Observations from a Post-MI Clinic; Does Prevalence of Specific Genetic Polymorphisms in CYP2D6 Influence Adoption of B-Blockers at Clinical Trial Dose Post Myocardial Infarction?

Abstract

β‐Blockers are first‐line therapy for treatment of heart failure, and for prevention of decline in LV systolic function in post-MI patients. Considerable variability exists in efficacy & tolerability of β‐blockers in HF patients, which may be associated with the genotype of drug-metabolizing enzymes and/or drug targets. Cytochrome P450 2D6 (CYP2D6) is a member of the CYP450 mixed-function oxidase system, which constitutes many important phase I drug metabolizing enzymes and contributes to the metabolism of up to 25% of clinically used drugs. Most genetic polymorphisms to the CYP2D6 gene result in either absent or decreased function of the enzyme activity. Four metabolizer phenotypes are typically used to characterize drug metabolism via CYP2D6: ultra-rapid metabolizer (UM); extensive metabolizer (EM); intermediate metabolizer (IM); and poor metabolizer (PM) phenotypes. Of the 3 β-blockers used for LV systolic dysfunction, CYP2D6 is the predominant metabolizing enzyme of both carvedilol and metoprolol; In contrast, Bisoprolol has a relatively constant β-adrenergic inhibition independent of CYP2D6 genotype. Aims Determine the prevalence of specific genetic CYP2D6 polymorphisms in patients admitted for Acute Coronary Syndromes with systolic dysfunction, and correlate with dose/tolerability or uptitration of metoprolol or carvedilol (BB) treatment. Methods Patients admitted with NSTEMI, ACS or ADHF, with elevated biomarkers had LVEF assessed during index admission. From 10/16/2013 to 07/17/2017, we followed 304 patients admitted for ACS with LVSD in a dedicated ‘post-MI Clinic’ having demonstrated echocardiographic evidence of reduced LVEF ( Results Beta blocker dosage was divided into high (CTD, >150mg daily Metoprolol; >50mg daily Carvedilol; >5mg daily Bisoprolol) or low dose. Within the ultra-rapid / extensive metabolizer (UM/EM) group, 78 patients (41%) were taking high dose BB at 1st visit (35), or successfully uptitrated (43) to high dose in clinic, compared to 9.5% of the (115) patients expressing intermediate metabolizer and poor metabolizer (IM/PM) phenotypes. Within the UM/EM group 36 patients (19%) presented to initial visit on CTD Bisoprolol, with a further 44 (23%) successfully transitioned from low dose BB to CTD Bisoprolol (compared to 12%, and 43%, respectively within the IM/PM group). Conclusion CYP2D6 polymorphisms in patients admitted with ACS and LV systolic dysfunction correlated with tolerability / uptitration of metoprolol and carvedilol, and may be of clinical use in prospectively determining β‐Blocker choice.