Search

Background: CYP2C19 loss-of-function (LOF) alleles impair clopidogrel effectiveness after percutaneous coronary intervention. The feasibility, sustainability, and clinical impact of using CYP2C19 genotype–guided dual antiplatelet therapy (DAPT) selection in practice remains unclear. Methods: A single-center observational study was conducted in 1193 patients who underwent percutaneous coronary intervention and received DAPT after implementation of an algorithm that recommends CYP2C19 testing in high-risk patients and alternative DAPT (prasugrel or ticagrelor) in LOF allele carriers. The frequency of genotype testing and alternative DAPT selection were the primary implementation end points. Risk of major adverse cardiovascular or cerebrovascular and clinically significant bleeding events over 12 months were compared across genotype and DAPT groups by proportional hazards regression. RESULTS: CYP2C19 genotype was obtained in 868 (72.8%) patients. Alternative DAPT was prescribed in 186 (70.7%) LOF allele carriers. CYP2C19 testing ( P P =0.001) varied over time. Risk for major adverse cardiovascular or cerebrovascular was significantly higher in LOF carriers prescribed clopidogrel versus alternative DAPT (adjusted hazard ratio, 4.65; 95% confidence interval, 2.22–10.0; P P =0.347). Bleeding event rates were similar across groups (log-rank P =0.816). Conclusions: Implementing CYP2C19 genotype–guided DAPT is feasible and sustainable in a real-world setting but challenging to maintain at a consistently high level of fidelity. The higher risk of major adverse cardiovascular or cerebrovascular associated with clopidogrel use in CYP2C19 LOF allele carriers suggests that use of genotype-guided DAPT in practice may improve clinical outcomes.

Aim: An algorithm that uses clinical factors and CYP2C19 genotype to guide P2Y12 inhibitor selection in high-risk patients undergoing percutaneous coronary intervention was implemented at our institution. We sought to evaluate use of this algorithm and identify which factors influenced P2Y12 inhibitor selection. Patients & methods: This retrospective cohort study included 264 patients receiving percutaneous coronary intervention from July–December 2012. Results: CYP2C19 genotype was obtained in 229 patients; of these, 30% were intermediate or poor metabolizers. CYP2C19 intermediate or poor metabolizer phenotype was among the strongest predictors for selecting prasugrel or ticagrelor as maintenance therapy (p < 0.001), and was the only significant predictor of a change in therapy (p < 0.001). Conclusion: These findings suggest that using CYP2C19 genotype to guide P2Y12 inhibitor selection is feasible. Original submitted 27 October 2014; revision submitted 19 December 2014

Pers. Med. (2014) 11(2), 135–138 ISSN 1741-0541 CYP2C19-guided antiplatelet therapy in coronary artery disease Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide [1]. Clinical practice guidelines currently recommend dual antiplatelet therapy with aspirin and a P2Y12 inhibitor in patients experiencing an acute coronary syndrome, with or without a percutaneous coronary intervention (PCI), and in stable CAD patients undergoing an elective PCI [2]. Clopidogrel, a prodrug that requires hepatic biotransformation into its active thiol metabolite via CYP450 isoenzyme CYP2C19, remains the most commonly prescribed P2Y12 inhibitor. Importantly, CYP2C19 is highly polymorphic and includes common loss-offunction alleles (*2 or *3) and a common gain-of-function (GOF) allele (*17) in multiple populations [3]. It is now clear that individuals carrying one or two loss-of-function alleles exhibit a significantly lower capacity to metabolize clopidogrel into its active metabolite and inhibit platelet activation, compared with wild-type individuals, and are, therefore, at significantly higher risk of adverse cardiovascular events following acute coronary syndrome or PCI [4]. These data led the US FDA to place a black-box warning in the clopidogrel prescribing information in March 2010 to alert clinicians of these risks [5]. Moreover, carriers of the GOF *17 allele, which enhances CYP2C19 transcription, have been reported to exhibit enhanced inhibition of platelet function and increased bleeding risk; however, conflicting results in the literature exist regarding the association between the *17 allele and bleeding risk [6]. By contrast, CYP2C19 genotype does not influence the pharmacokinetics, pharmacodynamics or clinical response to the more recently approved P2Y12 inhibitors, prasugrel and ticagrelor, which are more expensive than clopidogrel and associated with higher bleeding risk. The rapid accumulation of these data has generated considerable debate surrounding the following question: should CYP2C19 genotyping be used to guide selection of a P2Y12 inhibitor following PCI? Expert insight into this question, including the Clinical Pharmacogenetics Implementation Consortium [6] and the American College of Cardiology Foundation/American Heart Association [2], has collectively concluded that this approach should be considered in certain circumstances and more data are needed. Three notable gaps in knowledge have served as a barrier to more widespread implementation of CYP2C19-guided antiplatelet therapy in practice. First, it remains unclear whether clinically relevant associations between CYP2C19 genotype and clinical outcomes exist in clopidogrel-treated stable CAD patients undergoing elective PCI. Second, it remains unclear whether a clinically relevant association between the GOF CYP2C19*17 allele, clopidogrel use and bleeding risk truly exists. The third, and most important, gap in knowledge remains to be the lack of prospective, randomized clinical studies evaluating the impact of a CYP2C19-guided dual antiplatelet therapy strategy on clinical outcomes in patients undergoing PCI. The three studies highlighted below collectively offer new insight into each of these gaps in evidence regarding the potential clinical utility of CYP2C19 genotype-directed antiplatelet therapy in patients with CAD, part of Research Highlights

Purpose. Drug dose recommendations are not well defined in patients undergoing continuous renal replacement therapy (CRRT) due to limited published data. Several guidelines and pharmacokinetic equations have been proposed as tools for CRRT drug dosing. Dose recommendations derived from these methods have yet to be compared or prospectively evaluated.Methods. A literature search of PubMed, Micromedex, and Embase was conducted for 40 drugs commonly used in the ICU to gather pharmacokinetic data acquired from patients with acute and chronic kidney disease as well as healthy volunteers. These data and that obtained from drug package inserts were gathered for use in three published CRRT drug dosing equations. Doses calculated for a model patient using each method were compared to doses suggested in a commonly used dosing text.Results. Full pharmacokinetic data was available for 18, 31, and 40 agents using acute kidney injury, end stage renal disease, and normal patient data, respectively. On average, calculated doses differed by 30% or more from the doses recommended by the renal dosing text for >50% of the medications.Conclusion. Wide variability in dose recommendations for patients undergoing CRRT exists when these equations are used. Alternate, validated dosing methods need to be developed for this at-risk patient population.

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.