Safety and tolerability of once-daily controlled-release carvedilol 10-80 mg in Japanese patients with chronic heart failure

The aim of the present study was to assess the safety and tolerability of the controlled-release (CR) formulation of the β-blocker carvedilol in Japanese patients with chronic heart failure (HF). In this multicenter, randomized, open-label, phase I/II dose-escalation study, 41 patients receiving standard therapy for chronic HF were randomized in a ratio of 1:1 to carvedilol CR or immediate-release (IR) carvedilol. The primary objective was to evaluate the tolerability and safety of escalating doses of carvedilol CR (10-40 mg/day), with a reference arm of 5-20 mg/day of carvedilol IR. In addition, the tolerability and safety of titration to a carvedilol CR dose up to 80 mg/day were examined, as were plasma concentrations of carvedilol and changes in vital signs. The proportions of patients who completed 40-mg/day carvedilol CR and 20-mg/day carvedilol IR were 42% (8/19) and 50% (11/22), respectively. In the CR group, 7/19 (37%) attained a dose of 80 mg. During the primary evaluation period, 7/19 (37%) and 4/22 (18%) patients experienced drug-related adverse events in the CR and IR groups, respectively, the characteristics of which were similar between groups. No new safety issues emerged in Japanese chronic HF patients treated with carvedilol CR in contrast to those known in carvedilol IR.