Response to Comments: Genetic Testing for Cardiovascular Disease

A comment was submitted suggesting that the language in the LCD and the related article are contradictory. The commenter requests clarification regarding the grounds of indicating that the Current Procedural Terminology (CPT) codes included in the Billing and Coding Article are either inappropriate or non-covered.

Thank you for your comment. The language in the LCD outlines the indications for which genetic testing for cardiovascular disease would be considered medically reasonable and necessary. The criterion is applied to standardized reviews publicly available on the ClinGen website (https://www.clinicalgenome.org). The ClinGen analysis and posting of findings provides transparent information. The listed CPT codes either are or can be associated with cardiovascular testing, therefore the codes are included in the Article.

The chief Medical Director from Invitae spoke at the Open Meeting and offered the following comments: The recommendation was made to utilize the American Heart Association (AHA) statements to ensure the LCD is less restrictive and to allow for comprehensive cardiovascular panels. Also, to reduce the restrictive nature of the LCD to remove the outline of substantial and moderate evidence of disease likelihood, along with clinical validity & qualitative descriptors such as moderate, strong, or definitive. It was also recommended to utilize genes that were not reviewed by ClinGen.

Thank you for your comments and information provided. Musunuru 2020 states:

Genetic testing typically should be reserved for patients with a confirmed or suspected diagnosis of an inherited cardiovascular disease or for individuals at high a priori risk resulting from a previously identified pathogenic variant in their family (although similar in meaning, we use the term variant in preference to mutation in this statement). One crucial element is rigorous, disease-appropriate phenotyping, either by the provider or via referral to a specialist. The second element, which cannot be overemphasized, is a comprehensive family history that spans at least 3 generations.

We do not agree Musunuru 2020 supports genetic testing offered to Medicare patients when diagnosed with any form of cardiomyopathy, arrhythmic disorders, vascular disorder, or lipid disorder based solely on a suspected genetic variant.

As discussed in Musunuru 2020, “If the genetic testing is not performed, the patient should be managed according to the standard of care laid out by contemporary disease-specific clinical guidelines” suggesting a Medicare patient with history of inherited cardiovascular disease would be treated medically the same as if no genetic test is performed. The gene test alone will not confirm treatment in a Medicare patient at this time. However, the LCD does provide a rapid path forward for coverage of genetic testing based on a standardized, rigorous process for evidence review.

The National Institutes of Health (NIH) funded ClinGen, follows a standardized protocol for evidence generation that is transparent, with working groups comprised of scientific and clinical experts. In an effort to remain transparent and continually update genes for cardiovascular disease, genes are currently and continuously reviewed for their actionability, effectiveness and inherent link to cardiovascular diseases. ClinGen at this time, is the only subscription free, widely available resource to the public that has substantial & transparent reviews of genetic tests that can assist with individualized hands-on patient care. As such, it is felt that ClinGen is the strongest level of evidence to determine the medical necessity of genetic testing for cardiovascular diseases.

This LCD does not directly address comprehensive cardiac panels which open patient care to variants of uncertain significance, incidental findings, and secondary findings. Panel findings may add confusion and may not be relevant during treatment.

No written comment was provided by the presenter.

A comment was submitted by a Medicare Advantage program requesting that we include a list of tests (especially panel tests) that have been reviewed by the Contractor and determined AV/CV/CU has or has not been met.

Thank you for your comments. As you mentioned, Novitas is not part of the MolDx program. The field of molecular pathology is rapidly evolving which would make providing a complete list of tests/panels difficult to maintain.

The related Billing and Coding Article includes a list of CPT codes that are considered not appropriate to report for cardiovascular genetic testing and/or are considered non-covered. Any test/panel/gene that is described by these CPT codes would be considered not medically reasonable and necessary at this time. As new evidence is reviewed the Billing and Coding Article will be updated to provide any tests that are considered covered.

In consideration of analytic validity, the Centers for Medicare & Medicaid Services (CMS) regulates all laboratory testing (except research) performed on humans in the U.S. through the Clinical Laboratory Improvement Amendments (CLIA). The objective of the CLIA program is to ensure accurate and reliable laboratory testing. The FDA's review of a diagnostic test includes analytic validity and clinical validity. While some genetic tests have received FDA approval/clearance, most are laboratory developed tests (LDTs) and at this time are available without FDA approval/clearance. Further information for CMS’ authority regarding Laboratory Developed Tests (LDTs) and how it differs from FDA’s can be found at CMS (https://www.cms.gov) under LDT and CLIA facts and questions.

Comments were submitted by the American College of Cardiology (ACC) requesting that the covered indications be expanded to include symptomatic patients & extend eligibility for testing to those with a family history (1st or 2nd degree relative).

Additionally, the ACC would like the following limitations removed: A - Genetic testing in patients who do not demonstrate the disease-appropriate phenotype of the gene-disease association. B - Genetic testing of asymptomatic patients. C - Genetic testing solely for purposes of proband identification. D - Genetic testing with family history as the only indication.

Finally, the ACC feels that geneticists should be able to order genetic testing since they work as part of the team. The Pennsylvania Chapter of the ACC submitted a comment in support of the ACC comment.

Thank you for your comments. The Medicare benefit only extends to the covered patient and does not extend to proband identification to inform potentially at-risk family members. Genetic testing for beneficiaries who do not have signs or symptoms endeavors to prevent disease. Preventive benefits in the Medicare program cannot be added through the LCD process.

The review of Hunter 2016 and Musunuru 2020 both indicate the need for phenotyping related to cardiovascular disease in order to determine course of action and treatment.

As noted in Hunter 2016 "The ClinGen AWG [Actionability Working Group] framework provides a structure to enable research and clinical communities to make clear, streamlined, and consistent determinations of clinical actionability based on transparent criteria to guide analysis and reporting of genomic variation" as outlined in the LCD.

Regarding whom may order a test, this is limited by regulation. Per the Code of Federal Regulations (CFR 42 Section 410.32) diagnostic laboratory tests, and other diagnostic tests must be ordered by the physician who is treating the beneficiary, that is, the physician who furnishes a consultation or treats a beneficiary for a specific medical problem and who uses the results in the management of the beneficiary's specific medical problem. Tests not ordered by the physician who is treating the beneficiary are not medically reasonable and necessary. Non physician practitioners that are enrolled in the program, who are operating within the scope of their authority under State law and within the scope of their Medicare statutory benefit, may be treated for this purpose, as physicians treating beneficiaries. Certified genetic counselors are not currently eligible under Medicare rules and regulations to: (1) receive a Medicare billing number and be granted Medicare billing privileges; or (2) enroll to solely order, certify, or refer the items or services described in 42 CFR § 424.507.

Comments were submitted by PathemaGX, a molecular genetics company offering laboratory testing, requesting to expand eligibility to include cardiomyopathies, channelopathies or arrhythmias, valvular disorders, aortopathies and aneurysms, thrombotic/clotting disorders, and certain types of lipid disorders. An additional request to clarify coverage in relation to the CPT codes (Tier I and Tier II) that are listed in the related billing and coding article.

Thank you for your comments. Currently identified genes potentially associated with the above genetic disorders have been reviewed within ClinGen and do not meet the covered LCD indications. The intent of the LCD is to outline the indications for which genetic testing for cardiovascular disease would be considered medically reasonable and necessary. At this time, there were no genes related to cardiovascular disease that met the criteria outlined in the LCD.

The commentor provided web links to articles, which included the recent scientific statement from the AHA reviewed in the evidence section of the LCD. The additional list of references did not include studies supporting improved clinical outcomes in the Medicare population but did include articles discussing basic concepts and potential applications of genetic testing, diagnosis and treatment of patients with cardiomyopathy, and genetic recommendations based on expert opinion without a systematic literature review and without grading of evidence.

One article concluded, "The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families." Another article concluded, "More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine." The conclusion of another article included, “Our results contest the clinical validity of all but 1 gene clinically tested and reported to be associated with BrS. These findings warrant a systematic, evidence-based evaluation for reported gene-disease associations before use in patient care."

Comments were submitted by the College of American Pathologists requesting to clarify the types of tests or genes that are covered for testing and to amend the covered indications from "substantial or moderate evidence of a highly effective or moderately effective intervention" to "substantial or moderate evidence of change in patient management such as increased patient monitoring and/or, intervention."

It was also noted that the ‘limitations’ were too restrictive, citing these limitations as problematic: Limitation #2) Genetic testing in patients who do not demonstrate the disease-appropriate phenotype of the gene-disease association; Limitation #3) Genetic testing of asymptomatic patients; Limitation # 5) Genetic testing with family history as the only indication. It is stated the large proportion of genetic testing for cardiovascular disease is performed for family testing, and therefore request the limitations to be clarified to allow for cascade genetic testing for the familial variant in family members at 25% or greater risk of the condition.

In addition, it was requested that the following codes be added to the related billing and coding Article: 81413, 81414, 81406, 81407, 81439, 81401, 81405, ICD-10-CM Codes: E75.21, I45.81, I49.8, I42, I42.0, I42.1, I42.2, I42.5, E78.01

It was also noted, within the comment to allow repeat testing as advancements become available for the beneficiary.

Thank you for your comments. The field of molecular pathology is rapidly evolving. The language in the LCD outlines the indications for which genetic testing for cardiovascular disease would be considered medically reasonable and necessary and provides for ongoing change in coverage based on clinical evidence of improved outcomes in the Medicare population.

The reference list includes Musunuru et al (2020) reviewed in the evidence section. Additional references include recommendations based on expert opinion without a systematic literature review and without grading of evidence; congenital long QT syndrome prevalence, pathophysiology, and management; an article that concluded "The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families"; genetic testing for three familial arrythmia syndromes; and genetic testing for familial hypercholesterolemia. The additional articles do not provide evidence of improved clinical outcomes in the Medicare population for genetic testing for inherited cardiovascular diseases.

Medicare benefits only extend to the patient identified as covered and do not extend to proband identification to inform potentially at-risk family members. Genetic testing for beneficiaries who do not have signs or symptoms endeavors to prevent disease. Preventive benefits in the Medicare program cannot be added through the LCD process.

The request to amend the covered indications to state ‘increased patient monitoring and/or intervention’ is subjective and no specific evidence for improved clinical outcomes in the Medicare population is provided.

On August 12th and 13th, 2021 an open meeting was conducted for JN and JH/JL respectively. The meeting reviewed the outlined limitations of genetic testing within the LCD along with the coverage of a beneficiary in relation to cardiovascular genetic testing. The meeting provided explanation to the limitations and coverage outlined in this LCD and the indications for which genetic testing for cardiovascular disease would be considered medically reasonable and necessary.

Any laboratory test that investigates the same germline genetic content, for the same genetic information, that has already been tested in the same Medicare beneficiary is not reasonable and necessary as it is duplicative. The germline sequence of an individual does not change over time, and therefore repeat testing of the same germline content for the same genetic information does not provide new clinical information. Germline testing, including panels containing some genetic content already tested in the same Medicare beneficiary, may be considered medically reasonable and necessary if there is established clinical utility in the remaining, non-duplicative genetic components of the test.

The test/panel/gene described by the requested CPT codes currently does not meet the requirements listed in the LCD, therefore no changes will be made. As new evidence consistent with requirements of the LCD is reviewed the Billing and Coding Article will be updated to cover tests that are considered medically reasonable and necessary.