHF). METHODS: Pulmonary edema was defined as acute CHF leading to respiratory failure, as evidenced by an oxygen saturation (SO(2)) <90% by pulse oxymeter despite oxygen treatment. All patients received oxygen 8 l/min through a face mask, 3 mg of IV morphine, 80 mg of furosemide, and 1 to 3 mg/h continuous drip isosorbide-dinitrate according to their blood pressure level and were randomized to receive a placebo or tezosentan (50 or 100 mg/h) for up to 24 h. RESULTS: Eighty-four patients were randomized. The primary end point, the change in SO(2) from baseline to 1 h, was 9.1 +/- 6.3% in the placebo arm versus 7.6 +/- 10% in the tezosentan group (p = NS). The incidence of death, recurrent pulmonary edema, mechanical ventilation, and myocardial infarction during the first 24 h of treatment was 19% in both groups. Reduced baseline SO(2), lower echocardiographic ejection fraction, high baseline mean arterial blood pressure (MAP), and inappropriate vasodilation (MAP reduction at 30 min of <5% or >30%) correlated with worse outcomes. A post-hoc analysis revealed that the outcome of patients who received only 50 mg/h tezosentan was better than patients in the placebo group whereas patients receiving 100 mg/h had the worst outcomes. CONCLUSIONS: In the present study, tezosentan (an ET-1 antagonist) did not affect the outcome of pulmonary edema, possibly because of the high dose used.