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CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure.

ABSTRACT: PURPOSE:This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure. METHODS:Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n?=?65) or metoprolol (n?=?33). RESULTS:CYP2D6*4 was associated with lower maintenance dose of metoprolol (OR 0.13 [95% CI 0.02-0.75] p?=?0.023), and a trend was observed between CYP2D6*4 and higher maintenance dose of carvedilol (OR 2.94 [95% CI 0.84-10.30] p?=?0.093). None of the patients that carried CYP2D6*4 achieved the recommended target dose of metoprolol (200 mg/day). CONCLUSION:Consistent with the role of CYP2D6 in the metabolism of metoprolol, the tolerated maintenance dose of metoprolol was lower in CYP2D6*4 carriers compared to non-carriers. Consistent with the role of CYP2D6 in activation of carvedilol, tolerated maintenance dose of carvedilol was higher in CYP2D6*4 carriers compared to non-carriers. Further investigation is warranted to ascertain the potential of CYP2D6 as a potential predictive biomarker of beta-blocker maintenance dose in heart failure patients.

SUBMITTER: Luzum JA

PROVIDER: S-EPMC5500390 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure.

Luzum Jasmine A JA Sweet Kevin M KM Binkley Philip F PF Schmidlen Tara J TJ Jarvis Joseph P JP Christman Michael F MF Sadee Wolfgang W Kitzmiller Joseph P JP

Pharmaceutical research 20170208 8

<h4>Purpose</h4>This study examined whether a CYP2D6 polymorphism (CYP2D6*4) was related to beta-blocker maintenance dose in patients with heart failure.<h4>Methods</h4>Logistic regression modeling was utilized in a retrospective chart-review analysis of heart-failure patients (60% Male, 90% of European descent) to assess whether CYP2D6*4 (non-functional CYP2D6 allele present in 1 of 5 individuals of European descent) is associated with maintenance dose of carvedilol (n = 65) or metoprolol (n = ...[more]

PMID: 28181117

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Project description:BackgroundBeta-blockers reduce mortality among patients with systolic heart failure (HF), yet primary care provider prescription rates remain low.ObjectiveTo examine the association between primary care physician characteristics and both self-reported and actual prescription of beta-blockers among patients with systolic HF.DesignCross-sectional survey with supplementary retrospective chart review.ParticipantsPrimary care providers at three New York City Veterans Affairs medical centers.MeasurementsMAIN OUTCOMES WERE: 1) self-reported prescribing of beta-blockers, and 2) actual prescribing of beta-blockers among HF patients. Physician HF practice patterns and confidence levels, as well as socio-demographic and clinical characteristics, were also assessed.ResultsSixty-nine of 101 physicians (68%) completed the survey examining self-reported prescribing of beta-blockers. Physicians who served as inpatient ward attendings self-reported significantly higher rates of beta-blocker prescribing among their HF patients when compared with physicians who did not attend (78% vs. 58%; p = 0.002), as did physicians who were very confident in managing HF patients when compared with physicians who were not (82% vs. 68%; p = 0.009). Fifty-one of these 69 surveyed physicians (74%) were successfully matched to 287 HF patients for whom beta-blocker prescribing data was available. Physicians with greater self-reported rates of prescribing beta-blockers were significantly more likely to actually prescribe beta-blockers (p = 0.02); however, no other physician characteristics were significantly associated with actual prescribing of beta-blockers among HF patients.ConclusionsPhysician teaching responsibilities and confidence levels were associated with self-reported beta-blocker prescribing among their HF patients. Educational efforts focused on improving confidence levels in HF care and increasing exposure to teaching may improve beta-blocker presciption in HF patients managed in primary care.

Project description:ObjectivesThis study sought to examine the association between baseline beta-blocker (BB) dose and outcomes in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial.BackgroundBeta-blockers reduce morbidity and mortality in chronic heart failure (HF) patients with reduced ejection fraction, but it is unclear whether titrating to higher BB doses improves outcomes in this setting.MethodsThe HF-ACTION trial was a randomized, multicenter trial enrolling 2,331 ambulatory HF patients with systolic dysfunction (New York Heart Association functional class II to IV, left ventricular ejection fraction <0.35) randomized to exercise training versus usual care, with median follow-up of 2.5 years. The BB dose at baseline was standardized with carvedilol equivalents and analyzed as a continuous variable and by discrete dose groups. The relationship between BB dose and the primary endpoint of all-cause mortality or all-cause hospitalization and other cardiovascular secondary endpoints was determined before and after adjustment for variables significantly associated with outcomes in the HF-ACTION cohort.ResultsNinety-five percent of patients were receiving a BB. There was a significant inverse relationship between BB dose and all-cause death or hospitalization but not other cardiovascular endpoints after adjustment for other predictors of outcome, with a linear benefit up to the 50-mg daily dose. There was a significant association between BB dose and change in peak VO(2) at 3 months. There was no increase in bradycardia with higher doses of BB.ConclusionsThere was a significant inverse relationship between BB dose and the endpoint of all-cause death or all-cause hospitalization in this well-treated HF cohort with systolic dysfunction, supporting recommendations that titrating doses up to 50 mg/day might confer a benefit in such patients. (Exercise Training Program to Improve Clinical Outcomes in Individuals With Congestive Heart Failure; NCT00047437).

Project description:Backgroundβ-Blockers (BBs) are mainstay therapy for heart failure with reduced ejection fraction. However, individual patient responses to BB vary, which may be partially due to genetic variation. The goal of this study was to derive and validate the first polygenic response predictor (PRP) for BB survival benefit in heart failure with reduced ejection fraction patients.MethodsDerivation and validation analyses were performed in n=1436 total HF patients of European descent and with ejection fraction <50%. The PRP was derived in a random subset of the Henry Ford Heart Failure Pharmacogenomic Registry (n=248) and then validated in a meta-analysis of the remaining patients from Henry Ford Heart Failure Pharmacogenomic Registry (n=247), the TIME-CHF (Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure; n=431), and HF-ACTION trial (Heart Failure: a Controlled Trial Investigating Outcomes of Exercise Training; n=510). The PRP was constructed from a genome-wide analysis of BB×genotype interaction predicting time to all-cause mortality, adjusted for Meta-Analysis Global Group in Chronic Heart Failure score, genotype, level of BB exposure, and BB propensity score.ResultsFive-fold cross-validation summaries out to 1000 single-nucleotide polymorphisms identified optimal prediction with a 44 single-nucleotide polymorphism score and cutoff at the 30th percentile. In validation testing (n=1188), greater BB exposure was associated with reduced all-cause mortality in patients with low PRP score (n=251; hazard ratio, 0.19 [95% CI, 0.04-0.51]; P=0.0075) but not high PRP score (n=937; hazard ratio, 0.84 [95% CI, 0.53-1.3]; P=0.448)-a difference that was statistically significant (P interaction, 0.0235). Results were consistent regardless of atrial fibrillation, ejection fraction (≤40% versus 41%-50%), or when examining cardiovascular death.ConclusionsAmong patients of European ancestry with heart failure with reduced ejection fraction, a PRP distinguished patients who derived substantial survival benefit from BB exposure from a larger group that did not. Additional work is needed to prospectively test clinical utility and to develop PRPs for other population groups and other medications.

Project description:Background It remains unclear whether beta-blocker use at hospital admission is associated with better in-hospital outcomes in patients with acute decompensated heart failure. Methods and Results We evaluated the factors independently associated with beta-blocker use at admission, and the effect of beta-blocker use at admission on in-hospital mortality in 3817 patients with acute decompensated heart failure enrolled in the Kyoto Congestive Heart Failure registry. There were 1512 patients (39.7%) receiving, and 2305 patients (60.3%) not receiving beta-blockers at admission for the index acute decompensated heart failure hospitalization. Factors independently associated with beta-blocker use at admission were previous heart failure hospitalization, history of myocardial infarction, atrial fibrillation, cardiomyopathy, and estimated glomerular filtration rate <30 mL/min per 1.73 m2. Factors independently associated with no beta-blocker use were asthma, chronic obstructive pulmonary disease, lower body mass index, dementia, older age, and left ventricular ejection fraction <40%. Patients on beta-blockers had significantly lower in-hospital mortality rates (4.4% versus 7.6%, P<0.001). Even after adjusting for confounders, beta-blocker use at admission remained significantly associated with lower in-hospital mortality risk (odds ratio, 0.41; 95% CI, 0.27-0.60, P<0.001). Furthermore, beta-blocker use at admission was significantly associated with both lower cardiovascular mortality risk and lower noncardiovascular mortality risk. The association of beta-blocker use with lower in-hospital mortality risk was relatively more prominent in patients receiving high dose beta-blockers. The magnitude of the effect of beta-blocker use was greater in patients with previous heart failure hospitalization than in patients without (P for interaction 0.04). Conclusions Beta-blocker use at admission was associated with lower in-hospital mortality in patients with acute decompensated heart failure. Registration URL: https://www.upload.umin.ac.jp/; Unique identifier: UMIN000015238.

Dataset Information

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure.

Publications

CYP2D6 Genetic Variation and Beta-Blocker Maintenance Dose in Patients with Heart Failure.

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