Response to Comments: MolDX: Genetic Testing for Heritable Thoracic Aortic Disease

The following comment was submitted to Palmetto GBA, CGS, WPS and Noridian:

Thank you for your attention to the important matter of genetic testing for heritable thoracic aortic disease (HTAD), a diverse group of heritable conditions that can cause sudden death and significant morbidity and mortality. We have read the proposed LCD and encourage approval of this determination.

We suggest the following changes to this LCD:

1) Under “Coverage Indications, Limitations, and/or Medical Necessity,” for the first bullet point, which currently reads, “The patient presents with an aortic root/ascending aortic dilation, aneurysm or dissection (as defined by national consensus guidelines) AND at least one of the following are true:”

We suggest making the language more clear and consistent with the 2022 ACC/AHA Aortic Disease Guidelines, which states, “In patients with aortic root/ascending aortic aneurysms or aortic dissection and risk factors for HTAD (Table 8, Figure 17), genetic testing to identify pathogenic/likely pathogenic variants (ie, mutations) is recommended” (Table 6.1.2.1) and refers to thoracic aortic disease as the indication for genetic testing (Table 8 and Figure 17). In addition, the 2022 ACC/AHA guidelines include the descending aorta as part of Thoracic Aortic Disease: “HTAD most commonly involves the aortic root, ascending aorta, or both but may also present with distal aortic disease and aortic dissection” (PMID 36322642).

Based on the above, we would like to request changing the first bullet point of the indication to:
“The patient presents with a thoracic aortic dilation, aortic aneurysm or aortic dissection (as defined by national consensus guidelines) AND at least one of the following are true:”

If this suggested change is made, the appropriate ICD-10 codes for thoracic aortic diseases, including descending aortic diseases, should be added to “ICD-10-CM Codes that Support Medical Necessity.”

2) Consider providing the ICD-10 codes corresponding to “Presence of syndromic features of Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome, OR Family history of thoracic aortic disease or peripheral/intracranial aneurysm in a first- or second-degree relative, OR Family history of unexplained sudden death at a relatively young age in a first- or second-degree relative” and list them in the “ICD-10-CM Codes that Support Medical Necessity” section. Please see the suggested list attached to this email. These are based on published diagnostic criteria that specify these conditions and associated clinical features of Marfan syndrome (PMID: 20591885), vascular Ehlers Danlos syndrome (PMID: 28306229), and Loeys Dietz syndrome (PMID: 20301312, PMID 29392890 (Table 5)).

In addition we would appreciate clarification on the following bullet point: “The test does not include additional genetic content that can be considered harmful to the patient.” What constitutes genetic information that would be considered harmful (e.g., incidental findings, preliminary evidence genes, unrelated genes)?

We wish to express our sincere gratitude for developing this policy. Genetic testing is essential for diagnosis and treatment of many cardiac conditions including HTAD, and Medicare coverage of these tests will be lifesaving.

ICD-10 List was provided for review.

Thank you for your thoughtful comment. Each of the suggested changes is addressed below:

• Policy coverage criteria aim to identify patients with thoracic aortic aneurysms (TAA) who are most likely to harbor a genetic etiology and derive clinical benefit from changes in management based on their genetic findings. As noted in the 2022 ACC/AHA Guidelines, aneurysms of the aortic root, ascending aorta, or both account for the majority (60%) of thoracic aortic aneurysms (TAA), followed by those of the descending aorta (30%) and of the aortic arch (<10%).¹ Heritable causes are more likely to be identified for aortic root aneurysms and aneurysms of the ascending thoracic aorta, which are more likely to present at a younger age (60 years) when compared with aneurysms of the descending aorta (72 years).^1,2 Ascending TAAs also typically lack risk factors for atherosclerosis, such as diabetes, hypertension, and smoking and demonstrate low prevalence of aortic calcifications or atheromas, which are more prevalent in descending TAAs, wherein these “degenerative” injuries are considered preconditions.¹ The prevalence of aortic calcification or atheroma is relatively low (8-9%) in sporadic aneurysms of the aortic root and ascending thoracic aorta, and is significantly higher in aneurysms of the descending aorta (80% to 88%).^1,2 These observations suggest that aneurysms of the aortic root and ascending aorta are likely to have a congenital if not hereditary cause, whereas aneurysms of the descending aorta are more likely to have a degenerative etiology.

While HTAD may also present with distal aortic disease and aortic dissection, pathogenic genetic variants in genes predisposing to thoracic aortic disease are a major risk factor for aortic root aneurysms, ascending aortic aneurysms, and aortic dissection. For example, aneurysms in individuals with a pathogenic variant in certain genes (FBN1, SMAD3, TGFBR1, TGFBR2, TGFB2) almost always involve the aortic root and may also involve the ascending aorta. Causative HTAD variants are incorporated into surgical thresholds for prophylactic aortic root and ascending aortic replacement, demonstrating clinical utility through direct impact on patient management by informing the optimal timing of aortic repair and preventing adverse outcomes. For patients with intact descending aortic aneurysms, 2022 ACC/AHA Guidelines recommend repair when the diameter is ≥5.5 cm. In patients with intact descending TAA and risk factors for rupture (including Marfan, Loeys-Dietz, or vascular Ehlers-Danlos syndrome, or HTAD), repair may be considered at a diameter of <5.5 cm. It is noteworthy that these individuals often have aneurysms throughout the arterial tree. The presence of a descending TAA is not identified as a criterion for genetic testing.

Therefore, the policy criteria are aligned with the written guideline recommendations as relevant to Medicare patients and outlined in section 6.1.2.1 “HTAD: Genetic Testing and Screening of Family Members for TAD” of the 2022 ACC/AHA Guidelines. Specifically, recommendation #2 favors genetic testing in “patients with aortic root/ascending aortic aneurysms or aortic dissection and risk factors for heritable thoracic aortic disease (HTAD),” meaning that patients must have aortic root/ascending aortic aneurysms or aortic dissection alongside risk factors (as outlined in Table 8, Figure 17) for HTAD.

References:

1. Isselbacher EM, Preventza O, Hamilton Black J, 3rd, et al. 2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. Dec 13 2022; 146(24):e334-e482. doi:10.1161/cir.0000000000001106
2. Vapnik JS, Kim JB, Isselbacher EM, et al. Characteristics and Outcomes of Ascending Versus Descending Thoracic Aortic Aneurysms. Am J Cardiol. May 15 2016;117(10):1683-1690. doi:10.1016/j.amjcard.2016.02.048

• The 2022 ACC/AHA Guidelines recommend genetic testing in patients with aortic root/ascending aortic aneurysms or aortic dissection and risk factors for heritable thoracic aortic disease (HTAD), therefore risk factors for HTAD in and of themselves do not support medical necessity for this particular indication without the presence of an aortic root/ascending aortic aneurysm or aortic dissection and cannot be added into the “ICD-10-CM Codes that Support Medical Necessity” section.

• In order to provide greater clarity, the coverage criterion has been modified from “the test does not include additional genetic content that can be considered harmful to the patient” to “the test does not include additional genetic content that is not properly validated, or of unclear clinical validity or utility such that it could reasonably or possibly be mis-utilized by the patient or treating physician and result in impaired patient outcomes.”

The following comment was submitted to Palmetto GBA, Noridian, and WPS:

Thank you for the opportunity to review and comment on proposed coverage policies for MolDX: Genetic Testing for Heritable Thoracic Aortic Disease and MolDX: Molecular Testing for Identification and Management of Hereditary Transthyretin Amyloidosis. As the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the College of American Pathologists (CAP) serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide.

We commend MolDX for recognizing the vital importance of the role that molecular testing plays in the identification and treatment of Hereditary Transthyretin Amyloidosis (hATTR) and Heritable Thoracic Aortic Disease (HTAD). Given the level of evidence at this time, the CAP agrees with the coverage parameters outlined in the proposed policies. However, we offer the following recommendation regarding one of the criteria for coverage that is mandated in both policies:

Coverage Indications, Limitations, and/or Medical Necessity

Testing is covered when ALL the following are met:

The test does not include additional genetic content that could be considered harmful to the patient.

CAP recommendation: The current statement does not specify how genetic content that could be considered as harmful to the patient is defined. Further, we question the necessity of this criterion and recommend that Noridian define or provide an example of what is meant by this statement or remove it from these policies.

Thank you again for providing us the opportunity to comment on these proposed policies.

Reference was provided for review.

Thank you for your thoughtful comment. In order to provide greater clarity, the coverage criterion has been modified from “the test does not include additional genetic content that can be considered harmful to the patient” to “the test does not include additional genetic content that is not properly validated, or of unclear clinical validity or utility such that it could reasonably or possibly be mis-utilized by the patient or treating physician and result in impaired patient outcomes.” 

The following comment was submitted to Palmetto GBA and Noridian:

HCA Healthcare is a major hospital provider in the states of California and Nevada. We maintain a focus on patients and are engaged in many quality initiatives. These initiatives focus on the delivery of high quality patient care, including compliance with local and national coverage determinations. We are submitting the following comments based on detailed clinical analysis of Proposed LCD MolDX: Genetic Testing for Heritable Thoracic Aortic Disease.

Under criteria for coverage, the first bullet should be revised to specifically allow coverage for testing of patients who present before age 60 years with an aortic root/ascending aortic dilation, aneurysm or dissection as outlined by the 2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease (Figure 17 and Table 8). To be consistent with the Guideline, the remaining conditions should be covered regardless of the patient’s age. Therefore, the recommended revision would appear as follows:

• Genetic testing for Heritable Thoracic Aortic Disease (HTAD) is covered when one of the following are true:
• The patient presents with an aortic root/ascending aortic dilation, aneurysm or dissection (as defined by national consensus guidelines) before age 60 years, OR
• Presence of syndromic features of Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome, OR
• Family history of thoracic aortic disease or peripheral/intracranial aneurysm in a first- or second-degree relative, OR
• Family history of unexplained sudden death at a relatively young age in a first- or second-degree relative.

We appreciate your thoughtful review of our request. If you have any questions, please do not hesitate to contact me.

Reference was provided for review.

Thank you for your thoughtful comment. In order to provide greater clarity, the coverage criterion has been modified from “the test does not include additional genetic content that can be considered harmful to the patient” to “the test does not include additional genetic content that is not properly validated, or of unclear clinical validity or utility such that it could reasonably or possibly be mis-utilized by the patient or treating physician and result in impaired patient outcomes.” 

The following comment was submitted to Palmetto GBA:

Thank you for your attention to the important matter of genetic testing for aortopathies and amyloidosis, a (diverse group of) heritable condition(s) that can cause sudden death and significant morbidity and mortality. I encourage approval of this determination. Again, my sincere gratitude for developing this policy. Genetic testing is essential for diagnosis and treatment of many cardiac conditions including aortopathies/amyloidosis, and Medicare coverage of these tests will be lifesaving.

Thank you for your thoughtful comment. As currently written, the policy provides coverage for testing of patients who present before age 60 years with an aortic root/ascending aortic dilation, aneurysm or dissection, as outlined by the 2022 ACC/AHA guidelines. This clinical presentation is captured by coverage criteria wherein a patient must present with an aortic root/ascending aortic dilation, aneurysm or dissection (as defined by national consensus guidelines) AND at least one of the following:

• Presentation before age 60 years, OR
• presence of syndromic features of Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehlers-Danlos syndrome OR
• Family history of thoracic aortic disease or peripheral/intracranial aneurysm in a first- or second-degree relative, OR
• Family history of unexplained sudden death at a relatively young age in a first- or second-degree relative.

Therefore, following the above logic, genetic testing is covered in a patient with an aortic root/ascending aortic dilation, aneurysm or dissection (as defined by national consensus guidelines) who presents before age 60. Use of the word “OR” renders the remaining risk factors covered regardless of age in patients with aortic root/ascending aortic dilation, aneurysm or dissection.

The following comment was submitted to Palmetto GBA by multiple stakeholders:

Thank you for your attention to the important matter of genetic testing for aortopathies, a diverse group of heritable conditions that can cause sudden death and significant morbidity and mortality. I have read the proposed LCD in its entirety and find it to be very well written and researched. I encourage approval of this determination.

Again, my sincere gratitude for developing this policy. Genetic testing is essential for diagnosis and treatment of many cardiac conditions including aortopathies, and Medicare coverage of these tests will be lifesaving.

Thank you for your comment in support of this policy. 

The following comment was submitted to Palmetto GBA:

Thank you for your attention to the important matter of genetic testing for aortopathies, a diverse group of heritable conditions that can cause sudden death and significant morbidity and mortality. I have read the proposed LCD in its entirety and find it to be very well written and researched. I encourage approval of this determination.

The early diagnosis and treatment of aortic diseases is life saving and will ultimately result in saving healthcare dollars.

Again, my sincere gratitude for developing this policy. Genetic testing is essential for diagnosis and treatment of many cardiac conditions including aortopathies, and Medicare coverage of these tests will be lifesaving.

Thank you for your comment in support of this policy.

The following comment was submitted to Palmetto GBA:

I am writing to advocate for the coverage approval of genetic testing for heritable thoracic aortic disorders. As a researcher specializing in rare genetic vascular conditions, I can attest to the significant clinical utility and cost-effectiveness of such testing.

Genetic testing for thoracic aortic disease provides several crucial benefits:

1. Early Detection and Prevention
- Enables identification of at-risk individuals before acute presentations
- Allows for implementation of preventive measures and monitoring protocols
- Reduces the likelihood of catastrophic aortic events
2. Family-Based Care
- Facilitates cascade screening in families
- Enables targeted surveillance of asymptomatic carriers
- Promotes cost-effective risk stratification
3. Therapeutic Decision-Making
- Guides timing of prophylactic surgical intervention
- Informs medication choices and management strategies
- Supports personalized approach to patient care

The clinical evidence strongly supports the cost-effectiveness of genetic testing in this context, particularly for older adults who may be unaware of their genetic risk factors. Early identification through genetic testing can prevent costly emergency procedures and reduce overall healthcare expenditure through proactive management.

I respectfully urge the committee to approve coverage for this essential diagnostic tool, which has become a standard of care in the evaluation and management of thoracic aortic disease.

Thank you for your comment in support of this policy.

The following comment was submitted to Palmetto GBA:

I strongly recommend this new LCD for genetic testing in the patients with aortic root or ascending aortic aneurysms. Although traditionally the concern for heritable aortopathies has only been raised in those that are younger, there is now ample evidence that the heritable aortopathies may present at an older age in part due to the challenges of diagnosing aneurysms during their asymptomatic phase. Identifying the presence of a heritable aortopathy is both important for the patients health since current guidelines from the AHA as well as the ESC emphasize the importance of the genetic causes of aneurysms in deciding thresholds for prophylactic surgery and for guiding screening of family members at risk.

To deny a tool that is established in guiding care of the patient would deny the Medicare recipient from accessing what is accepted as the current standard of care.

Thank you for your comment in support of this policy.

The following comment was submitted to Palmetto GBA:

I am an Associate Professor. My research focuses on developing treatments for aortopathies, namely aortic aneurysms and dissection, including the ones of genetic origin. As a researcher, our strongest motivation is that our work one day may help prevent aortic aneurysms and dissections in people suffering from these vascular diseases. Research has advanced tremendously in the last 10 years, particularly in the field of genetics; we identified multiple genetic mutations that are causally associated with aortophaties; these findings are solidly demonstrated and supported by clinical practice. It is crucial that individuals suspected of carrying a genetic mutation linked to aortic aneurysm be identified as soon as possible so some form of monitoring and treatment can be commenced by their primary care doctor to slow down the growth of an aneurysm and, most importantly, prevent death by rupture or dissection of the aorta. Therefore, I fully support the initiative of local coverage determination that has been proposed to cover genetic testing via Medicare. This will make genetic testing accessible to all: it is equitable, medically sound and the right thing to do.

Thank you for your comment in support of this policy.

The following comment was submitted to Palmetto GBA:

Thank you for your attention to the important matter of genetic testing for Aortopathies, a (diverse group of) heritable condition(s) that can cause sudden death and significant morbidity and mortality.

The Marfan Foundation is a patient advocacy group that represents patients throughout the US with these types of conditions as well as the GenTAC Alliance, (Physician Alliance for Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions).

I have read the proposed LCD in its entirety and find it to be very well written and researched. I encourage approval of this determination.

Again, my sincere gratitude for developing this policy. Genetic testing is essential for diagnosis and treatment of many cardiac conditions including Aortopathies, and Medicare coverage of these tests will be lifesaving.

Thank you for your comment in support of this policy.

The following comment was submitted to Palmetto GBA:

Thank you for your attention to the important matter of genetic testing for aortopathies, a (diverse group of) heritable condition(s) that can cause sudden death and significant morbidity and mortality. I have read the proposed LCD in its entirety and find it to be very well written and researched. I encourage approval of this determination.

I am writing to express my strong support for the proposed expansion of coverage for genetic testing. This policy change is crucial as it will enable more individuals to access genetic testing, which is a cost-effective method for identifying those at risk for life-threatening conditions such as thoracic aortic aneurysm.

Thoracic aortic aneurysm is a serious condition that can lead to sudden death if not diagnosed and treated in a timely manner. Genetic testing allows for early identification of individuals at risk, facilitating timely medical intervention and potentially saving lives. The cost savings from preventing emergency medical situations and the associated healthcare expenses further underscore the value of this policy.

Expanding coverage for genetic testing will not only improve individual health outcomes but also contribute to the overall efficiency of our healthcare system. I urge the decision-makers to consider the profound benefits of this policy and move forward with its implementation.

Thank you for the opportunity to provide input on this important issue.

Again, my sincere gratitude for developing this policy. Genetic testing is essential for the diagnosis and treatment of many cardiac conditions including aortopathies, and Medicare coverage of these tests will be lifesaving.

Thank you for your comment in support of this policy.

The following comment was submitted to Palmetto GBA:

Thank you for your attention to the important matter of genetic testing for aortopathies, a diverse group of heritable conditions that can cause sudden death and significant morbidity and mortality. I have read the proposed LCD in its entirety and find it to be very well written and researched. I encourage approval of this determination. If any changes are to be made, I suggest removal of the caveat stating “The test does not include additional genetic content that can be considered harmful to the patient.” This is a rather subjective statement, and implies that exome and genome testing approaches should be excluded. On the contrary, for complex phenotypes, exome or genome are the most effective and cost-efficient approaches, and should be within the possible options available to clinicians diagnosing and treating aortopathies.

Again, my sincere gratitude for developing this policy. Genetic testing is essential for diagnosis and treatment of many cardiac conditions including aortopathies, and Medicare coverage of these tests will be lifesaving.

Thank you for your comment in support of this policy.

The following comment was submitted to Palmetto GBA:

As a genetic counselor specializing in cardiovascular genetic counseling, I strongly support increased access and genetic testing coverage for patients with suspected genetic aortopathy conditions. There are specific management guidelines from the American Heart Association (including “Cardiovascular Management of Aortopathy in Children: A Scientific Statement From the American Heart Association from Morris et al., 2024 and “2022 ACC/AHA Guideline for the Diagnosis and Management of Aortic Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines” from Isselbacher et al., 2022) that support genetic testing and counseling for management. Different genetic etiologies of aortopathy are managed differently as per evidence-based guidelines (e.g. medications, surveillance, surgical considerations). As such, genetic testing is a key tool in best patient outcomes and improving care for patients with heritable thoracic aortic diseases.

Thank you for your consideration.

Thank you for your comment in support of this policy.

The following comment was submitted to Palmetto GBA:

I have read the document re; Genetic testing for heritable thoracic aortic disease. This would be an important improvement in the care of patients with this condition. The management of individuals can be very different with regard to their genetic etiology. This could relate to other conditions the person might have as well as the problem with the aorta and also the timing of potential surgery.

I urge approval of this proposal.

Thank you for your comment in support of this policy.