Summary Of Evidence

Introduction

The focus of this evidence review is on genetic testing to assess clinical actionability in cardiovascular disease, and whether the evidence is adequate to draw conclusions about improved health outcomes for the Medicare population. In general, improved health outcomes of interest include patient mortality and morbidity, as well as patient quality of life and function. For genetic testing to be considered medically reasonable and necessary in the Medicare population, standardized evaluation of analytical validity, clinical validity, and clinical utility should be fully elucidated, and reflect the level of confidence that the performance of this test will directly benefit patients. Tests with analytic and clinical validity, with demonstrated clinical utility that provide confidence to accurately enhance clinician decision-making and satisfy requirements for accurate patient information, have the potential to alter clinical management leading to improved patient outcomes. Ideal patient outcomes demonstrate reduced mortality and morbidity and improved patient quality of life and function.

Genetic testing for genetic variants associated with cardiovascular disease endeavors to improve patient outcomes by guiding appropriate treatment, thereby maximizing treatment effectiveness. Outcomes of interest remain the patient-centered outcomes noted above.

Internal Technology Assessment

PubMed was searched for publications of clinical trials including the terms molecular cardiac and molecular cardiovascular, looking for evidence of clinical health outcomes. All countries of origin were included if broad inclusion for the clinical studies met the criteria with only publications in English considered. No studies were located. A search utilizing the terms cardiovascular genomics found no new studies. The terms panel and cardiac/cardiovascular had >100 results. A cardiovascular gene search within the Journal of Genetic Counseling had 38 results and PubMed had 28 results respectively. These studies were then screened for inclusion of adults and Medicare population that demonstrated evidence of clinical health outcomes, resulting in no applicable studies.

In a search for professional society guidelines for genetic testing in cardiovascular diseases, a professional society scientific statement was identified. A government funded publicly available resource was identified in the professional society statement article. Another professional society statement was identified in addition to a guideline within the same article.

Guidelines

Hershberger et al¹ is a practice guideline for genetic evaluation of cardiomyopathy, done in collaboration between the Heart Failure Society of America (HFSA) and the American College of Medical Genetics and Genomics (ACMG). Recommendations are considered expert opinion as no systematic approach to literature review was conducted.

Professional Society Statements

Ackerman et al² is an international consensus statement developed in partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA) to provide the state of genetic testing for channelopathies and cardiomyopathies in 2011. Recommendations are based on consensus of the writing group following the Heart Rhythm Society’s consensus process.

Musunuru et al³ is a scientific statement from the American Heart Association regarding genetic testing for inherited cardiovascular diseases. The statement “summarizes current best practices with respect to genetic testing and its implications for the management of inherited cardiovascular diseases.”³ Included in this publication are: an approach to the evaluation of patients with confirmed or suspected diagnosis of inherited cardiovascular disease; an approach to the evaluation of individuals with secondary or incidental genetic findings; a table listing genetics-guided diagnosis and management of cardiovascular conditions with condition listed, role in diagnosis, role in management, and source of information; and, a list of genes to be considered for testing from guidelines and statements. The authors note a “dearth of clinical trial evidence for the use of genetic testing in the practice of cardiovascular medicine.”³

Decision of the scope of testing is important. Testing can range from a single gene or a few genes to large panels. Next-generation sequencing has made complete genome sequencing readily available. However, these panels can include genes with little support for the gene-phenotype under investigation and may not increase the likelihood of clinically actionable results. These panels may also increase the number of variants of uncertain significance identified, or pick up secondary or incidental findings, causing confusion and uncertainty for both provider and patient. The authors note ClinGen is engaged in efforts to develop lists of genes with strong evidence linking them to diseases.³ Generally, genetic testing may not reveal a cause or confirm a diagnosis as the yield of genetic testing for any inherited cardiovascular disease is usually much less than 100%.¹

Interpreting and acting on genetic test results for a patient should include post-test genetic counseling. As a result of the current rapid gain in knowledge and privately held information, interpretations can vary between genetic testing laboratories as well as providers, and over time. The ACMG and the Association for Molecular Pathology have published a variant framework to promote standardization, and ClinGen is engaged in modifying the framework for specific genes. The authors state, “It is the implicit responsibility of patients’ providers to ensure that genetic testing is up to date, although formal mechanisms by which providers can ensure that this happens remain to be established.”³

It is acknowledged there is sparse clinical trial evidence for the use of genetic testing for clinical management in cardiovascular medicine. Guidance for disease specific testing from guidelines and statements include information from the HFSA, the ACMG, the Heart Rhythm Society/European Heart Rhythm Association, and the NIH-funded ClinGen. Methodologic evaluation of evidence is not included in this publication. Condition and gene association are listed.²

The authors note the field of clinical genetics is changing rapidly and that reliable classification of variants identified in genetic testing will remain a challenge.³ Efforts by ClinGen will be critical to refine gene-specific variant classification criteria.

National Institute of Health funded Clinical Genome Resource (ClinGen)

Strande et al⁴ describes a framework to define and evaluate the clinical validity of gene-disease pairs developed by the NIH-funded ClinGen. The framework evaluates evidence supporting or contradicting a gene-disease relationship. Validation of the posted framework using a set of representative gene-disease pairs is demonstrated. The framework provides a strength of evidence for the relationship. This standardized framework was developed as there is substantial variability in the level of evidence supporting claims of gene-disease relationships; therefore, a systematic method is needed to more confidently determine the clinical validity of a gene-disease relationship. The authors state, “This framework aims to provide a systematic, transparent method to evaluate a gene-disease relationship in an efficient and consistent manner suitable for a diverse set of users.”⁴

The framework classifies gene-disease relationships by both quantity and quality of evidence. The validity classification of evidence includes the levels definitive, strong, moderate, limited, no reported evidence, and conflicting evidence reported, with descriptions of each. Classes of genetic evidence and their relative weights used in the ClinGen clinical validity framework is provided, dividing the genetic evidence into the two categories of case-level data and case-control data with separate subtypes. Scoring varies based on a scoring matrix with detailed guidance. Additionally, experimental evidence at the gene-level is scored based on a separate framework.⁴

Use of the framework was evaluated with a number of gene-disease pairs. Reproducibility was examined. Experts agreed with the preliminary classifications for 87.1% of the gene-disease pairs with published evidence. Discrepancies between expert and curator classification were discussed and explained and differed only by a single category. The authors conclude, “Ultimately, our systematic, evidence-based method for evaluating gene-disease associations will provide a strong foundation for genomic medicine.”⁴

Hunter et al⁵ explains the approach of the NIH sponsored ClinGen to assess clinical actionability of genetic disorders associated with genomic variation. The assessment of clinical actionability is part of the effort to create a central resource of information for the clinical relevance of genomic variation. They developed a standardized protocol to identify evidence, generate a summary report of actionability with an applied metric for an actionability score. This effort is aimed at improving patient health outcomes.

In general, the evidence supporting clinical actionability for most genetic disorders varies significantly. Therefore, ClinGen developed and implemented a standardized, evidence-based method to determine actionability of genomic testing, as described in this article.⁵ The intent is to identify genetic disorders with greater clinical utility when identified by testing in previously undiagnosed adults. The working definition of clinical actionability is a clinically prescribed intervention specific to the genetic disorder under consideration, effective for prevention or delay of clinical disease, lowered clinical burden, or improved clinical outcome in a previously undiagnosed adult.⁵ Intervention included patient management, but also interventions to improve outcomes for at-risk family members, however genetic testing recommendations for at-risk family members alone did not meet the criteria for actionability.

The method for knowledge synthesis is described in the article and accompanying supplemental materials.⁵ The NIH funded ClinGen is a consortium of researchers and clinicians. They create the open-access and centralized resource to define the clinical relevance and actionability based on the documented framework. The clinical actionability scoring metric is described. The final product summary includes scoring for severity of disease, likelihood of disease, effectiveness of specific interventions, nature of intervention, and state of the knowledge base, i.e., level of evidence.

Furthermore, ClinGen provides a resource which is available to all clinicians and patients. It is a publicly available website that “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.”^5(p2)

The authors conclude, “The ClinGen framework for actionability assessment will assist research and clinical communities in making clear, efficient, and consistent determinations of actionability based on transparent criteria to guide analysis and reporting of findings from clinical genome-scale sequencing.”^5(p10)

Analysis of Evidence

Genetic testing for inherited cardiovascular disease seeks the goal of improving health through more accurate and precise patient management. Knowledge of gene-disease associations is accelerating. Despite the rapid acquisition of information, it is acknowledged there is a lack of clinical trial evidence demonstrating improved patient outcomes. Gene-disease association does not necessarily translate to improved health outcomes. A search for clinical trial data demonstrating outcomes of mortality and morbidity reduction, or improvement of function or quality of life in the Medicare population was non-yielding. However, clinical recommendations for testing are available. For determination of medically reasonable and necessary, a test must have analytic validity, clinical validity, and clinical utility. Recommendations with higher confidence demonstrate a standardized, transparent, systematic, peer-reviewed approach to evidence evaluation. Considering a dearth of clinical studies, recommendations for genetic testing for inherited cardiovascular diseases were examined within this framework.

Genomic tests must demonstrate analytic validity, clinical validity, and clinical utility for Medicare coverage. Substantial variability exists in the level of evidence supporting claims of clinical validity and clinical utility.⁴ Strande et al outlines the standardized approach developed by the Clinical Genome Resource to define and evaluate the clinical validity of gene-disease pairs. The ClinGen Gene Curation Working Group is comprised of a broad base of experts. The strength of evidence of a gene-disease relationship is based on a standard semiquantitative approach to evaluate available evidence and arrives at a defined classification.

In many instances, currently, clinical utility of genetic testing can be challenging to demonstrate with patient-oriented outcomes. Clinical utility addresses demonstrated improvement of health outcomes, with the health outcomes of interest in the Medicare population as noted previously. Hunter et al,⁵ which outlines work by the ClinGen Actionability Working Group (ClinGen AWG), defines actionability as clinically prescribed interventions specific to the genetic disorder under consideration that are effective for prevention or delay of clinical disease, lowered clinical burden, or improved clinical outcomes in a previously undiagnosed adult. This definition of actionability provides a framework for genetic testing health outcomes consideration. Evidence supporting clinical actionability for most genetic disorders varies widely, necessitating a standardized assessment. Presenting the method of ClinGen AWG systematic assessment, Hunter et al⁵ provides the standardized framework for clinical actionability of genes and associated disorders. Actionability including interventions to improve outcomes for at-risk family members is included, though this alone would not be a basis for Medicare coverage, and was not considered sufficient to meet criteria for actionability.

Genetic testing for inheritable cardiovascular disease, after a patient has received rigorous disease-appropriate phenotyping, is recommended by certain cardiovascular professional organizations. As Musunuru et al³ notes, a rigorous evaluation for disease-appropriate clinical manifestations must be determined before testing. The decision to perform genetic testing should be reserved for patients with a confirmed or suspected diagnosis of an inherited cardiovascular disease or for individuals at high risk from a previously identified pathogenic variant in their family. However, Medicare does not cover genetic screening for cardiovascular disease, in which case family history alone would be insufficient for coverage. A crucial element is rigorous, disease-appropriate phenotyping. Genetic testing does not provide a definite diagnostic result in most circumstances.

Adverse events can occur from genetic testing. Interpretation of clinical importance of a variant can differ between multiple laboratories.⁶ Patient care could be compromised if the interpretation is incorrect or based on data that is not broadly applicable. Patients could receive an inappropriate therapy or could fail to receive an appropriate therapy. In addition, stakeholders could have proprietary database of variant interpretations, which prevents the broad use of critical data.⁶ Broad, publicly available information derived from a systematic process by a group of experts in their respective fields is ideal.

The National Institutes of Health (NIH) funded ClinGen created an open-access resource to better define clinically relevant genes and variants based on a published, standardized, transparent, evidence assessment framework.³ The 2020 Scientific Statement for the American Heart Association notes the importance of ClinGen’s efforts. With the data and evidence available, this will prevent “panels that include genes with little support for the gene-phenotype association under investigation that may not increase the likelihood of clinically actionable results in adult patients.”³

In summary, reliable evidence for variants identified in genetic testing is critical. The information must be actionable for that patient, with the ability to improve patient management. Prior to testing, a rigorous disease-appropriate phenotyping is necessary. The NIH funded ClinGen follows a standardized protocol for evidence generation that is transparent, with working groups comprised of scientific and clinical experts. The information is available for public use. Coverage for genetic testing for inheritable cardiovascular disease is based on ClinGen gene-disease scoring where patients are likely to have beneficial health outcomes.

Compliance with the provisions in this LCD may be monitored and addressed through post payment data analysis and subsequent medical review audits.

History/Background and/or General Information

With advancement in science and technology comes the ability to incorporate genetic testing for hereditary cardiovascular disease into clinical care, with the goal of improved patient outcomes. The scope of this LCD is genetic testing in the practice of cardiovascular medicine in the Medicare population.

The genetic basis of cardiovascular disease is an area of rapidly expanding knowledge. To date, identification of genetic variants associated with cardiovascular disease includes hypertrophic and dilated cardiomyopathy (associated with mutations in sarcomere and structural genes), arrhythmogenic cardiomyopathy (associated with mutations in desmosome genes), inherited arrhythmias (associated with mutations in transmembrane ion channels genes), and Marfan and related syndromes (associated with mutations in genes encoding connective tissue elements). Association does not necessarily translate to improvement in patient care.

In certain circumstances, genetic testing for inherited cardiovascular disease in patients with the corresponding appropriate phenotypic medical condition could have the potential to assist patient management in the Medicare population. However, given the complexity and rapidly expanding knowledge in this topic area, there is also a potential for testing that does not help the patient or leads to confusion. Specialized clinical expertise in cardiovascular medicine in addition to advanced knowledge in both genetic variation and effect on gene function is required to facilitate optimal outcomes for patients.

Covered Indications

Genetic testing for hereditary cardiovascular disease will be considered medically reasonable and necessary if:

1. The patient has rigorous disease-appropriate phenotyping to establish clinical diagnosis or suspected diagnosis for which the test results would directly impact the management of the patient’s condition, prior to ordering the test
   AND
2. The evidence for the gene-disease association is evaluated by the evidence-based, transparent, peer-reviewed process of the National Institutes of Health (NIH) sponsored Clinical Genome Resource (ClinGen) and is determined to demonstrate actionability in clinical decision making, meeting all bulleted metrics:
   • Disease severity of sudden death, possible death or major morbidity, modest morbidity
   • Substantial or moderate evidence of a >40% likelihood of disease
   • Substantial or moderate evidence of a highly effective or moderately effective intervention
   • The nature of intervention is either low risk/medically acceptable/low intensity intervention or moderately acceptable/risk/intensive interventions,
     AND
3. Clinical validity and qualitative descriptors from Moderate, Strong & Definitive with contradictory evidence NOT being reported as disputed or refuted.

Limitations

The following are considered not medically reasonable and necessary:

1. A genetic test where either analytical validity, clinical validity, or clinical utility has not been established.
2. Genetic testing in patients who do not demonstrate the disease-appropriate phenotype of the gene-disease association.
3. Genetic testing of asymptomatic patients.
4. Genetic testing solely for purposes of proband identification.
5. Genetic testing with family history as the only indication.
6. Gene tests for cardiovascular disease are considered germline testing, and therefore only permitted once per beneficiary’s lifecycle.

Provider Qualifications

The ordering provider of a genetic test for a patient with a cardiovascular disease-appropriate phenotype:

• Must be the treating clinician who is responsible for the cardiovascular disease management of the patient’s condition; and,
• Understands how the test result will impact the patient’s condition; and,
• Has presented this information to the patient eliciting patient understanding.

Notice: Services performed for any given diagnosis must meet all of the indications and limitations stated in this LCD, the general requirements for medical necessity as stated in CMS payment policy manuals, any and all existing CMS national coverage determinations, and all Medicare payment rules.