| Coverage Policy Manual | |
| Policy #: | 2005003 |
| Category: | Laboratory |
| Initiated: | January 2005 |
| Last Review: | July 2023 |
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| Genetic Test: Cytochrome p450 Genotype Guided Treatment Strategy | |
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| Description: |
The cytochrome p450 (CYP450) family is involved in the metabolism of many currently administered drugs, and genetic variants in cytochrome p450 are associated with altered metabolism of many drugs. Genetic testing for cytochrome p450 variants may assist in selecting and dosing drugs that are impacted by these genetic variants.
Background
Drug efficacy and toxicity vary substantially across individuals. Because drugs and doses are typically adjusted, if needed, by trial and error, clinical consequences may include a prolonged time to optimal therapy. In some cases, serious adverse events may result.
Multiple factors may influence the variability of drug effects, including age, liver function, concomitant diseases, nutrition, smoking, and drug-drug interactions. Inherited (germline) DNA sequence variation (polymorphisms) in genes coding for drug metabolizing enzymes, drug receptors, drug transporters, and molecules involved in signal transduction pathways also may have major effects on the activity of those molecules and thus on the efficacy or toxicity of a drug.
Pharmacogenomics is the study of how an individual's genetic inheritance affects the body's response to drugs. It may be possible to predict therapeutic failures or severe adverse drug reactions in individual patients by testing for important DNA polymorphisms (genotyping) in genes related to the metabolic pathway (pharmacokinetics) or signal transduction pathway (pharmacodynamics) of the drug. Potentially, test results could be used to optimize drug choice and/or dose for more effective therapy, avoid serious adverse effects, and decrease medical costs.
The cytochrome p450 (CYP450) family is a major subset of all drug-metabolizing enzymes; several CYP450 enzymes are involved in the metabolism of a significant proportion of currently administered drugs. CYP2D6 metabolizes approximately 25% of all clinically used medications (e.g., dextromethorphan, β-blockers, antiarrhythmics, antidepressants, morphine derivatives), including most prescribed drugs. CYP2C19 metabolizes several important types of drugs, including proton pump inhibitors, diazepam, propranolol, imipramine, and amitriptyline.
Some CYP450 enzyme genes are highly polymorphic, resulting in some enzyme variants that have variable metabolic capacities among individuals, and some with little to no impact on activity. Thus, CYP450 enzyme variants constitute one important group of drug-gene interactions influencing the variability of effect of some CYP450 metabolized drugs.
Individuals with 2 copies (alleles) of the most common (wild type) DNA sequence of a particular CYP450 enzyme gene resulting in an active molecule are termed extensive metabolizers (EMs; normal). Poor metabolizers (PMs) lack active enzyme gene alleles, and intermediate metabolizers (IMs), who have one active and one inactive enzyme gene allele, may experience to a lesser degree some of the consequences of poor metabolizers. Ultrarapid metabolizers (UMs) are individuals with more than 2 alleles of an active enzyme gene. There is pronounced ethnic variability in the population distribution of metabolizer types for a given CYP enzyme.
Ultrarapid metabolizers administered an active drug may not reach therapeutic concentrations at usual recommended doses of active drugs, while PMs may suffer more adverse events at usual doses due to reduced metabolism and increased concentrations. Conversely, for administered prodrugs that must be converted by CYP450 enzymes into active metabolites, UMs may suffer adverse effects and PMs may not respond.
Many drugs are metabolized to varying degrees by more than one enzyme, either within or outside of the CYP450 superfamily. In addition, interaction between different metabolizing genes, interaction of genes and environment, and interactions among different non-genetic factors also influence CYP450-specific metabolizing functions. Thus, identification of a variant in a single gene in the metabolic pathway may be insufficient in all but a small proportion of drugs to explain inter-individual differences in metabolism and consequent efficacy or toxicity.
Genetically determined variability in drug response has been traditionally addressed using a trial-and-error approach to prescribing and dosing, along with therapeutic drug monitoring (TDM) for drugs with a very narrow therapeutic range and/or potential serious adverse effects outside that range. However, TDM is not available for all drugs of interest, and a cautious trial and error approach can lengthen the time to achieving an effective dose.
CYP450 enzyme phenotyping (identifying metabolizer status) can be accomplished by administering a test enzyme substrate to a patient and monitoring parent substrate and metabolite concentrations over time (e.g., in urine). However, testing and interpretation are time-consuming and inconvenient; as a result, phenotyping is seldom performed.
The clinical utility of CYP450 genotyping, i.e., the likelihood that genotyping will significantly improve drug choice/dosing and consequent patient outcomes, is favored when the drug under consideration has a narrow therapeutic dose range (window), when the consequences of treatment failure are severe, and/or when serious adverse reactions are more likely in patients with gene sequence variants. Under these circumstances, genotyping may direct early selection of the most effective drug or dose, and/or avoid drugs or doses likely to cause toxicity. For example, warfarin, some neuroleptics, and tricyclic antidepressants have narrow therapeutic windows and can cause serious adverse events when concentrations exceed certain limits, resulting in cautious dosing protocols. Yet, the potential severity of the disease condition may call for immediate and sufficient therapy; genotyping might speed the process of achieving a therapeutic dose and avoiding significant adverse events.
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Diagnostic genotyping tests for certain CYP450 enzymes are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.
Selected Testing Kits for CYP450 Genotyping Cleared for Marketing by the Food and Drug Administration
Several manufacturers market diagnostic genotyping panel tests for CYP450 genes, such as the YouScript Panel (Genelex Corp.), which includes CYP2D6, CYP2C19, CYP2C9, VKORC1, CYP3A4, and CYP3A5. Other panel tests include both CYP450 and other non-CYP450 genes involved in drug metabolism, such as the GeneSight Psychotropic panel (Assurex Health) and PersonaGene Genetic Panels (AIBioTech).
Pathway genomics offers a similar panel, Pain Management DNA Insight™.
Sky Toxicology offers SkyPGx a comprehensive pharmacogenetic panel which includes cytochrome genotyping. The test is marketed to identify a patient’s ability to metabolize a various prescription and non-prescription medications.
Food and Drug Administration Labeling on CYP450Genotyping
The FDA maintains online compendia of pharmacogenetic associations online under 3 categories: 1. pharmacogenetic associations for which the data support therapeutic management recommendations; 2. pharmacogenetic associations for which the data indicate a potential impact on safety or response and 3. pharmacogenetic associations for which the data demonstrate a potential impact on pharmacokinetic properties only. (FDA, 2022)
The FDA has included pharmacogenomics information in the physician prescribing information (drug labels) of multiple drugs. In most cases, this information is general and lacks specific directives for clinical decision making. In the following examples, the FDA has given clear and specific directives on either use of a specific dose (e.g., eliglustat, tetrabenazine) or when a drug may not be used at all (e.g., codeine).
Eliglustat
The FDA has approved eliglustat for treatment of adults with Gaucher disease type 1 who are CYP2D6 EMs, intermediate metabolizers, or PMs as detected by an FDA-cleared test. Further, the label acknowledges the limitation of use among UMs because they may not achieve adequate concentrations and a specific dosage was not recommended for patients with indeterminate CYP2D6 metabolizer status. Further, the label states that the dosing strategy should be 84 mg orally, twice daily for CYP2D6 EMs or intermediate metabolizers and 84 mg orally, once daily for CYP2D6 PMs. The FDA has included a black box to warn about the reduced effectiveness in PMs and to advise healthcare professionals to consider alternative dosing or to use of other medications in patients identified as potential PMs. (Cerdelga, 2021)
Tetrabenazine
The FDA has approved tetrabenazine for the treatment of chorea associated with Huntington disease. According to the label, patients requiring doses above 50 mg per day should be genotyped for the drug-metabolizing enzyme CYP2D6 to determine if the patient is a PM or EM. For patients categorized as PMs using an FDA-approved test, the maximum daily dose should not exceed 50 mg, with a maximum single dose of 25 mg. (Xenazine, 2019)
Codeine
The FDA does not recommend genotyping before prescribing codeine. The FDA has contraindicated codeine for treating pain or cough in children under 12 years of age and codeine is not recommended for use in adolescents ages 12 to 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease. There is an additional warning to mothers not to breastfeed when taking codeine. (FDA, 2017)
Siponimod
The FDA has approved siponimod for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. The recommended maintenance dosage is 2 mg. The recommended maintenance dosage in patients with a CYP2C9*1/*3 or *2/*3 genotype is 1 mg. Siponimod is contraindicated in patients with a CYP2C9*3/*3 genotype. (Mayzent, 2019)
Coding
Effective in 2012, there is specific CPT coding for this testing:
81225: CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *8, *17)
81226: CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)
81227: CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *5, *6)
There are also Tier 2 CPT codes that include cytochrome P450 testing:
81401: Molecular pathology procedure, Level 2 (e.g., 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) includes –
CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (e.g., drug metabolism), common variants (e.g., *2, *3, *4, *5, *6)
CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) (e.g., drug metabolism), common variants (e.g., *2, *3, *4, *5, *6)
81402: Molecular pathology procedure, Level 3 (e.g., >10 SNPs, 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants of 1 exon, loss of heterozygosity [LOH], uniparental disomy [UPD]) includes –
CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) (e.g., congenital adrenal hyperplasia, 21-hydroxylase deficiency), common variants (e.g., IVS2-13G, P30L, I172N, exon 6 mutation cluster [I235N, V236E, M238K], V281L, L307FfsX6, Q318X, R356W, P453S, G110VfsX21, 30- kb deletion variant)
81404: Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) includes –
CYP1B1 (cytochrome P450, family 1, subfamily B, polypeptide 1) (e.g., primary congenital glaucoma), full gene sequence
81405: Molecular pathology procedure, Level 6 (e.g., analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) includes –
CYP11B1 (cytochrome P450, family 11, subfamily B, polypeptide 1) (e.g., congenital adrenal hyperplasia), full gene sequence
CYP17A1 (cytochrome P450, family 17, subfamily A, polypeptide 1) (e.g., congenital adrenal hyperplasia), full gene sequence
CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) (e.g., steroid 21-hydroxylase isoform, congenital adrenal hyperplasia), full gene sequence
Related Polices
Separate policies have been developed to address genetic testing of CYP450 enzymes for Tamoxifen and Warfarin Treatment:
Policy 2009003-Genetic Test: Tamoxifen Treatment (CYP2D6).
Policy 2007015-Genetic Test: Warfarin Dose/Response
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Policy/ Coverage: |
Effective July 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
CYP2D6 genotyping to determine drug metabolizer status meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for individuals:
CYP2C9 genotyping to determine drug metabolizer status meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for individuals:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all other drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to, CYP450 genotyping for the following applications:
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all other drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to, CYP450 genotyping for the following applications:
The use of genetic testing panels that include multiple CYP450 mutations does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of genetic testing panels that include multiple CYP450 mutations is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
This policy does not address the use of genetic panel tests for genes other than CYP450-related genes (e.g., the Genecept Assay). Genetic testing for mental health conditions is discussed in coverage policy 2013046.
Effective Prior to July 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
CYP2D6 genotyping to determine drug metabolizer status meets member benefit certificate primary coverage criteria and is covered for patients:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to, CYP450 genotyping for the following applications:
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to, CYP450 genotyping for the applications listed above.
The use of genetic testing panels that include multiple CYP450 mutations does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of genetic testing panels that include multiple CYP450 mutations is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
This policy does not address the use of genetic panel tests for genes other than CYP450-related genes (eg, the Genecept Assay). Genetic testing for mental health conditions is discussed in coverage policy 2013046.
EFFECTIVE PRIOR TO JULY 2018
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
CYP2D6 genotyping to determine drug metabolizer status meets member benefit certificate primary coverage criteria and is covered for patients:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to, CYP450 genotyping for the following applications:
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to, CYP450 genotyping for the applications listed above.
The use of genetic testing panels that include multiple CYP450 mutations does not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of genetic testing panels that include multiple CYP450 mutations is investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
EFFECTIVE DECEMBER 2013 – FEBRUARY 2016
Cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to, CYP450 genotyping for the following applications:
For members with contracts without primary coverage criteria, cytochrome P450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all drugs, aside from determinations in the separate policies noted above in the policy Description, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. This includes, but is not limited to, CYP450 genotyping for the applications listed above.
Effective October 2013 to November 2013
CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following drugs:
For members with contracts without primary coverage criteria, CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for the above listed drugs is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Note: CYP450 genotyping for Tamoxifen, Warfarin, Clopidogrel and drugs used to treat depression are handled in separate policies.
Effective October 2012 – August 2013
CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following drugs:
For members with contracts without primary coverage criteria, CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for the above listed drugs is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Note: CYP450 genotyping for Tamoxifen, Warfarin, and clopidogrel are handled in separate policies.
Effective, May 2010
CYP450 phenotyping for CYP2C19 *2 and *3 alleles meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in patients with cardiovascular disease undergoing treatment with clopidogrel (Plavix) in order to identify those who are poor metabolizers of the drug (patients with CYP2C19*2/2,*3/3, and *2/3 genotypes) and who are therefore likely to exhibit poor response to the drug.
Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for any other indication does not meet member benefit certificate primary coverage criteria because there is insufficient evidence to indicate such testing will improve health outcomes or aid in patient management.
For contracts without Primary Coverage Criteria Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for any other indication is considered investigational. Investigational services are excluded in the member benefit certificate
Effective, January 2005 through April 2010
Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity is not covered because there is insufficient evidence to indicate such testing will improve health outcomes or aid in patient management. Therefore this testing does not meet Primary Coverage Criteria of effectiveness.
For contracts without Primary Coverage Criteria Genotyping to determine cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity is considered investigational. Investigational services are excluded in the member benefit certificate
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| Rationale: |
The primary goal of pharmacogenomics testing and personalized medicine is to achieve better clinical outcomes in compared with the standard of care. Drug response varies greatly between individuals, and genetic factors are known to play a role. However, in most cases, the genetic variation only explains a modest portion of the variance in the individual response because clinical outcomes are also affected by a wide variety of factors including alternate pathways of metabolism and patient- and disease-related factors that may affect absorption, distribution, and elimination of the drug. Therefore, assessment of clinical utility cannot be made by a chain of evidence from clinical validity data alone. In such cases, evidence evaluation requires studies that directly demonstrate that the pharmacogenomic test alters clinical outcomes; it is not sufficient to demonstrate that the test predicts a disorder or a phenotype.
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.
P450 genotype-guided TREATMENT strategy
Clinical Context and Therapy Purpose
The purpose of a P450 genotype-guided strategy is to tailor selection and dosing of drugs based on gene composition for drug metabolism. In theory, this should lead to early selection and optimal dosing of the most effective drugs, while minimizing treatment failures or toxicities.
The question addressed in this evidence review is: Does P450 genotype-guided strategy change patient management in a way that improves net health outcome?
The following PICOTS were used to select literature to inform this review.
Patients
The relevant populations of interest are patients being considered for treatment with clopidogrel, eliglustat, tetrabenazine, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, antipsychotic drugs, codeine, efavirenz and other antiretroviral therapies for HIV infection, immunosuppressants for organ transplantation, β-blockers (eg, metoprolol), and antitubercular medications.
Interventions
Commercial tests for individual genes or gene panels are available and are listed in the Regulatory Status section. Only those panels that include CYP450 genes are listed in that section.
Comparators
The following practice is currently being used: standard clinical management without genetic testing.
Timing
Outcomes in the first 3 months are relevant because the interest is in whether P450 genotype-guided strategy reduces adverse events or avoids treatment failure.
Setting
Consultations about the choice of the drug generally occur in an outpatient setting, and a variety of specialists may be involved including primary care providers (HIV, β-blockers, tuberculosis and cough medications), cardiologists (clopidogrel), psychiatrists (antidepressants, antipsychotics), neurologists (Huntington disease), and endocrinologists (Gaucher disease).
Clopidogrel
Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor) is the standard of care for the prevention of subsequent atherothrombotic events such as stent thrombosis or recurrent acute coronary syndrome in patients who undergo a percutaneous intervention or who have an acute coronary syndrome.
Clopidogrel is a prodrug that is converted to its active form by several CYP450 enzymes (particularly CYP2C19). Individuals with genetic variants that inactivate the CYP2C19 enzyme are associated with lack of response to clopidogrel. There are several variants of CYP2C19 but the 2 most frequent variants associated with loss of function alleles are CYP2C19*2 and CYP2C19*3. It is hypothesized that such individuals may benefit from other drugs such as prasugrel or ticagrelor or a higher dose of clopidogrel. Approximately 30% of whites and blacks and 65% of Asians carry a nonfunctional CYP2C19 gene variant (Scott, 2013). While CYP2C19 is the major enzyme involved in the generation of clopidogrel active metabolite, the variability in clinical response seen with clopidogrel may also result from other factors such as variable absorption, accelerated platelet turnover, reduced CYP3A metabolic activity, increased adenosine diphosphate exposure, or upregulation of P2Y12 pathways, drug-drug interactions, comorbidities (eg, diabetes, obesity), and medication adherence.
Multiple observational studies in patients undergoing percutaneous coronary intervention (PCI) have reported associations between the presence of loss of function alleles and lower levels of active clopidogrel metabolites, high platelet reactivity, and increased risk of adverse cardiovascular events. However, evidence of publication bias has been reported in these studies where smaller studies have reported larger benefits than larger studies which have reported no effect or smaller effect (Holmes, 2011). Wang et al reported post hoc analysis of the CHANCE trial conducted in China; it randomized patients with a transient ischemic attack or minor stroke to clopidogrel plus aspirin or aspirin alone. In a subgroup analysis of patients who did not have the loss of function alleles, clopidogrel plus aspirin vs aspirin alone was associated with statistical significant reduction in the risk of stroke (6.7% vs 12.4%; hazard ratio, 0.51; 95% confidence interval, 0.35 to 0.75) but not among those who carried loss of function alleles (9.4% vs 10.8%; hazard ratio, 0.93; 95% confidence interval, 0.69 to 1.26) (Wang, 2016). Results of this analysis have contributed to the formulation of the hypothesis of a differential effect of clopidogrel in patients with and without loss of function alleles.
Trials are important to validate such hypotheses. However, only a few trials of genotype-directed dosing or drug choice have been conducted. It is important to note that these trials use “high on-treatment platelet reactivity” as the outcome measure. Patients who exhibit “high on-treatment platelet reactivity” are referred to as being nonresponsive, hyporesponsive, or resistant to clopidogrel in the published literature.
Roberts et al reported on the results of RCT that allocated patients undergoing PCI for acute coronary syndrome or stable angina to genotype-guided management to select for treatment with prasugrel (carriers) or clopidogrel (noncarriers) or to standard treatment with clopidogrel (Roberts, 2012). Among those who received prasugrel and clopidogrel based on genotyping test, 0% and 10%, respectively, exhibited high on-treatment reactivity while 17% patients who received standard treatment with clopidogrel without any genotypes testing exhibited high on-treatment reactivity. This difference was not statistically significant. So et al reported on the results of an RCT that randomized ST-elevation myocardial infarction patients who were carriers of CYP2C19*2, ABCB1 TT, and CYP2C19*17 alleles to prasugrel 10 mg daily or an augmented dosing strategy of clopidogrel (150 mg/d for 6 days and subsequently 75 mg/d) (So, 2016). Results showed that (1) carriers did not respond to augmented clopidogrel as well as they did to prasugrel (24% patients with high platelet reactivity vs 0%) and (2) among noncarriers, physician-directed clopidogrel was effective for most patients (95% did not have high platelet reactivity).
The studies were, in general, well-designed and -conducted, the major limitation being the use of platelet activity, which is an intermediate outcome measure, and lack of reporting on health endpoints over a longer follow-up.
Platelet reactivity during treatment is an intermediate end point that has been shown to have a limited value in guiding therapeutic decisions based on results of the large ARTIC RCT (Collet, 2012; Montalsecot, 2014). Briefly, the ARCTIC trial randomized 2440 patients scheduled for coronary stenting to platelet-function monitoring or no monitoring. Platelet-function testing was performed in the monitored group both before and 14 to 30 days after PCI. Multiple therapeutic changes, including an additional loading dose of clopidogrel (at a dose ≥600 mg) or a loading dose of prasugrel (at a dose of 60 mg) before the procedure, followed by a daily maintenance dose of clopidogrel 150 mg or prasugrel 10 mg, were made according to a predefined protocol. There was no difference in the rate of the primary composite end point (death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization) at 1 year between the monitoring (34.6%) and no monitoring groups (31.1%). In the absence of results from well-performed randomized trials designed to evaluate this issue, performing routine genetic testing or ex vivo tests of platelet reactivity to predict CYP2C19 metabolic state and identify PMs has not been shown to improve health clinical outcomes. TAILOR-PCI (NCT01742117) is a large ongoing RCT that will randomize 5270 patients undergoing PCI to clopidogrel without prospective genotyping guidance or a prospective CYP2C19 genotype-based antiplatelet therapy approach (ticagrelor 90 mg bid in CYP2C19*2 or CYP2C19*3 reduced function allele patients, clopidogrel 75 mg once daily in non-CYP2C19*2 or -CYP2C19*3 patients). The trial is expected to be completed in March 2020.
Section Summary: Clopidogrel
Two RCTs have evaluated the role of genetic testing for CYP2C19 for selecting appropriate antiplatelet treatment and/or amplified dosing of clopidogrel using an intermediate outcome measure of platelet reactivity to predict CYP2C19 metabolic state. One RCT has shown there was no statistical difference in patients with “on-treatment high platelet reactivity” who received genotype-guided management or standard treatment with clopidogrel. The second RCT showed that carriers of loss of function alleles did not respond to augmented clopidogrel as well as they did to prasugrel, while physician-directed clopidogrel was effective for most noncarriers. However, routine testing using platelet reactivity as an outcome measure to predict CYP2C19 metabolic state has not been shown to improve health outcomes. Results of an ongoing RCT (TAILOR-PCI), assessing outcomes in 5270 patients randomized to genotype-based antiplatelet therapy approach or standard care, are expected in 2020 and likely to address this gap.
Selection and Dosing of Other Drugs
Antiretroviral Agents
Efavirenz is a widely used non-nucleoside reverse transcriptase inhibitor component of highly active antiretroviral therapy for patients with HIV infection. However, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with its use. Forty percent to 70% of patients have reported adverse central nervous system events. While most resolve in the first few weeks of treatment, about 6% of patients discontinue efavirenz due to adverse events (King, 2008). Efavirenz is primarily metabolized by the CYP2B6 enzyme, and inactivating variants such as CYP2B6*6 are associated with higher efavirenz exposure, although plasma levels appear not to correlate with adverse events. On the other hand, CYP2B6 PMs have markedly reduced adverse events while maintaining viral immunosuppression at substantially lower doses (Torno, 2008; Gatanaga, 2007). An increased early discontinuation rate with efavirenz has been reported in retrospective cohort studies evaluating multiple CYP450 variants including CYP2B6 (Wyen, 2011; Lubomirov, 2011). CYP2B6 G516T and T983C single nucleotide variants were reported by Ciccacci et al to be associated with susceptibility to Stevens-Johnson syndrome in a case-control study of 27 patients who received nevirapine-containing antiretroviral treatment (Ciccacci, 2013). The current evidence documenting the usefulness of CYP450 variant genotyping to prospectively guide antiretroviral medications and assess its impact on clinical outcomes is lacking.
Immunosuppressants for Therapy for Organ Transplantation
Tacrolimus is the mainstay immunosuppressant drug and multiple studies have shown that individuals who express CYP3A5 (extensive and intermediate metabolizers) generally have decreased dose-adjusted trough concentrations of tacrolimus, possibly delaying achievement of target blood concentrations compared with those who are CYP3A5 nonexpressers (PMs) in whom drug levels may be elevated and possibly result in nephrotoxicity. The current evidence demonstrating the impact of CYP3A5 genotyping to guide tacrolimus dosing and its impact on clinical outcomes is a limited RCT by Thervet et al (Thervet, 2010). This RCT compared the impact of CYP3A5 genotype-informed dosing with standard dosing strategies on tacrolimus drug levels. The trial was not powered to assess any clinical outcomes such as graft function or survival, which otherwise were similar between groups.
b-Blockers
Several reports have indicated that lipophilic b-blockers (eg, metoprolol), used in treating hypertension, may exhibit impaired elimination in patients with CYP2D6 variants (Bijl, 2009; Yuan, 2008). The current evidence documenting the usefulness of CYP2D6 genotyping to prospectively guide antitubercular medications and assess its impact on clinical outcomes is lacking.
Antitubercular Medications
A number of studies, summarized in a systematic review by Wang et al, have reported an association between CYP2E1 status and the risk of liver toxicity from antitubercular medications (Wang, 2016). The current evidence documenting the usefulness of CYP2E1 genotyping to prospectively guide antitubercular medications and assess its impact on clinical outcomes is lacking.
Section Summary: Selection and Dosing of Other Drugs
In general, most published CYP450 pharmacogenomic studies for highly active antiretroviral agents, b-blockers, and antitubercular medications are retrospective evaluations of CYP450 genotype associations, reporting intermediate outcomes (eg, circulating drug concentrations) or less often, final outcomes (eg, adverse events or efficacy). Many of these studies are small, underpowered, and hypothesis generating. Prospective intervention studies, including RCTs documenting clinical usefulness of CYP450 genotyping to improve existing clinical decision-making to guide dose or drug selection, which will then translate into improvement in patient outcomes, were not identified.
Summary of Evidence
Clopidogrel
For individuals with a need for antiplatelet therapy who are undergoing or being considered for clopidogrel therapy who receive a CYP2C19-guided treatment strategy, the evidence incudes 2 RCTs. Relevant outcomes are overall survival, medication use, and treatment-related morbidity. The 2 RCTs evaluated the impact of CYP2C19 genotyping using an intermediate outcome measure (platelet reactivity). One RCT showed no statistical difference between patients with on-treatment high platelet reactivity between genotype-guided management or standard treatment with clopidogrel. The second RCT showed carriers of loss of function alleles did not respond to augmented clopidogrel as well as they did to prasugrel, and physician-directed clopidogrel was effective for most noncarriers. However, routine testing using platelet reactivity as an outcome measure to predict CYP2C19 metabolic state has not been shown to improve health outcomes. Results of an ongoing RCT (TAILOR-PCI), assessing outcomes in 5270 patients randomized to genotype-based antiplatelet therapy approach or standard care, are expected in 2020 and likely to address this gap. The evidence is insufficient to determine the effects of the technology on health outcomes.
Other Drugs
For individuals who are undergoing or being considered for treatment with highly active antiretroviral agents, immunosuppressant therapy for organ transplantation, b-blockers, or antitubercular medications who receive a CYP2C19-guided treatment strategy, the evidence includes retrospective studies. Relevant outcomes are medication use and treatment-related morbidity. In general, most published CYP450 pharmacogenomic studies for these drugs consist of retrospective evaluations of CYP450 genotype associations, reporting intermediate outcomes (eg, circulating drug concentrations) or less often, final outcomes (eg, adverse events or efficacy). Many of these studies are small, underpowered and hypothesis generating. Prospective intervention studies, including RCTs documenting the clinical usefulness of CYP450 genotyping to improve existing clinical decision making to guide dose or drug selection, which may then translate into improvement in patient outcomes, were not identified. The evidence is insufficient to determine the effects of the technology on health outcomes.
Supplemental Information
Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
In response to requests, input was received from 4 physician specialty societies and 4 academic medical centers while this policy was under review in 2012. Opinions on use of genotype testing of patients being considered for clopidogrel treatment were mixed, with 5 suggesting the test be considered investigational and 3 suggesting it be considered medically necessary.
Practice Guidelines and Position Statements
A consensus statement by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) on genetic testing for the selection and dosing of clopidogrel was published in 2010 (Holmes, 2010). The recommendations for practice included the following statements:
2019 Update
A literature search was conducted through June 2019. There was no new information identified that would prompt a change in the coverage statement.
2020 Update
A literature search was conducted through June 2020. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Claassens et al reported on the results of the CYP2C19 Genotype Guided Treatment With Antiplatelet Drugs in Patients With ST-segment-elevation Myocardial Infarction Undergoing Immediate PCI With Stent Implantation: Optimization of Treatment (POPular Genetics) trial (Claassens, 2019). In this non-inferiority trial, patients with acute coronary syndrome were randomly assigned to receive standard treatment (prasugrel or ticagrelor) or genotype-guided treatment (clopidogrel in those without CYP2C19 loss of-function variants; standard treatment otherwise). Results of the primary combined endpoint met the P value for non-inferiority. Thus, one can conclude that a genotype guided strategy led to outcomes that were at least as good as, if not better than, outcomes with the standard approach of prescribing prasugrel or ticagrelor to all patients. However, the trial results do not inform whether using genotype based strategy for prescribing clopidogrel results in any incremental net health benefit versus standard treatment with clopidogrel. Furthermore, there was no difference in the incidence of PLATO major bleeding between the genotype-guided group and the standard-treatment group (2.3% in both groups; hazard ratio, 0.97; 95% CI, 0.58 to 1.63). The statistical significant difference observed in the primary bleeding outcome was primarily driven by PLATO minor bleeding events in the genotype-guided group versus standard-treatment group (7.6% vs. 10.5%; HR=0.72; 95% CI, 0.55 to 0.94).
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Pereira et al reported the results of the open-label randomized TAILOR-PCI trial (NCT01742117) of 5,302 patients undergoing PCI for acute coronary syndromes or stable coronary artery disease (Pereira, 2020). The genotype-guided group underwent point-of-care genotyping for detection of CYP2C19 carriers and were prescribed ticagrelor (prasugrel was recommended as an alternative for patients who did not tolerate ticagrelor) and noncarriers were prescribed clopidogrel. Patients randomized to the conventional group were prescribed clopidogrel and underwent genotyping after 12 months. Among 5,302 patients randomized (median age, 62 years; 25% women), 94% completed the trial. Of 1,849 CYP2C19 carriers, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point (a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months) occurred in 35 of 903 CYP2C19 carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (HR=0.66; 95% CI 0.43 to 1.02; p = 0.06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR= 1.22; 95% CI: 0.60 to 2.51; p = 0.58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR= 0.84; 95% CI: 0.65 to 1.07; p = 0.16). The trial failed to meet the pre-specified endpoint and the authors contend that the trial was underpowered to detect an effect size less than the 50% relative risk after a revised sample calculation. Despite the occurrence of 89 ischemic events observed in this trial, which exceeded the 76 events anticipated to provide adequate power, the observed RR reduction was 34% instead of the estimated 50%, hence a borderline p value of 0.056 was observed. Further, the authors also comment that the potential benefit of genotype-guided oral P2Y12 inhibitor therapy may be important early after PCI rather than 12 months after PCI. A post-hoc analysis of the data from the trial showed that a nearly 80% reduction in the rate of adverse events occurred in the first three months of treatment among patients who received genetically guided therapy compared with those who did not.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Wang et al published results of the Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA (CHANCE-2) trial (Wang, 2021). This double-blind, multicenter RCT in China compared ticagrelor and clopidogrel for the secondary prevention of stroke in individuals with minor ischemic stroke or TIA who were CYP2C19 loss of function carriers. Overall, 6412 individuals (98% Chinese) with ischemic stroke or TIA were determined to be loss of function carriers and were included and randomized 1:1 to receive either ticagrelor or clopidogrel for 90 days duration. All patients received aspirin for the first 21 days. The median time from symptom onset to randomization was 14 hours and the average turnaround time of point-of-care testing was 80.3 minutes. Of those included, 5001 (78%) were intermediate metabolizers and 1411 (22%) were poor metabolizers. A primary-outcome event of new ischemic or hemorrhagic stroke within 90 days occurred in 191 (6.0%) patients in the ticagrelor group and 243 (7.6%) patients in the clopidogrel group (HR, 0.77; 95% CI, 0.64 to 0.94). Severe or moderate bleeding occurred in 9 (0.3%) patients on ticagrelor and 11 (0.3%) on clopidogrel. Any bleeding event occurred in 170 (5.3%) patients and 80 (2.5%) patients in the ticagrelor and clopidogrel groups, respectively. In subgroup analysis, the primary outcome benefit with ticagrelor was consistent in individuals who were intermediate metabolizers (150 vs. 191 events; HR, 0.78; 95% CI, 0.63 to 0.97), but not in poor metabolizers (41 vs. 52 events; HR, 0.77; 95% CI, 0.50 to 1.18). The risk of recurrent stroke within 90 days among Chinese loss of function carriers was modestly lower with ticagrelor than with clopidogrel, without an increased risk of severe or moderate bleeding. Ticagrelor was associated with more total bleeding events compared to clopidogrel. This study is limited by its homogenous study population, making generalizability to populations other than Han Chinese patients difficult. Additionally, no patients with delayed presentation after stroke, receipt of thrombolysis, or cardioembolic stroke were included.
The CPIC published updated guidelines for CYP2C19 genotyping and clopidogrel therapy in 2022 (Lee, 2022). These guidelines provide recommended indications for CYP2C19 genotype-guided antiplatelet therapy based on a systematic review. Below is a summary of the recommendations from these CPIC guidelines.
CPIC Antiplatelet Therapy Recommendations Based on CYP2C19 Phenotype When Considering Clopidogrel for Neurovascular Indications (Neurovascular disease includes acute ischemic stroke or TIA, secondary prevention of stroke, or prevention of thromboembolic events following neurointerventional procedures, such as carotid artery stenting and stent-assisted coiling of intracranial aneurysms.):
CYP2C19 ultrarapid metabolizer
CYP2C19 rapid metabolizer
CYP2C19 normal metabolizer
CYP2C19 likely intermediate metabolizer
CYP2C19 intermediate metabolizer
CYP2C19 likely poor metabolizer
CYP2C19 poor metabolizer
In 2019, the CPIC published guidelines for CYP2B6 considerations and efavirenz-containing antiretroviral therapy (Desta, 2019). Below is a summary of efavirenz dosing recommendations based on CYP2B6 phenotype:
CYP2B6 ultrarapid metabolizer
CYP2B6 rapid metabolizer
CYP2B6 normal metabolizer
CYP2B6 intermediate metabolizer
CYP2B6 poor metabolizer
In 2015, the CPIC published guidelines for CYP3A5 genotype and tacrolimus dosing (Birdwell, 2015). Below is a summary of tacrolimus dosing recommendations based on CYP3A5 phenotype.
CPIC Tacrolimus Dosing Recommendations Based on CYP3A5 Phenotype
Extensive metabolizer (CYP3A5 expresser)
Intermediate metabolizer (CYP3A5 expresser)
Poor metabolizer (CYP3A5 nonexpresser)
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