Clinical Policy Title: Genetic testing for G1691A polymorphism factor V Leiden

Clinical Policy Title: Genetic testing for G1691A polymorphism factor V Leiden Clinical Policy Number: 05.01.03 Effective Date: January 1, 2016 Initial Review Date: July 15, 2015 Most Recent Review Date: August 17, 2016 Next Review Date: August 2017 Related policies: CP# 02.01.01 CP# 02.01.02 CP# 02.01.04 CP# 02.01.08 CP# 02.01.09 CP# 02.01.11 CP# 02.01.14 CP# 05.01.01 CP#13.01.01 Policy contains: Genetic testing. Maternal genetic testing G1691A. Genetic testing for breast and ovarian cancer Pharmacogenetic testing for warfarin Familial polyposis gene testing Genetic testing, rare diseases Afirma gene expression classifier for indeterminate thyroid nodules Gene expression profile testing for breast cancer Viral oncogene mutation testing Genetic testing for prostate cancer prognosis Factor V Leiden. Coagulation. Coagulopathy. Hypercoagubility. Polymorphism. ABOUT THIS POLICY: AmeriHealth Caritas Northeast has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas Northeast s 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 peerreviewed 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 Northeast 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 Northeast s 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 Northeast s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas Northeast will update its clinical policies as necessary. AmeriHealth Caritas Northeast s clinical policies are not guarantees of payment. Coverage policy AmeriHealth Caritas Northeast considers the use of genetic testing for factor V Leiden to be investigational, and therefore not medically necessary. Factor V Leiden testing can be considered as a program exception for medical necessity in select clinical scenarios, such as certain subgroups of pregnant women. 1

Alternative covered services: Routine laboratory tests for coagulopathy may be ordered by a family practice or primary physician. Background The protein product of the factor V gene G1691A is the natural thrombophilic agent factor V Leiden (FVL). Elevated blood concentrations of FVL are associated with an increased initial risk of thrombosis (i.e., in the homozygous individual) and of recurrence of thrombosis. Heterozygous individuals are also at increased for thrombus, but much less so than their homozygous counterparts. There is conjecture that screening for FVL may identify individuals at high risk for future thromboembolism and thus aid in selection of at-risk individuals for prophylactic anti-coagulant therapy. The status of FVL zygosity also impacts the likelihood of idiopathic venous thromboembolism (VTE). Finally, as VTE and cancer are frequently observed together, there is conjecture that identification of FVL may focus screening for malignancy. Searches AmeriHealth Caritas Northeast searched PubMed and the databases of: 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 August 1, 2016, using the terms "Leiden (MeSH)," "factor V (MeSH)" and "genetic test (MeSH)." 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 For cancer screenings, there is a modicum of evidence (Robertson 2015) that identification of cancer occurs earlier and the cancer is less advanced when VTE screening is employed. The authors evaluated the medical evidence concerning the effectiveness of testing for undiagnosed cancer in patients with a 2

first episode of unprovoked VTE in reducing cancer and VTE-related morbidity and mortality, though the pertinent studies did not indicate FVL zygosity. The results unfortunately were adjudged to be imprecise at best and could not be consistently aligned with either harm or benefit from the practice. The authors noted that further good-quality large-scale randomized controlled trials are required before firm conclusions can be made in this regard. The American College of Chest Physicians (ACCP) addressed the use of low-molecular weight heparin (LMWH) for antepartum prophylaxis in pregnant women with no personal history of VTE but whose family history is affirmative for VTE, and who are homozygous for FVL. The ACCP Evidence-based Clinical Practice Guidelines (Guyatt 2012) suggest antepartum and post-partum prophylaxis with LMWH for six weeks in these individuals. In the absence of family history of VTE the guidelines recommend antepartum observation and post-partum prophylaxis for six weeks. For pregnant women with no prior history of VTE known to be homozygous for prothrombin 20210A mutation who have a positive family history for VTE, ACCP suggest antepartum prophylaxis with prophylactic- or intermediate-dose LMWH and postpartum prophylaxis for six weeks with prophylactic- or intermediate-dose LMWH, or vitamin K antagonists (VKAs) targeted at international normalized ratio (INR) 2.0 to 3.0, rather than no prophylaxis. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group did not find enough evidence of change in physician management of VTE to recommend routine testing for FVL (EGAPP 2011). EGAPP added that potential benefits are unlikely to exceed potential harms. The recommendations do not extend to patients with other risk factors for thrombosis (e.g., contraceptive use). Pernod (2009) came to a similar conclusion, observing that the etiology of VTE is complex and FVL zygosity only one of numerous variables at work in thrombophilia disorders. Finally, Lijfering (2009) studied various blood clotting factors and found FVL to be among the least of several causes of clinical VTE. Hereditary deficiencies of antithrombin, protein C and protein S were of greater clinical significance compared to FVL testing. Policy updates: The Canadian Health Technology Expert Review Panel (HTERP 2014) developed evidence-based guidance on the optimal use of genetic testing for G1691A polymorphism in patients with unprovoked VTE. While an association was identified between FVL mutations and first unprovoked VTE, the evidence showed that the presence of these mutations did not increase the risk of VTE recurrence. No evidence was identified to guide changes in the clinical management of patients with a first unprovoked VTE on the basis of results from FVL mutation testing, and there was no evidence of improved health outcomes resulting from testing. Testing for FVL mutations is associated with additional costs because of the cost of the tests and frequent requests for consultation with a specialist, as well as costs associated with extended anticoagulation therapy for patients who test positive. In the absence of 3

evidence that testing is clinically effective, the costs of routine testing are not justified.hterp recommends that patients with a first unprovoked VTE should not routinely be tested for factor V Leiden and prothrombin mutations. Summary of clinical evidence: Citation Robertson (2015) Effect of testing for cancer on cancer- and venous thromboembolism (VTE)- related mortality and morbidity in patients with unprovoked VTE. HTERP (2014) Guidance on the use of factor V Leiden and prothrombin mutation testing in patients with a first unprovoked thromboembolic episode Guyatt (2012) Content, Methods, Recommendations SR of only two RCTs inclusive of 396 patients with previous VTE. Screening with non-genetic tests found malignancies were less advanced in screened group vs. unscreened controls. Screened patients were diagnosed with cancer earlier (mean one month versus 11 months). Study did not indicate FVL zygosity. While an association was identified between FVL mutations and first unprovoked VTE, the evidence showed that the presence of these mutations did not increase the risk of VTE recurrence. No evidence was identified to guide changes in the clinical management of patients with a first unprovoked VTE on the basis of results from FVL mutation testing, and there was no evidence of improved health outcomes resulting from testing. Testing for FVL mutations is associated with additional costs because of the cost of the tests and frequent requests for consultation with a specialist, as well as costs associated with extended anticoagulation therapy for patients who test positive. In the absence of evidence that testing is clinically effective, the costs of routine testing are not justified. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidencebased Clinical Practice Guidelines Prevention of VTE in pregnant women with thrombophilia and no prior VTE. For pregnant women with no prior history of VTE known to be homozygous for FVL or the prothrombin 20210A mutation who have a positive family history for VTE, ACCP suggests antepartum prophylaxis with prophylactic- or intermediate-dose LMWH and postpartum prophylaxis for six weeks with prophylactic- or intermediate-dose LMWH, or VKAs targeted at INR 2.0 to 3.0, rather than no prophylaxis. For pregnant women with all other thrombophilias and no prior VTE who have a positive family history for VTE, ACCP suggests antepartum clinical vigilance and postpartum prophylaxis with prophylactic- or intermediate-dose LMWH; or, in women who are not protein C or S deficient, VKAs targeted at INR 2.0 to 3.0, rather than routine care. For pregnant women with no prior history of VTE known to be homozygous for FVL or the prothrombin 20210A mutation and who do not have a positive family history for VTE, ACCP suggests antepartum clinical vigilance and postpartum prophylaxis for six weeks with prophylactic- or intermediate-dose LMWH or VKAs targeted at INR 2.0 to 3.0, rather than routine care. For pregnant women with all other thrombophilias and no prior VTE who do not have a 4

positive family history for VTE, ACCP suggests antepartum and postpartum clinical vigilance, rather than pharmacologic prophylaxis. EGAPP (2011) Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members Pernod (2009) Recommendations on testing for thrombophilia in venous thromboembolic disease: a French consensus guideline Lijfering (2009) Routine testing for FVL not recommended in persons with idiopathic VTE. Routine testing for FVL not recommended in family members of persons with idiopathic VTE. Risks exceed harms. As idiopathic VTE was the only disease studied, no conclusions were made about other risk factors for disease (e.g., users of oral contraceptives). Thrombosis is multi-factorial and FVL zygosity only one component. However, screening is indicated with proximal idiopathic VTE in persons < 60 years old and in women with any VTE of child-bearing age. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Studied various blood clotting factors and found FVL to be among the least of several causes of clinical VTE. Hereditary deficiencies of antithrombin, protein C and protein S were of greater clinical significance compared to FVL testing. Glossary Deep venous thrombosis (DVT) The formation of a blood clot (thrombus) within a deep vein. Pulmonary embolism (PE) A blockage of the lung's main artery or one of its branches by a substance that has traveled from elsewhere in the body through the bloodstream (embolism). Venous thromboembolism (VTE) Includes both DVT and PE. References Professional society guidelines/others: 5

Canadian Health Technology Expert Review Panel (HTERP). Guidance on the Use of Factor V Leiden and Prothrombin Mutation Testing in Patients With a First Unprovoked Thromboembolic Episode. Canadian Agency for Drugs and Technologies in Health; Ottawa (ON): 2015. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden (R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous thromboembolism and their adult family members. Genetics in Medicine. 2011;13(1):67 76. Guyatt G, Akl E, Crowther M, et. al. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012;141:7S 47S. Pernod G, Biron-Andreani C, Morange P, et. al. Recommendations on testing for thrombophilia in venous thromboembolic disease: a French consensus guideline. French group on haemostasis and thrombosis, and the French Society of vascular medicine. J Mal Vasc. 2009;34(3):156 203. Peer-reviewed references: Lijfering W, Brouwer J, Veeger N, et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood. 2009;113(21):5314 22. Robertson L, Yeoh SE, Stansby G, Agarwal R. Effect of testing for cancer on cancer- and venous thromboembolism (VTE)-related mortality and morbidity in patients with unprovoked VTE. Cochrane Database Syst Rev. 2015;(3):CD010837. Clinical trials: Searched clinicaltrials.gov on July 15, 2016 using terms factor V Leiden Open Studies. 17 studies found, one relevant. Casa Sollievo della Sofferenza IRCCS. A Proposal of a Prospective Study on Prevention of Pregnancy Loss in Women Carrying Inherited Thrombophilia. ClinicalTrials.gov Web site. https://clinicaltrials.gov/ct2/show/nct02385461?term=factor+v+leiden&recr=open&no_unk=y&rank= 1. Published March 5, 2015. Updated July 2016. Accessed August 3, 2016. CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): 6

No LCDs identified as of the writing of this policy. 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 in accordance with those manuals. CPT Code Description Comment 81241 FS coagulation factor 5 (e.g., heredity hypercoagulability gene analysis Leiden variant) ICD-10 Code Description Comment I24.9 Acute coronary syndrome HCPCS Level II N/A Description Comment 7