The heart wants what it wants: PGx and cardiac health

Cardiac disease kills 1 in 3 Americans each year. PGx can help.

One out of every 3 men and women will die from cardiovascular disease in the U.S. every year. Since so many drugs are available — and most cardiac regimens include a combination of them — pharmacogenomic (PGx) testing provides exceptional knowledge support to cardiologists, primary-care physicians and others prescribing meds to enable better cardiac health and longer and more satisfying lives across our population.

Studies to determine the efficacy of PGx by drug/gene combinations are ongoing. But in cardiac treatment, a number of the most-prescribed antiplatelet, anticoagulant and statin drugs today have sufficient studies following industry-recognized, evidence-based guidelines — studies that have determined that PGx delivers valuable, actionable information before these drugs are prescribed to individual patients.

Anticoagulants and antiplatelets: Warfarin and clopidogrel

Let’s start with what’s undoubtedly considered the granddaddy of blood thinners to help prevent clotting — warfarin (Coumadin and others). As an article published in 2006 in the British Journal of Clinical Pharmacology pointed out, warfarin has been prescribed for humans for more than 60 years, but it’s still causing challenges.

While warfarin is the most widely used oral anticoagulant in the world, it’s also legendary for its drug interactions, narrow therapeutic index and wide interindividual variability. Too low a dose and it can be ineffective in reducing the blood-clot formation. In that instance, it won’t sufficiently contribute to reducing the risk of stroke, heart attack or other serious CV conditions. Too much warfarin and a patient can experience life-threatening internal bleeding, which can lead to gastrointestinal issues and put people at significant risk of “bleeding out” after an accident or during or following surgery.

Pharmacogenomics can be used to predict some of warfarin’s variability, and PGx is highly rated for its ability to provide actionable information for prescribing the drug. In fact, since 2007, the FDA product label for warfarin reflects the potential value of incorporating genetic information into dose selection. Clinical pharmacists involved in cardiac medication therapy management can recommend a safe and effective initial warfarin dosage by knowing a patient’s CYP2C9 and VKORC1 genotypes in particular — pieces of each person’s complete heritable genetic identity.

As a cytochrome P450 enzyme, CYP2C9 affects plasma levels and clearance of warfarin depending on a patient’s metabolizer status: ultra-rapid, extensive (the norm), intermediate or poor. VKORC1 controls the oxidation state of vitamin K, and genotypic variations in VKORC1 help explain differences in warfarin sensitivity.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed PGx guidelines for warfarin dosing, based on CYP2C9/VKORC1 genotyping results.

The newer antiplatelet clopidogrel (Plavix and others, approved for medical use in 1998) is often viewed as a more easily managed alternative to warfarin, with less-frequent dosing and monitoring. However, PGx testing is also recommended for actionable information based on established guidelines for its prescribing and continued monitoring. The FDA-approved label for clopidogrel was updated in late September 2016 warning that patients who are poor metabolizers may have diminished effectiveness of clopidogrel as compared to patients with extended (normal) metabolization ability. This particularly includes several CYP enzymes including the hepatic CYP2C19.

Adding to the challenge of prescribing clopidogrel is that only 15% of the prodrug — prodrug describing a medication that only becomes active after it is ingested — can be transformed to the active agent. For patients who are already poor metabolizers, this means they could receive little to no benefit from the standard therapeutic dose of clopidogrel. (For more information on prodrugs and non-prodrugs, metabolism levels and other background details regarding PGx, see our blog.)

The potential benefits of PGx testing including CYP2C19 are that when considering treatment with clopidogrel in acute coronary syndrome (ACS) and/or following a percutaneous coronary intervention (PCI). Through PGx, ACS/PCI patients who are likely to have a greater risk of a cardiovascular event on clopidogrel can be identified, and an alternative antiplatelet strategy can be instituted.

Tick, tock

A caveat with both clopidogrel and warfarin: Not surprisingly, time is of the essence for PGx testing. Results must be turned around quickly — ideally before initiating therapy — because the largest number of potentially preventable adverse events tend to occur early in treatment. Thus, if the patient’s genetic makeup isn’t already known from prior testing, early testing and expedited reporting would be advantageous.

Statins: Lipitor, pravastatin and fluvastatin

Any discussion of the value of PGx in cardiology must discuss statins. They remain a mainstay in the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) and are among the most prescribed classes of medication.

Adverse effects of statin pharmacotherapy, however, result in significant cost and morbidity and can lead to nonadherence and discontinuation of therapy. Statin-associated muscle symptoms occur in approximately 10% of patients on statins and constitute the most commonly reported adverse effect associated with using statins.

Because the widely prescribed drug atorvastatin (Lipitor) is another prodrug, it may be cleared faster by phenotypes who are ultra-rapid metabolizers, indicating a possible need for a higher dose or a change in therapy to a non-prodrug. On the other hand, a person who is an ultra-rapid metabolizer could receive too much of the medication too quickly, potentially causing safety issues.

Those with a predisposition to muscle cramping would be served by the use of PGx information and prescribing an alternative water-soluble statin versus fat-soluble statins such as atorvastatin. These alternative statins, such as pravastatin or fluvastatin, have been found to be among those least-likely to cause myalgia, including muscle or joint cramping, pain and/or weakness.

A 2005 study of 7,924 hyperlipidemic patients receiving high-dose statin therapy, PRIMO — the Prediction of Muscular Risk in Observational conditions) — concluded that “mild to moderate muscular symptoms with high-dosage statin therapy may be more common and exert a greater impact on everyday lives than previously thought. Knowledge of the risk factors for muscular symptoms will allow identification and improved management of high-risk patients.” Authors noted that the risk of muscular symptoms with fluvastatin XL treatment, for example, may be lower than with high dosages of other statins.

Prevalence of cardiac disease cries out for PGx testing

It’s no secret that the combination of an aging U.S. population and the stress of daily living are taking a toll on the health of our nation, particularly the growing prevalence of cardiovascular disease and its ranking as the leading cause of death. As noted, almost 1 in 3 deaths are directly attributed to CV disease — one every 40 seconds — and direct and indirect costs of CVD and stroke are at $315 billion a year and rising.

With the extremely sensitive nature of the anticoagulants, antiplatelets and statin drugs prescribed to the estimated 15 million U.S. adults with coronary heart disease, PGx testing data — interpreted and shared by consultations with specially skilled clinical pharmacists — can have a major impact to empower clinicians in making the best-educated decisions for each person in a patient-centric, value-based world.


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Kristen Engelen, PharmD
Kristen Engelen, PharmD, is the chief pharmacy officer of RxLive and a certified consultant pharmacist; she has over a decade of experience in retail pharmacy settings. Kristen became an RxLive co-founder because of her passion for geriatric pharmacy, with a focus on the intersection of pharmacy and aging.