BACKGROUND: The purpose of this study was to determine the additive value of ibopamine in heart failure patients who are treated with angiotensin-converting enzyme inhibitors. Ibopamine exerts hemodynamic and neurohumoral effects, and is beneficial in mild heart failure; however, its additive value in more advanced disease in unclear. METHODS AND RESULTS: The study was a stand-alone, double-blind, randomized parallel group comparison of ibopamine (100 mg 3 times daily) and placebo in 59 patients with New York Heart Association functional class III-IV heart failure. Patients were clinically stable on drug treatment, including an angiotensin-converting enzyme inhibitor, and they were randomized to ibopamine (n = 29) or placebo (n = 30). Assessments were performed at baseline and after 3 months of treatment, and included measurement of peak oxygen consumption, plasma neurohormones, ambulatory arrhythmias, and heart rate variability. At baseline, the two groups were well matched, including age (mean, 63 years), left ventricular ejection fraction (0.23), and peak oxygen consumption (15.4 mL/min/kg). After 3 months, four patients had dropped out of the study because of progressive heart failure (ibopamine, n = 1; placebo, n = 3; not significant) and two because of side effects (n = 1/1). Exercise time and peak oxygen consumption were not significantly affected (exercise time: ibopamine, +54 [95% confidence interval, -12, 120] seconds; placebo, +19 [-42, 81] seconds; peak oxygen consumption: ibopamine, +0.3 [-0.5, 1,2] mL/min/kg; placebo, +0.2 [-0.7, 1.0] mL/min/kg). Plasma neurohormones and ventricular arrhythmias during ambulatory monitoring were also unaffected. In contrast, heart rate variability parameters, in particular those associated with vagal tone (rMMSD, high-frequency power), significantly increased after 3 months on ibopamine (P = .01 vs placebo). CONCLUSIONS: In this group of patients with clinically stable moderate to severe chronic heart failure, only a marginal and statistically nonsignificant effect on clinical parameters was observed after 3 months of treatment with ibopamine. Heart rate variability parameters, however, were significantly affected by ibopamine, despite the absence of an effect on plasma neurohormones.