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CLINICAL RESEARCH

Tezosentan in patients with acuteheart failure and acute coronary syndromes

Results of the randomized intravenous tezosentan study (ritz-4)

Christopher M. O’Connor, MD, FACC^*, Wendy A. Gattis, PharmD^*,*, Kirkwood F. Adams, Jr, MD, FACC, Vic Hasselblad, PhD^*, Bleakley Chandler, MD, FACC, Aline Frey, PharmD, Isaac Kobrin, MD, Maurizio Rainisio, PhD, Monica R. Shah, MD^*, John Teerlink, MD, FACC^||, Mihai Gheorghiade, MD, FACC^¶ RITZ-4 Investigators

^* Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina, USA
University of North Carolina, Chapel Hill, North Carolina, USA
University Hospital of Augusta, Augusta, Georgia, USA
Actelion Ltd., Basel, Switzerland
^|| University of California in San Francisco, San Francisco, California, USA
^¶ Northwestern University, Chicago, Illinois, USA

Manuscript received August 6, 2002; revised manuscript received October 22, 2002, accepted November 19, 2002.

^* Reprint requests and correspondence: Dr. Wendy A. Gattis, Duke Clinical Research Institute, 2400 N. Pratt Street, 0311 Terrace Level, Durham, North Carolina 27705, USA.
wendy.gattis{at}duke.edu

OBJECTIVES: We sought to determine the effect of tezosentan in patients with acute decompensated heart failure (HF) associated with acute coronary syndrome (ACS).

BACKGROUND: Tezosentan is a dual endothelin receptor antagonist that has been shown to improve cardiac output, decrease pulmonary capillary wedge pressure, and reduce pulmonary and systemic vascular resistance in initial clinical studies in acute decompensated HF.

METHODS: The Randomized Intravenous TeZosentan (RITZ)-4 study was a multicenter, randomized, double-blinded, placebo-controlled study of tezosentan in patients with acute decompensated HF associated with ACS. A total of 193 patients were randomized to receive tezosentan (25 mg/h for 1 h, then 50 mg/h for 23 to 47 h) or placebo. Patients with evidence of acute decompensated HF and ACS were eligible to participate. The primary end point was the composite of death, worsening HF, recurrent ischemia, and recurrent or new myocardial infarction within 72 h.

RESULTS: No significant differences were observed between placebo and 50 mg/h tezosentan in the composite primary end point: 24.2% (95% confidence interval [CI] 16.0% to 34.1%) and 28.9% (95% CI 20.1% to 39.0%), respectively (p = 0.5152). Symptomatic hypotension was more frequent in the treatment group.

CONCLUSIONS: At the doses studied, tezosentan did not result in a significant improvement in the composite primary clinical end point in the RITZ-4 trial. Tezosentan did not demonstrate pro-ischemic effects in this population. Symptomatic hypotension may have resulted in an increased number of adverse events in the treatment group. Further studies with lower tezosentan doses are warranted.

Abbreviations and Acronyms   ACS = acute coronary syndrome   HF = heart failure   IV = intravenous   MI = myocardial infarction   RITZ-4 = Randomized Intravenous TeZosentan program   SBP = systolic blood pressure

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