Randomized Intravenous Tezosentan Study - RITZ-4


The goal of the Randomized Intravenous TeZosentan (RITZ-4) study was to compare tezosentan, a nonselective endothelin antagonist, versus placebo in patients with acute decompensated heart failure (HF) associated with acute coronary syndrome (ACS).

Study Design

Study Design:

Patients Enrolled: 193
Mean Follow Up: Six months
Mean Patient Age: Median age 70 in placebo arm; 74 in tezosentan arm

Patient Populations:

Age ≥18 years; ACS (Q wave infarction within 12-48 hours, non–Q wave infarction within 6-48 hours, or unstable angina) associated with acute HF, defined as dyspnea at rest or with minimal activity from a cardiac etiology, associated with crackles more than at bases or evidence for ≥ interstitial edema on chest X-ray


Planned coronary procedure (angiography and/or percutaneous coronary intervention) within 24 hours after the start of randomized treatment; clinically significant hypotension (supine systolic blood pressure <105 mm Hg); atrial fibrillation or flutter (ventricular response >130 beats/min) or ventricular rhythm disturbances; digoxin toxicity; left ventricular assist devices, intra-aortic balloon counterpulsation, or mechanical ventilation; chronic or acute hemodialysis, ultrafiltration, or peritoneal dialysis, acute systemic infection or sepsis, terminal illness with expected survival of <30 days; treatment with another investigational drug within one month; known drug or alcohol dependence; previous exposure to tezosentan; and treatment with cyclosporin A or tacrolimus

Primary Endpoints:

Composite incidence of death, worsening HF, recurrent ischemia, and recurrent or new MI within the first 72 hours of study drug treatment

Secondary Endpoints:

1) Change in HF score at 24, 48, and 72 hours after treatment initiation; 2) death or worsening HF during 72 hours after treatment initiation; 3) recurrent ischemia or recurrent/new MI during 72 hours after treatment initiation; 4) total days alive out of the hospital within 30 days of treatment initiation; 5) all-cause mortality and rehospitalization 30 days after treatment initiation; 6) length of initial hospital stay; and 7) total dose of IV diuretics administered over 72 hours after treatment initiation

Drug/Procedures Used:

Patients were randomized to tezosentan (n=97) or placebo (n=95) for at least 24 and up to 48 hours. Tezosentan dosing was 25 mg/h intravenously (IV) for one hour, followed by 50 mg/h for 23 hours and up to 48 hours of treatment.

Principal Findings:

There was no significant difference in the primary endpoint of death, worsening HF, recurrent ischemia, or recurrent/new myocardial infarction (MI) within 72 hours between the treatment arms (28.9% in the tezosentan arm vs. 24.2% in the placebo arm, p=0.52). Among the components of the composite, there was no difference for tezosentan versus placebo in mortality (3.1% vs. 3.2%), recurrent ischemia (12.4% vs. 11.6%, p=0.84), or recurrent/new MI (0% vs. 2.1%, p=0.25).

Worsening HF trended higher in the tezosentan arm (19.6% vs. 11.6%, p=0.16). A serious adverse event occurred in 14.4% of patients in the tezosentan and 13.7% in the placebo arm. Renal failure occurred more frequently in the tezosentan arm (7.2%) than in the placebo arm (2.1%).


Among patients with acute HF associated with ACS, treatment with the nonselective endothelin antagonist tezosentan was not associated with a difference in the primary endpoint of death, worsening HF, recurrent ischemia, and recurrent or new MI within the first 72 hours of study drug treatment. In the RITZ-2 trial, tezosentan was associated with a significant improvement in the cardiac index at six hours, and a reduction in pulmonary capillary wedge pressure compared with placebo.

The authors suggest that the tezosentan dosing used in the present study may have been too high, given the tendency to be associated with increased adverse events (hypotension, headache, and nausea) in the tezosentan arm. Additional dose-ranging studies with tezosentan are ongoing to determine if lower doses will produce improved hemodynamic effects without the increased adverse events.


O'Connor CM, Gattis WA, Adams KF Jr, et al. Tezosentan in patients with acute heart failure and acute coronary syndromes: results of the Randomized Intravenous TeZosentan Study (RITZ-4). J Am Coll Cardiol 2003;41:1452–7.

Clinical Topics: Acute Coronary Syndromes, Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Nausea, Myocardial Infarction, Acute Coronary Syndrome, Renal Insufficiency, Pulmonary Wedge Pressure, Endothelins, Heart Failure, Coronary Disease, Hypotension, Pyridines, Tetrazoles, Headache

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