Clinical Policy Title: Genetic cardiac testing

Transcription

1 Clinical Policy Title: Genetic cardiac testing Clinical Policy Number: Effective Date: November 1, 2017 Initial Review Date: September 21, 2017 Most Recent Review Date: November 16, 2017 Next Review Date: November 2018 Policy contains: Cytochrome p450 Long QT syndrome Cardiomyopathy Related policies: CP# CP# CP# CP# CP# Genetic testing for cytochrome p450 Polymorphisms (CYP2C19) Genetic testing for long QT syndrome (LQTS) Pharmacogenetic testing for warfarin (Coumadin ) sensitivity Pharmacogenetic testing for cardiac meds Genetic testing for hereditary cardiomyopathy ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by AmeriHealth Caritas when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas clinical policies are not guarantees of payment. Coverage policy AmeriHealth Caritas considers the use of once-per-lifetime genetic testing for hereditary cardiomyopathy susceptibility to be clinically proven and, therefore, medically necessary for (Kayvanpour 2017, Elliott 2014, Gersh 2011, Hershberger 2009): Molecular confirmation of a clinical diagnosis in symptomatic patients. Molecular confirmation of anatomical abnormalities on imaging studies suggestive of hereditary cardiomyopathy. Risk assessment of asymptomatic family members of a proband with cardiomyopathy and/or arrhythmia. Differentiation of hereditary cardiomyopathy and/or arrhythmia from acquired (non-genetic) 1

2 cardiomyopathy and/or arrhythmia. Recurrence risk calculation. AmeriHealth Caritas considers once-per-lifetime genotyping for cytochrome P450 polymorphisms to be clinically proven and, therefore, medically necessary for people with acute coronary syndrome, undergoing percutaneous coronary intervention, in whom clopidogrel (Plavix ) is a treatment option (Sorich 2014, Jian 2013, Scott 2013, Mega 2009, O Connell 2009). AmeriHealth Caritas considers the use of once-per-lifetime genetic testing for long QT syndrome (LQTS), also known as Familion testing, to be clinically proven and therefore medically necessary when the following criteria are met (Beitland 2014, Modell 2012): The individual has a close relative (first-, second- or third-degree) with a known LQTS mutation. The individual has a close relative (first-, second- or third-degree) diagnosed with LQTS by clinical means and whose genetic status is unavailable. The individual has palpitations, syncope and/or dizziness with a history of a close relative (first-, second-, or third-degree) who experienced a sudden cardiac death. The individual has a prolonged QT interval (QTc) of greater than 440 msec without an identifiable acquired or external cause for the QTc prolongation (i.e., bradycardia, electrolyte imbalance or certain medications/drugs) (QTc values of 0.44 sec are treated as suspicious) The individual has signs and/or symptoms indicating a moderate-to-high pretest probability of LQTS. Limitations: AmeriHealth Caritas considers the routine and screening use of pharmacogenetic testing for cardiac medications and warfarin (Coumadin ) sensitivity to be investigational and, therefore, not medically necessary (Kimmel 2013, Pirmohamed 2013, Flockhart 2008, Iakoubova 2008, Link 2008). Alternative covered services: Laboratory testing for cardiac medications (e.g., digitalis level), prothrombin time and International Normalized Ratio values. Background The term hypertrophic cardiomyopathy is reserved for cardiomyopathy that is unaccounted for by known disease or disorder and is related to a genetic mutation that affects the sarcomere (the fundamental contractile unit of cardiac muscle). It is a fairly common condition in clinical practice, occurring in an estimated one in 500 individuals (Gersh 2011). 2

3 Dilated cardiomyopathy may arise as a primary genetic disorder or as a secondary manifestation of other cardiovascular or systemic conditions (Burke 2016). It, too, is relatively common in clinical practice, occurring in one in 250 individuals (Hershberger 2013). Altered myocardial calcium homeostasis is a common feature in genetic and acquired forms of dilated cardiomyopathy and can impact cardiac physiology by causing irregularities in contractile force, signaling pathways, and gene transcription. Arrhythmic right ventricular dysplasia is rare clinically, and characterized pathologically as a progressive fibro-fatty replacement of the right ventricular musculature. The first gene associated with this condition, coding for a desmosome protein, was discovered in Hereditary conditions known to cause this restrictive cardiomyopathy include hemochromatosis, glycogen storage diseases, Fabry disease, Gaucher disease, and Hurler syndrome. For those in whom the genetic mutation is present and expressed in phenotype the clinical consequences can be severe. Hypertrophic cardiomyopathy is the most common cause of sudden cardiac death among young athletes, and is also associated with malignant cardiac arrhythmias, stroke and need for heart transplantation; while dilated cardiomyopathy is a progressive disorder that most commonly leads to congestive heart failure and premature death. Arrhythmic right ventricular dysplasia predisposes towards malignant arrhythmias originating from the right ventricle and is a known cause of sudden death in young athletes. As a result, early detection of carriers of these genetic variations is desirable in order that prevention, diagnosis, treatment, follow-up and counseling (including pre-natal counseling) of those affected can be accomplished. In the late 2000 s observation suggested that clopidogrel (Plavix), given in the context of acute coronary syndrome and percutaneous coronary stenting, could be associated with perverse clotting of the stent (incidence 1 2 percent) and subsequent myocardial ischemia in treated patient populations (Mega 2009, O'Connell 2009). Research suggests that a genetic abnormality of the cytochrome P450 enzyme (i.e., CYP2C19), which is quite prevalent in Asian populations (incidence 50 percent), inhibits metabolism of clopidogrel from its precursor form to an active anti-coagulant metabolite. Tests are available to determine a patient's cytochrome P450 genotype and identify individuals at-risk for inadequate anticoagulation. Literature suggests that LQTS may be responsible for as many as 3,000 unexpected deaths in children and young adults in the United States each year (Modell, 2012). Younger individuals have a higher risk of unexpected sudden death than adults with a genetic cardiac disease. A family history of sudden death, possibly with genetic confirmation, may influence treatment decisions for those with suspected and ultimately confirmed LQTS. Because this disease is a primarily an electrical disorder, most individuals have no evidence of structural heart disease or left ventricular dysfunction, making the long-term prognosis excellent if the arrhythmia is controlled. Literature also suggests that LQTS can be an acquired condition from cardiovascular medications 3

4 administered to predisposed patients, often in the Intensive Care Unit. Treatment of acquired LQTS, which is essentially fatal, is essentially awareness, identification, and discontinuation of QT prolonging drugs (Beitland, 2014). Warfarin elimination from the body relies almost exclusively upon the metabolic conversion of inactive metabolites by cytochrome P450 enzymes in liver cells. The principal cytochrome P450 enzyme that modulates the anticoagulant activity of warfarin is CYP2C9 (Flockhart, 2008). The VKORC1 gene encodes the vitamin K epoxide reductase enzyme, the drug target of warfarin. Different races present different variances with allele types, and different allele types have varying warfarin sensitivity. Though pharmacogenetic testing is used to gain a better approximation of the optimal initial dosing of warfarin, it does not remove the need for coagulation testing as the standard diagnostic test for assessing an individual s reaction to warfarin dosing. Searches AmeriHealth Caritas searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on September 26, Search terms were: genetic cardiac testing. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings A systematic review inclusive of 8097 patients (Kayvanpour 2017) explored the relationship between genotypes and clinical phenotypes in dilated cardiomyopathy. The average frequency of mutations was between 1 and 5 percent. The mean age of dilated cardiomyopathy onset was the beginning of the fifth decade for all genes. Heart transplantation rate was highest in Lamin A mutation carriers (27 percent), while RBM20 mutation carriers were transplanted at a markedly younger age (mean 28.5 years). While 4

5 73 percent of dilated cardiomyopathy patients with Lamin A mutations showed cardiac conduction diseases, low voltage was the reported electrocardiographic hallmark in phospholamban mutation carriers. The frequency of ventricular arrhythmia in dilated cardiomyopathy patients with Lamin A (50 percent) and phospholamban (43 percent) mutations was significantly higher. The penetrance of dilated cardiomyopathy phenotype in subjects with titan truncating variants increased with age and reached 100 percent by age 70 years. Elliot (2014) wrote on behalf of the European Society of Cardiology a set of guidelines for diagnosis and management of hypertrophic cardiomyopathy: Genetic counseling is recommended in all patients when hypertrophic cardiomyopathy cannot be explained solely by a non-genetic cause. Genetic testing is recommended in patients fulfilling diagnostic criteria for hypertrophic cardiomyopathy to enable cascade genetic screening of their relatives. When a definite causative genetic mutation is identified in a patient, his or her relatives should be genetically tested, and then clinically evaluated if they are found to carry the same mutation. The phenomenon of age-related penetrance means that a normal clinical evaluation does not exclude the possibility of disease development in the future; first-degree relatives should therefore be offered repeat assessment. Clinical and genetic testing of children should be guided by the best interests of each child. Clinical data suggests that clinically important events in asymptomatic children are rare before puberty; thus, it is reasonable in these children to defer clinical and/or genetic screening until the age of 10 years. Gersh (2011) wrote on behalf of the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Task Force on Practice Guidelines that evaluation of familial inheritance and genetic counseling is recommended as part of the assessment of patients with hypertrophic cardiomyopathy, and that patients who undergo genetic testing should also undergo counseling by someone knowledgeable in the genetics of cardiovascular disease so that results and their clinical significance can be appropriately reviewed with the patient. The ACCF/AHA group also stated that screening (clinical, with or without genetic testing) is recommended in first-degree relatives of patients with hypertrophic cardiomyopathy, and genetic testing for hypertrophic cardiomyopathy and other genetic causes of unexplained cardiac hypertrophy is recommended in patients with an atypical clinical presentation of hypertrophic cardiomyopathy or when another genetic condition is suspected to be the cause. Testing is reasonable in the index patient to facilitate the identification of first-degree family members at risk for developing hypertrophic cardiomyopathy. The usefulness of genetic testing in the assessment of risk of unexpected sudden death in hypertrophic cardiomyopathy is uncertain and is not indicated in relatives when the index patient does not have a definitive pathogenic mutation. In individuals with pathogenic mutations who do not express the hypertrophic cardiomyopathy phenotype, it is recommended to perform serial electrocardiogram, transthoracic echocardiogram, and clinical assessment at periodic intervals (12 to 18 months in children and adolescents and about every 5 5

6 years in adults), based on the patient's age and change in clinical status. Sorich (2014) in a systematic review of 36,076 patients assessed genotype at risk and found that greater than 50 percent of Asians carry the CYP2C19 loss-of-function allele. Significant differences in therapeutic response to the intervention (i.e., stent plus clopidogrel) were demonstrated between control (non- percutaneous coronary stenting patients) versus whites with percutaneous coronary stenting on clopidogrel and Asians with percutaneous coronary stenting on clopidogrel. Jian (2013) in a systematic review of 23,035 patients showed an increased risk of adverse events in CYP2C19 variant-allele carriers (e.g., myocardial infarction, stent thrombosis, ischemic stroke and repeat revascularization) The Clinical Pharmacogenetics Implementation Consortium guidelines (Scott 2013) for CYP2C19 recommend that if a patient s genotype is unknown, the decision to perform CYP2C19 testing is up to the individual clinician. The use of the Familion genetic test may potentially have clinical utility in patients with LQTS. A negative result is also instructive, as with the high analytical sensitivity and low probability of a sporadic mutation, a negative result would indicate a low probability of the patient having LQTS. Thus, use of the Familion genetic test in first-degree relatives of those with a known LQTS mutation may allow better use of prophylactic treatment for payers and avoidance of unnecessary restrictive activity for patients. The condition is a significant factor in certain fetal disorders. It accounted for percent of fetal bradycardias of <110 beats per minute among fetuses with a normally structured heart; of patients with a significant prenatal finding of LQTS, percent exhibited reduced baseline fetal heart rate of beats per minute on electronic cardiotocography (Ishikawa, 2013). Testing in the early detection of LQTS was cost-effective compared with no testing in symptomatic cases, and not cost-effective when compared with watchful waiting in asymptomatic first-degree relatives of patients with established LQTS; in neonates, testing was highly cost-effective when compared with any screening strategy (Gonzalez, 2015). Pirmohamed (2013) studied pharmacogenetic-based dosing of warfarin and found that foreknowledge of genotype prompted therapeutic levels of anticoagulant faster than a standard blind dosing regimen of warfarin. The median time to reach a therapeutic INR was less in the genotype-guided group as compared with the control group by eight days (21 days versus 29 days, respectively; P < 0.001). On the other hand, a large randomized controlled trial of over 1,000 patients came to the opposite conclusion: genotype control did not improve anticoagulation control over the initial four weeks of therapy (Kimmel 2013). A meta-analysis of nine clopidogrel studies with a combined total of 10,000 participants found that carriers of CYP2C19 alleles suffered a 57 percent increase in risk of cardiovascular death, myocardial 6

7 infarction or ischemic stroke compared with noncarriers (Mega 2009). The new U.S. Food and Drug Administration (FDA) label for clopidogrel indicates that heterozygosity is associated with diminished response to clopidogrel (i.e., poorer anticoagulation) and that pharmacogenetic testing can identify these genotypes. Pharmacogenetic tests may predict response to statin therapy, specifically in the presence of the KIF6 (rs20455) gene. Carriers of the KIF6 genome experience greater protection against coronary heart disease with pravastatin therapy than noncarriers (Iakoubova 2008). Conversely, a single variant in SLCO1B1 (a hepatic gene) brings with it a 17-fold increased risk of myopathy with high doses of simvastatin (Link 2008). A recent relabeling of simvastatin warns of this risk. While existing algorithms for predicting warfarin dosing can account for approximately half of the interindividual variability in percentage of time in therapeutic range the evidence is insufficient to support incorporating genotype to improve control or other patient outcomes. Summary of clinical evidence: Citation Kayvanpour (2017) Genotype-phenotype associations in dilated cardiomyopathy: metaanalysis on more than 8000 individuals. Elliott (2014) Content, Methods, Recommendations A systematic review inclusive of 8097 patients explored the relationship between genotypes and clinical phenotypes in dilated cardiomyopathy. The average frequency of mutations was between 1 and 5 percent. The mean age of dilated cardiomyopathy onset was the beginning of the fifth decade for all genes. Transplant rate was highest in Lamin A mutation carriers (27 percent), while RBM20 mutation carriers were transplanted at a markedly younger age (mean 28.5 years). While 73 percent of dilated cardiomyopathy patients with Lamin A mutations showed cardiac conduction diseases, low voltage was the reported hallmark in phospholamban mutation carriers. The frequency of ventricular arrhythmia in dilated cardiomyopathy patients with Lamin A (50 percent) and phospholamban (43 percent) mutations was significantly higher. The penetrance of dilated cardiomyopathy phenotype in subjects increased with age and reached 100 percent by age 70 years. Guidelines on diagnosis and management of hypertrophic cardiomyopathy European Society of Cardiology guidelines for hereditary cardiomyopathy: o Genetic counseling is recommended in all patients when hereditary cardiomyopathy cannot be explained solely by a non-genetic cause. o Genetic testing is recommended in patients fulfilling diagnostic criteria for hereditary cardiomyopathy to enable cascade genetic screening of their relatives. o When a definite causative genetic mutation is identified in a patient, his or her relatives should be genetically tested, and then clinically evaluated if they are found to carry the same mutation. o The phenomenon of age-related penetrance means that a normal clinical 7

8 Citation Gersh (2011) ACCF/AHA Guideline for the diagnosis and treatment of hypertrophic cardiomyopathy Sorich (2014) CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a metaanalysis Jian (2013) Cytochrome CYP2C19 polymorphism and risk of adverse clinical events in clopidogrel-treated patients: a meta-analysis based on 23,035 subjects Scott (2013) Content, Methods, Recommendations evaluation does not exclude the possibility of disease development in the future; first-degree relatives should therefore be offered repeat assessment. o Clinical and genetic testing of children should be guided by the best interests of each child. Clinical data suggests that clinically important events in asymptomatic children are rare before puberty; thus, it is reasonable in these children to defer clinical and/or genetic screening until the age of 10 years. Evaluation of familial inheritance and genetic counseling is recommended as part of the assessment of patients with hereditary cardiomyopathy. Patients who undergo genetic testing should also undergo counseling by someone knowledgeable in the genetics of cardiovascular disease. Screening (clinical, with or without genetic testing) is recommended in first-degree relatives of patients with hereditary cardiomyopathy. Genetic testing for hereditary cardiomyopathy and other genetic causes of unexplained cardiac hypertrophy is recommended in patients with an atypical clinical presentation of hereditary cardiomyopathy or when another genetic condition is suspected to be the cause. Testing is reasonable in the index patient to facilitate the identification of first-degree family members at risk for developing hereditary cardiomyopathy. The usefulness of genetic testing in the assessment of risk in hereditary cardiomyopathy is uncertain and is not indicated in relatives when the index patient does not have a definitive pathogenic mutation. In individuals with pathogenic mutations who do not express the hereditary cardiomyopathy phenotype, it is recommended to perform serial clinical assessment at 12 to 18 months in children and adolescents and every 5 years in adults. Systematic review of 36,076 patients assessed genotype at risk Greater than 50% of Asians carry the loss of function allele. Significant differences in therapeutic response to clopidogrel exist Includes substudy of 200 patients with stent-specific indication. Systematic review of 23,035 patients shows increased risk of adverse events CYP2C19 variant allele carriers had an increased risk of adverse clinical events: myocardial infarction, stent thrombosis, ischemic stroke and repeat revascularization. Clinical Pharmacogenetics Guidelines for clopidogrel in presence of CYP2C19 loss of function. 8

9 Citation Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update Kimmel (2013) A pharmacogenetic versus a clinical algorithm for warfarin dosing Pirmohamed (2013) European commission seventh framework program and others Hershberger (2009) Genetic evaluation of cardiomyopathy--a Heart Failure Society of America practice guideline. Mega (2009) Reduced-Function CYP2C19 Genotype and Risk of Adverse Clinical Outcomes Among Patients Treated With Clopidogrel O Connell (2009) Content, Methods, Recommendations If a patient s genotype is unknown, the decision to perform CYP2C19 testing is up to the individual clinician. 1,015 patients were randomized to receive doses of warfarin during the first five days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. At four weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P = 0.91). Genotype-guided dosing of warfarin did not improve anticoagulation control during the first four weeks of therapy. Multicenter trial (n = 455) genotype-guided dosing versus standard dosing in patients with atrial fibrillation or venous thromboembolism primary Results: genotype versus control (67.4% versus 60.3%; adjusted difference, 7.0% points; 95% confidence interval [CI] 3.3 to 10.6; P < 0.001). Significantly fewer incidences of excessive anticoagulation (INR >/= 4.0) in the genotype-guided group. Median time to reach a therapeutic range: genotype versus control (21 days versus 29 days; P < 0.001). The Heart Failure Society of America's guideline on genetic evaluation of cardiomyopathy. Genetic testing is indicated for risk assessment in at-risk relatives who have little or no clinical evidence of cardiovascular disease. Genetic testing for hereditary cardiomyopathy should be considered for the one most clearly affected person in a family to facilitate family screening and management. Systematic review of 9,685 patients links loss of function allele to stent thrombosis Among patients treated with clopidogrel, carriage of even one reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis. Carriers of at least one CYP2C19 reduced-function allele had a relative reduction of 32.4% in plasma levels of the active metabolite of clopidogrel. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy Loss of function allele tied to ischemia and mortality post intervention Trial (n=429) found among patients following coronary intervention with CYP2C19 variant allele, twice as many suffered an ischemic event or death at one year. 9

10 Citation Iakoubova (2008) Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease Link (2008) Content, Methods, Recommendations Trial evaluated the association between genotype and recurrent myocardial infarction and between genotype and primary coronary heart disease. Also evaluated if Trp719Arg (rs20455) in KIF6 was associated with coronary events. In placebo-treated patients, carriers of the KIF6 719Arg allele (59.4% of the trial cohort) had a hazard ratio of 1.50 (95% CI 1.05 to 2.15) in the trial and an odds ratio of 1.55 (95% CI 1.14 to 2.09). Among carriers, the absolute risk reduction by pravastatin was 4.89% (95% CI 1.81% to 7.97%) in the trial and 5.49% (95% CI 3.52% to 7.46%). Carriers of the KIF6 719Arg allele had an increased risk of coronary events, and pravastatin treatment substantially reduced that risk. SLCO1B1 variants and statininduced myopathy Compared 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily. The genome-wide scan yielded a single strong association of myopathy with the rs single-nucleotide polymorphism located within SLCO1B1 on chromosome 12 (P = 4x10-9 ). The association of rs with myopathy was replicated in a trial of 40 mg of simvastatin daily. Common variants in SLCO1B1 are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively. References Professional society guidelines/other: Elliott P, Anastasakis A, Borger F, et al European Society of Cardiology Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 2014;35(39): Flockhart DA, O'Kane D, Williams MS, et al. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med. 2008; 10(2): Gersh BJ, Maron BJ, Bonow RO, et al ACCF/AHA Guideline for the Diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines developed in collaboration with the American Association for Thoracic Surgery, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;58(25):

11 Scott SA, Sangkuhl K, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013; 94(3): Peer-reviewed references: Beitland S, Platou ES, Sunde K. Drug-induced long QT syndrome and fatal arrhythmias in the intensive care unit. Acta Anaesthesiol Scand. 2014;58(3): Burke MA, Chang S, Wakimoto H, et al. Molecular profiling of dilated cardiomyopathy that progresses to heart failure. JCI insight. 2016;1(6):e Published May 5, Accessed September 26, Gonzalez FM, Veneziano MA, Puggina A, Boccia S. A systematic review on the cost-effectiveness of genetic and electrocardiogram testing for Long QT syndrome in infants and young adults. Value Health. 2015;18(5): Ishikawa S, Yamada T, Kuwata T, et al. Fetal presentation of long QT syndrome evaluation of prenatal risk factors: a systematic review. Fetal Diagn Ther. 2013;33(1):1 7. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10(9): Iakoubova OA, Tong CH, Rowland CM, et al. Association of the Trp719Arg polymorphism in kinesin-like protein 6 with myocardial infarction and coronary heart disease in 2 prospective trials: the CARE and WOSCOPS trials. J Am Coll Cardiol. 2008; 51: Jian C, Dan H, Suihua H, et al. Cytochrome CYP2C19 polymorphism and risk of adverse clinical events in clopidogrel-treated patients: a meta-analysis based on 23,035 subjects. Arch Cardiovasc Dis. 2013; 106(10): Kayvanpour E, Sedaghat-Hamedani F, Amr A, et al. Genotype-phenotype associations in dilated cardiomyopathy: meta-analysis on more than 8000 individuals. Clin Res Cardiol. 2017;106(2): Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013; 369(24): Modell S, Bradley D, Lehmann M. Genetic testing for long QT syndrome and the category of cardiac ion channelopathies. PLoS Curr Doi: /4f9995f69e6c7. Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, et al. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013; 369(24):

12 Sorich MJ, Rowland A. McKinnon RA, et al. CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a meta-analysis. Circ Cardiovasc Genet. 2014; 7(6): CMS National Coverage Determinations (NCDs): 90.1 Pharmacogenomic Testing for Warfarin Response. CMS website. arfarin+response&bc=beaaaaaacaaaaa%3d%3d&. Accessed September 26, National Coverage Determination (NCD) for Cytogenetic Studies (190.3). CMS Medicare Coverage Database Web site. Accessed September 26, NCD for cytogenetic studies (). Accessed September 26, Local Coverage Determinations (LCDs): L MolDX: CYP2C19, CYP2D6, CYP2C9, and VKORC1 GENETIC TESTING. CMS Medicare Coverage Database Web site. KeyWord=genetic+testing&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAAABAAIAAAAA% 3d%3d& Accessed September 26, L Pathology and Laboratory: CYP2C19, CYP2D6, CYP2C9, and VKORC1 GENETIC TESTING. CMS Medicare Coverage Database Web site. eyword=genetic+testing&keywordlookup=title&keywordsearchtype=and&bc=gaaaabaaiaaaaa%3 d%3d& Accessed September 26, L Pathology and Laboratory: CYP2C19, CYP2D6, CYP2C9, and VKORC1 GENETIC TESTING. CMS Medicare Coverage Database Web site. eyword=genetic+testing&keywordlookup=title&keywordsearchtype=and&bc=gaaaabaaiaaaaa%3 d%3d& Accessed September 26, L Pathology and Laboratory: CYP2C19, CYP2D6, CYP2C9, and VKORC1 GENETIC TESTING. CMS Medicare Coverage Database Web site. 12

13 eyword=genetic+testing&keywordlookup=title&keywordsearchtype=and&bc=gaaaabaaaaaaaa%3 d%3d& Accessed September 26, L MolecularPathologyProcedures. CMS Medicare Coverage Database Web site. Accessed September 26, Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comments Inherited cardiomyopathy (eg, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy) genomic sequence analysis panel, must include sequencing of at least 5 genes, including DSG2, MYBPC3, MYH7, PKP2, and TTN ICD-10 Code Description Comments I42.0 Dilated cardiomyopathy I42.1 Obstructive hypertrophic cardiomyopathy I42.2 Other hypertrophic cardiomyopathy I42.5 Other restrictive cardiomyopathy I42.9 Cardiomyopathy, unspecified Q24.8 Other specified congenital malformations of heart HCPCS Level II Code N/A Description Not applicable Comments 13