Medical Policy

Policy Num:     11.003.008
Policy Name:    Cytochrome P450 Genotype-Guided Treatment Strategy
Policy ID:          [11.003.008]  [Ac / B / M+ / P+]  [2.04.38]

Last Review:      July 17, 2024
Next Review:     July 20, 2025
 

Related Policies: 

11.003.039 - Pharmacogenomic and Metabolite Markers for Patients Treated With Thiopurines
11.003.095 - Genotype-Guided Tamoxifen Treatment
11.003.049 - Genetic Testing for Diagnosis and Management of Mental Health Conditions
11.003.067 - Genotype-Guided Warfarin Dosing

Cytochrome P450 Genotype-Guided Treatment Strategy

Summary

Description

The cytochrome P450 (CYP450) family is involved in the metabolism of many currently administered drugs, and genetic variants in CYP450 are associated with altered metabolism of many drugs. Testing for CYP450 variants may assist in selecting and dosing drugs affected by these genetic variants.

Summary of Evidence

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 includes 4 randomized controlled trials (RCTs). Relevant outcomes are overall survival, medication use, and treatment-related morbidity. Four 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. The third non-inferiority RCT showed that 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. Results of this trial do not inform whether using genotype based strategy for prescribing clopidogrel results in any incremental net health benefit versus standard treatment with clopidogrel. Furthermore, the statistical significant difference observed in favor of genotype guided strategy for bleeding outcome was primarily driven by minor bleeding events. There was no difference in the incidence of major bleeding between the 2 groups. Results of TAILOR-PCI reported no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia among patients with CYP2C19 loss-of-function alleles who underwent percutaneous coronary intervention (PCI), genotype-guided selection of an oral P2Y12 inhibitor compared with conventional clopidogrel therapy. In a trial comparing ticagrelor and clopidogrel use in individuals with stroke, results of the CHANCE-2 RCT reported a statistically significant decrease in risk of recurrent stroke in CYP2C19 loss-of-function carriers taking ticagrelor compared to clopidogrel in the first 90 days after presentation, without an increased risk of significant bleeding. Ticagrelor was associated with a higher number of total bleeding events compared to clopidogrel. These results are limited, however, by the homogenous Han Chinese population, lack of inclusion of those with delayed presentation, receipt of thrombolysis, or cardioembolic stroke, and majority of patients genotyped as intermediate metabolizers, limiting generalizability. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are undergoing or being considered for treatment with highly active antiretroviral agents, immunosuppressant therapy for organ transplantation, beta-blockers, or antitubercular medications who receive a CYP450-guided treatment strategy, the evidence includes retrospective studies and underpowered RCTs. 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 that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to evaluate whether testing for cytochrome P450 variants improves the net health outcome by influencing the selection and dosing of drugs metabolized by CYP450 enzymes.

Policy Statements

Cytochrome P450 (CYP450) genotyping for the purpose of aiding in the choice of clopidogrel versus alternative antiplatelet agents, or in decisions on the optimal dosing for clopidogrel, is considered investigational.

CYP2D6 genotyping to determine drug metabolizer status may be considered medically necessary for individuals :

• With Gaucher disease being considered for treatment with eliglustat; OR

• With Huntington disease being considered for treatment with tetrabenazine in a dosage greater than 50 mg per day

CYP2C9 genotyping to determine drug metabolizer status may be considered medically necessary for individuals:

• With relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, being considered for treatment with siponimod.

CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for the following drugs is considered investigational, aside from determinations in the separate related policies noted above:

• selection or dosage of codeine

• dosing of efavirenz and other antiretroviral therapies for HIV infection

• dosing of immunosuppressants for organ transplantation

• selection or dosing of β-blockers (eg, metoprolol)

• dosing and management of antitubercular medications.

The use of genetic testing panels that include multiple CYP450 variants is considered investigational.

Policy Guidelines

This policy does not address the use of genetic panel tests for genes other than CYP450-related genes (eg, the Genecept Assay), which are discussed in evidence review 11.003.049 (Genetic Testing for Mental Health Conditions).

The Food and Drug Administration maintains a database of pharmacogenomic biomarkers in drug labeling. See section "Regulatory Status" for details.

Coding

Please see the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Drug Efficacy and Toxicity

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 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 studies 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 variants (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 events, and decrease medical costs.

Cytochrome P450 System

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 (eg, 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 enzymes 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 enzymes constitute an important group of drug-gene interactions influencing the variability of the 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, who have one active and one inactive enzyme gene allele, may experience to a lesser degree some of the consequences of PMs. Ultrarapid metabolizers (UMs) are individuals with more than two alleles of an active enzyme gene. There is pronounced ethnic variability in the population distribution of metabolizer types for a given CYP enzyme.

UMs 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 events, andPMs may not respond.

Many drugs are metabolized to varying degrees by more than 1 enzyme, either within or outside of the CYP450 superfamily. Also, the interaction between different metabolizing genes, the interaction between genes and environment, and interactions among different nongenetic 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 interindividual differences in metabolism and consequent efficacy or toxicity.

Determining Genetic Variability in Drug Response

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 for drugs with a very narrow therapeutic range and/orpotentially serious adverse events outside that range. However, therapeutic drug monitoring 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 (eg, in urine). However, testing and interpretation are time-consuming and inconvenient; as a result, phenotyping is seldom performed.

The clinical utility of CYP450 genotyping (ie, the likelihood that genotyping will significantly improve drug choice, dosing, and patient outcomes) may be favored when the drug under consideration has a narrow therapeutic dose range, 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. The potential severity of the disease condition may call for immediate and sufficient therapy; genotyping might speed up 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.

Several testing kits for CYP450 genotyping cleared for marketing by the FDA (FDA product code: NTI) are summarized in Table 1.

Table 1. Testing Kits for CYP450 Genotyping Cleared for Marketing by FDA

Several manufacturers market diagnostic genotyping panel tests for CYP450 genes, such as the YouScript Panel (Genelex Corp.), which 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). These tests are beyond the scope of this evidence review.

Food and Drug Administration Labeling on CYP450 Genotyping

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.^1,

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 (eg, eliglustat, tetrabenazine) or when a drug may not be used at all (eg, codeine) and therefore evidence in such cases is not reviewed in the Rationale section.

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.^2,

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.^3,

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.^4,

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.^5,

Rationale

This evidence review was created in April 2005 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through April 22,2024.

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 technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and 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 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Cytochrome 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 following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest is 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.

Outcomes

Specific outcomes of interest are listed in Table 2.

Table 2. Outcomes of Interest for Individuals With Altered Drug Metabolism

Review of Evidence

Clopidogrel

Randomized Controlled Trials

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.^6, 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.^7, Wang et al (2016) reported post hoc analysis of the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events 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 versus aspirin alone was associated with statistical significant reduction in the risk of stroke (6.7% vs. 12.4%; hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.35 to 0.75) but not among those who carried loss of function alleles (9.4% vs. 10.8%; HR, 0.93; 95% CI, 0.69 to 1.26).^8, 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; they are summarized in Tables 3 and 4 and discussed next. 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.

Randomized Controlled Trials

Roberts et al (2012) reported on the results of an 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.^9, Among those who received prasugrel and clopidogrel based on genotyping test, 0% and 10%, respectively, exhibited high on-treatment platelet reactivity while 17% patients who received standard treatment with clopidogrel without any genotypes testing exhibited high on-treatment platelet reactivity. This difference was not statistically significant. So et al (2016) 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 per day for 6 days and subsequently 75 mg per day).^10, 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).

Claassens et al (2019) ^11, 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. 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; HR, 0.97; 95% CI, 0.58 to 1.63). The statistically 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).

Pereira et al (2021) reported the results of the open-label randomized TAILOR-PCI trial of 5302 patients undergoing PCI for acute coronary syndromes or stable coronary artery disease.^12, 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 5302 patients randomized (median age, 62 years; 25% women), 94% completed the trial. Of 1849 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=.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%) versus the conventional therapy group (1.6%) at 12 months (HR , 1.22; 95% CI , 0.60 to 2.51; p=.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=.16). The trial failed to meet the pre-specified end point 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 relative risk reduction was 34% instead of the estimated 50%, hence a borderline p value of.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.

Wang et al (2021) published results of the Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA (CHANCE-2) trial.^13, 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. One-year follow-up data were published by Meng et al (2024).^14, At 1 year, 7.91% of patients in the ticagrelor and 9.73% of patients in the clopidogrel group had a new stroke (HR, 0.80; 95% CI, 0.68 to 0.95; p=.007); however, new stroke occurring between 3 months and 1 year was not difference between groups (2.07% vs. 2.32%; p=.48).

Table 3. Summary of Key Randomized Controlled Trial Characteristics

ACS: acute coronary syndrome; CAD: coronary artery disease; CHANCE-2: Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II trial; CYP: cytochrome P450; LOF: loss-of-function; PCI: Percutaneous coronary intervention; POC; point of care; POPular Genetics: Cost-effectiveness of CYP2C19 Genotype Guided Treatment With Antiplatelet Drugs in Patients With ST-segment-elevation Myocardial Infarction Undergoing Immediate PCI With Stent Implantation: Optimization of Treatment; RAPID GENE: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy Based on GENetic Evaluation; RAPID STEMI: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy in Patients With ST-segment Elevation Myocardial Infarction; STEMI; ST-elevation myocardial infarction; TIA: transient ischemic attack.

Table 4. Summary of Key Randomized Controlled Trial Results

CI: confidence interval; CHANCE-2: Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II trial; HR: hazard ratio; NA; not applicable; NS: not significant; POPular Genetics: Cost-effectiveness of CYP2C19 Genotype Guided Treatment With Antiplatelet Drugs in Patients With ST-segment-elevation Myocardial Infarction Undergoing Immediate PCI With Stent Implantation: Optimization of Treatment; RAPID GENE: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy Based on GENetic Evaluation; RAPID STEMI: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy in Patients With ST-segment Elevation Myocardial Infarction.a P2Y12 reaction unit >234 (a measure of high on-treatment platelet reactivity).b Prasugrel vs. augmented clopidogrel.c Prasugrel vs. physician-directed clopidogrel.dAt 30 days.e At 1 week.f Death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding as defined by Platelet Inhibition and Patient Outcomes (PLATO) criteria at 12 months.g PLATO major bleeding (coronary artery bypass graft [CABG]-related and non–CABG-related) or minor bleeding at 12 months (primary bleeding outcome).h Cardiovascular death, myocardial infarction, stroke, severe recurrent ischemia, stent thrombosis.i Major or minor bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.

The purpose of the limitation tables (see Tables 5 and 6) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement. 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 endpoint that has been shown to have a limited value in guiding therapeutic decisions based on results of the large Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting (ARCTIC) RCT ^15,16,  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 endpoint (death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization) at 1 year between the monitoring (34.6%) and no monitoring groups (31.1%). Further, an adequately powered TAILOR-PCI RCT reported no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia among patients with CYP2C19 loss-of-function alleles who underwent PCI, genotype-guided selection of an oral P2Y12 inhibitor compared with conventional clopidogrel therapy. Limitations of this trial included the possibility of being underpowered when sample size calculations were revised, some patients not receiving designated antiplatelet therapy and the open-label nature of the trial. However, the adjudication of all events was blinded.

Table 5. Study Relevance Limitations

CHANCE-2: Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II trial; POPular Genetics: Cost-effectiveness of CYP2C19 Genotype Guided Treatment With Antiplatelet Drugs in Patients With ST-segment-elevation Myocardial Infarction Undergoing Immediate PCI With Stent Implantation: Optimization of Treatment; RAPID GENE: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy Based on GENetic Evaluation; RAPID STEMI: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy in Patients With ST-segment Elevation Myocardial Infarction.The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 6. Study Design and Conduct Limitations

CHANCE-2: Ticagrelor or Clopidogrel with Aspirin in High-Risk Patients with Acute Nondisabling Cerebrovascular Events II trial; POPular Genetics: Cost-effectiveness of CYP2C19 Genotype Guided Treatment With Antiplatelet Drugs in Patients With ST-segment-elevation Myocardial Infarction Undergoing Immediate PCI With Stent Implantation: Optimization of Treatment; RAPID GENE: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy Based on GENetic Evaluation; RAPID STEMI: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy in Patients With ST-segment Elevation Myocardial Infarction.The evidence limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Clopidogrel

Four 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. The third non-inferiority RCT compared showed that 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. Results of this trial do not inform whether using genotype based strategy for prescribing clopidogrel results in any incremental net health benefit versus standard treatment with clopidogrel. Furthermore, the statistical significant difference observed in favor of genotype guided strategy for bleeding outcome was primarily driven by minor bleeding events. There was no difference in the incidence of major bleeding between the 2 groups. Results of TAILOR-PCI reported no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia among patients with CYP2C19 loss-of-function alleles who underwent PCI, genotype-guided selection of an oral P2Y12 inhibitor compared with conventional clopidogrel therapy. In a trial comparing ticagrelor and clopidogrel use in individuals with stroke, results of the CHANCE-2 RCT reported a statistically significant decrease in risk of recurrent stroke in CYP2C19 LOF carriers taking ticagrelor compared to clopidogrel in the first 90 days after presentation, without an increased risk of significant bleeding. Ticagrelor was associated with a higher number of total bleeding events compared to clopidogrel. These results are limited, however, by the homogenous Han Chinese population, lack of inclusion of those with delayed presentation, receipt of thrombolysis, or cardioembolic stroke, and majority of patients genotyped as intermediate metabolizers, limiting generalizability.

For individuals with a need for antiplatelet therapy who are undergoing or being considered for clopidogrel therapy who receive a cytochrome P450 (CYP) 2C19 guided treatment strategy, the evidence includes 3 randomized controlled trials (RCTs). Relevant outcomes are overall survival, medication use, and treatment-related morbidity. Four 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. The third non-inferiority RCT showed that 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. Results of this trial do not inform whether using genotype based strategy for prescribing clopidogrel results in any incremental net health benefit versus standard treatment with clopidogrel. Furthermore, the statistical significant difference observed in favor of genotype guided strategy for bleeding outcome was primarily driven by minor bleeding events. There was no difference in the incidence of major bleeding between the 2 groups. Results of TAILOR-PCI reported no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia among patients with CYP2C19 loss-of-function alleles who underwent percutaneous coronary intervention (PCI), genotype-guided selection of an oral P2Y12 inhibitor compared with conventional clopidogrel therapy. In a trial comparing ticagrelor and clopidogrel use in individuals with stroke, results of the CHANCE-2 RCT reported a statistically significant decrease in risk of recurrent stroke in CYP2C19 loss-of-function carriers taking ticagrelor compared to clopidogrel in the first 90 days after presentation, without an increased risk of significant bleeding. Ticagrelor was associated with a higher number of total bleeding events compared to clopidogrel. These results are limited, however, by the homogenous Han Chinese population, lack of inclusion of those with delayed presentation, receipt of thrombolysis, or cardioembolic stroke, and majority of patients genotyped as intermediate metabolizers, limiting generalizability. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Selection and Dosing of Other Drugs

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.^17, 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 poor metabolizers have markedly reduced adverse events while maintaining viral immunosuppression at substantially lower doses, based on a case report of 1 patient (Torno et al [2008]) and a case series of 12 patients (Gatanaga et al [2007]).^18,19, An increased early discontinuation rate with efavirenz has been reported in retrospective cohort studies evaluating multiple CYP450 variants including CYP2B6.^20,21,CYP2B6 G516T and T983C single nucleotide variants were reported by Ciccacci et al (2013) to be associated with susceptibility to Stevens-Johnson syndrome in a case-control study of 27 patients who received nevirapine-containing antiretroviral treatment.^22, However, no RCTs or large observational studies have been identified indicating that genetic testing prior to treatment initiation results in an avoidance of treatment failure, reduction of adverse events, or guides dose selection. 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 (poor metabolizers) 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 includes RCTs by Thervet et al (2010)^23, and Min et al (2018).^24, Both RCTs compared the impact of CYP3A5 genotype-informed dosing with standard dosing strategies on tacrolimus drug levels. The trials were not powered to assess any clinical outcomes such as graft function or survival, which otherwise were similar between groups in Thervet et al (2010).^23,

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.^25,26, 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 (2016), have reported an association between CYP2E1 status and the risk of liver toxicity from antitubercular medications.^27, The current evidence documenting the usefulness of CYP2E1 genotyping to prospectively guide antitubercular medications and assess its impact on clinical outcomes is lacking.

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.

Population Reference No. 3

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 (poor metabolizers) 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 includes RCTs by Thervet et al (2010)^22, and Min et al (2018).^23, Both RCTs compared the impact of CYP3A5 genotype-informed dosing with standard dosing strategies on tacrolimus drug levels. The trials were not powered to assess any clinical outcomes such as graft function or survival, which otherwise were similar between groups in Thervet et al (2010).^22,

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.

Population Reference No. 4

b-Blockers

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.^24,25, The current evidence documenting the usefulness of CYP2D6 genotyping to prospectively guide antitubercular medications and assess its impact on clinical outcomes is lacking.

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.

Population Reference No. 5

Antitubercular Medications

A number of studies, summarized in a systematic review by Wang et al (2016), have reported an association between CYP2E1 status and the risk of liver toxicity from antitubercular medications.^26, 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.

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.

Population Reference No. 6

Gaucher disease is a rare autosomal recessive lipid storage disorder in which deficiency or absence of the enzyme β-glucocerebrosidase leads to lysosomal accumulation of the glycosphingolipid glucosylceramide. Untreated, this accumulation can lead to a range of effects, including anemia and thrombocytopenia, splenomegaly, bone disease, pulmonary fibrosis, and central nervous system involvement. Gaucher disease has been treated using enzyme replacement. Treatments for Gaucher disease include the use of enzyme replacement therapy (imiglucerase, velaglucerase alfa, taliglucerase alfa) or substrate reduction therapy (miglustat, eliglustat tartrate). Eliglustat tartrate is an orally administered selective inhibitor of glucosylceramide synthase that received FDA approval in 2014 and, in 3 phase 3 clinical trials, led to improvements in hematologic metrics and organomegaly. Eliglustat tartrate is primarily metabolized by the CYP2D6 enzyme. FDA labeling requires that patients be tested for CYP2D6 metabolizer status as determined by genotype and that ultrarapid metabolizers (UMs) not be given eliglustat because these patients may not achieve adequate concentrations to achieve a therapeutic effect.30 FDA reviews have reported that, at doses as high of 200 mg twice daily, the exposure in UMs was about 57% and about 82% lower than the exposures for extensive metabolizers (EMs) and intermediate metabolizers (IMs) at 100 mg twice daily, respectively.31 The approved dose is 84 mg twice daily for EMs and IMs and 84 mg once daily for PMs.

For individuals with Gaucher disease type 1 who are undergoing or being considered for treatment with eliglustat who receive testing for CYP2D6 metabolizer status by CYP2D6 genotyping, the evidence includes subgroup analysis of clinical trial data submitted to FDA by the manufacturer as part of regulatory submission. Relevant outcomes are test accuracy and validity, morbid events, medication use, and treatment-related morbidity. Eliglustat tartrate is primarily metabolized by the CYP2D6 enzyme. FDA review reported that, at doses as high of 200 mg twice daily, the exposure in ultrarapid metabolizers (UMs) was about 57% and about 82% lower than the exposures for extensive metabolizers and intermediate metabolizers at 100 mg twice daily, respectively. Based on this high variation in drug exposure based on metabolizer status, the FDA label requirement for genotyping of CYP2D6 to determine metabolizer status before the use of eliglustat may be clinically reasonable and UMs be excluded from being prescribed eliglustat because these patients may not achieve adequate concentrations for therapeutic effect. Although there is no published evidence about outcome changes associated with genotype-directed therapy for this medication, there are changes in management that are likely to occur with differences in genotypes that may be associated with improved health outcomes. The evidence is sufficient to determine the effects of the technology on health outcomes.

Population Reference No. 7

Huntington disease is an autosomal dominant genetic neurodegenerative disorder characterized by progressive cognitive and motor dysfunction, including chorea. In 2008, FDA approved tetrabenazine, a centrally acting vesicular monoamine transporter inhibitor, as an orphan drug for the treatment of chorea in Huntington disease, based on evidence from a 2006 RCT of improved chorea symptoms in ambulatory patients with Huntington disease.32 Tetrabenazine is primarily metabolized by the CYP2D6 enzyme. FDA labeling (2015) for tetrabenazine includes recommendations for CYP2D6 genotyping in patients who require doses above 50 mg per day. The labeling states: “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 an EM. Maximum daily dose in PMs: 50 mg with a maximum single dose of 25 mg. Maximum daily dose in EMs and IMs: 100 mg with a maximum single dose of 37.5 mg.”

For individuals with Huntington disease who are undergoing or being considered for treatment with tetrabenazine who receive testing for CYP2C19 metabolizer status by CYP2C19 genotyping, the evidence consists of a single cohort study. Relevant outcomes are test accuracy and validity, morbid events, medication use, and treatment-related morbidity. The FDA labeling for the orphan drug tetrabenazine for Huntington disease recommends CYP2D6 genotyping before use. There is limited published evidence about outcome changes associated with genotype-directed therapy for this medication. One cohort study has reported that patients categorized as UMs by a CYP450 genotype test require a high dose of tetrabenazine compared to those who are not. However, this finding was based in a sample of 127 patients of whom only 2 were categorized as UMs. Therefore, these findings must be reproduced in a larger cohort. The evidence is insufficient to determine the effects of the technology on health outcomes. Although the evidence is limited on the use of CYP2C19 genotyping in patients undergoing or being considered for treatment with tetrabenazine, given the FDA labeling and the potential for high variation in drug exposure based on metabolizer status, genotyping of CYP2D6 to determine metabolizer status before use of tetrabenazine may be clinically reasonable. CYP2C19 may be considered medically necessary in patients with Huntington disease being considered for treatment with tetrabenazine at a dosage greater than 50 mg per day.

Population Reference No. 8

Multiple Sclerosis: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.^5,

For individuals with relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, being considered for treatment with siponimod.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

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.

2012 Input

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

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

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.

American College of Cardiology Foundation

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. .²⁸  The recommendations for practice included the following statements:

1. "Adherence to existing ACCF/AHA guidelines for the use of antiplatelet therapy should remain the foundation for therapy. Careful clinical judgment is required to assess the importance of the variability in response to clopidogrel for an individual patient and its associated risk to the patient…

2. Clinicians must be aware that genetic variability in CYP [cytochrome P450] enzymes alter clopidogrel metabolism, which in turn can affect its inhibition of platelet function. Diminished responsiveness to clopidogrel has been associated with adverse patient outcomes in registry experiences and clinical trials.

3. The specific impact of the individual genetic polymorphisms on clinical outcome remains to be determined....

4. Information regarding the predictive value of pharmacogenomic testing is very limited at this time; resolution of this issue is the focus of multiple ongoing studies. The selection of the specific test, as well as the issue of reimbursement, is both important additional considerations.

5. The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time….

6. There are several possible therapeutic options for patients who experience an adverse event while taking clopidogrel in the absence of any concern about medication compliance."

U.S. Preventive Services Task Force Recommendations

No U.S. Preventive Services Task Force recommendations for cytochrome P450 testing have been identified.

Ongoing and Unpublished Clinical Trials

Some currently ongoing or unpublished trials that might influence this review are listed in Table 7.

Table 7. Summary of Key Trials

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

 medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing or unpublished trials that might influence this review are listed in Table 7.

Table 7. Summary of Key Trials

NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.

References

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3. Prescribing Label: Xenazine (tetrabenazine). 2019; Available at https://www.lundbeck.com/content/dam/lundbeck-com/americas/united-states/products/neurology/xenazine_pi_us_en.pdf. Accessed April 22, 2024.
4. FDA statement from Douglas Throckmorton, M.D., deputy center director for regulatory programs, Center for Drug Evaluation and Research, on new warnings about the use of codeine and tramadol in children & nursing mothers. Published April 20, 2017. Updated February 28, 2019; https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm553285.htm. Accessed April 22, 2024.
5. Prescribing Label: Mayzent (siponimod) tablets, for oral use. 2023; Available at https://www.novartis.us/sites/www.novartis.us/files/mayzent.pdf Accessed April 22, 2024.
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7. Holmes MV, Perel P, Shah T, et al. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. Dec 28 2011; 306(24): 2704-14. PMID 22203539
8. Wang Y, Zhao X, Lin J, et al. Association Between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction Among Patients With Minor Stroke or Transient Ischemic Attack. JAMA. Jul 05 2016; 316(1): 70-8. PMID 27348249
9. Roberts JD, Wells GA, Le May MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet. May 05 2012; 379(9827): 1705-11. PMID 22464343
10. So DY, Wells GA, McPherson R, et al. A prospective randomized evaluation of a pharmacogenomic approach to antiplatelet therapy among patients with ST-elevation myocardial infarction: the RAPID STEMI study. Pharmacogenomics J. Feb 2016; 16(1): 71-8. PMID 25850030
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