CYP2C19 Genetic Testing Guides Personalized Blood Thinner Therapy

For decades, patients with cardiovascular conditions have received the same antiplatelet medication for blood thinning following a heart attack or other vascular events. Recently, however, CYP2C19 genetic testing has become available to personalize this treatment and provide the best option for each patient. The simple test can tell whether commonly prescribed antiplatelet medications will work for a patient, or if a more effective alternative is available.

Clinical Evidence From the American Heart Association (AHA)

There are several clinical studies that have examined the use of CYP2C19 genetic information in the emergency cardiac care setting. For example, in a study that included more than 5,000 patients who had undergone percutaneous coronary intervention (PCI) using stents, patients who had certain loss-of-function variants of the CYP2C19 gene had fewer cardiovascular events when treated with ticagrelor compared to those patients treated with clopidogrel.

Why It Matters

For decades, one antiplatelet medication has been prescribed for decades to treat patients following a heart attack, stent placement, and some stroke patients. The medication, clopidogrel, is inexpensive, widely available, and easy for health care providers to prescribe. It requires, however, the activation of the CYP2C19 enzyme produced by the CYP2C19 gene. Unfortunately, many individuals have versions of the CYP2C19 gene that produce less CYP2C19 enzyme, which means that clopidogrel is not fully activated for these individuals. Thus, these individuals are at increased risk of stent thrombosis and subsequent heart attacks and strokes. Although these individuals are at risk of excessive or severe bleeding complications, the complications are expected to be worse because the ineffective antiplatelet drug cannot be counterbalanced by an increase in the dose of the medication.

Tailoring Treatment to Genetics

Genetic testing can identify loss-of-function variants of the CYP2C19 gene. For patients identified as poor metabolizers, the standard antiplatelet therapy will not be fully activated. An alternative, more effective antiplatelet agent can be prescribed for these patients. The correct amount of protection against stent thrombosis will be provided while the risk of excessive and potentially hazardous bleeding will be kept to a minimum.

What the Research Says

Approximately 30% of the population are intermediate or poor metabolizers of clopidogrel, and as such are at increased risk for a major adverse cardiovascular event with standard antiplatelet therapy.

• Precision Dosing: Genetic testing enables a “precision-medicine approach” that moves clinicians away from trial-and-error prescribing.
• Reduced Complications: In the studied population, genotype-guided therapy led to a 34% reduction in the risk of serious complications for those with the loss-of-function variants.
• Informed Safety: Conversely, for patients who do not carry these variants, the standard drug remains a safe, highly effective, and cost-efficient option, allowing clinicians to avoid the higher bleeding risks associated with alternative medications when they aren’t strictly necessary.

Systems-Level Implications: Systemic Integration and Timing

A systems perspective is needed to apply clinical application of genotype-guided prescribing for drugs that require activation by CYP2C19. In addition to issues relevant at a systems level such as laboratory capacity and time to results and integration of genetic information into the electronic health record, there are also a number of important issues to consider at the bedside including training of the workforce, use of clinical decision support, and development of reports that are easily interpreted by clinicians.

Ultimately, the successful implementation of this approach will depend on a number of factors, not the least of which will be the time from which a patient’s genes are analyzed and the results of analysis are returned to his/her health care provider. Ideally, a decision to switch from one antiplatelet medication to another will be made within hours of stenting a patient’s coronary artery or arteries. A number of point-of-care genetic testing strategies are being explored by a variety of health systems. It will be the goal of such an approach to identify as quickly and efficiently as possible the patients who are most at risk for an adverse cardiovascular event while on antiplatelet therapy, including stent thrombosis, heart attack or stroke, and to ensure that each such patient receives the best available antiplatelet therapy. In the ideal situation, this testing could occur at the patient’s bedside in the cardiac catheterization laboratory, for example. To that end, a number of steps could be taken to establish a number of components that would comprise a genetic testing work flow in this setting.

Who It Affects

Patients

The patients who will be impacted most by this method of treatment are those who have been diagnosed with acute coronary syndromes and are taking antiplatelet medications. Patients who have undergone percutaneous coronary interventions (PCI) with stent placement will also be impacted by this method of treatment. Other patients who may be impacted by this form of treatment are those who have suffered from strokes and have been placed with stents as well as those who have been diagnosed with peripheral arterial disease and have been treated with stents or other vascular modalities and are prescribed antiplatelet medications.

Cardiologists and Interventional Teams

In the first instance the patients will be treated by the cardiologists and the teams that work with them. These health care providers will test their patients and treat them on the basis of the test results. The clinician needs to test the patient as quickly as possible and have the results of the test available to the hospitalists who are taking care of the patient as he or she is recovering from a stent placement in the hospital. The other health care providers that will need to know how to manage the patients on antiplatelet therapy are the primary care providers and the neurologists. They will also need to know how to take care of the patient who has been transferred from another hospital on antiplatelet therapy.

Payers, Healthsystems, and Policymakers

Payers and the healthsystem also will be affected by several factors. Initially, the test will be paid for by someone. However, the cost of alternative antiplatelet medications for life could be greater than that of clopidogrel and could have a greater risk of serious bleeding. Decisions regarding use of a test for genetic variants that affect clopidogrel metabolism and prescription of an alternative antiplatelet agent will involve a number of stakeholders including payers, pharmacy benefit managers, and health systems. Quality measures could be developed and implemented by a variety of organizations including professional societies and, at the federal level, by CMS. It is likely that some of these stakeholders will advocate for inclusion of genotype-guided antiplatelet prescribing in clinical practice guidelines as well as in measures of quality of care for the treatment of patients with cardiovascular disease.

What Changes

• Practical prescribing: Clinicians will increasingly use CYP2C19 genetic test results to guide the selection of antiplatelet therapy. If a patient has a loss-of-function variant, the clinician will often pick a drug that does not depend on that enzyme.
• Testing models: Hospitals and clinics will need protocols for when to test. Options include reactive testing at the time of an acute event, rapid point-of-care tests to return results within hours, or preemptive panel testing recorded in the medical record long before the drug is needed.
• Care coordination: Electronic health records will need to display genetic results clearly and trigger decision support so the information is used correctly. Without this, test results can sit unused or be misinterpreted.
• Trade-offs and informed consent: Alternatives to the standard drug can lower clot risk in people with the genetic variants, but come with a higher bleeding risk and higher cost for some patients. Clinicians will need to discuss these trade-offs with patients and document the shared decision-making process.

Genetic Variants =/= Same Clinical Effects

Each genetic variant is likely to have different clinical effects for different individuals. Thus, a list of variants identified in a patient’s genes will be of little use to health care providers unless they are able to translate this information into a number of clinical decisions to improve patient care in the acute setting of cardiac care as well as in other settings of health care.

Additional Barriers:

1) Turnaround Time

Most genetic tests have a turn around time of days to weeks for results. The results from genetic tests can be obtained within hours for some tests and some health systems are even exploring bedside testing for the cardiac management of stented patients. Some centers use a clinical heuristic to start high-risk patients on an alternative antiplatelet agent and then switch to the other antiplatelet agent once test results are available.

2) Bleeding Risk

Another set of limitations to consider are the limitations to the use of the alternative antiplatelet agents, particularly with respect to increased risk of bleeding. Although it is true that for patients of all genotypes the alternative antiplatelet agents are as effective or more effective than standard antiplatelet therapy for preventing cardiovascular events, there are many patients for whom the risk of bleeding with these agents is significant, and for some patients these agents are even contraindicated (e.g. older patients, prior stroke). The use of a patient’s genetic information to guide the choice of antiplatelet therapy is a useful clinical heuristic, but it is only one of several variables that must be taken into account. Other important variables include the patient’s risk of bleeding, other comorbidities of the patient, potential drug-drug interactions, and the cost of the alternative antiplatelet agents to the patient.

3) Equality Concerns

Equity. There are considerable differences in the frequency of loss-of-function CYP2C19 variants among different populations. Thus, patients with such loss-of-function variants would particularly benefit from testing for genotypes that guide antiplatelet therapy. However, there are also considerable differences in access to testing for CYP2C19 variants as well as to alternative drugs for patients on antiplatelet therapy who are on standard drugs because of their CYP2C19 genotype. In the context of significant disparities in the use of genetic-guided prescribing for various conditions, considerable disparities in clinical outcomes for patients will occur, which will need to be addressed by more than inclusion of genetic-guided prescribing in clinical guidelines. Adequate coverage, availability of rapid testing, and education of clinicians practicing in under-resourced clinical settings will be required.

4) Privacy and Patient Counseling

Privacy and patient counseling: Information about a patient’s genetic make-up can be highly sensitive. This means that the results of the test and the patient’s genetic predisposition to be affected in a different way by a number of medications need to be explained to the patient. The patient must understand how the test works and how the results of the test could affect the patient’s treatment. A number of countries have laws that protect genetic information from being disclosed. These laws may or may not apply to disclosure in health care, to employment, or to life and disability insurance. Information about a patient’s genetic make-up must be kept private and patients must be provided with appropriate consent for testing. Written records of the consent process must be kept.

Looking Ahead

This is just the beginning. As a first application of pharmacogenomics to many diseases and their treatments, CYP2C19 testing for antiplatelet drugs has the potential to improve the treatment of patients with vascular disease. By identifying a patient’s genotype prior to treatment and storing the information in their electronic medical record for future reference by other healthcare providers and their treatments, it is now possible to provide the most appropriate treatment for individual patients to prevent serious and potentially life-threatening complications of vascular disease. However, Development of an infrastructure to support such an approach will, however, require considerable time and resources. In the meantime, the key elements for all clinicians and the health systems in which they work and manage their patients are: 1) a clear protocol for when to test; 2) the use of rapid testing where appropriate; and 3) the test results incorporated into the patient’s medical record with decision support. A heuristic for clinical decision making for the management of patients on antiplatelet therapy would also be helpful before a point of failure. A pilot study to identify potential problems in the clinical workflow and financial implications would be sensible before a large-scale implementation is rolled out.

Pharmacogenetic tools will not solve all the problems of the treatment of patients with coronary artery disease. The most important will be the patient’s adherence to the treatment as well as timely follow-up of the patient after the procedure. Healthy life style of the patient is also very important. High-quality of procedural care and using the latest available technology for percutaneous interventions will prevent new events of vascular origin. Only by using all of the above approaches and by incorporating genetic tool in clinical decision making we will be able to offer the best possible treatment to our patients.

Reference

1. Pereira NL, Cresci S, Angiolillo DJ, et al. CYP2C19 Genetic Testing for Oral P2Y12 Inhibitor Therapy: A Scientific Statement From the American Heart Association. Circulation. 2024;150(6):e129-e150. doi:10.1161/CIR.0000000000001257