National Coverage Analysis (NCA) Decision Memo

Transcatheter Mitral Valve Repair (TMVR)

CAG-00438R

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Decision Summary

For clarity, we are replacing the term Transcatheter Mitral Valve Repair (TMVR) with mitral valve Transcatheter Edge-to-Edge Repair (TEER) to more precisely define the treatment addressed in this proposed NCD, which is applicable to TEER for the treatment of functional mitral regurgitation (MR) and degenerative MR.

TEER of the mitral valve is covered under Coverage with Evidence Development (CED) as follows:

  1. For the treatment of symptomatic moderate-to-severe or severe functional mitral regurgitation (MR) when the patient remains symptomatic despite stable doses of maximally tolerated guideline-directed medical therapy (GDMT) plus cardiac resynchronization therapy, if appropriate, or for the treatment of significant symptomatic degenerative MR when furnished according to an FDA-approved indication and when all of the following conditions are met:

    1. The procedure is furnished with a mitral valve TEER system that has received FDA premarket approval (PMA).

    2. The patient (preoperatively and postoperatively) is under the care of a heart team: a cohesive, multidisciplinary, team of medical professionals.  The heart team concept embodies collaboration and dedication across medical specialties to offer optimal patient-centered care. The heart team must include the following members with experience and training as specified:
      1. Cardiac surgeon
        1. With ≥ 20 mitral valve surgeries per year or ≥ 40 over two years, 50% of which are mitral valve repairs; and
        2. Who is board eligible or certified in cardiothoracic surgery or similar foreign equivalent.
      2. Interventional cardiologist
        1. With professional experience of ≥ 50 career structural heart disease procedures; or ≥ 30 left-sided structural procedures per year; and
        2. With participation in ≥ 20 career trans-septal interventions including 10 as primary or co-primary operator; and
        3. Who is board eligible or certified in interventional cardiology or similar foreign equivalent.
      3. Interventional echocardiographer (cardiologist or anesthesiologist)
        1. With professional experience of ≥ 10 trans-septal guidance procedures and ≥ 30 structural heart procedures; and
        2. Who is board eligible or certified in transesophageal echocardiography with advanced training as required for privileging by the hospital where the TEER is performed.
      4. Heart failure cardiologist experienced in treating patients with advanced heart failure (only required for functional MR patients); and
      5. Providers from other physician groups as well as advanced patient practitioners, nurses, research personnel, and administrators.

    3. Each patient’s suitability for surgical mitral valve repair, TEER, or palliative therapy must be evaluated, documented, and made available to other heart team members. Additionally, for patients with functional MR, the heart team heart failure cardiologist must document that the patient has persistent symptoms despite maximally tolerated GDMT and cardiac resynchronization therapy, if appropriate, as described below:
      1. For patients with functional MR: the heart team interventional cardiologist and heart team heart failure cardiologist independently evaluate the patient using information in the medical record and a face-to-face examination.  To decrease patient burden, the heart team heart failure cardiologist may meet this requirement through a review of the patient’s records and images if the patient has an established relationship with a cardiologist experienced in treating patients with advanced heart failure.
      2. For patients with degenerative MR: the heart team interventional cardiologist and heart team cardiac surgeon must independently evaluate the patient using information in the medical record and a face-to-face examination.

    4. An interventional cardiologist or cardiac surgeon from the heart team must perform the mitral valve TEER and an interventional echocardiographer from the heart team must perform transesophageal echocardiography during the procedure.  The interventional echocardiographer may not also furnish anesthesiology during the same procedure. The interventional cardiologist and cardiac surgeon may jointly participate in the intra-operative technical aspects of TEER as appropriate. All physicians who participate in the procedure must have device-specific training as required by the manufacturer.

    5. Mitral valve TEERs must be furnished in a hospital with appropriate infrastructure and experience that includes, but is not limited to:
      1. On-site heart valve surgery and interventional cardiology programs;
      2. Post-procedure intensive care facility with personnel experienced in managing patients who have undergone open-heart procedures;
      3. Hospital volume requirements below must be met and maintained:
        1. ≥ 20 mitral valve surgical procedures for severe MR per year or ≥ 40 over two years, of which at least 10 (or 20 over two years) must be mitral valve repairs; and
        2. ≥ 2 physicians with cardiac surgery privileges experienced in valvular surgery; and
        3. ≥ 1 physician with interventional cardiology privileges; and
        4. ≥ 300 percutaneous coronary interventions (PCIs) per year.

    6. The heart team and hospital are participating in a prospective, national, audited registry that: 1) comprehensively enrolls TEER patients; 2) accepts all manufactured devices; 3) follows the patient for at least one year; and, 4) complies with relevant regulations relating to protecting human research subjects, including 45 CFR Part 46 and 21 CFR Parts 50 & 56.

      The following outcomes must be tracked by the registry, and the registry must be designed to permit identification and analysis of patient, practitioner, and facility level variables that predict each of these outcomes:

      1. Stroke;
      2. All-cause mortality;
      3. Repeat TEER or other mitral procedures;
      4. Transient Ischemic Attacks (TIAs);
      5. Major vascular events;
      6. Renal complications;
      7. Functional capacity; and
      8. Quality of Life (QoL).

    7. The registry shall collect all data necessary and have a written executable analysis plan in place to address the following questions. Specifically, for the CED question d, this must be addressed through a composite metric. For the below CED questions (a-e), the results must be reported publicly as described in CED criterion k.

      1. When TEER procedures are performed outside a controlled clinical study, how do outcomes and adverse events compare to the pivotal clinical studies?
      2. How do outcomes and adverse events in subpopulations compare to patients in the pivotal clinical studies?
      3. What is the long-term (≥ 5 year) durability of the device?
      4. What are the long-term (≥ 5 year) outcomes and adverse events?
      5. How do the demographics of registry patients compare to the pivotal studies?

      Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions.

  2. Mitral valve TEERs are covered for uses that are not expressly listed as an FDA-approved indication when performed within a clinical study that fulfills all of the following:

    1. An interventional cardiologist or cardiac surgeon must perform the mitral valve TEER and an interventional echocardiographer must perform transesophageal echocardiography during the procedure. The interventional echocardiographer may not also furnish anesthesiology during the same procedure.  The interventional cardiologist and cardiac surgeon may jointly participate in the intra-operative technical aspects of TEER as appropriate. All physicians who participate in the procedure must have device specific training as required by the manufacturer.

    2. As a fully-described, written part of its protocol, the clinical research trial must critically evaluate the following questions at 12 months or longer follow-up:
      1. What is the rate of all-cause mortality in the intervention group?
      2. What is the rate of re-operations (open surgical or transcatheter) of the mitral valve in the intervention group?
      3. What is the rate of moderate-to-severe or severe MR in the intervention groups?

    3. As a fully-described, written part of its protocol, the clinical research study must critically evaluate not only each patient’s quality of life pre- and post-TEER (minimum 1 year), but must also address at least one of the following questions:
      1. What is the incidence of stroke?
      2. What is the incidence of TIAs?
      3. What is the incidence of major vascular events?
      4. What is the incidence of renal complications?
      5. What is the incidence of worsening MR?
      6. What is the change in quality of life after TEER?
      7. What is the change in the patient’s functional capacity after TEER?

    4. The clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population:
      1. The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects.
      2. The rationale for the study is well supported by available scientific and medical evidence.
      3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
      4. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination.
      5. The study is sponsored by an organization or individual capable of completing it successfully.
      6. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and /or services, and the use and eventual disposition of the collected data.
      7. All aspects of the research study are conducted according to appropriate standards of scientific integrity.
      8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
      9. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options.
      10. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR).
      11. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results).
      12. The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
      13. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

      Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that meet the above-listed standards and address the above-listed research questions.

      The principal investigator must submit the complete study protocol, identify the relevant CMS research question(s) that will be addressed, and cite the location of the detailed analysis plan for those questions in the protocol, plus provide a statement addressing how the study satisfies each of the standards of scientific integrity (a. through m. listed above), as well as the investigator's contact information, to the address below. The information will be reviewed, and approved studies will be identified on the CMS Website.

      Director, Coverage and Analysis Group
      Re: TEER CED
      Centers for Medicare & Medicaid Services (CMS)
      7500 Security Blvd., Mail Stop S3-02-01
      Baltimore, MD 21244-1850

      Email address for protocol submissions: clinicalstudynotification@cms.hhs.gov
      Email subject line: "CED TEER [name of sponsor/primary investigator]"

  3. TEER of the mitral valve is not covered under the following circumstances:
    1. For patients in whom existing co-morbidities would preclude the expected benefit from a mitral valve TEER procedure.
    2. In patients with untreated severe aortic stenosis.

  4. CMS will consider published, peer-reviewed evidence periodically, following the effective date of this NCD and reconsider the policy when appropriate.  The NCD will expire 10 years from the effective date if it is not reconsidered during that time.  Upon expiration, coverage will be at the discretion of Medicare Administrative Contractors (MACs). 

See Appendix B for NCD Manual language.

Decision Memo

TO: 			Administrative File:  CAG-00438R

FROM: 		Tamara Syrek Jensen, JD
			Director, Coverage and Analysis Group
		
			Joseph Chin, MD, MS
			Deputy Director, Coverage and Analysis Group
		
			Steven A. Farmer, MD, PhD
			Chief Strategy Officer and Lead Medical Officer
		
			Melissa A. Evans, PhD, MSAE
			Director, Division of Policy and Evidence Review

			Lori Ashby, MA
			Deputy Director, Division of Policy and Evidence Review
		
			Andrew Ward, PhD, MPH
			Director, Evidence Development Division
		
			Sarah Fulton, MHS
			Technical Advisor
		
			Kimberly Long
			Lead Analyst
		
SUBJECT: 	National Coverage Determination for Transcatheter Edge-to-Edge Repair (TEER) for Mitral Valve Regurgitation

DATE: 		January 19, 2021

I. Decision

For clarity, we are replacing the term Transcatheter Mitral Valve Repair (TMVR) with mitral valve Transcatheter Edge-to-Edge Repair (TEER) to more precisely define the treatment addressed in this proposed NCD, which is applicable to TEER for the treatment of functional mitral regurgitation (MR) and degenerative MR.

TEER of the mitral valve is covered under Coverage with Evidence Development (CED) as follows:

  1. For the treatment of symptomatic moderate-to-severe or severe functional mitral regurgitation (MR) when the patient remains symptomatic despite stable doses of maximally tolerated guideline-directed medical therapy (GDMT) plus cardiac resynchronization therapy, if appropriate, or for the treatment of significant symptomatic degenerative MR when furnished according to an FDA-approved indication and when all of the following conditions are met:

    1. The procedure is furnished with a mitral valve TEER system that has received FDA premarket approval (PMA).

    2. The patient (preoperatively and postoperatively) is under the care of a heart team: a cohesive, multidisciplinary, team of medical professionals.  The heart team concept embodies collaboration and dedication across medical specialties to offer optimal patient-centered care. The heart team must include the following members with experience and training as specified:
      1. Cardiac surgeon
        1. With ≥ 20 mitral valve surgeries per year or ≥ 40 over two years, 50% of which are mitral valve repairs; and
        2. Who is board eligible or certified in cardiothoracic surgery or similar foreign equivalent.
      2. Interventional cardiologist
        1. With professional experience of ≥ 50 career structural heart disease procedures; or ≥ 30 left-sided structural procedures per year; and
        2. With participation in ≥ 20 career trans-septal interventions including 10 as primary or co-primary operator; and
        3. Who is board eligible or certified in interventional cardiology or similar foreign equivalent.
      3. Interventional echocardiographer (cardiologist or anesthesiologist)
        1. With professional experience of ≥ 10 trans-septal guidance procedures and ≥ 30 structural heart procedures; and
        2. Who is board eligible or certified in transesophageal echocardiography with advanced training as required for privileging by the hospital where the TEER is performed.
      4. Heart failure cardiologist experienced in treating patients with advanced heart failure (only required for functional MR patients); and
      5. Providers from other physician groups as well as advanced patient practitioners, nurses, research personnel, and administrators.

    3. Each patient’s suitability for surgical mitral valve repair, TEER, or palliative therapy must be evaluated, documented, and made available to other heart team members. Additionally, for patients with functional MR, the heart team heart failure cardiologist must document that the patient has persistent symptoms despite maximally tolerated GDMT and cardiac resynchronization therapy, if appropriate, as described below:
      1. For patients with functional MR: the heart team interventional cardiologist and heart team heart failure cardiologist independently evaluate the patient using information in the medical record and a face-to-face examination.  To decrease patient burden, the heart team heart failure cardiologist may meet this requirement through a review of the patient’s records and images if the patient has an established relationship with a cardiologist experienced in treating patients with advanced heart failure.
      2. For patients with degenerative MR: the heart team interventional cardiologist and heart team cardiac surgeon must independently evaluate the patient using information in the medical record and a face-to-face examination.

    4. An interventional cardiologist or cardiac surgeon from the heart team must perform the mitral valve TEER and an interventional echocardiographer from the heart team must perform transesophageal echocardiography during the procedure.  The interventional echocardiographer may not also furnish anesthesiology during the same procedure. The interventional cardiologist and cardiac surgeon may jointly participate in the intra-operative technical aspects of TEER as appropriate. All physicians who participate in the procedure must have device-specific training as required by the manufacturer.

    5. Mitral valve TEERs must be furnished in a hospital with appropriate infrastructure and experience that includes, but is not limited to:
      1. On-site heart valve surgery and interventional cardiology programs;
      2. Post-procedure intensive care facility with personnel experienced in managing patients who have undergone open-heart procedures;
      3. Hospital volume requirements below must be met and maintained:
        1. ≥ 20 mitral valve surgical procedures for severe MR per year or ≥ 40 over two years, of which at least 10 (or 20 over two years) must be mitral valve repairs; and
        2. ≥ 2 physicians with cardiac surgery privileges experienced in valvular surgery; and
        3. ≥ 1 physician with interventional cardiology privileges; and
        4. ≥ 300 percutaneous coronary interventions (PCIs) per year.

    6. The heart team and hospital are participating in a prospective, national, audited registry that: 1) comprehensively enrolls TEER patients; 2) accepts all manufactured devices; 3) follows the patient for at least one year; and, 4) complies with relevant regulations relating to protecting human research subjects, including 45 CFR Part 46 and 21 CFR Parts 50 & 56.

      The following outcomes must be tracked by the registry, and the registry must be designed to permit identification and analysis of patient, practitioner, and facility level variables that predict each of these outcomes:

      1. Stroke;
      2. All-cause mortality;
      3. Repeat TEER or other mitral procedures;
      4. Transient Ischemic Attacks (TIAs);
      5. Major vascular events;
      6. Renal complications;
      7. Functional capacity; and
      8. Quality of Life (QoL).

    7. The registry shall collect all data necessary and have a written executable analysis plan in place to address the following questions. Specifically, for the CED question d, this must be addressed through a composite metric. For the below CED questions (a-e), the results must be reported publicly as described in CED criterion k.

      1. When TEER procedures are performed outside a controlled clinical study, how do outcomes and adverse events compare to the pivotal clinical studies?
      2. How do outcomes and adverse events in subpopulations compare to patients in the pivotal clinical studies?
      3. What is the long-term (≥ 5 year) durability of the device?
      4. What are the long-term (≥ 5 year) outcomes and adverse events?
      5. How do the demographics of registry patients compare to the pivotal studies?

      Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions.

  2. Mitral valve TEERs are covered for uses that are not expressly listed as an FDA-approved indication when performed within a clinical study that fulfills all of the following:

    1. An interventional cardiologist or cardiac surgeon must perform the mitral valve TEER and an interventional echocardiographer must perform transesophageal echocardiography during the procedure. The interventional echocardiographer may not also furnish anesthesiology during the same procedure.  The interventional cardiologist and cardiac surgeon may jointly participate in the intra-operative technical aspects of TEER as appropriate. All physicians who participate in the procedure must have device specific training as required by the manufacturer.

    2. As a fully-described, written part of its protocol, the clinical research trial must critically evaluate the following questions at 12 months or longer follow-up:
      1. What is the rate of all-cause mortality in the intervention group?
      2. What is the rate of re-operations (open surgical or transcatheter) of the mitral valve in the intervention group?
      3. What is the rate of moderate-to-severe or severe MR in the intervention groups?

    3. As a fully-described, written part of its protocol, the clinical research study must critically evaluate not only each patient’s quality of life pre- and post-TEER (minimum 1 year), but must also address at least one of the following questions:
      1. What is the incidence of stroke?
      2. What is the incidence of TIAs?
      3. What is the incidence of major vascular events?
      4. What is the incidence of renal complications?
      5. What is the incidence of worsening MR?
      6. What is the change in quality of life after TEER?
      7. What is the change in the patient’s functional capacity after TEER?

    4. The clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population:
      1. The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects.
      2. The rationale for the study is well supported by available scientific and medical evidence.
      3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
      4. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination.
      5. The study is sponsored by an organization or individual capable of completing it successfully.
      6. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and /or services, and the use and eventual disposition of the collected data.
      7. All aspects of the research study are conducted according to appropriate standards of scientific integrity.
      8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
      9. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options.
      10. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR).
      11. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results).
      12. The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
      13. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

      Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that meet the above-listed standards and address the above-listed research questions.

      The principal investigator must submit the complete study protocol, identify the relevant CMS research question(s) that will be addressed, and cite the location of the detailed analysis plan for those questions in the protocol, plus provide a statement addressing how the study satisfies each of the standards of scientific integrity (a. through m. listed above), as well as the investigator's contact information, to the address below. The information will be reviewed, and approved studies will be identified on the CMS Website.

      Director, Coverage and Analysis Group
      Re: TEER CED
      Centers for Medicare & Medicaid Services (CMS)
      7500 Security Blvd., Mail Stop S3-02-01
      Baltimore, MD 21244-1850

      Email address for protocol submissions: clinicalstudynotification@cms.hhs.gov
      Email subject line: "CED TEER [name of sponsor/primary investigator]"

  3. TEER of the mitral valve is not covered under the following circumstances:
    1. For patients in whom existing co-morbidities would preclude the expected benefit from a mitral valve TEER procedure.
    2. In patients with untreated severe aortic stenosis.

  4. CMS will consider published, peer-reviewed evidence periodically, following the effective date of this NCD and reconsider the policy when appropriate.  The NCD will expire 10 years from the effective date if it is not reconsidered during that time.  Upon expiration, coverage will be at the discretion of Medicare Administrative Contractors (MACs). 

See Appendix B for NCD Manual language.

II. Background

Throughout this document, we use numerous acronyms, some of which are not defined as they are presented in direct quotations.  Please find below a list of these acronyms and corresponding full terminology:

6-MWT - 6 minute walk test
AATS - American Association for Thoracic Surgery
ACC - American College of Cardiology
ACCF – American College of Cardiology Foundation
AHA – American Heart Association
CAP – continuous access protocol
CDS – clip delivery system
CED - Coverage with Evidence Development
CFR – Code of Federal Regulations
CHF - congestive heart failure
CMS - Centers for Medicare & Medicaid Services
COAPT – Clinical Outcomes Assessment of the MitraClip™ Percutaneous Therapy
DMR - degenerative mitral regurgitation
EACTS – European Association for Cardio-Thoracic Surgery
ESC – European Society of Cardiology
FDA - U.S. Food and Drug Administration
FDM - final decision memorandum
FMR - functional mitral regurgitation
GDMT – guideline directed medical therapy
GI – gastrointestinal
HRR – high risk registry
HRS – high risk study
IVC – inferior vena cava
KCCQ – Kansas City Cardiomyopathy Questionnaire
LV- left ventricle
LVEF - left ventricular ejection fraction
MCS – Mental Component Summary
MELD – model for end stage liver disease
MI - myocardial infarction
MLHFQ – Minnesota Living with Heart Failure Questionnaire
MR - mitral regurgitation
MV - mitral valve
NCA - National Coverage Analysis
NCD - National Coverage Determination
NCDR - National Cardiovascular Data Registry
NYHA - New York Heart Association
PCI – percutaneous coronary intervention
PSC – Physical Component Summary
PDM – proposed decision memorandum
PMA – FDA premarket approval
PR – prohibitive risk
QoL - Quality of Life
RCT - randomized controlled trial
RoPR - Registry of Patient Registries
SCAI - Society for Cardiovascular Angiography and Interventions
SSED – Summary of Safety and Effectiveness Data
STS - Society of Thoracic Surgeons
TA – technology assessment
TAVR – Transcatheter Aortic Valve Replacement
TEE – transesophageal echocardiography
TIA – transient ischemic attack
TMVR - Transcatheter Mitral Valve Repair
TR – tricuspid regurgitation
TRAMI – transcatheter mitral valve interventions
U - unit
US - United States

Mitral Regurgitation

Mitral regurgitation (MR) is the backward flow of blood during left ventricular (LV) systole, which over time may lead to progressive symptoms and structural changes to the heart, including progressive ventricular dilation and worsening left ventricular function.  Degenerative (primary) MR (DMR) results from structural failure of the mitral valve; functional (secondary) MR (FMR) results from left ventricular (LV) dysfunction with a largely preserved mitral valve.  The underlying left ventricular dysfunction may be caused by coronary artery disease or numerous other causes.1 Thus, primary and secondary MR are distinct conditions and are considered separately in this NCD.  Throughout this decision memorandum the terms “primary” and “degenerative” and the terms “secondary” and “functional” are used interchangeably.

An estimated 5.7 million people have systolic heart failure, of whom approximately 15% have moderate-to-severe or severe MR 2,3; the prognosis is worse for heart-failure patients who also have MR.4-7 Impairment of LV function decreases survival, and the prognosis is variable depending on the cause.  Addition of significant secondary MR to a dysfunctional LV compounds the problem by contributing to heart wall stress, ventricular dilation, and heart failure.1

Treatment of Secondary Mitral Regurgitation

The normal heart has four one-way valves that help to direct blood flow from the body, through the lungs, and back to the body.  These valves may malfunction, either by resisting blood flow (e.g., stenosis) or by allowing blood flow in the wrong direction (e.g., regurgitation).  The mitral valve is located on the left side of the heart between the left atrium and the left ventricle.  It is a complex geometric structure and may malfunction over time, either because one or more of its components fail (e.g., valve leaflets, annulus, chordae tendinae, or papillary muscles) or because the left ventricle is not functioning properly.  When the valve structure itself fails, it is termed primary or degenerative MR (DMR); when the valve remains relatively normal but closes incompletely because the left ventricle is abnormal, it is termed secondary or functional MR (FMR).  Common causes of DMR include abnormalities present from birth, infection, and degeneration over time.  The causes of FMR include coronary artery disease and heart failure with left ventricular enlargement due to a number of causes.  Patients with moderate-to-severe or severe MR may experience a number of symptoms, including shortness of breath, decreased stamina, palpitations, and fluid retention. 

For many patients with DMR, cardiac surgery with valve repair or replacement offers a durable treatment, with favorable quality of life and survival outcomes.8-10 For patients at prohibitive surgical risk, a less invasive catheter-based repair may decrease symptoms, improve quality of life, and improve survival, but its efficacy to reduce mitral regurgitation remains inferior to surgery.11,12 The only catheter-based treatment that is available as of early 2021 involves clipping of the mitral valve leaflets together to create a double or triple mitral valve opening that improves closure of the valve and decreases regurgitation.  This transcatheter edge-to-edge repair (TEER) treatment approximates the anterior and posterior mitral valve leaflets by grasping them with a clipping device in an approach similar to a treatment developed in cardiac surgery called the Alfieri stich.  TEER (formerly termed transcatheter mitral valve repair, TMVR) was the subject of a national coverage determination (20.33) in 2014. 

Because secondary MR is largely a consequence of LV dysfunction, the initial approach to treatment addresses the underlying heart failure.  FMR is more dynamic than DMR, and the severity may change over a short time frame as a consequence of alterations to blood pressure, blood volume, or medications. 3,13,14 Thus, the severity of secondary MR can only be reliably assessed following introduction of maximally tolerated doses of guideline directed medical treatment (GDMT), with sufficient time to gauge response to therapy.  If significant symptomatic MR persists despite GDMT and cardiac resynchronization therapy (if the patient is a candidate), the prognosis is worse, and interventions to address the MR may be appropriate and beneficial.15 Cardiac surgery for secondary MR has been shown to improve symptoms but not survival, and consequently it carries a Class of Recommendation IIb, Level of Evidence B guidance from the American Heart Association / American College of Cardiology.16 A Class IIb recommendation means that the procedure might be reasonable, but its effectiveness is not well established. However, recent evidence reviewed here demonstrates that TEER may improve symptoms, quality of life, and survival of appropriately selected patients with secondary MR.17,18

Guideline Directed Medical Treatment (GDMT)

The specialty societies publish detailed guidelines for the diagnosis and management of heart failure.  The most recent full guideline was published in 2013, with a focused update in 2016.19,20 In addition to lifestyle changes, cornerstones of pharmacologic treatment of systolic heart failure include angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid antagonists (MRA), and diuretics.  For eligible patients, implantable cardiac defibrillators (ICD) can improve survival,21 while cardiac resynchronization therapy (CRT) can improve symptoms, reduce MR, reduce hospitalizations, and increase survival.22

Isolated Mitral Valve Surgery

The evidence to support TEER for secondary MR is limited.  As described above, mitral valve surgery may reduce the severity of MR, but it does not consistently lead to improvement in left ventricular function or functional status, and there is no clear evidence of improved survival.23 Consequently, the AHA/ACC guideline for the management of valve disease does not recommend isolated mitral valve surgery for secondary MR but states that surgery may be “considered” in patients with severe symptomatic MR despite GDMT (class IIb indication).16 The ACC/AHA heart failure guidelines notes that isolated mitral valve surgery for secondary MR is “of uncertain benefit,” but may be “considered” in carefully selected patients.19 (As part of the consideration, the clinical team needs to weigh the benefit in the context of the patient’s surgical risk [high, intermediate, or low].)  Consequently, approximately half of patients with symptomatic moderate or severe secondary MR do not undergo surgery, in part due to under-referral and under-treatment.24,25

III. History of Medicare Coverage

CMS issued an NCD on August 7, 2014 establishing coverage for TMVR under Coverage with Evidence Development (CED). For TMVR procedures used to treat significant symptomatic DMR when furnished according to a Food and Drug Administration (FDA)-approved indication, the NCD contained requirements including volume requirements for heart teams and hospitals as well as participation in a prospective, national, audited registry.

The NCD required TMVR procedures for uses that are not expressly listed as an FDA-approved indication to be performed in an FDA-approved randomized controlled trial (RCT) that meets requirements set forth in the NCD and are approved by CMS.  In the existing NCD TEER (TMVR) for secondary MR is essentially non-covered.

The policy was codified in section 20.33 of the Medicare National Coverage Determination Manual (Pub. 100-03). Section 20.33 of the NCD Manual is included in Appendix C.

A.  Current Request

CMS received a complete, formal request to reconsider the TMVR NCD from the Society of Thoracic Surgeons (STS), the American College of Cardiology (ACC), the American Association for Thoracic Surgery (AATS), and the Society for Cardiovascular Angiography & Interventions (SCAI). The request letter is available at https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id297.pdf.

B.  Benefit Category

For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act [§1812 (Scope of Part A); §1832 (Scope of Part B); §1861(s) (Definition of Medical and Other Health Services)].
TEER qualifies as:

  • Inpatient hospital services.
  • Physicians’ services.

Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

IV. Timeline of Recent Activities 


DateAction

August 14, 2019

CMS posts a tracking sheet announcing the opening of the NCA. The initial 30-day public comment period begins.

September 13, 2019

First public comment period ends.  CMS receives 26 comments.

June 30, 2020

Proposed decision memorandum posted. 30-day public comment period begins.

July 30, 2020

30-day public comment period ends. CMS receives 295 comments.


V.  Food and Drug Administration (FDA) Status

On October 24, 2013, the FDA approved the first TMVR device, Abbott Vascular’s MitraClip™ “for the percutaneous reduction of significant symptomatic mitral regurgitation (MR ≥ 3+) due to primary abnormality of the mitral apparatus [degenerative MR] in patients who have been determined to be at prohibitive risk for mitral valve surgery by a heart team, which includes a cardiac surgeon experienced in mitral valve surgery and a cardiologist experienced in mitral valve disease, and in whom existing comorbidities would not preclude the expected benefit from reduction of the mitral regurgitation.” FDA approval included requirements for annual reporting and two post approval studies (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P100009).

On March 14, 2019, the FDA expanded the approved indications for MitraClip™ to include the treatment, when used with maximally tolerated guideline-directed medical therapy (GDMT), of symptomatic, moderate-to-severe or severe secondary (or functional) mitral regurgitation (MR ≥  Grade III  per American Society of Echocardiography criteria) in patients with a left ventricular ejection fraction (LVEF) ≥ 20% and ≤ 50%, and a left ventricular end systolic dimension (LVESD) ≤ 70 mm whose symptoms and MR severity persist despite maximally tolerated GDMT as determined by a multidisciplinary heart team experienced in the evaluation and treatment of heart failure and mitral valve disease. FDA approval also included requirements for annual reporting as well as one post-approval study and one post-approval surveillance (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P100009S028).

VI. General Methodological Principles

When making NCDs, CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.  The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries.  An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.

A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A.

Public comments sometimes cite published clinical evidence and give CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. Public comments that contain personal health information will be redacted or will not be made available to the public. CMS responds in detail to the public comments on a proposed national coverage determination when issuing the final national coverage determination.

VII. Evidence

A.  Introduction

This section provides a summary of the evidence we considered during our review.  The evidence presented here includes the published medical literature on pertinent clinical research of TEER for moderate-to-severe or severe secondary (functional) MR along with additional evidence relating to primary (degenerative) MR.  This proposed NCD applies to all TEER procedures for mitral valve regurgitation.  Transcatheter edge-to-edge repair (TEER) approximates the anterior and posterior mitral valve leaflets by grasping them with a clipping device in an approach similar to a treatment first developed in cardiac surgery called the Alfieri stich.  As of early 2021, the MitraClip™ is the only FDA market authorized TEER device and the reviewed literature references MitraClip™. This assessment does not address distinct approaches, such as technologies that involve transcatheter valve replacement, transcatheter annular modification, transcatheter chordal repair, and others.

B.  Discussion of Evidence

1.  Evidence Question(s)

The following questions guide our review and analysis of the evidence on the clinical utility of TEER for secondary MR in Medicare beneficiaries with cardiac symptoms, reduced left ventricular function, and moderate-to-severe or severe MR despite stable maximal doses of guideline-directed medical therapy (GDMT) (also referred to as optimized medical therapy [OMT]):

  • Is the evidence sufficient to conclude that TEER improves health outcomes for Medicare beneficiaries with cardiac symptoms, reduced left ventricular function, and moderate-to-severe or severe secondary MR despite stable maximal doses of GDMT and does surgical risk (high, intermediate, or low) affect this determination?

If the answer is positive for any of the surgical risk categories:

  • Is the available evidence adequate to identify the characteristics of the patient, practitioner or facility to predict which beneficiaries are more likely to experience overall benefit or harm from TEER for cardiac symptoms, reduced left ventricular function, and moderate-to-severe or severe secondary MR despite stable maximal doses of GDMT?

2.  External Technology Assessments

CMS did not request an external technology assessment (TA) on this issue. Our review did not identify Cochrane or Evidence-based Practice Center (EPC) reviews of TEER. 

3.  Internal Technology Assessment

Literature Search Methods

For this reconsideration, we performed a systematic literature review of PubMed, Scopus, and Cochrane with the following search terms: (1) English language; (2) functional mitral regurgitation or secondary mitral regurgitation; and (3) edge-to-edge mitral valve repair or transcatheter mitral valve repair.  The review included published medical literature from 2006 to early 2020 to determine reasonable and necessary indications for TEER for secondary mitral regurgitation.  Our review found that varied patient populations have been included in the publisheed studies, consensus statements, and guidelines.

This section provides a summary of the evidence we considered during our review.  The evidence focused on TEER for secondary MR, population risk factors, and endpoints.  It excluded research reports with fewer than 50 patients or that followed patients for less than 1 year.

Two randomized controlled trials published before October 2019 evaluated the effectiveness and safety of TEER in patients with cardiac symptoms, reduced left ventricular function and moderate-to-severe or severe secondary MR.  The trials included patient populations with cardiac symptoms and reduced left ventricular function despite GDMT and followed outcomes for 12 – 24 months.  The Evidence Review below provides further details on these trials followed by a summary of evidence from other study designs, including four reports on the multicenter German Transcatheter Mitral Valve Interventions (TRAMI) Registry.

Randomized Controlled Trials

Obadia, J. F., Messika-Zeitoun, G. Leurent, B. et al. (2018). “Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation.” N Engl J Med 379(24):2297‐2306.26

Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR) was a multicenter trial performed in France.  The aim of this prospective, parallel, randomized controlled trial was to compare transcatheter edge-to-edge repair (TEER) of the mitral valve using the MitraClip device against standard medical therapy for patients with reduced left ventricular function and severe secondary MR.  Severe secondary MR was defined as an effective regurgitant orifice area of >20 mm2 or a regurgitant volume of >30 ml per beat; left ventricular systolic dysfunction was defined as a left ventricular ejection fraction (LVEF) between 15 and 40%; all patients were symptomatic.  Notable exclusions included severe tricuspid regurgitation and severe lung disease.

The study randomized 152 patients to TEER (plus GDMT) and 152 to GDMT alone.  The demographics for the TEER (plus GDMT) patients were age 70.1 years, 78.9% male, and New York Heart Association (NYHA) classes II (36.8%), III (53.9%), and IV (9.2%).  The median EuroSCORE II was 6.6, the mean LVEF was 33.3%, and the median indexed LVEDV was 136.2 ml/m2.  For the GDMT alone group, the study demographics were: 70.6 years, 70.4% male, NYHA class II 28.9%, III 63.2%, IV 7.9%, median EuroSCORE II: 5.9, mean LVEF 32.9%, and median indexed LVEDV 134.5 ml/m2, respectively.  The primary efficacy outcome was a composite of death from any cause or unplanned hospitalization for heart failure at 12 months. 

In 14 patients (9.2%) in the intervention group, either the procedure was not performed or the device implantation failed; the device was successfully implanted in 95.8% of those in whom it was attempted.  A total of 21 of the 144 patients (14.6%) in whom implantation was attempted had periprocedural complications, including device implantation failure, hemorrhage resulting in transfusion, atrial septum lesion or defect, cardiogenic shock requiring inotropic support, cardiac embolism, tamponade, or urgent conversion to heart surgery.  At 12 months, the rate of the primary outcome was 54.6% (83 of 152 patients) in the TEER (plus GDMT) group and 51.3% (78 of 152 patients) in the group receiving GDMT alone (odds ratio, 1.16; 95% confidence interval [CI], 0.73 to 1.84; P=0.53).  The rate of death from any cause was 24.3% (37 of 152 patients) in the TEER (plus GDMT) group and 22.4% (34 of 152 patients) in the group receiving GDMT alone (hazard ratio, 1.11; 95% CI: 0.69 to 1.77).  The rate of unplanned hospitalization for heart failure was 48.7% (74 of 152 patients) in the TEER (plus GDMT) group and 47.4% (72 of 152 patients) in the group receiving GDMT alone (hazard ratio, 1.13; 95% CI: 0.81 to 1.56).

The authors acknowledged the following limitations: First, 14 patients (9.2%) in the intervention group either did not undergo the procedure or the device implantation failed.  However, in the per-protocol analysis that excluded the data from these patients, there were no significant differences in outcomes between the two groups at 12 months.  Second, there was missing follow-up data for the assessments of echocardiographic, functional status, natriuretic peptide, and quality of life.  However, 99% of the patients had complete data at 12 months.  Third, the trial was not powered to detect small differences between the groups.

The authors concluded that “the rate of death or unplanned hospitalization for heart failure at 1 year did not differ significantly between patients who underwent [TEER] in addition to receiving medical therapy and those who received medical therapy alone.”

Stone, G. W., Lindenfeld, J. A., Abraham, S. et al. (2018). “Transcatheter Mitral-Valve Repair in Patients with Heart Failure.” N Engl J Med 379(24):2307-2318.17

The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (COAPT) Trial was a multicenter study conducted in the United States and Canada.  The aim of this randomized, controlled trial was to compare transcatheter edge-to-edge (TEER) mitral valve repair using the MitraClip device (plus GDMT) against GDMT alone for patients with reduced left ventricular function and moderate-to-severe or severe secondary MR.  Patients were eligible for enrollment only if they remained symptomatic despite the use of stable maximal doses of GDMT, with cardiac resynchronization therapy if appropriate, and were supervised by a heart-failure specialist.  The heart team, which consisted of a heart-failure specialist, an interventional cardiologist, and a cardiothoracic surgeon with expertise in mitral valve disease, assessed patients for TEER.  The interventional cardiologist confirmed that the patient was anatomically eligible for device implantation, and the cardiothoracic surgeon determined that mitral valve surgery was not appropriate.  Notable exclusions included severe tricuspid regurgitation and severe lung disease. 

Clinical follow-up was scheduled at 1 week and at 1, 6, 12, 18, and 24 months after the implantation procedure in the device (plus GDMT) group and after a visit with the site heart-failure specialist in the GDMT alone group and then annually through 5 years.  The primary effectiveness endpoint was all hospitalizations for heart failure within 24 months of follow-up.  The primary safety endpoint was freedom from device-related complications at 12 months; the investigators compared the rate for this endpoint with a pre-specified objective performance goal of 88.0%.  They conducted the analysis of the primary effectiveness endpoint including all hospitalizations for heart failure using a joint frailty model to account for correlated events and the competing risk of death.  All effectiveness analyses were performed from the time of randomization according to intention-to-treat.

Of the 614 enrolled patients in the trial, 302 were assigned to the device group and 312 to the medical therapy group.  The study demographics for the TEER (plus GDMT) group included: median age 71.7 years, 66.6% male, and a mean STS risk score of 7.8%.  The NYHA classes were: I 0.3%, II 42.7%, III 51.0%, and IV but ambulatory (IVa) 6.0%.  The mean LVEF for TEER (plus GDMT) patients was 31.3%, and the indexed LVEDV was 101 ml/m2.  For the GDMT alone group, these baseline demographics included: 72.8 years, 61.5% male, STS risk score 8.5%, NYHA classes I 0%, II 35.4%, III 54.0%, IVa 10.6%, and mean left EF 31.3%. 

The clip implantation rate was 98% with 95% achieving an immediate MR grade of ≤ 2+.  The annualized rate of all hospitalizations for heart failure within 24 months was 35.8% per patient-year in the device (plus GDMT) group as compared with 67.9% per patient-year in the group receiving GDMT alone (hazard ratio, 0.53; 95% confidence interval [CI], 0.40 to 0.70; P<0.001). Freedom from device-related complications at 12 months was 96.6% (lower 95% confidence limit, 94.8%; P<0.001), exceeding the pre-specified safety threshold of 88%.  Death from any cause within 24 months occurred in 29.1% in the device (plus GDMT) group versus 46.1% in the GDMT alone group (hazard ratio, 0.62; 95% CI: 0.46 to 0.82; P<0.001).  The lower rate of hospitalization for heart failure with a device-based treatment emerged within 30 days after treatment.  The lower mortality predominantly emerged more than 1 year after treatment. 

The authors acknowledged the following limitations:  First, the investigators were aware of assignments because the TEER device was visible on imaging studies.  Efforts to mitigate bias included rigorous protocol-specified procedures to standardize GDMT, the use of an independent events committee and a central echocardiographic core laboratory.  Second, the median follow-up was longer in the device (plus GDMT) group than in the GDMT alone group, in part an artifact of the lower mortality in the device group.  Conversely, withdrawal from the trial was more frequent in the GDMT alone group.  The principal results were consistent after imputation for missing data.  Third, agents that affect the renin-angiotensin axis were used more frequently at baseline in the device (plus GDMT) group by chance.  However, the principal findings were robust after adjustment for these differences.  Fourth, the trial is ongoing and long-term follow-up is necessary to fully characterize the safety and effectiveness of the device.  Lastly, the enrolled patients were symptomatic despite the use of maximal doses of GDMT and had moderate-to-severe or severe MR, a LVEF of 20 – 50%, and frequent coexisting conditions.   Results in patients who are less or more critically ill or in those with less severe MR is unknown.

The authors concluded that TEER of the mitral valve (plus GDMT) resulted in a lower rate of hospitalization for heart failure and lower all-cause mortality within 24 months of follow-up than GDMT alone.  The benefits were consistent across numerous subgroups, including patients who had ischemic and non-ischemic cardiomyopathy and those who were and were not at high risk for surgery-related complications and death; the benefits were independent of the MR grade and LV volume and function at baseline.

Arnold, S. V., Khaja, M. Chinnakondepalli, M. S. et al. (2019). “Health Status after Transcatheter Mitral-Valve Repair in Heart Failure and Secondary Mitral Regurgitation: COAPT Trial.”  J Am Coll Cardiol 73(17):2123-2132.18

This study presents additional data from the COAPT trial.  The aim was to describe health status outcomes following transcatheter edge-to-edge repair (TEER) of the mitral valve (plus GDMT) versus GDMT alone.  Investigators assessed health status at baseline and at 1, 6, 12, and 24 months with the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the SF-36 health status survey.  The primary health status endpoint was the KCCQ overall summary score (KCCQ-OS). 

The COAPT trial randomized patients with heart failure and 3+ to 4+ secondary MR to TEER (plus GDMT) (n = 302) or GDMT alone (n = 312).  The study demographics for the TEER (plus GDMT) group were median age 71.7 years, 66.6% male, and a mean STS risk score of 7.8%.  The NYHA classes were: I 0.3%, II 42.7%, III 51.0%, and IVa 6.0%.  The mean LVEF for TEER (plus GDMT) patients was 31.3%, and the indexed LVEDV was 101 ml/m2.  (See Stone et al. for the baseline demographics on the comparator group of GDMT alone.)  At baseline, patients had substantially impaired health status (mean KCCQ-OS 52.4 ± 23.0: TEER [plus GDMT] 53.2 versus GDMT alone 51.6).  While health status was unchanged over time in the GDMT alone arm, patients randomized to TEER (plus GDMT) demonstrated substantial improvement in the KCCQ-OS at 1 month (mean between-group difference 15.9 points; 95% CI: 12.3 to 19.5 points), with only slight attenuation of this benefit through 24 months (mean between-group difference 12.8 points; 95% CI: 7.5 to 18.2 points).  At 24 months, 36.4% of TEER (plus GDMT) patients were alive with a moderately large (≥10-point) improvement versus 16.6% in the GDMT alone patients (p < 0.001), for a number needed to treat of 5.1 patients (95% CI: 3.6 to 8.7 patients).  TEER (plus GDMT) patients also reported better generic health status (a physical and mental summary score with minimal clinically important change at approximately 2.5 points) at each time point (24-month mean difference in SF-36 summary scores: physical 3.6 points; 95% CI: 1.4 to 5.8 points; mental 3.6 points; 95% CI: 0.8 to 6.4 points).

The authors noted the following limitations: First, COAPT was a non-blinded trial, which may introduce bias.  Although lack of blinding should have minimal impact on outcomes such as mortality, there is a possibility for a placebo effect when examining patient-reported measures.  However, the authors offered the counter argument that given the magnitude of sustained health status benefit and the concordance of the results with other less-subjective outcomes (including death and rehospitalization), it is unlikely that the health status benefit of TEER is simply a placebo effect.  Second, the authors performed analyses that integrated mortality with health status and health status can only be measured in surviving patients.  Third, the durability of the health status benefit of TEER beyond 24 months is not known.  Finally, the health status results observed in COAPT may not be generalizable to patients outside of the inclusion/exclusion criteria of the trial.  The authors further commented that given the conflicting results of the COAPT and MITRA-FR trials and the limited health status data collected in MITRA-FR, it will be important to investigate the health status outcomes of patients with heart failure and secondary MR treated with TEER both in the real world and among patients who would have been ineligible for COAPT.

The authors concluded that among patients with symptomatic heart failure and 3+ to 4+ secondary MR receiving maximally-tolerated medical therapy, TEER resulted in substantial early and sustained health status improvement compared with medical therapy alone.

Controlled Observational Studies

Whitlow, P., Feldman, T., Pedersen, W.R., et al.  (2012). “Acute and 12-month results with catheter-based mitral valve leaflet repair: the EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study.”  J Am Coll Cardiol 59(2):  130-9.27

The aim of this multicenter, observational study was to evaluate TEER outcomes in a subset of the EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study (HRS) patient cohort with severe symptomatic MR who were at high risk of surgical mortality.  The study enrolled patients with an estimated surgical mortality rate of ≥12%.  The comparator group was comprised of patients with MR severity of >3+ and a predicted surgical mortality rate of >12%, who were screened for enrollment in the HRS but did not enroll or were not anatomically eligible for TEER device placement (identified after the investigators knew the results of the high surgical risk TEER patients).  To analyze the data, investigators used the intention to treat approach, compared mortality using the Clopper-Pearson exact binomial method, and compared survival using the Kaplan-Meier method. 

Seventy-eight patients underwent the TEER procedure.  Their mean age was 77 years, 62.8% were male, and 89.7% had NYHA functional class III or IVa, 62.8% had previous cardiac surgery, 46 had secondary MR, and 32 had primary MR.  TEER devices were successfully placed in 96% of patients.  Sixty-two patients (79.5%) were implanted with a device and achieved at least a 1-grade reduction in MR as determined by the echocardiography core laboratory, and 56 patients (71.8%) had successful device placement and reduction in MR grade to ≤2+.  MR reduction was achieved in 62/75 patients (83%), while no MR reduction was achieved in 13/75 (17%).

The comparator group had 36 patients; mean age 77.2 years, 50% male, NYHA class III or IVa 83.9%, 72.2% had previous cardiac surgery, 23 had secondary MR, and 13 had primary MR. 

The investigators predicted surgical mortality rate based on either the Society of Thoracic Surgeons risk calculator or surgeon co-investigator estimated mortality risk following pre-specified protocol criteria.  They predicted surgical mortality in the HRS and concurrent comparator group to be 18.2% and 17.4%, respectively.  The Society of Thoracic Surgeons calculator estimated mortality rate was 14.2% and 14.9%, respectively.  The 30-day mortality rate was 7.7% in the HRS and 8.3% in the comparator group (p = NS).  The 12-month survival rate was 76% in the HRS and 55% in the concurrent comparator group (p = 0.047).  In surviving patients with matched baseline and 12-month data, 78% had an MR grade of ≤ 2+.  LVEDV improved from 172 ml to 140 ml and end-systolic volume improved from 82 ml to 73 ml (both p = 0.001).  NYHA functional class improved from III/IV at baseline in 89% to class I/II in 74% (p < 0.0001).  Quality of life was improved (Short Form-36 physical component score increased from 32.1 to 36.1 [p = 0.014] and the mental component score from 45.5 to 48.7 [p = 0.065]) at 12 months. The annual rate of hospitalization for congestive heart failure in surviving patients with matched data decreased from 0.59 to 0.32 (p < 0.034).

Of the 78 patients, 46 had secondary MR.  By 12-months, 12 of the 46 (26%) had died.  Of the 34 secondary MR patients with matching baseline data, 79% had sustained MR reduction with ≤ 2+ MR at 1 year by ECL determination.  Twenty-five of 34 (74%) had improvement to NYHA functional class I/II.  LVEDV improved from 192 ml to 153 ml and end-systolic volume improved from 103 ml to 87 ml (both p < 0.001). 

The authors noted the following limitations: The comparator group was recruited retrospectively after investigators knew the results of the TEER patients, the patient number was limited, transesophageal echocardiograms were not available for review in all patients, and several patients did not have appropriate anatomic criteria for TEER and selectively entered the comparator group.  In addition, the echocardiology core lab did not review the transthoracic echocardiograms that determined patient eligibility for the comparator group.  These differences could potentially cause confounding of important variables when comparing the HRS patients with the comparator group.  Despite these limitations, the comparator patients all had symptomatic 3 to 4+ MR by site and contract echocardiographic assessment and had comorbidities and STS scores similar to those of the HRS group.  However, direct comparisons between HRS and the concurrent comparator group should be done with caution.  The authors also cautioned that the matched data comparing baseline to 12-month follow-up may represent an overestimation of the true benefit provided by TEER because it was limited to the patients that survived.

The authors concluded that TEER reduced MR in a majority of patients at high risk of surgery, resulting in improvement in clinical symptoms and significant left ventricular reverse remodeling over 12 months.  They argued that favorable LV remodeling demonstrated that MR reduction achieved by TEER is hemodynamically important.  Long-term follow-up is ongoing and needed to confirm whether the benefits observed at 12 months were sustained.

Swaans M.J., Bakker, A.L., Alipour, A., et al. (2014). “Survival of transcatheter mitral valve repair compared with surgical and conservative treatment in high-surgical-risk patients.” JACC Cardiovasc Interv 7(8):875-81.28

The aim of this observational study was to compare survival between TEER using the MitraClip system, mitral valve surgery, and GDMT in high-surgical risk patients with symptomatic, severe, MR.  The study included 139 consecutive patients treated with TEER.  The investigators retrospectively identified patients discussed by the heart team who would have met TEER criteria but were assessed two years prior to the availability of TEER; these surgically (n = 53) and conservatively (GDMT alone, n = 59) treated patients comprised the comparator group.  Surgical risk was based on the logistic European System for Cardiac Operative Risk Evaluation (log EuroSCORE) or the presence of relevant risk factors, as judged by the heart team.  The investigators used propensity scores with inverse probability weighting, and analyzed the data using a Cox proportional hazards model.

The study demographics for the TEER cohort were as follows: The mean age was 74.6 years, 67.6 were male, and 77% had secondary MR.  Among the high-risk surgery comparator patients, mean age was 70.2 years, 50.9% were male, and 58.5% had secondary MR.  Among the patients treated with GDMT alone, mean age was 71.7 years, 54.2% were male, and 81.3% had secondary MR.  The log EuroSCORE was higher in the TEER group (23.9±16.1%) than in the surgically (14.2±8.9%) and GDMT (18.7±13.2%, p < 0.0001) treated patients.  LVEF was higher in surgical patients (43.9 +/- 14.4%, p = 0.003), with similar values for the TEER cohort (36.8±15.3%) and GDMT treated (34.5±16.5%) groups.

After 1 year of follow-up, the TEER and surgery groups showed similar survival rates (85.8% and 85.2%, respectively), whereas 67.7% of GDMT treated patients survived.  The same trend was observed after the second and third years.  After weighting by propensity score and controlling for risk factors, both the TEER (hazard ratio [HR]: 0.41, 95% CI: 0.22 to 0.78, p = 0.006) and surgical (HR: 0.52, 95% CI: 0.30 to 0.88, p = 0.014) groups showed better survival than the conservatively treated group.  The TEER and surgical groups did not differ (HR: 1.25, 95% CI: 0.72 to 2.16, p = 0.430).

The authors noted the following limitations included the non-randomized design and retrospective recruitment of the comparator groups.  The study was also limited to the primary endpoint of mortality in the three different treatment strategies and secondary endpoints were beyond the scope of the study.

The authors concluded that “Despite a higher log EuroSCORE, high-surgical-risk patients with symptomatic severe MR treated with [TEER] show similar survival rates compared with surgically treated patients, with both displaying survival benefit compared with conservative treatment.”

Velazquez, E. J., Samad, Z., Al-Khalidi, H.R., et al. (2015). “The MitraClip and survival in patients with mitral regurgitation at high risk for surgery: A propensity-matched comparison.” Am Heart J 170(5): 1050-1059.24

The aim of this retrospective observational study of patients drawn from the Duke Echocardiography Laboratory Database (DELD) was to compare high-risk, moderate to severe or severe MR patients treated with TEER using the MitraClip system against propensity matched non-surgically treated patients.  The investigators enrolled patients in the DELD between 2000 and 2010.  They used Kaplan-Meier estimates and stratified Cox proportional hazards models to compare survival at 30 days and 1 year.

The study demographics for TEER patients following propensity score matching were as follows:  The mean age was 73.7, 59.8% were male, and 78.2% had NYHA functional class III or IVa.  The high-risk DELD comparator patients had a mean age of 73.7, 54.4% were male, and 79.8% had NYHA functional class III or IVa.  Close matches were obtained for 239 of the 351 TEER patients.  In the TEER cohort, 82.8% had secondary MR and 17.2% had primary MR.  In the high risk DELD comparator group, 90.8% had secondary MR and 9.2% had primary.  The 30-day mortality in TEER patients was lower (4.2%) when compared with matched DELD patients (7.2%).  The 1-year mortality in TEER patients was lower (22.4%) when compared with matched DELD patients (0.66%).  The 1-year relative risk of mortality of the TEER cohort compared with the high risk DELD comparator cohort was 0.66 (95% CI 0.45-0.99; p = .043). 

The authors noted the following limitations:  Unmeasured but predictive variables could have introduced confounding.  Incomplete matching may have introduced an additional bias.  There were differing methods used between the TEER cohort and the high risk DELD comparator.  The investigators used a blinded core laboratory to define quantitative echocardiographic parameters for TEER patients; this was not performed for the Duke patients.  All patients included in the TEER registries and trials required transesophageal echocardiography to confirm MR etiology and severity, whereas the Duke cohort inception was based on the index transthoracic echocardiogram.  TEER patients completed a left heart catheterization prior to their intervention, but Duke patients did not.  Duke patients were drawn from a time period five years earlier than the TEER cohort, and the authors cannot exclude the possibility that this difference influenced mortality in the two groups.  However, the results were consistent and directionally similar when comparing the total populations without matching, with different levels of matching, and after inverse proportionate weight adjustment, which suggests that confounding is unlikely to have contributed substantially to the findings.  Medication and device use were not systematically collected and are not reported.  All patients were drawn from academic medical centers.

The authors concluded that “this matched comparison of severe MR patients at high surgical risk supports the safety of [TEER using the MitraClip system] relative to medical therapy at 30 days and a survival benefit at 1 year.”

Giannini, C., Fiorelli, F., De Carlo, M., et al. (2016) “Comparison of Percutaneous Mitral Valve Repair versus Conservative Treatment in Severe Functional Mitral Regurgitation.” Am J Cardiol 117(2): 271-277.29

The aim of this prospective observational study was to assess survival rates and clinical outcomes of patients with severe, secondary MR treated with GDMT compared with those treated with GDMT, plus TEER using the MitraClip device.  All patients were enrolled at a single center in Pisa, Italy.  Investigators compared sixty patients treated with GDMT with a cohort of 60 patients who underwent TEER.  GDMT patients were referred for TEER but were not anatomically suitable.  The data were analyzed using propensity score matching and the Kaplan-Meier method.

Baseline demographics and echocardiographic variables were similar between the 2 groups after matching.  The mean age of patients was 75 years, and 67% were men.  The median logistic EuroSCORE and EuroSCORE II were 17% and 6%, respectively.  The mechanism of MR was ischemic in 52% of patients.  Median LVEF was 34%.  All the patients were symptomatic for dyspnea with 63% and 12% in NYHA class III and IV, respectively.

TEER was associated with a very low incidence of procedural complications, with no occurrence of procedural or in hospital mortality.  After a median follow-up of 515 days (248 to 828 days), patients treated with TEER (plus GDMT) demonstrated overall survival, survival freedom from cardiac death and survival free of readmission due to cardiac disease curves higher than patients treated conservatively (p = 0.007, p = 0.002, and p = 0.04, respectively).  Overall probability of survival was 100% at 30 days, 89.7% at 1 year, 71.2% at 2 years, and 61.4% at 3 years in the TEER (plus GDMT) group versus 98.3% at 30 days, 64.3% at 1 year, 51.7% at 2 years, and 34.9% at 3 years in the GDMT group (Hazard ratio 2.31, 95% CI 1.30 to 4.09; log-rank test p=0.007). 

The authors noted the following limitations:  The study was not randomized and had a relatively small sample size.  There was no comparison to a surgical cohort.  The authors did not describe follow-up data, such as NT-proBNP, NYHA functional classification, and echocardiographic parameters and limited reporting on outcomes to overall mortality, cardiac mortality, and rehospitalization rate in the 2 different treatment strategies.

The authors concluded that TEER “offers a valid option for selected patients with high surgical risk and severe, [secondary] MR and entails better survival outcomes compared with [GDMT].”

Armeni, P., Boscolo, P.R., Tarricone, R., et al. (2016) “Real-world cost effectiveness of MitraClip combined with Medical Therapy Versus Medical therapy alone in patients with moderate or severe mitral regurgitation.”  Int J Cardiol 209:153-60.30

The aim of this retrospective observational study was to evaluate the real-world cost-effectiveness of TEER plus GDMT versus GDMT for patients with moderate/severe MR.  Clinical records of patients with moderate to severe secondary MR treated with TEER (N=232) between 2008 and 2012 were compared with a randomly selected sample of those treated with GDMT (N=151) between 2007 and 2009.  The outcomes of interest were life expectancy, incremental quality adjusted life years, hospitalizations, and NYHA functional class.  The investigators analyzed the data using a Cox proportional hazard regression model with propensity score adjustment to reduce selection bias.

The study demographics for TEER (plus GDMT) patients were as follows:  the mean age was 71 years and 73% were male.  For the cohort that used GDMT alone, the mean age was also 71 years and 74% were male.  Baseline demographics and echocardiographic variables were similar between the 2 groups as well.  After propensity score adjustment, the average treatment effect was -9.5% probability of dying at 12 months, and following lifetime modeling, 3.35±0.75 incremental life years and 3.01±0.57 incremental quality-adjusted life years.  TEER contributed to a higher decrease in rehospitalizations at 12 months (difference=-0.54±0.08) and generated a more likely improvement in the NYHA class at 12 months versus NYHA at enrollment.  There was evidence of a learning curve, with procedure time decreasing by 1.3% with each additional intervention.  After 80 patients, the procedure time curve was nearly flat.

The authors noted the following limitations:  First, the study is limited to a relatively low sample size of patients from retrospective observational cohorts.  Despite attempts to account for co-morbidities and the excellent discrimination of the propensity model used for adjustment (c statistic = 0.87), there may have been unmeasured confounding, such as choice of adjunctive treatments.  Reasons for rehospitalization were not conclusively assessed.

The authors concluded that, “compared to MT alone and given conventional threshold values, [TEER that uses the MitraClip system] can be considered a cost-effective procedure.  The cost-effectiveness of [TEER that uses the MitraClip system] is in line or superior to the one of other non-pharmaceutical strategies for heart failure.”

Asgar, A.W., Khairy, P., Guertin, M., et al. (2017) “Clinical outcomes and economic impact of transcatheter mitral leaflet repair in heart failure patients.” J Med Econ 20(1):82-90.31

The aim of this single-center, prospective, Canadian observational study was to evaluate the clinical outcomes and economic impact of GDMT plus TEER using the MitraClip system compared to GDMT alone in heart-failure patients with symptomatic moderate-to-severe or severe MR.  Investigators applied results from an observational study to estimate parameters for the decision model, which estimated costs, and benefits in a hypothetical cohort of patients with heart failure who received GDMT only and moderate-to-severe MR treated with either TEER plus GDMT or GDMT alone.  The investigators used propensity scores to match a cohort of patients treated with TEER (plus GDMT) to a population of heart-failure patients, and extrapolated their outcomes using parametric survival models for a time horizon of 10 years.  They performed exponential, log-normal, and Weibull extrapolations, and choose a Weibull distribution as it was a better fit for the data by Akaike information criteria.

The study demographics for TEER (plus GDMT) patients were as follows:  The mean age of TEER (plus GDMT) patients was 75.4 years, 74% were male, 58% had moderate-to-severe MR, and 42% had severe MR.  The NYHA functional classification for the TEER (plus GDMT) cohort was 2% class II, 32% III, and 66% IVa; for the GDMT alone cohort it was 74% class II, 21.4%  III, and 0% IVa.  At a mean follow-up of 22 months, all-cause mortality was 21% in the TEER (plus GDMT) cohort and 42% in the GDMT alone cohort (p = .007).  The decision model demonstrated that TEER (plus GDMT) increased life expectancy from 1.87-3.60 years and quality-adjusted life years (QALY) from 1.13-2.76 years.

The authors noted the following limitations:  The study had a small sample size, there were baseline differences in NYHA functional class between groups, there was limited follow-up data available, requiring certain assumptions for the purposes of the economic model.  Patients treated with TEER (plus GDMT) represent the early experience of the operators and include the procedural learning curve of this technology.  The medical management cohort was comprised of patients followed in the Heart Failure Clinic in the 2 years prior to availability of the MitraClip. The patients in this cohort had a lower EF than the TEER (plus GDMT) cohort, despite the matching process, and this may be related to their higher mortality at follow-up.  Given the significant differences in baseline functional class between the TEER (plus GDMT) and GDMT alone cohorts, NYHA class was not included in the propensity matching.  As a result, the impact of TEER (plus GDMT) on improved survival, reduced hospitalization costs, ER costs, and mitral valve surgery costs may have been underestimated given that higher NYHA functional classes are associated with increased risk of hospitalization and mortality in heart-failure.

The authors concluded that, TEER using the MitraClip system “in heart failure patients is associated with improved survival compared to standard medical therapy.  The ultimate place for this technology within the armamentarium of heart failure therapy remains to be determined once long-term outcome data become available.  However, treatment decisions for these patients will be required prior to the availability of these data, as such clinicians must make such decisions given the best available data.  Using such data, this analysis indicates that the [TEER] may represent a clinically effective and cost-effective treatment strategy when compared with medical therapy in patients with [secondary MR].”

Kortlandt, F., Velu, J., Schurer, R., et al.  (2018)  “Survival after MitraClip Treatment Compared to Surgical and Conservative Treatment for High-Surgical-Risk Patients with Mitral Regurgitation.” Circ Cardiovasc Interv 11(6): e005985.32

The aim of this multi-center, Dutch, observational study was to examine survival outcomes after TEER, compared with surgical or medical treatment in patients with symptomatic, moderate-to-severe or severe, secondary MR.  Investigators enrolled consecutive high-surgical-risk patients who underwent TEER using the MitraClip device between 2009 and 2016. Investigators retrospectively identified control patients to populate a surgical and conservative treatment control group by examining heart team documentation in the two years prior to MitraClip availability at each participating site.  The investigators analyzed the data using a Cox proportional hazards model built using the backwards stepwise (likelihood ratio) method.

The study demographics for TEER patients were as follows:  the mean age was 74.0 years and 56.5% were male.  For the surgical comparator cohort, the mean age was 69 years and 55% were male.  For the conservative treatment comparator cohort, the mean age was 74 years and 52% were male.  There were significant differences between the baseline characteristics of the 3 studied cohorts, with the TEER cohort having the highest comorbidity burden (See Table).  One thousand thirty-six patients were included in 4 Dutch centers, of which 568 were treated with the TEER, 173 were treated with surgery, and 295 were treated with medical therapy.  The percentage of patients with secondary MR was 64.4% for the TEER, 56.2% for the surgery, and 78.9% for the conservative treatment cohorts.  After adjusting for baseline differences by using Cox regression, the TEER and surgical cohorts showed similar survival ratios (hazard ratio, 0.92; 95% confidence interval, 0.67-1.26; P=0.609), and both showed a lower mortality hazard relative to the conservative treatment cohort (hazard ratio, 0.61; 95% confidence interval, 0.49-0.77; P<0.001 and hazard ratio, 0.56; 95% confidence interval, 0.42-0.76; P<0.001, respectively).

The authors noted the following limitations:  The study, which had a retrospective design. The retrospective selection of controls may have introduced selection bias.  The unadjusted mortality differences varied significantly between enrollment centers, although the study applied advanced statistical methods to account for differences between the samples.  The study was unable to account for unmeasured confounding variables. 

The authors concluded that “this multicenter study strengthens the already existing concept that high-risk patients with symptomatic severe MR being treated with [TEER], have a lower mortality hazard compared with patients who receive conservative treatment, whereas they have a similar survival compared with patients undergoing surgical treatment.  Randomized controlled trials have yet to confirm this.”

Uncontrolled Observational Studies

Schillinger W, Athanasiou, T., Weicken, N., et al. (2011). “Impact of the learning curve on outcomes after percutaneous mitral valve repair with MitraClip and lessons learned after the first 75 consecutive patients.” European journal of heart failure 13(12): 1331‐1339.33

The aim of this German, single-center, prospective, observational study was to investigate the impact of the learning curve on outcomes after TEER, using the MitraClip system.  Investigators grouped outcomes of the first 75 consecutive patients treated with TEER at the center into three cohorts of 25 patients each.  They tested the differences in repeated measures by one way analysis of variance followed by a paired t-test with Bonferroni adjustment.

The study demographics for the 75 patients were:  mean age of 73 years, and 69% were male.  The mean LVEF was 37%, 88% had a NYHA class of III or IV, the etiology was secondary MR in 65%. 

Median total procedure time and device time decreased from 180 and 105 min in period 1 to 95 and 55 min in period 3 (P < 0.005 each).  There was an excess of total safety events in period 1 (n = 16) that decreased in periods 2 and 3 (n = 6 and 3, P = 0.0003).  Acute procedural success [APS; clip successfully placed and MR grade ≤ 2+ at discharge] was 80% in periods 1 and 2, but 92% in period 3 (P = 0.46).  At 6 months, improvement in success of TEER was evident: 89.4% of patients in period 3 and 65.0% in period 1 had MR ≤ 2+ at 6 months (P = 0.03).  Within 30 days, no patient sustained myocardial infarction or stroke, and mortality was 2.7% for all patients without significant differences regarding periods.  Furthermore, while treatment period did not affect mid-term survival and hospitalization for heart failure, failure of APS, STS (Society of Thoracic Surgeons) score ≥15%, and overt right heart failure at baseline predicted increased mortality.

The authors did not note any limitations of their study.  They concluded that the study “could demonstrate that [TEER using the MitraClip system] could be effectively used in a high surgical risk cohort of patients with predominantly functional MR right from the first procedure.  There was an institutional learning curve that became evident in decreasing procedural times and safety events over time.  In addition, the durability and completeness of MR repair increased over time.  The University Medical Center of Gottingen was among the first European centers performing [TEER with the MitraClip system] and therefore also experienced the initial part of the global learning curve.  Centers that have recently initiated percutaneous MV repair programs probably benefit from first-generation centers and start a higher level.”

Auricchio, A., Schillinger, W., Meyer, S., et al. (2011) “Correction of mitral regurgitation in nonresponders to cardiac resynchronization therapy by MitraClip improves symptoms and promotes reverse remodeling.” J Am Coll Cardiol 58(21):2183-9.34

The aim of this prospective, multicenter, European, observational study was to evaluate the safety, efficacy, and effect of TEER using the MitraClip system on symptoms and left ventricular (LV) remodeling in patients who did not symptomatically improve after cardiac resynchronization therapy (CRT).  All patients had chronic moderate-to-severe or severe FMR and were previously treated with CRT for at least 6 months and remained NYHA class III or IV despite optimal medical therapy.  Investigators recorded changes in NYHA functional class, degree of secondary MR, LVEF, and LVEDV/end-systolic volumes (ESV) before and after (3, 6, and 12 months) TEER.  They also collected mortality data, including cause of death and assessed survival using a Kaplan-Meier curve and medial follow-up using an inverse Kaplan-Meier method.  To compare survival according to baseline characteristics, the analysis used the log-rank test and Cox regression.

Fifty-one severely symptomatic CRT nonresponders with significant secondary MR (grade ≥ 2, 100%) underwent TEER.  The study demographics were as follows:  The mean age was 70.26 years, and 86 % were male.  MC treatment was feasible in all patients (49% 1 clip, 46% 2 clips).  There were 2 periprocedural deaths.  Median follow-up was 14 months (25th to 75th percentile: 8 to 17 months).  NYHA functional class improved acutely at discharge (73%) and continued to improve progressively during follow-up (regression model, p < 0.001).  The proportion of patients with significant residual secondary MR (grade ≥ 2) progressively decreased during follow-up (regression model, p < 0.001).  Reverse LV remodeling and improved LVEF were detected at 6 months, with further improvement at 12 months (regression model, p = 0.001, p = 0.008, and p = 0.031 for ESV, EDV, and LVEF, respectively).  Overall 30-day mortality was 4.2%.  Overall mortality during follow-up was 19.9 per 100 person-years (95% confidence interval: 10.3 to 38.3).  Nonsurvivors had more compromised clinical baseline conditions, longer QRS duration, and a more dilated heart.

The authors noted the following limitations:  The total number of 51 CRT nonresponders was small.  This was an observational study and changes in pharmacological therapies during follow-up may have influenced MR severity, outcome, and remodeling.  Finally, the value of surgical repair compared with replacement is also debatable because secondary MR often recurs after repair as a consequence of continued ventricular remodeling, which results in recurrent valve tenting.  Although an echocardiographic protocol was not pre-defined, all examinations were reviewed by an independent experienced echocardiographer, which partially mitigates the issue of institutional variability in self-reporting.

The authors concluded that “[TEER using the MitraClip system] treatment in CRT nonresponders with clinically significant secondary MR was feasible and safe, and produced improved NYHA functional class, increased LVEF, and reverse LV remodeling in a significant proportion of these study patients.  Prospective studies are warranted to confirm our findings and to evaluate appropriate timing of [TEER] treatment after CRT.”

Braun, D., Lesevic, H., Orban, M. et al. (2014) “Percutaneous edge-to-edge repair of the mitral valve in patients with degenerative versus functional mitral regurgitation.” Catheter Cardiovasc Interv 84(1):137-46.35

The aim of this prospective observational study was to assess the outcome of TEER in patients with primary versus secondary MR.  The study defined the primary endpoints as procedural success (MR grade reduction ≥1 grade) as well as a composite endpoint defined as freedom from MR 3+ or 4+, mitral valve reintervention and death 12 months after clip implantation.  In patients with successful clip placement the authors further analyzed MR grade, NYHA functional class, distance in the 6 min walking test, and left ventricular volumes 12 months after clip implantation.  The authors used Fisher’s exact test to compare categorical variables.  To compare continuous variables as appropriate, the analysis used the Mann-Whitney-U-test and the Wilcoxon test.  The Logrank test was used to compare overall survival.

The study included 119 patients treated by TEER for symptomatic MR, 72 patients with primary and 47 patients with secondary MR.  The demographics for secondary MR patients were as follows:  the mean age was 70.7 years and 76.6% were male.  NYHA functional class was ≥3 in 97.8% of patients, and the mean LVEF was 35.2%.

The primary success rate of all intended clipping procedures was 83.3% for primary and 89.4% for secondary MR (P = 0.42).  Regarding the composite endpoint, the authors observed an event free survival of 59.7% in patients treated for primary MR and 63.8% in patients treated for secondary MR (P = 0.73).  The authors observed a highly significant reduction in MR grade as well as improvement in NYHA functional status in both groups 12 months after clip implantation.  However, there was a more pronounced MR grade reduction in patients treated for primary MR compared with patients treated for secondary MR.  At 12 months, 83.3% of primary MR and 72.2% of secondary MR patients had an MR grade ≤ 2.

The authors noted the following limitations:  The study had a relatively small patient population.  Furthermore, a considerable number of patients did not have complete clinical follow-up.  The lack of follow-up data of patients who died before clinical assessment may have led to an overestimation of the positive effect of TEER.  Also, echocardiographic MR quantification after TEER tends to be subjective due to the frequent occurrence of eccentric MR jets.

The authors concluded that “[TEER] of the mitral valve is feasible in patients with [primary] as well as [secondary] MR.  Although the clipping procedure is technically more demanding, patients with primary MR benefit at least as much as patients with a [secondary] MR etiology.”

Maisano, F., Franzen, O., Baldus, S., et al.  (2013) “Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post-approval study of the MitraClip therapy in Europe.”  J Am Coll Cardiol 62(12):1052-1061.36

The aim of this study was to provide a snapshot of the real-world clinical demographic data and outcomes from the ACCESS-EU registry.  The ACCESS-Europe A Two-Phase Observational Study of the MitraClip System in Europe (ACCESS-EU) trial was a prospective, nonrandomized, multicenter, post-approval study of TEER using the MitraClip system.  The study generated survival rates up to 12 months using Kaplan-Meier curves.

TEER was implanted in 567 patients with significant MR across 14 European sites.  Of these, 117 patients had primary MR and 393 patients had secondary MR.  The study demographics of the secondary MR patients were as follows:  the mean age was 73.0 years, and 67.9 % were male.  Mean logistic EuroSCORE at baseline was 23.0±18.3; 84.9% patients were in NYHA functional class III or IV, and 52.7% of patients had an EF ≤ 40%. 

The TEER implant rate was 99.6%.  A total of 19 patients (3.4%) died within 30 days after the TEER procedure.  Kaplan-Meier survival at 1 year was 81.8%.  Single leaflet device attachment was reported in 27 patients (4.8%) but there were no device embolizations.  Thirty-six subjects (6.3%) required mitral valve surgery within 12 months after TEER implantation.  At 12 months, 78.9% of patients free from MR severity of >2+ (p < 0.0001), and 71.4% of patients had NYHA functional class I or II. Six-min-walk-test improved 59.5±112.4 m, and Minnesota-living-with-heart-failure score improved 13.5±20.5 points.

The authors noted the following limitations:  lack of a core-laboratory adjudication of echocardiographic parameters; details with regard to morphological evaluation (number of segments involved, annular dimensions, jet geometry) were not recorded. These data would have great impact on defining anatomical risk factors for success.  In addition, echocardiographic data on baseline and follow-up ventricular dimensions were insufficient to prove favorable geometrical remodeling in this high-risk population.  Another limitation of the study was that there were no pre-defined enrollment criteria: indication for TEER therapy as well as anatomical eligibility were left to the individual centers, according to their experience.  Finally, because there was no pre-specified medical therapy strategy, changes in medical therapy during the conduction of the study might have affected outcomes.

The authors concluded that “in the real-world, post-approval experience in Europe, patients undergoing [TEER using the MitraClip system] are high-risk, elderly patients, mainly affected by [secondary] MR.  In this patient population, the MitraClip procedure is effective with low rates of hospital mortality and adverse events.  The ACCESS-EU study is the first large database reporting outcomes of [TEER] in a high-risk population of patients with prevalence of secondary MR.  In this patient population, [TEER] is safe, with low rates of hospital mortality and adverse events.  Most patients have been treated successfully, which might be attributed in part to improved learning curve.  As a result, meaningful clinical improvement has been observed in most patients in the mid-term, with objective improvement of quality of life and functional status.”

Rudolph, V., Lubos, E., Schluter, M., et al.  (2013) “Aetiology of mitral regurgitation differentially affects 2-year adverse outcomes after MitraClip therapy in high-risk patients.” Eur J Heart Fail 15(7):796-807.37

The aim of this single-center, prospective, observational study wass to assess and identify predictors of 2-year adverse outcomes of surgical high-risk patients after successful TEER using the MitraClip system, differentiated by the etiology of MR.  The study enrolled patients with moderate-to-severe or severe MR and prohibitive surgical risk between 2008 and 2011.  Study outcomes included mortality, heart failure rehospitalization, and reintervention.  Investigators used Kaplan-Meier analysis to assess survival free from death, heart failure rehospitalization, and reintervention.  Predictors for study endpoints were determined using Cox regression analyses.

Of the 230 patients with available follow-up, TEER was successful in 202 patients.  Of the 230 patients, including 153 patients had secondary MR.  The study demographics of the secondary MR patients were as follows:  The mean age was 73 years, and 71% were male.  Of these, the distribution of NHYA functional was 3% class II, 61% III, and 35% IVa. 

Mortality was 20% at 1 year and 33% at 2 years in both primary and secondary MR patients; independent predictors of death were reduced forward stroke volume, impaired LV function, and renal failure in primary MR, yet only an increased logistic EuroSCORE in secondary MR patients.  The rate of rehospitalizations was not different between the patient subgroups for 6 months, but then diverged significantly in favor of primary MR patients (estimated 2-year incidence, primary MR 40% vs. secondary MR 66%).  No predictor was found for primary MR patients, but increased LVEDV significantly increased the risk of rehospitalization in secondary MR patients.  Reinterventions were rare (7.4% at 1 year, 9.7% at 2 years); primary MR patients required all except one reintervention within 2 months of TEER, whereas secondary MR patients exhibited a steadily declining freedom from reintervention curve throughout follow-up.

The authors noted the following limitations:  Some analyses were limited by the low number of observed events, which particularly affects analyses comprising only the subgroup of primary MR patients and those regarding reintervention rates.  In addition, despite the strict separation of patients with primary and secondary MR, these two subgroups (particularly secondary MR) each summarize a multitude of diverging pathologies of MR, which very probably respond in distinct ways to TEER.  Ideally, these pathologies should also be separated from each other.  However, this would lead to excessive sectioning of data, thus affecting statistical validity.  Furthermore, from a strict statistical standpoint, a comparison between patients with primary and secondary MR was complicated by the fact that the two populations exhibit significantly distinct baseline characteristics.  Thus, differences in outcome between both groups were probably a manifestation not only of the different etiologies of MR but also of a number of other factors. 

The authors concluded that “This study includes one of the largest cohorts of surgical high-risk patients investigated to date and provides crucial long-term outcome information for such patients undergoing [TEER].  Our results might be helpful for patient selection, risk stratification, and planning of future trials.  The study suggests that secondary MR patients undergoing [TEER] – who comprised about two-thirds of our study cohort – should preferably be treated aggressively, with the aim of reducing MR to a minimal grade.  Thus, our study corroborates [TEER] as a viable therapeutic option for high-risk surgical patients.  Moreover, it reveals that MR etiology critically determines the long-term outcome of [TEER].”

Nickenig, G., Estevez-Loureiro, R, Franzen, O., et al.  (2014)  “Percutaneous mitral valve edge-to-edge repair: in-hospital results and 1-year follow-up of 628 patients of the 2011-2012 Pilot European Sentinel Registry.”  J Am Coll Cardiol 64(9):875-84.38

The aim of this multinational, prospective observational study was to present a real-world overview of TEER use in Europe.  The investigators performed clinical and echocardiographic follow-up at discharge and at 1 and 12 months after implantation.  The echocardiographic analysis included centers (15/25) with a follow-up rate of at least 90% (n=383).  Only patients with paired echocardiographic observations during follow-up were included in the analysis (n=368 [61%]).  Procedural success was defined as a reduction in the degree of MR to ≤ than moderate (< 2+) without complications.  The investigators used multivariate logistic regression to identify the variables independently associated with the combined endpoint of death or readmission because of heart failure at 1 year.  Survival rates up to 12 months were presented as Kaplan-Meier curves.

A total of 628 patients (mean age 74.2± 9.7 years, 63.1% men) underwent TEER between January 2011 and December 2012 across 25 centers in 8 European countries.  The prevalent pathogenesis was secondary MR (n = 452 [72.0%]).  The majority of patients (85.5%) were highly symptomatic (NYHA functional class III or higher), with a high logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) (20.4±16.7%).

Acute procedural success was high (95.4%) and similar in secondary MR and primary MR (p = 0.304).  One clip was implanted in 61.4% of patients.

In-hospital mortality was low (2.9%), without significant differences between groups.  The estimated 1-year mortality was 15.3%, which was similar for secondary MR (15.0%) and primary MR (16.2%).  The estimated 1-year rate of heart failure rehospitalization was 22.8%, which was significantly higher in the secondary MR group (25.8% vs. 12.0%, p = 0.009).  Paired echocardiographic data from the 1-year follow-up was available for 368 patients across 15 centers and showed a durable reduction in MR at 1 year.  Rates of recurrent severe MR were 5.9% for secondary MR and 6.6% for primary MR.

The authors noted the following limitations:  First, the TVT registry is a pilot, voluntary registry with procedural complications, adverse events, and echocardiography parameters self-reported.  Second, the follow-up data were simplified and excluded, for instance, drug regimen. Also, the follow-up for clinical events (88%) and especially echocardiographic data (61%) were incomplete. 

The authors concluded that “In this large contemporary registry addressing the effect of [TEER] on MR reduction, functional class improvement, and clinical events, both [primary and secondary MR] exhibited an immediate reduction in the severity of MR and improvement in functional class that persisted for 1 year.  Procedural and late mortality was low and lower than expected in such a high-risk cohort, without differences between [primary and secondary MR].”

Glower, D.D., Kar, S., Trento, A., et al. (2014). “Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study.” J Am Coll Cardiol 64(2): 172-181.39

The aim of this study was to report 12-month outcomes in high-risk patients treated with TEER, using the MitraClip device.  The study enrolled patients with grades 3 to 4+ MR and a surgical mortality risk of ≥12%, based on the Society of Thoracic Surgeons risk calculator or the estimate of a surgeon coinvestigator following pre-specified protocol criteria.  Data were collected from two prospective EVEREST II registries.  The analysis used Kaplan-Meier methods for survival analysis and estimated the rate of hospitalization for heart failure using a Poisson regression model.

In the studies, 327 of 351 patients completed 12 months of follow-up.  Patients were elderly (76±11 years of age), and 61.0% were male, with 70% having secondary MR and 60% having prior cardiac surgery.  NYHA function was as follows:  2.6% had class I, 12.5% II, 61.5% III, and 23.4% had IVa.  The mean LVEF was 47.5%.

The mitral valve device reduced MR to ≤ 2+ in 86% of patients at discharge (279 of 325; p < 0.0001).  Major adverse events at 30 days included death in 4.8%, myocardial infarction in 1.1%, and stroke in 2.6%.  At 12 months, MR was ≤ 2+ in 84% of patients (n = 225; p < 0.0001).  From baseline to 12 months, LVEDV improved from 161±56 ml to 143± 53 ml (n = 203; p < 0.0001) and LV end-systolic volume improved from 87±47 ml to 79±44 ml (n = 202; p < 0.0001).  NYHA functional class improved from 82% in class III/IV at baseline to 83% in class I/II at 12 months (n = 234; p < 0.0001).  The 36-item Short Form Health Survey physical and mental quality-of-life scores improved from baseline to 12 months (n = 191; p < 0.0001).  Annual hospitalization rate for heart failure fell from 0.79% pre-procedure to 0.41% post-procedure (n = 338; p < 0.0001).  Kaplan-Meier survival estimate at 12 months was 77.2%.

The authors noted the following limitations:  These data were collected in a narrowly defined group of patients based on specific surgical risk factors and specific anatomic suitability for the MV device raising concerns with generalizability.  Further refinement in all patient selection criteria such as secondary MR verses primary MR, severe pulmonary hypertension, right ventricular dysfunction, tricuspid regurgitation, severe obstructive/restrictive lung disease, dialysis, patient frailty, and a range of EF that is suitable for the MV device need to be examined in larger studies with greater numbers in each of these subsets and/or appropriate controls. The study provided only 12 months of data, leaving concerns that MV repair without ring stabilization of the mitral annulus could diminish the long-term benefits of the TEER.  There was no parallel surgical or medical control group in this study. 

The current study had an unblinded control of medical therapy prior to TEER, with demonstrated clinical and physiological improvements over time after device therapy relative to baseline medical therapy.  Although a placebo effect on quality-of-life measures cannot be excluded, 36% of device patients had a 2-grade improvement in NYHA functional class.  Moreover, the placebo effect is unlikely to explain reductions in MR and LV volumes.  Improvement in clinical parameters was evaluated only in surviving patients with paired data at baseline and at 12 months, which may introduce bias.

The authors concluded that “These data are unique in that they represent the largest prospective dataset evaluating the outcomes of [TEER] in symptomatic patients with grade 3 to 4+ MR who are at high risk of mortality with MV surgery.  The MV device is feasible and relatively safe and is effective in reducing symptoms and improving clinical status in this high-risk group of patients who are unlikely to receive surgery and essentially have no other option to reduce MR.”

Wiebe, J., Franke, J., Lubos, E., et al. (2014) “Percutaneous mitral valve repair with the MitraClip system according to the predicted risk by the logistic EuroSCORE: Preliminary results from the German Transcatheter Mitral Valve Interventions (TRAMI) registry.” Catheterization and Cardiovascular Interventions 84(4): 591-598.40

The aim of this study was to evaluate in-hospital and short-term outcomes of TEER, using the MitraClip system, according to patients' logistic EuroSCORE (logEuroSCORE) in a voluntary multicenter registry.  The study evaluated data from 1002 patients who underwent TEER with the MitraClip system in the TRAMI Registry.  A logEuroSCORE (mortality risk in %) ≥ 20 was considered high risk.  Study outcomes included procedural success, complication rates, and in-hospital mortality rate.  Continuous variables were expressed as means with standard deviation or as medians with quartiles.  Categorical variables were expressed by counts and percentages.  To compare data between both groups, the investigators used the Mann-Whitney-Wilcoxon test for continuous variables and the Chi-square test for categorical variables.

Of all patients, 557 (55.6%) had a logEuroSCORE ≥ 20.  The mean age of patients with a Logistic EuroSCORE ≥ 20 was 77.0% while the mean age of patients with a Logistic EuroSCORE < 20 was 73.0 years.  Of patients with a Logistic EuroSCORE > 20, 64.9% were male, while for patients with a Logistic EuroSCORE < 20, 59.3% were male.  TEER was successful in 95.5% (942/986) patients. Moderate residual MR was more often detected in patients with a logEuroSCORE ≥ 20 (23.8% vs. 17.1%, respectively, P < 0.05). In patients with a logEuroSCORE ≥ 20 the procedural complication rate was 8.9% (vs. 6.4, n.s.) and the in-hospital MACE rate was 4.9% (vs. 1.4% P < 0.01).  The in-hospital mortality rate in patients with a logEuroSCORE ≥ 20 and logEuroSCORE < 20 was 4.3 and 1.1%, respectively (P ≤ 0.01). 

The authors noted the following limitations:  Data was entered prospectively for approximately half of the cohort.  Data stratification based upon EuroSCORE does not reflect valve morphology or the etiology of MR.  A new version of the logEuroSCORE has been developed, and it remains unknown which version is more applicable to TEER patients.  Data for this registry were collected before the updated EuroSCORE II was available. As the focus of the registry was on acute in-hospital results, the validity of post-procedural results (available in only 63.1% of all registry patients) may be limited.

The authors concluded that “[TEER] with the MitraClip system is feasible in patients with a logEuroSCORE ≥20 with similar procedural results compared to patients with lower predicted risk.  Although mortality was four times higher than in patients with logEuroSCORE < 20, mortality in high risk patients was lower than predicted by the logEuroSCORE.  In those with a logEuroSCORE ≥20, moderate residual [MR] was more frequent.”

Matsumoto, T. Nakamura, M., Yeow, W., et al. (2014) “Impact of pulmonary hypertension on outcomes in patients with functional mitral regurgitation undergoing percutaneous edge-to-edge repair.”  Am J Cardiol 114(11):1735-9.41

The aim of this study was to evaluate the impact of preexisting PH on TEER using the MitraClip system for patients with secondary MR.  All patients underwent TEER under the EVEREST II clinical trial (n=15), the REALISM registry (n=68), or the compassionate-use program (n=8).  All patients were candidates for mitral valve surgery, had moderate-to-severe or severe chronic MR with LVEF >25% and left ventricular end-systolic dimensions ≤ 55 mm.  Asymptomatic patients despite significant chronic MR were required to have new-onset atrial fibrillation, PH, or evidence of LV dysfunction (LVEF 25% to 60%).  PH was defined as pulmonary artery systolic pressure >50 mm Hg using Doppler echocardiography. Procedural success (defined as magnetic resonance reduction to grade 2+ or less) and 30-day mortality were similar in the 2 groups.  Survival was estimated using the Kaplan-Meier; to determine predictors of all-cause death after TEER, multivariate analyses of time to events was performed using a Cox proportional-hazards model.

Ninety-one consecutive patients who had secondary MR and who underwent the TEER procedure were studied.  They were divided into 2 groups on the basis of pulmonary artery systolic pressure: the PH group (n = 48) and the non-PH group (n = 43).  The average age of those with no PH was 73.7 years, while the average age of those with PH was 76.5 years.  Of those with no PH, 58.1% were men; of those with PH, 64.6% were men.  At 12 months, NYHA functional class had improved to class I or II in most patients in the PH (from 2.9% to 94.3%) and non-PH (from 9.4% to 96.9%) groups.  The mean pulmonary artery systolic pressure of the PH group significantly decreased from baseline but remained higher than that of the non-PH group (50.8±15.3 vs 36.7±11.6 mm Hg, p <0.001).  After a mean of 25.0±16.9 months of follow-up, Kaplan-Meier analysis demonstrated significantly higher freedom from all-cause mortality in the Non-PH group (45.4% vs. 84.7%, respectively).  In Cox regression analysis, preexisting PH was the most powerful predictor of all-cause mortality (hazard ratio 3.731, 95% confidence interval 1.653 to 8.475, p = 0.002).

The authors noted the following limitations:  First, the study had a retrospective design and was conducted at a single center.  Second, PASP which was used to group the patients, was measured noninvasively by Doppler transthoracic echocardiography.  Although direct measurement of pulmonary artery pressure by cardiac catheterization is a gold-standard approach in the diagnosis of PH, a previous study validated this noninvasive method as an alternative method, specifically in cases of required serial follow-up.  Additionally, Doppler measured PASP is widely and routinely used to manage patients with valvular heart disease.

The authors concluded that TEER “achieved significant improvements of MR grade and NYHA functional class and a trend toward reverse LV remodeling at 12 month follow-up.  Despite these clinical benefits, preexisting PH was associated with all-cause mortality in this study.  Likewise, PH was also reported as an independent predictor of worse clinical outcomes after MV surgery in patients with [secondary MR].  However, the exact mechanism of these poor prognoses in the setting of PH is unclear.  Further studies will be required to elucidate the mechanism underlying our observations.”

Taramasso, M., Maisano F. Latib, A., et al.  (2014) “Clinical outcomes of MitraClip for the treatment of functional mitral regurgitation.” EuroIntervention 10(6):746-52.42

The aim of this single-center, retrospective, observational study was to report medium-term outcomes of TEER using the MitraClip in inoperable or high-risk surgical candidates with moderate-to-severe or severe secondary MR.  Outcome measures included survival and freedom from ≥3+ MR.  Outcomes were assess using the Kaplan-Meier method; comparisons were performed using the log-rank test.

The mean age was 69±9 years, 83.5% were men, and 82% were NYHA class III-IV. Logistic EuroSCORE was 22±16%, and the mean EF was 28±11%.  Procedural success was 99% and 30-day mortality was 1.8%.  At discharge, 87% patients had MR ≤ 2+.  At 12 months, EF was 34.7±10.4% (p=0.002 compared to preoperative value).  Actuarial survival at three years was 74.5±7%.  Actuarial freedom from MR ≥3+ at 2.5 years was 70±6%.  At 1-year follow-up, 86% of patients were in NYHA class I-II.  Preoperative pro-BNP level ≥1,600 pg/ml was identified as an independent risk factor of mortality at follow-up.

The authors noted the following limitations:  The study was an observational, retrospective single-center study.  The sample size was too small to make firm conclusions.  Moreover, the results include an initial learning curve.

The authors concluded that, TEER therapy is a “safe procedure in selected high-risk patients with [secondary] MR and can be accomplished with low morbidity and mortality.  Moreover, [TEER] is associated with an improvement in functional status and quality of life at one year as well as significant LV reverse remodeling.  Although an acute reduction of MR can be obtained in the majority of patients after [TEER], further studies are needed to determine the clinical impact of residual MR after [TEER].  Thus, [TEER] is a valuable clinical option in patients with adequate anatomy who are considered inoperable or with a high surgical risk and should be considered as an important therapeutic modality in the multidisciplinary treatment of heart failure.”

Melisurgo G, Ajello S, Pappalardo F, et al. (2014) “Afterload mismatch after MitraClip insertion for functional mitral regurgitation.”  Am J Cardiol 113(11):1844-50.43

The study aim was to investigate the incidence and prognostic role of afterload mismatch (the increased left ventricular afterload and occurrence of abrupt reduction in EF that can take place following a MVR procedure due to increased impedance and which has the potential to impair systolic function).  For methodologic purposes, the investigators defined afterload mismatch as an acute 28% LVEF reduction after MVR compared with baseline, calculated as (early postoperative LVEF – preoperative LVEF)/preoperative LVEF.  (The authors selected the median LVEF reduction from baseline [28%] as the threshold for defining afterload mismatch.)  The authors retrospectively analyzed patients with secondary MR who underwent TEER with the MitraClip system between October 2008 and December 2012.  The investigators assigned patients to two groups according to the occurrence of the afterload mismatch: patients with afterload mismatch (AM+) and without afterload mismatch (AM-).

Of 78 patients with complete clinical and echocardiographic baseline and follow-up data, five patients were excluded (3 with post-procedural MR ≥ 3 and two patients requiring emergent open mitral surgery).  The remaining study population (n = 73) had a mean age of 69 years; 61 patients (84%) were male.  Mean logistical EuroSCORE was 24% ± 17 and 60 (82%) had NYHA III-IV. 

Study results showed that 19 (26%) of the 73 study patients experienced afterload mismatch in the early postoperative period.  Baseline characteristics were balanced among patients with and without postoperative afterload mismatch for: age, gender, BMI, NYHA III-IV, logistic EuroSCORE, and STS risk score.  However, patients with afterload mismatch had larger measurements for the following preoperative variables, end-diastolic diameter (71 ±- 8 vs 67±7 mm, p = 0.02) and end-systolic diameter (57±9 vs 53±7 mm, p = 0.04) but lower systolic blood pressure (109.4±11.7 vs 118.6±18.4 mm Hg).  

Post-procedural echocardiographic assessments identified an increase in the afterload mismatch group of: end-diastolic diameter (68±9 vs 62±8, p = 0.01), ESD (60.7±7.4 vs 49.7±6.6 mm), LVESS (263.3±60.5 vs 226.5± 52.4, dynes/cm2, p = 0.0068), right ventricular dysfunction (68% vs 31%, p = 0.049) and pulmonary hypertension (49 ± 10  vs 40 ± 10 mm Hg, p = 0.0009) but a decrease in the afterload mismatch group of LVEF (%) 17±7 vs 29 ± 10, p < 0.0001) and LVEF ≤ 25% (18 [95%] vs 25 [46%], p = 0.0068).  LVEF became similar in both groups (31±9% vs 33± 11%, p = 0.65) prior to discharge and long-term survival was comparable between the two groups (81.2±9.9% vs 75.2±8.7%, p = 0.44).  However, a low LVEF in the early postoperative period (LVEF <17%) was associated with higher mortality rate in long-term follow-up (29.0±12.6% vs 21.05±8.02%, p = 0.048).

The authors identified the retrospective design and small study population as limitations, as well as the lack of standardization in perioperative use of inotropes.

The authors concluded that “reduction of [MR with TEER that uses the MitraClip system] can cause afterload mismatch; however, this phenomenon is transient, without long-term prognostic implications.”

Capodanno D, Adamo M, Barbanti M, et al. (2015)  “Predictors of clinical outcomes after edge-to-edge percutaneous mitral valve repair.” Am Heart J 170(1):187-95.44

The study aim was to investigate clinical outcomes and predictors of mortality from a multicenter registry that enrolled consecutive patients with MR undergoing TEER with the MitraClip system between October 2008 and November 2013 at four Italian centers.  The primary endpoint was mortality following TEER; there was no comparison group.  The secondary end point was the composite of all-cause death or rehospitalization for heart failure.

The study population included 304 patients with a mean age of 72 years of which 64% were male, 79% had secondary MR, and 17% were in NYHA functional class IV. 

The study resulted in no intraprocedural deaths; 92% obtained procedural success.  A multivariate stepwise Cox regression model identified NYHA functional class IV at baseline and ischemic MR etiology to significantly and independently predict both the primary and the secondary end points.  A baseline, left ventricular end-systolic volume >110 mL independently predicted the secondary endpoint.  Acute procedural success was independently associated with a lower risk of the primary and secondary endpoints at long-term follow-up.

The authors identified the following study limitations:  The sample size for the study was relatively small.  The study lacked detailed clinical information, including post procedural echocardiographic findings, quality of life, and functional status.  As an observational study, there was no standardized approach to medical therapy, and the decision to pursue TEER was left to clinical discretion.  The results are subject to selection and referral biases. 

The authors concluded that, “in a cohort of patients undergoing [TEER], those presenting at baseline with ischemic functional etiology, severely dilated ventricles, or advanced heart failure and those undergoing unsuccessful procedures carried the worst prognosis.”

Puls M, Lubos E, Boekstegers P, et al.  (2016). “One-year outcomes and predictors of mortality after MitraClip therapy in contemporary clinical practice: results from the German transcatheter mitral valve interventions registry.”  Eur Heart J. 37(8):703-12.45

The aim of this study was to present 1-year outcome data of the TRAMI Registry and to identify predictors of 1-year mortality.  The study presents the 1-year outcome in this cohort (the largest at the date of publication).  Outcomes included mortality, major adverse cardiovascular event rates, and NYHA class.

The study population consisted of patients who joined the TRAMI registry between August 2010 and July 2013, who had prospective data collection, and who were available for 1-year follow-up.  The registry prospectively enrolled 828 TEER patients.  One year follow-up data were available for 749 patients (median age 76 years, 61.4% male, median logistic EuroSCORE 20.0%), of which 478 (71.3%) had secondary MR.  The study did not include a comparator population. 

The study results demonstrated a high procedural success rate (97%), with a 1-year mortality of 20.3%.  The authors conducted multivariate analysis using a Cox regression model with stepwise forward selection to identify predictors of 1-year mortality.  These included NYHA class IV (hazard ratio, HR 1.62, P = 0.02), anemia (HR 2.44, P = 0.02), previous aortic valve intervention (HR 2.12, P = 0.002), serum creatinine ≥1.5 mg/dL (HR 1.77, P = 0.002), peripheral artery disease (HR 2.12, P = 0.0003), LVEF < 30% (HR 1.58, P = 0.01), severe tricuspid regurgitation (HR 1.84, P = 0.003), and procedural failure (including operator-reported failure, conversion to surgery, failure of clip placement, or residual post-procedural severe MR) (HR 4.36, P < 0.0001).  At 1 year, 63.3% of TRAMI patients had NYHA functional classes I or II (compared with 11.0% at baseline), and self-rated EuroQuol health status also improved by 10 points (70.0 vs.60.0 at baseline, P < 0.0001).  A significant proportion of patients regained complete independence in self-care after TEER implantation (independence in 74.0 vs. 58.6% at baseline, P = 0.005).

The authors noted important study limitations.  The study included patients who were prospectively enrolled into TRAMI and who were available for 1 year follow-up.  Of patients lost to follow-up, 16/79 withdrew their consent and 63/79 were lost to follow-up.  These missing patients may overestimate the functional and survival impact of TEER.  The investigators conducted follow-up at 30 days and 1 year by telephone and did not include echocardiography.  All baseline and in-hospital data were based on reports from the site without external monitoring for data integrity.  There was likely non-consecutive enrolment in several centers, which may also introduce bias.  Echocardiographic data were not core-lab adjudicated, and interpretation may have been inconsistent. 

The authors concluded that “treatment of significant MR with [TEER] resulted in significant clinical improvements in a high proportion of TRAMI patients after 12 months.”

Schafer U, Maisano F, Butter C, et al.(2016) “Impact of Preprocedural Left Ventricular Ejection Fraction on 1-Year Outcomes After MitraClip Implantation (from the ACCESS-EU Phase I, a Prospective, Multicenter, Nonrandomized Post-approval Study of the MitraClip Therapy in Europe).” Am J Cardiol 118(6):873-880.46

The aim was to describe the 12-month outcomes of a prospective, multicenter, nonrandomized post-approval study of the TEER that used the MitraClip system in Europe (ACCESS-EU post-approval study of MitraClip therapy) with respect to preprocedural LVEF.  The study included patients who had moderate to-severe (>3) or severe (>4) MR as determined by transthoracic and transesophageal echocardiography and underwent TEER in 14 centers located in Denmark, Germany, Italy, or Switzerland; no exclusion criteria were described.  The study did not have a comparator population.  The investigators assessed procedural safety, efficacy, and treatment outcomes including MR grade, NYHA functional class, 6-minute walk test, and the Minnesota Living with Heart Failure Questionnaire at baseline, 30 days, and 12 months.

The study population included a total of 567 patients with significant MR that underwent TEER therapy.  Of those, 393 had secondary MR; 41% were >75 years and 68% were male.  The patients were subdivided by pre-procedural LVEF.

Study results found that the baseline mean logistic EuroSCORE was 25%±19; 87% of patients were in NYHA classes III or IV.  There was no incidence of intra-procedural death or stroke.  Eleven patients died within 30 days with no differences among baseline LVEF subgroups.  Kaplan-Meier survival at 12 months was 81.8%.  There was a significant improvement in MR severity as evaluated by transthoracic echocardiography at each site at 12 months (p <0.0001).  At 12 months, there was similar improvements in NYHA class, 6-minute walk test, and Minnesota Living with Heart Failure Questionnaire across all subgroups.

The authors identified a number of limitations.  This study is a post-marketing analysis of registry data and there were no inclusion or exclusion criteria.  Echocardiographic findings were not adjudicated by a core echocardiography laboratory, and valve morphology details were not available.  Guideline directed medical therapy was not defined. 

The authors concluded that “the low rates of hospital mortality and adverse events in patients with [secondary] MR - even in patients with severely reduced LVEF - provide additional evidence of substantial benefits after [TEER].”

Schueler R, Nickenig G, May A, et al. (2016) “Predictors for short-term outcomes of patients undergoing transcatheter mitral valve interventions: analysis of 778 prospective patients from the German TRAMI registry focusing on baseline renal function.” EuroIntervention 12(4):508-14.47

The aim of this observational study was to examine the relationship between renal function and short-term outcomes of patients enrolled in the TRAMI registry.  Twenty participating German centers prospectively enrolled patients between August 2010 and October 2013 who were at high surgical risk and undergoing TEER with the MitraClip system for the treatment of symptomatic secondary or primary MR.  The outcome of interest was all cause death at 30 days.

The study population included 778 consecutive patients: mean age 76.0 years (70-80), 38.8% female, mean logistical EuroSCORE 20%, with 70% secondary MR and 30% primary MR.  When restricted to patients with secondary MR, there were 505 patients: mean age 75.0 years (71-81), 37.6% female, mean logistical EuroSCORE 20%.  The investigators stratified patients by renal function prior to clip implantation; among those with secondary MR, there were: 184 patients with mild/normal (GFR >60 ml/min), 252 patients with moderate (GFR 30-60 ml/min), and 69 patients with severe renal impairment (GFR <30 ml/min).  For patients with secondary MR, baseline variables differed (p < 0.05) across renal function groups on: logistical EuroSCORE, STS score, history of cardiac decompensation, diabetes mellitus, and 6-minute walking distance.  

Study results found that in patients with secondary MR, TEER was successfully completed in 79.7%, 84.9%, and 85.9% of cases with severe, moderate, and mild/normal renal impairment, respectively.  Secondary MR patients with severe renal impairment had significantly worse outcomes for in-hospital mortality (7.2%, 1.2%, 2.2%; p<0.01) and 30-day mortality rates (13.6%, 3.3%, 4.0%; p<0.001).  The investigators used Cox regression analysis to identify predictors of 30-day mortality in all patients, but did not provide distinct multivariate analyses for patients with secondary MR or primary MR.  In that assessment, the prevalence of severe renal impairment at the time of TEER was the only predictor for increased 30-day mortality rates (hazard ratio 3.42, 95% confidence interval 1.88-6.2; p<0.0001).

The authors noted the following study limitations: the study relied on reporting from the site without external monitoring for data integrity, the follow-up time was limited, and there was potentially incomplete adjustment for covariates in the multivariate analysis. 

The authors concluded that “renal function at the time of [TEER] with the MitraClip system is a strong predictor for procedural outcomes.  Patients with severe renal impairment have a more than threefold increased risk for acute procedural failure, in-hospital death and 30-day mortality.”

Azzalini L, Millán X, Khan R, et al. (2016) “Impact of left ventricular function on clinical outcomes of functional mitral regurgitation patients undergoing transcatheter mitral valve repair. ” Catheter Cardiovasc Interv 88(7):1124-1133.48

The aim of this study was to evaluate the impact of baseline left ventricular (LV) function on the clinical outcomes of patients with secondary MR treated with TEER using the MitraClip system.  The investigators enrolled consecutive patients with significant secondary MR undergoing the TEER procedure between December 2010 and January 2015 and categorized patients into tertiles by baseline LVEF.  The primary outcome was all-cause mortality at follow-up.

The study population included 77 patients.  Most patients were male (78%) and had an average age of 71.4 years.  Baseline comorbidities were generally similar across the LVEF tertiles of < 27% (n = 27), 27-37% (n = 25), >37% (n = 25); however, patients with a lower LVEF had a higher EuroSCORE of 29.2%, 21.1%, and 16.3%, respectively.  Also, implantable cardioverter defibrillators were more common in those with the lower LVEF with 19, 7, and 3 having defibrillators across tertiles, respectively.  Medical therapy was similar at baseline across the three groups.

The study results showed an overall procedural success of 94%, differences among groups did not achieve statistical significance (LVEF <27%: 89%; LVEF 27-37%: 100%; LVEF >37%: 92%; P = 0.25).  Three in-hospital deaths (4%) were equally distributed with one across each LVEF group.  Median follow-up was 372 days (interquartile range: 128-627 days) with clinical data available for 88% (n = 65).  Echocardiographic data were available for 73%; < 27% (n = 16), 27-37% (n = 18), and >37% (n = 19).  MR severity improved from baseline in all three groups.  There were no differences in the prevalence of MR </=2+ across groups of follow-up (P = 0.40).  A total of 16 patients died during follow-up with 12 attributed to cardiac deaths; all-cause mortality was highest in patients with LVEF < 27% (41%), as compared with LVEF 27-37% (16%) and LVEF >37% (4%), P = 0.004.  Cardiac deaths were also higher in patients with LVEF < 27% (37%), as compared with LVEF 27-37% (8%) and LVEF >37% (0), P = 0.001.  The baseline LVEF for patients who died was lower compared to those who survived (24.8±7.7% versus 35.5±13.7%, P < 0.001).  Using the Kaplan–Meier method to estimate survival, identified LVEF < 27% to be an independent predictor of mortality after adjusting for procedural success: hazard ratio 3.4 (95% CI: 1.1 to 10.0; P = 0.030).

The authors identified small sample size and incomplete follow-up as study limitations. 

The authors concluded that “[TEER] is effective in [secondary] MR patients regardless of the severity of LV dysfunction. However, low baseline LVEF is associated with increased mortality, despite procedural success.”

Sorajja P, Vemulapalli S, Feldman T, et al.  (2017) “Outcomes With Transcatheter Mitral Valve Repair in the United States: An STS/ACC TVT Registry Report.” J Am Coll Cardiol 70(19): 2315-2327.49

The aim of the study was to examine the in-hospital, 30-day, and 1-year outcomes of TEER in the United States.  Investigators analyzed data from the Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapy (STS/ACC TVT) Registry.  Participating centers in the TVT Registry have standardized data collection for demographics, morbidities, functional status, quality of life, hemodynamics, procedural details, and outcomes (in-hospital, 30-day, and 1-year).

The study population consisted of 2,952 patients treated at 145 hospitals between November 2013 and September 2015 who underwent commercial TEER in the United States and had data entered into the STS/ACC TVT Registry.  The study did not have a comparator population.  The median age was 82 years, 55.8% were men, 85% had NYHA classes III or IV.  Most patients had primary MR (85.9%), 8.6% had secondary MR alone and 262 (8.9%) had both reported.  The study was able to link data from 1,867 patients with patient-specific Centers for Medicare and Medicaid Services administrative claims.  Those with linked data compared to those with unlinked data had a median age of 83 years vs 78 years, were more commonly white (93.5% vs. for 84.5%; p < 0.0001) had a lower prevalence of smoking (3.9% vs. 8.8%; p < 0.0001), diabetes mellitus (23.5% vs. 27.7%; p = 0.01), hemodialysis (2.9% vs. 6.3%; p < 0.0001), and prior myocardial infarction (25.4% vs. 30.5%; p = 0.002).  Patients with linked CMS claims data also were less likely to have secondary MR reported as compared patients with unlinked data (15.9% vs. 20.3%; p < 0.0001). 

The study results found that among the 1,867 patients with linked data, acute procedural success was 92%, in-hospital mortality was 2.7%, mortality at 30 days and at 1 year was 5.2% and 25.8%, respectively, and repeat hospitalization for heart failure at 1 year occurred in 20.2%.  One-year outcomes differed depending on the mitral pathology treated.  The cumulative incidences of mortality (24.7%), rehospitalization for heart failure (20.5%), and the combined endpoint for mortality and rehospitalization (35.7%) were lower for patients with primary MR compared to patients with secondary MR (31.2%, 32.6%, and 49.0%, respectively).

Variables associated with mortality or rehospitalization for heart failure after multivariate adjustment using proportional hazards modeling were increasing age, lower baseline LVEF, worse post-procedural MR, moderate or severe lung disease, dialysis, and severe tricuspid regurgitation.  The investigators did not run separate models based on type of mitral pathology treated.

The authors report several study limitations.  The existing National Coverage Determination covers primary MR only, and so the registry included only a small proportion of patients with secondary MR.  CMS administrative claims data do not include a clinical justification for hospitalization or repeat surgical procedures.  Some patients could not be linked to CMS claims data (such as those who have third-party insurance or Medicare Advantage).  Therefore, study results may not be generalizable to such patients.  TVT registry participation is voluntary and data is susceptible to biased reporting.  MR etiology and severity grading were not adjudicated by an echocardiography core laboratory.  The study reports outcomes from a single-arm registry, without an available comparator group.

The authors concluded that “our findings demonstrate that commercial [TEER] is being performed in the United States with acute effectiveness and safety.”

Geis N, Puls M, Lubos E. et al. (2018) Safety and efficacy of MitraClip therapy in patients with severely impaired left ventricular ejection fraction: results from the German transcatheter mitral valve interventions (TRAMI) registry.”  Eur J Heart Fail 20(3):598-608.50

The aim of this prospective registry-based study was to assess the safety and efficacy of TEER using the MitraClip device in patients with severely reduced systolic left ventricular (LV) function.  The multicenter TRAMI registry was established in August 2010 to evaluate safety and efficacy of TEER using the MitraClip system in daily clinical practice.  The registry had 21 participating German centers at the time of study publication.  The study evaluated procedural safety, efficacy, and 1-year outcomes.

The study population consisted of 777 patients with TEER who enrolled in the German mitral valve registry between August 2010 and July 2013 and who had prospective data collection.  The study did not include a comparator population.  Investigators stratified patients into three groups according to baseline cardiac ejection fraction (EF <30%, 30–50% and >50%).

Study results identified 256 patients with severely reduced LV function (EF <30%), 280 patients with EF 30-50%, and 241 patients with EF >50% with successful TEER.  Some baseline characteristics differed across EF groups (< 30%, 30-50%, >50%), such as female sex (26.6%, 37.9%, 54.8%, p<0.0001), mean age (72.5, 76.0, 79.0 years, p<0.0001), logistical EuroSCORE (22.0%, 21.0%, 17.0%, p<0.001), and secondary MR (81.4%, 69.6%, and 59.1%, p<0.0001), respectively.  Across EF groups (LVEF < 30%, 30-50%, >50%), procedural success rates were high (procedural success [MR ≤ 2+]: 98.8% 97.5%, 95.9%, p=0.11), periprocedural complications were low (0%, 0.7%, 1.2%), and severe residual MR at discharge was low (2.9%, 3.8%, 5.7%), respectively.  In-hospital mortality was low and comparable across EF groups (3.1%, 2.1%, 1.7%, p=0.54).  One-year follow-up data were available in 683/758 patients (90.1%).  Of the 75 missing, 14/75 withdrew their consent and 61/75 were lost to follow-up.  After 1 year, overall mortality across EF groups was 24.2%, 17.3%, and 18.9%, respectively.  Major adverse cardiac or cardiovascular event rates (including death, MI, stroke) were 29.7%, 24.4%, and 23.5%.  Using multivariable Cox regression, the authors identified procedural failure as the main predictor for mortality in EF < 30% patients (hazard ratio 10.38; 95% CI 3.71-29.02).

The authors conducted a subgroup analysis of patients that presented with secondary MR (EF groups: < 30% [n = 193], 30-50% [n = 179], >50% [n = 133]).  After 1 year, overall mortality rates in patients that presented with secondary MR across EF groups (< 30%, 30-50%, >50%), were 23.2%, 17.7%, and 16.9%, respectively (p=0.29).  Major adverse cardiac or cardiovascular event rates (including death, MI, stroke) in patients that presented with secondary MR were 29.2%, 26.7%, and 22.7%, respectively. 

This authors reported several limitations.  TRAMI is a post-market registry that reflects real world experience but there are no formal inclusion or exclusion criteria, and the population is eterogeneous.  Follow-up data at one year were available for 90.1%, and no structured echocardiographic data were acquired after hospital discharge.  These missing patients may overestimate the survival impact of TEER.  Echocardiographic findings were not reviewed by a core lab. 

The authors concluded that “in patients with severely reduced systolic LV function undergoing [TEER with the MitraClip system], procedural safety, efficacy, and clinical improvement after 1 year are comparable to patients with preserved LV function.”

Systematic Reviews/Meta-Analysis

Mendirichaga R, Sing V, Blumer V, et al. (2017) “Transcatheter Mitral Valve Repair With MitraClip for Symptomatic Functional Mitral Valve Regurgitation.”  Am J Cardiol 120(4):708-715.51

This aim of this study was to evaluate the use of TEER using the MitraClip system in patients with symptomatic moderate or severe secondary MR and a high surgical risk.  The authors performed a systematic review searching PubMed, Scopus, and Cochrane Library using the following search terms: “functional mitral regurgitation,” “secondary mitral regurgitation,” “high-risk,” “MitraClip,” and “edge-to-edge.”  The authors searched for additional studies using reference lists from previous reviews and from the identified studies.  Only publications in English were considered.  Although the authors did not specify a time period, the earliest publication was from 2011 and the time period was bounded by the search date (June 2016).  Inclusion criteria required that “(1) the studies analyzing the use of MitraClip for high surgical risk patients (defined as a logistic EuroSCORE ≥ 20, a EuroSCORE II ≥ 6, or a Society of Thoracic Surgeons score ≥10) with moderate or severe secondary MR and NYHA functional class II to IV symptoms, (2) with secondary MR etiology in ≥ 97% of patients, (3) reporting outcomes of interest, and (4) with follow-up ≥12 months.  In the case of studies with overlapping populations, only the study with the greatest number of patients was included.”  The authors did not require that the studies utilize a comparator group.  Survival at 12 months was the primary outcome of interest; the authors also pre-specified other outcomes of interest that covered a range of efficacy and safety findings.

The review included 12 studies that enrolled between 24 and 452 patients each who underwent TEER with MitraClip with an average acute procedural success across the 12 studies of 89% (interquartile range [IQR] 85.5–92%).  The review reported on a collective population of 1,695 patients (age 73 [IQR 70.5-74], 69.8% men, LVEF 32.5% [IQR 29.5-36%], NYHA class II - IV).   The most common cause of ischemic cardiomyopathy was left ventricular dysfunction (62%; IQR 59.5 to 74).  Of the 1,695 patients, over 2/3 had known coronary artery disease, 35% had a previous myocardial infarction, and 38.5% had a previous cardiac surgery.

Results across the studies showed that 98% (IQR 97-100%) survived to hospital discharge; 30-day survival was 97% (IQR 96-98).  Overall survival at 12 months (the primary outcome) was 82% (IQR 77-87%).  Patients did not require mitral valve re-intervention often (12 months: 3%; IQR 2-6.5).  The most common complication was bleeding requiring transfusion (7%; IQR 2-8.5), followed by new-onset atrial fibrillation (3%; IQR 0 to 4).

The authors identified several limitations.  Baseline characteristics, procedural characteristics, and outcomes were not systematically reported in all studies.  Data presented were from observational studies and may have been subject to selection bias, publication bias, and confounder effects. 

The authors concluded that “our pooled analysis suggests that [TEER] with MitraClip is feasible, safe, and carries a low rate of mitral valve re-intervention at 12 months in patients with symptomatic moderate or severe FMR and a high surgical risk.”

De Rosa R, Silverio A, Baldi C, et al. (2018) “Transcatheter repair of functional mitral regurgitation in heart failure patients: A meta-analysis of 23 studies on MitraClip implantation.” Circulation Journal 82(11):2800-2810.52

This aim of this meta-analysis was to investigate long-term survival, clinical status, and echocardiographic findings of patients with severe secondary mitral regurgitation (MR) undergoing MitraClip (MC) treatment and explore the role of baseline characteristics on outcomes.  The authors searched for randomized trials or observational studies up to January 2017 in Medline, Cochrane, ISI Web of Science, and SCOPUS databases using the following search terms: “mitral regurgitation” (MR), “mitral insufficiency,” “MC,” “TMVr,” “FMR,” “secondary MR,” “outcome,” “echocardiography,” and “ventricular remodeling.”  Only publications in English were considered.  The authors included full text publications from peer review journals and abstracts from international scientific meetings.  For inclusion in the meta-analysis, the authors also required the following: “(1) inclusion of patients with severe or moderate-to-severe FMR undergoing TEER with MC; (2) reports of all-cause mortality after MC with a minimum of 30 days follow-up; and (3) availability of patient baseline data.  Studies reporting only composite endpoints, but no specific data on all-cause mortality, and those with fewer than 10 patients were excluded.”  The authors did not require that the studies utilize a comparator group.  The primary outcome was all cause mortality: in-hospital, 30-day, 6-months, 1 and 2 years.  The authors estimated the mean survival rates using random effects models with a restricted maximum likelihood estimator; studies with a larger sample size received more weight when calculating the mean survival rates.  The authors also pre-specified a list of secondary outcomes. 

The meta-analysis included 23 studies that enrolled between 10 and 505 patients each for a total population of 3,253 across studies.  Across the 23 studies, mean age ranged from 60.8-75.2 years, percent male ranged from 61.5-90%, mean Log EuroSCORE ranged from 12-34%, percent LVEF ranged from 19-46%, percent with NYHA class III/IV ranged from 77-100% (with one outlier study at 17.9%).

Study results found an in-hospital death rate of 2.31% (15 studies), a mortality rate of 5.37% at 1 month (16 studies), 11.87% at 6 months (13 studies), 18.47% at 1 year (16 studies), and 31.08% at 2 years (6 studies).  Of 2252 patients who were candidates for TEER in 19 of the 23 studies, 92.76% had Grade 1+ or 2+ residual MR at discharge and, at a mean follow-up of 11.7 months, 83.36% patients had MR Grade 3+.  At a mean follow-up of 11.5 months (11 studies), 76.63% of patients were in NYHA class I-II.  At a mean follow-up of 12.4 months, there were significant improvements in left ventricular (LV) volume, EF, and pulmonary pressure, although there was moderate to high grade heterogeneity (inconsistency of studies’ results).

The authors used meta-regression analysis to evaluate for clinical and echocardiographic baseline characteristics associated with overall death.  In-hospital death was associated with worse LVEF (evaluated by echocardiography) (β=−0.17±0.08 [P=0.0241].  Reduced 1-year survival was found in patients with COPD (β=0.44±0.22 [P=0.0429]).  Analysis of 13 studies reporting both AF prevalence at baseline and mortality rate at 12 months found that atrial fibrillation (AF) had a significant negative effect on 1-year survival (beta= 0.18±0.06; P=0.0047) and on the reduction in LVEDV and end-systolic volume (beta= -1.05±0.47 [P=0.0248] and beta= -2.60±0.53 [P=0.0024], respectively).

The authors identified several study limitations.  The value of meta-analyses depends on the limitations of the individual studies included.  This study includes one unpublished study and only one randomized study.  Heterogeneity of outcomes may depend in part on the study cohorts included in individual studies.  The correlation between atrial fibrillation and mortality at one year was not confirmed at two years; likely due to the low number of studies reporting the survival rate at two years.  The authors could not use a multivariate random effect model because of the limited number of studies available for meta-regression. 

The authors concluded that “[TEER using the MitraClip system] results in durable reductions in [MR] associated with significant clinical and echocardiographic improvements in heart-failure patients. AF negatively affects LV reverse remodeling and 1-year survival after [TEER] treatment.”

Giannini C, D’ascenzo F, Fiorelli F et al.  (2018)  “A meta-analysis of MitraClip combined with medical therapy vs. medical therapy alone for treatment of mitral regurgitation in heart failure patients.”  ESC Heart Fail 5(6): 1150 – 1158.53

The aim of this meta-analysis was to compare survival outcomes in patients with secondary MR following TEER with MitraClip versus those of medical therapy alone.  The authors searched for observational studies in PubMed, Cochrane and Google scholar using the following search terms: “mitral regurgitation,” “MitraClip,” and “medical therapy.”  The authors did not state whether they restricted to publications in English.  Although the authors did not specify a time period, the earliest publication was from 2014 and the most recent publication was 2017.  For inclusion in the meta-analysis, the authors also required the following: “Inclusion criteria were (i) human studies, (ii) studies comparing MitraClip vs. medical therapy, (iii) follow-up longer than 1 year, (iv) at least 80% of the patients with secondary MR, and (v) studies with multivariate adjustment.”  

The primary outcome was all cause mortality and the secondary outcome was rehospitalization for cardiac cause.  The authors estimated incidence estimates using statistical methods corresponding to a random effects model with generic inverse-variance weighting.  In addition to study level data, the analyses were performed at patient level including only secondary MR when available, evaluating the effect of TEER in different subgroups according to age, ischemic etiology, presence of implantable cardioverter defibrillator/cardiac resynchronization therapy, and LVEF and LV volumes.

The meta-analysis included six observational studies; four of the six exclusively enrolled patients with secondary MR.  The six studies had between 33 and 232 patients who underwent TEER with MitraClip (total = 833); 70-100% of which had secondary MR.  The six studies had comparator patients using medical therapy alone that ranged in number from 33 to 953 patients (total = 1,288); 93-100% of which had secondary MR.  Five of the six studies used propensity score matching to minimize imbalance in key baseline characteristics between the TEER and medical therapy alone groups and all studies had a priori inclusion criteria.

The study-level data (regardless of TEER versus medical therapy and regardless of secondary MR) had a total of 2,121 patients.  When assessing across studies, the mean age was 71 years, 78% were male, mean Log EuroSCORE was 21%, and 95% were NYHA class III - IV).  Among the patient-level data available from the six studies (n=344 patients), the mean age was 74 years, 81% were male, mean Log EuroSCORE was 22, and 91% were NYHA class III - IV).  Data from 344 patients with secondary MR included 172 (50%) patients treated with TEER and 172 (50%) propensity score-matched patients who used medical therapy alone.

The studies contributed a median follow-up of 400 days.  Meta-analysis results found that there were a total of 133 deaths: 52 (30%) in the TEER group and 81 (47%) in the group with medical therapy alone.  The risk estimate comparing TEER using MitraClip System to medical therapy alone showed a significant relative risk reduction of death from any cause in favor of TEER with homogeneity across reports (Odds Ratio [OR] = 0.79, 95% CI: 0.68–0.92, P = 0.002).  Heart-failure rehospitalization data were reported in three studies: 26 (48%) patients in the TEER arm and 47 (60%) patients in the medical therapy group were rehospitalized (P = 0.02).  The Meta-analysis found, a significant difference in survival free from readmission due to cardiac disease favoring TEER over medical therapy alone with homogeneity across reports (OR 0.73, 95% CI: 0.59–0.91, P = 0.005).  The patient-level analysis had a median follow-up of 304 days, and included 344 patients with secondary MR. TEER increased survival over medical therapy alone for all patients with secondary MR. 

This authors reported a number of study limitations.  The meta-analysis did not include any randomized controlled trials, and the quality of the meta-analysis is contingent on the quality of the included observational studies.  One study included patients from a non-published report.  Also, the studies likely have differing patient bases contributing to clinical heterogeneity across the studies.

The authors concluded that “compared with conservative treatment, [TEER using the MitraClip system] is associated with a significant survival benefit.  This superiority is particularly pronounced among patients with functional MR and across all the main subgroups.”

4.  Medicare Evidence Development & Coverage Advisory Committee (MEDCAC)

A MEDCAC meeting was not convened on this issue.

5.  Evidence-Based Guidelines

Nishimura, R. et al.  (2014)  “2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.” J Am Coll Cardiol. 63(22):e57-185.54

Nishimura, R. et al.  (2017)  “2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.” J Am Coll Cardiol 70(2):252-289.16

The 2017 Guideline is an update to the "2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease" (2014 VHD guideline) to incorporate findings from several randomized controlled trials (RCTs) that were published since its release. Clinical trials presented at annual professional society scientific meetings were reviewed in addition to peer-reviewed published literature from October 2013 through November 2016.

The guidelines document was approved for publication by the governing bodies of the ACC and the AHA and was endorsed by the American Association for Thoracic Surgery (AATS), American Society of Echocardiography (ASE), Society for Cardiovascular Angiography and Interventions (SCAI), Society of Cardiovascular Anesthesiologists (SCA), and Society of Thoracic Surgeons (STS).

The Class of Recommendation (COR) indicates the strength of the recommendation and estimates the magnitude of benefit versus risk.

  • Class 1 (Strong): Is recommended. Should be performed/administered.
  • Class IIa (Moderate): Is reasonable. Can be useful/effective/beneficial.
  • Class IIb (Weak): May/might be reasonable. Usefulness/effectiveness is unknown/unclear/uncertain or not well established.
  • Class III: No Benefit (Moderate): Is not recommended. Is not indicated/useful/effective/beneficial.
  • Class III: Harm (Strong): Potentially harmful/Causes harm. Should not be performed/administered/other.

The Level of Evidence (LOE) rates the quality of the evidence based on the type, quantity, and consistency of the data from clinical trials and other sources.

  • Level A
    • High-quality evidence from more than 1 RCT
    • Meta-analyses of high quality RCTs
    • One or more RCTs corroborated by high-quality registry studies
  • Level B-Randomized (R)
    • Moderate-quality evidence from 1 or more RCTs
    • Meta-analyses of moderate-quality RCTs
  • Level B-nonrandomized (NR)
    • Moderate-quality evidence from 1 or more well-designed, well-executed nonrandomized studies, observational studies, or registry studies
    • Meta-analysis of such studies
  • Level C-Limited Data (LD)
    • Randomized or nonrandomized observational or registry studies with limitations of design or execution
    • Meta-analyses of such studies
    • Physiological or mechanistic studies in human subjects
  • Level C-Expert Opinion (EO)
    • Consensus of expert opinion based on clinical experience The following Class 1 Level A and B recommendations were put forward: CLASS 1
  • Severely symptomatic patients with chronic severe secondary MR despite optimal GDMT:
    Mitral valve repair or replacement may be considered for severely symptomatic patients (NYHA class II to IV) with chronic severe secondary MR (stage D) who have persistent symptoms despite optimal GDMT for HF (class IIb; Level of Evidence B).
  • Chronic, moderate, ischemic MR (stage B) undergoing CABG:
    In patients with chronic, moderate, ischemic MR (stage B) undergoing CABG, the usefulness of mitral valve repair is uncertain (class IIb; Level of Evidence B-R).

Diagnosis and Management of Heart Failure

Yancy, C et al (2013) “2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines.” Circulation 128(16): p. e240-327.19

Yancy, C. et al. (2016) “2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.” Circulation, 134(13): p. e282-93.20

Yancy, C. et al.  (2017)  “2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.” J Am Coll Cardiol. 70(6):776-803.55

These publications provide detailed guidelines for the diagnosis and management of heart failure and include the full guideline published in 2013, a focused update in 2016, and a 2017 update that addresses biomarkers, pharmacological treatment for Stage C HF and comorbidities.

Only the 2013 Guideline addressed TEER and used the same framework of:

  • The Class of Recommendation (COR) indicating the strength of the recommendation and estimating the magnitude of benefit versus risk.
  • The Level of Evidence (LOE) rating the quality of the evidence based on the type, quantity, and consistency of the data from clinical trials and other sources.

Recommendations for Surgical/Percutaneous/Transcatheter Interventional Treatments of HF:

  • TEER for secondary MR
    Transcatheter mitral valve repair or mitral valve surgery for secondary mitral insufficiency is of uncertain benefit and should only be considered after careful candidate selection and with a background of GDMT (Level of Evidence: B)

6.  Professional Society Recommendations / Consensus Statements / Other Expert Opinion

Bonow, R.O., O’Gara, P.T., Adams, D. H., et al.  “2020 Focused Update of the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation.”  J Am Coll Cardiol (2020), Epublished DOI:10.1016/j.jacc.2020.02.00556

This document is a focused update of the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation.

Selected key Points include:

  • Once MR is recognized, its etiology, mechanism, and severity should be defined using semi-quantitative and quantitative echocardiography and other imaging and physiologic testing as indicated.
  • Standardized echocardiographic reporting and timely access to accurate information are critical for effective patient management.
  • A [Heart Team] consensus treatment recommendation should be discussed with the patient and family to enable shared decision making.
  • Use of [TEER] in the United States has expanded from treatment of severely symptomatic patients with primary, severe MR who are poor operative candidates to carefully selected secondary MR patients with persistent HF symptoms despite rigorous GDMT (and CRT when indicated).  The roles of the [Heart Team] and its individual members are critical to decision making and consensus treatment recommendations.

Bonow, R.O., O’Gara, P.T., Adams, D. H., et al.  “2019 AATS/ACC/SCAI/STS Expert Consensus Systems of Care Document:  Operator and Institutional Recommendations and Requirements for Transcatheter Mitral Valve Intervention.”  J Am Coll Cardiol (2020), https://doi.org/10.1016/j.jacc.2019.12.002.57

The document presents operator and institutional recommendations and requirements for transcatheter mitral valve interventions.  These recommendations are directed to the nature and composition of the heart team and operator and institutional requirements.

Heart Team and Shared Decision Making (SDM):

The authors note that “No one individual, group, or specialty possesses all the necessary skills for optimal management of these complex patients.”  Therefore, “a cohesive and highly functional multi-disciplinary team (MDT) is the foundation of the enterprise, surrounding the informed patient with the services, navigational aids and counseling necessary for a successful outcome.” 

To replicate the outcomes achieved in the COAPT trial, the authors make the following recommendations:

  • The MDT is supported through institutional resources and consists of the medical professionals necessary to deliver optimal patient centered care.  The formal, collaborative MDT should have expertise in valvular heart disease, heart failure, electrophysiology, cardiac imaging, interventional cardiology, cardiac valve surgery, and cardiac anesthesia. 
  • MR etiology (primary vs. secondary vs. mixed) and severity should be documented by an echocardiography expert knowledgeable and experienced in the integrative assessment of MR. 
  • GDMT should be determined and verified by a cardiologist experienced in caring for patients with heart failure who can supervise extended optimization of treatment, including the use of cardiac resynchronization therapy when indicated, in collaboration with an electrophysiologist.
  • The transcatheter operator must be experienced and able to select patients for whom there is a high likelihood of a safe and durable repair with this technique.
  • A cardiac surgeon expert in MV repair and replacement techniques should be available for patient consultation and surgical intervention when this approach is deemed preferable by the MDT whose consensus recommendation should be communicated to the patient as part of a SDM process.
  • This document recommends that sites incorporate methods and processes promoting patient-and family-centered care with informed SDM.  This recommendation specifically includes an individualized approach utilizing patient-specific, data-driven risk assessment; clear explanation of treatment options; the rationale for the recommendations of the MDT; and the incorporation of patient goals, preferences, and values into treatment decisions.

Operator and Institutional Requirements:

  • The MDT echocardiography expert should have the skills necessary to acquire and interpret transthoracic (TTE) and transesophageal echocardiographic (TEE) studies, including with the use of semi-quantitative and quantitative measurements as well as with 3D TEE assessment of MV anatomy and function.  Echocardiographic guidance is critical to procedural success and the interventional echocardiographer should be highly skilled.  The implanting physician also must be able to interpret intra-procedural images.
  • Minimum requirements for transcatheter MV interventions include an understanding of basic radiation safety necessary for optimal imaging, operator and patient exposure protection, and knowledge of the use of X-ray contrast agents.  Training in the interpretation of MV hemodynamics and the selective use of contrast injections will facilitate optimal catheterization laboratory and hybrid suite utilization.  Catheter and wire skills, including knowledge of the use of various techniques and the equipment available to access complex anatomy and negotiate vascular and anatomic structures, are required.  Transseptal access to the MV is a pre-requisite and fundamental skill.  Prior experience with TAVR is highly desirable as it reflects an understanding of the proper structure and process of a MDT. However, it should not be considered adequate experience for the performance of transcatheter MV interventions.  There is a premium to be placed on cumulative transcatheter valve interventions.
  • The institution should have an active cardiac surgical program supported by at least two institutionally based cardiac surgeons experienced in the treatment of patients with valvular heart disease.  One surgeon would be available for MDT participation as dictated by patient and procedural factors and the second surgeon would be available for coverage of the cardiac surgical service and emergency assistance. 
  • The institution should maintain a full range of diagnostic imaging and therapeutic facilities including: cardiac catheterization laboratory or hybrid operating room; an Intersocietal Accreditation Commission (IAC) – accredited echocardiography laboratory with sonographers, Level 3 trained and National Board of Echocardiography certified echocardiographers and cardiac anesthesiologists with training and experience in the acquisition and quantitative interpretation of TTE, TEE, and 3D TEE studies in patients with MV disease; vascular laboratory with vascular specialists capable of performing and interpreting vascular studies; CT laboratory with multidetector CT scanner, technologists, and specialists who can acquire and interpret cardiac CT studies; a magnetic resonance imaging (MRI) laboratory with technologists and specialists who can acquire and interpret cardiac MRI studies in patients with VHD is desirable; and post-procedural recovery and intensive care facilities should be available with personnel trained and experienced in managing patients who have undergone transcatheter valve repair.
  • These complex procedures should only be undertaken in institutions that routinely perform surgical MV operations and participate in the STS Adult Cardiac Surgical Database with outcomes that equal or exceed those expected for their case mix as compared to national benchmarks.  Intervention cardiology programs should have established programs in PCI, balloon valvuloplasty, TAVR, catheter closure of periprosthetic leaks and deployment of septal closure devices, with outcomes that equal or exceed those established nationally for similar procedures.
  • There must be dedication on the part of the institution to provide these services and support, both financially and with no time constraints on staff involved.  Arrangements between the institution and the physicians need to be in place to cover physician efforts dedicated to non-reimbursable hours of clinical care and medical management of the program.

Appropriate Use Criteria

There are no currently applicable appropriate use criteria.

7. Public Comment

Public comments sometimes cite the published clinical evidence and give CMS useful information.  Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. 

CMS uses the initial public comments to inform its proposed decision.  CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum.  All comments that were submitted without excessive personal health information may be viewed by using the following link https://www.cms.gov/medicare-coverage-database/details/nca-view-public-comments.aspx?NCAId=297

Initial Comment Period:  8/14/2019 – 9/13/2019

During the initial 30-day public comment period CMS received 26 comments.  All comments supported expansion of coverage of TMVR for the treatment of significant symptomatic functional (secondary) MR. The majority of commenters also supported the removal of the requirement for randomized controlled trials of non-FDA approved indications as well as revisions to the title of the NCD. Many commenters also addressed some of the hospital and operator requirements offering various recommendations for revisions to these criteria, particularly taking into consideration differences between degenerative (primary) MR, which the current NCD is limited to, and functional MR.

The majority of comments were provided by physicians, other health care professionals, hospitals and health systems. Four comments were received from TMVR medical technology manufacturers including Abbott, Boston Scientific, Edwards Lifesciences and Cardiac Dimensions.  Three comments were from patient advocacy/non-profit groups with one comment representing six patient advocacy/non-profit groups.  Two of the groups included in this comment also submitted separate comments contributing to the three total comments received from patient advocacy/non-profit organizations. These groups include the Alliance for Aging Research, Mended Hearts, and Heart Valve Voices, as well as the Caregiver Action Network, HealthyWomen and Men’s Health Network. Two comments were received from professional associations including AdvaMed and the American Osteopathic Association.

Second Comment Period: 6/30/2020 – 7/30/2020

During the 30-day comment period following the release of the proposed NCD and decision memorandum, CMS received 296 comments from 292 separate commenters.  Of these comments, 101 were form letters and one other comment was omitted from publication on the CMS website due to personal health information content, but was considered as we finalized this decision.  Commenters were fully supportive of expanding coverage of TEER to FMR, but largely disagreed with the proposals to non-cover indications consistent with the clinical trial exclusion criteria.  Commenters also largely disagreed with establishing coverage for DMR at MAC discretion and favored continued national coverage for MR.  Similarly, commenters largely disagreed with discontinuing CED and/or the registry participation requirement.  Commenters stressed the importance of CED and registry participation for both functional and degenerative MR to address gaps in the evidence and outstanding questions for indications unlikely to be studied in future clinical trials, to gather data on long-term outcomes of TEER in a real world setting, and to ensure access to TEER for Medicare beneficiaries.  Commenters also challenged the proposed volume requirements, largely commenting that they were too high, and expressed varying opinions on the composition of the heart team and role of certain members and/or other physicians both before and during the procedure.

The majority of comments were provided by healthcare professionals and physicians including cardiologists, interventional cardiologists, cardiac surgeons and anesthesiologists. Six comments were provided by professional associations including AdvaMed, the American Society of Anesthesiologists, the Society of Cardiovascular Anesthesiologists, the American Society of Echocardiography, the Federation of American Hospitals (FAH) and one comment from four professional societies including the Society of Thoracic Surgeons (STS), the American College of Cardiology (ACC), the American Association for Thoracic Surgery (AATS) and the Society for Cardiovascular Angiography & Interventions (SCAI).  Six comments were from medical technology manufacturers including Abbott, Boston Scientific, Cardiac Dimensions, Edwards Lifesciences, WL Gore and Associates, and Medtronic.  Five comments were from patient advocacy/non-profit groups, including one comment letter submitted on behalf of nine organizations, one of which also submitted a separate comment.  These nine organizations include the Alliance for Aging Research, Association of Black Cardiologists, Caregiver Action Network, HealthyWomen, Heart Valve Voice US, National Hispanic Medical Association, Mended Hearts, Men’s Health Network, and RetireSafe.  The other patient advocacy/non-profit groups that submitted separate comments were the Heart Failure Society of America, the Duke Margolis Center for Health Policy, and the Heart Valve Collaboratory.

Twenty-six articles as well as one updated article were submitted with public comments that were not available or considered for the proposed decision. These articles have been reviewed and those that fall within the scope of this reconsideration as well as our literature search and review parameters have been considered in the analysis section.

Timeline for Decision
Comment: One commenter expressed concern with the amount of time that has elapsed between FDA approval for TEER in FMR patients and the finalization of this NCD and asserted that the process from FDA approval to CMS coverage should be significantly shortened.  The commenter asserted that a shorter timeline can be accomplished without sacrificing careful review, while accelerating beneficiary access to new technologies, and while preserving patient safety.  Another commenter requested that the timeframe between FDA approval of new indications and coverage determinations be shortened and encouraged a rapid process to ensure appropriate coverage for Medicare patients is warranted and necessary.

Response:  CMS acknowledges the delayed publication of this final NCD.  CMS always aims to expeditiously complete rigorous national coverage analyses (NCAs) within statutory timeframes.  2020 was particularly challenging due to the COVID public health emergency. 

NCD Name Change and Scope
Comment: Three commenters supported revising the name of this NCD from TMVR to TEER.  One commenter recommended using TMVr and another commenter suggested revising the name to transcathter mitral leaflet approximation (TMLA). One commenter recommended changing the name to encompass future therapies and another commenter supported a name that uses inclusive terminology to reflect other transcathter mitral valve repair interventions.  One commenter stated that the name change to TEER serves no purpose as the technology is already well known as TMVR.

Response:  CMS appreciates these thoughtful NCD naming suggestions.  CMS is finalizing this NCD with terminology as proposed to provide clarity on which specific mitral valve intervention is addressed by this decision.  At this time, there is only one available FDA market authorized transcatheter mitral valve intervention for MR, and while related technologies may be available in the future, CMS has not evaluated the evidence supporting their use in this NCD. 

Comment: One commenter recommended that CMS more clearly define technical features of therapies and their anatomical placement that will or will not fall within the parameters of the NCD.  Another commenter requested that TEER be clearly defined, and if it does not include the CARILLON system, a more inclusive term be used that does. 

Response:  This NCD addresses transcatheter edge-to-edge repair (TEER) of the mitral valve, which includes transcatheter devices that approximate the mitral leaflet edges by grasping the anterior and posterior mitral valve leaflets in a fashion analogous to a surgical Alfieri repair.  It does not include other potential transcatheter approaches, for example those that modify or supplement the mitral valve annulus or the chordal apparatus.  This NCD does not address transcatheter mitral valve replacement.

Comment: One commenter preferred an evergreen NCD that addresses the broad category of transcatheter mitral valve therapy with coverage consistent with FDA-approved indications to avoid additional reconsiderations to add devices or indications.  One commenter stated that the proposed NCD is not structured to accommodate future percutaneous therapies for MR.  Another commenter recommended a single broad mitral valve policy that covers all transcatheter mitral valve technology types according to their FDA-approved indications. 

Response:  CMS is finalizing this NCD with the TEER terminology as proposed to provide clarity on which specific mitral valve intervention is addressed by this decision.  At this time, there is only one available FDA market authorized transcatheter mitral valve intervention for MR, and while related technologies may be available in the future, CMS has not evaluated the evidence supporting their use in this NCD.  Coverage of transcatheter mitral valve repair interventions that do not fall under this NCD per the definition of TEER is at the discretion of the MACs.

Comment: One commenter asserted that limitations on TEER should also be placed on mitral valve surgeries through an NCD.

Response:  We thank the commenter for this suggestion.  Surgical mitral valve repair or replacement are beyond the scope of this NCD so they are not addressed in this final decision. 

Coverage with Evidence Development
Comment:  CMS received 23 comments on the application of coverage with evidence development (CED) for TEER.  Of these, 21 supported either CED or mandatory data submission to a registry as a condition of coverage.  The 21 who supported CED or mandatory data submission to a registry as a condition of coverage included medical specialty societies, cardiac device manufacturers and patient advocates. Further, several of the 21 commenters cited the importance of CED in identifying which patients are most or least likely to benefit from TEER and under what conditions.  One commenter asserted that ongoing data collection through a CMS-approved registry is the best vehicle for assessing chronological trends and enabling treatment comparisons that are impractical within controlled clinical trials.  One commenter stated that registry data is essential for detecting if patient characteristics or anatomical determinants impact outcomes for FMR and DMR.  Another commenter noted that high-quality registry data is vital to the growing field of mitral valve transcatheter treatments, particularly because administrative codes poorly differentiate between FMR and DMR.  Another commenter supported CED because additional evidence will help ensure issues do not arise with patient access and will grow and mature the limited evidence base for TEER.  Two commenters asserted that eliminating CED data collection requirements would materially reduce the amount of information available for clinical decision-making. 

Response:  CMS appreciates these comments and has revised this NCD to cover TEER under CED for both DMR and FMR.  After careful review of the evidence, and consideration of the numerous public comments supportive of CED, CMS agrees with the consensus of the experts, including all of the professional societies and organizations that commented.  There are important evidence gaps that remain for both DMR and FMR and CED is the best path to address those.  It also permits more robust coverage than what we proposed. CMS also acknowledges that while DMR and FMR are important concepts, an important proportion of patients may have mixed degenerative and functional MR.  Furthermore, we believe that CED for both DMR and FMR better preserves the reliability of data submitted through registries and avoids potential reporting bias.

Comment: Five commenters specifically addressed the role CED and registry participation may play in TEER access. One commenter noted that elimination of CED data collection would limit patient TEER access because coverage would be based upon incomplete evidence.  One commenter stated that CED is an essential coverage pathway for patients who were excluded from clinical trials.  Another commenter noted that CED allows beneficiary access to promising technologies that do not yet meet the reasonable and necessary standard, while promoting evidence development.  One of these commenters supported CED and mandatory registry participation in order to provide TEER access for patients with comorbidities that were excluded from the COAPT trial that resulted in the FDA labeling expansion for FMR.  Another commenter asserted that CED accelerates evidence development such that TEER may reach the reasonable and necessary threshold for both FMR and DMR in the future.  One commenter supported CED and asserted that the introduction of policies that would reduce access to care in the midst of a protracted pandemic and racial unrest is antithetical to the espoused patient-centered goals of the FDA and CMS. 

Response:  This NCA identified considerable uncertainty about the generalizability of patient outcomes beyond the circumstances of the COAPT study.  For example, the COAPT study excluded patients with a range of clinical conditions that commonly occur together with moderate-to-severe or severe MR.  CMS concludes that there is insufficient evidence to conclude that TEER is reasonable and necessary for the treatment of specifically excluded patient populations.  The CED paradigm allows coverage where evidence is promising but does not yet fully assess the appropriateness of TEER, which is a key element of meeting the reasonable and necessary standard, by conditioning coverage on further evidence development.  Because CMS is finalizing this NCD with CED requirements, CMS has removed exclusions that aligned with the COAPT study inclusion and exclusion criteria and will instead cover TEER to the FDA labeling.

Comment:  One commenter asserted that eliminating CED for TEER will have negative ramifications for the management and safety of patients with significant symptomatic DMR and FMR.  This commenter further noted that over the coming years, there will be substantial device iterations for TEER, the long-term effectiveness of which can be assessed using CED coverage.  Another commenter stated that registries allow specialty societies and CMS to track patient safety issues.  One commenter recommended reconsidering the proposed decision to eliminate CED and stated that it will have a negative impact on the infrastructure needed to follow long-term outcomes for heart failure patients.  One commenter supported CED because it allows evaluation of the influences of access, race and sex on patient outcomes.

Response:  Beneficiary safety is a core CMS priority, and CMS agrees that, in addition to addressing evidence gaps, required registry participation allows real-time tracking of TEER safety and real world outcomes.  CMS concludes that the registry requirement is especially important given the conflicting findings of the COAPT and MITRA-FR studies.  As noted in our analysis, two potential reasons for the discrepant findings of these two studies are insufficient institutional and implanter experience and inappropriate patient selection in the MITRA-FR study.  CMS believes that registry participation also provides important beneficiary safeguards in that it allows specialty societies and facilities to quickly identify and address any quality or safety problems.  The registry mechanism offers more comprehensive and near contemporaneous feedback than can be provided through other mechanisms and provides context on performance relative to other TEER implanting facilities.

Comment:  Six commenters noted the importance of CED to track quality and outcomes.  One of these commenters asserted that all TEER patients must be included in a national registry to ensure quality and to facilitate public reporting of outcomes. Another commenter argued that registry data will allow development of risk-adjusted, validated outcome measures that may be incorporated into practice guidelines.  This commenter also asserted that removing CED would prevent development of a TEER quality metric and is an abandonment of CMS’s commitment to quality care for beneficiaries.  One of these commenters supported requiring the TVT and any other registries to regularly report physician and hospital specific outcomes to federal agencies involved with patient safety and efficacy efforts and recommended consideration of broader reporting in the future as TEER volume increases.  One of these commenters, who supports continued registry reporting but does not support continued CED, asserted that CMS should require post-market data collection as a condition of coverage to ensure measurement of quality outcomes and to support the development or improvement of new or existing therapies.  This commenter asserted that CMS has previously finalized other NCDs with continuous registry reporting requirements after ending CED.  This commenter also requested that registries be required to publicly provide, at minimum, annual reports to evaluate outcomes like the NY Department of Health does for hospital and surgeon coronary artery bypass grafting procedures.

Response:  CMS appreciates these detailed comments on the value of registries for quality reporting. CMS agrees with the commenters that CED is appropriate for this NCD. CMS also agrees that registry participation offers a mechanism to develop validated, risk-adjusted quality measures that are necessary for delivery of high-value care for Medicare beneficiaries.  CMS also notes that the TVT registry plans to use registry data for public reporting of transcatheter aortic valve replacement (TAVR) outcomes beginning in 2021, and registry data could be similarly used for TEER in the future.

Comment: Ten commenters supported continued mandatory registry participation through CED.  One commenter argued that without CED there is less incentive to complete additional studies that address outstanding questions.  Fourteen commenters expressed support for mandating registry use or data reporting.  One commenter supported the proposal to remove CED, but recommended a continued data collection requirement.  Two commenters supported removal of CED and the registry reporting requirement.  One of these two stated that the FDA-approved trial provides adequate evidence because it met all endpoints and showed an overwhelming mortality benefit.  One commenter agreed that real world evidence is an important and valid tool for filling evidentiary gaps but did not support mandatory registry participation.

Response:  CMS agrees that important evidence gaps remain for both DMR and FMR and has revised this NCD to cover TEER under CED for both MR mechanisms.  CMS concludes that mandatory registry participation is necessary not only to fully address generalizability concerns for patients with comorbidities not studied in the COAPT trial, but also to address concerns that clinician and institutional inexperience resulted in poor outcomes in the MITRA-FR trial.  Universal registry participation will also provide a more fair basis of quality and outcomes comparisons across programs that offer TEER if risk-adjusted quality measures are developed through the registry in the future.

Comment: One commenter noted that an appropriately structured CED design can facilitate minimally burdensome and non-duplicative real-world evidence development.  Some commenters supporting CED and/or continued registry participation also recommended new approaches to the CED requirements.  Two commenters supported generation of real world evidence using administrative claims.  Three commenters recommended that CED be less burdensome and expensive to clinical sites and that the evidence obtained be more accessible.  Six commenters encouraged CMS to work with providers and the TVT registry on streamlining data collection requirements to reduce providers’ burden and participation costs.

One commenter noted that when Medicare coverage is contingent on collecting additional evidence CMS should apply guardrails to the requirement: 1) collaborate with stakeholders to clearly identify the data collection objectives; 2) consider the minimum data necessary to achieve those objectives; 3) clearly identify, with input from interested stakeholders, scientifically supported study endpoints and the duration of data collection in advance (including clear stopping rules for data collection under CED); and 4) identify appropriate mechanisms to ensure continuous coverage of an item or service after a study ends, to avoid disruption in coverage and continue to allow Medicare beneficiaries to benefit from important FDA-approved technologies and services until a new or revised coverage determination is issued. 

Response:  This NCA identified considerable uncertainty about the generalizability of patient outcomes beyond the circumstances studied in the COAPT study.  CMS is aware that registries may have extensive data entry requirements, and we strive to strike an appropriate balance between reducing burden on providers and obtaining necessary data to inform future coverage determinations.  While CMS supports use of data elements from existing data sources where they are valid and reliable, an adequate assessment of TEER requires essential data elements that are not consistently or reliably available through electronic medical records or administrative claims.  Consequently, some custom data entry into a registry, using standardized definitions, is necessary to address evidence gaps identified in this NCA. 

CMS is aware of efforts by multiple stakeholders to streamline data collection in the TVT registry, which could considerably reduce provider burden.  CMS applauds these efforts to reduce the burden of registry participation and continues to more broadly explore how real world evidence may be used to efficiently meet CED requirements.  Clinical studies conducted within registries frequently result in peer-reviewed publications that are available in the public domain and provide important information about the risks and benefits of treatment to the FDA, CMS, patients, and clinicians.  We encourage researchers and investigators to develop rigorous evidence development strategies that make use of real world evidence, and we continue to consider robust studies using real world evidence when conducting NCAs.  CAG will consider published, peer-reviewed evidence periodically, following the effective date of this coverage decision and reconsider the policy when appropriate.  The NCD will expire 10 years from the effective date if it is not reconsidered during that time.  Upon expiration, coverage will be at the discretion of the MACs.

Covered Indications
Comment: Some commenters addressed the specificity of the proposed covered indications.  Five commenters recommended that CMS revise and simplify the language to cover FDA approved indications for TEER. Three commenters specifically recommend that coverage criteria not include clinical trial inclusion and exclusion criteria, and another commenter argued that coverage to label instead of using trial inclusion and exclusion criteria would balance patient safety with access.  One commenter supported coverage of FDA-approved, on-label uses in a manner consistent with the TAVR NCD where the policy encompasses broad coverage for a range of emerging technologies. One commenter suggested allowing heart teams to make tailored decisions for individual patients based on available clinical trial evidence and clinical experience.  One commenter asserted that limiting coverage to patient populations included in the COAPT trial is overly prescriptive and restricts access for some patients who may benefit from TEER. 

Another commenter stated that TEER should be covered in patients similar to those enrolled in the COAPT trial.  One commenter requested less specific language in proposal A.1.a. by replacing “stable doses of maximally tolerated” with “appropriate” to allow clinicians to offer TEER in a timely fashion. This commenter also recommended simplifying language in A.1.b. to describe cardiomyopathy as symptomatic which would encompass NYHA class and other factors without needing to list them separately.  One commenter stated that requiring documentation of GDMT is reasonable but needs clarification. One commenter noted that the proposal does not define time dependent objective parameters for severity of FMR beyond the subjective description as moderate to severe.  One commenter requested that patients with asymptomatic FMR be covered as this would be proactive and cost effective. 

Four commenters disagreed with including coverage criteria specific to LVEF with one commenter noting that LVEF parameters are already captured in language referencing FDA-approved indications and another asserting that the language is too narrow and patients falling outside these specifications may still benefit from TEER.  One commenter requested that CMS reconsider the proposed exclusion of patients with an ejection fraction (EF) < 20% and > 50%.  Another commenter asserted that an EF < 50% is too low, two commenters supported the lower LVEF limit of >20%, but recommended removing the upper limit of 50%. Two commenters noted that patients with severely reduced LVEF may benefit from TEER and should not be excluded.  Another commenter recommended that local heart teams determine whether to offer TEER to patients with LVEF < 20% as many of these symptomatic patients have exhausted other treatment options and TEER has been shown to delay the need for LVAD and/or transplant.

Two commenters disagreed with including coverage criteria specific to NYHA class.  Four commenters disagreed with coverage requirements for left ventricular end-systolic dimension (LVED).  One commenter noted that LVED parameters are already captured in language referencing FDA-approved indications.  Together these commenters asserted that the language as proposed is too narrow and patients falling outside these requirements may still benefit from TEER.

Response:  This NCA identified considerable uncertainty about the generalizability of patient outcomes beyond the circumstances of the COAPT study.  For example, the COAPT study excluded patients with a range of clinical conditions that commonly occur together with moderate-to-severe or severe MR.  CMS has determined that there is insufficient evidence to conclude that TEER is reasonable and necessary for the treatment of patients specifically excluded from the COAPT study.  The CED paradigm allows coverage where evidence is promising but does not yet reach the reasonable and necessary evidentiary standard by conditioning payment on further evidence development.  Because CMS is finalizing this NCD with CED requirements, CMS has removed exclusions that aligned with the COAPT study and instead will cover TEER to the FDA labelling.  Both GDMT and standards for assessment of MR severity are extensively detailed in guidelines reviewed in this NCA and may change over time.

Comment: Nine commenters disagreed with requiring the local heart team to determine that mitral valve surgery will not be offered as a treatment option because mitral valve surgery is not a treatment option for most FMR patients.  One commenter further asserted that this requirement unfairly favors surgical mitral valve replacement / repair (which has a lower level of evidence) over TEER (which has a higher level of evidence).

Response:  CMS appreciates these comments.  The COAPT study where benefit was demonstrated for FMR required that a cardiac surgeon determine that mitral valve surgery would not be offered as a treatment option.  However, CMS will finalize the TEER NCD under CED to the FDA labelling.  The CED paradigm allows coverage where evidence is promising but does not yet fully assess the appropriateness of TEER, which is a key element of meeting the reasonable and necessary standard, by conditioning coverage on further evidence development.  Consequently, CMS will remove the requirement that a cardiac surgeon examine the patient and determine that they are ineligible for mitral valve surgery.

Non-Covered Indications
Comment: Eighteen commenters disagreed with the proposal to non-cover the coexisting conditions listed in the proposed decision.  One commenter noted that the limitations would require additional reconsiderations to expand coverage in the future and another commenter asserted that aligning noncoverage with the COAPT inclusion and exclusion criteria would potentially cause an inappropriate restriction on Medicare coverage and beneficiary access.  Four commenters recommended that the heart team or cardiologist should determine if a patient should undergo TEER rather than noncovering the COAPT exclusion criteria.

In response to the proposal to noncover TEER when there is coexisting aortic or tricuspid valve disease requiring surgery or transcatheter intervention, 57 commenters disagreed with noncovering patients with tricuspid regurgitation (TR), 20 commenters disagreed with noncovering patients with multivalve disease/aortic or tricuspid valve disease, one commenter asserted that patients with tricuspid disease who need surgery should be covered and one commenter supported excluding patients with severe TR from coverage.

Commenters provided more detailed comments to further explain their concerns. Eleven commenters noted that limiting coverage for patients with multivalve disease or concomitant tricuspid valve disease is not appropriate and would prevent providers from using a staged approach to treat their structural heart disorders.  They also asserted that noncoverage would prevent clinical trial enrollment, such as in the TRILUMINATE clinical trial.

Three commenters noted that multivalve disease is common and patients with other valve diseases should not be excluded from coverage.  Three commenters asserted that TR improves after MR is corrected, with one noting that there are limited tricuspid treatment options since there are no FDA approved tricuspid transcatheter therapies.  Two commenters asserted that excluding coverage for patients with aortic and tricuspid disease will limit patient access to TEER, one commenter asserted that it will compromise the health of patients, and another stated that it will lead to higher costs.  One commenter stated that patients with TR and aortic disease will not improve after valve surgery but do benefit from percutaneous therapies.  Another commenter asserted that patients with tricuspid disease have good outcomes, and one commenter recommended that patients with tricuspid disease should be able to have individualized treatments.  One commenter supported coverage of TEER in patients with concomitant tricuspid intervention.

Twenty-four commenters disagreed with the proposal to noncover COPD requiring continuous home oxygen therapy or chronic outpatient oral steroid use and stated that the treatment plan should be established by the heart team. One commenter recommended that TEER be covered in patients with compromised respiratory capacity.  One commenter suggested CMS specify that patients with COPD on continuous oxygen are excluded from coverage only if they have a life expectancy of less than 12 months due to other severe medical conditions.

Two commenters disagreed with excluding patients with ACC/AHA stage D heart failure, with one noting that treatments, including TEER, may improve heart failure and the other asserting that no other effective treatment is available for symptom relief.

Six commenters disagreed with excluding patients with significant pulmonary hypertension from coverage.

Forty-eight commenters disagreed with noncovering TEER in patients with hemodynamic instability requiring inotropic support or mechanical heart assistance. Four commenters requested that patients with cardiogenic shock not be excluded from coverage.  Two commenters asserted that evidence supports coverage of patients with hemodynamic instability, with one commenter citing an article showing that these patients may benefit from TEER and the other commenter citing an abstract submitted for TCT suggesting safety and efficacy of TEER in these patients.  Three commenters asserted that the treatment decision should be made by the heart team and one asserted that this patient population must be studied further.

Three commenters requested that patients with right ventricular dysfunction not be excluded from coverage and one commenter requested that patients with right ventricular heart failure not be excluded from coverage.  One commenter noted that patients with right ventricular dysfunction as assessed by echocardiography not be excluded because echocardiography is an inadequate assessment of right ventricular function.

Three commenters recommended allowing coverage for patients who are expected to need cardiac surgery within 12 months.

Response:  CMS appreciates these comments.  The COAPT study that demonstrated benefit for FMR included a broad range of specific inclusion and exclusion criteria.  By contrast, the MITRA-FR study, where inclusion and exclusion criteria were less stringent, did not demonstrate that TEER confers a benefit to patients with moderate to severe or severe FMR.  CMS is finalizing the TEER NCD with CED to the FDA labelling.  Further evidence is needed to assess why the COAPT and MITRA-FR studies reached markedly different conclusions about the benefits of TEER in FMR.  The CED paradigm allows coverage where evidence is promising but does not yet fully assess the appropriateness of TEER, which is a key element of meeting the reasonable and necessary standard, by conditioning coverage on further evidence development.  In the context of CED, CMS will cover TEER to the FDA labelling. However, the presence of severe aortic stenosis may worsen heart failure symptoms and may substantially increase MR severity.58-60 Therefore, we are clarifying that TEER is non-covered in patients with untreated severe aortic stenosis because intervention to the mitral valve may be unnecessary after the aortic stenosis is addressed.

Patient Evaluation
Comment: Seventy-five commenters disagreed with the proposed requirement that a cardiac surgeon independently examine FMR patients face-to-face.  Twenty-seven of these commenters asserted that surgery is not the standard of care for FMR, with some specifying that there is no data to support surgery in these patients.  Sixteen of these commenters noted that there should be no surgical consultation because there is no surgical treatment for FMR and three of these commenters noted that requiring a surgical consultation for FMR patients deviates from expert consensus.

Eight commenters noted that requiring a surgical consultation for FMR will delay or create obstacles or barriers to care with four also noting that a surgical visit may subject patients to a higher risk procedure which has not demonstrated significant benefit.  Two commenters asserted that requiring FMR patients to see a surgeon face-to-face before undergoing TEER will increase costs and another commenter asserted that a chart review is more reasonable than a surgical consultation.  One commenter stated that requiring a heart team cardiac surgeon to independently examine the patient face-to-face undermines the spirit of the heart team and defeats the objectives of shared decision making.  Three commenters requested removal of the in-person surgical consultation requirement for every FMR patient, but noted that one may be conducted on a case-by case basis.

Two commenters supported requiring a surgical opinion for FMR patients.  One commenter stated that the heart team approach is appropriate, with face-to-face cardiologist and cardiac surgeon input and another commenter agreed that the role of the cardiac surgeon is important in the evaluation of patients before consideration for TEER for FMR.

Commenters offered recommendations regarding the types of physicians with whom an evaluation or consultation is more appropriate for FMR.  Fifteen commenters supported evaluations by heart failure specialists, two commenters supported including the heart failure specialist on the heart team to support the determination of appropriateness and two other commenters asserted that a face-to-face consultation with a heart failure specialist is too burdensome since most practices do not have a heart failure specialist. One commenter asserted that requiring an interaction with a heart failure physician is unnecessary.  One commenter noted that a heart failure specialist must perform the evaluation and that a general cardiologist managing heart failure and FMR patients cannot qualify as a heart failure specialist.  One commenter stressed the importance of adding a consultation from a heart failure physician or noninvasive cardiologist with strong interest in valvular disease management to prevent potential misuse.

Six commenters recommended the evaluation for FMR be performed by a heart failure physician and interventional cardiologist, one commenter suggested a heart failure specialist and the proceduralist (either an interventional cardiologist or cardiovascular surgeon) perform the consultation and another commenter recommended adding independent examination by a heart failure specialist.  Another commenter supported shared decision making between a heart failure specialist and the interventionalist, but with no independent surgeon evaluation. Four commenters asserted that instead of a face-to-face visit with a surgeon, the heart team should review the case.  One commenter supported the evaluation by the operator/interventional cardiologist, another commenter recommended an interventional cardiologist and general cardiologist perform the consultation and another commenter asserted that an interventional cardiologist with or without a heart failure physician should evaluate FMR patients.  One commenter recommended only the interventional cardiologist perform the evaluation following a referral and documentation by another cardiologist, who could be a heart failure physician.  Another commenter stated that the suitability decision can be made by the referring cardiologist.  One commenter suggested that the independent evaluation be performed by the heart team interventional cardiologist or the interventional echocardiographer or cardiac surgeon if the surgeon is performing the TEER procedure and another specified that the cardiac surgeon or interventional cardiologist independently examine the patient.

One commenter disagreed with requiring a cardiovascular surgeon and interventional cardiologist to consult for FMR because many centers do not have surgical mitral expertise to support the consultations needed to address a large number of patients.  One commenter asserted that a cardiac surgery consultation is unnecessary for FMR unless patients have concomitant aortic valve disease or coronary artery disease and could otherwise benefit from surgical intervention.  One commenter agreed that the role of the cardiac surgeon and heart failure specialist is important in the evaluation of these patients before consideration for TEER.

Fifteen commenters requested that CMS allow face-to-face interactions to be fulfilled using telehealth with one of these commenters recommending possibly eliminating the face-to-face requirement entirely to reduce burden on patients.

One commenter, supporting national coverage for DMR patients, recommended that a surgeon and interventionalist be involved in shared decision making for TEER.

Response:  CMS appreciates these comments.  CMS has removed the requirement that a cardiac surgeon examine FMR patients to determine that they are ineligible for mitral valve surgery.  CMS agrees that for FMR, cardiac surgery is not generally the standard of care and requiring this consultation would present an undue burden; instead, optimization of GDMT with cardiac resynchronization therapy, if appropriate, is essential.  Therefore, for FMR, CMS is requiring that a cardiologist experienced in treating patients with advanced heart failure must independently examine the patient face-to-face. CMS recognizes that cardiologists may have extensive experience with advanced heart failure without being board eligible/board certified and that a board eligible/board certified Advanced Heart Failure/Transplant cardiologist is not available in some communities. Nonetheless, whenever possible, the heart failure cardiologist should be board certified in Advanced Heart Failure/Transplant.  For DMR, CMS continues to require that a cardiac surgeon independently examine the patient face-to-face because surgery is generally the standard of care.  CMS supports the concept of shared decision-making for all TEER patients.  Regarding the use of telehealth, CMS notes that this final NCD does not change telehealth rules and any services eligible to be furnished via telehealth under existing telehealth rules are allowable under this policy.

Heart Team
Comment: Commenters offered a variety of opinions regarding the composition of the heart team.  Three commenters agreed that the heart team should be comprised of an interventional cardiologist, a cardiac surgeon and a cardiac imager, while one commenter supported a team comprised of an interventional cardiologist, a cardiac surgeon, and a heart failure specialist.  One commenter recommended that the heart team include an interventional cardiologist or a cardiac surgeon but not both.  Another commenter supported a combination of an interventional cardiologist, a radiologist, a cardiac surgeon and a heart failure specialist and any other specialists who may be pertinent to a patient’s case.  One commenter expressed support for the heart team model and recommended that it include a heart failure cardiologist and an electrophysiologist.  Another commenter requested that an electrophysiologist be added to the list of physicians that may be primary or co-primary operators for TEER, stating that they are adept at complex procedures like LA ablation and LAA closure and that their expertise allows them to lead a TEER team.  One commenter asserted that competent, properly trained cardiologists and cardiac surgeons should be allowed to be co-primary operators for TEER. 

Response: CMS believes the heart team must be comprised of multiple practitioners with the expertise to optimally treat patients with DMR and FMR.  CMS has determined that the heart team must be comprised of an interventional cardiologist, a cardiac surgeon, an interventional echocardiographer, a heart failure cardiologist with experience treating patients with advanced heart failure (for FMR patients only) and other providers from other specialty areas as appropriate, along with advanced patient practitioners, nurses, research personnel, and administrators.

Comment: One commenter recommended condensing the heart team requirements to one section of the policy.

Response:  We appreciate this recommendation and have worked to streamline the requirements for each member of the heart team under one section.

Comment: One commenter asserted that it is important to include a cardiac surgeon on the heart team and in decision making while another commenter stated that there is no need for a cardiac surgeon on the heart team because surgery is not a consideration for patients with FMR. 

Response:  This final NCD addresses both DMR and FMR and does not include a requirement for the cardiac surgeon to examine the patient face-to-face for FMR. However, the final NCD does require the cardiac surgeon to examine DMR patients face-to-face. CMS agrees that it is important to have the cardiac surgeon perspective on the heart team.

Comment: Eight commenters supported including a heart failure physician specialist on the heart team with four noting that a heart failure specialist is important for appropriate patient selection.  One of these commenters further explained that the heart failure specialist could review the patient’s medical therapy and suggest that further optimization may be warranted before assessing MR severity and proceeding with TEER.  Another commenter supported the proposed language describing the heart failure specialist on the heart team as experienced in care and treatment of FMR that parallels the expert consensus document.  One commenter recommended requiring the heart team to include a heart failure physician specialist without the additional requirements in A.1.c.iii. specifying that the heart failure physician specialist be experienced in the care and treatment of mitral valve disease.

Some commenters expressed concerns about the proposed requirements that patients are under the care of a heart failure physician specialist experienced in the care and treatment of mitral valve disease and that the heart team also includes a heart failure physician specialist experienced in the care and treatment of mitral valve disease.  Five commenters stated that the heart failure physician specialist requirement is redundant because all interventional cardiologists are capable of managing heart failure patents according to guidelines.  For this reason, two other commenters recommended revising requirement A.1.c.ii. to “The patient is under the care of a board-certified cardiologist, experienced in the treatment of heart failure with mitral valve disease and has indicated that guideline based maximal goal directed medical therapy has been achieved.” One commenter noted that requiring patients to be under the care of a heart failure physician specialist experienced in the care and treatment of mitral valve disease is challenging and recommended instead that the heart team document that robust attempts have been made to optimize GDMT.  Three commenters requested that heart failure specialist be further defined. 

Eight commenters also asserted that the heart failure specialist requirement would be a barrier to care.  One commenter noted that in centers that do not have heart failure specialists, a referral to a heart failure team would cause delay and another commenter stated that over ¾ of TEER centers do not have access to heart failure specialists so the requirement will permanently shut down many programs.  Another commenter asserted that requiring consultation with a heart failure specialist is a major barrier to a lifesaving therapy and supported requiring documentation of failure of GDMT instead.  One commenter noted that the heart failure physician specialist language as proposed could limit mitral therapies to only the largest hospitals and limit access to care as many patients with congestive heart failure are treated in hospitals that may not have specialists in heart failure management.  Another commenter agreed that the proposed language would restrict care and require very ill patients to see up to four different cardiovascular specialists. Another commenter asserted that the requirement would place undue hardships on institutions and cause patients to be seen out of town by a heart failure specialist since not all TEER centers have a fellowship trained heart failure specialist.  One commenter asserted that most heart failure care is delivered by general cardiologists, interventional cardiologists with an interest in structural/valvular heart disease, and advanced cardiac imagers while most board certified heart failure specialists deal with advanced heart failure, inotropes, LVADs, and transplant and noted that the proposed policy excludes stage D heart failure patients.  One commenter agreed with these commenters that the proposed requirement is concerning because many areas of the country have less access to such physician specialists and asserted that many heart failure physician specialists are not experienced in the care and treatment of mitral valve disease while also noting that multiple physician visits are burdensome and difficult to coordinate.  This commenter stated that advanced practice providers that are not board certified heart failure specialists are capable of optimizing medical therapy for heart failure and referring patients for cardiac resynchronization therapy as appropriate.

Response:  CMS has finalized the requirement for a cardiologist experienced in treating patients with advanced heart failure (the heart failure cardiologist) be included on the heart team specifically for patients with FMR.  For FMR, discrepancies in the outcomes achieved in the COAPT and MITRA-FR studies that included patients with ostensibly similar patient characteristics demonstrates clearly the critical role of patient selection and of reaching maximally tolerated GDMT prior to pursuing TEER.  CMS agrees with specialty societies and the FDA that optimization of GDMT is essential for achieving good patient outcomes, and therefore, CMS is requiring that the heart team heart failure cardiologist experienced in treating patients with advanced heart failure evaluate TEER candidates with FMR.  There is no requirement that patients with DMR be evaluated by the heart team heart failure cardiologist.  Because this NCD represents an expansion of coverage to FMR, CMS disagrees that a requirement for the heart team heart failure cardiologist to appropriately evaluate FMR patients for maximal GDMT will shut down TEER programs.

Comment: Twelve commenters supported the inclusion and identification of the echocardiographer as a key member of the heart team and during TEER procedures.  Six of these commenters supported recognition by CMS that specialized expertise and training in interventional echocardiography for cardiologists and cardiac anesthesiologists is necessary for TEER.  Three commenters asserted that interventional echocardiographers may be anesthesiologists or cardiologists.  Eleven commenters specifically stated that the physicians performing the imaging should be reimbursed appropriately for the procedure.  One commenter asserted that TEER is not a single operator procedure because equal time is required on a second operator to perform transesophageal echocardiography and two other commenters recommended revising requirement A.2.b. to require the heart team’s interventional cardiologist or cardiac surgeon and the interventional echocardiographer perform the procedure.  One commenter requested that the requirement to include an interventional echocardiographer be removed to allow anesthesiologists to perform the imaging.

Response:  CMS agrees that the interventional echocardiographer is an important member of the heart team and is critical during TEER procedures.  We have more completely specified the role of the interventional echocardiographer in TEER procedures in the final NCD.

General Volume Requirement Comments
CMS received numerous comments that generally addressed the proposed volume requirements, but did not identify exactly what proposal and/or type of MR to which they applied.  These general comments represented ideas on how volume requirements affect patient access, the relationship between volume requirements and outcomes, whether separate volume requirements are appropriate based on hospital and heart team experience with TEER and the role of quality metrics.  The themes of these general comments are encompassed in the more specific comments summarized and responded to in detail below.

Hospital and Heart Team Requirements to Begin TEER Programs
Comment: Four commenters supported the proposed volume requirements for hospitals to begin TEER programs.  These requirements keep the procedure quality high, which is essential.

Three commenters requested maintaining the volume requirements specified in the existing TMVR NCD and not update the requirements to what CMS proposed in the NCD.  At least one commenter noted that the proposed cardiac surgical volume to begin a program is challenging.  Another commenter asserted that there should be a common standard to begin or maintain a TEER program and that it should not change from the existing TMVR NCD.

Response: We agree.  Based on the comments and finalizing this decision as CED, we have finalized a common standard for all TEER programs under this NCD.  Further, we have reduced the cardiac surgical volume for hospitals to ≥ 20 per year which is half of what we proposed.  These final volume requirements reflect elements of the Expert Consensus document, our review of currently available clinical evidence, and our efforts to align with the TAVR NCD volume requirements for consistency across valve programs that perform both TEER and TAVR.

We note that evidence supports an association between procedural volumes and improved outcomes for both cardiac surgery and TEER, and we agree with the Expert Consensus document that volume requirements are appropriate to ensure good outcomes.  We are finalizing this decision to include CED which requires submission of data to a qualified registry. We believe that these data will assist hospitals in assessing and improving program quality which will be valuable in closely monitoring their TEER programs and ensuring good health outcomes for Medicare patients. 

Surgical Volume Requirements
Comment: One commenter recommended consideration of a more flexible, hybrid or blended approach to requirements for new TEER hospitals to align with requirements established in the TAVR NCD where hospitals must perform a defined number of open heart surgeries including a small portion of mitral valve surgeries.  Fourteen commenters expressed disagreement with the proposed mitral valve surgical volume requirements to begin a TEER program stating that they are too high. 

Some commenters offered suggestions on alternate surgical volume requirements to begin TEER programs. Three commenters recommended 20 mitral valve surgeries to begin a TEER program, one suggested maintaining the requirement for 25 mitral valve surgeries and two recommended 50 open heart surgeries in the previous year prior and 20 mitral valve related procedures in the two years prior to program initiation. Two stated that the mitral valve surgical volume requirements to begin a TEER program should be eliminated or reduced to the same volume requirements for hospitals with TEER experience. One commenter suggested that in the previous year prior to program initiation, hospitals perform > 50 heart valve surgeries and transcatheter procedures (including TAVR), at least 20 of which are mitral valve surgeries (including repair and replacement).

Response: CMS has finalized a lower surgical volume requirement for hospitals of ≥ 20 mitral valve surgical procedures for severe MR per year or ≥ 40 over two years, of which at least 10 (or 20 over two years) must be mitral valve repairs. The final requirement is half of what we proposed for hospitals without TEER experience. With this lower number, we do not agree that a hybrid approach would ensure sufficient experience and expertise in mitral valve surgical procedures, particularly for patients with DMR. We believe the final, lower, mitral valve surgical volume requirement will accomplish a similar result as the recommended hybrid approach by enabling a larger number of hospitals to meet the NCD requirements.   

Comment: Twenty-five commenters expressed concerns that the proposed mitral valve surgical volume requirements would limit TEER access. Six of these commenters asserted that the proposals would disproportionately affect smaller and rural hospitals and those in underserved and underprivileged areas.  Two of these commenters asserted that the proposed volume requirements would reduce the number of hospitals offering TEER.  One commenter noted that the increased volume requirements would hinder community hospitals with established structural heart programs from offering TEER and another commenter asserted that the proposals would eliminate most centers with successful structural programs.  One commenter noted that patients are best cared for locally. One commenter stated that most hospitals perform less than half of the proposed minimum surgical volume requirements. One commenter noted that a report by Vemulapalli et. al. demonstrates that access would be limited and another commenter suggested that a “care gap” would be established. Five commenters asserted that patients would have to travel to undergo TEER and three commenters noted that patients might forego treatment altogether if TEER is not available nearby. 

Four commenters stated that hospitals will have trouble meeting the proposed requirements to begin TEER programs with one specifically noting that few programs will meet ≥ 40 mitral valve surgical procedures and another commenter stated that few will be able to specifically meet the mitral valve repair requirement.  One commenter asserted that most programs do not meet mitral valve surgical volume requirements in the 2014 NCD of ≥ 25 per year.  One commenter stated that the increased mitral valve surgical volumes would place financial burden on referring physicians and facilities and another commenter noted that the increased volume requirements to begin a TEER program would restrict structural heart programs to large facilities.  Several commenters echoed similar concerns about access in response to the proposed volume requirements for hospitals to maintain TEER programs.

Response:  CMS supports the provision of high quality care for our beneficiaries.  Evidence supports an association between procedural volumes and improved outcomes for both cardiac surgery and TEER, and CMS agrees with the Expert Consensus document that volume requirements are appropriate.  Because TEER coverage under CED will require submission of data to a qualified registry, CMS believes that these data will assist hospitals in assessing and improving program quality.  Therefore, CMS is finalizing lower hospital cardiac surgery volume requirements than proposed and applying this requirement for both new and existing programs.  CMS agrees that ensuring patients have appropriate access to TEER is important but also recognizes that having access includes ensuring that patients have good quality care. We believe the reduced hospital surgical volume requirements and other requirements set forth in this final NCD are important to ensure Medicare beneficiaries have access to TEER in programs that deliver high quality care and achieve optimal health outcomes. The final NCD requirements reflect our intent to strike a balance between ensuring hospitals have the experience and capabilities to handle complex structural heart disease cases with an evolving evidence base while also ensuring Medicare beneficiaries have access to needed treatment.

Physicians with Cardiac Surgery Privileges
Comment: One commenter recommended reducing the required number of surgeons from two to one.

Response: CMS disagrees with reducing the required number of physicians with cardiac surgery privileges experienced in valvular surgery from two to one because it is important that hospitals performing TEER have a robust cardiac surgery program, particularly for DMR.  This requirement is supported by the Expert Consensus document that recommends institutions have an active cardiac surgical program supported by at least two institutionally based cardiac surgeons experienced in the treatment of patients with valvular heart disease.  The rationale offered in the Expert Consensus document for two cardiac surgeons is so one would be available for heart team participation and the other would be available for coverage of cardiac surgical service and emergency assistance.

PCIs
Comment: Three commenters disagreed with the proposed requirement for hospitals to perform 300 PCIs per year.  One asserted that 300 PCIs is arbitrary and not supported by data, especially as PCI numbers are declining.  One commenter noted that PCI volume requirements are unnecessary because the skills for PCI and TEER are distinct. One commenter asserted that 300 PCIs per year is unreasonable and restricts TEER to large academic hospitals.  Another commenter requested that the term PCI be changed to “cardiac interventions” to allow for inclusion of other closely aligned procedural experience like TAVR, left atrial appendage occlusion, atrial septal defect closure or other structural/transeptal interventions.

Response: CMS believes that a PCI volume requirement is important to ensure that hospital programs have sufficient experience with catheter and wire handling, vascular access, and procedural complications, which may require vascular surgery repairs. CMS is finalizing the PCI volume requirement as proposed which reduces the PCI volume requirement from the 2014 NCD (≥ 400) to ≥ 300 PCIs per year. This reduction is consistent with the Expert Consensus document, which is based on current evidence from clinical trials, analysis of the TVT registry, and current medical practice.

Evidence on Volume Requirements and Outcomes
Comment: Nine commenters asserted that there is no proven relationship between the number of surgical mitral valve repair procedures performed and TEER outcomes.  Another commenter noted that publications demonstrate little relationship between mitral valve surgical volume and TEER outcomes.  Five commenters cited Barker (2020) and Vemulapalli (2020) to show that there is no association between mitral valve surgical volumes and TEER outcomes.  Three commenters supported maintaining the existing volume requirements despite studies that show no link between TEER outcomes and surgical volumes.  One commenter questioned why surgical volume has any relation to TEER outcomes considering TEER for FMR is a heart failure treatment.  One commenter asserted that TEER procedures have increased since 2013 without any safety concerns and that surgical intervention is not the standard of care for FMR.

Response: TVT registry data demonstrate a clear relationship between procedural experience and optimal TEER outcomes, reduced procedural time, and reduced procedural complications.61,62 Studies have also demonstrated a relationship between volume and outcomes for mitral valve surgical repair or replacement.25,63 A robust cardiac surgery program is especially important where TEER is considered for DMR, but is also relevant for patients with multi-valve disease and those considered for CABG.  For patients with DMR and prohibitive surgical risk, TEER may decrease symptoms, improve quality of life, and improve survival, but its efficacy to reduce mitral regurgitation remains inferior to surgery.12 Patients with advanced heart failure and FMR will similarly benefit from a full complement of specialists on the heart team.  As such, CMS has maintained procedural volume requirements for hospitals and heart teams in this final NCD, albeit with modifications from the proposed volume requirements.  The final volume requirements reflect elements of the Expert Consensus document, our review of currently available clinical evidence and our efforts to align with the TAVR NCD volume requirements for consistency across valve programs that perform both TEER and TAVR. We believe the final volume requirements strike a balance between ensuring hospitals have the experience and capabilities to handle complex structural heart disease cases with an evolving evidence base and providing sufficient access to quality TEER programs.

Heart Team
Comment: Two commenters supported the proposed volume requirements for the heart team with one noting that the requirements keep the quality of procedures high, which is essential.  One commenter noted that it is unclear why the board eligibility or certification requirements for the cardiac surgeon, interventional cardiologist and echocardiographer are needed and requested that they be removed or, if needed, the foreign equivalents be included as in the existing TMVR NCD.  One commenter asserted that placing isolated requirements on clinician volume might create an incentive or bias for selecting one therapeutic option over another to meet guidelines and instead suggested using a hybrid model.

Response: In response to public comments, CMS has finalized the heart team requirements with modifications to the board certification requirements and lifetime experience for interventional cardiologists consistent with the Expert Consensus document.  The operator requirements are based on stakeholder input, published evidence and the Expert Consensus document. We believe these requirements strike a balance between ensuring hospitals and providers have the experience and capabilities to handle complex structural heart disease cases with an evolving evidence base and providing sufficient access to quality TEER programs.

Cardiac Surgeon
Comment: One commenter requested that the volume requirements for cardiac surgeons be removed or at least lowered to reflect lower hospital volume requirements.  Another commenter recommended revising the cardiac surgeon volume requirements to ≥ 50 heart valve surgeries and transcatheter procedures (including TAVR) in the previous year or ≥ 100 in the two years prior to program initiation.  Two commenters suggested that the volume requirements for cardiac surgeons be > 50 mitral valve surgeries in the last 5 years and more than 90% repair rate in the program, and each surgeon with > 50 career mitral valve open heart surgeries.  One commenter disagreed with including mitral valve surgical requirements for surgeons because publications have shown no link between TEER outcomes and surgical volumes and another commenter echoed the concern that there is no link between mitral valve surgical volume and TEER outcomes.  One commenter questioned why cardiac surgeons can do mitral valve repairs in centers without structural cardiology experience in mitral valve percutaneous repair.

Response: CMS believes the proposed volume requirements for cardiac surgeons are appropriate, and we have finalized these requirements.  The operator requirements are based on stakeholder input, published evidence, and the Expert Consensus document. We believe these requirements strike a balance between ensuring cardiac surgeons have the experience and capabilities to handle complex structural heart disease cases with an evolving evidence base and providing sufficient access to quality TEER programs.

Interventional Echocardiographer
Comment: One hundred and two commenters requested that the requirements for the interventional echocardiographer be revised to “board eligible or certified in transesophageal echocardiography with advanced training that qualifies the individual to be credentialed at the facility performing the procedures.”  These commenters noted that this change would enable anesthesiologists with appropriate training and experience to provide the transesophageal echocardiography during TEER procedures in addition to cardiologists.  They explained that the proposed requirements to be board eligible or certified in transthoracic and transesophageal echocardiography would exclude anesthesiologists from providing the service as they are not typically board eligible or certified in transthoracic echocardiography.  These commenters also noted that transesophageal echocardiography is superior to transthoracic echocardiography in guiding TEER and is most commonly used.  One commenter questioned why certification in transthoracic echocardiography is needed for a procedure that requires transesophageal echocardiography guidance.  Two other commenters asserted that since mitral procedures are currently performed with transesophageal echocardiography, cardiac anesthesiologists and cardiologists who are appropriately trained in transesophageal echocardiography should guide TEER interventions to optimize care.  Another commenter stated that cardiac anesthesiologists should be able to provide anesthetic and interventional transesophageal echocardiography at the same time as it is the most efficient use of personnel and reduces the number of people in the room.  One commenter supported appropriate echocardiography training to optimize care of patients.  One commenter recommended revising the professional experience to ≥10 trans-septal guidance procedures and ≥ 20 structural heart procedures and two commenters requested that the requirement be revised to specify the “interventional imaging physician” with professional experience of ≥ 25 trans-septal guidance procedures with ≥ 10 as primary transesophageal echocardiography operator.

Response: CMS agrees that both anesthesiologists and cardiologists that are board eligible or board certified in transesophageal echocardiography and that have additional specified experience in structural heart disease interventions may serve as the interventional echocardiographer for TEER.  CMS has revised the proposed requirements for the interventional echocardiographer accordingly.  However, because of the intensive imaging feedback required to achieve optimal TEER outcomes, CMS disagrees that the physician furnishing anesthesia may also perform the transesophageal echocardiography during TEER procedures.  Therefore, CMS has clarified that the interventional echocardiographer may not simultaneously furnish anesthesia.

Hospital Requirements to Maintain TEER Programs
Comment: Two commenters supported the proposed volume requirements with one noting that they would keep the quality of the procedure high.  Two commenters noted that with respect to maintaining a TEER center, no data supports that any number of mitral valve surgeries is associated with better outcomes. One commenter asserted that volume requirements should be replaced with quality standards and recommended using existing NCDR valve metrics to recertify existing programs.

Response: CMS supports the provision of high quality care for our beneficiaries.  Evidence supports an association between procedural volumes and improved outcomes for both cardiac surgery and TEER, and CMS agrees with the Expert Consensus document that volume requirements are appropriate. Therefore, based on public comment, the Expert Consensus document and the evidence reviewed we are not removing volume requirements or replacing them with quality standards because of the association with good health outcomes, however we have finalized lower volume requirements that apply to all programs regardless of experience level. 

Comment:  One commenter recommended using an approach similar to TAVR where the total number of mitral valve interventions including transcatheter and open surgical procedures are used to meet volume benchmarks of ≥ 25 mitral valve procedures per year or ≥ 50 mitral valve procedures over two years.  Another commenter suggested using a hybrid approach with ≥ 40 mitral valve interventions (mitral valve surgery or TEER) per year or ≥ 80 interventions every two years.  One commenter recommended reducing the requirement to 20 TEERs per year and 10 surgical mitral valve procedures per year or 20 per two years.  Another commenter supported reducing the requirements to ≥ 20 transcatheter mitral valve interventions per year at least 10 of which are mitral valve surgeries or ≥ 40 interventions in two years.  One commenter requested that the requirements be revised to ≥ 50 heart valve surgeries and transcatheter procedures (including TAVR) per year or ≥ 100 every two years. One commenter cited Chhatriwalla et al (2019) in support of volume requirements and argued that the proposed requirements are too low.

Response:  CMS has finalized a lower surgical volume requirement for hospitals of ≥ 20 mitral valve surgical procedures for severe MR per year or ≥ 40 over two years, of which at least 10 (or 20 over two years) must be mitral valve repairs and reduced the PCI volume requirement from the 2014 NCD (≥ 400) to ≥ 300 PCIs per year.  These volume requirements reflect elements of the Expert Consensus document, our review of currently available clinical evidence and our efforts to align with the TAVR NCD volume requirements for consistency across valve programs that perform both TEER and TAVR.  We believe these volume requirements strike an appropriate balance between ensuring that TEER programs and providers have the experience and capabilities to handle complex structural heart disease cases with an evolving evidence base and providing sufficient access to quality TEER programs.

Mitral Valve Interventions
Comment: One commenter asserted that the proposed requirement of ≥ 20 mitral valve interventions per year or ≥ 40 every two years is high and few existing TEER programs would likely meet this requirement.  One commenter supported maintaining a minimum volume of TEER procedures and another commenter stated that > 20 TEER per year is reasonable.  Two commenters recommended 30 mitral valve interventions per year including 15 mitral valve TEERs in the prior year or 60 mitral valve interventions every two years including 30 mitral valve TEER procedures.

Response: There is a relationship between operator and institutional experience with TEER and patient outcomes, and CMS strongly encourages programs to consider expert consensus guidance when deciding to initiate or maintain TEER programs.  Nonetheless, CMS is not finalizing TEER volume requirements in this NCD.  CMS has reached this decision because of the considerable disruptions to elective procedural volumes that have occurred during the current public health emergency, because multiple alternative or complementary transcatheter mitral valve interventions are currently in development, and because this NCD involves mandatory registry participation.

Mitral Valve Surgeries
Comment: Three commenters stated that the proposed surgical volumes are too high. One of these commenters noted that the volume requirements would not allow sustained treatment at many centers and surgical mitral valve repair volumes have no correlation with TEER outcomes.  This commenter also recommended that the requirement should focus on the success of the team in evaluation and performing TEER instead of surgical mitral valve repairs. Two commenters recommended 10 mitral valve surgeries per year or 20 every two years.  One commenter noted that, according to Gammie et. al (2018) less than 15% of hospitals in the country perform >10 isolated mitral valve surgeries for DMR per year.  Another commenter asserted that the proposed surgical volume requirements are exceedingly high particularly since the expanded indications for TEER and new therapies will result in lower surgical numbers.  One commenter stated that the increased mitral valve surgical volume requirements will result in the closure of currently existing mitral valve TEER programs that will be unable to maintain the higher volume.  One commenter asserted that there should be no surgical volume requirements to maintain TEER programs.

Response: As noted above, CMS has finalized lower mitral valve surgical procedure volume requirements. The final NCD requirements apply to both FMR and DMR and do not differ between hospitals with and without TEER experience.  We believe these requirements strike a balance between ensuring TEER programs have the experience and capabilities to handle complex structural heart disease cases with an evolving evidence base and providing sufficient access to quality TEER programs.

PCIs
Comment: Two commenters stated that requiring 300 PCIs is arbitrary and not supported by data, particularly as improved stents and delivery methods cause PCI numbers to decline. One commenter asserted that 300 PCIs/year is unreasonable and intended to restrict TEER to large academic hospitals and another noted that PCI numbers for interventional cardiology do not seem necessary as the skill set required for structural cardiologists are not necessarily related to PCI skills.  One commenter requested that PCI be changed to “cardiac interventions” to allow for inclusion of other closely aligned procedural experience like TAVR, left atrial appendage occlusion, atrial septal defect or other structural/transeptal interventions.

Response: CMS believes that a PCI volume requirement is important to ensure that hospital programs have sufficient experience with catheter and wire handling, vascular access, and procedural complications, which may require vascular surgery repairs. CMS is finalizing the reduced PCI volume requirement as proposed (from ≥ 400 to ≥ 300), consistent with the Expert Consensus document, which is based on current evidence from clinical trials, analysis of the TVT registry, and current medical practice.  As stated above, the final volume requirements apply to all hospitals both with and without TEER experience.

Additional Requirements
Comment: One commenter recommended adding ≥1 physician with interventional imaging privileges for transcatheter guidance and analysis to the requirements for hospitals with TEER experience.

Response: We appreciate this recommendation and note that under the final NCD, the heart team is required to include an interventional echocardiographer.

DMR at MAC Discretion
Comment: No commenters supported the proposal to move coverage of TEER for DMR to local MAC discretion.  Three commenters challenged the rationale that MAC discretion is appropriate due to the low number of TEER procedures for DMR performed in the Medicare population (<1%).  Commenters noted that clinical guidelines, best practices and experience recommendations exist for many services covered under NCDs so justifying the elimination of the NCD based on the existence of published procedural volume recommendations from professional societies does not make sense.

Fifteen commenters supported maintaining national coverage for TEER for DMR with 11 of these commenters asserting that MAC discretion will lead to inconsistent coverage across the country.  Another commenter supported national coverage of DMR, noting that MAC discretion could negatively impact patient access if restrictive local policies are implemented.

Two commenters stated that a bifurcated coverage policy for MR would create confusion for clinicians, patients and payers and adversely affect access to expeditious and appropriate care. One commenter noted that multiple coverage policies enforced by multiple authorities is operationally challenging and the absence of a systematic and predictable approach for coverage can increase administrative burdens on health care providers.  This commenter further noted the possibility for uneven coverage for an established procedure and stated that the policy may undermine equal access to care and two other commenters echoed these concerns.  One commenter supported a national coverage policy for both DMR and FMR to support the science behind treatments and best serve patients in need of TEER. Another commenter cautioned that national coverage for FMR and MAC discretion for DMR may create unanticipated incentives for clinicians to classify patients inappropriately in order to provide what they believe to be the best care. Two commenters asserted that separate institutional and operator requirements are not needed for DMR and another commenter, in support of national coverage for both DMR and FMR, recommended that volume requirements should be required for FMR.

Response:  We agree with commenters that coverage of DMR should be at the national level through this final NCD.  Therefore, CMS is not finalizing our proposal to leave coverage of TEER for DMR at MAC discretion.  After review of public comment, CMS agrees that coverage of TEER for both DMR and FMR is appropriate under CED with ongoing registry participation to address remaining evidence gaps as expressed by the public commenters.  Evidence supports an association between procedural volumes and improved outcomes for both cardiac surgery and TEER, and CMS agrees with the Expert Consensus document that volume requirements are appropriate for all TEER programs. Therefore, we disagree that the volume requirements should not apply to DMR, so the final heart team and hospital volume requirements apply to TEER for DMR and FMR.

Comment: One commenter asserted that there are still questions on long-term health outcomes and durability beyond five years and continued data collection through a registry would more efficiently address these questions, but local coverage would limit future data collection since MACs cannot enforce CED. This commenter further stated that even if a MAC requires CED, data may be inconsistent and vary between jurisdictions and there is a need for reliable and efficient evidence development for TEER, particularly on how well the intervention works in particular practice settings and important subpopulation effects.  Another commenter noted that without an NCD for DMR, there would be no national mechanism for tracking real-world use of TEER for DMR which could result in widespread use of TEER in operable DMR patients and other patients who may not benefit from the procedure.  One commenter, supporting coverage of TEER for DMR to label, recommended continued CED for DMR to gather evidence as FDA-approved devices and indications expand.  One commenter asserted that despite the increased amount of evidence on DMR from 2014, it is important to continue data collection and monitoring through continued CED to ensure quality and improve care since a minority of patients with DMR are now treated with TEER.

Response: We agree. After review of public comment, CMS agrees that coverage of TEER for both DMR and FMR is appropriate under CED with ongoing registry participation to address remaining evidence gaps.  CMS recognizes that while DMR and FMR are important concepts, an important proportion of patients may have mixed degenerative and functional MR.  CED for both DMR and FMR better preserves the reliability of data submitted through registries and avoids potential reporting bias. 

CMS also recognizes that CED requirements should not be indefinite. CAG will consider published, peer-reviewed evidence periodically, following the effective date of this NCD and reconsider the NCD when appropriate.  The NCD will expire 10 years from the effective date if it is not reconsidered during that time.  Upon expiration, coverage will be at MAC discretion.

VIII. CMS Analysis

National coverage determinations are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally by Medicare (§1869(f)(1)(B) of the Act). In order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B, and must not be otherwise excluded from coverage. Moreover, with limited exceptions, the expenses incurred for items or services must be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member (§1862(a)(1)(A) of the Act).

In addition to §1862(a)(1)(A) of the Act, a second statutory provision may permit Medicare payment for items and services in some circumstances. That statute, section 1862(a)(1)(E) of the Act, provides, in pertinent part, that:

(a) Notwithstanding any other provision of this title, no payment may be made under part A or part B for any expenses incurred for items or services—
. . .
(1)(E) in the case of research conducted pursuant to section 1142, which is not reasonable and necessary to carry out the purposes of that section.

Section 1142 of the Act describes the authority of the AHRQ to conduct and support research on outcomes, effectiveness, and appropriateness of services and procedures to identify the most effective and appropriate means to prevent, diagnose, treat, and manage diseases, disorders, and other health conditions. That section includes a requirement that the Secretary assure that AHRQ research priorities under Section 1142 appropriately reflect the needs and priorities of the Medicare program.

CED is a paradigm whereby Medicare covers items and services on the condition that they are furnished in the context of approved clinical studies or with the collection of additional clinical data. In making coverage decisions involving CED, CMS decides after a formal review of the medical literature to cover an item or service only in the context of an approved clinical study or when additional clinical data are collected to assess the appropriateness of an item or service for use with a particular beneficiary.

The 2014 CED Guidance Document is available at https://www.cms.gov/medicare-coverage-database/details/medicare-coverage-document-details.aspx?MCDId=27.

When making national coverage determinations, we evaluate the evidence related to our analytic questions based on the quality, strength and totality of evidence presented in the reviewed literature. As part of this evaluation, it is important to consider whether the evidence is relevant to the Medicare beneficiary population. In determining the generalizability of the results of the body of evidence to the Medicare population, we consider, at minimum, the age, race and gender of the study participants.

Evidence Review Summary:

For this reconsideration, CMS focused on the following questions:

  • Is the evidence sufficient to conclude that TEER improves health outcomes for Medicare beneficiaries with cardiac symptoms, reduced left ventricular function, and moderate-to-severe or severe secondary MR despite stable maximal doses of GDMT and does surgical risk (high, intermediate, or low) affect this determination?

If the answer is positive for any of the surgical risk categories:

  • Is the available evidence adequate to identify the characteristics of the patient, practitioner or facility that predict which beneficiaries are more likely to experience overall benefit or harm from TEER for cardiac symptoms, reduced left ventricular function, and moderate-to-severe or severe secondary MR despite stable maximal doses of GDMT?

Is the evidence sufficient to conclude that TEER improves health outcomes for Medicare beneficiaries with cardiac symptoms, reduced left ventricular function, and moderate-to-severe or severe secondary MR despite stable maximal doses of GDMT?

The assessment considered two major randomized trials, twenty-five observational studies and three meta-analyses.

The two major randomized trials were:

  • The Percutaneous Repair with the MitraClip device for Severe Functional / Secondary Mitral Regurgitation (MITRA-FR)
  • The Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) 

MITRA-FR found no benefit from TEER versus GDMT on a composite primary outcome of death or unplanned hospitalization for heart failure at 12 months.26  By contrast, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial found that TEER resulted in a lower rate of hospitalization for heart failure, lower mortality, and better quality of life and functional capacity 24 months following implantation.  Additionally, the pre-specified goal of freedom from device-related complications was met.17  These two studies are compared in detail below.

i.     Trial Design
The MITRA-FR and COAPT trials were similar in overall study design.  Both MITRA-FR and COAPT were multicenter, open-label, randomized, controlled trials using Abbott’s MitraClip device for TEER.  Patients were randomized on a 1:1 basis between transcatheter TEER plus GDMT or GDMT alone.  Both studies analyzed results on an intention-to-treat basis.  Treatment allocation could not be blinded in either study because of the nature of the intervention, and patients, clinicians, and reviewers were aware of treatment assignment.  However, both studies used an Echocardiography Core Laboratory to ensure that enrolled patients met pre-specified inclusion and exclusion criteria and an independent events committee to adjudicate outcomes. 

ii.    Study population
The MITRA-FR and COAPT trial populations differed in their baseline disease characteristics.  MITRA-FR included patients from France with severe secondary MR, an EF between 15-40%, and NYHA functional class II, III, or IV.  Patients were excluded if they were considered to be candidates for mitral valve surgery.  Patient eligibility was adjudicated by a multispecialty team.  The COAPT trial included patients from the United States and Canada with moderate-to-severe or severe secondary MR symptoms despite maximal doses of GDMT, an EF between 20-50%, and NYHA classes II, III, or IVa (ambulatory).  Patient eligibility was adjudicated by a heart team comprised of a heart failure specialist, an interventional cardiologist, and a cardiothoracic surgeon with expertise in mitral valve disease as well as a central eligibility committee.

The trials differed in sample size and in certain baseline clinical characteristics.  MITRA-FR enrolled 152 patients in both the device and control groups.  COAPT enrolled 302 patients in the device group and 312 patients in the control group.  Both trials enrolled similarly aged patients, though the MITRA-FR trial enrolled more men.  LVEFs were similar between the two trials, but indexed left ventricular diastolic volumes were larger in MITRA-FR (135±35 vs. 101±34 mL/m2).  The effective regurgitation orifice areas were also smaller in MITRA-FR, and the N-terminal pro-B-type natriuretic peptide levels were lower with similar mean glomerular filtration rates (Table 1).

Table 1.  Comparison of baseline patient characteristics in the MITRA-FR and COAPT trials.

MITRA – FR COAPT

Device (n=152)

Control (n=152)

Device (n=302)

Control (n=312)

Age (yr)

70.1

70.6

71.7

72.8

Male (%)

78.9

70.4

66.6

61.5

LVEF (%)

33.3

32.9

31.3

31.3

Indexed LVEDV (ml/m2)

136.2

134.5

101 (Not stratified by exposure group)

ERO (mm2)

31

31

41

40

NT-proBNP (ng/l)

3407

3292

5174

5943

Legend:  Device = transcatheter edge-to-edge repair; LVEF = Left Ventricular Ejection Fraction; LVEDV = Left Ventricular End Diastolic Volume; ERO = Effective Regurgitant Orifice Area; NT-proBNP = N-terminal pro-B type natriuretic peptide level.

iii.    Background Medical Therapy
Patients in the MITRA-FR trial were more likely be on an angiotensin converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor-neprilysin inhibitor medication.  Hydralazine and nitrate use was not reported in MITRA-FR.  Beta-blocker use was similar between the two trials, but mineralocorticoid receptor antagonist use was higher in MITRA-FR.  Implantable cardioverter defibrillators rates were similar between the two trials but cardiac resynchronization therapy was less common in the MITRA-FR trial (Table 2).  In addition to baseline GDMT doses, medication changes during follow-up could have influenced outcomes in both trials.  Medication doses were not reported in either trial.  Further, the MITRA-FR trial did not limit or track medication changes after enrollment, while the COAPT study did, and changes are reported in an online appendix.

Table 2.  Baseline rates of GDMT and device implantations in the MITRA-FR and COAPT trials.

#D5DCE4
MITRA-FR COAPT

Device (n=152)

Control (n=152)

Device (n=302)

Control (n=312)

ACE / ARB

73

74.3

67.6

60

ARNI

10

12.1

4.3

2.9

Hydral / Nitrates

5

5.8

Beta Blockers

88.2

90.8

91.1

89.7

MRA

56.6

53

50.7

49.7

Anticoagulants

61.2

61.2

46.4

10.1

ICD

31.8

37.5

30.1

32.4

CRT-D

30.5

23

38.1

34.9

Legend: Device = transcatheter edge-to-edge repair; ACE / ARB = Angiotensin Converting Enzyme Inhibitor / Angiotensin Receptor Blocker; ARNI = Angiotensin Receptor-Neprilysin Inhibitor; Hydral / Nitrates = Hydralazine and Nitrates; MRA = Mineralocorticoid Receptor Antagonist; Anticoagulants = Oral Anticoagulants; ICD = Implantable Cardioverter Defibrillator; CRT-D = Cardiac Resynchronization Therapy with Defibrillation.

iv.    Intervention Setting
The MITRA-FR study recruited patients from 37 trial centers in France, each of which must have performed at least five implantation procedures prior to selection as a trial site.  Abbott Vascular proctored the procedures for implantation of the device, though the contributions of the proctor are not described.  The COAPT study recruited patients from 78 centers in the United States and Canada.  The COAPT investigators did not describe institutional criteria for participation in the study but note that enrollment centers were experienced with the device.  Greater experience in the COAPT trial is likely to have contributed to superior intervention outcomes.

v.    Outcomes
For the primary outcome, the MITRA-FR study used a composite of death from any cause or unplanned hospitalization for heart failure at 12 months after randomization.  The secondary endpoints were the individual components of the primary outcome, death from cardiovascular causes, and survival free from major adverse cardiovascular events.  For the primary outcome, the COAPT study used all hospitalizations for heart failure within 24 months of follow-up, including recurrent events in patients with more than one event.  The primary safety endpoint was freedom from device-related complications at 12 months.

vi.    RCT Study Quality
MITRA-FR was a smaller study and 14 of 152 (9.2%) patients in the intervention arm had no study device implanted.  Among patients where implantation was attempted, technical success was 95.8%; 14.6% of patients had periprocedural complications.  Of 138 patients who completed the procedure, 63 (45.7%) had one device implanted, 62 (44.9%) had two devices implanted, and 13 (9.4%) had three or more devices implanted.  There were 13 patients who did not meet pre-specified criteria or who had a protocol deviation in both the intervention and control arms of the study.  A large amount of follow-up data on echocardiographic outcomes, functional status, natriuretic peptide levels, and quality of life outcomes at 1 year were missing.  Consequently, no formal statistical analysis was performed on secondary outcomes for the study.

COAPT was a larger study and device implantation was attempted in 293 of 302 (97%) patients in the treatment arm.  Among patients where implantation was attempted, the technical success rate was 98%; 96.6% of patients were free from device-related complications at 1 year.  A mean of 1.7 + 0.7 clips were implanted per patient (range, 1 to 4).  Follow-up data was available for 97.7% of patients in the intervention group and 94.2% of the patients in the control group at 1 year; the median follow-up was 22.7 months and 16.5 months, respectively.

The MITRA-FR study has important limitations that make it less compelling than the COAPT trial.  The limitations of a smaller sample size are compounded by a larger percentage of patients in whom implantation was not attempted, higher rates of implantation failure, higher rates of periprocedural complications, and extensive missing follow-up data that preclude quantitative analysis of secondary outcomes.  The MITRA-FR study only followed patients for 1 year, while the COAPT study followed patients who underwent TEER for nearly 2 years.  Importantly, the mortality benefit seen in the COAPT trial was largely manifest after 1 year.

vii.    Synthesizing the Clinical Trial Evidence
The MITRA-FR trial found that in patients with severe secondary MR, TEER plus GDMT did not result in a lower rate of the composite outcome of death from any cause or unplanned hospitalization for heart failure at 12 months relative to GDMT alone.  Because of smaller numbers, and extensive missing data, secondary analyses were not possible.26  By contrast, the COAPT study found that TEER in patients with heart failure and moderate-to-severe or severe secondary MR who remained symptomatic despite maximal doses of GDMT and CRT (if appropriate), intervention resulted in significantly lower rates of hospitalization for heart failure, lower mortality, and better quality of life and functional capacity at 24 months of follow up relative to medical therapy alone.17

Several factors may account for these apparently opposite outcomes.  First, while GDMT appears to be more complete in MITRA-FR with a higher proportion of patients on guideline appropriate therapy drug classes, medication doses are not reported and may not have been maximized; medication changes during follow up were not tracked or reported.  By contrast, the COAPT trial required maximal doses of GDMT, and these were confirmed by a heart failure specialist as part of the heart team review prior to enrollment; major medication changes during follow-up were infrequent in the two trial groups.  Notably, the N-terminal pro-B type natriuretic peptide levels were substantially higher in the COAPT trial than in MITRA-FR, potentially reflecting the fact that patients in the COAPT trial were truly refractory to medical therapy.64 Even so, it is not possible to assess the relative intensity of medical therapy between the two trials from the available data. 

Second, despite similarities in the inclusion and exclusion criteria between the two trials, the included patient populations were different in important respects.  The LVEFs were relatively similar between the two trials.  However, while patients in the MITRA-FR trial had indexed LVEDV of 136.2 ml/m2 in the device (plus GDMT) arm and 134.5 ml/m2 in the GDMT alone arm, patients in the COAPT trial had indexed LVEDVs of 101 ml/m2 (Indexed values not stratified by exposure group).  Grayburn, Sannino, and Packer note that “when the patients enrolled in the COAPT trial are compared with those in the MITRA-FR trial, the EROA was approximately 30% higher but their [indexed] LV volumes were approximately 30% smaller.”64 These differences have advanced the argument that COAPT patients had disproportionately severe MR.  The ACC has incorporated this concept into the most recent focused update to the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation.56 However, mortality in the control arms of the two trials were similar at 1 year (23% vs 22%), and the clinical utility of this theory requires further examination. 

Third, TEER is a complex procedure that requires close coordination by multiple physician specialties, and there is a learning curve.33,65 Yet, centers enrolling patients in the MITRA-FR trial were required to have performed “at least 5 procedures” prior to participating in the trial; the actual experience of implanters in the MITRA-FR and COAPT trials was not reported.  However, relative to the COAPT trial, a high number of patients in the MITRA-FR trial (9.2%) did not receive a device or had implantation failure, and the complication rate (14.6%) was also higher.  Patients in the COAPT trial were more likely to receive more than a single clip, and the rates of moderate to severe MR were lower in the COAPT trial at 1 year.  These differences suggest that MITRA-FR implanters may have been less experienced either in patient selection or in performing the procedure itself, a factor that may have impacted patient outcomes.  However, it is not possible to assess the experience of the implanters in the two trials from publicly available data.

Last, the MITRA-FR trial required unspecified follow up and had a considerable amount of missing data.  By contrast, the COAPT trial required follow up at 1 week and at 1, 6, 12, 18, and 24 months following implantation.  Closer follow-up may have influenced medication adjustments and other interventions in COAPT patients that may have impacted the outcomes seen in the trial.  While the readmission benefit was evident at 1 month in the COAPT trial, the mortality benefit did not emerge until 1 year following treatment and might not have been evident in the MITRA-FR trial as a consequence.

Overall, the COAPT randomized controlled trial is more compelling than MITRA-FR randomized control trial.  It was a larger study that followed patients for longer, the data were more complete, and the implantation results were better.  Differences between the two trials may have resulted from any combination of the factors described above.  The COAPT findings are also more compelling because they demonstrated physiologic changes, including a reduction in MR and decreased LVEDV in addition to decreased hospitalization and improved survival.  Nonetheless, the marked discrepancy between these two trials result in persistent uncertainty about the generalizability of the COAPT trial to real-world application.

viii.    Evidence from observational studies/meta-analyses and relevance to Medicare beneficiaries
In addition to the two published randomized controlled trials of TEER for the treatment of secondary MR, a series of publications reflect the real-world experience of patients who received the procedure for secondary MR.  The COAPT outcomes are broadly consistent with the observational studies and meta-analyses reviewed here, both in terms of enrolled patients and 1-year survival outcomes.  Because TEER only received FDA approval for secondary MR in 2019, most of the published experience for this indication comes from Europe.

  1. Controlled Observational Studies

Seven controlled observational studies met criteria for inclusion in this analysis.  With the exception of one, the studies included patients with both primary and secondary MR.  The study by Giannini et al. compared patients who received TEER to patients judged not suitable for the intervention, while the remaining studies used propensity score matching to identify control patients.29

Giannini et al. studied patients drawn from a prospective registry with symptomatic, severe, secondary MR who were treated with TEER plus GDMT compared to GDMT alone.29 Patients in their study were referred for TEER because they were estimated to be at high or prohibitive surgical risk.  Patients were evaluated for suitability for the procedure by a heart team composed of a cardiac surgeon, an interventional cardiologist, a clinical cardiologist, and a cardiac anesthesiologist.  They state that all patients were on stable doses of GDMT, including ICD or CRT-D, if indicated.  The controls were enrolled in the registry but were judged not suitable for TEER.  (The appropriateness as controls assumes the anatomical differences contraindicating TEER did not affect outcomes).  Included patients had reduced LVEF (device 33%; control 34%) and LVEDV values that were similar to the COAPT trial (device 187 ml; control 178 ml).  Baseline use of GDMT, by NHYA class, was lower than in COAPT for beta blockers at 67% (vs. 91.1%) of device patients, but higher for ace inhibitor / angiotensin receptor blockers at 70% (vs. 67.6%) of device patients and for mineralocorticoid receptor antagonists at 58% (vs. 50.7%).  ICD use was lower 7% (vs. 30.1%) but CRT-D use was similar at 40% (vs. 38.1%).  The acute procedural success rate was 98% (vs. 95%), and the procedures times were 142 minutes (vs. 162.9).  Of treated patients, 32% received more than one clip (vs. 61.8%).  Survival outcomes in this prospective registry for patients who received the device were better than the COAPT trial at 1 year (89.7% vs. 80.9%) but were similar at two years (71.2% vs. 70.9%).   Survival outcomes for GDMT-only were worse than COAPT at one year (64.3% vs. 76.9) but similar at 2 years (51.7 % vs. 53.9%). 

The remaining observational studies combined patients with primary and secondary MR, and results for secondary MR patients could not be separately evaluated.24,27,28,30-32 The majority of patients in these studies had secondary MR, with a percentage range from 59 – 90%.  Where they were reported, EFs ranged between 33 – 54.4%.  LVEDV was reported for only one of the six studies; a sub-analysis of patients with secondary MR, showed that LVEDV improved from 192 ml to 153 ml at 1 year (n=34).  Where they were reported, acute procedural success rates ranged from 93.4 – 96%.  Survival at 12 months ranged from 75.7 – 91.4 %; the lowest survival rate at 12 months was similar to the MITRA-FR trial 75.7% (vs. 75.3).

  1. Uncontrolled Observational Studies

Eighteen uncontrolled observational studies were published in peer reviewed literature and met our review criteria.  Five were exclusive to secondary MR,34,41-43,48 while 13 included a mixed population but reported secondary MR separately.33,35-40,44-47,49,50 These studies lacked strict entry requirements and relied on clinical judgment for inclusion.  There were no consistent criteria for GDMT, and medication changes were not tracked in follow up.  There was no control group for comparison.  Most echocardiograms were not reviewed by an independent core echocardiography laboratory, and follow-up was limited and often incomplete, particularly for echocardiographic measurements.  Nonetheless, these studies offer additional perspective on real-world use of TEER for secondary MR.

Data are summarized here as they are available and are compared to values derived from the COAPT trial.  Among studies that included mixed populations of primary and secondary MR, the proportion of secondary MR patients ranged from 39 – 79%.  These studies included as few as 39 patients and as many as 505.  Ages ranged from 69 – 75.2 (vs. 71.17 years); 51.6 to 86% were men (vs. 66.6%).  Average EFs ranged from 27 – 42.1% (vs. 31.3%).  Importantly, LVEDV values ranged from 171.1 to 238.7 (vs. 194.4 ml).  Acute procedural success ranged from 84.6 – 95.5% (vs. 95%).  Lastly, 30 day survival ranged from 95.4 – 98.9% (not reported in COAPT), while 1 year survival ranged from 75.2 – 86.8% (vs. 80.9%).

Nine of the studies examined the relationship between specific patient risk factors and functional and survival outcomes.  Three studies examined the feasibility of TEER in patients at high cardiac surgical risk and demonstrated that the procedure was feasible, with a good safety profile, and reduced MR.37-39  Two examined the relationship between pre-treatment LVEF and outcomes, demonstrating good procedural success across the range of EFs with similar MR reductions.46,48 However, one demonstrated that an LVEF < 27% resulted in more than a 3 fold increase in mortality risk at 1 year despite procedural success.48 One study demonstrated that end stage renal disease (ESRD) was predictive of acute procedural failure and was associated with more than a 3 fold increase in 30 day mortality.47 One study demonstrated that pulmonary hypertension was improved after intervention but was associated with worse survival nonetheless.41 Finally, one study examined the impact of TEER in CRT non-responders and demonstrated that the procedure was feasible with a good safety profile, decreased MR and LVEDV, increased LVEF, and improved symptoms.34

These observational studies generate real world evidence for a fuller understanding of the safety and effectiveness profile of TEER in a less stringent setting than clinical trials.  However, resulting data may also reflect less stringent or consistent procedures than in a clinical trial.  Such challenges may include inconsistent reporting on prescribing and adherence to GDMT, potential loss to follow-up leading to under-reporting of adverse events/mortality, varied procedural experience across sites, and varied time points across patients for data collection.  Therefore, while the data from the observational studies appears reassuring for acute procedural success and 1-year survival, they provide insufficient evidence to elucidate the discrepant results in the MITRA-FR and COAPT trials.

Eight additional studies submitted in public comments addressed health outcomes in patients with severe mitral regurgitation and specific comorbidities but did not meet inclusion criteria for consideration in this NCA (see section VII for inclusion criteria).  One study of patients with pulmonary hypertension who were treated with TEER did not differentiate between degenerative or functional MR; however, the study used data derived from the TVT registry prior to FDA market authorization for the FMR indication.66 Four additional small case series addressed patients with cardiogenic shock who were treated with TEER.67-70 Two studies addressed the relationship between mitral valve surgery and tricuspid regurgitation.71,72 One study addressed the relationship between chronic obstructive pulmonary disease and health outcomes following mitral valve repair or replacement.73

  1. Meta-Analyses

Three meta-analyses were reviewed, with little overlap between them.  One predominantly focused on secondary MR,53 and two exclusively focused on secondary MR.51,52 All three summarized observational studies and followed recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews Statement.74 Use of GDMT was not reported in two of the meta-analyses, which is an important limitation.  The mean age of included patients were similar, with a range from 71 – 73 years, while 68.8 – 78% of included patients were male.  LVEFs ranged from 24 – 35.3%, and LVEDV was reported for two of the three meta-analyses (both 187 ml).

The first meta-analysis reviewed 12 uncontrolled observational studies of patients (n=1,695) with moderate to severe or severe secondary MR and high surgical risk.51 All of the included studies followed patients for at least 1 year.  Studied patients had a high rate of GDMT, with 87% on beta blockers, 85% on ACE inhibitors or ARBs, 53% on a mineralocorticoid receptor antagonist, and 30% on CRT.  Acute procedural success was 89%, and patients experienced a durable reduction of MR with a low reintervention rate (3%) at 1 year.  Thirty-day survival was 97%, and overall survival at 1 year was 82%.

The second meta-analysis included 23 uncontrolled observational studies of patients with moderate to severe or severe secondary MR who were treated with TEER.52 A combined 3,253 patients were studied using random effects models with a restricted maximum likelihood estimator.  Mortality improvements were accompanied by significant reductions in LVEDV (-21.96 ml; p<0.0001) and improvements in LVEF (+2.4%; p=0.0315).  The rate of in-hospital survival was 97.69%, while 30 day and 1-year mortality were 94.63% and 81.53%, respectively.  There was no significant heterogeneity in mortality between the studies for the time points reported. 

The third meta-analysis reviewed case-control observational studies of symptomatic moderate to severe or severe MR; 93% of patients had secondary MR.53 Six studies met criteria for inclusion, including 2,121 patients in the study level cohort, and 344 patients in the patient level cohort.  The analysis used meta-regression and propensity score matching to synthesize the data.  The acute procedural success rate was 93%, with 36% of patients receiving 2 or more clips.  The device arm had a reduced risk of death (OR 0.79; p< 0.001) and hospital readmission (OR 0.73; p = 0.005) at 1 year.

These meta-analyses are well designed, involved pre-specified criteria, followed a methodical approach, and offered the benefit of pooled data as well as a systematic assessment across studies.  The patient procedural and health outcomes appeared generally consistent with COAPT; however, the meta-analyses were not designed to address the methodologic details needed to disentangle the discrepant MITRA-FR and COAPT results.  The underlying studies did not have consistent rigor in reporting data on potential confounders (such as GDMT) and many lacked a comparator population as a reference for interpreting the risk/benefit profile of TEER.  Therefore, while the meta-analyses results are encouraging, they do not offer detailed evidence to optimize patient selection, facility standards, and understand the biologic underpinnings driving the differing results between MITRA-FR and COAPT.  Additional evidence is needed to clarify these discrepant results and improve outcomes of TEER in patients with secondary MR.

  1. Relevance to Medicare Population

The COAPT trial used stringent enrollment criteria to identify candidates with secondary MR for TEER.  With a mean age of approximately 72 years, the U.S. COAPT patients had demographics suggesting qualification as Medicare beneficiaries; however, there are limits in extrapolating trial results to the broader pool of Medicare beneficiaries eligible for TEER.  Randomized controlled trials are conducted on select populations with stringent inclusion and exclusion criteria and are managed in a highly controlled setting.  Findings may not be generalizable to a patient population with a greater breadth of characteristics and receiving variable baseline clinical care, such as diversity in prescribing and adherence to GDMT.  The three meta-analyses, informed by data from real world practice, considered data across multiple studies.  The mean age in the three meta-analyses were: 73 years51], 60.8-75.2 years (across 23 studies)52, and 71 years.53 The three meta-analyses concluded that TEER improved health outcomes in their patient populations.  However, many of the studies were conducted outside of the United States. 

Real-world evidence from beneficiaries that underwent TEER derived from a clinical registry and Medicare insurance claims will offer additional insight on use of TEER in the Medicare population.

Lowenstern, Lippman, and Brennan et al., identified a base population of 706 U.S. patients enrolled in either the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study II) High-Risk Registry or the REALISM (Real World Expanded Multicenter Study of the MitraClip System) Continued-Access Registry databases with an index hospitalization between January 1, 2007, and December 31, 2013.75 Of the 706 registry patients, only 84 were < 65 years old and 15 patients died prior to discharge; ≥ 86% of the patients in these two U.S. TEER registries were likely Medicare beneficiaries.

The study used probabilistic matching to link the 607 patients to Medicare administrative claims.  The authors were able to match 418 of 607 patients.  Baseline characteristics for the 418 patients showed a mean age of 79.7 years, 60.0% were men, 93.8% were white, 83.8% had a NYHA class ≥ III, and 63.6 had secondary MR.  The authors excluded patients who could not be matched, but noted that excluded patients were similar to the included population on observable characteristics.

Agreement between claims and registry data was near perfect for mortality, with a sensitivity, specificity, and positive and negative predictive values of 100%, 99%, 97%, and 100%, respectively.  For other outcomes, the Medicare claims were less concordant.  At 1 year, the cumulative incidence of mortality was 21.1% (n=87) based on physician adjudication and 21.8% (n=90) based on CMS outcomes captured in claims data.

While the study lacked a comparator population to assess whether the 1-year all-cause mortality rate in TEER patients of approximately 21% conferred an advantage over similar patients on GDMT that did not receive TEER, the findings confirm that the patient population receiving TEER in the United States are largely Medicare beneficiaries. Approximately, two thirds of the CMS linked population that received TEER had secondary MR. 

Kundi, Popma, and Valsdottir et al. identified TEER patients who used the MitraClip system from CMS MedPAR files including administrative billing claims for all hospitalizations of Medicare fee-for-service beneficiaries and using a principal International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) procedure code “3597” between September 27, 2010, and September 30, 2015.76

The study identified 3,782 U.S. patients from 280 clinical sites that underwent TEER.  The baseline characteristics for patients that survived until the end of the study period included a mean age of 79.4 years, 55.2% were men, and 77.7% had chronic heart failure.  The all-cause mortality rate was 23.1% at 1 year, 30.0% at 2-years, and 43.6% at 3-years after TEER.  The study identified: chronic heart failure, atrial fibrillation, liver disease, dialysis, admission with shock at index hospitalization, and other bacterial infections (p<0.001) as covariates strongly associated with increased mortality over the long-term.  However, the study did not consider variables related to TEER indication, patient selection, success rate for MitraClip procedures, and use of GDMT.  Also, by reporting baseline characteristics for only the survivors, these demographics are not representative of patients that had poor outcomes following TEER that led to death before the study end.  Nonetheless, the study suggests that many patients that receive TEER in the United States are Medicare beneficiaries. 

Evidence from the COAPT trial, the observational studies, and the studies of Medicare insurance claims suggest that many Medicare beneficiaries have indications applicable for TEER consideration and that use of TEER for secondary MR is promising and relevant for the Medicare population.

The totality of literature offers evidence that in carefully selected patients with moderate to severe or severe secondary MR despite stable maximal doses of GDMT, including cardiac resynchronization therapy if applicable, TEER can reduce hospital readmissions and improve survival.  A large proportion of patients in the United States that receive TEER are Medicare beneficiaries.  However, patient selection and facility/operator experience strongly influence the benefit of this procedure, and concerns persist whether patients in real world application will achieve outcomes similar to those demonstrated in the COAPT trial.  Evidentiary gaps remain regarding patient, interventionalist, and facility characteristics that would optimize the risk/benefit balance for TEER in Medicare beneficiaries.

Does surgical risk [high, intermediate, or low] affect this determination?

The question prompts two considerations:

  • whether TEER is the preferred option only when patients are not candidates for surgical treatment due to higher surgical risk categorization;
  • whether patients at higher surgical risk (distinct from any consideration of surgical interventions) are likely to have favorable health outcomes when they undergo TEER intervention or whether high surgical risk might contraindicate TEER.

Unlike DMR, where surgical repair is of proven benefit in appropriately selected patients, surgical intervention has not been shown to extend survival for patients with FMR in clinical trials, although some patients may experience improved functional outcomes and quality of life.  TEER is a treatment option for patients with FMR who are first managed with stable, maximal doses of GDMT but remain highly symptomatic, rather than a consideration when surgical risk precludes operative intervention.  However, some FMR patients may benefit from surgical intervention; such determinations are deferred to the heart team comprised of a balanced panel of experts who are able to weigh patient-specific risks and benefits when assessing treatment options.  CMS supports inclusion of a cardiac surgeon on the heart team who is an expert in MV repair and replacement techniques to help the heart team make the determination when a surgical approach should be considered.

Three observational studies assessed outcomes following TEER in patients at high surgical risk and concluded that TEER is a viable therapeutic option for high-risk surgical patients.37-39 There is sufficient evidence that in carefully selected patients with moderate to severe or severe secondary MR despite stable maximal doses of GDMT, including cardiac resynchronization therapy if applicable, TEER reduces hospital readmissions and improves survival.  Nonetheless, weighing patient-specific risks, including the patients’ surgical risk when considering treatment options is the purview of the heart team. 

Is the available evidence adequate to identify the characteristics of the patient, practitioner or facility to predict which beneficiaries are more likely to experience overall benefit or harm from TEER for cardiac symptoms, reduced left ventricular systolic function, and moderate-to-severe or severe secondary MR despite stable, maximal doses of GDMT?

The evidence is inadequate to fully assess which characteristics of the patient, practitioner, or facility predict the most successful patient outcomes from TEER:

  • The MITRA-FR and COAPT trials produced differing results.  These apparently opposite outcomes may have resulted in part due to:
    • Differing prescribing and compliance with GDMT across trials,
    • COAPT patients potentially having disproportionately severe MR,
    • MITRA-FR implanters may have been less experienced either in patient selection or in performing the procedure,
    • Differences in duration, frequency, or completeness of follow-up.

The relative contributions of patient, practitioner or facility characteristics in producing disparate outcomes from TEER cannot be fully assessed from available data.

  • The observational studies generated real world evidence and offer a more complete understanding of the risks and benefits of TEER in a less stringent setting than clinical trials.  However, resulting data also reflect inconsistent procedures across studies.  These potential differences in approach raise the same uncertainties that arose when comparing the MITRA-FR and COAPT trials:
    • inconsistent reporting on prescribing and adherence to GDMT,
    • incomplete follow-up resulting in under-reporting of adverse events/mortality,
    • varied procedural experience across sites, and
    • varied time points across patients for data collection. 

In addition to the above evidence limitations, other evidentiary gaps raised in the literature include the need to:

  • Further refine patient selection criteria for appropriate TEER candidates, including the presence of severe pulmonary hypertension, right ventricular dysfunction, severe tricuspid regurgitation, severe obstructive/restrictive lung disease, ESRD, marked patient frailty, and an extremely low LVEF.39
  • Better understand the durability of benefits over longer time periods and the impact of residual MR after TEER.42

To better serve Medicare beneficiaries, additional evidence might help address:

  1. What are the appropriate standards for facilities, operators, and heart teams in TEER for secondary MR?
  2. Are there subpopulations among patients with secondary MR that may experience a different risk/benefit profile from TEER?
  3. What role should the emerging theory of disproportionately severe MR play in patient selection for TEER?
  4. How can maximal GDMT improve patient outcomes following TEER?
  5. Are reductions in mitral regurgitation durable over longer periods after TEER?

Given the sharp discrepancy between the MITRA-FR and COAPT trials, CMS has concerns that real-world outcomes may not replicate those achieved in the COAPT trial.  MITRA-FR included less stringent criteria for both implanting sites and patient eligibility and resulted in no benefit from TEER at one year.26  In the COAPT trial, only 42% of patients referred for TEER met stringent criteria and were ultimately enrolled, which raises questions about generalizability of the results.77  Notably, nearly a third of patients thought to meet inclusion criteria by COAPT trial sites did not ultimately qualify after echo core laboratory review.78  

Based on public comment, while CMS finds the evidence for trials and studies of TEER to be promising, after further review of the evidence and comments we agree with the public commenters there is a need for continuing data collection and evidence development.  Notably, the MITRA-FR trial suggests no benefit from TEER for patients with FMR, while the COAPT trial suggests significant benefits on several important outcomes.  Clinical controversy endures about the cause of these disparate findings.  Further evidence is needed to establish which patients benefit most from this intervention and whether outcomes are durable beyond 24 months. We await reports on longer-term outcomes of the risks and benefits of TEER, including improvements in quality of life.  In the interim, Coverage with Evidence Development (CED) balances quality and access, while simultaneously promoting the development of a fuller evidentiary base needed to assess the appropriateness of TEER for Medicare beneficiaries.

Conditions of Coverage

CMS is finalizing coverage of TEER for both degenerative and functional MR under CED. After careful review of the evidence, and consideration of the numerous public comments supportive of CED, CMS agrees with the consensus of the experts, including all of the professional societies and organizations that commented.  There are important evidence gaps that remain for both DMR and FMR and CED is the best path to address those.  It also permits more robust coverage than what we proposed.  CED allows better patient protections while at the same time gathering data to inform patients and clinicians.  Therefore, CMS is finalizing the NCD by broadening coverage of TEER to Medicare beneficiaries with moderate to severe or severe FMR under select conditions designed to address gaps in existing evidence and optimize patient outcomes.  This expansion of coverage maintains coverage of TEER for the treatment of significant symptomatic DMR according to an FDA-approved indication.  Because gaps in existing evidence specific to TEER for the treatment of significant symptomatic DMR persist, we believe continued coverage under CED is needed to address these gaps and optimize patient outcomes.

We are also modifying some requirements around patient evaluation, facility infrastructure, heart team composition and procedural volume requirements as discussed in detail below.  These modifications from the 2014 TMVR NCD reflect elements of the updated specialty society consensus document from 2019 as well as our review of currently available clinical evidence.  These modifications also reflect an effort to align as much as possible valve program requirements for programs performing both TEER and TAVR so as to minimize burden on facilities in meeting procedural volume requirements set forth across different policies.

Along with the expansion of coverage and modifications to the patient evaluation, facility infrastructure, heart team composition and procedural volume requirements, we are renaming the NCD to TEER for mitral valve regurgitation to more specifically identify the covered procedure.  TEER approximates the anterior and posterior mitral valve leaflets by grasping them with a clipping device in an approach similar to a treatment first developed in cardiac surgery called the Alfieri stich.  This NCD does not address distinct approaches, such as technologies that involve transcatheter valve replacement, transcatheter annular modification, transcatheter chordal repair, and others that may be in development.79

The final conditions for coverage include the following:

Patient Population: In March 2019, FDA approved the MitraClip system [a TEER intervention] for the indication of FMR. CMS concurs with the FDA’s March 14, 2019 recommendations, requirements, and labeling regarding the indicated patient population.

As of early 2021, physician instructions specify the following TEER indication for secondary MR:

  • The MitraClip™ NT Clip Delivery System, when used with maximally tolerated guideline-directed medical therapy (GDMT), is indicated for the treatment of symptomatic, moderate-to-severe or severe secondary (or functional) mitral regurgitation (MR; MR ≥ Grade III per American Society of Echocardiography criteria) in patients with a left ventricular ejection fraction (LVEF) ≥ 20% and ≤ 50%, and a left ventricular end systolic dimension (LVESD) ≤ 70 mm whose symptoms and MR severity persist despite maximally tolerated GDMT as determined by a multidisciplinary heart team experienced in the evaluation and treatment of heart failure and mitral valve disease.

In response to public comments, we are not finalizing the proposal to establish MAC discretion for coverage of TEER for DMR.  We agree that an NCD provides the most consistent approach to coverage of TEER for patients with both degenerative and functional MR.  Therefore, CMS is maintaining coverage of TEER for the treatment of significant symptomatic DMR, according to an FDA-approved indication, under CED.  CMS is also expanding coverage of TEER for the treatment of symptomatic moderate-to-severe or severe FMR when used with maximally tolerated GDMT and furnished according to an FDA-approved indication under CED. 

CMS proposed to non-cover patients meeting the exclusion criteria for COAPT. However, the CED paradigm allows coverage where evidence is promising but does not yet fully assess the appropriateness of TEER, which is a key element of meeting the reasonable and necessary standard.  Therefore, we are covering TEER for both DMR and FMR under CED to ensure access to this technology.  This NCD will support further evidence development with patient protections to ensure good outcomes. Because CMS is finalizing this NCD with CED requirements, CMS is not finalizing non-coverage for patients meeting the COAPT exclusion criteria. However, the presence of severe aortic stenosis may worsen heart failure symptoms and may substantially increase MR severity.58-60 Therefore, we are clarifying that TEER is non-covered in patients with untreated severe aortic stenosis because intervention to the mitral valve may be unnecessary after the aortic stenosis is addressed.

Patient Evaluation: The final NCD requirements, further addressed under “Heart Team Composition,” stipulate the inclusion of a cardiologist experienced in treating patients with advanced heart failure on the heart team, the heart team heart failure cardiologist, for patients undergoing evaluation for FMR.  Each patient’s suitability for surgical mitral valve repair, TEER or palliative therapy must be evaluated, documented, and made available to other heart team members.  Additionally, the heart team heart failure cardiologist must document that patients with FMR have persistent symptoms despite maximally tolerated GDMT and cardiac resynchronization therapy, if appropriate.  For patients with FMR, the heart team interventional cardiologist and the heart team heart failure cardiologist must independently evaluate the patient using information in the medical record and a face-to-face examination.  To decrease patient burden, the heart team heart failure cardiologist may meet this requirement through a review of the patient’s medical records and images if the patient has an established relationship with a cardiologist experienced in treating patients with advanced heart failure.  For patients with DMR, the heart team interventional cardiologist and heart team cardiac surgeon must independently evaluate the patient using information in the patient’s medical record and a face-to-face examination. (To reduce patient burden, these evaluations can be accomplished jointly and simultaneously when feasible.)  Physicians evaluating patients for TEER must document the rationale for their recommendations and make records available to the other heart team members.  The heart team fosters a balanced multidisciplinary consideration of medical, interventional, and palliative therapy options that optimize the risk and benefit profile for each patient.

In the interim final rule with comment period [CMS-1744-IFC], CMS finalized that to the extent an NCD or LCD would otherwise require a face-to-face or in-person encounter for evaluations, assessments, certifications or other implied face-to-face services those requirements would not apply during the public health emergency (PHE) for the COVID-19 pandemic.  This includes the face-to-face examination by the heart team interventional cardiologist and cardiac surgeon or heart team heart failure cardiologist.

TEER Heart Team Composition: The multi-disciplinary heart team is a patient-centered concept that supports evidence-based medical decision making and promotes the best possible outcomes.  We have finalized that the heart team provide both pre and post-operative care and include: a cardiac surgeon who should be an expert in MV repair and replacement techniques for patient consultation and surgical intervention when this approach is deemed preferable by the heart team; an interventional cardiologist; a cardiologist experienced in treating patients with advanced heart failure; and an interventional echocardiographer (cardiologist or anesthesiologist) who should be knowledgeable and experienced in the integrative assessment of MR.57 In response to public comments, we have also adjusted the board certification requirements in the final NCD.  The heart team must also include providers from other physician groups, as appropriate, as well as advanced patient practitioners, nurses, research personnel and administrators. 

The requirement for a heart team cardiologist experienced in treating patients with advanced heart failure (the heart team heart failure cardiologist) in the context of TEER for FMR is, in part, a response to clinical trial findings.  Although GDMT appeared to be more complete in MITRA-FR with a higher proportion of patients on guideline appropriate therapy drug classes, medication doses and subsequent changes were not reported.  By contrast, the COAPT trial required maximal doses of GDMT confirmed by a cardiologist experienced in treating patients with advanced heart failure prior to enrollment.  Including a cardiologist experienced in treating patients with advanced heart failure on the multi-disciplinary heart team more closely aligns with the methods used in the COAPT trial and may translate to better patient outcomes.

Asch, Grayburn, and Siegel, et al. stated that heart failure patients in the COAPT trial with 3+ or 4+ secondary MR, were selected using strict echocardiographic criteria, and that these criteria led to benefits from [TEER] with reduced 2-year rates of death and HF hospitalization. This reinforces the need for an interventional echocardiographer knowledgeable and experienced in the integrative assessment of MR to be included on the heart team.78,/p>

Joint Participation of Heart Team Operators: The expansion of coverage to include FMR does not change the requirement that the heart team's interventional cardiologist or the heart team’s cardiac surgeon perform the TEER. TEER for mitral valve regurgitation is performed acceptably by a single operator under most circumstances, regardless of the mechanism of MR.  When in the patient’s interest, the heart team’s interventional cardiologist and cardiac surgeon may jointly participate in the intra-operative technical aspects of TEER for FMR.  In response to public comments, we have included language to highlight the critical role played by the heart team interventional echocardiographer during TEER procedures.  The heart team interventional echocardiographer is responsible for guiding the TEER operator(s) throughout the procedure.  Furthermore, while either a cardiologist or an anesthesiologist with the requisite training and board eligibility or board certification may serve as the interventional echocardiographer during TEER, the interventional echocardiographer may not simultaneously furnish anesthesia during the procedure.

Facility Infrastructure Requirements: CMS is finalizing the infrastructure requirements as proposed for hospitals to have an on-site heart valve surgery and interventional cardiology program, post-procedure intensive care facility with personnel experienced in managing patients who have undergone open-heart valve procedures, and procedural volumes as specified below. 

Hospital Volume Requirements and Heart Team Volume Requirements (with and without prior TEER experience): Final hospital volume requirements for this TEER NCD are enumerated in the Decision and Conclusion sections.  We are modifying the volume requirements to reflect elements of the Expert Consensus document, with the final volume requirements either consistent with or lower than recommended, as well as our review of currently available clinical evidence.  Additionally, these modifications reflect our efforts to align with TAVR NCD volume requirements for consistency in valve programs that perform both TEER and TAVR.  The professional society recommendations are detailed in the 2019 AATS/ACC/SCAI/STS Expert Consensus guidance (Table 3), titled “2019 Transcatheter MV Intervention [TEER] Site and Operator Requirements.”57 The 2019 AATS/ACC/SCAI/STS Expert Consensus recommendations address the primary interventionist may be either the cardiac surgeon or the interventional cardiologist.  The 2014 TMVR NCD included requirements for the interventional cardiologist and we continue to believe that interventional cardiologists must have experience with structural heart disease procedures.  We are modifying our proposed requirements for the interventional cardiologist, which were consistent with the same requirement for the interventional cardiologist as set forth in the June 2019 TAVR NCD, to instead reflect the lower structural heart disease procedure lifetime experience of ≥50 as specified in the Expert Consensus document.  We are finalizing the volume requirements for the heart team cardiac surgeon as proposed.

Several commenters submitted published reports and objected to the proposed volume requirements for TEER.  One analysis of administrative claims demonstrated no statistically significant association between mitral valve surgical volume and in-hospital mortality, post discharge mortality, or cardiovascular hospitalizations at six months.80 However, the authors adjusted for hospital bed number in their statistical model, which is likely to correlate with both TEER and cardiac surgical volumes; additionally, their follow up was brief.  A second study used Medicare administrative claims from 2016 to assess the relationship between mitral valve surgical volume and TEER outcomes at one year, including 1-year mortality, 1-year heart failure hospitalization, and 1-year mitral re-intervention.  Finally, one analysis evaluated administrative claims from 2016 and found no association between percutaneous coronary intervention (PCI) volume and in-hospital mortality or 30-day readmission rates for TEER.81 However, in-hospital mortality and 1-year re-intervention were both rare in the COAPT study, and while the COAPT study demonstrated an early reduction in heart failure admissions, the impact on mortality emerged more than a year after TEER.17,26 Furthermore, none of these studies assessed post- intervention MR severity, which is associated with operator experience. 

At the time of writing this decision memorandum, the Expert Consensus document is the extent of evidence based information available specific to appropriate facility procedural volume requirements for TEER programs.  CMS recognizes the importance of professional society recommendations in establishing requirements that strike a balance between ensuring hospitals have the experience and capabilities to handle complex structural heart disease cases and reducing the burden of unnecessary requirements on hospitals and patients.  Data from the TVT registry demonstrates a clear relationship between procedural experience and optimal procedural success, procedural time, and procedural complications.61 CMS further believes that inexperience and poor case selection in the MITRA-FR study contributed to the lack of benefit in that study.26 Studies have also demonstrated a relationship between volume and outcomes for mitral valve surgical repair or replacement.25,63 A robust cardiac surgery program is especially important where TEER is considered for DMR.  For patients at prohibitive surgical risk, TEER may decrease symptoms, improve quality of life, and improve survival, but its efficacy to reduce MR remains inferior to surgery.12 Patients with advanced heart failure and FMR will similarly benefit from a full complement of specialists on the heart team.  A robust valve program reflecting both experienced interventional cardiology, interventional echocardiography, and cardiac surgery will become even more important if additional transcatheter mitral valve devices obtain FDA market authorization in the future.79

After review of public comments and submitted evidence and in light of coverage under CED, CMS has finalized a lower surgical volume requirement for hospitals of ≥ 20 mitral valve surgical procedures for severe MR per year or ≥ 40 over two years, of which at least 10 (or 20 over two years) must be mitral valve repairs.  Furthermore, we and have not established separate volume requirements for hospitals to begin and maintain TEER programs as proposed.  Additionally, we are finalizing the PCI volume requirement as proposed.  As such, the volume requirements in this NCD apply to all hospitals and heart teams both with and without mitral valve TEER program experience.  The final volume requirements include elements of the updated Expert Consensus document and reflect our efforts to better align NCD volume requirements for valve programs that perform both TEER and TAVR.

In the interim final rule with comment period [CMS-3401-IFC], CMS announced that we will not enforce certain procedural volume requirements in order for facilities and practitioners to maintain Medicare coverage under specific NCDs, including NCD 20.33. This applies to facilities and practitioners that, prior to the PHE for COVID-19, met the volume requirements for these NCDs.

Coverage with Evidence Development
As noted above, we are finalizing this decision to cover TEER for both degenerative and functional MR under CED. CMS agrees with the consensus of the experts, including all of the professional societies and organizations that commented that important evidence gaps continue to remain for both DMR and FMR and CED is the best path to address those.  It also permits more robust coverage than what we proposed.

In 2014, CMS covered TMVR for the treatment of significant symptomatic DMR under CED when specific conditions were applicable.  On March 14, 2019, the FDA expanded MitraClip™ approval for a new indication — treatment of patients with structurally normal mitral valves and moderate-to-severe or severe MR because of diminished left heart function (commonly known as secondary or functional MR) despite being treated with optimal medical therapy. 

CMS maintains an interest in data collection for the health outcomes that parallel the outcomes assessed as part of the 2014 TMVR determination for DMR in order to better understand the risk-benefit profile in the context of TEER for treatment of FMR. As such, we are continuing CED requirements for participation in a CMS approved prospective, national, audited registry.

The 2019 AATS/ACC/SCAI/STS Expert Consensus guidance document states:

“FDA approval of a novel transcatheter valve repair [inclusive of TEER] or replacement system does not guarantee that the device will continue to demonstrate long-term efficacy that is comparable to other options, which are or will become available, or that its use will remain limited to the initially approved indication. Both postmarket surveillance organized through individual institutions or multicenter research groups and outcomes reported in multistakeholder registries are essential to track continued device safety and efficacy.”

The outcomes of interest to CMS include: 

  • stroke;
  • all-cause mortality;
  • repeat TEER or other mitral procedures;
  • transient ischemic attacks (TIAs);
  • major vascular events;
  • renal complications;
  • functional capacity;
  • Quality of life.

All-cause mortality, Stroke, and Transient Ischemic Attacks (TIAs). CMS maintains an interest in monitoring outcomes of stroke, TIA, and all-cause mortality as important components of cardiac morbidity and mortality as the indication for TEER is expanded to the treatment of FMR. 

Repeat TEER or other mitral procedures. Assessing recurrence of FMR and potential repeat need for TEER or other mitral procedures is an important health outcome to monitor; secondary MR may recur after TEER as a consequence of continued ventricular remodeling, which may lead to recurrent valve tenting.  

Major vascular events.  Vascular complications remain an important consideration for patients and for the heart team in weighing procedural harms and benefits.  Vascular events remain an outcome of interest for further data collection and consideration.

Renal complications. In MITRA-FR trial renal-replacement therapy was needed for 5/152 patients (3.3%) in the TEER arm as compared to 1/152 (0.7%) in the control group.  The study by Schueler et al., assessed short-term outcomes of patients undergoing TEER in the German TRAMI registry stratified by baseline renal function.47 The authors concluded that renal function at the time of TEER with the MitraClip system is a strong predictor for procedural outcomes.  Patients with severe renal impairment had a more than threefold increased risk for acute procedural failure, in-hospital death and 30-day mortality.  Therefore, CMS has an interest in gathering information on baseline and renal status following TEER.

Functional Capacity. Patients often pursue TEER to decrease symptoms and improve survival, but for many patients, an improvement in the ability to complete activities of daily living and maintain independence may be as or more important. Therefore, CMS believes that studies are needed to assess the impact of TEER on functional capacity as an outcome of considerable importance to patients.

Quality of Life (QoL). In the study by Whitlow et al., QoL improved as measured by the Short Form-36 physical component score with an increase from 32.1 to 36.1 [p = 0.014].27 The study by Armeni et al., found that TEER was associated with 3.01±0.57 incremental quality-adjusted life years.30 The study by Asgar et al., found that TEER (plus GDMT) increased quality-adjusted life years (QALY) from 1.13-2.76 years.83 The study by Glower et al., also used the 36-item Short Form Health Survey, physical and mental QoL scores improved from baseline to 12 months (p < 0.0001).39 The authors of the Taramasso study commented that [TEER] was associated with an improvement in functional status and QoL at 1 year as well as significant LV reverse remodeling. Such QoL outcomes are important considerations for Medicare beneficiaries to help as they weigh their goals, preferences, and values as part of the shared-decision making process in considering treatment decisions.

Conclusion: After reviewing public comments and the published literature in this assessment, CMS has identified some gaps in the current evidence base that preclude fully assessing which characteristics of the patient, practitioner or facility predict the most successful patient outcomes from TEER.  CMS maintains an interest in monitoring important health outcomes to better inform our understanding of the risk/benefit profile, particularly for subpopulations, as the indication for TEER is expanded to the indication of treatment of FMR. 

Based on the evidence review, we are requiring that the following outcomes be critically evaluated through a minimum of 1 year:

  • stroke;
  • all-cause mortality;
  • repeat TEER or other mitral procedures;
  • transient ischemic attacks (TIAs);
  • major vascular events;
  • renal complications;
  • functional capacity; and
  • Quality of Life.

Registry Requirement:
In addition to the 1-year outcomes detailed above, CMS has additional questions regarding TEER for the treatment of degenerative and functional MR when furnished according to an FDA approved indication.

As such, we are requiring that the CMS-approved registry needs to collect all data necessary, and have a written executable analysis plan in place, to address the following questions:

  • When TEER procedures are performed outside a controlled clinical study, how do outcomes and adverse events compare to the pivotal clinical studies?
  • How do outcomes and adverse events in subpopulations compare to patients in the pivotal clinical studies?
  • What is the long term (≥ 5 year) durability of the device?
  • What are the long term (≥ 5 year) outcomes and adverse events?
  • How do the demographics of registry patients compare to the pivotal studies?

In sum, CMS believes that evidence gaps remain which result in uncertainty about the overall impact of TEER on beneficiary outcomes, particularly regarding which characteristics of the patient, practitioner or facility predict the most successful patient outcomes from TEER.

Despite great progress, important gaps remain in the evidence base, which may be addressed through CED, including:

  • What are the outcomes (e.g., survival, quality of life, complications, device durability, ancillary needs) for patients during follow-up? What are the long term (5-year) survival and device durability outcomes?  Are the outcomes similar to those observed in trials/studies?
  • How does TEER performance (e.g., MR, LVEF, LVEDD), as assessed by echocardiography, change over time?
  • Within patient subpopulations for which TEER has a demonstrated benefit, what are the pre-procedural patient characteristics that predict outcomes?  What subgroups of patients within a given population may benefit substantially more or less from the procedure?
  • Can standardized, patient- and family-friendly, evidence-based risk assessment tools improve patient-physician shared decision making?
  • What morbidity and procedure-related factors contribute to TEER outcomes?

Coverage of Non-FDA Approved Uses:

In 2014, the TMVR final NCD included a provision for coverage of TMVR for MR uses that are not expressly listed as an FDA-approved indication when performed within an FDA-approved RCT that meets specific requirements and addresses specific outcomes and research questions.  We note that the COAPT trial (NCT01626079) was performed under this section.  MITRA-FR was also an RCT conducted in France.  We believe the evidence has grown and implementation of studies in real world settings in the U.S. would also add to the evidence base in this patient population given the growth in TEER since the 2014 TMVR NCD. To that end, we have removed the requirement that non-FDA approved uses be covered only in FDA-approved RCTs and to provide coverage for any clinical studies that meet the criteria outlined in this document.  We believe this change will facilitate and encourage continued and new research within the rapidly evolving TEER landscape.

Sunset of TEER CED NCD

Based on public comments, CMS is aware that stakeholders desire clarity on how long CED will be required for TEER.  CMS will consider published, peer-reviewed evidence periodically, following the effective date of this NCD and reconsider the policy when appropriate.  The NCD will expire 10 years from the effective date if it is not reconsidered during that time.  Upon expiration, coverage will be at the discretion of the MACs. 

Considerations for Further Research

CMS recognizes the importance of shared decision-making (SDM) in many clinical scenarios and has required SDM in other NCDs (for example, implantable cardiac defibrillators: https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=110).  CMS supports patient SDM in TEER but there is no fully developed tool available at this time.  CMS strongly encourages standardized decision aids or tools [the National Quality Forum (NQF) has published standards for decision aids (www.qualityforum.org/Projects/c-/Decision_Aids/Final_Report.aspx)] to facilitate the decision making process between a patient and physician and will be monitoring this space closely.  Tools are in development for other conditions and procedures.  For example, the Patient-Centered Outcomes Research Institute (PCORI) funded research (CER-1306-04350/ NCT02266251), to create and assess a personalized decision assistance tool designed to evaluate important health outcomes between SAVR to TAVR for operable patients with aortic valve disease considering aortic valve replacement.  The work also aims to develop and assess a personalized risk assessment tool designed to evaluate expected health outcomes with TAVR for inoperable patients considering aortic valve replacement.

Health Disparities

Gender and race: Approximately 64% of COAPT patients were male; the Kansas City Cardiomyopathy Questionnaire overall summary score was consistent across men and women at 1 year.  However, COAPT was unlikely powered to perform a subgroup analysis by race.18

The Lowenstern study evaluated data from TEER patients using the MitraClip system that were enrolled in the EVEREST II High-Risk or the REALISM Continued-Access Registries and attempted to link patients to Medicare claims.75 Of the 706 total registry patients, 418 could be linked; 60% were men and 93.8% were white.  The publication did not report outcomes based by sex or race.

The Kundi study identified TEER patients who used the MitraClip system from CMS MedPAR files linked to CMS denominator files.76 The study identified 3,782 U.S. patients from 280 clinical sites that underwent TEER; 55.2% were men.  Sex was retained as one of 18 final covariates in a predictive model assessing 1-year mortality following TEER.  The study did not provide demographics or results corresponding to race.

CMS is interested in broader evidence on characteristics predicting successful outcomes, including the influence of sex and race.  There is a particular paucity of evidence in the literature assessing the impact of race following TEER for FMR.  In addition, CMS is interested in information on access to TEER by race to assess whether unintended barriers might preclude TEER access for minority populations among Medicare beneficiaries.

IX.   Conclusion

For clarity, we are replacing the term Transcatheter Mitral Valve Repair (TMVR) with mitral valve Transcatheter Edge-to-Edge Repair (TEER) to more precisely define the treatment addressed in this proposed NCD, which is applicable to TEER for the treatment of functional mitral regurgitation (MR) and degenerative MR.

TEER of the mitral valve is covered under Coverage with Evidence Development (CED) as follows:

  1. For the treatment of symptomatic moderate-to-severe or severe functional mitral regurgitation (MR) when the patient remains symptomatic despite stable doses of maximally tolerated guideline-directed medical therapy (GDMT) plus cardiac resynchronization therapy, if appropriate, or for the treatment of significant symptomatic degenerative MR when furnished according to an FDA-approved indication and when all of the following conditions are met:

    1. The procedure is furnished with a mitral valve TEER system that has received FDA premarket approval (PMA).

    2. The patient (preoperatively and postoperatively) is under the care of a heart team: a cohesive, multidisciplinary, team of medical professionals.  The heart team concept embodies collaboration and dedication across medical specialties to offer optimal patient-centered care. The heart team must include the following members with experience and training as specified:
      1. Cardiac surgeon
        1. With ≥ 20 mitral valve surgeries per year or ≥ 40 over two years, 50% of which are mitral valve repairs; and
        2. Who is board eligible or certified in cardiothoracic surgery or similar foreign equivalent.
      2. Interventional cardiologist
        1. With professional experience of ≥ 50 career structural heart disease procedures; or ≥ 30 left-sided structural procedures per year; and
        2. With participation in ≥ 20 career trans-septal interventions including 10 as primary or co-primary operator; and
        3. Who is board eligible or certified in interventional cardiology or similar foreign equivalent.
      3. Interventional echocardiographer (cardiologist or anesthesiologist)
        1. With professional experience of ≥ 10 trans-septal guidance procedures and ≥ 30 structural heart procedures; and
        2. Who is board eligible or certified in transesophageal echocardiography with advanced training as required for privileging by the hospital where the TEER is performed.
      4. Heart failure cardiologist experienced in treating patients with advanced heart failure (only required for functional MR patients); and
      5. Providers from other physician groups as well as advanced patient practitioners, nurses, research personnel, and administrators.

    3. Each patient’s suitability for surgical mitral valve repair, TEER, or palliative therapy must be evaluated, documented, and made available to other heart team members. Additionally, for patients with functional MR, the heart team heart failure cardiologist must document that the patient has persistent symptoms despite maximally tolerated GDMT and cardiac resynchronization therapy, if appropriate, as described below:
      1. For patients with functional MR: the heart team interventional cardiologist and heart team heart failure cardiologist independently evaluate the patient using information in the medical record and a face-to-face examination.  To decrease patient burden, the heart team heart failure cardiologist may meet this requirement through a review of the patient’s records and images if the patient has an established relationship with a cardiologist experienced in treating patients with advanced heart failure.
      2. For patients with degenerative MR: the heart team interventional cardiologist and heart team cardiac surgeon must independently evaluate the patient using information in the medical record and a face-to-face examination.

    4. An interventional cardiologist or cardiac surgeon from the heart team must perform the mitral valve TEER and an interventional echocardiographer from the heart team must perform transesophageal echocardiography during the procedure.  The interventional echocardiographer may not also furnish anesthesiology during the same procedure. The interventional cardiologist and cardiac surgeon may jointly participate in the intra-operative technical aspects of TEER as appropriate. All physicians who participate in the procedure must have device-specific training as required by the manufacturer.

    5. Mitral valve TEERs must be furnished in a hospital with appropriate infrastructure and experience that includes, but is not limited to:
      1. On-site heart valve surgery and interventional cardiology programs;
      2. Post-procedure intensive care facility with personnel experienced in managing patients who have undergone open-heart procedures;
      3. Hospital volume requirements below must be met and maintained:
        1. ≥ 20 mitral valve surgical procedures for severe MR per year or ≥ 40 over two years, of which at least 10 (or 20 over two years) must be mitral valve repairs; and
        2. ≥ 2 physicians with cardiac surgery privileges experienced in valvular surgery; and
        3. ≥ 1 physician with interventional cardiology privileges; and
        4. ≥ 300 percutaneous coronary interventions (PCIs) per year.

    6. The heart team and hospital are participating in a prospective, national, audited registry that: 1) comprehensively enrolls TEER patients; 2) accepts all manufactured devices; 3) follows the patient for at least one year; and, 4) complies with relevant regulations relating to protecting human research subjects, including 45 CFR Part 46 and 21 CFR Parts 50 & 56.

      The following outcomes must be tracked by the registry, and the registry must be designed to permit identification and analysis of patient, practitioner, and facility level variables that predict each of these outcomes:

      1. Stroke;
      2. All-cause mortality;
      3. Repeat TEER or other mitral procedures;
      4. Transient Ischemic Attacks (TIAs);
      5. Major vascular events;
      6. Renal complications;
      7. Functional capacity; and
      8. Quality of Life (QoL).

    7. The registry shall collect all data necessary and have a written executable analysis plan in place to address the following questions. Specifically, for the CED question d, this must be addressed through a composite metric. For the below CED questions (a-e), the results must be reported publicly as described in CED criterion k.

      1. When TEER procedures are performed outside a controlled clinical study, how do outcomes and adverse events compare to the pivotal clinical studies?
      2. How do outcomes and adverse events in subpopulations compare to patients in the pivotal clinical studies?
      3. What is the long-term (≥ 5 year) durability of the device?
      4. What are the long-term (≥ 5 year) outcomes and adverse events?
      5. How do the demographics of registry patients compare to the pivotal studies?

      Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions.

  2. Mitral valve TEERs are covered for uses that are not expressly listed as an FDA-approved indication when performed within a clinical study that fulfills all of the following:

    1. An interventional cardiologist or cardiac surgeon must perform the mitral valve TEER and an interventional echocardiographer must perform transesophageal echocardiography during the procedure. The interventional echocardiographer may not also furnish anesthesiology during the same procedure.  The interventional cardiologist and cardiac surgeon may jointly participate in the intra-operative technical aspects of TEER as appropriate. All physicians who participate in the procedure must have device specific training as required by the manufacturer.

    2. As a fully-described, written part of its protocol, the clinical research trial must critically evaluate the following questions at 12 months or longer follow-up:
      1. What is the rate of all-cause mortality in the intervention group?
      2. What is the rate of re-operations (open surgical or transcatheter) of the mitral valve in the intervention group?
      3. What is the rate of moderate-to-severe or severe MR in the intervention groups?

    3. As a fully-described, written part of its protocol, the clinical research study must critically evaluate not only each patient’s quality of life pre- and post-TEER (minimum 1 year), but must also address at least one of the following questions:
      1. What is the incidence of stroke?
      2. What is the incidence of TIAs?
      3. What is the incidence of major vascular events?
      4. What is the incidence of renal complications?
      5. What is the incidence of worsening MR?
      6. What is the change in quality of life after TEER?
      7. What is the change in the patient’s functional capacity after TEER?

    4. The clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population:
      1. The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects.
      2. The rationale for the study is well supported by available scientific and medical evidence.
      3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
      4. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination.
      5. The study is sponsored by an organization or individual capable of completing it successfully.
      6. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and /or services, and the use and eventual disposition of the collected data.
      7. All aspects of the research study are conducted according to appropriate standards of scientific integrity.
      8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
      9. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options.
      10. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR).
      11. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results).
      12. The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
      13. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

      Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that meet the above-listed standards and address the above-listed research questions.

      The principal investigator must submit the complete study protocol, identify the relevant CMS research question(s) that will be addressed, and cite the location of the detailed analysis plan for those questions in the protocol, plus provide a statement addressing how the study satisfies each of the standards of scientific integrity (a. through m. listed above), as well as the investigator's contact information, to the address below. The information will be reviewed, and approved studies will be identified on the CMS Website.

      Director, Coverage and Analysis Group
      Re: TEER CED
      Centers for Medicare & Medicaid Services (CMS)
      7500 Security Blvd., Mail Stop S3-02-01
      Baltimore, MD 21244-1850

      Email address for protocol submissions: clinicalstudynotification@cms.hhs.gov
      Email subject line: "CED TEER [name of sponsor/primary investigator]"

  3. TEER of the mitral valve is not covered under the following circumstances:
    1. For patients in whom existing co-morbidities would preclude the expected benefit from a mitral valve TEER procedure.
    2. In patients with untreated severe aortic stenosis.

  4. CMS will consider published, peer-reviewed evidence periodically, following the effective date of this NCD and reconsider the policy when appropriate.  The NCD will expire 10 years from the effective date if it is not reconsidered during that time.  Upon expiration, coverage will be at the discretion of Medicare Administrative Contractors (MACs). 

See Appendix B for NCD Manual language.


APPENDIX A
General Methodological Principles of Study Design

(Section VI of the Decision Memorandum)

When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary. The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients.

We divide the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the generalizability of findings from individual studies to the Medicare population; and 3) overarching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential risks and benefits.

The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence. However, it should be noted that each coverage determination has its unique methodological aspects.

Assessing Individual Studies

Methodologists have developed criteria to determine weaknesses and strengths of clinical research. Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias. In general, some of the methodological attributes associated with stronger evidence include those listed below:

  • Use of randomization (allocation of patients to either intervention or control group) in order to minimize bias.
  • Use of contemporaneous control groups (rather than historical controls) in order to ensure comparability between the intervention and control groups.
  • Prospective (rather than retrospective) studies to ensure a more thorough and systematical assessment of factors related to outcomes.
  • Larger sample sizes in studies to demonstrate both statistically significant as well as clinically significant outcomes that can be extrapolated to the Medicare population. Sample size should be large enough to make chance an unlikely explanation for what was found.
  • Masking (blinding) to ensure patients and investigators do not know to that group patients were assigned (intervention or control). This is important especially in subjective outcomes, such as pain or quality of life, where enthusiasm and psychological factors may lead to an improved perceived outcome by either the patient or assessor.

Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is to the extent that differences between intervention and control groups can be attributed to the intervention studied. This is known as internal validity. Various types of bias can undermine internal validity. These include:

  • Different characteristics between patients participating and those theoretically eligible for study but not participating (selection bias).
  • Co-interventions or provision of care apart from the intervention under evaluation (performance bias).
  • Differential assessment of outcome (detection bias).
  • Occurrence and reporting of patients who do not complete the study (attrition bias).

In principle, rankings of research design have been based on the ability of each study design category to minimize these biases. A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups. Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The design, conduct and analysis of trials are important factors as well. For example, a well-designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size. The following is a representative list of study designs (some of that have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias:

Randomized controlled trials
Non-randomized controlled trials
Prospective cohort studies
Retrospective case control studies
Cross-sectional studies
Surveillance studies (e.g., using registries or surveys)
Consecutive case series
Single case reports

When there are merely associations but not causal relationships between a study’s variables and outcomes, it is important not to draw causal inferences. Confounding refers to independent variables that systematically vary with the causal variable. This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors. For observational, and in some cases randomized controlled trials, the method in that confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern. For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.

Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study. In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence.

Generalizability of Clinical Evidence to the Medicare Population

The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity. Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population. Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered but would suffer from limited generalizability.

The extent to that the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider). Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up.

The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity. Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings. For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.

Given the evidence available in the research literature, some degree of generalization about an intervention’s potential benefits and harms is invariably required in making coverage determinations for the Medicare population. Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice.

A study's selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations. One of the goals of our determination process is to assess health outcomes. These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality. In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study. In addition, it is important that an intervention's benefits are clinically significant and durable, rather than marginal or short-lived. Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.

If key health outcomes have not been studied or the direction of clinical effect is inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest.

Assessing the Relative Magnitude of Risks and Benefits

Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits. Health outcomes are one of several considerations in determining whether an item or service is reasonable and necessary. CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses. The direction, magnitude, and consistency of the risks and benefits across studies are also important considerations. Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology' benefits and risk of harm to Medicare beneficiaries.

APPENDIX B
Medicare National Coverage Determinations Manual

Draft
This information is representative of Medicare's national coverage determination (NCD) for implementation purposes only. The information is subject to formal revisions and formatting changes prior to the release of the final NCD contractor instructions and publication in the Medicare National Coverage Determinations Manual.

Table of Contents
(Rev.)

NCD 20.33 - Transcatheter Edge-to-Edge Repair (TEER) for Mitral Valve Regurgitation

A.    General

Transcatheter Edge-to-Edge Repair (TEER) of the mitral valve is used in the treatment of mitral regurgitation. TEER approximates the anterior and posterior mitral valve leaflets by grasping them with a clipping device in an approach similar to a treatment developed in cardiac surgery called the Alfieri stich.

B.    Nationally Covered Indications

The Centers for Medicare & Medicaid Services (CMS) covers Transcatheter Edge-to-Edge Repair (TEER) of the mitral valve under Coverage with Evidence Development (CED) with the following conditions:

A.    For the treatment of symptomatic moderate-to-severe or severe functional mitral regurgitation (MR) when the patient remains symptomatic despite stable doses of maximally tolerated guideline-directed medical therapy (GDMT) plus cardiac resynchronization therapy, if appropriate, or for the treatment of significant symptomatic degenerative MR when furnished according to an FDA-approved indication and when all of the following conditions are met:

  1. The procedure is furnished with a mitral valve TEER system that has received FDA premarket approval (PMA).
  2. The patient (preoperatively and postoperatively) is under the care of a heart team: a cohesive, multidisciplinary, team of medical professionals. The heart team concept embodies collaboration and dedication across medical specialties to offer optimal patient-centered care. The heart team must include the following members with experience and training as specified:
    1. Cardiac surgeon
      1. With ≥ 20 mitral valve surgeries per year or ≥ 40 over two years, 50% of which are mitral valve repairs; and
      2. Who is board eligible or certified in cardiothoracic surgery or similar foreign equivalent.
    2. Interventional cardiologist
      1. With professional experience of ≥ 50 career structural heart disease procedures; or ≥ 30 left-sided structural procedures per year; and
      2. With participation in ≥ 20 career trans-septal interventions including 10 as primary or co-primary operator; and
      3. Who is board eligible or certified in interventional cardiology or similar foreign equivalent.
    3. Interventional echocardiographer (cardiologist or anesthesiologist)
      1. With professional experience of ≥ 10 trans-septal guidance procedures and ≥ 30 structural heart procedures; and
      2. Who is board eligible or certified in transesophageal echocardiography with advanced training as required for privileging by the hospital where the TEER is performed.
    4. Heart failure cardiologist experienced in treating patients with advanced heart failure (only required for functional MR patients); and
    5. Providers from other physician groups as well as advanced patient practitioners, nurses, research personnel, and administrators.

  3. Each patient’s suitability for surgical mitral valve repair, TEER, or palliative therapy must be evaluated, documented, and made available to other heart team members. Additionally, for patients with functional MR, the heart team heart failure cardiologist must document that the patient has persistent symptoms despite maximally tolerated GDMT and cardiac resynchronization therapy, if appropriate, as described below:
    1. For patients with functional MR: the heart team interventional cardiologist and heart team heart failure cardiologist independently evaluate the patient using information in the medical record and a face-to-face examination. To decrease patient burden, the heart team heart failure cardiologist may meet this requirement through a review of the patient’s records and images if the patient has an established relationship with a cardiologist experienced in treating patients with advanced heart failure.
    2. For patients with degenerative MR: the heart team interventional cardiologist and heart team cardiac surgeon must independently evaluate the patient using information in the medical record and a face-to-face examination.

  4. An interventional cardiologist or cardiac surgeon from the heart team must perform the mitral valve TEER and an interventional echocardiographer from the heart team must perform transesophageal echocardiography during the procedure. The interventional echocardiographer may not also furnish anesthesiology during the same procedure. The interventional cardiologist and cardiac surgeon may jointly participate in the intra-operative technical aspects of TEER as appropriate. All physicians who participate in the procedure must have device-specific training as required by the manufacturer.

  5. Mitral valve TEERs must be furnished in a hospital with appropriate infrastructure and experience that includes, but is not limited to:
    1. On-site heart valve surgery and interventional cardiology programs;
    2. Post-procedure intensive care facility with personnel experienced in managing patients who have undergone open-heart procedures;
    3. Hospital volume requirements below must be met and maintained:
      1. ≥ 20 mitral valve surgical procedures for severe MR per year or ≥ 40 over two years, of which at least 10 (or 20 over two years) must be mitral valve repairs; and
      2. ≥ 2 physicians with cardiac surgery privileges experienced in valvular surgery; and
      3. ≥ 1 physician with interventional cardiology privileges; and
      4. ≥ 300 percutaneous coronary interventions (PCIs) per year.
  6. The heart team and hospital are participating in a prospective, national, audited registry that: 1) comprehensively enrolls TEER patients; 2) accepts all manufactured devices; 3) follows the patient for at least one year; and, 4) complies with relevant regulations relating to protecting human research subjects, including 45 CFR Part 46 and 21 CFR Parts 50 & 56.

    The following outcomes must be tracked by the registry, and the registry must be designed to permit identification and analysis of patient, practitioner, and facility level variables that predict each of these outcomes:

    1. Stroke;
    2. All-cause mortality;
    3. Repeat TEER or other mitral procedures;
    4. Transient Ischemic Attacks (TIAs);
    5. Major vascular events;
    6. Renal complications;
    7. Functional capacity; and
    8. Quality of Life (QoL).
  7. The registry shall collect all data necessary and have a written executable analysis plan in place to address the following questions. Specifically, for the CED question d, this must be addressed through a composite metric. For the below CED questions (a-e), the results must be reported publicly as described in CED criterion k.
    1. When TEER procedures are performed outside a controlled clinical study, how do outcomes and adverse events compare to the pivotal clinical studies?
    2. How do outcomes and adverse events in subpopulations compare to patients in the pivotal clinical studies?
    3. What is the long-term (≥ 5 year) durability of the device?
    4. What are the long-term (≥ 5 year) outcomes and adverse events?
    5. How do the demographics of registry patients compare to the pivotal studies?

    Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions.

B.    Mitral valve TEERs are covered for uses that are not expressly listed as an FDA-approved indication when performed within a clinical study that fulfills all of the following:

  1. An interventional cardiologist or cardiac surgeon must perform the mitral valve TEER and an interventional echocardiographer must perform transesophageal echocardiography during the procedure. The interventional echocardiographer may not also furnish anesthesiology during the same procedure. The interventional cardiologist and cardiac surgeon may jointly participate in the intra-operative technical aspects of TEER as appropriate. All physicians who participate in the procedure must have device specific training as required by the manufacturer.

  2. As a fully-described, written part of its protocol, the clinical research trial must critically evaluate the following questions at 12 months or longer follow-up:
    1. What is the rate of all-cause mortality in the intervention group?
    2. What is the rate of re-operations (open surgical or transcatheter) of the mitral valve in the intervention group?
    3. What is the rate of moderate-to-severe or severe MR in the intervention groups?

  3. As a fully-described, written part of its protocol, the clinical research study must critically evaluate not only each patient’s quality of life pre- and post-TEER (minimum 1 year), but must also address at least one of the following questions:
    1. What is the incidence of stroke?
    2. What is the incidence of TIAs?
    3. What is the incidence of major vascular events?
    4. What is the incidence of renal complications?
    5. What is the incidence of worsening MR?
    6. What is the change in quality of life after TEER?
    7. What is the change in the patient’s functional capacity after TEER?

  4. The clinical study must adhere to the following standards of scientific integrity and relevance to the Medicare population:
    1. The principal purpose of the study is to test whether the item or service meaningfully improves health outcomes of affected beneficiaries who are represented by the enrolled subjects.
    2. The rationale for the study is well supported by available scientific and medical evidence.
    3. The study results are not anticipated to unjustifiably duplicate existing knowledge.
    4. The study design is methodologically appropriate and the anticipated number of enrolled subjects is sufficient to answer the research question(s) being asked in the National Coverage Determination.
    5. The study is sponsored by an organization or individual capable of completing it successfully.
    6. The research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found in the Code of Federal Regulations (CFR) at 45 CFR Part 46. If a study is regulated by the Food and Drug Administration (FDA), it is also in compliance with 21 CFR Parts 50 and 56. In addition, to further enhance the protection of human subjects in studies conducted under CED, the study must provide and obtain meaningful informed consent from patients regarding the risks associated with the study items and /or services, and the use and eventual disposition of the collected data.
    7. All aspects of the research study are conducted according to appropriate standards of scientific integrity.
    8. The study has a written protocol that clearly demonstrates adherence to the standards listed here as Medicare requirements.
    9. The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Such studies may meet this requirement only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options.
    10. The clinical research studies and registries are registered on the www.ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject. Registries are also registered in the Agency for Healthcare Quality (AHRQ) Registry of Patient Registries (RoPR).
    11. The research study protocol specifies the method and timing of public release of all prespecified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 12 months of the study’s primary completion date, which is the date the final subject had final data collection for the primary endpoint, even if the trial does not achieve its primary aim. The results must include number started/completed, summary results for primary and secondary outcome measures, statistical analyses, and adverse events. Final results must be reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative or incomplete results).
    12. The study protocol must explicitly discuss beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
    13. The study protocol explicitly discusses how the results are or are not expected to be generalizable to affected beneficiary subpopulations. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.
    14. Consistent with section 1142 of the Act, the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that meet the above-listed standards and address the above-listed research questions.

      The principal investigator must submit the complete study protocol, identify the relevant CMS research question(s) that will be addressed, and cite the location of the detailed analysis plan for those questions in the protocol, plus provide a statement addressing how the study satisfies each of the standards of scientific integrity (a. through m. listed above), as well as the investigator's contact information, to the address below. The information will be reviewed, and approved studies will be identified on the CMS Website.

      Director, Coverage and Analysis Group
      Re: TEER CED
      Centers for Medicare & Medicaid Services (CMS)
      7500 Security Blvd., Mail Stop S3-02-01
      Baltimore, MD 21244-1850

      Email address for protocol submissions: clinicalstudynotification@cms.hhs.gov
      Email subject line: "CED TEER [name of sponsor/primary investigator]"

C.    Nationally Non-Covered Indications

TEER of the mitral valve is not covered under the following circumstances:

  1. For patients in whom existing co-morbidities would preclude the expected benefit from a mitral valve TEER procedure.
  2. In patients with untreated severe aortic stenosis.

D.    Other

CMS will consider published, peer-reviewed evidence periodically, following the effective date of this NCD and reconsider the policy when appropriate. The NCD will expire 10 years from the effective date if it is not reconsidered during that time. Upon expiration, coverage will be at the discretion of Medicare Administrative Contractors (MACs).

APPENDIX C

20.33 - Transcatheter Mitral Valve Repair (TMVR)
(Rev. 178, Issued: 12-05-14, Effective: 08-07-14, Implementation: 04-06-15)

A. General

Transcatheter mitral valve repair (TMVR) is used in the treatment of mitral regurgitation.

A TMVR device involves clipping