β-Receptor Selectivity of Carvedilol and Metoprolol Succinate in Patients with Heart Failure (SELECT Trial): A Randomized Dose-Ranging Trial

Study Objective. To determine whether metoprolol succinate (a beta(1)-selective beta-blocker) remains beta(1)-selective compared with carvedilol (a nonselective beta-blocker) during upward titration of doses in patients with American College of Cardiology (ACC) stage C heart failure. Design. Prospective, randomized, parallel-arm study. Setting. General clinical research center. Patients. Twenty-five beta-blocker-naive adults with New York Heart Association functional classes 11 or III heart failure (i.e., ACC stage Q. Intervention. Patients received either immediate-release carvedilol 3.125 mg twice/day or controlled-release metoprolol succinate 25 mg once/day; doses were titrated upward by doubling the dose every 2 weeks until reaching a maximum tolerated dose or a goal dose of carvedilol 25 mg twice/day and metoprolol 200 mg/day Before each dose titration, terbutaline (a beta-receptor agonist) was infused at 6 mg/kg over I hour for determination Of beta(2)-blockade. Measurements and Main Results. Patients were studied at baseline and after each dose titration of metoprolol succinate (at 25, 50, 100, and 200 mg once/day) and immediate-release carvedilol (at 3.125, 6.25, 12.5, and 25 mg twice/day). Glucose and potassium concentrations were measured twice serially at baseline, every 10 minutes during infusion, every 15 minutes for the first hour after infusion, and every 30 minutes for the second hour after infusion. The median area under the concentration-time curve (AUC) was calculated for changes in glucose and potassium concentrations. As assessed by glucose AUC, there was no significant difference in the degree Of beta(2)-blockade between metoprolol 200 mg and carvedilol 25 mg. In contrast to these data, the degree Of beta(2)-blockade as assessed by potassium AUC was greater for carvedilol compared with metoprolol across all doses. Conclusion. In this ACC stage C heart failure population, carvedilol was nonselective at all clinically relevant doses, whereas metoprolol succinate was beta(1)-selective at low doses and became progressively nonselective at higher doses.