Transcatheter Mitral Valve Repair (TMVR)

The Centers for Medicare & Medicaid Services (CMS) proposes to cover transcatheter mitral valve repair (TMVR) under Coverage with Evidence Development (CED) with the following conditions:

A. TMVR is covered for the treatment of significant symptomatic mitral regurgitation when furnished according to an FDA approved indication and when all of the following conditions are met.

1. The procedure is furnished with a complete transcatheter mitral valve repair system that has received FDA premarket approval (PMA) for that system’s FDA approved indication.


2. Both a cardiac surgeon experienced in mitral valve surgery and a cardiologist experienced in mitral valve disease have independently examined the patient face-to-face and evaluated the patient’s suitability for mitral valve surgery and determination of prohibitive risk; and both physicians have documented the rationale for their clinical judgment and the rationale is available to the heart team.


3. The patient (preoperatively and postoperatively) is under the care of a heart team: a cohesive, multi-disciplinary, team of medical professionals.  The heart team concept embodies collaboration and dedication across medical specialties to offer optimal patient-centered care. 

   TMVR must be furnished in a hospital with the appropriate infrastructure that includes but is not limited to:

   1. On-site heart valve surgery program,
   2. Cardiac catheterization lab or hybrid operating room/catheterization lab equipped with a fixed radiographic imaging system with flat-panel fluoroscopy offering catheterization laboratory-quality imaging,
   3. Non-invasive imaging including expertise in transthoracic and transesophageal echocardiography,
   4. Sufficient space, in a sterile environment, to accommodate necessary equipment for cases with and without complications,
   5. Post-procedure intensive care facility with personnel experienced in managing patients who have undergone open-heart valve procedures,
   6. Appropriate volume requirements per the applicable qualifications below.

   Outlined below are qualification requirements for hospital surgical programs wishing to perform TMVR procedures. 

   The hospital surgical program must have the following:

   1. ≥ 25 total mitral valve procedures in the previous year of which at least 10 must be mitral valve repairs; 
   2. ≥1000 catheterizations per year, including ≥ 400 percutaneous coronary interventions (PCIs) per year;
   3. Interventionalist with: ≥ 50 structural procedures per year including atrial septal defects (ASD) and patent foramen ovale (PFO) and trans-septal punctures; and
   4. Additional members of the heart team including echocardiographers, other imaging specialists, heart valve and heart failure specialists, electrophysiologists, cardiac anesthesiologists, intensive care and cardiac imaging departments, congenital heart disease specialists and surgeons, nurse practitioners, data/research coordinators and a dedicated administrator; and device-specific training as required by the manufacturer.


4. The heart team’s interventional cardiologist(s) and cardiac surgeon(s) must jointly participate in the intra-operative technical aspects of TMVR.



5. The heart team and hospital are participating in a prospective, national, audited registry that:  1) consecutively enrolls TMVR 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. Quality of Life (QoL);
   2. Functional capacity
   3. Stroke;
   4. All-cause mortality;
   5. Transient ischemic events (TIAs);
   6. Major vascular events;
   7. Renal complications;
   8. Repeat mitral valve surgery or other mitral procedures;
   9. Worsening mitral regurgitation.

   The registry should collect all data necessary and have a written executable analysis plan in place to address the following questions (to appropriately address some questions, Medicare claims or other outside data may be necessary):

   • When 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?

   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. TMVR is covered for uses that are not expressly listed as an FDA approved indication when performed within a FDA-approved randomized clinical trial that fulfills all of the following: 

1. The heart team’s interventional cardiologist(s) and cardiac surgeon(s) must jointly participate in the intra-operative technical aspects of TMVR.



2. As a fully-described, written part of its protocol, the clinical research study must critically evaluate the following questions:
   • What is the patient’s post-TMVR quality of life (compared to pre-TMVR) at one year?
   • What is the patient’s post-TMVR functional capacity (compared to pre-TMVR) at one year?
3. In addition, the clinical research study must address all of the following questions at one year post procedure:
   • What is the incidence of stroke?
   • What is the rate of all-cause mortality?
   • What is the incidence of transient ischemic attacks (TIAs)?
   • What is the incidence of major vascular events?
   • What is the incidence of renal complications?
   • What is the incidence of subsequent mitral valve surgery or other mitral valve procedures?
   • What is the incidence of worsening mitral regurgitation?

C.   All CMS-approved clinical studies and registries must adhere to the following standards of scientific integrity and relevance to the Medicare population:

1. The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes. 
2. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use.
3. The research study does not unjustifiably duplicate existing studies. 
4. The research study design is appropriate to answer the research question being asked in the study. 
5. The research study is sponsored by an organization or individual capable of executing the proposed study 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 also must be in compliance with 21 CFR Parts 50 and 56. 
7. All aspects of the research study are conducted according to appropriate standards of scientific integrity. 
8. The research study has a written protocol that clearly addresses, or incorporates by reference; the standards listed as Medicare coverage requirements. 
9. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals.  Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard 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 research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria affect 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 research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention.  Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

CMS is seeking comments on our proposed decision.  We will respond to public comments in a final decision memorandum, as required by §1862(l)(3) of the Social Security Act.

TO:		Administrative File: (CAG-00438N)   
  
FROM:	Tamara Syrek Jensen, JD  
		Acting Director/Deputy Director  
		Coverage and Analysis Group  
		  
		Lori Ashby  
		Acting Director  
		Division of Medical and Surgical Services  
  
		Jyme Schafer, MD, MPH  
		Director  
		Division of Medical and Surgical Services  
  
		Lori Paserchia, MD  
		Medical Officer  
		Division of Medical and Surgical Services  
  
		Rosemarie Hakim, PhD  
		Epidemiologist  
		Coverage and Analysis Group  
  
SUBJECT:	Proposed Decision Memorandum for Transcatheter Mitral Valve (TMV) Procedures  
  
DATE:		May 15, 2014

I. Proposed Decision

The Centers for Medicare & Medicaid Services (CMS) proposes to cover transcatheter mitral valve repair (TMVR) under Coverage with Evidence Development (CED) with the following conditions:

A. TMVR is covered for the treatment of significant symptomatic mitral regurgitation when furnished according to an FDA approved indication and when all of the following conditions are met.

1. The procedure is furnished with a complete transcatheter mitral valve repair system that has received FDA premarket approval (PMA) for that system’s FDA approved indication.


2. Both a cardiac surgeon experienced in mitral valve surgery and a cardiologist experienced in mitral valve disease have independently examined the patient face-to-face and evaluated the patient’s suitability for mitral valve surgery and determination of prohibitive risk; and both physicians have documented the rationale for their clinical judgment and the rationale is available to the heart team.


3. The patient (preoperatively and postoperatively) is under the care of a heart team: a cohesive, multi-disciplinary, team of medical professionals. The heart team concept embodies collaboration and dedication across medical specialties to offer optimal patient-centered care.

   TMVR must be furnished in a hospital with the appropriate infrastructure that includes but is not limited to:

   1. On-site heart valve surgery program,
   2. Cardiac catheterization lab or hybrid operating room/catheterization lab equipped with a fixed radiographic imaging system with flat-panel fluoroscopy offering catheterization laboratory-quality imaging,
   3. Non-invasive imaging including expertise in transthoracic and transesophageal echocardiography,
   4. Sufficient space, in a sterile environment, to accommodate necessary equipment for cases with and without complications,
   5. Post-procedure intensive care facility with personnel experienced in managing patients who have undergone open-heart valve procedures,
   6. Appropriate volume requirements per the applicable qualifications below.

   Outlined below are qualification requirements for hospital surgical programs wishing to perform TMVR procedures.

   The hospital surgical program must have the following:

   1. ≥ 25 total mitral valve procedures in the previous year of which at least 10 must be mitral valve repairs;
   2. ≥1000 catheterizations per year, including ≥ 400 percutaneous coronary interventions (PCIs) per year;
   3. Interventionalist with: ≥ 50 structural procedures per year including atrial septal defects (ASD) and patent foramen ovale (PFO) and trans-septal punctures; and
   4. Additional members of the heart team including echocardiographers, other imaging specialists, heart valve and heart failure specialists, electrophysiologists, cardiac anesthesiologists, intensive care and cardiac imaging departments, congenital heart disease specialists and surgeons, nurse practitioners, data/research coordinators and a dedicated administrator; and device-specific training as required by the manufacturer.


4. The heart team’s interventional cardiologist(s) and cardiac surgeon(s) must jointly participate in the intra-operative technical aspects of TMVR.


5. The heart team and hospital are participating in a prospective, national, audited registry that: 1) consecutively enrolls TMVR 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. Quality of Life (QoL);
   2. Functional capacity
   3. Stroke;
   4. All-cause mortality;
   5. Transient ischemic events (TIAs);
   6. Major vascular events;
   7. Renal complications;
   8. Repeat mitral valve surgery or other mitral procedures;
   9. Worsening mitral regurgitation.

   The registry should collect all data necessary and have a written executable analysis plan in place to address the following questions (to appropriately address some questions, Medicare claims or other outside data may be necessary):

   • When 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?

   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. TMVR is covered for uses that are not expressly listed as an FDA approved indication when performed within a FDA-approved randomized clinical trial that fulfills all of the following:

1. The heart team’s interventional cardiologist(s) and cardiac surgeon(s) must jointly participate in the intra-operative technical aspects of TMVR.


2. As a fully-described, written part of its protocol, the clinical research study must critically evaluate the following questions:
   • What is the patient’s post-TMVR quality of life (compared to pre-TMVR) at one year?
   • What is the patient’s post-TMVR functional capacity (compared to pre-TMVR) at one year?
3. In addition, the clinical research study must address all of the following questions at one year post procedure:
   • What is the incidence of stroke?
   • What is the rate of all-cause mortality?
   • What is the incidence of transient ischemic attacks (TIAs)?
   • What is the incidence of major vascular events?
   • What is the incidence of renal complications?
   • What is the incidence of subsequent mitral valve surgery or other mitral valve procedures?
   • What is the incidence of worsening mitral regurgitation?

C. All CMS-approved clinical studies and registries must adhere to the following standards of scientific integrity and relevance to the Medicare population:

1. The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.
2. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use.
3. The research study does not unjustifiably duplicate existing studies.
4. The research study design is appropriate to answer the research question being asked in the study.
5. The research study is sponsored by an organization or individual capable of executing the proposed study 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 also must be in compliance with 21 CFR Parts 50 and 56.
7. All aspects of the research study are conducted according to appropriate standards of scientific integrity.
8. The research study has a written protocol that clearly addresses, or incorporates by reference; the standards listed as Medicare coverage requirements.
9. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard 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 research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria affect 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 research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

CMS is seeking comments on our proposed decision. We will respond to public comments in a final decision memorandum, as required by §1862(l)(3) of the Social Security Act.

II. Background

The following acronyms are used throughout this document. For the readers convenience they are listed here in alphabetical order.

6-MWT - 6 minute walk test
AATS - American Association for Thoracic Surgery
AHRQ - Agency for Healthcare Research and Quality
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
DMR - degenerative mitral regurgitation
EACTS – European Association for Cardio-Thoracic Surgery
ESC – European Society of Cardiology
FDA - U.S. Food and Drug Administration
FMR - functional mitral regurgitation
GDMT – guideline determined 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 Decision
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
SCAI - Society for Cardiovascular Angiography and Interventions
SSED – Summary of Safety and Effectiveness Data
STS - Society of Thoracic Surgeons
TA – technology assessment
TEE – transesophageal echocardiography
TIA – transient ischemic attack
U - unit
TMV – transcatheter mitral valve
TMVR - Transcatheter Mitral Valve Repair
TRAMI – transcatheter mitral valve interventions

Mitral Regurgitation

Mitral regurgitation (MR) is the most common type of heart valve insufficiency in the United States. According to de Marchena (2011), “due to an aging population, its increasing prevalence continues unabated. In 2000, it was estimated that MR affected 2 to 2.5 million people in the United States, a number that is expected to double by 2030.” In a recent analysis of the U.S. population, the prevalence of MR was found to vary from 10 per million (congenital) to 16,250 per million depending on the etiology of the MR (de Marchena 2011). Singh (1999) reported similar prevalence of MR of more than or equal to mild severity in men (19%) and women (19.1%). In addition, Singh (1999) noted that the prevalence of MR of more than or equal to mild severity “increased with advancing age in both sexes.”

The mitral valve comprises two valve leaflets, and the attached papillary muscles normally prevent the leaflets from prolapsing back into the left atrium. MR occurs when the leaflets of the mitral valve do not close properly and blood flows from the left ventricle back into the left atrium. This causes the heart to work harder to pump blood through the body, and in turn, is accompanied by an increase in the size of the left ventricle, potentially leading to heart failure. MR also is often associated with irregular heartbeats, stroke, myocardial infarction (a.k.a., heart attack) or death. The natural history of MR varies. MR may present as acute and severe or it may progress over a period of time (Bonow 2008). The need for treatment will usually depend on the condition and function of the heart.

There are numerous causes of MR, including mitral valve prolapse, rheumatic heart disease, coronary artery disease, infective endocarditis, certain drugs and collagen vascular disease (Bonow 2008). Additionally, there are two types of MR: 1) degenerative MR (DMR) or primary MR, which refers to leaflet abnormalities and 2) functional MR (FMR), or secondary MR, where the valve structure is normal, but the papillary muscles are displaced and the annulus is stretched. As Rosenhek (2013) notes, “Degenerative and functional mitral regurgitation (MR) constitute 2 separate disease entities. Although the pathophysiological problem is directly addressed by a successful intervention on the valve in the first case, the underlying ventricular disease persists in the latter.” Echocardiography is typically used to establish the severity of MR and guide treatment options.

Surgical repair

The standard treatment for individuals with severe and symptomatic MR is surgical treatment to repair or replace the mitral valve and well-defined treatment guidelines exist (Bonow 2006 and 2008). There are three surgical options available: 1) MV repair; 2) MV replacement with preservation of part or all of the mitral apparatus; and 3) MV replacement with removal of the mitral apparatus. However, patients with advanced age, LV dysfunction and comorbidities are deemed to be high risk surgical candidates and therefore surgery is often not presented as an option for these individuals (Bonow 2008). In response, there are currently several less invasive treatment options, including percutaneous techniques, in various stages of development.

Transcatheter Mitral Valve Repair

Currently, there are several TMVR procedures under various stages of development, which involve different techniques including the clipping of the mitral valve leaflets, mitral valve annular reduction, or chordal implants. Abbott Vascular’s MitraClip®, is currently the only FDA-approved TMVR device. The procedure involves clipping together a portion of the mitral valve leaflets as a treatment for reducing MR with the intended outcomes to improve recovery of the heart from overwork, improve function and potentially halt the progression of heart failure. The procedure is performed under general anesthesia via echocardiographic and fluoroscopic guidance. The device is typically delivered to the heart through a percutaneous transvenous approach. The heart beats normally during the procedure, and heart-lung bypass support is generally not required. This primary focus of this review is to evaluate the available evidence on the clipping of the mitral valve leaflets.

III. History of Medicare Coverage

CMS does not currently have an NCD on TMVR procedures.

A. Current Request

CMS received a formal request from the Society of Thoracic Surgeons (STS), the American College of Cardiology Foundation (ACCF), the Society for Cardiovascular Angiography and Interventions (SCAI), and the American Association for Thoracic Surgery (AATS) jointly asking that CMS cover TMV procedures using a system that has received FDA premarket approval (PMA) for the treatment of MR when performed according to an FDA-approved indication.

This request “incorporates indications from the recent FDA approval of the MitraClip®, highlights the value of data collection for this emerging technology, and takes steps to ensure TMVR patients will be cared for by a collaborative heart team at high quality facilities.” Specifically, the four societies stated the importance of establishing (1) regional centers of excellence for heart valve diseases, (2) multidisciplinary heart teams, (3) a national registry and (4) training and credentialing criteria.”

CMS opened this national coverage analysis (NCA) to thoroughly review the evidence on whether the TMVR technology is reasonable and necessary. The scope of our review in this PDM focuses on the only FDA-approved TMVR device, MitraClip®. In addition, this PDM focuses only on the repair of the mitral valve specifically by clipping the mitral valve leaflets rather than by annular reduction or by chordal implantation. Lastly, the scope of our review in this PDM or the resulting proposed policy does not include mitral valve balloon annuloplasty or commissurotomy.

B. Benefit Category

Medicare is a defined benefit program. 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 (the Act). TMVR falls under the benefit categories set forth in section §1861(b)(3) (inpatient hospital services), a Part A benefit under §1812(a)(1), and §1861(s)(1) (physician services), a Part B benefit. This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

IV. Timeline of Recent Activities

V. Food and Drug Administration (FDA) Status

On October 24, 2013, the FDA approved the first TMVR device.

Abbott Vascular’s MitraClip® was approved “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 includes statements on Annual Report requirements and requirements for two post approval studies.

(http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/Recently-ApprovedDevices/ucm375149.htm)

VI. General Methodological Principles

When making national coverage decisions under §1862(a)(1)(A), 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 patients. 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. In general, features of clinical studies that improve quality and decrease bias include the selection of a clinically relevant cohort, the consistent use of a single good reference standard, and the blinding of readers of the index test, and reference test results.

Public comment sometimes cites the published clinical evidence and gives 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.

VII. Evidence

This presentation of evidence primarily focuses upon whether the current data on TMV therapy are adequate to draw conclusions about health outcomes, as well as whether the body of evidence is generalizable to the Medicare population. The evidence CMS examines has as its focus health outcomes, i.e., the benefits and harms of a particular treatment. Key outcomes of interest to CMS are periprocedural and long-term risk of stroke, heart failure or death, adverse event profile, as well as health-related quality of life and function post-mitral valve implant. Independently assessed, validated instruments are most heavily weighted.

We summarize the evidence relating to the treatment of mitral regurgitation with transcatheter mitral valve repair. For FDA approval, the sponsor performed multiple clinical studies beginning in 2003. This series of studies is referred to as the EVEREST series. A recent systematic review and meta-analysis are available as is registry data from Europe as MitraClip® received CE Mark in 2008. In treatment of mitral regurgitation, the primary clinical focus is reduction in symptoms (chest pain, shortness of breath, fatigue and weakness), cardiovascular events (heart failure, stroke, myocardial infarction and arrhythmia) and mortality (cardiovascular mortality), as well as improvement in QoL and function.

Study endpoints should be clearly defined a priori to both improve the quality of clinical research and so as to allow comparison between clinical trials. Functional outcome measures for mitral regurgitation include the New York Heart Association (NYHA) classification (I - IV) and the six minute walk test (6MWT). The NYHA classification is a subjective symptom measure. The six minute walk test is (as the name describes) a standardized approach, which can be effort dependent, and the 6MWT is similar to the fifty meter walk test

Quality of life is important to Medicare beneficiaries and can weigh heavily in patients’ decision-making. Therefore, valid and reliable measurement is important to inform patients. Quality of life measures can be disease specific or general. A common disease specific measure used in heart failure is the Kansas City Cardiomyopathy Questionnaire (KCCQ), which is a 23-item questionnaire for assessment of disability and quality of life impairment due to congestive heart failure. A similar tool is the Minnesota Living with Heart Failure Questionnaire (MLHFQ). General QoL assessments include PROMISE, the SF-36 and the SF-12. Frequently, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) of the SF-36 are reported. A three point PCS difference has been associated with a 40% higher risk of being unable to work and a 20% increase in mortality rates at two years. (PMA P100009: FDA SSED) Similarly, a three point MCS difference is associated with a 30% increased risk of depression and use of mental health services (PMA P100009: FDA SSED). There are advantages and disadvantages to each tool, and the end use can help with tool choice, i.e., disease specific to measure within the population, and general for a broad population comparison. Physiologic measures such as hemodynamic measurement by echocardiography are also used but their relationship to clinical outcomes is less clear.

The development of an assessment in support of Medicare coverage decisions is based on the same general question for almost all national coverage analyses (NCAs): "Is the evidence sufficient to conclude that the application of the item or service under study will improve health outcomes for Medicare patients?" For this NCD, the questions of interest are:

1. Questions

1. Is the evidence adequate to conclude that transcatheter mitral valve repair improves health outcomes for Medicare beneficiaries with significant symptomatic degenerative mitral regurgitation who are at prohibitive risk for surgical mitral valve repair or replacement?


2. Is the evidence adequate to conclude that transcatheter mitral valve repair improves health outcomes for Medicare beneficiaries with significant symptomatic mitral regurgitation who are candidates for surgical mitral valve repair or replacement?

If the answer to either or both of the questions above is positive, 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 TMVR?

2. External Technology Assessment (TA)

CMS did not commission an external TA on this topic. No English language TA was identified.

3. Internal Technology Assessment

CMS performed literature searches on January 27-30, 2014 utilizing PubMed for studies that included MitraClip®. Studies must have been published in peer-reviewed English language journals. Abstracts were excluded because they do not provide sufficient information about the study to support further review. The literature search was limited to the English language and specific to the human population, but included studies conducted in all countries. When studies had multiple publications with accumulating numbers of patients or increased lengths of follow-up only the most recent article is mentioned, or studies are mentioned together if there is non-duplicative information. Studies with less than 50 patients were not included because studies limited by such small numbers are of insufficient evidentiary weight for the analytic questions we must address in this review.

The literature search found 226 articles, of which there was: one RCT (Mauri 2013); one systematic review (Munkholm-Larsen 2013); one meta-analysis (Wan 2013), and the remainder included registry studies, reviews, case reports of adverse events, and commentaries. Of the registry studies found, six were included for review in this PDM (Whitlow 2012; Lim 2013; Armoiry 2013; Schillinger 2013; Maisano 2013; Reichenspurner 2013). Reviews, case reports of adverse events and commentaries were not included in this PDM because they did not present the results of a data analysis (reviews), were limited by small numbers of patients and therefore were of insufficient evidentiary weight, or were subjective (commentaries).

Publicly accessible information from the FDA website, including the executive summary from the March 20, 2013 Circulatory System Devices Panel meeting as well as the Summary of Safety and Effectiveness Data (SSED) document produced after completion of the PMA review, were also included in this PDM.

Systematic Review

Munkholm-Larsen S, Wan B, Tian D, et al. A systematic review on the safety and efficacy of percutaneous edge-to-edge mitral valve repair with the MitraClip system for high surgical risk candidates. Heart Published Online First: 04022013 doi:10.1136/heartjnl-2013-304049.

The purpose of this review was to assess the safety, success rate, clinical efficacy, and survival outcomes of the MitraClip® procedure in managing high surgical risk MR (functional or degenerative) patients. High surgical risk was defined as an STS score or EuroSCORE of ≥ 12% or the presence of surgical risk factors assessed in a multidisciplinary team setting. The primary end points included 30 day mortality, procedural success, number of clips used, partial clip detachment, transseptal complications, cardiac tamponade, fluoroscopy duration, and length of intensive care unit and hospital stay. Secondary outcomes included echocardiographic data, function and quality of life, and survival at 6 months and/or 12 months. Experimental or observational studies were included while case reports, series with less than 10 patients, and abstracts were excluded. Studies that were not limited to high risk surgical patients were excluded. Six electronic databases were searched.

After selection criteria and accounting for serial publications, 12 publications were included. All 12 studies were prospective observational in design from specialized tertiary referral centers. Three studies had 100 or greater patients (202, 117, and 100 patients) while the other studies each had less than one hundred patients (range 16 - 85). All studies had a predicted perioperative mortality ≥ 12% although the definition for high risk varied among studies. Seven studies had a median follow-up of 1 year while three studies had a median follow-up of 6 months and one study reported outcomes beyond 12 months.

Procedural success ranged from 71.8 to 100%. Length of ICU stay was 1 or 2 days with the median length of hospital stay ranging from 5 - 12 days. Thirty day mortality ranged from 0 - 7.8%, cerebrovascular accident ranged from 0 - 6%, the need for early mitral surgery ranged from 0 - 6.2%, cardiac tamponade ranged from 0 - 2%, transseptal complications ranged from 1.2 to 3%, partial clip detachment ranged from 0 - 12.5% and transfusion of ≥ 2 units of packed red blood cells ranged from 0 - 17.9%. Results were not reported separately by type of MR.

A reduction in MR to ≤ grade 2+ was achieved in 73 - 100% of patients, with studies that reported 6 - 12 month follow-up reporting 61 - 99% achieving this reduction. Nine studies reported a decline in the number of patients with NYHA class III/IV, although studies that reported out to 12 months still had 11 - 35% of patients with functional class III/IV. Several studies reported improvement in the 6 minute walk test at 3 and 6 months. Quality of life was assessed in one study using the SF-36 and reported an improvement in the physical component at 12 months. Another study used the MLHFQ, which showed improvement at 6 month follow-up. One year survival was reported in six studies and ranged from 75 - 90%. Twelve-month mortality ranged from 10 - 25%.

The authors noted that limitations of the review included the complexity of combining valvular pathologies in all but three studies, a paucity of data on patient prognostication, and low quality evidence since the majority of evidence came from either registry or observational studies. The authors concluded, “The current evidence suggests that MitraClip can be implanted with reproducible safety and feasibility profile in this subgroup of patients.” However the authors also noted, “Before further convincing evidence becomes available, the use of MitraClip implantation should be considered only within the boundaries of clinical trials with special arrangements for clinical governance, consent, and audit or research. MitraClip interventions should only take place in centres with appropriate cardiothoracic surgical support to manage the potential intraoperative complications. It is likely that progressive development of technology, familiarity with techniques, and better understanding of appropriate criteria for patient selection will continue to refine the indications for this procedure.”

Meta-analysis

Wan B, Rahnavardi M, Tain D, et al. A meta-analysis of MitraClip system versus surgery for treatment of severe mitral regurgitation. Annals of Cardiothoracic Surgery 2013;2(6):683-692.

The purpose of this meta-analysis was to compare the safety, clinical efficacy, and survival outcomes of MitraClip® with surgical correction of severe MR in DMR and/or FMR. Six databases were searched for studies from January 2000 to August 2013. Selection criteria included surgical candidates as well as high-risk surgical patients with significant DMR and/or FMR who had the MitraClip® procedure. Experimental or observational studies were included. Case reports, series with less than ten patients, abstracts, editorials, and expert opinions were excluded. For repeated publications of the same trial, only the most complete reports were included. Preoperative study variables included LVEF, EuroSCORE, and age. Postoperative study variables included early MR ≤ 2+ and acute procedural success.

After applying the criteria and removing serial publications, there was one RCT and three prospective observational studies. At baseline, patients in the MitraClip® group were significantly older, had significantly lower LVEF and significantly higher EuroSCORE. All studies were from specialized tertiary referral centers. One study had a cohort of patients with FMR, while the remaining studies consisted of patients with FMR and DMR. One study treated 178 MitraClip® patients and 80 surgical patients, but the other three studies had fewer than 100 patients in each treatment group (range 24 - 95 MitraClip®; range 26 - 91 surgical). Two studies had a follow-up of 12 months, one study had a median follow-up of 6 months, and one study had a follow-up of 8.5 months in the MitraClip® group and 18 months in the surgical group.

The number of patients with MR > 2 after the procedure was significantly higher in the MitraClip® group compared to the surgical group (17.2% vs. 0.4%). Mortality difference at both 30 days and 12 months was not statistically significant, nor was neurological events, reoperations for failed MV procedures, and NYHA Class III/IV. Publication bias was not assessed.

The authors noted a number of limitations including the inability for subgroup meta-analysis based on MV etiology (i.e., FMR or DMR). The authors stated that the "COAPT and RESHAPE-HF trials are randomized studies comparing MitraClip versus optimal medical therapy alone in high-surgical risk patients with clinically significant FMR. The results of these trials will provide more insight into the value of MitraClip in treating FMR." Other limitations noted by the authors included limited information comparing surgery to MitraClip® as a function of age, a lack of consistent reporting between trials, and the inclusion of only one RCT. The authors stated, “[i]n view of our findings, we conclude the non-inferiority of the MitraClip as a treatment for severe, symptomatic MR, in comparison to conventional valvular surgery. Despite a higher risk profile in the MitraClip patients, the clinical outcomes were comparable although surgery was more effective in reducing MR in the early post procedure period. In light of the apparent clinical benefits of the MitraClip in a real world patient population with significant comorbidities and high surgical risk, as well as the need for a safer solution in such patient populations, this meta-analysis supports the indication for MitraClip therapy in high risk patients. Further randomized controlled trials with more consistent reporting of outcomes and longer follow-up periods will better evaluate the clinical benefits of the MitraClip system.”

EVEREST II Studies

EVEREST II RCT

Mauri L, Foster E, Glower D, et al. 4-Year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation. Journal of the American College of Cardiology 2013; 62: 317-328.

The authors reported the 4-year outcomes of the industry funded EVEREST II PMA trial, a multicenter, nonblinded, randomized controlled trial comparing MitraClip® therapy to surgery for 3+ or 4+ MR of either functional or degenerative etiology.

Patients were originally recruited at 37 centers in North America that were required to have experience with percutaneous interventions, transseptal punctures, and mitral-valve surgery, along with a “strong multidisciplinary clinical team.” (Feldman 2011) The multidisciplinary team included specialists in interventional cardiology, cardiac surgery and echocardiography. (Mauri 2010) Eligibility criteria included grade 3+ or 4+ chronic MR, symptomatic with a LVEF > 25% and a left ventricular end-systolic diameter of 55 mm or less; or if asymptomatic, had at least 1 of the following: an LVEF of 25% to 60%, a left ventricular end-systolic diameter of 40 mm to 55 mm, new atrial fibrillation, or pulmonary hypertension. All eligible patients were candidates for mitral-valve repair or replacement surgery and cardiopulmonary bypass. Exclusion criteria included a baseline mitral valve area < 4.0 cm², presence of severe leaflet or annular calcification, flail width ≥ 15 mm, flail gap ≥ 10 mm, and in patients with FMR, a coaptation depth > 11 mm below the annulus or a coaptation length < 2 mm. Echocardiographic measurements were done at a core laboratory.

Originally, 279 patients underwent randomization, with 184 patient in the MitraClip® group and 95 patients in the surgery group. The groups were balanced with the exception of a greater percentage of history of heart failure in the MitraClip® group. Randomized patients who did not receive treatment and did not have subsequent MR assessment were considered for imputation purposes to maintain the same grade of MR as baseline for the analysis. Patients in the MitraClip® group received either one (50.6%) or two (38.2%) clips. Within the first 12 months, 9 patients had partial clip attachment. After 12 months, one additional patient was identified.

The 1-year outcome of the trial showed superior safety for the MitraClip® group but less reduction in MR, with planned 5-year follow-up. In the 4-year follow-up, 161 (88%) of patients were included in the MitraClip® group and 73 (77%) were included in the surgical group. The index surgeries of the surgical cohort included replacement (14%) and repair (86%). Repair procedures included leaflet resection and annuloplasty, annuloplasty alone, and complete leaflet or chordal repair with annuloplasty. Excluded patients were missing due to either being withdrawn, lost to follow-up or had missing MR grade. There were no embolizations of any devices. The patients with partial clip attachment all had surgery. There was one case of mitral stenosis in the MitraClip® group.

Table 1: Results of effectiveness analysis

By echocardiography, both groups had improvements in left ventricular end-diastolic volume, left ventricular internal diameter (diastolic). Both groups showed an improvement in NYHA functional class from baseline to 12 months, which was sustained at 4 years. Without imputed values, the surgical arm had a lower rate of 3+ or 4+ MR.

The authors noted a number of limitations with the study including “the findings in the subgroup with functional MR, even with a positive test for interaction, should be viewed as exploratory. Given the overall sample size, further categorizing subgroups according to components of the primary endpoint or secondary endpoints is limited by power and multiple testing.” In addition, the authors stated that “the sample size and relatively low mortality rate precludes sufficient power to fully understand the impact of the degree of reduction of mitral regurgitation on long-term survival in operative candidates.”

The authors concluded, “[a]t 4 years, surgery remains the standard of care for treatment of MR among eligible patients. Percutaneous repair is associated with similar mortality and symptomatic improvement but a higher rate of MR requiring repeat procedures, and less improvement in left ventricular dimensions than surgery.” They added, “further studies are necessary in patients with functional MR where percutaneous treatment was most comparable to surgery in terms of late efficacy.”

EVEREST II High Risk Registry (HRR)

Whitlow P, Feldman T, Pedersen W, et al. Acute and 12-month results with catheter-based mitral valve leaflet repair. The EVEREST II (endovascular valve edge-to-edge repair) high risk study. Journal of the American College of Cardiology 2012;59:130-139.

This prospective, multicenter, single-arm study (which, as an arm of the EVEREST II trial, used much of the same methodology as EVEREST II) enrolled symptomatic patients with severe (3+ or 4+) MR for whom surgical risk for perioperative mortality rate was estimated to be ≥ 12% using either the STS score or surgeon coinvestigator estimated mortality risk based on prespecified criteria. Potentially qualifying criteria included patients with porcelain aorta, mobile ascending aorta atheroma, post-mediastinal radiation, functional MR with LVEF < 40%, age older than 75 years with LVEF < 40%, previous median sternotomy with patent bypass graft, > 2 previous chest surgeries, hepatic cirrhosis, or ≥ 3 of the following STS high-risk criteria: creatinine level > 2.5 mg/dl, previous chest surgery, age older than 75 years, or LVEF <35%. Determined by transesophageal echocardiography and transthoracic echocardiography, the primary regurgitant jet had to meet certain criteria. Patients were excluded if they had evidence of an acute MI within 2 weeks, LVEF < 20% and/or a LV end-systolic dimension > 60 mm; an MV area < 4.0 cm²; leaflet anatomy that might preclude successful device implantation; a history of MV leaflet surgery; echocardiographic evidence of an intracardiac mass, thrombus, or vegetation, or active endocarditis. Echocardiographic data were graded by a core laboratory. A group of patients that was screened but not enrolled were identified retrospectively and were used as a comparison group for a survival analysis. Data were analyzed by intention to treat unless otherwise noted. Results were not reported separately by MR etiology (i.e., FMR or DMR) except where noted.

The MitraClip® group had 78 patients; the retrospective comparator group had 36 patients. Mean age in the MitraClip® group was 77 years, with 46 having FMR and 32 having DMR. Mean age in the comparator group was 77 years, with 23 having FMR and 13 having DMR. Six patients died within 30 days of the procedure; the central events committee adjudicated deaths as probably related to the procedure. Overall 30-day procedure-related mortality was 7.7% in the MitraClip® group and 8.3% in the comparator group (p = n. s.). The 12-month survival rate was 76% in the MitraClip® group and 55% in the comparator group (p = 0.047).

Limitations of the study, as noted by the authors, included “the comparator group was recruited retrospectively, the patient number is limited, transesophageal echocardiograms were not available for review in all patients, and several of the patients included did not have appropriate anatomic criteria for MitraClip placement.” In addition, the authors stated that “[a] second concern is that 12-month echocardiographic and functional data were obtained and reported for surviving patients only, and no imputation for deceased patients’ data was performed. Thus, the matched data reported may represent an overestimation of the true benefit provided by MitraClip placement.”

The authors concluded, “[t]he data from this HRS suggest a role for the MitraClip device in treating symptomatic patients with 3 to 4+ MR who are at high risk of mortality with MV surgery. MitraClip device placement in this selected high-risk group is feasible, effective in reducing symptoms and improving clinical status, and relatively safe in patients who otherwise have no safe option to reduce MR.”

EVEREST II HRR and REALISM Registry Subset of Prohibitive Risk DMR patients
(Basis for PMA)

Lim DS, Reynolds MR, Feldman T, et al. Improved functional status and quality of life in prohibitive surgical risk patients with degenerative mitral regurgitation following transcatheter mitral valve repair with the MitraClip® system. Journal of the American College of Cardiology 2013, doi:10.1016/j.jacc.2013.10.021.

The authors reported the results of an analysis of data from a retrospectively-identified prohibitive risk DMR cohort from the EVEREST II studies; these results served as the basis for the PMA approval. The EVEREST II studies included patients from the EVEREST I feasibility study, EVEREST II RCT, the EVEREST II single arm HRR, and the REALISM CAP registry that included high risk and non-high risk enrollment. From 2003-2012, 544 patients with ≥ 3+ DMR were prospectively enrolled in EVEREST I, EVEREST II RCT, EVEREST II HRR registry and the REALISM CAP registry. Of these 544 patients, 141 were chosen. The charts for these 141 patients were retrospectively reviewed by a multidisciplinary team that included two experienced mitral valve surgeons and one experienced mitral valve cardiologist for what the authors defined as “prohibitive risk.” The team also included echocardiographers to assess MR severity. From this group of 141 patients, 127 met the definition of prohibitive risk and had at least one year follow-up. Prohibitive risk in this study was defined as one or more of the following factors: STS score 30-day mortality ≥ 8%; porcelain aorta; frailty; hostile chest; liver disease with MELD score > 12; severe pulmonary hypertension; and a variety of other factors which the authors refer to as extenuating circumstances.

This cohort included 25 patients from EVEREST II HRR, 98 from the REALISM CAP registry and 4 other patients. This cohort of patients had a mean age of 82 years, 87% NYHA functional class III/IV, with STS score of 13.2 ± 7.3%. Comorbidities included congestive heart failure (125/127), coronary artery disease (95/125), cerebrovascular disease history (24/127), chronic obstructive pulmonary disease (40/127), and diabetes (38/127). Adverse events were adjudicated by an independent Clinical Events Committee.

In patients who received the device, either one (44.1%) or two (51.2%) clips were implanted. Six patients did not receive a device, with 4 of these failures due to technical reasons and the remaining two having complications during the procedure that included tamponade and hemodynamic instability. Despite being determined to be at prohibitive risk for surgery 3 patients did have open surgery, with 2 of the 3 alive at one year. Adverse events at one year included 30 deaths (23.6%) as well as stroke (2.4%), renal failure (3.9%), bleeding complication (15.7%), vascular complication (7.1%), and GI complication requiring surgery (2.4%). Most surviving patients (82.9%) at one year had MR ≤ 2+ and were in NYHA functional class I or II. One year survival appeared to be better for patients who had 1+ or 2+ MR at discharge versus those who had 3+ or 4+. SF-36 scores improved and the authors reported that hospitalizations were reduced “in patients whose MR was reduced.”

The authors stated that the data were “limited in that it was not completely from a randomized trial, due to not having a control arm to randomize to (as medical therapy lacks a treatment role in degenerative MR, and surgical options are not standard in prohibitive surgical risk patients). Because the cohort was retrospectively identified, all analyses were post-hoc. Another limitation is that follow-up echocardiographic and functional data were obtained and reported for surviving patients only.”

The authors concluded, “MitraClip therapy is safe in patients with severe degenerative (primary) MR for whom a heart team has determined that mitral valve surgery is associated with a prohibitive risk/benefit ratio. Transcatheter reduction of degenerative MR in these patients provides significant benefits including improvements in symptoms and functional status, a decrease in hospitalizations, and favorable LV remodeling at 1 year.”

Armoiry X, Brochet E, Lefevre T, et al. Initial French experience of percutaneous mitral valve repair with the MitraClip: a multicenter national registry. Archives of Cardiovascular Disease 2013: 106; 287-294.

The purpose of this study was to report MitraClip® therapy results from a French national registry. Eligible patients were judged to be high surgical risk or inoperable and included all patients who underwent MitraClip® therapy between December 2010 and September 2012. Patients were judged to be eligible by a heart team that included an interventional cardiologist, a cardiac surgeon, an echocardiographer and an anesthesiologist. Echocardiographic exams were not centralized. Sixty-two patients (mean age of 72.7 years, 81% NYHA class III or IV, EuroSCORE mean of 18.7, 93.3% ≥ 3+ MR, 73.8% FMR) underwent the procedure. Procedural success was 95.2%.

The in-hospital mortality included two patients. Two surgical MV repairs were required. Other non-fatal adverse events occurred in seven patients and included tamponade (one patient), deep venous thrombosis (one patient), bleeding at puncture site (one patient), new-onset atrial fibrillation (one patient), and false venous aneurysm (one patient). Blood transfusion was necessary in five patients. The survival rate at six months was estimated at 83.1%, with 90.9% of patients in NYHA class I or II and MR ≤ grade 2 in 80% of patients.

The authors stated that the primary limitation of their study was “the significant amount of missing data corresponding to variables not reported from each centre.” In addition, the authors noted that “[m]id-term follow-up data (at 6 months) on efficacy and tolerance were only available for a limited number of patients.”

The authors concluded, “[t]his initial French experience, despite being in its learning phase, showed promising results in patients considered ineligible for surgery, as observed in more experienced centres. Randomized studies are mandatory to confirm these preliminary data.”

Schillinger W, Hünlich M, Baldus S, et al. Acute outcomes after MitraClip® therapy in highly aged patients: results from the German Transcatheter Mitral valve Interventions (TRAMI) Registry. EuroIntervention 2013:9;84-90.

The purpose of this analysis was to examine how age influences the MitraClip® therapy outcomes. Data came from the German TRAMI registry and included all 1,064 patients. Results were stratified by age, < 76 years (a.k.a., younger cohort; 539 patients) and ≥ 76 years (a.k.a., elder cohort; 525 patients); the age of 76 years was selected based on the median age in the cohort. In comparing baseline demographics, the elder cohort had a higher EuroSCORE (mean of 25% versus 18%), a greater proportion of women (47.2% versus 29.3%), higher LVEF > 50% (40.1% versus 21.8%) and was more likely to have DMR rather than FMR (35.3% versus 25.6%).

For determining surgical risk, age was the most frequent reported reason for the transcatheter therapy. The in-hospital adverse events composite outcome (death, MI, stoke) was low in both groups (3.5% in the elder cohort versus 3.4% in the younger cohort; p = 0.93). The estimate of 30-day mortality was 6.7% for the elder cohort versus 4.7% for the younger cohort (p = 0.29). The authors stated, “The majority of patients had a substantial clinical benefit concerning the relief of heart failure symptoms, with 69.5% and 61.4% (n.s.) linked to NYHA functional classes of heart failure.” The majority of patients (81.2% versus 86.2%) were discharged home.

The authors noted that the main limitation of the study was that “all data were site reported and echo data were not core lab adjudicated.” The authors noted additional limitations including voluntary enrollment that was not reported as consecutive, the lack of predefined enrollment criteria, limited follow-up and inconsistent follow-up time from post-discharge.

The authors concluded, “[e]lderly and younger patients have similar benefits from MitraClip therapy.”

Maisano F, Franzen O, Baldus S, et al. 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. Journal of the American College of Cardiology 2013;62:1052-1061.

Reichenspurner H, Schillinger W, Baldus S, et al. Clinical outcomes through 12 months in patients with degenerative mitral regurgitation treated with the MitraClip® device in the ACCESS-Europe phase I trial. European Journal of Cardio-Thoracic Surgery 2013 Oct; 44 (4):e280-8.

In these articles the authors reported outcomes of the ACCESS-Europe A Two-Phase Observational Study of the MitraClip System in Europe (ACCESS-EU) registry, which is for patients with significant MR who underwent MitraClip therapy at 14 European sites. Maisano et al. reported the results of an analysis conducted on the whole group of patients with MR (n = 567) while Reichenspurner et al. reported on the results of an analysis of a subset of this group (117 patients with MR of degenerative etiology).

For the entire group, Maisano et al. noted the mean EuroScore was 23.0 ± 18.3 at baseline, with 84.9% of patients classified as NYHA functional class III or IV, and 52.7% of patients had an ejection fraction ≤ 40%. Eligible patients included those with symptomatic MR or asymptomatic 3+ or 4+ MR. Baseline characteristics are in Appendix B, Table 3.

Device implant rate was 99.6%, with two patients not successfully implanted. Patients received one clip (60.1%), two clips (36.7%), or three (<3%). Single leaflet attachment was reported in 27 patients, with 10 undergoing a second MitraClip® procedure, and six having surgery. Thirty-six subjects (6.3%) underwent a mitral valve surgery within 12 months after the MitraClip® implant procedure.

For the entire group, Maisano et al. noted that the NYHA functional class improved, with 71.4% (245/ 343) of patients having NYHA class I or II at 12 months, and 78.9% (258/327) of patients with MR severity ≤2+ at 12 months. The 6MWT improved from 274.7 ± 118.7 at baseline to 334.2 ±127.9 at 12 months in 216 patients. The Minnesota Living with Heart Failure questionnaire score improved from baseline (41.6 ± 18.9) to 12 months (28.1 ± 20.1) in 264 patients.

Results from the subset analysis performed by Reichenspurner et al. were similar to the results reported by Maisano et al. Successful device implant rate was 94.9%. The mortality rate was 6.0% at 30 days and 17.1% at 12 months. In addition, “[a]t 12 months, 74.6% (53 of 71) of patients in follow-up achieved MR ≤ grade 2+ and 80.8% (63 of 78) were in NYHA functional class I/II. Both MLHFQ scores and 6MWT distance improved significantly at 12 months compared with baseline (P = 0.03 and P < 0.0001, respectively).”

Maisano et al. noted some limitations including “the lack of a core-laboratory adjudication of echocardiographic parameters,” as well as the lack of pre-defined enrollment criteria, and the lack of pre-specified medical therapy strategy (therefore changes in medical therapy could affect outcomes).

Reichenspurner et al. noted limitations as well including the lack of randomization. In addition, “[o]utcomes of surgical and medical treatment comparator groups have not been reported to date. The process of patient selection as well as determination of the aetiology of MR were not guided by a detailed study protocol with inclusion/exclusion criteria but was rather conducted following standard local clinical practice. Thus, the eligibility of patients for MitraClip therapy may have been judged differently among participating sites. Furthermore, there were no clinical events committee definitions for important parameters such as clinical end-points (e.g. procedural success) or major adverse events.”

Maisano et al. concluded, “In the real-world, post-approval experience in Europe, patients undergoing the MitraClip therapy are high-risk, elderly patients, mainly affected by functional MR. In this patient population, the MitraClip procedure is effective with low rates of hospital mortality and adverse events.”

Reichenspurner et al. concluded, “The MitraClip procedure resulted in significant reductions in MR and improvements in clinical outcomes at 12 months in selected patients with severe DMR. MitraClip therapy may serve as a complementary non-surgical therapeutic option for DMR patients who are considered at high risk or ineligible for surgery by an inter-disciplinary dedicated heart team.”

FDA Regulatory History and Review for MitraClip®

The following excerpts from FDA materials are included to provide background on the complex nature of the evidence base for MitraClip®.

FDA Circulatory System Devices Panel Meeting

The FDA Executive Summary for the March 20, 2013 meeting of the FDA's Circulatory System Devices Panel contained an extensive discussion of the regulatory history for MitraClip®, including the clinical study designs and results as well as a summary of key findings following FDA review, and FDA's recommendations and a presentation of the requirements for a post-approval study.

As stated in the FDA Executive Summary, “FDA conditionally approved the EVEREST II pivotal clinical trial on November 3, 2004. The EVEREST II RCT was designed as a prospective, randomized, active controlled, multicenter clinical trial to evaluate the safety and effectiveness of the MitraClip in the treatment of moderate-to-severe (3+) or severe (4+) chronic mitral regurgitation (MR). The RCT was designed to demonstrate superiority of the device to mitral valve surgery for the primary safety endpoint and to demonstrate that the device would be no worse than mitral valve surgery for the primary effectiveness endpoint. Beginning prior to initial study approval, FDA repeatedly expressed many concerns with the trial design, including, but not limited to the use of MR ≤ 2+ as the criterion for success in the primary effectiveness endpoint, a large margin of reduced effectiveness for the primary endpoint hypothesis, the heterogeneity of MR etiology, and the relative inexperience with mitral valve repair of a substantial proportion of the surgeons operating on the control group. A single arm registry was conditionally approved for “high risk” non-operative patients (High Risk Registry or HRR) on November 16, 2006. FDA repeatedly expressed the concern that this registry study, without a rigorous pivotal trial with positive results, could not by itself support PMA approval of the MitraClip CDS due to a number of study limitations (described in more detail below).

The REALISM continued access protocol (CAP) was approved with conditions in November 2008. This trial allows enrollment for patients based on the same inclusion and exclusion criteria as those in EVEREST II. 545 patients have been treated and completed 1 year of follow-up as part of the REALISM study reported in the PMA. This continued access protocol includes an extension of the High Risk Registry – REALISM High Risk. In February 2012, FDA conditionally approved the COAPT clinical trial which is a prospective, randomized, active controlled, multi-center clinical trial to evaluate the safety and effectiveness of the MitraClip device in the treatment of symptomatic (NYHA Functional Class II, III or ambulatory IV) functional mitral regurgitation (≥ 3+) in patients that have comorbidities that preclude surgery (i.e., the probability of death or serious morbidity exceeds the probability of meaningful improvement). For more information on the COAPT study, please visit: http://www.clinicaltrials.gov/ct2/show/NCT01626079?term=mitraclip&rank=3.” Of note, this trial is ongoing.

The proposed indication for use at the time of the panel meeting was “for the percutaneous reduction of significant symptomatic mitral regurgitation (MR ≥3+) in patients who have been determined by a cardiac surgeon to be too high risk for open mitral valve surgery and in whom existing co morbidities would not preclude the expected benefit from correction of the mitral regurgitation.” (FDA Executive Summary)

In its review, the FDA considered a number of studies (EVEREST II RCT; EVEREST II HHRR; REALISM CAP; ACCESS-EU) as well as some post-hoc additional data analyses of the Integrated High Surgical Risk Cohort, which included data pooled from EVEREST II HRR and REALISM High Risk CAP. The FDA also reviewed the results of additional post-hoc analyses conducted by the sponsor (Duke Database Propensity Score Matching Analysis; Ohio State Database Comparison). As presented in the section titled “FDA’s Summary of Key Findings” of the FDA Executive Summary:

“FDA’s review of the data included in this PMA has raised a number of important concerns, which can be summarized as follows:

• The EVEREST II RCT did not demonstrate an appropriate benefit-risk profile when compared to standard mitral valve surgery in a selected mitral valve patient population.
• For a variety of reasons, the EVEREST II HRR single arm registry data are not easily interpretable.
• REALISM HR is a continued access protocol cohort that was not intended to be used as a pivotal data set and is difficult to interpret.
• The Integrated High Surgical Risk Cohort, developed by pooling two registry data sets in a post-hoc manner, has major design limitations.
• The Duke Propensity Score Analysis was a retrospective, subset analysis with results that are difficult to interpret and where the matched cohorts do not represent any well-defined population.”

Based on the findings of its review, the FDA made the following recommendation to the panel

“The FDA believes that the analyses provided in the PMA are interesting and important. However, for the reasons discussed above, FDA believes these analyses are hypothesis generating and do not constitute valid scientific evidence of safety and effectiveness for the MitraClip CDS for the proposed Indication for use in an inoperable MR population.

Because there are limited options for high risk inoperable and high risk mitral valve patients, the FDA has recently worked with the sponsor in a highly interactive manner to develop a new U.S. randomized controlled trial for this patient population called the COAPT Trial. In addition, the sponsor has also recently developed a European randomized trial for this patient population.

FDA firmly believes that the currently enrolling COAPT and European trials are well-designed trials that will help to answer the many important questions posed by the very limited data analyses presented in this PMA and the mitral regurgitation literature. Therefore, FDA recommends that the MitraClip CDS continue to remain available to this vulnerable patient population as an investigational device so that Abbott Vascular can conduct the COAPT and European trials in an optimal manner. PMA approval is not appropriate at this time as major questions of safety and effectiveness, as well as the overall benefit-risk profile for this device, remain unanswered per the regulatory standards set forth in 21 CFR 860.7 (c)2, (d)1 and (e)1. Specifically, FDA cannot determine that in a significant portion of the target inoperable population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results without a valid comparator group, to support an indication for use for inoperable patients based on patients who were not necessarily inoperable.” (FDA Executive Summary)

Post FDA Panel Review and Actions

The FDA approved the PMA on October 24, 2013 for the indication stated in the FDA Status section of this PDM.

FDA indicated in the SSED for MitraClip®:

“Following the FDA Advisory Panel meeting, the Sponsor and FDA worked interactively and determined that patients with primary MR etiology (DMR) at prohibitive risk for surgery (PR DMR) were the appropriate patient population to evaluate the risks and benefits of the MitraClip device. While all patients with significant symptomatic MR who are not surgical candidates have an unmet clinical need, the value of intervention to reduce MR is clearest for patients with DMR etiology. It is broadly accepted that DMR is a mechanical problem in which there is a primary abnormality of the mitral apparatus and the ‘leaflets are broken.’ There is no medical therapy for reduction of DMR, which must be treated with mechanical correction of the mitral valve. For secondary or functional MR (FMR), the relative benefits of MR reduction versus optimal medical therapy are less clear because MR is secondary to left ventricular dysfunction, which can and does improve with medical therapy, revascularization, and/or cardiac resynchronization therapy in some patients. Thus, the clinical benefit of MitraClip in FMR could not be discerned with the existing single arm study results. For DMR patients considered surgical candidates, surgery remains the standard of care treatment option and the ACC/AHA Guidelines define surgery for these patients as Class I and IIa indications. The patients indicated for the MitraClip device are DMR patients at prohibitive risk for surgery and therefore have no other effective treatment options.”

4. Medicare Evidence Development and Coverage Advisory Committee (MEDCAC) Meeting.

CMS did not hold a MEDCAC meeting on this topic.

5. Evidence-based clinical guidelines

Two evidence-based clinical guidelines for MitraClip® were found and are summarized below.

American Heart Association (AHA)/American College of Cardiology (ACC)

In 2014, Nishimura et al. released a U.S. evidence-based guideline for the management of patients with valvular heart disease that for the first-time addressed the percutaneous treatment of the mitral valve:

“An RCT of percutaneous mitral valve repair using the MitraClip device versus surgical mitral repair was conducted in the United States. The clip was found to be safe but less effective than surgical repair because residual MR was more prevalent in the percutaneous group. However, the clip did reduce severity of MR, improved symptoms, and led to reverse LV remodeling. Percutaneous mitral valve repair should only be considered for patients with chronic primary MR who remain severely symptomatic with NYHA class III to IV HF symptoms despite optimal GDMT for HF and who are considered inoperable.”

“Transcatheter mitral valve repair may be considered for severely symptomatic patients (NYHA class III to IV) with chronic severe primary MR (stage D) who have favorable anatomy for the repair procedure and a reasonable life expectancy but who have a prohibitive surgical risk because of severe comorbidities and remain severely symptomatic despite optimal GDMT for HF.” AHA/ACC designated this recommendation as Class IIb, Level of Evidence: B, where Class IIB is defined as “Benefit ≥ risk; Additional studies with broad objectives needed; additional registry data would be helpful; Procedure/Treatment MAY BE CONSIDERED” and Level B Evidence is defined as “Limited populations evaluated; Data derived from a single randomized trial or nonrandomized studies.”

European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS)

In 2012, Vahanian et al. published a European evidence-based guideline for the management of valvular heart disease that addressed percutaneous-based treatment of the mitral valve:

“Catheter-based interventions have been developed to correct MR percutaneously. The only one which has been evaluated in organic MR is the edge-to-edge procedure. Data from the EVEREST (Endovascular Valve Edge-to-Edge REpair STudy) trials’ 136 patients and the results of registries in Europe and the USA suggest that the MitraClip procedure has a procedural success rate (i.e. postprocedural MR ≤ 2+) of around 75%, is relatively safe and generally well-tolerated, even by patients in poor clinical condition. One-year freedom from death, mitral valve surgery or more than moderate MR is 55%. The procedure reduces MR less effectively than mitral valve surgery. The follow-up remains limited to a maximum of 2 years and recurrence—or worsening of MR—is more likely to occur during follow-up since 20% of patients required reintervention within 1 year in EVEREST II. The applicability of the procedure is limited because precise echocardiographic criteria have to be respected to make a patient eligible. Mitral valve repair has been reported after an unsuccessful clip procedure, although valve replacement may be necessary in up to 50% of such patients.”

“Percutaneous edge-to-edge procedure may be considered in patients with symptomatic severe primary MR who fulfill the echo criteria of eligibility, are judged inoperable or at high surgical risk by a ‘heart team’, and have a life expectancy greater than 1 year (recommendation: Class IIb, Level of evidence C).” Class IIb is defined by ESC/EACTS as “Usefulness/efficacy is less well established by evidence/opinion.” Level of evidence C is defined as “Consensus of opinion of the experts and/or small studies, retrospective studies, registries.”

6. Professional Society Position Statements

Four professional societies, The Society of Thoracic Surgeons (STS), the American College of Cardiology Foundation (ACCF), the Society for Cardiovascular Angiography and Interventions (SCAI), and the American Association for Thoracic Surgery (AATS), issued a joint position statement (O'Gara 2014) that stated:

“Transcatheter therapies hold promise for the management of carefully selected patients with severe MR using less invasive means whereby the experience of care may be improved. Although registry experience in the United States and Europe has been encouraging, only a single randomized trial using a specific device in patients with MR has been reported with recent FDA approval for use of this device in eligible U.S. patients with degenerative MR. Further research involving a wider spectrum of patients and devices is strongly encouraged. It is recognized that the intricate structure and complex function of the mitral apparatus pose challenging technical hurdles. It is imperative that professional societies, industry, payers, and regulatory agencies work collaboratively to promote needed research and ensure that the technology is disseminated rationally and responsibly in the best interests of patients. The following recommendations for a path forward closely mirror those enunciated in a previous ACCF/STS Societal Overview.

The leadership of our organizations proposes:

1. Continued development of regional heart valve referral centers of excellence. Criteria for the performance of transcatheter therapy for MR in such centers should be established and refined. Availability of new devices and reimbursement for their application should be limited to those centers that meet national criteria.

2. A heart valve referral center of excellence is defined in part by the competence and experience of the individual members of a dedicated, multidisciplinary heart team, each of whom has a clearly defined role and works collaboratively in the best interest of patients. Input is required from general cardiologists, heart valve and heart failure experts, advanced imagers, interventionalists, cardiac surgeons, and allied members of the heart team (e.g., anesthesia, geriatrics, neurology, nephrology, nursing, care coordination, pharmacy, physical therapy, and social work). All aspects of patient evaluation and care must be addressed, including late follow-up. Lack of dedicated care pathways should disqualify a center from participation.

3. All centers are required to participate in an ongoing TVT registry to benchmark quality and enable outcomes and cost analysis, as well as comparative effectiveness research. Data quality, as well as productivity in publication of research projects from the registry, should be monitored.

4. Operator training and credentialing criteria for mitral valve procedures must be established and are the subject of a joint professional competency document in development.

5. Guidelines for transcatheter mitral valve interventions should be substantiated and developed. Performance measures and appropriate use criteria would follow. Presently, the MitraClip is approved only for prohibitive surgical risk patients with degenerative MR who meet anatomic eligibility criteria. The COAPT trial (NCT01626079) will address the role of the MitraClip device in high surgical risk patients with functional MR. The ACCF, AATS, SCAI, and STS are committed to the principle of working collaboratively together as professional societies and in partnership with the FDA, CMS, and industry partners to bring promising, innovative mitral valve technologies into clinical practice as validated by the evidence and in the best interests of patients.”

7. Public Comments

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.

Initial Public Comments

During the initial comment period (November 18, 2013-December 18, 2013), CMS received seven comments. CMS received comments from a physician professional society, a trade association; two individuals who did not identify an associated organization or profession; two from physicians affiliated with academic institutions; and one from a device manufacturer.

Almost all of the comments were generally supportive of coverage with several commenters advocating for coverage for TMV procedures with restrictions. We were not able to determine if two comments supported or opposed coverage.

The comments can be viewed in their entirety on our website at http://www.cms.gov/medicare-coverage-database/details/nca-view-public-comments.aspx?NCAId=273

VIII. CMS Analysis

National coverage determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally under title XVIII of the Social Security Act. §1869(f)(1)(B). 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, section 1862(a)(1) of the Act in part states, with limited exceptions, no payment may be made under Part A or Part B for any expenses incurred for items or services:

• Which, are not 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)) or


• in the case of research conducted pursuant to section 1142, which is not reasonable and necessary to carry out the purposes of that section. ((§1862(a)(1)(E)).

Section 1142 of the Act describes the authority of the AHRQ. Under section 1142, research may be conducted and supported on the outcomes, effectiveness, and appropriateness of health care services and procedures to identify the manner in which diseases, disorders, and other health conditions can be prevented, diagnosed, treated, and managed clinically.

Section 1862(a)(1)(E) of the Act allows Medicare to cover under coverage with evidence development (CED) certain items or services for which the evidence is not adequate to support coverage under section 1862(a)(1)(A) and where additional data gathered in the context of a clinical setting would further clarify the impact of these items and services on the health of Medicare beneficiaries. For your convenience, the 2006 CED guidance document is available at [http://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads//ced.pdf].

Our review sought answers to the questions below. We have repeated them here for the convenience of the reader.

1. Is the evidence adequate to conclude that transcatheter mitral valve repair improves health outcomes for Medicare beneficiaries with significant symptomatic degenerative mitral regurgitation who are at prohibitive risk for surgical mitral valve repair or replacement?


2. Is the evidence adequate to conclude that transcatheter mitral valve repair improves health outcomes for Medicare beneficiaries with significant symptomatic mitral regurgitation who are candidates for surgical mitral valve repair or replacement?

As stated earlier, transcatheter therapies are in development in an attempt to reduce adverse events and recovery time related to open surgical procedures. MitraClip® is the first-of-a-kind FDA-approved transcatheter therapy for the repair of the mitral valve to treat mitral regurgitation. Other devices with various designs are in development; there is also consideration of a combination of percutaneous procedures.

MitraClip® received the CE Mark in 2008. Registries were initiated to study the use in patients treated in Europe and early to midterm data are available. Overall, CMS found the evidence from the European registry data to show similar and promising results across a number of analyses thus far. In Armoiry et al. as well as in Maisano et al. the procedural success rate was 95 - 99% and about 80% of patients were reported to have ≤ 2+ MR six to 12 months after the procedure. Reichenspurner et al. reported a 30-day mortality rate of six percent, while Schillinger et al. found the 30-day mortality rate to range from 4.7% in patients less than 76 years old and 6.7% in patients 76 years old or more. Reichenspurner et al. also reported a similar and low rate (about 3%) of in-hospital adverse events in both age groups. All of these analyses, are limited by the observational nature of the data, the lack of stratification for etiology of MR (i.e., functional or degenerative; except for Reichenspurner et al., which analyzed data only from patients with DMR) and short-term (i.e., less than one year) duration of follow-up after the procedure.

During pre-market development in the U.S., the targeted patient indication for the MitraClip device had to be narrowed over time due to risk-benefit considerations. The EVEREST II study (Mauri 2013) was a randomized, blinded, controlled, multi-center study initiated as a pivotal study to compare MitraClip® to the standard of care mitral valve repair or replacement surgery in patients with moderate to severe (3+) or severe (4+) MR of either degenerative or functional etiology who were considered able to undergo surgery. A multidisciplinary team of specialists including interventional cardiologist and cardiac surgeons managed the assessment and treatment of the patients. During the course of this RCT, a number of evaluated patients could not be randomized as the patients were deemed to be at too high a risk for surgery (PMA P100009: FDA SSED). While Mauri et al. found a similar rate of 3+ or 4+ MR at follow-up between the MitraClip group and the surgical group (21% v. 20.2%, respectively; not statistically significantly different), there were highly statistically-significant differences in the rate of MV surgery or reoperation in favor of the surgical group (20.4% in the MitraClip® group v. 2.2% in the surgical group). The composite endpoint of freedom from death, MV surgery or reoperation, and 3+ or 4+ MR was also highly statistically-significantly different (55.2% for the MitraClip® group v. 73% for the surgical group). Mauri et al. acknowledged the sample size limitations of the study but concluded that “percutaneous repair is associated with similar mortality and symptomatic improvement but a higher rate of MR requiring repeat procedures.” The FDA concluded that the “EVEREST II RCT did not demonstrate an appropriate benefit-risk profile when compared to standard mitral valve surgery in a selected mitral valve patient population.” (FDA Executive Summary)

Patients too sick to enroll in EVEREST II were subsequently enrolled in the EVEREST II High Risk Registry (HRR). As reported by Whitlow et al., EVEREST II HRR was a single-arm study to evaluate the device in patients who were considered too high risk for surgery. A multidisciplinary team of specialists including interventional cardiologist and cardiac surgeons managed the assessment and treatment of the patients. The mean age in the study was 77 years; patients had MR of either degenerative or functional etiology. The study was limited by a small sample size and a retrospectively-identified comparator group. Thirty-day mortality was 7.7% in the MitraClip® group and 8.3% in the comparator group (difference not statistically significant). Surgical procedures were found to be superior for MR reduction in comparison to MitraClip®. More adverse events occurred in the surgery cohort, but after the exclusion of blood transfusions (concomitant surgery occurred in 47.5% of the surgical cohort) there was no difference between groups. The authors concluded that the results of their study “suggest a role for the MitraClip device in treating symptomatic patients with 3 to 4+ MR who are at high risk of mortality with MV surgery. MitraClip device placement in this selected high-risk group is feasible, effective in reducing symptoms and improving clinical status, and relatively safe in patients who otherwise have no safe option to reduce MR.” The FDA found the data from this study to be “not easily interpretable.” (FDA Executive Summary)

A PMA based on the above results from EVEREST II was filed in March 2010 for an indication that included surgical candidates and patients too high risk for surgery with either DMR or FMR. The FDA determined that the data were inadequate to support approval in a surgical candidate population. (FDA Executive Summary)

After the RCT and HRR were fully enrolled, a continued access study (CAP) of the device began enrollment for RCT eligible patients as well as HRR eligible patients (REALISM HR). Lim et al. reported the results of this study that focused on a small and retrospectively-identified cohort of patients with only DMR who were judged to be a high surgical risk (now referred to as "prohibitive risk"). A multidisciplinary team of specialists including interventional cardiologist and cardiac surgeons managed the assessment and treatment of the patients. This analysis also ultimately served as the basis for the FDA-approved indication. The mean age of these patients was 82 years and there was a high rate of adverse events at one year after the procedure including deaths (23.6%) and stroke (2.4%) however 82.9% of those who survived to one year had MR ≤ 2+. A significant limitation to this analysis was the post-hoc design.

CMS found a recent systematic review by Munkholm-Larsen et al. that focused only on studies of MitraClip® in high surgical risk patients with severe FMR and DMR. High surgical risk was defined as an STS score or EuroSCORE ≥ 12% as assessed by a multidisciplinary team. Results were not reported by MR etiology. Follow-up duration was only 12 months. The mean age was 70 years. Twelve studies were included in the review however most were observational in nature and none were RCTs. Post-procedure MR was ≤ 2+ in 73 - 100% of patients. The 30-day mortality rate ranged from zero to 7.8% and the stroke rate ranged from zero to six percent. The 12-month mortality ranged from 10 - 25%. The authors stated that “MitraClip can be implanted with reproducible safety and feasibility profile in this subgroup of patients” but that “[t]he voluminous research of short term outcomes of MitraClip implants underlines the infancy of this device, and draws attention to the limited understanding of long term outcomes. It is not known whether subsequent MR surgery after device implantation, which occurs in up to 22% of patients, affects outcomes or survival. Durability of the device is also not known beyond 3 years. Furthermore, the majority of existing trials, in particular the EVEREST series, are performed in high volume tertiary care centres, therefore limiting the universal generalisability of results. Higher powered studies are required to investigate differences in outcomes stratified by aetiology (functional versus degenerative).”

Wan et al. performed a meta-analysis of studies comparing MitraClip® to surgery in patients with severe MR from either degenerative or functional etiology. Only four studies were included and only one of these studies was an RCT. Results were not reported by type of MR. The maximum duration of follow-up was only 12 months. The median age for the MitraClip® group was 67 years or older and for the surgical groups was 63 years and older. The authors found that the number of patients with MR > 2 after the procedure was significantly higher in the MitraClip® group compared to the surgical group (17.2% v. 0.4%) however the mortality difference was not statistically-significantly different between the groups at 30 days or 12 months.

CMS acknowledges the evidence-based guideline by a number of professional organizations. The AHA/ACC recommended TMVR for severely symptomatic patients (despite optimal medical therapy) with DMR but who are a prohibitive surgical risk. We also note the categorization of this recommendation acknowledges that additional studies and registry data are needed. The ESC/EACTS recommended TMVR for patients with symptomatic severe degenerative MR who were deemed to be inoperable or at high risk by a heart team. CMS also noted that this recommendation was found to be based on “less well established” usefulness/efficacy evidence.

CMS acknowledges the regulatory path of the MitraClip® device. The original scope of the PMA was eventually narrowed to severe symptomatic FMR and DMR patients who were too high risk for surgery, based on STS predicted procedural mortality replacement score or judgment of a cardiothoracic surgeon. The data from the EVEREST II HRR and REALISM HR were presented to the FDA Circulatory System Devices Advisory Panel on March 2013. Limitations of this database included heterogeneity of MR etiology, questionable data pooling, post hoc control group, post hoc analysis, data accountability issues, and difficulty defining the surgical risk status of the patient population. The Advisory Panel concluded that while the device appeared safe for use in patients who are too high risk for surgery they were unable to conclude that there was reasonable assurance of effectiveness of the MitraClip® in this population. (PMA P100009: FDA SSED).

After the panel meeting, further FDA-sponsor deliberations concluded that, “While all patients with significant symptomatic MR who are not surgical candidates have an unmet clinical need, the value of intervention to reduce MR is clearest for patients with DMR etiology.”

Hence, the current FDA approval is for a limited population of patients that only includes patients with significant symptomatic MR of degenerative etiology who are not surgical candidates (i.e., prohibitive risk) and have an unmet clinical need. This prohibitive risk DMR cohort is elderly with a high burden of comorbidities and in spite of receiving treatment with MitraClip®, the death rate is 23.6% at one year. There were no reports of device embolization or single leaflet device attachment, which have been problems previously and in other studies. With some noted improvement in NYHA functional class and the components of the SF-36 in this hypothesized inoperable patient cohort, there appears to be a signal of clinical benefit. However, interpretation of this manipulated data is problematic for many reasons as previously mentioned but also there is no comparator. The comparator cohort mentioned in the FDA SSED suggests that there is no elevated risk of mortality in these patients who receive the MitraClip® device, however this inference is limited (PMA P100009: FDA SSED). The prohibitive risk MitraClip® data can be viewed as compelling only in circumstances where patient options are very limited and in whom existing comorbidities would not preclude the expected benefit.

The FDA Executive Summary notes this important observation: “The similarity of 1 year results in these three device treated cohorts (EVEREST RCT, Integrated High Surgical Risk Cohort and REALISM non-High Risk Cohort) despite marked differences in baseline demographics and procedural risks suggests that the observed longitudinal outcomes for the device treated cohorts may reflect the natural history of the disease in the absence of more complete initial relief of MR (i.e., surgical intervention), and that device therapy where the relief of MR is incomplete may be ineffective in altering its course.” The data and multiple analyses to date still have not proven that MitraClip® alters the course of the disease. Continuing data collection in this regard will be important.

The requesters for this NCD acknowledge the limitations of the evidence to date:

“We recommend that CMS cover TMVR using a system that has received FDA premarket approval (PMA) for the treatment of MR when performed according to an FDA-approved indication.” In addition, the requesters stated that “[a]doption of TMVR using the MitraClip system to populations beyond those described in the EVEREST II High Risk Registry and REALISM studies is not appropriate at the current time. However, in view of the promising results obtained in these limited population subsets, further randomized trials in other patient groups is strongly encouraged. Trials involving the other TMVR technologies are in development.”

The evidence is not adequate to confidently conclude that TMVR furnished according to the FDA approved indication improves health outcomes for the Medicare population. While the evidence shows a high procedural success rate with the use of the MitraClip® device as well as a reduction in MR and improvement in heart failure symptoms, there is also evidence of risk such as death and stroke. The long-term (i.e., past one year) durability of the device is still to be determined. However, overall, based on the evidence, FDA panel review and SSED, the Societies expert consensus document and the position statements of two professional organizations, TMVR shows promise and may improve health outcomes in very highly selected, well-informed, patients with significant, symptomatic DMR who are at prohibitive risk for surgery when furnished according to an FDA approved indication and when added safety and patient protections are in place as provided by expert multi-disciplinary heart teams in facilities that furnish an appropriate environment with data collection, as allowed through CED under §1862(a)(1)(E) of the Act. We believe a well-designed registry could carefully monitor a clinical study for this purpose.

We believe the available evidence is adequate to identify the characteristics of the patient, practitioner and facility that predict which beneficiaries are more likely to experience overall benefit or harm from TMVR.

Proposed Medicare Patient Population

Current evidence for TMVR for MR is limited to patients who are considered to have a poor prognosis without treatment and/or are at high risk if treated by conventional surgical mitral valve repair or replacement. These patients carry a high mortality risk due to advanced age and/or the presence of concomitant illnesses. TMVR is not intended for use in Medicare beneficiaries who are considered acceptable operative candidates as defined by STS and ACC guidelines and the multidisciplinary team treating the patient or in those patients with such advanced age and comorbidities that good clinical outcomes could not be achieved even with TMVR. Quality of life and functional status beyond one year following the procedure will be considered essential in deciding which patients will benefit from these procedures.

This is further supported by the NCD requestors that stated, “[i]n accordance with current and potential future FDA-approved indications, patients must have moderate-to-severe (3+) or severe (4+) symptomatic degenerative mitral regurgitation and be deemed extremely high risk or inoperable for mitral valve surgery.” The NCD requestors added that the target Medicare patient population for treatment of mitral regurgitation with TMVR should be limited to Medicare beneficiaries who are considered high-risk operative candidates or inoperable as defined by FDA labeling.

The FDA-approved label states that prohibitive risk (based on advanced age and/or other comorbidities as determined by the STS risk scores) is determined by the clinical judgment of a heart team and is due to the presence of one or more of the following documented surgical risk factors:

• 30-day STS predicted operative mortality risk score of
• ≥ 8% for patients deemed likely to undergo mitral valve replacement or
• ≥ 6% for patients deemed likely to undergo mitral valve repair
• Porcelain aorta or extensively calcified ascending aorta
• Frailty (assessed by in-person cardiac surgeon consultation)
• Hostile chest
• Severe liver disease / cirrhosis (MELD Score > 12)
• Severe pulmonary hypertension (systolic pulmonary artery pressure > 2/3 systemic pressure)
• Unusual extenuating circumstance, such as right ventricular dysfunction with severe tricuspid regurgitation, chemotherapy for malignancy, major bleeding diathesis, immobility, AIDS, severe dementia, high risk of aspiration, internal mammary artery (IMA) at high risk of injury.

Proposed Operator and Institutional Requirements

Operator and institutional requirements are important to maximize a beneficiary’s chance for improved health outcomes with this technically difficult procedure. The mitral valve structure is complex and unique and as a result is more challenging than the aortic valve. For mitral valve surgery, volume has been demonstrated as important for good surgical outcomes. High volume programs (> 140 mitral valve operations per year) are known to have the lowest mortality and highest repair rates (Cikirikcioglu 2011). Increasing surgeon-specific volume (> 50 cases per year) is associated with a higher probability of successful mitral valve repair (> 80%) (Cikirikcioglu 2011). There is some movement in Europe to propose standards (a minimum of 25 repairs per surgeon and 50 repairs per hospital each year) and mortality and reoperation rates, which should not exceed 1% and 5% at 5 years (Cikirikcioglu 2011). In studies in US and Europe, the heart team concept is accepted as a broad range of skills are essential for good patient outcomes. An imaging essential for therapy guidance is a skilled echocardiographer (Grayburn and Roberts 2011). Interventional cardiologists must have experience with left sided heart procedures and transseptal puncture. The studies that were performed to support the PMA to the FDA incorporated a multidisciplinary team approach to patient care. The position statements from two professional organizations as well as the recently released SCAI/AATS/ACCF/STS Operator and Institutional Requirements for Transcatheter Valve Repair and Replacement, Part III – Mitral (Appendix B of this document) align with the use of a multidisciplinary team as employed during these studies.

The NCD requesters noted that “the multidisciplinary structural heart valve disease team, which includes the primary cardiologists, echocardiographers, cardiac surgeons experienced in mitral valve repair and interventional cardiologists experienced in transseptal approaches to the mitral valve, will be central in applying scoring systems to evaluate risk-benefit profiles in this diverse group of patients. The multidisciplinary team should have specific protocols for care related to pre-procedure assessment and screening. These protocols should be implemented and executed jointly by the multidisciplinary team. These protocols will involve screening for the presence, degree, and severity of comorbidities, issues related to the mitral pathology that may affect outcome and identification of optimal strategies and other procedures that may be required to ensure good outcomes (e.g., the treatment of coronary obstructive lesions prior to the performance of a percutaneous TMVR). Such protocols and procedures should be contained in well-defined patient-care pathways. Adherence to these principles will not only prevent inappropriate use of these devices, but will ensure best patient outcomes and optimal device utilization.”

We note that the data used for the FDA PMA approval were generated under rigorous clinical trial conditions. To enhance the likelihood that beneficiaries experience similar improved health outcomes overall, operator and facility criteria are important and need definition. Our criteria, listed in section I of this document, are informed by the information in the formal NCD request and subsequent information submitted to CMS by the requestors including the Operator and Institutional Requirements mentioned above as well as our own review of the evidence. As such, we are proposing the operator and institutional requirements that we believe are appropriate in section I of this document. We are asking for public comment on these proposed criteria.

Proposed Registry Questions

As explained above, these Medicare patients we propose to be covered under this proposed NCD carry a high mortality risk due to advanced age and/or the presence of concomitant illnesses. These patients and this procedure must be watched to ensure it is improving patient outcomes. Therefore, we propose that any approved CMS registry must meet the following criteria:

The registry should collect all data necessary and have a written executable analysis plan in place to address the following questions (to appropriately address some questions, Medicare claims or other outside data may be necessary):

• When performed outside a controlled clinical study, how do outcomes and adverse events compare to the pivotal clinical studies?
• How do utcomes 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?

For patients with significant symptomatic MR who are candidates for surgical mitral valve repair or replacement, TMVR provided no mortality benefit compared to surgery, a higher rate of subsequent MR surgery and a lower rate of MR reduction compared to surgery. Based on the evidence reviewed, the FDA panel review and SSED, the NCD requestor and position statements from two professional organizations, TMVR may yet demonstrate improved health outcomes in very highly selected, well-informed, operable patients when performed with added safety and patient protection available in carefully monitored clinical trials performed by expert multi-disciplinary heart teams in facilities that furnish an appropriate environment under §1862(a)(1)(E)of the Act.

We believe there are gaps in the current evidence base that lead to uncertainty about the overall impact of TMVR on beneficiary outcomes when furnished outside of the setting of evidence development or clinical trial protocols. However, we acknowledge this is a patient population that has an unmet clinical need. By balancing the benefit and harms, we believe these concerns can be addressed by requiring that patients be treated under rigorous clinical trial conditions. To enhance the likelihood that beneficiaries experience similar improved health outcomes overall, operator and facility criteria are important and need definition. The Societies’ formal request broadly outlined desirable operator and facility criteria for performing TMVR. Our criteria, listed in section I of this decision memorandum, are informed by the information included in the formal request and subsequent information submitted to CMS by the requestors. (see Appendix C) As such, we are incorporating the operator and facility criteria that we believe are appropriate in section I of this decision. We request the public comment with appropriate evidence on the operator and facility criteria specifically as it applies to clinical trials.

In this rapidly evolving technology, effectiveness as well as the avoidance of adverse outcomes may be maximized with improvements in patient selection, device characteristics, and procedural practices. Therefore, closely monitoring these changes that ultimately lead to improvements in morbidity and mortality is extremely critical. We recognize this TMVR procedure has promise to improve health outcomes, however, we also must balance the harms of the new procedure, therefore, we are proposing that a CMS clinical trial that meets all of the trial criteria outlined in Section IB of the proposed NCD must be designed to answer one of the following important questions:

1. As a fully-described, written part of its protocol, the clinical research study must critically evaluate the following questions:
   • What is the patient’s post-TMVR quality of life (compared to pre-TMVR) at one year?
   • What is the patient’s post-TMVR functional capacity (compared to pre-TMVR) at one year?


2. In addition, the clinical research study, must address all of the following questions at one year post procedure:
   • What is the incidence of stroke?
   • What is the rate of all-cause mortality?
   • What is the incidence of transient ischemic attacks (TIAs)?
   • What is the incidence of major vascular events?
   • What is the incidence of renal complications?
   • What is the incidence of subsequent mitral valve surgery or other mitral valve procedures?
   • What is the incidence of worsening mitral regurgitation?

Disparities

Females were included in the EVEREST and European studies with the gender mix about 30%-40% females. No data on race, socioeconomic status, or urban versus rural were identified.

Summary

As indicated earlier in this document, the evidentiary persuasiveness of the available studies is limited for a number of reasons. The historical record for these procedures as described in FDA documents demonstrates ongoing uncertainty about important outstanding clinical questions for both labeled and previously requested but currently unlabeled uses.

We believe that there is promising but inconclusive evidence whether TMVR improves health outcomes for a defined subset of the Medicare population. Therefore, we conclude at this time that TMVR as a treatment for MR has promising evidence of improved health outcomes only for Medicare beneficiaries with significant symptomatic MR and only if it is furnished under conditions that maximize the beneficiary’s chances for successful treatment. These include evaluation and operation by physicians with sufficient expertise who perform the procedure in facilities that can successfully treat patients who may experience less than hoped-for outcomes otherwise and where the institutional infrastructure is in place to efficiently furnish this specialized care.

Upon review of the available evidence and initial public comments, we believe that our decision to cover FDA indicated uses under CED (i.e., CMS-approved registry participation) is consistent with the evidence reviewed and formal request for coverage from the professional societies. The requestors presented supportable arguments that are consistent with the available evidence for restricting coverage to FDA-indicated uses to practitioners and facilities meeting specified criteria, the derivation of which is from a consensus among the professional societies, and for requiring ongoing data collection through a CMS-approved registry. We agree that robust and reasonable practitioner and facility criteria as outlined by the consensus statement of the Societies (Appendix C) are supported by the evidence. Further, the practitioner and facility criteria are necessary because of the clinical concerns for this Medicare population and that their presence will improve beneficiary outcomes. We believe that CMS criteria for data collection and analysis of FDA approved indications can be met through enrollment and participation in a national prospective TMVR registry. Additionally, this decision is consistent with the FDA requirement for continuing data collection and analysis of TMVR.

For all non-FDA indicated uses of TMVR, we believe that there is promising but inadequate evidence to conclude at this time that TMVR generally improves health outcomes for Medicare beneficiaries with MR. We believe that the beneficiaries’ ability to attain improved health outcomes is maximized when TMVR is furnished in settings that reflect those in the EVEREST II studies, by appropriately trained, experienced operators in the context of a multidisciplinary team in a setting that assures sufficient volume to maintain proficiency. We are also mindful of ongoing research and recognize that an alternative to open surgical mitral valve repair or replacement may be clinically appropriate and preferable in carefully selected patients when certain protections are in place to enhance the likelihood of benefit. We also believe that the additional data collected in the context of a clinical trial setting can further clarify the impact of TMVR on the health of this Medicare patient population. Based on the above evidence and conclusions, we are proposing Medicare coverage under the Coverage with Study Participation CED paradigm (i.e., clinical trials meeting certain requirements) balances these evidentiary considerations and the interests of our beneficiaries.

IX. Conclusion

The Centers for Medicare & Medicaid Services (CMS) proposes to cover transcatheter mitral valve repair (TMVR) under Coverage with Evidence Development (CED) with the following conditions:

A. TMVR is covered for the treatment of significant symptomatic mitral regurgitation when furnished according to an FDA approved indication and when all of the following conditions are met.

1. The procedure is furnished with a complete transcatheter mitral valve repair system that has received FDA premarket approval (PMA) for that system’s FDA approved indication.


2. Both a cardiac surgeon experienced in mitral valve surgery and a cardiologist experienced in mitral valve disease have independently examined the patient face-to-face and evaluated the patient’s suitability for mitral valve surgery and determination of prohibitive risk; and both physicians have documented the rationale for their clinical judgment and the rationale is available to the heart team.


3. The patient (preoperatively and postoperatively) is under the care of a heart team: a cohesive, multi-disciplinary, team of medical professionals. The heart team concept embodies collaboration and dedication across medical specialties to offer optimal patient-centered care.

   TMVR must be furnished in a hospital with the appropriate infrastructure that includes but is not limited to:

   1. On-site heart valve surgery program,
   2. Cardiac catheterization lab or hybrid operating room/catheterization lab equipped with a fixed radiographic imaging system with flat-panel fluoroscopy offering catheterization laboratory-quality imaging,
   3. Non-invasive imaging including expertise in transthoracic and transesophageal echocardiography,
   4. Sufficient space, in a sterile environment, to accommodate necessary equipment for cases with and without complications,
   5. Post-procedure intensive care facility with personnel experienced in managing patients who have undergone open-heart valve procedures,
   6. Appropriate volume requirements per the applicable qualifications below.

   Outlined below are qualification requirements for hospital surgical programs wishing to perform TMVR procedures.

   The hospital surgical program must have the following:

   1. ≥ 25 total mitral valve procedures in the previous year of which at least 10 must be mitral valve repairs;
   2. ≥1000 catheterizations per year, including ≥ 400 percutaneous coronary interventions (PCIs) per year;
   3. Interventionalist with: ≥ 50 structural procedures per year including atrial septal defects (ASD) and patent foramen ovale (PFO) and trans-septal punctures; and
   4. Additional members of the heart team including echocardiographers, other imaging specialists, heart valve and heart failure specialists, electrophysiologists, cardiac anesthesiologists, intensive care and cardiac imaging departments, congenital heart disease specialists and surgeons, nurse practitioners, data/research coordinators and a dedicated administrator; and device-specific training as required by the manufacturer.
4. The heart team’s interventional cardiologist(s) and cardiac surgeon(s) must jointly participate in the intra-operative technical aspects of TMVR.


5. The heart team and hospital are participating in a prospective, national, audited registry that: 1) consecutively enrolls TMVR 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. Quality of Life (QoL);
   2. Functional capacity
   3. Stroke;
   4. All-cause mortality;
   5. Transient ischemic events (TIAs);
   6. Major vascular events;
   7. Renal complications;
   8. Repeat mitral valve surgery or other mitral procedures;
   9. Worsening mitral regurgitation.

   The registry should collect all data necessary and have a written executable analysis plan in place to address the following questions (to appropriately address some questions, Medicare claims or other outside data may be necessary):

   • When 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?

   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. TMVR is covered for uses that are not expressly listed as an FDA approved indication when performed within an FDA-approved randomized clinical trial that fulfills all of the following:

1. The heart team’s interventional cardiologist(s) and cardiac surgeon(s) must jointly participate in the intra-operative technical aspects of TMVR.


2. As a fully-described, written part of its protocol, the clinical research study must critically evaluate the following questions:
   • What is the patient’s post-TMVR quality of life (compared to pre-TMVR) at one year?
   • What is the patient’s post-TMVR functional capacity (compared to pre-TMVR) at one year?
3. In addition, the clinical research study must address all of the following questions at one year post procedure:
   • What is the incidence of stroke?
   • What is the rate of all-cause mortality?
   • What is the incidence of transient ischemic attacks (TIAs)?
   • What is the incidence of major vascular events?
   • What is the incidence of renal complications?
   • What is the incidence of subsequent mitral valve surgery or other mitral valve procedures?
   • What is the incidence of worsening mitral regurgitation?

C. All CMS-approved clinical studies and registries must adhere to the following standards of scientific integrity and relevance to the Medicare population:

1. The principal purpose of the research study is to test whether a particular intervention potentially improves the participants’ health outcomes.
2. The research study is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use.
3. The research study does not unjustifiably duplicate existing studies.
4. The research study design is appropriate to answer the research question being asked in the study.
5. The research study is sponsored by an organization or individual capable of executing the proposed study 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 also must be in compliance with 21 CFR Parts 50 and 56.
7. All aspects of the research study are conducted according to appropriate standards of scientific integrity.
8. The research study has a written protocol that clearly addresses, or incorporates by reference; the standards listed as Medicare coverage requirements.
9. The clinical research study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard 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 research study protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria affect 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 research study protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

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 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 whether: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.

CMS divides the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the relevance 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 risks and benefits.

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

1. 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 help ensure adequate numbers of patients are enrolled 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 which 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 the extent to which 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 (confounding)
• 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, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies. The following is a representative list of study designs (some of which 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 which 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’s selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess the evidence.

2. 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 which 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 decisions 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 because one of the goals of our determination process is to assess health outcomes. We are interested in the results of changed patient management not just altered management. 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.

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.

3. 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. For most determinations, CMS evaluates whether reported benefits translate into improved health outcomes. 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’s benefits and risk of harm to Medicare beneficiaries.

CMS does from time to time include requirements for facility and/or physician standards, or certain certification requirements in our NCDs; however, we exercise this option after considered counsel and cognizant of the responsibility such requirements establish. Some of the considerations that may inform our decision to include facility and/or physician standards, or certification requirements are: intended patients who are medically fragile undergoing high risk procedures; procedures that are new or not generally disseminated in the medical community at large; technically complex procedures; procedures experiencing a rapid growth in the medical community before the opportunity for the establishment of generally accepted standards; procedures that impose what we believe to be a significantly higher risk for our Medicare beneficiaries. While this is not intended to be an all-inclusive list of what may inform CMS’s decision to include facility and/or physician standards, or certification requirements, it is provided to give some insight into our decision making process. Ultimately, it is the convincing nature of the circumstances and/or the evidence surrounding the item or service under review that guides CMS to conclude that such standards and/or certification requirements will benefit our Medicare beneficiaries.

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