Impact of the β1-adrenoceptor Arg389Gly polymorphism on heart-rate responses to bisoprolol and carvedilol in heart-failure patients

• Published in: Clinical pharmacology and therapeutics Vol. 92; no. 1; p. 21
• Main Authors: Rau, T, Düngen, H-D, Edelmann, F, Waagstein, F, Lainščak, M, Dimković, S, Apostolović, S, Nešković, A N, Haverkamp, W, Gelbrich, G, Eschenhagen, T
• Format: Journal Article
• Language: English
• Published: United States 01.07.2012
• Subjects: Adrenergic beta-1 Receptor Antagonists - administration & dosage; Adrenergic beta-1 Receptor Antagonists - pharmacokinetics; Aged; Atrial Fibrillation - complications; Atrial Fibrillation - drug therapy; Atrial Fibrillation - genetics; Bisoprolol - administration & dosage; Bisoprolol - pharmacokinetics; Carbazoles - administration & dosage; Carbazoles - pharmacokinetics; Dose-Response Relationship, Drug; Double-Blind Method; Female; Heart Failure - complications; Heart Failure - drug therapy; Heart Failure - genetics; Heart Rate - drug effects; Heart Rate - genetics; Humans; Male; Polymorphism, Single Nucleotide; Propanolamines - administration & dosage; Propanolamines - pharmacokinetics; Receptors, Adrenergic, beta-1 - genetics; Treatment Outcome
• ISSN: 1532-6535
• DOI: 10.1038/clpt.2012.18

This pharmacogenetic substudy of the prospective, double-blind, randomized CIBIS-ELD trial determined the impact of the β1-adrenoceptor Arg189Gly polymorphism on heart-rate responses to bisoprolol or carvedilol in elderly patients with heart failure (421 with sinus rhythm, 107 with atrial fibrillation). Patients were randomized 1:1 to bisoprolol or carvedilol with a fortnightly dose-doubling scheme and guideline target doses. Patients with sinus rhythm responded essentially identically to bisoprolol and carvedilol, independent of genotype. Atrial fibrillation patients homozygous for Arg389 had a much smaller response to carvedilol than carriers of at least one Gly389 allele (mean difference 12 bpm, P < 0.00001). Carvedilol up to 2 × 12.5 mg did not reduce heart rate in Arg389Arg homozygotes at all. Interestingly, the immediate response to carvedilol did not differ between genotypes. The Arg389Gly polymorphism has a major impact on the heart-rate response to carvedilol (but not bisoprolol) in patients with heart failure plus atrial fibrillation.