Personalized antiplatelet and anticoagulation therapy: applications and significance of pharmacogenomics

Abstract

In recent years, substantial effort has been made to better understand the influence of genetic factors on the efficacy and safety of numerous medications. These investigations suggest that the use of pharmacogenetic data to inform physician decision-making has great potential to enhance patient care by reducing on-treatment clinical events, adverse drug reactions, and health care-related costs. In fact, integration of such information into the clinical setting may be particularly applicable for antiplatelet and anticoagulation therapeutics, given the increasing body of evidence implicating genetic variation in variable drug response. In this review, we summarize currently available pharmacogenetic information for the most commonly used antiplatelet (ie, clopidogrel and aspirin) and anticoagulation (ie, warfarin) medications. Furthermore, we highlight the currently known role of genetic variability in response to next-generation antiplatelet (prasugrel and ticagrelor) and anticoagulant (dabigatran) agents. While compelling evidence suggests that genetic variants are important determinants of antiplatelet and anticoagulation therapy response, significant barriers to clinical implementation of pharmacogenetic testing exist and are described herein. In addition, we briefly discuss development of new diagnostic targets and therapeutic strategies as well as implications for enhanced patient care. In conclusion, pharmacogenetic testing can provide important information to assist clinicians with prescribing the most personalized and effective antiplatelet and anticoagulation therapy. However, several factors may limit its usefulness and should be considered.

Keywords: anticoagulant; aspirin; clopidogrel; pharmacogenetics; precision medicine; warfarin.

Figure 1

Major proteins involved in clopidogrel transport and metabolism. Note: Copyright © Pharmacogenomics Knowledge Base (PharmGKB). Reprinted by permission from the Pharmacogenomics Knowledge Base (PharmGKB) and Stanford University. Sangkuhl K, Klein TE, Altman RB. Clopidogrel pathway. Pharmacogenetics and genomics [webpage on the Internet]. PharmGKB; 2010. Available from: http://www.pharmgkb.org/pathway/PA154424674. Accessed May 7, 2014. Abbreviations: ABCB1, ATP-binding cassette subfamily B member 1; CES1, carboxylesterase 1; CYP1A2, cytochrome P450, family 1, subfamily A, polypeptide 2; CYP2C9, cytochrome P450, family 2, subfamily C, polypeptide 9; CYP2C19, cytochrome P450, family 2, subfamily C, polypeptide 19; CYP2B6, cytochrome P450, family 2, subfamily B, polypeptide 6; CYP3A4, cytochrome P450, family 3, subfamily A, polypeptide 4; CYP3A5, cytochrome P450, family 3, subfamily A, polypeptide 5; PON1, paraoxonase 1; P2RY12, purinergic receptor P2Y, G-protein coupled, 12.

Figure 2

Theoretical implementation of clopidogrel and warfarin pharmacogenomics. Notes: (A) Increasing evidence suggests that benefit from clopidogrel pharmacogenomics is dependent on clinical indication, whereby patients with ACS undergoing PCI derive the most benefit. (B) Patient A represents a typical individual initiating warfarin therapy, while patient B represents an individual at high risk during warfarin initiation (eg, elderly, concomitant dual antiplatelet therapy, prior history of pathological bleeding, etc). Abbreviations: ACS, acute coronary syndrome; AF, atrial fibrillation; CAD, coronary artery disease; PCI, percutaneous coronary intervention.

Figure 3

Pharmacogenetic algorithm for initiation of antiplatelet therapy based on CYP2C19 genotype recommended by the Clinical Pharmacogenetics Implementation Consortium. Note: Adapted by permission from Macmillan Publishers Ltd: Clinical Pharmacology and Therapeutics. Scott SA, Sangkuhl K, Stein CM, et al; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 1 Abbreviations: ACS, acute coronary syndrome; CYP2C19, cytochrome P450, family 2, subfamily C, member 19; EM, extensive metabolizer; IM, intermediate metabolizer; PCI, percutaneous coronary intervention; PM, poor metabolizer; UM, ultrarapid metabolizer.