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CLINICAL STUDIES

Dose-related beneficial long-term hemodynamic and clinical efficacy of irbesartan in heart failure

Edward P. Havranek, MD, FACC^*, Ignatius Thomas, MD, William B. Smith, MD, George A. Ponce, MD, Martin Bilsker, MD, FACC^||, Mark A. Munger, PharmD^¶, Robert A. Wolf, MD, FACC^# for the Irbesartan Heart Failure Group

^* Denver Health Medical Center, University of Colorado Health Sciences Center, Denver, Colorado, USA
Slidell Memorial Hospital, Slidell, Louisiana, USA
Louisiana Cardiovascular Research Center, New Orleans, Louisiana, USA
Adult Cardiovascular Disease, Hemet, California, USA
^|| University of Miami School of Medicine, Miami, Florida, USA
^¶ University of Utah Heart Failure Treatment Program, Salt Lake City, Utah, USA
^# Bristol-Myers Squibb, Princeton, New Jersey, USA

Manuscript received February 19, 1998; revised manuscript received October 9, 1998, accepted December 22, 1998.

Reprint requests and correspondence: Dr. Edward P. Havranek, Denver Health Medical Center #0960, 777 Bannock Street, Denver, Colorado 80204-4507
ehavrane{at}dhha.org

OBJECTIVES

The primary purpose of this study was to determine the acute and long-term hemodynamic and clinical effects of irbesartan in patients with heart failure.

BACKGROUND

Inhibition of angiotensin II production by angiotensin-converting enzyme (ACE) inhibitors reduces morbidity and mortality in patients with heart failure. Irbesartan is an orally active antagonist of the angiotensin II AT₁ receptor subtype with potential efficacy in heart failure.

METHODS

Two hundred eighteen patients with symptomatic heart failure (New York Heart Association [NYHA] class II–IV) and left ventricular ejection fraction 40% participated in the study. Serial hemodynamic measurements were made over 24 h following randomization to irbesartan 12.5 mg, 37.5 mg, 75 mg, 150 mg or placebo. After the first dose of study medication, patients receiving placebo were reallocated to one of the four irbesartan doses, treatment was continued for 12 weeks and hemodynamic measurements were repeated.

RESULTS

Irbesartan induced significant dose-related decreases in pulmonary capillary wedge pressure (average change –5.9 ± 0.9 mm Hg and –5.3 ± 0.9 mm Hg for irbesartan 75 mg and 150 mg, respectively) after 12 weeks of therapy without causing reflex tachycardia and without increasing plasma norepinephrine. The neurohormonal effects of irbesartan were highly variable and none of the changes was statistically significant. There was a significant dose-related decrease in the percentage of patients discontinuing study medication because of worsening heart failure. Irbesartan was well tolerated without evidence of dose-related cough or azotemia.

CONCLUSIONS

Irbesartan, at once-daily doses of 75 mg and 150 mg, induced sustained hemodynamic improvement and prevented worsening heart failure.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   BUN = blood urea nitrogen   CI = cardiac index   LVEF = left ventricular ejection fraction   MPAP = mean pulmonary arterial pressure   MRAP = mean right atrial pressure   MSAP = mean systemic arterial pressure   NYHA = New York Heart Association   PCWP = pulmonary capillary wedge pressure

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