ByTanvi Patil, PharmD, BCPS

BySidney Rorrer, PharmD candidate

ByAmanda D. McQuillan, PharmD, BCPS, BCPP

BySarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology)

Fact checked byRichard Smith

February 27, 2024

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Integration of pharmacist-led pharmacogenomics testing in cardiology clinical practice

ByTanvi Patil, PharmD, BCPS

BySidney Rorrer, PharmD candidate

ByAmanda D. McQuillan, PharmD, BCPS, BCPP

BySarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology)

Fact checked byRichard Smith

Key takeaways:

Pharmacists can play a key role in integrating pharmacogenomics data into clinical practice.
Antiplatelet, statin and beta-blocker agents are among the therapies in which pharmacogenomics data are important.

Tanvi Patil

Pharmacists are one of the most accessible health care providers and singularly well positioned to lead efforts in integrating pharmacogenomics testing to improve medication-related outcomes.

Sidney Rorrer

With evolving evidence as well as incorporation of pharmacogenomics (PGx) data into drug development, approval process and labeling, the need for ways to integrate PGx into clinical practice is inevitable.

Amanda D. McQuillan

The Clinical Pharmacogenetics Implementation Consortium (CPIC) was created in 2009 by the NIH and Pharmacogenomics Knowledge Base. CPIC has published more than 28 guidelines summarizing the evidence and providing recommendations for clinical care incorporating PGx testing. Current CPIC, FDA and American Heart Association/American College of Cardiology guidance on PGx testing related to CV medications includes recommendations for clopidogrel, statins and beta-blockers.

PGx-guided antiplatelet therapy

Sarah Spinler

Clopidogrel is a P2Y12 inhibitor that is a prodrug requiring hepatic biotransformation to its active metabolite by CYP2C19. Patients with a CYP2C19 loss-of-function (LOF) genotype cannot metabolize clopidogrel to its active metabolite and these CYP2C19 polymorphisms have been associated with reduced antiplatelet effects and clinical outcomes.

A recent update in the CPIC guidelines for clopidogrel strongly recommends avoiding clopidogrel in patients with ACS and/or those undergoing PCI who are CYP2C19 intermediate metabolizers and poor metabolizers (PMs). Three randomized controlled trials that support the CPIC recommendations (IGNITE, POPular Genetics trial, TAILOR-PCI) in patients with ACS with or without PCI are summarized in Table 1. A meta-analysis of 15,949 patients from seven randomized controlled trials by Pereira and colleagues suggested that the benefit of using prasugrel or ticagrelor (Brilinta, AstraZeneca) over clopidogrel in patients with ACS regardless of whether they underwent PCI is greatest in patients with CYP2C19 LOF genotype.
CPIC provides a moderate recommendation to consider alternative antiplatelet therapy over clopidogrel in patients with stroke or transient ischemic attack for treatment or prevention as well as for thromboprophylaxis after carotid artery stenting, endarterectomy or stent-assisted coiling in patients with intracranial aneurysms. This recommendation is based on results from the CHANCE-2 trial (Table 1). A meta-analysis by Pan and colleagues of 15 studies consisting of 4,762 patients treated with clopidogrel confirmed higher risk for stroke in patients with CYP2C19 LOF genotype compared with those without. (12% vs. 5.8%; P < .001).
Limited data are available on the potential benefit of CYP2C19-guided antiplatelet therapy in these areas: PCI without an ACS, peripheral artery disease or stable CAD following recent MI. However, given strong pharmacokinetic data, there may still be a benefit from genotype-guided antiplatelet therapy consistent with the FDA boxed warning that recommends alternative therapy regardless of the indication in patients with CYP2C19 PM phenotype. It should be noted that neither prasugrel nor ticagrelor is approved for the indication of elective PCI.
Pharmacogenomic testing is just one piece of the puzzle and it is important to take into consideration the various factors such as older age, high BMI, chronic kidney disease, diabetes, drug-drug interactions and available alternative therapy (ie, prasugrel’s contraindication in stroke, and dyspnea side effect and twice-daily dosing with ticagrelor).

* Pertinent phenotype/SNP
UM = ultrarapid metabolizer, RM = rapid metabolizer, NM = normal metabolizer, IM = intermediate metabolizer, PM = poor metabolizer, SNP = single nucleotide polymorphism, LOE = level of evidence
Data were derived from Cavallari LH, et al. *JACC Cardiovasc Interv*. 2018;doi:10.1016/j.jcin.2017.07.022; Claassens DMF, et al. *N Engl J Med*. 2019;doi:10.1056/NEJMoa1907096; Pereira NL, et al. *JAMA*. 2020;doi:10.1001/jama.2020.12443; and Wang Y, et al. *N Engl J Med*. 2019;doi:10.1056/NEJMoa2111749.
Table provided by authors.

PGx-guided statin therapy

Statin-associated musculoskeletal symptoms (SAMS) are the most frequently reported adverse effect of statins and range from muscle symptoms (1 in 10 persons) to muscle pain (1 in 2,000 persons) to rare rhabdomyolysis (1 in 10,000 persons). SAMS are responsible for statin therapy discontinuation with estimated rates reported to be as high as 40%.
The mechanism of SAMS is not well understood and is likely statin concentration-dependent. Onset can be weeks to months and risk factors include increased age, higher dose, drug interactions and gene variants, including the genes SLCO1B1 and ABCG2 and polymorphisms of CYP2C9.
The SLCO1B1 gene encodes for OATP1B1, which facilitates the uptake of statins into hepatocytes. Variants are associated with reduced uptake and increased concentrations. ABCG2 is an efflux transporter. The functional polymorphism 421 C>A in ABCG2 results in higher tissue concentrations. CYP2C9 is involved in metabolism of several statins.
Updated 2022 CPIC guidance now includes atorvastatin, rosuvastatin and fluvastatin recommendations in addition to a previous statement on simvastatin (Table 1). CPIC guidelines not only provide safety recommendations for maximum statin doses or statins that should be avoided, but also provides guidance on the duration for the impact of PGx results on statin medication adjustment (Table 2).
Statin testing can be done preemptively (before starting statin) or completed reactively in patients with history of SAMS. An ideal setting for implementation would be as part of pharmacy services in primary care or cardiology clinics or before hospital discharge after ACS or PCI.
Clinicians should also evaluate other factors known to impact statin intolerance (drug interactions, high-dose, advanced age, female sex, hypothyroidism, etc) when evaluating SAMS.

* Pertinent phenotype/SNP
NM = normal metabolizer, IM = intermediate metabolizer, PM = poor metabolizer, SNP = single nucleotide polymorphism
Data were derived from Keskitalo JE, et al. *Clin Pharmacol Ther*. 2009;doi: 10.1038/clpt.2009.38; Lönnberg KI, et al. *Pharmacogenet Genomics*. 2023;doi:10.1097/FPC.0000000000000504; Lu B, et al. *Clin Pharmacol Ther*. 2021;doi:10.1002/cpt.2337; Mirosevic Skvrce N, et al. *Pharmacogenomics*. 2013;doi:10.2217/pgs.13.135; Turner RM, et al. *Clin Pharmacol Ther*. 2020;doi: 10.1002/cpt.1820; and Zhang D, et al. *Eur J Clin Pharmacol*. 2020;doi:10.1007/s00228-020-02882-4.
Table provided by authors.

PGx-guided beta-blocker therapy

PGx-guided beta-blocker selection is a rapidly emerging practice because the enzyme CYP2D6 is highly polymorphic and involved in metabolism of common beta-blockers like carvedilol, metoprolol, nebivolol and propranolol.
For example, 70% to 80% of metoprolol’s metabolism is fulfilled by CYP2D6.
Higher prevalence of CYP2D6 PM is found in those of European ancestry. When these patients take a beta-blocker, it results in higher concentrations, requiring lower doses or careful titration to avoid bradycardia, heart block and hypotension.
The FDA table of pharmacogenetic associations includes information on the CYP2D6 gene variants affecting the aforementioned four beta-blockers. (Table 3)
The CPIC guidelines on PGx-guided beta-blocker therapy is under development and expected to be released shortly.
The Dutch Pharmacogenetics Working Group (DPWG) has published recommendations for metoprolol and CYP2D6 phenotypes (Table 3).
Another gene variant, ADRB1 (common variants, Ser49Gly and Arg389Gly), which encodes for G protein-coupled beta-1-adrenergic receptors, may result in reduced beta-1-adrenergic activity, thereby diminishing beta-blockade response.
The increased-function Gln41Leu allele of G protein-coupled receptor kinase 5 (GRK5) functions to desensitize beta-1-adrenergic receptors, resulting in receptor downregulation, and has been associated with improved CV outcomes irrespective of beta-blocker use in patients with hypertension.
Key evidence with relevant phenotypes and clinical implications are summarized in Table 3.

* Pertinent phenotype/SNP
UM = ultrarapid metabolizer, NM = normal metabolizer, IM = intermediate metabolizer, PM = poor metabolizer, SNP = single nucleotide polymorphism, BB = beta-blocker
Data were derived from Batty JA, et al. *Clin Pharmacol Ther*. 2014;doi:10.1038/clpt.2013.193; Blake CM, et al. *Clin Pharmacol Ther*. 2013;doi:10.1038/clpt.2013.96; Johnson JA, et al. *Clin Pharmacol Ther*. 2003;doi:10.1016/S0009-9236(03)00068-7; Liggett SB, et al. *Nat Med*. 2008;doi:10.1038/nm1750; Liggett SB, et al. *Proc Natl Acad Sci U S A*. 2006:doi: 10.1073/pnas.0509937103; and Lobmeier MT, et al. *Pharmacogenet Genomics*. 2011;doi:10.1097/FPC.0b013e328341e911.
Table provided by authors.

Pharmacist role in PGx-guided medication management

Pharmacists have been successfully integrated into clinical areas where they have led PGx implementation by collecting or ordering, interpreting, reporting and utilizing PGx data to improve patient outcomes and medication safety. For example, in a randomized controlled trial of patients aged 50 years or older discharged from hospital who were taking medications with identified potential for significant gene-based interactions and were being cared for by the hospital-affiliated home care agency, pharmacists provided recommendations for therapy changes using a clinical decision-based support tool. The study compared those who had home PGx testing with those not tested and showed that the number of emergency visits and hospitalization in these patients with polypharmacy was decreased roughly by 50% and was associated with cost savings of $4,382 within 60 days of the study period.

A scoping review of 43 studies published from 2007 to 2020 aimed to identify the evidence to date of PGx use in non-oncologic pharmacy practice and how they benefited patient outcomes. This review (72.1% of studies conducted in the U.S.) reported results from 14,758 patients receiving PGx-based services. The most commonly tested genes were CYP2C19, CYP2D6 and CYP2C9, and clopidogrel was the most commonly identified medication (30% patients had indication for alternative therapy). Common barriers reported were pharmacist time (approximately 15 minutes for one gene vs. up to 60 minutes for comprehensive review). Pharmacist education on PGx, collaborative team dynamics and the use of clinical decision tools were identified as facilitators.

Both the American Society of Health-System Pharmacists and the American College of Clinical Pharmacy have articulated the role of pharmacists in the application of real-world genotype test-guided pharmacotherapy recognizing the need to continue developing infrastructure and resources to support application and implementation of PGx in comprehensive medication management.

One benefit in the Veterans Health Administration is that pharmacists are considered advanced practice providers and have a scope of practice, making this an ideal environment to pilot innovative pharmacy practice models. In 2019, Deepak Voora, MD, director of the Veterans Affairs’ Pharmacogenomic Testing for Veterans (PHASER) program, implemented one of the largest integrated PGx programs nationally, which incorporates more than 100 pharmacy staff across nationwide VA hospitals. This program allows a preemptive approach to PGx by utilizing an 11-gene test panel that influences more than 40 medications. An example of pharmacist interventions in the PHASER program includes alerting prescribers to the risk of SAMS through SLCO1B1 phenotypes. In a discussion with Voora, future direction specifically in cardiology space includes implementation of pharmacist-driven PGx testing workflow in all patients undergoing PCI. Utilizing a PGx dashboard, pharmacists will review flag alerts for escalation and de-escalation of antiplatelet therapy in the outpatient setting and will complete clinical reviews and communicate with cardiology providers as well as follow through on any actionable findings.

Future directions for PGx in CVD

Given the large number of drug interactions, adverse effects and narrow therapeutic index drugs, PGx-guided antiarrhythmic therapy is being explored for agents with CYP2D6 metabolism including flecainide and propafenone, for which there are DPWG guidelines.
Another novel emerging concept that requires further validation is use of polygenic risk score approach to predict a patient’s response to being prescribed multiple CV drugs.
Studies have yet to report costs and clinical outcomes associated with a pharmacist-led PGx service or pharmacist based on PGx results prescribing via a collaborative practice agreement.
Given new and emerging published guidance on the impact of PGx testing, pharmacists can play an integral role to bring PGx knowledge to the CV and primary care teams.

References:

For more information:

Tanvi Patil, PharmD, BCPS, DPLA, is associate chief of Pharmacy, Clinical Services and Education; PGY1/PGY2 pharmacy resident program coordinator; clinical pharmacy specialist-cardiology; and pharmacogenomics pharmacy site champion at Salem Veteran Affairs Health Care System, Virginia. Patil can be reached at tanvipatil@gmail.com.

Sidney Rorrer, PharmD candidate, is a doctor of pharmacy student at Shenandoah University, Virginia.

Amanda D. McQuillan, PharmD, BCPS, BCPP, is the pharmacogenomic program manager at Veterans Integrated Services Network 4, U.S. Department of Veterans Affairs, Greater Pittsburgh region, Pennsylvania.

Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Healio | Cardiology Today Pharmacology Consult column editor. Spinler is professor and chair of the department of pharmacy services in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. Spinler can be reached at sspinler@binghamton.edu.

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Disclosures: The authors report no relevant financial disclosures.

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