Pharmacogenetics in Cardiovascular Disease: The Challenge of Moving From Promise to Realization

Abstract

Pharmacogenetics in cardiovascular medicine brings the potential for personalized therapeutic strategies that improve efficacy and reduce harm. Studies evaluating the impact of genetic variation on pharmacologic effects have been undertaken for most major cardiovascular drugs, including antithrombotic agents, β-adrenergic receptor blockers, statins, and angiotensin-converting enzyme inhibitors. Across these drug classes, many polymorphisms associated with pharmacodynamic, pharmacokinetic, or surrogate outcomes have been identified. However, their impact on clinical outcomes and their ability to improve clinical practice remains unclear. This review will examine the current clinical evidence supporting pharmacogenetic testing in cardiovascular medicine, provide clinical guidance based on the current evidence, and identify further steps needed to determine the utility of pharmacogenetics in cardiovascular care. IntroductionPharmacologic effects can vary significantly between individuals, leading to reduced drug efficacy, decreased adherence, or increased adverse events. Identifying individuals who are at risk for poor therapeutic responses may be useful for amending treatment decisions to optimize benefit and minimize harm. 1 Many factors influence the effectiveness of a given pharmacologic agent, including adherence, pharmacologic and environmental interactions, and genetic effects. 2 Genetic markers have been proposed as stratification tools to predict therapeutic effects, such that pharmacologic regimens are tailored to specific genetic profiles to maximize efficacy and minimize harm. Although this approach could herald an innovative departure from current clinical cardiology practice, significant limitations in the current literature exist that make the realization of this practice difficult. This review will evaluate the clinical evidence examining pharmacogenetics in the management of cardiovascularThe authors have no funding, financial relationships, or conflicts of interest to disclose.(CV) disease (CVD) across major drug classes. We will focus on common drugs used for the treatment of CVD and thrombosis: warfarin, aspirin, clopidogrel, β-blockers, statins, and angiotensin-converting enzyme (ACE) inhibitors (ACEis). Moreover, based on the current evidence, we will provide clinical guidance regarding the current use of pharmacogenetic testing in CVD and outline future directions in research. Warfarin ResponseWarfarin is among the most effective agents to prevent thromboembolic events in patients with atrial fibrillation. However, the efficacy of warfarin is highly dependent on achieving and maintaining a narrow therapeutic window (usually an international normalized ratio [INR] between 2 and 3). Through the inhibition of vitamin K epoxide reductase complex 1 (VKORC1), warfarin limits the generation of the vitamin K hydroquinone, a necessary cofactor to sustain vitamin K-dependent coagulation factors II, VII, IX, and X. 3 Metabolism of warfarin to its inactive metabolites occurs through the cytochrome p450 ...

Quantitative LC–HRMS determination of selected cardiovascular drugs, in dried blood spots, as an indicator of adherence to medication

“…Several studies have demonstrated a significant link between angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and cardiovascular outcomes. However, the impact of this genetic polymorphism on ACE inhibitor response is not well understood [40,41].…”

Pharmacogenetic Risk Stratification in Angiotensin-Converting Enzyme Inhibitor-Treated Patients with Congestive Heart Failure: A Retrospective Cohort Study

“…The individual response to various drugs used for treatment of CHF is highly variable and this variability cannot solely be explained by differences in clinical characteristics of patients [ 19 – 21 ]. Accordingly, genetic variations have been suggested to have a considerable effect on drug response and in patients treated with ACEIs the ACE I/D polymorphism has been a focus of attention [ 9 , 22 , 23 ]. Indeed, high circulating ACE activity has been associated with this polymorphism and with worse cardiovascular outcomes in CHF patients [ 24 ].…”

“…Indeed, high circulating ACE activity has been associated with this polymorphism and with worse cardiovascular outcomes in CHF patients [ 24 ]. Nonetheless, the utility of the ACE I/D polymorphism for pharmacogenetic risk stratification in CHF patients remains contentious, which may be explained, in part, by an anticipated small impact of this polymorphism on ACEI efficacy, and by the fact that published results have been limited by small study populations [ 22 , 25 , 26 ]. A few other genetic polymorphisms have separately been associated with the efficacy and safety of ACEIs, including some of those represented in the current study (rs4343, rs495828 and rs817646) [ 10 , 27 ].…”

“…A few other genetic polymorphisms have separately been associated with the efficacy and safety of ACEIs, including some of those represented in the current study (rs4343, rs495828 and rs817646) [ 10 , 27 ]. However, to our knowledge only one study, which examined the SNPs comprising score A of our study in patients with stable IHD, has hitherto used more than one SNP to provide an incremental pharmacogenetic risk score for prediction of survival in ACEI-treated patients [ 9 , 11 , 22 ].…”

From Metabonomics to Pharmacometabonomics: The Role of Metabolic Profiling in Personalized Medicine

“…However, the successful use of pharmacogenomics in the clinic has been limited (Urban and Goldstein, 2014) and recent reviews of the use of pharmacogenomics in randomized clinical trials in cardiovascular disease (Joseph et al, 2014), type-2 diabetes (Maruthur et al, 2014), and depression (Perlis, 2014) have failed to show clear value.…”