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CLINICAL STUDY: CARDIAC ARREST AND PULMONARY EDEMA

RITZ-5: randomized intravenousTeZosentan (an endothelin-A/B antagonist)for the treatment of pulmonary edema

A prospective, multicenter, double-blind, placebo-controlled study

Edo Kaluski, MD, FACC^*,*, Isaac Kobrin, MD^||, Reuven Zimlichman, MD, Alon Marmor, MD, Oscar Krakov, MD, Olga Milo, MD^*, Aline Frey, PharmD^||, Shoshana Kaplan, MD^*, Rikardo Krakover, MD^*, Avi Caspi, MD^||, Zvi Vered, MD, FACC^*, Gad Cotter, MD^* RITZ-5 Investigators

^* Cardiology Division, Assaf-Harofeh Medical Center, Zerifin, Israel
Department of Medicine-Edith Wolfson Medical Center, Holon, Israel
Cardiology Department–Rivka Ziv Medical Center, Safad, Israel
Cardiology Division–Kaplan Medical Center, Rehovot, Israel
^|| Actelion Ltd., Allschwil, Switzerland

Manuscript received May 7, 2002; revised manuscript received August 13, 2002, accepted September 6, 2002.

^* Reprint requests and correspondence: Dr. Edo Kaluski, Director of Coronary Care Unit, Assaf Harofeh Medical Center, Zerifin, DN Beer Yacov, 70300 Israel.
ekaluski{at}asaf.health.gov.il

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 (SO₂) <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 SO₂ 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 SO₂, 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.

Abbreviations and Acronyms   CHF   congestive heart failure   EF   ejection fraction   ET   endothelin   IV   intravenous   MAP   mean arterial blood pressure   MI   myocardial infarction   RITZ   Randomized Intravenous TeZosentan   SO2   oxygen saturation

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