Activation of the renin-angiotensin system in patients with congestive heart failure (CHF) leads to vasoconstriction and retention of sodium and water. These patients are often treated with angiotensin-converting enzyme (ACE) inhibitors, which inhibit the production of angiotensin II. Despite the known benefits of treatment with ACE inhibitors, morbidity and mortality rates remain unacceptably high in these patients. The hemodynamic and clinical benefits of ACE inhibitors may be limited by enzymes that are resistant to ACE inhibition. Treatment with a newer angiotensin-II antagonist has been shown to provide a more complete blockade of the renin-angiotensin system and to avoid some of the side effects associated with ACE inhibitors. Havranek and colleagues evaluated the effectiveness of irbesartan in reducing pulmonary capillary wedge pressure in patients with heart failure. In addition, the drug was evaluated for acute and long-term hemodynamic effects, safety and clinical effects.
Adults with left ventricular function of 40 percent or less and symptomatic heart failure that required treatment with diuretics were eligible for the three-phase multicenter study. A placebo lead-in period that lasted up to two weeks was followed by a two-day acute placebo-controlled, double-blinded period and then a 12-week double-blinded period. During the lead-in period, diuretic therapy was stabilized, and all ACE therapy and other prohibited heart medications were discontinued at least three to four days before baseline hemodynamic measurements. Patients were randomized to receive placebo or irbesartan in a dosage of 12.5, 37.5, 75 or 150 mg per day. Patients continued their assigned dosage for the duration of the study. Those who required additional heart medications were dropped from the study. Hemodynamic measurements were obtained several times during the first day of treatment, and again at the end of the study period. The safety of irbesartan was assessed by a series of clinical examinations, laboratory studies, and electrocardiograms. Adverse events were also recorded.
Baseline demographic, clinical and hemodynamic characteristics were similar among groups. Irbesartan caused a significant improvement in pulmonary capillary wedge pressure measurements acutely, with the higher dosages having a greater impact. These improvements were sustained over the 12-week study period. The higher dosages also proved to be more effective clinically, as few patients in the higher dose groups discontinued the study medication. Irbesartan was well tolerated by most patients. Orthostatic hypotension was the principal adverse event, and there was no evidence of coughing or changes in renal function during the course of the study.
The authors conclude that irbesartan taken once daily was clinically and hemodynamically effective. The medication was more effective at the 75- and 150-mg dosages, was well tolerated and prevented worsening heart failure. Irbesartan appears to be a promising new agent in the treatment of CHF and may be indicated in the treatment of patients who cannot tolerate the side effects of ACE inhibitors.