In order to achieve comprehensive pharmacotherapy management of the patient with cardiovascular disease, it is critical to appreciate various concepts in pharmacology beyond the traditional pharmacokinetic and therapeutic principles widely taught. These concepts include pharmacogenomics, pharmacoeconomics, pharmacovigilance, and pharmacoepidemiology. These principles can directly impact a single patient at the time of treatment while also leading to population-level changes to potentially optimize cardiovascular medication use. This chapter focuses on the four aforementioned topics in efforts to provide an overview and examples of each.

Pharmacogenomics is defined as the genome in the drug response.¹ This encompasses pharmacogenetics, a subcategory of pharmacogenomics, which refers to single genetic variation in response to a medication.¹ Pharmacogenetics has largely been used to study the inherited genetic differences in drug metabolic pathways.¹ The impact from genetic differences on pharmacotherapy is typically categorized into four influences: (1) the effect on a drug’s pharmacokinetics; (2) the effect on a drug’s pharmacodynamics; (3) the effect on idiosyncratic reactions; and (4) the effect on disease pathogenesis or severity and response to specific therapy.²,³ The central concept is the interindividual response to drug therapy with aims to maximize efficacy while minimizing adverse drug events as opposed to the “one-size-fits-all” approach.² The detailed overview of genetic principles is beyond the scope of this chapter.

Since the mid-2000s, regulatory agencies, such as the Food and Drug Administration (FDA), have increased the focus on the impact of pharmacogenetics on drug efficacy and safety.⁴ From the FDA perspective, this voluntary effort has led to over 300 medications having pharmacogenetic information included in the labeling.⁵ Although the vast majority are medications used for oncologic indications, close to 30 medications are cardiovascular specific. Well-known examples include clopidogrel and the CYP2C19 genotype, warfarin with both CYP2C9 and VKORC1 genotypes, and simvastatin and the SLCO1B1 genotype (Table 3.1). As cardio-oncology has emerged as a subspecialty, the pharmacogenomics of anticancer agents are also increasingly relevant to cardiovascular practice.⁶ An example of this is ongoing efforts and partial successes in identifying genetic polymorphisms that may help predict the risk of cardiotoxicity with doxorubicin.⁷

Despite the continued efforts to identify genetic ties to medication response, widespread incorporation of pharmacogenetic data into clinical practice currently remains a challenge. The reasons behind this is multifactorial and include availability and timing of testing, education about or ability to interpret the results, and real or perceived cost.⁸ In terms of timing, genotype testing can be done preemptively or reactively. Preemptive genotyping is completed through a multigene, chip-based approach that leads to several genes and/or genetic polymorphisms being tested simultaneously and leads to availability of information when needed in the future.⁹ The advantages of this include reduced cost and more compressive profiling, whereas, the disadvantages may include denial of reimbursement. Outside of this limited disadvantage, preemptive genetic testing allows the clinician to be proactive during therapy selection. In contrast, reactive genotyping typically tests a single gene or a few selected genes at the time the information is needed.⁹ Third-party reimbursement is more likely with reactive testing; however, since the results are not usually available at the time of treatment assignment or dosing, it may delay and increase the cost of optimal care.

Other considerations of pharmacogenetic testing include analytic validity, clinical validity, and clinical utility.¹⁰ Analytic validity refers to the ability of a test to accurately detect the presence or absence of a genetic variant. Clinical validity is the relevance of the variant to the drug’s response. An example of this, as noted above, is the CYP2C19 genetic variation’s impact on the bioactivation of clopidogrel. Finally, clinical utility is the test’s usefulness in guiding the prevention, diagnosis, treatment, and management of therapy. It is critical for the selected test to be highly accurate and clinically valid for use; however, the biggest determinate of a test’s value is its clinical utility. For example, in regard to simvastatin therapy, since most statins are now generic (ie, widely available and inexpensive), the utility of SLCO1B1 genotype testing to avoid simvastatin-induced myopathy is of questionable value, as clinicians can readily
prescribe alternative generic statins that are unaffected by this gene. In this example, if suddenly all other statins became unavailable, the clinical utility of testing for the SLCO1B1 genotype to guide simvastatin therapy would change. In contrast, experts have generally outlined a significant number of scenarios where genetic testing may be utilized in personalizing P2Y₁₂ inhibitor therapy for patients receiving dual antiplatelet therapy,¹¹ despite the availability of newer agents that circumvent this concern.

As described previously, understanding how to interpret the results of genetic tests is critical for successful clinical implementation of pharmacogenetics. In order to assist with this, the Clinical Pharmacogenetic Implementation Consortium (CPIC) was established in 2009.¹² Consisting of experts in pharmacogenomics and laboratory medicine, the CPIC devises guidelines recommending what to do with genetic information that has been obtained. For example, several of the aforementioned cardiovascular drug gene pairs have robust evidence regarding use in clinical practice. It is important that providers using this information have full understanding of the results or know how to consult someone who can assist. In terms of implementation, several programs at the forefront of the adoption of cardiovascular pharmacogenomics have outlined how to initiate and develop this service.¹³ The central elements for implementation include engaging all key stakeholders, prioritizing gene-drug pairs to include informed test selection, establishing an electronic health record infrastructure, demonstrating value, and maintaining sustainability. These challenges need to be addressed on both a national and health-system level in order to facilitate widespread adoption.

As health care moves toward a value-based care system, it is imperative to understand the efficacy and safety of our therapies in the context of their cost. Pharmacoeconomics is a type of outcomes research that can be used to quantify the value of pharmacotherapy. It is the description and analysis of the costs of medications and pharmaceutical services and their effects on individuals, health care systems, and society.¹⁴ The means through which value is determined is by way of economic evaluations, which identify, measure, and compare the costs and consequences of a pharmaceutical product or service. The four common types of economic evaluations utilized in pharmacoeconomics are (1) cost-minimization analysis; (2) cost-benefit analysis; (3) cost-effectiveness analysis; and (4) cost-utility analysis.¹⁵

Before one can elucidate the differences between these analyses, one must have a general grasp on what constitutes cost. In economics, costs are the combination of losses of any goods that have value attached to them by any one individual.¹² Cost can be broken down into direct, indirect, intangible, and incremental.¹⁵ In health care, direct costs are resources consumed in the prevention, detection, or treatment of disease or illness. This can be further divided into cost associated with medical care and nonmedical cost. Within medical cost, there can be fixed cost, which remains constant, and variable cost. Fixed costs include items like electricity or lighting and are not routinely included in an analysis. Variable costs include items like medications, hospitalization, and laboratory costs. Examples of nonmedical costs are costs as a result of the disease or illness, like transportation to appointments. The aforementioned indirect costs are costs that occur as a result of morbidity or mortality, such as income lost because of premature death. Intangible costs are cost that represent nonfinancial outcomes of the disease and medical care. Examples of this cost include costs from pain and suffering; assigning value to these is challenging. The final cost, incremental cost, is the extra cost needed to purchase an additional benefit or effect of the medical care. For
example, in heart failure it would be additional medications beyond the standard of care to control the disease state.

The above mentioned costs create the backbone of the economic evaluations previously outlined. Understanding the difference between analyses helps clinicians answer pharmacoeconomic questions and interpret results published in the literature.¹¹ The first evaluation tool is the cost-minimization analysis.¹⁵ In this analysis, costs are expressed in monetary terms, and outcomes are considered equivalent. In this design, investigators can compare the cost of two or more treatment alternatives, treatments, or services that are determined to be equal in efficacy. This type of analysis provides results in terms of cost savings and provides information on the least expensive alternative. The advantage of this type of analysis is that it is relatively simple, but the disadvantage is the need for the intervention(s) to be equivalent.