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β‐adrenergic Receptor Polymorphisms and Responses during Titration of Metoprolol Controlled Release/extended Release in Heart Failure
Author(s) -
Terra Steven G.,
Pauly Daniel F.,
Lee Craig R.,
Patterson J. Herbert,
Adams Kirkwood F.,
Schofield Richard S.,
Belgado Bernadette S.,
Hamilton Karen K.,
Aranda Juan M.,
Hill James A.,
Yarandi Hossein N.,
Walker Joseph R.,
Phillips Michael S.,
Gelfand Craig A.,
Johnson Julie A.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.10.006
Subject(s) - metoprolol , heart failure , decompensation , tolerability , medicine , beta blocker , atenolol , heart rate , pharmacology , cardiology , anesthesia , adverse effect , blood pressure
Objective β‐Blockers require careful initiation and titration when used in patients with heart failure. Some patients tolerate β‐blocker therapy initiation without difficulty, whereas in other patients this period presents clinical challenges. We tested the hypothesis that polymorphisms at codons 389 (Arg389Gly) and 49 (Ser49Gly) of the β 1 ‐adrenergic receptor would be associated with differences in initial tolerability of β‐blocker therapy in patients with heart failure. We also tested whether polymorphisms in the β 2 ‐adrenergic receptor, G‐protein α s subunit (G s α), and cytochrome P450 (CYP) 2D6 genes or S ‐metoprolol plasma concentrations were associated with β‐blocker tolerability. Methods Sixty‐one β‐blocker‐naive patients with systolic heart failure were prospectively enrolled. Patients began taking 12.5 to 25 mg metoprolol controlled release/extended release with titration every 2 weeks (as tolerated) to 200 mg/d or the maximum tolerated dose over a period of 8 to 10 weeks. Decompensation was the composite of death, heart failure hospitalization, increase in other heart failure medications, or need to discontinue metoprolol. End points were assessed during the titration period. Results The overall rate of decompensation was not different between the codon 49 or 389 genotypes. However, a significantly greater percentage of patients with the Gly389 variant required increases in heart failure medications as compared with Arg389 homozygotes (48% versus 14%, respectively; P = .006). Similarly, patients with the Ser49 homozygous genotype were significantly more likely to require increases in concomitant heart failure therapy as compared with Gly49 carriers (41% versus 11%, respectively; P = .03). Neither CYP2D6 genotypes nor metoprolol pharmacokinetics differed between patients with and those without a decompensation event. There was no association between the β 2 ‐adrenergic receptor or G s α polymorphisms with decompensated heart failure. Conclusions Patients with the Gly389 variant and Ser49Ser genotype were significantly more likely to require increases in heart failure medications during β‐blocker titration and thus may require more frequent follow‐up during titration. Clinical Pharmacology & Therapeutics (2005) 77 , 127–137; doi: 10.1016/j.clpt.2004.10.006