- Identify key candidate genes and polymorphisms that influence the pharmacokinetics, clinical response, and toxicity of cardiovascular medications.
- Describe, in depth, how key polymorphisms affect the pharmacokinetics, clinical response, and toxicity of cardiovascular medications such as clopidogrel, statins, and β-blockers.
- Discuss the role of genome-wide association studies in identifying genes and polymorphisms associated with response to cardiovascular medications.
- Weigh the evidence of available pharmacogenomic literature to determine the clinical utility of genetic testing in the management of cardiovascular diseases.
- Using a case-based approach, illustrate how genomic information may be used to guide drug selection and management of clopidogrel and statins.
Over the past decade, significant progress has been made in the field of cardiovascular pharmacogenomics. Pharmacogenomic literature is now available for most major cardiovascular disease states and includes medications that are at various stages in the pharmacogenomic research process. In some cases, the use of a patient's genetic makeup to individualize drug therapy is far from being used in the clinic. However, in other cases, genetic information is included in prescribing information, and published guidelines exist to facilitate the use of genotype-guided drug therapy in clinical practice. This chapter will cover major cardiovascular disease states for which there exists a moderate to high amount of pharmacogenomic research. Within this framework, each disease state will highlight one or two genes of interest in which there are well-documented associations between genetic polymorphisms and variability in drug disposition, response, toxicity, or clinical outcomes. In addition, other pharmacokinetic and pharmacodynamic genes of interest will be presented in each section.
Acute coronary syndromes (ACS) describe a group of cardiovascular disorders including unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI).1 The common theme underlying these disorders is the rupture of a vulnerable atherosclerotic plaque followed by partial or complete thrombotic occlusion of an artery. Platelets play a key role in the pathophysiology of ACS and thrombus formation. As such, most ACS pharmacotherapy is geared toward inhibition of platelet adhesion, activation, and aggregation. Pharmacologic antiplatelet agents that are routinely used in the treatment of ACS include aspirin, thienopyridines (e.g., clopidogrel and prasugrel), and glycoprotein IIb/IIIa inhibitors (e.g., abciximab, eptifibatide, tirofiban).2 Recently, the Food and Drug Administration approved ticagrelor, a cyclopentyltriazolopyrimidine, to reduce the rate of thrombotic cardiovascular events in patients with ACS. The goal of antiplatelet therapy in ACS is to decrease ischemia, limit the extent of infarction, and decrease the risk of death and recurrent cardiovascular events. To date, clopidogrel is the agent that has been studied most extensively in antiplatelet pharmacogenomics and is the focus of this discussion.
Clopidogrel, typically used in combination with aspirin, is indicated for the treatment of UA and NSTEMI, including patients who undergo percutaneous coronary interventions (PCI) and those who are managed medically.3 Clopidogrel is also indicated for patients with STEMI, and patients with recent myocardial infarction, recent stroke, or established peripheral arterial ...