Back to Transcatheter Tricuspid Valve Replacement (TTVR)

National Coverage Analysis (NCA) Proposed Decision Memo

Transcatheter Tricuspid Valve Replacement (TTVR)

CAG-00467N

Decision Summary

A. Proposed Decision

The Centers for Medicare & Medicaid Services (CMS) proposes to cover transcatheter tricuspid valve replacement (TTVR) under Coverage with Evidence Development (CED) for the treatment of symptomatic tricuspid regurgitation (TR) graded as at least severe according to the provisions in sections I.B. and I.C. below.

B. Coverage Criteria

We propose that TTVR is covered when furnished with an FDA-approved complete TTVR system, and all the following conditions are met:

1. Patient Criteria

Despite optimal therapy (OMT), patients must have symptomatic TR graded as at least severe with tricuspid valve replacement being considered as appropriate by a heart team.

2. Physician Criteria

The patient (preoperatively and postoperatively) is under the care of a heart team, which includes, at minimum, the following:

a) Cardiac surgeon;
b) Interventional cardiologist;
c) Heart failure cardiologist;
d) Electrophysiologist;
e) Multi-modality imaging specialists; and
f) Interventional echocardiographer.

All of the specialists listed above must have experience in the care and treatment of tricuspid regurgitation.

3. CED Study Criteria

The TTVR items and services are furnished in the context of a CMS-approved CED study. We propose that CMS-approved CED study protocols must include only those patients who meet the criteria in section I.B.1; furnish items and services only through practitioners who meet the criteria in section I.B.2; and include all of the following:

a) Primary outcomes of all-cause mortality, hospitalizations, or a composite of these, through a minimum of 24 months. For composite outcome measures, physiologic, patient-reported, and other relevant health outcomes should be co-directional (i.e., all outcomes comprising the composite outcome should demonstrate movement in the same direction). Each component of a composite outcome must be individually reported.

b) An active comparator.

c) A care management plan that includes the experience and role of each member of the heart team described in section I.B.2.

d) Design sufficient for subgroup analyses by:

Age;
Sex;
Race and ethnicity;
Patient, practitioner, and facility level variables that predict the primary outcomes of the study;
Left ventricular ejection fraction (by guideline-defined subgroups);
Previous tricuspid surgery or intervention;
Severe aortic or mitral stenosis or regurgitation;
Patients with chronic kidney disease;
Patients with indwelling cardiac implantable electronic devices

e) CMS-approved studies must adhere to the following standards of scientific integrity (criteria 1-17 below) that have been identified by the Agency for Healthcare Research and Quality (AHRQ) as set forth in Section VI of CMS’ Coverage with Evidence Development Guidance Document, published August 7, 2024 (the “CED Guidance Document”):

Sponsor/Investigator: The study is conducted by sponsors/investigators with the resources and skills to complete it successfully.
Milestones: A written plan is in place that describes a detailed schedule for completion of key study milestones, including study initiation, enrollment progress, interim results reporting, and results reporting, to ensure timely completion of the CED process.
Study Protocol: The CED study is registered with ClinicalTrials.gov and a complete final protocol, including the statistical analysis plan, is delivered to CMS prior to study initiation. The published protocol includes sufficient detail to allow a judgment of whether the study is fit-for-purpose and whether reasonable efforts will be taken to minimize the risk of bias. Any changes to approved study protocols should be explained and publicly reported.
Study Context: The rationale for the study is supported by scientific evidence and study results are expected to fill the specified CMS-identified evidence deficiency and provide evidence sufficient to assess health outcomes.
Study Design: The study design is selected to safely and efficiently generate valid evidence of health outcomes. The sponsors/investigators minimize the impact of confounding and biases on inferences through rigorous design and appropriate statistical techniques. If a contemporaneous comparison group is not included, this choice should be justified, and the sponsors/investigators discuss in detail how the design contributes useful information on issues such as durability or adverse event frequency that are not clearly answered in comparative studies.
Study Population: The study population reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended population of the intervention, particularly when there is good clinical or scientific reason to expect that the results observed in premarket studies might not be observed in older adults or subpopulations identified by other clinical or demographic factors. At a minimum, this includes attention to the intended population’s racial and ethnic backgrounds, gender, age, disabilities, important comorbidities, and, dependent on data availability, relevant health related social needs. For instance, more than half of Medicare beneficiaries are women so study designs should, as appropriate, consider the prevalence in women of the condition being studied as well as in the clinical trial and subsequent data reporting and analyses.
Subgroup Analyses: The study protocol explicitly discusses beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion requirements effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. In the protocol, the sponsors/investigators describe plans for analyzing demographic subpopulations as well as clinically-relevant subgroups as identified in existing evidence. Description of plans for exploratory analyses, as relevant subgroups emerge, are also included.
Care Setting: When feasible and appropriate for answering the CED question, data for the study should come from beneficiaries in their expected sites of care.
Health Outcomes: The primary health outcome(s) for the study are those important to patients and their caregivers and that are clinically meaningful. A validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions. Generally, when study sponsors propose using surrogate endpoints to measure outcomes, they should cite validation studies published in peer-reviewed journals to provide a rationale for assuming these endpoints predict the health outcomes of interest. The cited validation studies should be longitudinal and demonstrate a statistical association between the surrogate endpoint and the health outcomes it is thought to predict.
Objective Success Criteria: In consultation with CMS and AHRQ, sponsors/investigators establish an evidentiary threshold for the primary health outcome(s) so as to demonstrate clinically meaningful differences with sufficient precision.
Data Quality: The data are generated or selected with attention to provenance, bias, completeness, accuracy, sufficiency of duration of observation to demonstrate durability of health outcomes, and sufficiency of sample size as required by the question.
Construct Validity: Sponsors/investigators provide information about the validity of drawing warranted conclusions about the study population, primary exposure(s) (intervention, control), health outcome measures, and core covariates when using either primary data collected for the study about individuals or proxies of the variables of interest, or existing (secondary) data about individuals or proxies of the variables of interest.
Sensitivity Analyses: Sponsors/investigators will demonstrate robustness of results by conducting pre-specified sensitivity testing using alternative variable or model specifications as appropriate.
Reporting: Final results are provided to CMS and submitted for publication or reported in a publicly accessible manner within 12 months of the study’s primary completion date. Wherever possible, the study is submitted for peer review with the goal of publication using a reporting guideline appropriate for the study design and structured to enable replication. If peer-reviewed publication is not possible, results may also be published in an online 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 incomplete results).
Sharing: The sponsors/investigators commit to making study data publicly available by sharing data, methods, analytic code, and analytical output with CMS or with a CMS-approved third party. The study should comply with all applicable laws regarding subject privacy, including 45 CFR § 164.514 within the regulations promulgated under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient Records.
Governance: The protocol describes the information governance and data security provisions that have been established to satisfy Federal security regulations issued pursuant to HIPAA and codified at 45 CFR Parts 160 and 164 (Subparts A & C), United States Department of Health and Human Services (HHS) regulations at 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient and HHS regulations at 45 CFR Part 46, regarding informed consent for clinical study involving human subjects. In addition to the requirements under 42 CFR and 45 CFR, studies that are subject to FDA regulation must also comply with regulations at 21 CFR Parts 50 and 56 regarding the protection of human subjects and institutional review boards, respectively.
Legal: The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals, although it is acceptable for a study to test a reduction in toxicity of a product relative to standard of care or an appropriate comparator. For studies that involve researching the safety and effectiveness of new drugs and biological products aimed at treating life-threatening or severely-debilitating diseases, refer to additional requirements set forth in 21 CFR § 312.81(a).

Consistent with section 1142 of the Act, AHRQ supports clinical research studies that CMS determines meet all the criteria and standards identified above.

C. Other Uses of TTVR

1) Transcatheter tricuspid valve replacement (TTVR) is not covered for patients outside of a CMS-approved study.

2) Nothing in this proposed NCD would preclude coverage of TTVR through NCD 310.1 (Clinical Trial Policy) or through the Investigational Device Exemption (IDE) Policy.

See Appendix A for proposed Medicare National Coverage Determinations Manual language.

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 Act.

Proposed Decision Memo

Table of Contents

Proposed Decision

Proposed Decision

Coverage Criteria

Patient Criteria
Physician Criteria
CED Study Criteria

Other Uses of TTVR

Clinical Review

Background

Food and Drug Administration Status

Evidence

Evidence Questions

Technology Assessments

Medicare Evidence Development and Coverage Advisory Committee (MEDCAC)

Clinical Literature Search

Summary of Evidence

Assessment of the Evidence
Trial Design and Enrollment Criteria: Pivotal Trials
Other Publications
Study Populations
Background Therapy
Intervention Setting
Endpoints
Study Quality and Risk of Bias
Synthesizing the Clinical Trial Evidence
Evidence from Observational Studies
Limitations of Evidence
Considerations for Further Research

Evidence-Based Guidelines

Professional Society Recommendations / Consensus Statements / Other Expert Opinion

Appropriate Use Criteria

Public Comment

Health Disparities

CMS Coverage Analysis

CMS Coverage Authority

CMS Analysis for Coverage of TTVR for TR

Rationale for Coverage Requirements for TTVR for TR (Patient, Physician, and CED Study Criteria)

Evidence Questions – Answered

Benefit Category

Shared-Decision Making

History of Medicare Coverage

Current National Coverage Request

Timeline of NCA Milestones

Appendices
Appendix A: Proposed Medicare National Coverage Determinations Manual Language

Proposed Decision

Coverage Criteria

Patient Criteria

Physician Criteria

CED Study Criteria

Other Uses of TTVR

Appendix B: Referenced Materials

Appendix C: Heart Failure Quality of Life and Functional Measures

Bibliography

Abbreviations used throughout the Proposed Decision Memorandum for Transcatheter Tricuspid Valve Replacement (TTVR)

6MWD – 6-Minute Walk Distance
ACC – American College of Cardiology
ADL – Activities of Daily Living
AE – Adverse Event
AF – Atrial Fibrillation
AHA – American Heart Association
AHRQ – Agency for Healthcare Research and Quality
AS – Aortic Stenosis
BL – Baseline
BNP – B-type natriuretic peptide
CABG – Coronary Artery Bypass Graft
CAD – Coronary Artery Disease
CED – Coverage with Evidence Development
CFR – Code of Federal Regulations
CI – Confidence Interval
CIED – Cardiovascular Implantable Electronic Device
CKD – Chronic Kidney Disease
CMS – Centers for Medicare & Medicaid Services
COPD – Chronic Obstructive Pulmonary Disease
CT – Computed Tomography
CV – Cardiovascular
DVT – Deep Vein Thrombosis
EAPCI – European Association of Percutaneous Cardiovascular Interventions
EDP – Evidence Development Plan
EP – Electrophysiologist
EROA – Effective Regurgitant Orifice Area
ESC – European Society of Cardiology
EuroSCORE II – European System for Cardiac Operative Risk Evaluation II
FAC – Fractional Area Change
FDA – Food and Drug Administration
GDMT – Guideline-Directed Therapy
HF – Heart Failure
HFH – Heart Failure Hospitalizations
HR – Hazard Ratio
ICD – Implantable Cardioverter Defibrillator
IDE – Investigational Device Exemption
IVC – Inferior Vena Cava
KCCQ – Kansas City Cardiomyopathy Questionnaire
LVEF – Left Ventricular Ejection Fraction
MAE – Major Adverse Event
MEDCAC – Medicare Evidence Development and Coverage Advisory Committee
MI – Myocardial Infarction
MLHFQ – Minnesota Living with Heart Failure Questionnaire
NCA – National Coverage Analysis
NCD – National Coverage Determination
NYHA – New York Heart Association
NT-proBNP – Aminoterminal pro B-type Natriuretic Peptide
OMT – Optimal Therapy
OR – Odds Ratio
PA – Pulmonary Artery
PAP – Pulmonary Artery Pressure
PASP – Pulmonary Artery Systolic Pressure
PE – Pulmonary Embolism
PH – Pulmonary Hypertension
PM – Pacemaker
PPM – Permanent Pacemaker
PVL – Perivalvular Leak
QoL – Quality of Life
RA – Right Atrium
RCT – Randomized Controlled Trial
RHC – Right Heart Catheterization
RHF – Right Heart Failure
RV – Right Ventricle
RVAD – Right Ventricular Assist Device
RVEDD – Right Ventricular End Diastolic Diameter
RV-EDV – Right Ventricular End Diastolic Volume
RV-EF – Right Ventricular Ejection Fraction
SD – Standard Deviation
SDM – Shared Decision Making
SF-36 – Short Form Health Survey
sPAP – Systolic Pulmonary Artery Pressure
SSED – Summary of Safety and Effectiveness Data
STS – Society of Thoracic Surgeons
TAPSE – Tricuspid Annular Plane Systolic Excursion
TAVR – Transcatheter Aortic Valve Replacement
TCET – Transitional Coverage for Emerging Technologies
TEE – Transesophageal Echocardiography
TR – Tricuspid Regurgitation
TTE – Transthoracic Echocardiography
TTVI – Transcatheter Tricuspid Valve Intervention
TTVR – Transcatheter Tricuspid Valve Replacement
TV – Tricuspid Valve
TVARC – Tricuspid Valve Academic Research Consortium
VHD – Valvular Heart Disease
US – United States

I. Proposed Decision

A. Proposed Decision

B. Coverage Criteria

We propose that TTVR is covered when furnished with an FDA-approved complete TTVR system, and all the following conditions are met:

1. Patient Criteria

Despite optimal therapy (OMT), patients must have symptomatic TR graded as at least severe with tricuspid valve replacement being considered as appropriate by a heart team.

2. Physician Criteria

The patient (preoperatively and postoperatively) is under the care of a heart team, which includes, at minimum, the following:

a) Cardiac surgeon;
b) Interventional cardiologist;
c) Heart failure cardiologist;
d) Electrophysiologist;
e) Multi-modality imaging specialists; and
f) Interventional echocardiographer.

All of the specialists listed above must have experience in the care and treatment of tricuspid regurgitation.

3. CED Study Criteria

b) An active comparator.

c) A care management plan that includes the experience and role of each member of the heart team described in section I.B.2.

d) Design sufficient for subgroup analyses by:

Age;
Sex;
Race and ethnicity;
Patient, practitioner, and facility level variables that predict the primary outcomes of the study;
Left ventricular ejection fraction (by guideline-defined subgroups);
Previous tricuspid surgery or intervention;
Severe aortic or mitral stenosis or regurgitation;
Patients with chronic kidney disease;
Patients with indwelling cardiac implantable electronic devices

Sponsor/Investigator: The study is conducted by sponsors/investigators with the resources and skills to complete it successfully.
Milestones: A written plan is in place that describes a detailed schedule for completion of key study milestones, including study initiation, enrollment progress, interim results reporting, and results reporting, to ensure timely completion of the CED process.
Study Protocol: The CED study is registered with ClinicalTrials.gov and a complete final protocol, including the statistical analysis plan, is delivered to CMS prior to study initiation. The published protocol includes sufficient detail to allow a judgment of whether the study is fit-for-purpose and whether reasonable efforts will be taken to minimize the risk of bias. Any changes to approved study protocols should be explained and publicly reported.
Study Context: The rationale for the study is supported by scientific evidence and study results are expected to fill the specified CMS-identified evidence deficiency and provide evidence sufficient to assess health outcomes.
Study Design: The study design is selected to safely and efficiently generate valid evidence of health outcomes. The sponsors/investigators minimize the impact of confounding and biases on inferences through rigorous design and appropriate statistical techniques. If a contemporaneous comparison group is not included, this choice should be justified, and the sponsors/investigators discuss in detail how the design contributes useful information on issues such as durability or adverse event frequency that are not clearly answered in comparative studies.
Study Population: The study population reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended population of the intervention, particularly when there is good clinical or scientific reason to expect that the results observed in premarket studies might not be observed in older adults or subpopulations identified by other clinical or demographic factors. At a minimum, this includes attention to the intended population’s racial and ethnic backgrounds, gender, age, disabilities, important comorbidities, and, dependent on data availability, relevant health related social needs. For instance, more than half of Medicare beneficiaries are women so study designs should, as appropriate, consider the prevalence in women of the condition being studied as well as in the clinical trial and subsequent data reporting and analyses.
Subgroup Analyses: The study protocol explicitly discusses beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion requirements effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. In the protocol, the sponsors/investigators describe plans for analyzing demographic subpopulations as well as clinically-relevant subgroups as identified in existing evidence. Description of plans for exploratory analyses, as relevant subgroups emerge, are also included.
Care Setting: When feasible and appropriate for answering the CED question, data for the study should come from beneficiaries in their expected sites of care.
Health Outcomes: The primary health outcome(s) for the study are those important to patients and their caregivers and that are clinically meaningful. A validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions. Generally, when study sponsors propose using surrogate endpoints to measure outcomes, they should cite validation studies published in peer-reviewed journals to provide a rationale for assuming these endpoints predict the health outcomes of interest. The cited validation studies should be longitudinal and demonstrate a statistical association between the surrogate endpoint and the health outcomes it is thought to predict.
Objective Success Criteria: In consultation with CMS and AHRQ, sponsors/investigators establish an evidentiary threshold for the primary health outcome(s) so as to demonstrate clinically meaningful differences with sufficient precision.
Data Quality: The data are generated or selected with attention to provenance, bias, completeness, accuracy, sufficiency of duration of observation to demonstrate durability of health outcomes, and sufficiency of sample size as required by the question.
Construct Validity: Sponsors/investigators provide information about the validity of drawing warranted conclusions about the study population, primary exposure(s) (intervention, control), health outcome measures, and core covariates when using either primary data collected for the study about individuals or proxies of the variables of interest, or existing (secondary) data about individuals or proxies of the variables of interest.
Sensitivity Analyses: Sponsors/investigators will demonstrate robustness of results by conducting pre-specified sensitivity testing using alternative variable or model specifications as appropriate.
Reporting: Final results are provided to CMS and submitted for publication or reported in a publicly accessible manner within 12 months of the study’s primary completion date. Wherever possible, the study is submitted for peer review with the goal of publication using a reporting guideline appropriate for the study design and structured to enable replication. If peer-reviewed publication is not possible, results may also be published in an online 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 incomplete results).
Sharing: The sponsors/investigators commit to making study data publicly available by sharing data, methods, analytic code, and analytical output with CMS or with a CMS-approved third party. The study should comply with all applicable laws regarding subject privacy, including 45 CFR § 164.514 within the regulations promulgated under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient Records.
Governance: The protocol describes the information governance and data security provisions that have been established to satisfy Federal security regulations issued pursuant to HIPAA and codified at 45 CFR Parts 160 and 164 (Subparts A & C), United States Department of Health and Human Services (HHS) regulations at 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient and HHS regulations at 45 CFR Part 46, regarding informed consent for clinical study involving human subjects. In addition to the requirements under 42 CFR and 45 CFR, studies that are subject to FDA regulation must also comply with regulations at 21 CFR Parts 50 and 56 regarding the protection of human subjects and institutional review boards, respectively.
Legal: The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals, although it is acceptable for a study to test a reduction in toxicity of a product relative to standard of care or an appropriate comparator. For studies that involve researching the safety and effectiveness of new drugs and biological products aimed at treating life-threatening or severely-debilitating diseases, refer to additional requirements set forth in 21 CFR § 312.81(a).

Consistent with section 1142 of the Act, AHRQ supports clinical research studies that CMS determines meet all the criteria and standards identified above.

C. Other Uses of TTVR

1) Transcatheter tricuspid valve replacement (TTVR) is not covered for patients outside of a CMS-approved study.

2) Nothing in this proposed NCD would preclude coverage of TTVR through NCD 310.1 (Clinical Trial Policy) or through the Investigational Device Exemption (IDE) Policy.

See Appendix A for proposed Medicare National Coverage Determinations Manual language.

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 Act.

II. Clinical Review

A. Background

Etiology and Clinical Presentation:

Tricuspid regurgitation (TR) is a cardiac condition that occurs when the tricuspid valve (TV) between the right atrium (RA) and right ventricle (RV) does not function properly, allowing blood to flow backwards from the RV to the RA. TR is historically classified as either primary or secondary based on its etiology. Primary, or degenerative, TR results from an intrinsic valve or sub-valvular abnormality, commonly originating from Ebstein anomaly, rheumatic valve disease, chest wall trauma, or complications from implantable device leads. Secondary TR, also called functional TR, is commonly caused by RV and RA dilatation with tricuspid annulus dilation and/or leaflet tethering from remodeling due to pulmonary hypertension, atrial fibrillation (AF), or other conditions that cause elevation in RV systolic pressure or RV dilation. Contemporary recommendations for classification further subdivide primary and secondary TR by etiology, as outcomes differ for different pathophysiologic etiologies (Hahn et al., 2023). It is notable that TR severity can change with changes in volume status and pulmonary pressure (Otto et al., 2021). Most adults in the general population experience at least trivial degrees of TR and most are asymptomatic, even in the presence of severe TR (Otto et al., 2021). When present, symptoms are those of right heart failure (HF), including peripheral edema, ascites, and painful hepatosplenomegaly. Sequelae include congestive hepatopathy with liver failure and renal impairment due to venous hypertension. Symptoms can include those of left-sided HF, such as shortness of breath, fatigue, weakness, and exercise intolerance, when this is the underlying etiology of TR.

Epidemiology:

An estimated 1.6 million individuals in the United States have moderate or greater TR (Cahill et al., 2021) and prevalence increases with age (Hahn, 2023). Approximately 80-95% of TR is secondary (Condello et al., 2021; Prihadi et al., 2019, Wang et al., 2022). TR is more frequent in women than men and female sex predicts greater severity of disease (Hahn, 2023). An analysis of the Framingham data (Singh et al., 1999) indicated that risk factors for TR were age (OR 1.5/9.9 years), body mass index (OR 0.7/4.3 kg/m²), and female gender (OR 1.2). Other risk factors include atrial fibrillation, pulmonary hypertension, and left atrial enlargement (Hahn, 2023) and at least moderate TR develops in about 50% of individuals with severe mitral regurgitation (MR) and 25% of those with severe aortic stenosis (AS) (Condello et al., 2021), with risk persisting following repair.

Diagnosis and Assessment:

According to the 2020 American College of Cardiology/American Heart Association valve guidelines, transthoracic echocardiography (TTE) is currently the standard for TR diagnosis and severity assessment (Otto et al., 2021). Transesophageal echocardiography (TEE) can be considered when TTE images are suboptimal or in specific cases such as endocarditis or the presence of pacemaker leads. The current American Society of Echocardiography parameters for grading the severity of chronic TR (mild, moderate, severe) include TV morphology, RV and right atrial (RA) size, inferior vena cava diameter, color flow jet area, flow convergence zone, hepatic vein flow, and effective regurgitant orifice area (Zoghbi et al., 2017). To better characterize the variability of TR seen in patients considered for transcatheter valvular interventions, an expanded grading scale for assessing TR severity was proposed by Hahn & Zamorano (2017); the scale further expands the “severe” grade to include “massive” and “torrential” grades. Echocardiographic evaluation for TR should be performed when the patient is medically optimized in the judgement of a physician with experience in treating right-sided HF. In clinical practice, physicians will consider these quantitative measures as well as unique patient characteristics, existing comorbidities, and risk factors to determine the most appropriate treatment pathway for patients with TR.

Prognosis:

Adjusted for other cardiac comorbidities, severe TR more than doubles the risk of mortality compared with no/trivial TR (Offen et al., 2022), with one-year mortality reported in this observational study at 42%. In patients with left ventricular dysfunction, tricuspid regurgitation was shown to be an independent predictor of increased mortality, with median survival 4.9 years for nonsignificant, 2.3 years for moderate, and 1.6 years for severe TR (Kazum et al., 2019).

Treatment and Response to Therapy:

Management is determined by the etiology and severity of symptoms, taking into consideration associated conditions such as pulmonary hypertension, presence of a cardiovascular implantable electronic device (CIEDs), comorbidities (e.g., atrial arrhythmias, hyperlipidemia, ischemic heart disease, and diabetes), and left-sided cardiac conditions, including left sided valve disease (Chorin et al., 2020). Treatment of severe or greater TR consists of therapy with diuretics and addressing the underlying causes of secondary TR (Hahn et al., 2023; Fender et al., 2018; Messika-Zeitoun et al., 2023); both approaches are class 2a recommendations in the 2020 American College of Cardiology/ American Heart Association valve guidelines (Otto et al., 2021).

Mortality has long been understood to be high in patients undergoing tricuspid valve surgery. Previously reported in-hospital mortality rates were up to 10% to 12% for isolated TV repair/ replacement surgery (Dreyfus et al., 2020; Scotti et al., 2022). However, in patients with isolated TR without comorbidities, as in trauma patients, surgical risk has been reported as low as <1 to 2% (Otto et al., 2021). As such, an argument has been made for earlier surgery in severe TR before significant cardiac remodeling and other systemic sequelae develop (Otto et al., 2021). A recent analysis of the Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database evaluated 14,704 isolated tricuspid valve operations performed between 2011 and 2020, showing an increase in volume from 983 cases in 2012 to 2155 cases in 2019 (Chen et al., 2023). Another contemporary analysis of the same database (Thourani et al., 2024) was performed to establish a TV-specific surgical risk model and found 5,553 isolated TV repairs and 8,004 TV replacements performed between 2017 and 2023, with TV replacements primarily performed in younger patients (45.3 ± 18.0 years) and with a higher likelihood of endocarditis. These studies show that surgical mortality has improved in recent years. In the Thourani analysis, operative mortality was 5.6% overall and was similar for repairs and replacements (5.5% and 5.7%, respectively). Mortality with replacement was significantly lower in patients with endocarditis, compared to those with other etiologies of TR (4.1% vs. 7.1%, respectively). The surgical cohort analyzed by Chen et al. excluded patients with endocarditis, tricuspid stenosis, emergent surgery, and previous heart transplants, yielding a group with a median age of 65 years, 40% NYHA Class III/IV heart failure, and 24% nonelective operations. This cohort had an operative mortality of 7.3% overall, and new permanent pacemaker implant rate of 10.8%. Increased risk for mortality was associated with age > 50 years, chronic lung disease, atrial fibrillation, aortic stenosis, NYHA Class III/IV heart failure, nonelective operation, tricuspid valve replacement, annual hospital case volume of 5 or fewer surgeries, and liver dysfunction. Guidelines for TV surgery are discussed in detail below.

Transcatheter Tricuspid Valve Devices:

A minimally-invasive, percutaneous, transvenous, catheter-based approach to TV replacement has emerged as a potential treatment for TR. The Edwards Lifesciences EVOQUE system is the first FDA cleared transcatheter TV replacement device in the US.

B. Food and Drug Administration Status

On February 1, 2024, the FDA approved the Edwards EVOQUE Tricuspid Valve Replacement System (EVOQUE system) premarket approval (PMA) application (P230013). The device is indicated for the improvement of health status in patients with symptomatic severe tricuspid regurgitation despite optimal therapy, for whom tricuspid valve replacement is deemed appropriate by a heart team.

III. Evidence

This section provides a summary of the evidence considered during this review. The evidence presented here includes the pertinent published clinical research on transcatheter tricuspid valve replacement for moderate to severe tricuspid regurgitation (TR). This proposed NCD addresses a family of devices that deploy a prosthetic valve within the native tricuspid annulus via a percutaneous, minimally invasive, catheter directed approach. The NCD applies only to transcatheter tricuspid valve replacement for symptomatic TR graded as at least severe. It does not address transcatheter tricuspid valve repair devices, nor devices deployed outside the tricuspid annulus.

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 the CMS National Coverage Analysis Evidence Review Guidance Document, published August 7, 2024, or any successor document.

A. Evidence Questions

The following questions guide our review and analysis of the evidence on the clinical utility of transcatheter tricuspid valve replacement (TTVR) for severe or greater TR:

Q1: Is the evidence sufficient to conclude that TTVR is reasonable and necessary for the treatment of Medicare beneficiaries with symptomatic severe-or-greater tricuspid regurgitation?

Q2: Is there evidence that specific characteristics or comorbidities make patients more or less likely to benefit from TTVR?

Q3: Are specific treatment conditions necessary to achieve TTVR outcomes similar to those demonstrated in the clinical studies reviewed in this analysis?

B. Technology Assessments

CMS did not request an external technology assessment on this topic.

C. Medicare Evidence Development and Coverage Advisory Committee (MEDCAC)

A MEDCAC meeting was not convened on this topic.

D. Clinical Literature Search

A systematic review was undertaken to address the evidence questions defined above and focused on TTVR for tricuspid regurgitation, population risk factors, and endpoints. Literature searches were conducted in PubMed and Embase with the following search terms: (1) “tricuspid valve regurgitation;” (2) “tricuspid valve replacement;” (3) “percutaneous heart valve bioprosthesis;” and (4) “EVOQUE.” The review included all published, peer-reviewed English language literature up to March 29, 2024. This review had no minimum requirements for patient enrollment or patient follow-up. Shortly prior to publication of this proposed decision memo, the one-year results of the only randomized control trial (RCT) of EVOQUE were published (October 30, 2024) and results from that trial have been incorporated into the evidence and analysis sections.

Of 805 references identified in the searches, two studies and three case reports in nine publications as well as the SSED were deemed eligible for inclusion. Following publication of the RCT, priority was given to the pivotal trials for this analysis.

Summary of Evidence

One RCT, TRISCEND II, was reviewed. The published literature evaluated also encompassed two publications reporting on data generated in the non-randomized pivotal TRISCEND trial, as well as the publicly available Summary of Safety and Effectiveness Data (SSED) that formed the basis of the FDA’s premarket approval of the EVOQUE system.

The TRISCEND and TRISCEND II trials enrolled patients with an average age ranging from 71 to 86 years and 71% to 76% of all included patients were female. Information on race was provided in the TRISCEND II trial report, with no reported subgroup analyses by race or sex. Reviewed studies reported on outcomes from 30 days to one year. At baseline, patients possessed a variety of comorbidities, had symptomatic TR of at least moderate severity, were considered at high risk for valve surgery, and deemed eligible for TTVR by a heart team.

An overview of studies included in this systematic review is provided in Table 1. For a more detailed summary of the peer-reviewed studies that preceded TRISCEND II, see Appendix B.

Table 1. Key Studies Reviewed to Assess TTVR for TR

Study				Patients				Outcomes
#	Author	Year	Study Design	(n)	Age Mean years (SD)	Female (%)	Follow-up	TR grade severity	NYHA functional class	6MWD	KCCQ score (QoL)	All-cause mortality	Cardiovasc. Mortality	HF Hosp.	Safety Events (p< 0.05)
Randomized Control Trial
	Hahn et al. (TRISCEND II Pivotal Clinical Trial)	2024	Randomized 2:1, Stratified by site, Cross-over	Device (randomized): 267 Control: 133	D: 79.3 (7.4) C: 79.1 (7.8)	D: 74.9 C: 76.7	1-yr	TR grade moderate or less: Device 99.1% (N=212) Control 16.1% (N=87)	Improve ≥1 class: D: 78.9% (N=213) C: 24.0% (N=96)	Improve ≥30 meters: D: 47.6% (N=185) C: 31.8% (N=88)	Improve ≥ 10 points D: 66.4% (N=211) C: 36.5% (N=96)	D: 11.6% (N=259) C: 10.5% (N=133)	D: 8.5% (N=259) C: 7.5% (N=133)	Events/ patient-year, wins: D: 9.7% C: 10.0%	Severe bleeding (P=0.003): D: 15.4% C: 5.3% New permanent pacemaker (PM) (P<0.001): D: 17.8% C: 2.3% New PM in PM-naïve pt (P<0.001): D: 27.8% C: 3.8%
Prospective Single-Arm Studies
	Kodali et al. (TRISCEND, 1-Year results)	2023	Prospective, interventional	176	78.7 (7.3)	71	1-yr	Reduction of: 1 TR grade: 100 % ≥ 2 TR grade: 97.6 % ≥ 4 TR grade: 33.3 % n=84	BL vs. 1-yr, n (%): Class I or II: 25.8 vs. 93.3 (P < .001). Class III or IV: 3.4 vs. NR 6.7 n=89	Mean (SD): + 56.2 (117) m (P < .001) n=102	BL vs. 1 yr, mean (SD): 46.0 (21.8) points to 71.7 (22) points (P < .001). n=102	9.1%	n (%): 14 (9.4)	74.9% relative reduction, 12 mos before/ after procedure	Severe bleeding (1-yr): 25.5% New PM in PM-naïve (30-d): 13.3%
	Kodali et al. (TRISCEND, 30-day results)	2022	Prospective, interventional	Enrolled = 56 30-d f/u = 53	79.3 (7.7)	76.8	30-days	30 days, reduction %: ≥ 1 grade: 100 ≥ 2 grades: 98.1 ≥ 3 grades: 80.7 ≥ 4 grades: 26.9 5 grades: 11.5	BL vs. 30-days, n/N (%): III/IV: 49/56 (87.5) at BL vs. I/II: (78.8) 41/52 at 30-days p<0.001	BL to 30-Days, mean (SD): + 49.8 (80.5) m (P <0.001)	BL to 30-Days, mean (SD): 19.0 (20.5) points (P <0.001)	30-Day: 3.6% (n=2)	n (%): 1 (1.8%)	NR	Composite MAE: 26.8% CV death: 1.8% Reintervention: 3.6% Access site/vasc. Complication: 1.8% Severe bleeding: 26.8% Device embolization: 3.6% Device migration: 1.8% New PM: 11.1%

Note: SSED: Summary of Safety and Effectiveness Data; NYHA: New York Heart Association Functional Classification; TR: Tricuspid Regurgitation; 6MWD: 6-min walk distance; KCCQ: Kansas City Cardiomyopathy Questionnaire; QoL: Quality of Life; HF: Heart Failure; BL: Baseline; MLHFQ: Minnesota LIVING WITH HEART FAILURE Questionnaire; Echo: Echocardiogram; MAE: major adverse event; CV: cardiovascular; PM: pacemaker

E. Assessment of the Evidence

i. Trial Design and Enrollment Criteria: Pivotal Trials

Two pivotal trials informed FDA clearance of the EVOQUE device. The Edwards EVOQUE Tricuspid Valve Replacement: Investigation of Safety and Clinical Efficacy after Replacement of Tricuspid Valve with Transcatheter Device (TRISCEND) Study was a single arm, prospective, multicenter, open-label, interventional feasibility and safety study evaluating the safety and performance of the EVOQUE system in the treatment of patients with symptomatic, moderate or greater TR despite therapy, or patients with prior HF hospitalization for TR. Two published studies (Kodali et al., 2022; Kodali et al., 2023) reported results at 30-day and 1-year follow-up. Patients with at least moderate secondary or degenerative TR despite therapy were eligible and therapy was at investigator discretion. Anticoagulation was recommended for 6 months following the procedure. The original exclusion criteria included anatomic unsuitability, prior TV repair or replacement, severe pulmonary hypertension, left ventricular ejection fraction (LVEF) less than 25%, estimated glomerular filtration rate (eGFR) of 25 mL/min/1.73 m² or on dialysis, or any comorbidity excluded by the investigator (Kodali et al., 2022). Eligibility requirements changed during the trial to also exclude patients with hemodynamic instability, severe RV dysfunction, refractory HF requiring advanced intervention, or need for emergent surgery or planned cardiac surgery in the next 12 months (Kodali et al., 2023), although the impetus for this change was not described. Baseline, discharge, and 30-day post-procedure TTE and screening and intraprocedural TEE were performed.

The second pivotal trial, the TRISCEND II study, is an ongoing multicenter, prospective, open-label, randomized control interventional study conducted across 45 sites in the US and Germany. The trial used a 2:1 randomization of 400 eligible subjects to device plus optimal therapy (OMT) vs. OMT alone. Inclusion criteria included signs or symptoms of TR or prior HF hospitalization from TR with at least severe TR on TTE, despite OMT and on OMT, as defined by the investigator, at the time of TR assessment with echocardiography. The study heart team determined eligibility for TTVR. The patient population for TRISCEND II was highly selected, with 37 exclusion criteria listed in the trial protocol. Broadly, the exclusion criteria included: tricuspid valve anatomic contraindications, need for emergent or urgent surgery or any planned cardiac surgery within the next 12 months, hemodynamic instability, refractory heart failure requiring advanced intervention, currently participating in another investigational study, or having any condition that the investigators deem likely to limit the patient's ability to participate. Additional exclusions were LVEF <25%, severe RV dysfunction, pulmonary hypertension, previous tricuspid surgery or intervention, trans-tricuspid pacemaker or defibrillator lead under certain circumstances, etc. Follow-up clinic visits, which are still ongoing, occurred at discharge, 30 days, 6 months, 1 year, and will be continued annually through 5 years. Assessments during the patient site visits included but were not limited to targeted physical exams, laboratory measurements, imaging tests, and patient-reported health status.

The FDA used preliminary data reported in a summary of safety and effectiveness data (SSED) as the basis for premarket approval. The publicly available SSED reported on health status improvement at 6 months in the first 150 enrolled patients (Breakthrough Pathway Cohort) and provided partial data on the full, randomized cohort. Based on the findings from the TRISCEND II trial Breakthrough Pathway Cohort and Full Cohort, summarized in the SSED, FDA concluded that there was a reasonable assurance of safety and effectiveness of the EVOQUE system when utilized according to its Instructions for Use “for the improvement of health status in patients with symptomatic severe TR despite being treated optimally with therapy for whom tricuspid valve replacement is deemed appropriate by a Heart Team.” The one-year results of TRISCEND II were published on October 30, 2024.

ii. Other Publications

Two prospective (Fam et al., 2021; Webb et al., 2022) and two retrospective analyses (Stolz et al., 2023; Weckbach et al., 2023) of a multicenter, observational, first in human compassionate use study of the EVOQUE system were identified. These papers covered follow-up of the compassionate use patient cohort at 30 days (Fam et al., 2021), 1 year (Webb et al., 2022), and 2 years (Stolz et al., 2023). The fourth paper that analyzed this cohort retrospectively investigated the impact of TTVR on right ventricular reverse remodeling (Weckbach et al., 2023).

iii. Study Populations

Table 2 provides details of patient characteristics in TRISCEND and TRISCEND II, the pivotal trials included in this analysis. The average patient age in the two trials was 78.7 to 79.1 years. Most patients were female, ranging from 71% to 76% of patients studied. Race was captured in the TRISCEND Single-Arm study and TRISCEND II Pivotal trial. However, sub-analyses by race were not reported in the currently available peer-reviewed literature. Comorbidities commonly reported at baseline included atrial fibrillation (AF), systemic hypertension, and renal impairment. Trial subjects in TRISCEND had symptomatic TR that was at least moderate in severity, despite therapy as per investigator discretion. Enrollment in TRISCEND II was limited to patients with symptomatic TR despite therapy, graded as severe or greater. Available follow up in the pivotal trials ranged from 30 days to 1 year.

Table 2. Comparison of baseline patient characteristics in the TRISCEND and TRISCEND II trials.

	TRISCEND (enrolled)	TRISCEND II (mITT safety)
	EVOQUE (n=176)	EVOQUE + OMT (n=259)	OMT (n=133)
Age (yr), mean ± SD / mean (CI)	78.7 ± 7.33	79.3 (78.4, 80.2)	79.1 (77.8, 80.4)
Female, n (%)	125 (71.0)	194 (74.9)	102 (76.7)
Race, n (%)	NR	American Indian/ Alaskan Native:2(0.8) Asian:14 (5.4) Black or African American: 12(4.6) Native Hawaiian or Other Pacific Islander: 0(0.0) White: 195(75.3) Not available: 23(8.9) Other: 13 (5.0)	American Indian or Alaskan Native: 0(0) Asian: 8(6.0) Black or African American: 5(3.8) Native Hawaiian or Other Pacific Islander: 1(0.8) White: 98(73.7) Not available: 11(8.3) Other: 10(7.5)
TR Grade, %	Moderate: 11.9% Severe: 47.6% Massive: 16.7% Torrential: 23.8%	Severe: 47.1% Massive: 23.2% Torrential: 29.7%	Severe: 37.6% Massive: 25.6% Torrential: 36.8%
NYHA Functional Class, n (%)	Class I: 0% Class II: 25.8% Class III:70.8% Class IV: 3.4% (data presented graphically)	Class I: 2 (0.8) Class II: 70 (27.0) Class III:177 (68.3) Class IV: 10 (3.9)	Class I: 0 (0) Class II: 41 (30.8) Class III: 87 (65.4) Class IV: 5 (3.8)
TAPSE (mm), mean ±SD (%) / mean (CI)	15.3 ± 5.2 (46)	16.2 (15.4,16.9) n=151	15.8 (14.7,16.9) n=70

Legend: TAPSE: Tricuspid annular plane systolic excursion; NYHA: New York Heart Association, OPI: Other Pacific Islander; SD: Standard deviation; CI: Confidence interval; mITT safety: patients who had a study procedure attempted by skin incision to access the femoral vein for introduction of the study device or were treated with medical therapy

iv. Background Therapy

The TRISCEND single-arm study allowed therapy at investigator discretion, requiring stable diuretic doses for 30 days prior to the procedure in patients without diuretic intolerance. Maintenance of diuretic regimen for three months following procedure and addition of anticoagulation for up to 6 months post-procedure were recommended in the study guidelines. It should be noted, therefore, that background therapy varied depending upon patient need and was not uniform.

Patients enrolled in TRISCEND II received clinician-defined OMT in both the control and device groups. As in the TRISCEND single-arm study, OMT varied depending upon patient need and was not uniform. Baseline, 30-day, and 1-year medications for the device and control groups were reported in Table S10 of the trial report supplement (Hahn et al., 2024).

v. Intervention Setting

The TRISCEND single-arm study was a multicenter, single-arm, open-label, interventional study that enrolled patients across 22 sites in the US, Canada, and Europe. The TRISCEND II study was a multicenter, prospective, open-label, randomized controlled interventional study conducted across 45 sites in the US and Germany. As reported in the TRISCEND II trial publication, the number of patients enrolled at a site ranged from 1 to 39 and all sites identified, at minimum, a heart failure specialist, an echocardiologist, interventional cardiologist, and cardiac surgeon as members of the research team. To reduce the impact of a device learning curve on safety and effectiveness outcomes, each site was subject to a roll-in requirement that included a formal didactic and hands-on training program. Prior to randomization of patients into TRISCEND II, physicians and sites without prior experience were required to enroll into the “roll-in cohort,” 1-3 patients with successful device deployment.

vi. Endpoints

TRISCEND II:

The primary safety and effectiveness endpoint at 1 year was a win ratio (WR) on a hierarchical composite, using unmatched pairs. The hierarchical composite included, in rank order, all-cause mortality, right ventricular assist device (RVAD) implantation or heart transplant, TV surgical or percutaneous intervention, annualized rate of HF hospitalization, KCCQ score improvement of ≥ 10 points, NYHA functional class improvement of ≥ 1, and 6MWD improvement of ≥ 30 meters. The endpoint was adjudicated in the modified intent to treat safety population (mITT safety: patients with guide sheath insertion attempted and controls treated with therapy). Crossovers to device were permitted after completion of the 12-month follow-up visit and 22 patients crossed over within the one-year visit window (320–410 days after completing their one-year visit). The study was not powered to detect differences in each component of the composite primary outcome.

Secondary endpoints were divided into effectiveness, echocardiographic, and clinical. The secondary effectiveness endpoint analysis were tested in the modified intent to treat population (mITT: those who had undergone guide-sheath insertion and controls treated with therapy) using the hierarchical testing method: reduction in TR grade by ≥ 1 grade, reduction in NYHA functional class by ≥ 1 grade, change in QOL (KCCQ) from baseline, death and heart failure hospitalization, all-cause hospitalization, all-cause mortality, change in 6MWD from baseline.

Secondary clinical endpoints included all-cause mortality, heart failure hospitalizations, non-elective tricuspid valve intervention, durable RVAD implantation or heart transplant, and need for paracentesis at 12 months and annually through 5 years. Further, volume assessment by physical examination and patient questionnaire was evaluated at 30 days, 6 and 12 months, and annually through 5 years.

An echo core lab was used to adjudicate the secondary echocardiography endpoint of reduction in TR severity on TTE, comparing TTE at screening and at index procedure discharge for the intervention group. Numerous additional echocardiographic parameters were evaluated in both groups at baseline, discharge (intervention group), 30 days, 6 months, and 12 months, and will be evaluated annually through 5 years.

Functional status and quality of life were assessed. Baseline completion of a patient preference survey, Canadian Study of Health and Aging Clinical Frailty Scale, and Katz Index of Independence in Activities of Daily Living were combined with evaluation of NYHA classification, 6MWD, KCCQ, the EuroQuol 5 dimension, 5 level survey (EQ-5D-5L), and the Short Form Health Survey (SF-36v2) at baseline and at various points, including at 12 months, with a plan to measure annually through 5 years.

Other measures included laboratory parameters as well as economic endpoints and exploratory endpoints included technical success (periprocedural), device success (30 day, 6 month, 12 month, annually to 5 years), and procedural success (30 day) measures.

TRISCEND Single-Arm:

Endpoints were separately specified for safety and performance. A composite of major adverse events (MAEs) included cardiovascular mortality, myocardial infarction, stroke, unplanned dialysis/renal replacement therapy, bleeding (fatal, life threatening, extensive, major bleeding per Mitral Valve Academic Research Consortium), nonelective TV reintervention, major vascular and access site complications, major cardiac structural complication, and device-related pulmonary embolism (PE). Performance endpoints were device, procedural, and clinical success. Procedural success was defined as device deployment success with no clinically significant perivalvular leak (PVL) on TTE immediately post-procedure. Clinical success was characterized as procedural success without MAE at 30 days.

Echocardiographic endpoints were described in the 1-year results (Kodali et al., 2023) and consisted of reduction in TR grade from screening to discharge TTE. Additional reported parameters included mean valve gradient, cardiac output, stroke volume, right atrial volume, LVEF, inferior vena cava (IVC) diameter and respiratory variation, RV end-diastolic diameter (RVEDD), pulmonary artery systolic pressure (PASP), tricuspid annular plane systolic excursion (TAPSE), RV fractional area change (FAC) and hepatic vein flow reversal. Echocardiograms underwent independent core lab adjudication.

At baseline, 30 days, 6 months, and one year, clinical, functional, and quality of life (QoL) endpoints were assessed. Measures included New York Heart Association (NYHA) classification, Kansas City Cardiomyopathy Questionnaire (KCCQ), Short Form Health Survey (SF-36) version 2, and 6-minute walk distance (6MWD). Also assessed at 1 year and annually (projected through 5 years) were all-cause mortality, HF hospitalization, and non-elective TV re-intervention.

vii. Study Quality and Risk of Bias

Formal risk of bias assessment was not conducted. Under the framework of most risk of bias assessment tools, studies in which patients, clinical staff, investigators, and outcome assessors, such as echocardiographers, are not blind to study procedures are judged to be at high risk of bias (or ‘Poor’ study quality). Additionally, the published studies were insufficiently powered for conclusive evaluation of individual endpoints, including all-cause mortality and heart failure hospitalization. The follow-up periods limited the ability to critically assess important health outcomes and determine device durability.

Published outcomes in the randomized trial, TRISCEND II, emphasize quality of life outcomes, which are subject to bias in an open-label study. The primary endpoint succeeded on quality of life alone. Also notable in TRISCEND II is the 2:1 randomization, which may boost enrollment but compromise internal validity. To maintain adequate statistical power, a larger sample size is required in a 2:1 allocation than in a 1:1 ratio, a limitation acknowledged by the authors. Treatment preferences in an open-label study can impact participant behavior and subjective reporting. It is notable that significant dropout was observed in the small control group in the follow-up period, as well as high crossover to device when permitted by the protocol.

viii. Synthesizing the Clinical Trial Evidence

TRISCEND II Study Results

Trial results are provided in Table 1 and baseline characteristics of the study groups are provided in Table 2. Common comorbidities in trial patients included AF (TTVR+OMT: 96.1%, OMT: 92.5%), systemic hypertension (TTVR+OMT: 90.7%, OMT: 91.7), and chronic kidney disease (TTVR+OMT: 54.1%, OMT: 59.4%). At baseline, 38.2% of TTVR+OMT patients and 39.8% of OMT patients had a CIED. Between group differences were reported as statistically non-significant.

Of 267 subjects randomized to the intervention arm, the procedure was attempted in 259 subjects (mITT safety population) and device was attempted in 258 (mITT effectiveness population), with 247 device implantations performed (as-treated population). Three procedures were converted to open surgery (1.2%). One year follow-up was completed in 215 device subjects. All 133 subjects randomized to the control arm (ITT population) received therapy (mITT safety/effectiveness population). Of these, 97 completed a one-year follow-up visit.

At one year, all-cause mortality had occurred in 30 intervention subjects (11.6%), with 9 deaths in the intervention group (3.5%) in the first 30 days. In the control group, no deaths occurred in the first 30 days, and total mortality was 10.5% at one year. Cardiovascular mortality occurred in 22 intervention subjects (8.5%) by one year, 8 of these (3.1%) occurring within 30 days of procedure. At one year, mortality was 7.5% in the control group. Kaplan-Meier estimates for death from any cause were mean (±SE) of 12.6±2.1% vs. 15.2±3.3% in device vs. control, respectively, at one year. All-cause and cardiovascular mortality differences between groups were not statistically significant.

Significant safety events were more common in the intervention group. Statistically significant differences were seen in severe bleeding (TTVR+OMT 15.4%, OMT 5.3%; p=0.003) and arrhythmia/conduction disorder requiring permanent pacing (TTVR+OMT 17.4%, OMT 2.3%; p<0.001). New pacemaker placement occurred in 27.8% of all pacemaker-naïve patients randomized to the intervention group (most in the first 30 days) and in 3.8% of patients in the OMT group, with statistically significant difference between groups (p<0.001). New renal replacement therapy was initiated in 8 (3.1%) of the intervention group but this endpoint was not adjudicated in the control group for comparison.

The primary safety and effectiveness endpoint win ratio favored TTVR+OMT over OMT-only (WR: 2.02, p<0.001). Device group wins were dominated by performance on KCCQ-OS score and NYHA class improvement. In the device group, 66.4% of patients had an increase of ≥10 points on the KCCQ-OS score, 78.9% had a decrease of at least one NYHA class, and 47.6% increased 6MWD by ≥30 m, compared with 36.5%, 24%, and 31.8%, respectively, in controls.

Echocardiography adjudicated by the study’s core lab was available for 212 device subjects and 87 OMT subjects at one year. In the device group, prevalence of severe TR was 0.9% compared with 49.5% at baseline, with no documented massive (20.8% BL) or torrential (29.7% BL) TR in remaining subjects. No TR was seen in 72.6% of remaining subjects in the device group and TR was graded as mild on echocardiography in 22.6%. In the OMT group, 2.3% had no documented TR, and 16% had ≤ moderate TR.

ix. Evidence from Observational Studies

The literature search identified two observational studies of TTVR for TR described above. Overall, the included studies provided modest evidence regarding the effectiveness of TTVR. In TRISCEND, all-cause mortality at one year was 9.1%, using as the denominator all patients enrolled in the study. The 1-year composite MAE reported on 149 remaining trial subjects was 30.2%. New permanent pacing was required in 13.3% of patients without pre-existing CIEDs at 30 days, and no additional new pacemakers were placed after 30 days. Major bleeding had occurred in 25.5% of patients and non-elective reintervention was 4.0% at one year. Procedural success was 93.0% and clinical success 77.1%. Improvements were seen in TR grade following intervention, from 88.0% ≥ severe at baseline to 97.6% ≤ mild at one year. NYHA class III-IV declined from 75.4% at baseline assessment to 6.7% at one year visit. KCCQ score increased by 25.7 points on average, and average 6MWD increase was 56.2 m.

x. Limitations of Evidence

Because EVOQUE received FDA approval for tricuspid regurgitation in 2024, the literature for TTVR is limited. The two pivotal trials, TRISCEND and TRISCEND II, and a small cohort of patients enrolled in a compassionate use study represent the extent of published experience with this new technology.

Patients in the trials had various underlying causes of TR. Due to small sample sizes, subgroup analysis based on TR etiology is not possible, limiting understanding of the benefit of the intervention for specific pathophysiologic entities and disease phenotypes.

Lack of standardization of optimal therapy in the trials was partially an artifact of the many underlying causes of TR. Improvement in health outcomes following TTVR for each phenotype cannot be assessed in comparison to optimal therapy for TR in this circumstance. It is notable that a meaningful percentage of patients in the arm improved, suggesting that there was benefit from optimizing therapy. Given the trial design, the magnitude of benefit of the device over standardized OMT is unclear.

As there are not accepted criteria to guide which patients benefit from TV intervention, analysis of factors including severity of TR, underlying etiology, measures of cardiac remodeling, degree of hepatic and renal dysfunction, and relationship of TR improvement to morbidity and mortality are necessary to establish whether TTVR is reasonable and necessary for specific subgroups of Medicare beneficiaries.

The identified limitations of the reviewed published studies are summarized in the following evidence deficiencies:

Studies with larger sample sizes with long-term follow-up are needed to demonstrate improved health outcomes in general and identify patient characteristics to select patients most likely to benefit from TTVR, stratified by patient groups, including racial and ethnic minority groups and males;
More evidence is needed to identify which sizes of the EVOQUE valve are most appropriate for specific patients;
More evidence is needed to define the treatment conditions necessary to achieve optimal TTVR outcomes and reduce major adverse events (e.g., Heart Team evaluation, cardiac surgery program, echocardiographer requirements, operator training/experience, etc.);
Quality of life measures as stand-alone primary health outcomes or within a composite outcome (e.g., NYHA functional class, 6-min hall walk distance, Kansas City Cardiomyopathy Questionnaire (KCCQ)), should be demonstrated for a minimum of one year;
In composite outcome measures, physiologic, patient-reported, and other relevant health outcomes should be co-directional (i.e., all outcomes comprising the composite outcome should demonstrate movement in the same direction);
One or more objective clinical outcomes, especially mortality and hospitalizations, should be demonstrated for at least two years; if studies combine patients from multiple countries, analyses should be stratified by country;
More evidence is needed for patients with chronic kidney disease and patients with indwelling cardiac implantable electronic devices;
The durability of treatment benefit for hospitalization, total hospitalizations, or survival should be demonstrated for a minimum of two years.

Patients enrolled in TRISCEND and TRISCEND II had a mean age over 65 years and most patients had at least one comorbidity; however, there are limits in extrapolating trial results to the broader pool of Medicare beneficiaries eligible for TTVR. TRISCEND and TRISCEND II were trials conducted on select populations with stringent inclusion and exclusion criteria and patients were assessed, treated, and managed in highly controlled settings. Exclusion criteria were extensive in TRISCEND II, limiting generalizability of the trial results. Findings cannot be considered applicable to a patient population with a greater breadth of characteristics and receiving variable clinical care. In the SSED, the FDA noted the need for a post-approval study “to assess the real-world performance of the EVOQUE system and the clinical outcomes of the device in patient populations underrepresented in the TRISCEND II pivotal trial.”

xi. Considerations for Further Research

CMS maintains an interest in monitoring important health outcomes to better inform our understanding of the risk/benefit profile, particularly for subpopulations, as coverage for TTVR is considered for the treatment of severe-or-greater symptomatic tricuspid regurgitation.

To better serve Medicare beneficiaries, additional evidence should address:

Sufficient patient enrollment to have confidence that expected outcomes will be reliably achieved in real-world use;
Sufficient representation of Medicare beneficiaries, disease subgroups, and minority populations in clinical studies of the EVOQUE valve to demonstrate generalizability to those populations;
Clinical studies of sufficient duration to demonstrate that observed outcomes are durable to an extent appropriate to the item/service;
Clinical studies clarifying the site of service, clinical staffing, and experience profiles associated with expected outcomes in real-world use of the transcatheter tricuspid valve.

Based upon a review of published studies for interventions for tricuspid regurgitation, CMS believes that evidence published in the peer-reviewed literature should critically evaluate one or more of the following outcomes through a minimum of 1 year:

Quality of life as stand-alone primary health outcomes or within a composite outcome with a change measure from baseline to prespecified time points;
Exercise capacity measures (6MWD);
Functional assessments as meaningful primary health outcomes within a composite outcome.

CMS believes that evidence published in the peer-reviewed literature should critically evaluate one or more of the following outcomes through a minimum of 2 years:

For right heart failure or severe tricuspid regurgitation, surrogate or intermediate endpoints (e.g., need for re-intervention or replacement of the tricuspid valve; complications related to right heart pacing);
Heart failure hospitalization;
Heart failure hospitalization equivalent events;
Total hospitalizations;
Total mortality;
Survival.

F. Evidence-Based Guidelines

We identified two professional society guidelines relevant to the contemporary care of patients with TR. Both guidelines focus on appropriate and surgical care of the TR patient. Only the European guideline makes recommendations related to TTVR.

European Society of Cardiology (ESC) / European Association for Cardio-Thoracic Surgery (EACTS) Guidelines 2021 (Vahanian et al., 2022):

In primary tricuspid regurgitation, “surgery should be considered in asymptomatic or mildly symptomatic patients with isolated severe primary tricuspid regurgitation and RV dilatation who are appropriate for surgery.(IIa)”

In secondary tricuspid regurgitation, “surgery should be considered in patients with severe secondary tricuspid regurgitation (with or without previous left-sided surgery) who are symptomatic or have RV dilatation, in the absence of severe RV or LV dysfunction and severe pulmonary vascular disease/hypertension.”

“Transcatheter treatment of symptomatic secondary severe tricuspid regurgitation may be considered in inoperable patients at a Heart Valve Centre with expertise in the treatment of tricuspid valve disease.” Transcatheter treatment “may be considered by the Heart Team at experienced Heart Valve Centers in symptomatic, inoperable, anatomically eligible patients in whom symptomatic or prognostic improvement can be expected.”

In patients with bioprosthetic failure, transcatheter valve-in-valve implantation in the tricuspid position “may be considered in selected patients at high-risk for surgical reintervention.”

American College of Cardiology (ACC) / American Heart Association (AHA) Joint Committee on Clinical Practice Guidelines 2020 (Otto et al., 2021):

“In appropriately selected symptomatic patients with AF-related severe TR, quality of life and symptoms can be improved by surgical intervention for TR. In patients undergoing intervention, overall outcomes are better in those without severe RV dysfunction or end-organ damage.”

“Correction of symptomatic severe primary TR (Stage D) in patients without left-sided valve disease would preferentially be performed before the onset of significant RV dysfunction or end-organ damage. Randomized studies of early intervention are lacking, and the benefit might be limited by the risk of intervention, suboptimal reduction in TR severity, or suboptimal durability of currently available approaches to tricuspid valve repair and replacement.”

“In patients with signs and symptoms of right-sided HF and severe isolated secondary TR attributable to annular dilation (in the absence of pulmonary hypertension or left-sided disease) who are poorly responsive to therapy (Stage D), isolated tricuspid valve surgery can be beneficial to reduce symptoms and recurrent hospitalizations. (2a)”

“In asymptomatic patients with severe primary TR (Stage C) and progressive RV dilation or systolic dysfunction, isolated tricuspid valve surgery may be considered. (2b)”

“In patients with signs and symptoms of right-sided HF and severe TR (Stage D) who have undergone previous left-sided valve surgery, reoperation with isolated tricuspid valve surgery may be considered in the absence of severe pulmonary hypertension or severe RV systolic dysfunction. (2b)”

The guideline does not address transcatheter tricuspid valve interventions.

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

We identified five relevant professional consensus documents. These provide context for the standard of care in managing TR.

Scientific Statement from the American Heart Association 2024 (Davidson et al., 2024)

Use of the 5-grade scale (mild, moderate, severe, massive, and torrential) for reporting of TEE “allows a more specific classification of TR that is severe or greater.”

“At present, there are no guidelines to determine whether an individual patient may be better suited for transcatheter TV repair or replacement.”

“It is…also important to consider the lifetime management of patients with TV disease. When a young patient presents with severe TR, they will need a durable device and ideally the potential option of a second transcatheter device in the future should the first device deteriorate over time… For an elderly, frail patient, alleviating symptoms and improving their present quality of life may be the primary goal; therefore, long-term lifetime management may not be as applicable. As clinical studies continue, a greater understanding of device durability will allow clinicians to better advise patients about the long-term management of TV disease.”

A clinical consensus statement of the Heart Failure Association (HFA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the European Society of Cardiology 2024 (Adamo et al., 2024)

“Notably, there are no specific drugs (i.e. neurohormonal modulators) shown to have beneficial effects on the symptoms, clinical course and prognosis of patients with RHF and TR. Current guidelines clearly state that therapy (i.e. diuretics) should not delay TR intervention when indicated.”

“Recently, a dedicated risk model, the TRI-SCORE, was proposed to estimate in-hospital mortality in patients undergoing isolated TR surgery. Notably, most of the variables included in this model (age ≥70 years, NYHA functional class III–IV, right-sided HF signs, daily dose of furosemide ≥125 mg, glomerular filtration rate <30 ml/min, elevated total bilirubin, LVEF <60%, moderate/severe RVD) are HF- and congestion-related confirming the prognostic importance of HF stage and presentation.”

“Further randomized controlled studies, including more symptomatic patients and correctly powered for hard endpoints and with long follow-up are urgently needed to clearly understand whether TR correction may improve prognosis in these patients in addition to the benefit in quality of life.”

Tricuspid regurgitation management: a systematic review of clinical practice guidelines and recommendations (Ricci et al., 2022)

“There is consensus on definition of TR severity, utility of multimodality imaging and right heart catheterization, management of symptomatic and asymptomatic TR, choice of surgical techniques, and indications for conservative management.”

“Gaps in evidence include: TTVI indications, endpoint definition for TTVI, risk assessment models, indications for minimally invasive tricuspid valve surgery.”

“Pending results of RCTs of TTVI, currently only the European guidelines makes (sic) a weak, class IIb indication for the use of transcatheter treatment of TR in symptomatic, inoperable, and anatomically eligible patients, in whom symptomatic or prognostic improvement can be expected according to evaluation by the heart team.”

“The clinical efficacy of TTVI and optimal candidate profile are yet to be delineated, and will need to be tested in randomized controlled trials. The current evidence is limited to small numbers of patients, but demonstrates a favourable safety profile and improvement in clinical symptoms.”

Uncertainties and challenges in surgical and transcatheter tricuspid valve therapy: a state-of-the-art expert review (Chang et al., 2020)
The review emphasized that clinical data on most of the devices are not sufficient to draw conclusions about their safety and efficacy. They recommended that when evaluating the early clinical data, the following issues should be addressed: (1) Patients enrolled in first-in-man studies differ markedly in terms of TR severity, EROA, vena contracta area, with some studies focusing on severe TR as compared to torrential TR. This must be considered when efficacy in TR reduction and potential for clinical improvements of different devices/approaches are assessed. (2) General application and comparison between studies are hindered by the differences in study design. (3) Clinical and echocardiographic endpoints, device, and procedural success, and optimal TR reduction should be clearly defined. (4) Most of the surgical data on the TV are derived from patients who underwent left-sided heart surgery which is not fully transferable to dedicated transcatheter interventions.

Tricuspid Valve Academic Research Consortium Definitions for Tricuspid Regurgitation and Trial Endpoints (Hahn et al., 2023)
The Tricuspid Valve Academic Research Consortium (TVARC) has published guidance on meaningful efficacy endpoints in trials of tricuspid valve interventions. As part of the TVARC analysis, the authors identified important knowledge gaps, including around how to stratify patient outcomes, value of the extended TR severity grading scale, how to define optimal therapy in TR, how to define risk of adverse outcomes with different management strategies, and how to determine patient selection, goals of therapy, and clinically meaningful outcomes for transcatheter device therapies. The goal of defined trial endpoints is to facilitate closure of these knowledge gaps.

Endpoints of value that were highlighted were all-cause mortality as the primary mortality endpoint; reporting of all-cause hospitalization as well as CV and HF hospitalizations, including whether valve or procedure related; and reporting of “heart failure hospitalization equivalent” events, which include aggressive outpatient management of heart failure exacerbations. The Consortium recommended adjudicating cardiovascular mortality as a secondary outcome and asserted that procedure or device relatedness should be reported. Patient-centered outcomes were considered important, but the authors highlighted the placebo effect inherent in the use of KCCQ, acknowledging up to 10-12 point improvements seen in the control arms of heart failure trials. For functional outcomes, a 25-50 m increase in 6MWD was described as clinically significant, depending on functional level at baseline.

Regarding imaging endpoints, the authors acknowledge the shortcomings of quantitative methods in echocardiography following device implantation and advocate for development of consensus algorithms for post-intervention imaging. Included in imaging parameters were cardiac output, hepatic vein flow reversal, and measures of RV function and RV-PA coupling, and the authors stated that studies on reverse remodeling following TV intervention have reported conflicting results. Finally, the authors addressed biomarkers and end-organ function as important endpoints. Natriuretic peptide levels, reduction in septal shift, and CA 125 may be good indicators of cardiac function, and markers of liver and renal function may improve with reduced congestion. Biomarkers recommended as endpoints were included in the document.

The guidance document also addressed important safety endpoints, including TV reintervention, bleeding, injuries (vascular, access-related, and cardiac), conduction disturbances and complications involving CIEDs, neurological events due to paradoxical emboli, PE/DVT, and acute kidney injury. The authors made an important distinction between device- and procedure-related complications, providing guidance on how to adjudicate and report and acknowledges differences in expected complications between repair and replacement procedures, advocating for use of the TVARC definitions by clinical events committees for objectivity and consistency.

Finally, measures of success were outlined for both the short- and long-term. Intraprocedural success was defined as successful device deployment and satisfactory immediate performance of the device, without serious complications. Clinical success was defined as correct positioning of the device with adequate function, without procedure related complications, need for reintervention, or readmission for TR. Additionally, clinical success at ≥ 30 days incorporates valve performance, MAE, clinical outcomes, functional status, and quality of life. The authors acknowledge an intent to simplify success endpoints compared with mitral valve criteria for ease of implementation.

H. Appropriate Use Criteria

There are no relevant, published appropriate use criteria.

I. Public Comment

CMS uses the initial public comments to inform its proposed decision. Public comments that cite published clinical evidence give CMS useful information. Public comments that contain 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.

First Comment Period: June 20, 2024 – July 20, 2024

During the first 30-day public comment period CMS received 58 comments. Of these comments, two were omitted from publication on the CMS website due to excessive personal health information content, for a total of 56 comments posted to the CMS website. The majority of commenters spoke positively of the use TTVR. A few commenters did not support coverage of TTVR because of limited evidence. All comments that were submitted during the comment period without personal health information may be viewed by using the following link https://www.cms.gov/medicare-coverage-database/view/ncacal-public-comments.aspx?ncaId=314&fromTracking=Y&.

The majority of comments were anecdotes provided by physicians who utilized TTVR among their patients. Three comments were received from technology manufacturers, including Edwards Lifesciences, Medtronic, and VDyne, Inc. Two comments were received from trade associations, including the Advanced Technology Association and the Device Manufacturers Association. Three comments were received from professional associations, including Doctors for America, the Doctors for America FDA Task Force, and a joint comment from the American Association for Thoracic Surgery, the Association of Black Cardiologists, the American College of Cardiology, the American Society of Echocardiography, the Heart Rhythm Society, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons. Two comments were received from patient/consumer advocacy groups, including Heart Valve Voice US and the Heart Valve Disease Policy Task Force. One comment was received from the Patient, Consumer, and Public Health Coalition. One comment was received from the Stanford Byers Center for Biodesign Policy Program.

Second Comment Period: December 19, 2024 – January 18, 2025

Publication of this proposed decision initiates the second 30-day public comment period. CMS will summarize and provide detailed responses to the public comments when issuing the final decision memorandum.

J. Health Disparities

The included studies provided limited data on the effects of TTVR stratified by gender, race/ethnicity, and other demographic factors. Conclusions cannot be made about health disparities in the treatment of tricuspid regurgitation with TTVR. These gaps in the data were recognized by the FDA and in the FDA approval order for EVOQUE, the applicant was required to conduct a post approval study that includes evaluation of all-cause mortality, stroke, TV reintervention, and hospitalization through 5 years of follow up in specified underrepresented racial and ethnic groups.

CMS is interested in broader evidence on characteristics predicting successful outcomes, including the influence of sex and race/ethnicity. Male patients were underrepresented in the trials and there is no evidence in the peer-reviewed literature assessing the impact of race/ethnicity following TTVR for tricuspid regurgitation. In addition, CMS is interested in information on access to TTVR by race/ethnicity to assess whether unintended barriers might impede TTVR access for minority populations.

IV. CMS Coverage Analysis

A. CMS Coverage Authority

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

When the available evidence is insufficient to demonstrate that the items and services are reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member under section 1862(a)(1)(A) of the Act, coverage with evidence development (CED) has been used to support evidence development for certain items and services that are likely to show benefit for the Medicare population. [1] CED has been a pathway whereby, after a CMS and AHRQ review, Medicare covers items and services on the condition that they are furnished in the context of clinical studies or with the collection of additional clinical data.[2] (See CMS’ CED Guidance Document.) CED relies primarily on the statutory exception in section 1862(a)(1)(E) of the Act, which effectively permits Medicare payment for items and services that are reasonable and necessary to carry out research conducted pursuant to section 1142 of the Act.

Section 1142 of the Act describes the authority of AHRQ to conduct and support research that appropriately reflect the needs and priorities of the Medicare program.[3]

B. CMS Analysis for Coverage of TTVR for TR

1. Rationale for Coverage Requirements for TTVR for TR (Patient, Physician, and CED Study Criteria)

The Centers for Medicare & Medicaid Services (CMS) proposes to cover transcatheter tricuspid valve replacement (TTVR) under Coverage with Evidence Development (CED) for the treatment of symptomatic tricuspid regurgitation graded as at least severe according to the provisions in sections I.B (Coverage Criteria) and I.C (Other Uses of TTVR) under the Proposed Decision section of this document, which are explained below.

Context of care:
1. Patient Criteria:

Despite optimal therapy (OMT), patients must have symptomatic TR graded as at least severe with tricuspid valve replacement being considered as appropriate by a heart team.

The patient criteria reflect the TRISCEND II trial inclusion criteria and FDA labeled indication. TRISCEND II, the only randomized trial of the EVOQUE system, enrolled patients with severe-or-greater TR, as graded on the 5-grade classification, with changes in echocardiographic severity of TR reported in the trial using the 5-grade classification. The FDA label applies to patients with severe TR and CMS presumes that the term, “severe” in the label is inclusive of severe, massive, and torrential TR based on the TRISCEND II data reviewed in the SSED. Therefore, we are proposing that patients undergoing TTVR should also have TR graded as at least severe.

2. Physician Criteria
The patient (preoperatively and postoperatively) is under the care of a heart team, which includes, at minimum, the following:

Cardiac surgeon;
Interventional cardiologist;
Heart failure cardiologist;
Electrophysiologist;
Multi-modality imaging specialists; and
Interventional echocardiographer.

All of the specialists listed above must have experience in the care and treatment of patients with tricuspid regurgitation.

TTVR Heart Team Composition: The multi-disciplinary heart team is a patient-centered concept that supports evidence-based decision making and promotes the best possible outcomes. We propose that the heart team provide comprehensive pre-procedural evaluation of a patient’s care options, collaborative peri-procedural care, and post-procedural care until the patient’s outpatient condition is stabilized following TTVR, allowing for transition to a community cardiologist for routine care. This requirement is consistent with the FDA label for the EVOQUE system, and management of patients with cardiac valvular disorders, consensus documents supporting the concept of a heart team include European Society of Cardiology (ESC) / European Association for Cardio-Thoracic Surgery (EACTS) Guidelines 2021, which states, “Decisions concerning treatment and intervention should be made by an active and collaborative Heart Team with expertise in valvular heart disease (VHD), comprising clinical and interventional cardiologists, cardiac surgeons, imaging specialists with expertise in interventional imaging, cardiovascular anaesthesiologists, and other specialists if necessary (e.g. heart failure specialists or electrophysiologists).”

Cardiac surgeon: CMS recognizes the importance of the cardiac surgeon to the integrity and quality of a transcatheter valve program, as articulated in the 2018 AATS/ACC/SCAI/STS Expert Consensus Systems of Care Document: Operator and Institutional Recommendations and Requirements for Transcatheter Aortic Valve Replacement and the subsequent consensus statements on transcatheter valves. Guidelines on the necessity of surgical consultation and surgeon availability before, during, and following valve procedures have been consistent and are well-accepted in the clinical community. FDA labeling for EVOQUE specifies that “the implanting physicians must have prompt access to facilities with the necessary equipment, instruments, supplies, and personnel to perform emergency tricuspid valve surgery, if required.” Such rescue procedures mandate the inclusion of a cardiac surgeon.

Interventional cardiologist: Interventional cardiologists are universally recognized as providers of catheter-based structural heart interventions and structural heart interventions are specified in interventional cardiology fellowship training requirements. European Society of Cardiology (ESC) / European Association for Cardio-Thoracic Surgery (EACTS) Guidelines 2021: “Expertise in interventional and surgical management of coronary artery disease (CAD), vascular diseases, and complications must be available.”

Heart failure cardiologist: As supported by multiple consensus documents, including the American College of Cardiology (ACC) / American Heart Association (AHA) Joint Committee on Clinical Practice Guidelines 2020, the European Society of Cardiology (ESC) / European Association for Cardio-Thoracic Surgery (EACTS) Guidelines 2021, and A clinical consensus statement of the Heart Failure Association (HFA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the European Society of Cardiology 2024, right heart catheterization (RHC) can be critical to the decision-making of the heart team. Diagnostic RHC is often performed by heart failure cardiologists as part of comprehensive management of patients with complex heart failure. These recommendations underscore the importance of attentive, expert management of patients with TR by heart failure specialists familiar with the complexities of TR.

Electrophysiologist: The inclusion of an electrophysiologist (EP) on the heart team for TTVR is based on the frequency of complications related to the conduction system and the need for new implantation of pacemakers in a high percentage of device recipients in the pivotal RCT. Patients with pre-existing CIEDs may require expert EP evaluation as part of the heart team’s process of determining a preferred treatment for TR, and all clinical trial sites in TRISCEND II had an electrophysiologist identified as a member of the research team.

Multimodality cardiac imaging specialists: Multimodality cardiac imaging specialists are also necessary to the success of a TTVR heart team. Comprehensive, multimodality cardiac imaging requires expertise in the fundamentals of complex imaging modalities as well as an understanding of cardiac structure, function, and pathophysiology, as conferred through advanced post-graduate training dedicated to cardiovascular imaging, following radiology residency or cardiology fellowship. This requirement for expertise is reflected in the ESC/EACTS statement of core membership in the valvular heart team, in which the authors state that “Cardiac MRI (CMR) and Cardiac CT may be required for structural evaluation,” and the AHA states in its 2024 Scientific Statement that, “a comprehensive evaluation of the RV should be performed and may require the use of multimodality imaging.” A clinical consensus statement of the Heart Failure Association (HFA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the European Society of Cardiology 2024 (Adamo et al., 2024) acknowledges that, “the importance of a novel, multimodality approach to TV imaging is increasingly recognized.” According to Tricuspid regurgitation management: a systematic review of clinical practice guidelines and recommendations (Ricci et al., 2022), the utility of multimodality imaging is a matter of consensus, stating that, “multimodality cardiovascular imaging plays a major role in the diagnosis, prognosis, and management of valvular heart disease.” Given that multimodality imaging expertise may not reside in a single individual in any given institution, this expertise may need to be provided by a collaborative group of cardiovascular imaging experts, as seen amongst the research teams in the TRISCEND II trial.

Interventional Echocardiographer: We are specifying a need for expertise in interventional echocardiography due to the complexity of visualization of the tricuspid valve and the need for continuous echocardiographic guidance during placement of the transcatheter tricuspid valve. Literature in support of this complexity and supporting this requirement can be found in the ESC/EACTS guideline, which establishes a requirement for “intraprocedural transesophageal echo, preferably 3D, is used to guide transcatheter mitral and tricuspid valve procedures and to assess the immediate result of surgical valve operations. The guideline supports use of the 5-level grading system…” The American Society of Echocardiography has published a guideline outlining competencies for echocardiographic guidance of structural heart disease endorsed by the Society of Cardiovascular Anesthesiologists and multiple international echocardiography societies, that describes the tricuspid valve as “more difficult to image than the mitral valve” and endorses and describes requirements for level III interventional echocardiography (Little et al., 2023). FDA labeling for EVOQUE specifies that “Facilities that intend to perform an implantation procedure utilizing the EVOQUE system must have access to cine fluoroscopy and transesophageal echocardiography (TEE) throughout the procedure” (FDA, 2024).

3. Coverage with Evidence Development

CMS acknowledges limitations in the published evidence available to assist the heart team in optimal patient selection for TTVR. Because evidentiary gaps remain relative to optimization of patient selection for TTVR, CMS will carefully monitor and assess patient outcomes during CED and through evidence published in the peer reviewed literature.

All CMS-approved CED studies must meet the patient and physician criteria above and include:

Rationale for (a):

All-cause mortality is a core patient-centered outcome that accounts for competing causes of death without further adjudication and appears in composite primary outcomes of reviewed trials along with HF hospitalizations. In their endpoints guidance (Hahn et al., 2023), the TVARC prioritized all-cause mortality in studies of trans-catheter valves due to the observation of death from non-cardiac sequelae of TR, such as hepatic and renal disease. The endpoints guidance also prioritizes all-cause hospitalization as well as CV and HF hospitalizations. The TRISCEND II trial did not show statistically significant differences in all-cause or cardiovascular mortality between groups at one year.

The 24-month minimum period for CED studies expands evidence for durability of outcomes beyond past trials.

Each component of a composite outcome must be individually reported to assess which component(s) is(are) driving the outcome. For example, if a substantial reduction in a composite of all-cause mortality and HF hospitalizations were driven by the latter, and mortality actually increased slightly, that benefit (substantially decreased hospitalizations) and harm (slightly increased mortality) would be important for physicians and patients to know when making decisions.

b) An active comparator.

Rationale for (b):
Benefits and harms cannot be assessed without a comparator. An “active comparator” is inherent in RCTs that prospectively compare randomized intervention and control groups, but may be seen in other study designs, such as those employing propensity-score matching or instrumental variables. The latter studies can be many times larger than RCTs, and we believe can help fill in evidence gaps, especially for subgroups, left in the wake of the foundational but limited studies of TTVR.

c) A care management plan that includes the experience and role of each member of the heart team described in section I.B.2 and IV.B.1.

Rationale for (c):
The trials that generated the promising evidence for TTVR were performed in highly-specialized centers with expertise at transcatheter valve intervention. No data are available on the selection criteria for centers and operators utilized in the trials, and the randomized trial utilized a roll-in period prior to randomization of patients to develop competency in the performance of the procedure. Active data collection on treatment conditions, including operator, facility, and procedure team characteristics, is needed in CED studies to understand conditions that can replicate or exceed those trial results. The entire care plan that details the experience and role of each member of the heart team, as well as patient outcomes stratified by operator and facility characteristics, developed by study investigators and embedded in CED study protocols would provide an evidence-based roadmap for real-world clinical care after CED studies are completed.

d) Design sufficient for subgroup analyses by:

Age;
Sex;
Race and ethnicity;
Patient, practitioner, and facility level variables that predict the primary outcomes of the study;
Left ventricular ejection fraction (by guideline-defined subgroups);
Previous tricuspid surgery or intervention;
Severe aortic or mitral stenosis or regurgitation;
Patients with chronic kidney disease;
Patients with indwelling cardiac implantable electronic devices.

Rationale for (d):

More evidence is needed about the above subgroups to determine which patients will clinically benefit from, or be harmed by, TTVR, and under what treatment conditions. Note that patients with LVEF ≤ 25%, previous tricuspid surgery or intervention, severe aortic or mitral stenosis or regurgitation, and many with advanced renal disease, including on dialysis, were excluded from trials. We do not exclude these patients from CED studies, but instead require subgroup analysis of them, because these are core Medicare subpopulations or subpopulations with symptomatic TR. Further, the 2024 American Heart Association Scientific Statement on valvular disease asserts, “the presence of CIED leads may inform choices about transcatheter TV therapy for each individual. It must be understood how the location of the leads may or may not interfere with device placement and what pacemaker options will be available to the patient in the future once a transcatheter TV device is in place.” Understanding complications and outcomes in patients with CIEDs following TTVR is necessary to guide appropriate therapy in this group of patients with TR.

A CED study would be considered successful if it demonstrated:

Clinically meaningful improvement in health outcomes in Medicare beneficiaries following TTVR for treatment of symptomatic TR graded as severe or greater, in comparison to optimal therapy.
Satisfactory risk/benefit profile of TTVR compared with tricuspid valve surgery in Medicare beneficiaries with symptomatic TR, graded as severe or greater.
Specific patient and disease phenotype subgroups likely to benefit from TTVR.
Treatment conditions (operator, procedure, and facility characteristics) that contribute to expected outcomes described above.

At the time of writing this proposed decision memorandum, there are no published professional society guidelines for appropriate facility procedural volume requirements specific to TTVR programs. Further, there are no data on treatment conditions that support outcomes comparable to those in the published RCT on TTVR. CED requirements included in this proposed decision seek to create the evidence basis for a future NCD that articulates the treatment conditions that promote best patient outcomes following TTVR.

2. Evidence Questions – Answered

Our initial literature search and review of the evidence on the clinical utility of TTVR for Medicare beneficiaries with TR were guided by three general questions. Answers to these questions inform the overarching question of whether TTVR meets the reasonable and necessary standard under § 1862(a)(1)(A) of the Act.

Q1: Is the evidence sufficient to conclude that TTVR is reasonable and necessary for the treatment of Medicare beneficiaries with symptomatic tricuspid regurgitation graded as at least severe?

No - The quality and strength of the evidence, discussed above and below, are insufficient to make this determination and TTVR in this population is not reasonable and necessary under § 1862(a)(1)(A) of the Act because critical evidentiary gaps remain.

Benefits vs. Harms
The TRISCEND II trial was not powered to demonstrate superiority of individual components of the composite primary outcome and critical secondary endpoints, including all-cause mortality and heart failure hospitalizations, did not show statistically significant differences between groups. Performance on the primary outcome was driven by quality-of-life measures. In this context, it is impossible to assess true benefit against OMT alone, and treatment benefit for hospitalization, total hospitalizations, and survival have not been shown.

Because OMT was not standardized and because of the lack of analysis of disease subgroups, improvement in health outcomes following TTVR is not yet thoroughly understood in comparison to optimal therapy for TR. It is notable that a large percentage of patients in the arm improved, suggesting that there was benefit from optimizing therapy. Given the trial design, the magnitude of benefit of the device over standardized OMT is unclear.

Durability of potential treatment benefit remains a question, as comparative outcomes for hospitalizations and survival are available for only one year. Expected longitudinal outcomes of TRISCEND II beyond one year will be helpful to further understanding of the benefits of this intervention.

Specific risks of device implantation were identified in the trials, including arrhythmia/conduction disorder requiring new permanent PM and severe bleeding, the majority of which was determined to be procedure related. Differences between groups were statistically significant for these safety events.

Q2: Is there evidence that specific characteristics or comorbidities make patients more or less likely to benefit from TTVR?

Uncertain. – Evidence is lacking.

Subgroup Analysis
Patients in the trials had various underlying causes of TR, yet no subgroup analyses are available to support patient selection. Due to small sample sizes, subgroup analysis based on TR etiology is not possible, limiting understanding of the benefit of the intervention for specific tricuspid regurgitation phenotypes. In patients with LH failure, GDMT is well-defined. Analysis of this specific subgroup, with adherence to GDMT documented in the trial, would help to clarify device benefit in this population.

More evidence is needed for patients with chronic kidney disease and patients with indwelling CIEDs. TRISCEND II excluded patients with stage 5 CKD, as well as a proportion of patients with stage 4 CKD. As such, not all stages of CKD were represented and outcomes in patients with CKD cannot be inferred. Rhythm disturbances following device placement were significant and no data are available specific to outcomes in patients with pre-existing CIEDs.

Excluded Patients
Patients in the pivotal trials were highly selected, leading to significant evidence gaps related to generalizability of benefit. Some of the trial exclusion criteria are reflected in the FDA’s precautions in the device labeling. However, other exclusions that may be significant to outcomes were not included in the label. It cannot be concluded from the trials that benefits seen in the trials will accrue to patients with excluded characteristics.

Q3: Are specific treatment conditions necessary to achieve TTVR outcomes similar to those demonstrated in the clinical studies reviewed in this analysis?

Uncertain - There is little evidence to date that outcomes achieved in rigorous trials at highly selective sites can be replicated in the real world. Based on the totality of the evidence, CMS finds further justification that coverage under CED is appropriate. No stratification or subgroup analysis is available based on treatment conditions. There are no published studies or guidelines that address the impact of the qualifications of procedural operators on patient outcomes during and after TTVR. However, as with many interventions, data on transcatheter aortic valve replacement (TAVR), surgical valve replacement, and transcatheter mitral valve repair suggest that facility and/or practitioner volumes may predict patient outcomes (Vemulapalli et al., 2019; Salemi et al., 2019; Awtry et al., 2024; Vassileva et al., 2015; Chhatriwalla et al., 2019). The clinical trials of EVOQUE were performed in specialized centers with selected procedural operators with experience in performance of percutaneous structural heart procedures. However, no data are available on the operator, procedural, or facility characteristics that supported trial outcomes. Treatment conditions that provide an appropriate balance of satisfactory health outcomes and optimal patient access are currently unknown for this technology. We anticipate that CED with pre-specified analyses of the impact of operator and facility characteristics on outcomes, will help to guide future decisions relative to treatment conditions for TTVR.

C. Benefit Category

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

TTVR qualifies as:

Inpatient hospital services
Physicians’ services

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

D. Shared-Decision Making

CMS recognizes the importance of shared decision-making (SDM) in many clinical scenarios and has required shared decision making in other NCDs (for example, implantable cardiac defibrillators: https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=110). CMS supports clinician-patient SDM for TTVR for TR, but recognizes that there is no fully developed tool available at this time. CMS strongly encourages standardized decision aids or tools. The National Quality Forum (NQF) has published standards for decision aids (www.qualityforum.org/Projects/c-d/Decision_Aids/Final_Report.aspx) to facilitate the decision-making process between a patient and physician and will be monitoring this space closely.

V. History of Medicare Coverage

A. Current National Coverage Request

At this time, coverage of TTVR for TR is at the discretion of Medicare Administrative Contractors (MAC)s.

This is CMS’ first NCA on transcatheter tricuspid valve replacement. This request was externally initiated. CMS received a complete, formal request to open an NCA on the topic of transcatheter tricuspid valve replacement from Edwards Lifesciences. The request letter is available at https://www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/id314.pdf. Edwards Lifesciences is participating in the Transitional Coverage for Emerging Technologies (TCET) pilot program and tested the processes and concepts of TCET.

B. Timeline of NCA Milestones

Date	Milestone
June 20, 2024	CMS posts a tracking sheet announcing the opening of the NCA. The first 30-day public comment period begins.
July 20, 2024	First public comment period ends. CMS receives 58 comments.
December 19, 2024	CMS posts proposed Decision Memorandum. Second 30-day public comment period begins.
January 18, 2025	Second public comment period ends.
March 20, 2025	CMS estimates posting final Decision Memorandum.

VI. Appendices

Appendix A: Proposed Medicare National Coverage Determinations Manual Language

A. Proposed Decision

B. Coverage Criteria

We propose that TTVR is covered when furnished with an FDA-approved complete TTVR system, and all the following conditions are met:

1. Patient Criteria

Despite optimal therapy (OMT), patients must have symptomatic TR graded as at least severe with tricuspid valve replacement being considered as appropriate by a heart team.

2. Physician Criteria

The patient (preoperatively and postoperatively) is under the care of a heart team, which includes, at minimum, the following:

a) Cardiac surgeon;
b) Interventional cardiologist;
c) Heart failure cardiologist;
d) Electrophysiologist;
e) Multi-modality imaging specialists; and
f) Interventional echocardiographer.

All of the specialists listed above must have experience in the care and treatment of tricuspid regurgitation.

3. CED Study Criteria

b) An active comparator.

c) A care management plan that includes the experience and role of each member of the heart team described in section I.B.2.

d) Design sufficient for subgroup analyses by:

Age;
Sex;
Race and ethnicity;
Patient, practitioner, and facility level variables that predict the primary outcomes of the study;
Left ventricular ejection fraction (by guideline-defined subgroups);
Previous tricuspid surgery or intervention;
Severe aortic or mitral stenosis or regurgitation;
Patients with chronic kidney disease;
Patients with indwelling cardiac implantable electronic devices.

Sponsor/Investigator: The study is conducted by sponsors/investigators with the resources and skills to complete it successfully.
Milestones: A written plan is in place that describes a detailed schedule for completion of key study milestones, including study initiation, enrollment progress, interim results reporting, and results reporting, to ensure timely completion of the CED process.
Study Protocol: The CED study is registered with ClinicalTrials.gov and a complete final protocol, including the statistical analysis plan, is delivered to CMS prior to study initiation. The published protocol includes sufficient detail to allow a judgment of whether the study is fit-for-purpose and whether reasonable efforts will be taken to minimize the risk of bias. Any changes to approved study protocols should be explained and publicly reported.
Study Context: The rationale for the study is supported by scientific evidence and study results are expected to fill the specified CMS-identified evidence deficiency and provide evidence sufficient to assess health outcomes.
Study Design: The study design is selected to safely and efficiently generate valid evidence of health outcomes. The sponsors/investigators minimize the impact of confounding and biases on inferences through rigorous design and appropriate statistical techniques. If a contemporaneous comparison group is not included, this choice should be justified, and the sponsors/investigators discuss in detail how the design contributes useful information on issues such as durability or adverse event frequency that are not clearly answered in comparative studies.
Study Population: The study population reflects the demographic and clinical diversity among the Medicare beneficiaries who are the intended population of the intervention, particularly when there is good clinical or scientific reason to expect that the results observed in premarket studies might not be observed in older adults or subpopulations identified by other clinical or demographic factors. At a minimum, this includes attention to the intended population’s racial and ethnic backgrounds, gender, age, disabilities, important comorbidities, and, dependent on data availability, relevant health related social needs. For instance, more than half of Medicare beneficiaries are women so study designs should, as appropriate, consider the prevalence in women of the condition being studied as well as in the clinical trial and subsequent data reporting and analyses.
Subgroup Analyses: The study protocol explicitly discusses beneficiary subpopulations affected by the item or service under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion requirements effect enrollment of these populations, and a plan for the retention and reporting of said populations in the trial. In the protocol, the sponsors/investigators describe plans for analyzing demographic subpopulations as well as clinically-relevant subgroups as identified in existing evidence. Description of plans for exploratory analyses, as relevant subgroups emerge, are also included.
Care Setting: When feasible and appropriate for answering the CED question, data for the study should come from beneficiaries in their expected sites of care.
Health Outcomes: The primary health outcome(s) for the study are those important to patients and their caregivers and that are clinically meaningful. A validated surrogate outcome that reliably predicts these outcomes may be appropriate for some questions. Generally, when study sponsors propose using surrogate endpoints to measure outcomes, they should cite validation studies published in peer-reviewed journals to provide a rationale for assuming these endpoints predict the health outcomes of interest. The cited validation studies should be longitudinal and demonstrate a statistical association between the surrogate endpoint and the health outcomes it is thought to predict.
Objective Success Criteria: In consultation with CMS and AHRQ, sponsors/investigators establish an evidentiary threshold for the primary health outcome(s) so as to demonstrate clinically meaningful differences with sufficient precision.
Data Quality: The data are generated or selected with attention to provenance, bias, completeness, accuracy, sufficiency of duration of observation to demonstrate durability of health outcomes, and sufficiency of sample size as required by the question.
Construct Validity: Sponsors/investigators provide information about the validity of drawing warranted conclusions about the study population, primary exposure(s) (intervention, control), health outcome measures, and core covariates when using either primary data collected for the study about individuals or proxies of the variables of interest, or existing (secondary) data about individuals or proxies of the variables of interest.
Sensitivity Analyses: Sponsors/investigators will demonstrate robustness of results by conducting pre-specified sensitivity testing using alternative variable or model specifications as appropriate.
Reporting: Final results are provided to CMS and submitted for publication or reported in a publicly accessible manner within 12 months of the study’s primary completion date. Wherever possible, the study is submitted for peer review with the goal of publication using a reporting guideline appropriate for the study design and structured to enable replication. If peer-reviewed publication is not possible, results may also be published in an online 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 incomplete results).
Sharing: The sponsors/investigators commit to making study data publicly available by sharing data, methods, analytic code, and analytical output with CMS or with a CMS-approved third party. The study should comply with all applicable laws regarding subject privacy, including 45 CFR § 164.514 within the regulations promulgated under the Health Insurance Portability and Accountability Act of 1996 (HIPAA) and 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient Records.
Governance: The protocol describes the information governance and data security provisions that have been established to satisfy Federal security regulations issued pursuant to HIPAA and codified at 45 CFR Parts 160 and 164 (Subparts A & C), United States Department of Health and Human Services (HHS) regulations at 42 CFR, Part 2: Confidentiality of Substance Use Disorder Patient and HHS regulations at 45 CFR Part 46, regarding informed consent for clinical study involving human subjects. In addition to the requirements under 42 CFR and 45 CFR, studies that are subject to FDA regulation must also comply with regulations at 21 CFR Parts 50 and 56 regarding the protection of human subjects and institutional review boards, respectively.
Legal: The study is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals, although it is acceptable for a study to test a reduction in toxicity of a product relative to standard of care or an appropriate comparator. For studies that involve researching the safety and effectiveness of new drugs and biological products aimed at treating life-threatening or severely-debilitating diseases, refer to additional requirements set forth in 21 CFR § 312.81(a).

Consistent with section 1142 of the Act, AHRQ supports clinical research studies that CMS determines meet all the criteria and standards identified above.

C. Other Uses of TTVR

1) Transcatheter tricuspid valve replacement (TTVR) is not covered for patients outside of a CMS-approved study.

2) Nothing in this proposed NCD would preclude coverage of TTVR through NCD 310.1 (Clinical Trial Policy) or through the Investigational Device Exemption (IDE) Policy.

Appendix B: Referenced Materials

Study Characteristics

Intervention(s) and Patient Characteristics

Outcomes

Efficacy

Safety

TRISCEND Single Arm

Reference: Kodali et al. 2023 (TRISCEND Study, 1 Year results)

Country: US, Europe

Study Design: Multicenter (20 sites), prospective, single arm, interventional Study

Purpose: To evaluate the safety and performance of transfemoral TTVR in patients with clinically significant TR and elevated surgical risk

Funding Source: Edwards Lifesciences

Quality: NA; No formal quality assessment was performed to single-arm study design.

Nonrandomized trial with no comparator arm. No blinding of study participant/investigator. Adjudication of MAEs and hospitalization for HF or TR by independent clinical events committee. Echocardiographic core lab used.

Intervention: EVOQUE TTVR

Valve size: 44-mm, 48-mm, and 52-mm in

diameters; 28 Fr percutaneous delivery system.

Comparator: NA

Length of follow-up: 1 year

Patients (N): 176

Age, years, mean (SD): 78.7 (7.3)

Age ≥ 65 n (%): NR

Sex, female, n (%): 125 (71.0)

Race: NR

Diagnosis:

High surgical risk:

STS, mitral valve repair, mean (SD) %: 7.4 (5.3)

EuroSCORE II, mean (SD) %: 5.1 (4.0)

NYHA Class II or IV, n (%): 132/175 (75.4)

TR Grade ≥ Severe (Grade 3), n (%): 154/175

(88.0)

KCCQ score, mean (SD): NR

TR pathology, n (%):

Degenerative (primary): 17 (9.7)

Functional (secondary): 120 (68.2)

Mixed: 25 (14.2)

Pacer related: 5 (2.8)

Indeterminate: 9 (5.1)

Comorbidities, n (%):

Atrial fibrillation: 162 (92.0)

Hypertension (treated): 148 (84.1)

Pulmonary hypertension in last 12 months: 132 (75.0)

Dyslipidemia/hyperlipidemia: 115 (65.3)

Renal insufficiency: 103 (58.5)

Ascites: 39 (22.2)

Diabetes: 36 (20.5)

CAD (≥ 50% stenosis): 36 (20.5)

Coronary artery bypass grafting: 29 (16.5)

Prior MI: 14 (8.0)

Cerebrovascular disease (stroke or TIA): 24 (13.6)

Peripheral arterial disease: 11 (6.3)

Prior cardiac treatments, n (%):

Prior valve surgery/intervention (mitral, aortic, tricuspid): 66 (37.5)

Pacemaker: 57 (32.4)

Prior carotid stenting/surgery: 3 (1.7)

Other clinical parameters, N (%), or median (interquartile range):

Gastrointestinal or esophageal bleeding: 29 (16.5)

Albumin, g/dL: 4.0 (3.7, 4.2)

Alanine transaminase, U/L: 18.0 (13.0, 25.0)

Aspartate transaminase, U/L: 26.0 (20.0, 35.0)

Alkaline phosphatase, U/L: 110.0 (81.0, 146.0)

Gamma-glutamyl transferase, U/L: 75.0 (36.0, 137.0)

Brain natriuretic peptide, pg/mL: 332.0 (189.0, 580.0)

Prothrombin time, s: 16.6 (14.4, 22.2)

INR: 1.4 (1.2, 2.0)

eGFR, mL/min: 1.73 m2 52.0 (39.5, 60.0)

NT-proBNP, pg/mL: 1465.0 (972.0, 2495.0)

Creatinine, mg/dL: 1.1 (0.9, 1.4)

Reduction in TR grade severity (paired analysis from baseline to 1 year), %:

Reduction of 1 TR grade severity: 100

Reduction of ≥ 2 TR grade severity: 97.6

Reduction of ≥ 4 TR grade severity: 33.3

NYHA functional class, BL vs. 1 year, n (%):

Class I or II: NR (25.8) vs. NR (93.3)

Class III or IV: NR (3.4) vs. NR (6.7)

6MWD, mean (SD) m: (N=102)

BL vs. 1 year: NR (NR) vs. 56.2 (117.0 m)

QoL, KCCQ score, mean (SD) points:

(n=102)

BL vs. 1 year: 46.0 (21.8) vs. 71.7 (22.0)

Improvement in edema:

Edema via standard pitting test, BL vs. 1 year, p< 0.001, %: 63.9 vs. 86.6

Body weight, mean (SD) kg, 1 year, p=

0.005: 1.8 (6.3)

Ankle circumference, mean (SD) cm, BL vs. 1 year:

Left: NR (NR)

Right: NR (NR)

Echocardiographic parameters, mean (SD), BL vs. 1 year:

RV end-diastolic mid diameter, mm, N= (69): 41.4 (8.8) vs. 35.0 (7.4)

Difference at 1 year: 6.3 (9.5), p <0.001

RV fractional area change, %, N= (59): 38.7 (10.1) vs. 30.3 (10.6)

Difference at 1 year: 8.4 (13.8)

IVC diameter expiration, mm, N= (76): 27.6 (7.7) vs. 20.4 (5.1)

Difference at 1 year: 7.2 (5.9), p < 0.001

RA volume systolic, mL, N= (73): 144.4 (54.1) vs. 140.5 (53.8)

Difference at 1 year: 3.9 (42.3)

TAPSE/PASP, N= (22): 0.48 (0.26) vs. 0.41 (0.21)

Difference at 1 year: 0.07 (0.36)

Uric acid, mg/dL: 7.0 (5.3, 9.2)

TAPSE, mm, N= (46): 15.3 (5.2) vs. 12.5 (4.2)

Difference at 1 year: 2.8 (6.5)

TV mean gradient, mmHg, N= (82): 1.7 (1.0) vs. (3.4 (1.4)

Difference at 1 year: 1.7 (1.6)

LVEF, %, N= (70): 54.1 (11.2) vs. 55.6 (10.9)

Difference at 1 year: 1.5 (9.7)

Cardiac output (LVOT), L/min, N= (81): 4.0 (1.1) vs. 4.5 (1.1)

Difference at 1 year: 0.6 (1.2)

Stroke volume (LVOT), mL, N= (81): 54.8 (15.8) vs. 65.3 (17.6)

Difference at 1 year: 10.5 (16.8)

RA pressure systolic, mmHG, N= (75): 12.0 (4.8) vs. 8.7 (4.7)

Difference at 1 year: 3.3 (5.9)

IVC respiratory variation (derived), %, N= (74): 30.2 (16.9) vs. 40.5 (17.3)

Difference at 1 year: 10.3 (24.2)

PASP, mmHg, N= (40): 39.3 (12.8) vs. 32.5 (11.0)

Difference at 1 year: 6.8 (13.6)

All-cause mortality, 1 year, n (%): NR (9.1)

HF Hospitalization reduction, 1 year, n (%): NR (74.9)

CEC Adjudicated MAEs, 30 days (N=172) vs. 1 year (N=149), n (%):

Composite MAE rate at 30 Days vs. 1 year, n (%): 32 (18.6)

vs. 45 (30.2)

Cardiovascular mortality (30 days vs. 1 year), n (%): 3 (1.7)

vs. 14 (9.4)

Severe bleeding (per Mitral Valve Academic Research Consortium), 30 days vs. 1 year, n (%): 29 (16.9) vs. 38 (25.5)

Major: 14 (8.1) vs. 16 (10.7)

Extensive: 12 (7.0) vs. 16 (10.7)

Life-threatening: 3 (1.7) vs. 7 (4.7)

Fatal: 1 (0.6) vs. 1 (0.7)

Non-elective tricuspid valve re-intervention, 30 days vs. 1 year, n (%): 4 (2.3) vs. 6 (4.0)

Major access site and vascular complications, 30 days vs. 1 year, n (%): 4 (2.3) vs. 4 (2.7)

Renal complications requiring unplanned dialysis or renal replacement therapy, 30 days vs. 1 year, n (%): 3 (1.7) vs. 5

(3.4)

Major cardiac structural complications, 30 days vs. 1 year, n (%): 0 (0) vs. 0 (0)

Device related pulmonary embolism, 30 days vs. 1 year, n (%): 0 (0) vs. 0 (0)

MI, 30 days vs. 1 year, n (%): 0 (0) vs. 0 (0)

Cerebrovascular disease (stroke or TIA), 30 days vs. 1 year, n (%): 1 (0.6) vs. 2 (1.3)

Performance endpoints, n (%):

Device success: NR (94.4)

Procedural success: NR (93.0)

Reference: Kodali et al. 2022 (TRISCEND, 30-day results)

Country: US

Study Design: Multicenter (9 sites), prospective, single arm, interventional study

Purpose: To evaluate the safety and performance of transfemoral TTVR in patients with clinically significant TR and elevated surgical risk

Funding Source: Edwards Lifesciences

Quality: NA

No formal quality assessment was performed due to single-arm study design.

Notes: ITT analysis used for all endpoints. Patients with missing data were excluded from the denominator for endpoint calculations. Limited number of patients and follow-up of 30-days (n=53 completed 30-day follow-up). Non-randomized trial with No comparator arm. No blinding of study participant/investigator. Adjudication of MAEs and hospitalizations for HF or TR by independent clinical events committee. Echocardiographic core lab used.

Intervention: EVOQUE TTVR

Valve size: 44-mm, 48-mm, and 52-mm in diameter; 28-F percutaneous delivery system

Comparator: NA

Length of follow-up: 30-days

Patients (N): 56 (note: 53 completed 30-d follow-up)

Age, years, mean (SD): 79.3 (7.7)

Age ≥ 65, n (%): NR

Sex, female, n (%): 43 (76.8)

Race, n (%): NR

Diagnosis: High surgical risk:

STS, mitral valve repair, mean (SD) %: 7.7 (5.3)

EuroSCORE II, mean (SD) %: 5.6 (4.9)

NYHA Class III or IV, n (%): 49 (87.5)

Severity of TR, n (%) (N=55):

Moderate (Grade 2): 5 (9.1)

Severe (Grade 3): 25 (45.5)

Massive (Grade 4): 15 (27.3)

Torrential (Grade 5): 10 (18.2)

KCCQ score, mean (SD): 46.5 (23.1)

TR pathology, n (%):

Degenerative (primary): 6 (10.7)

Functional (secondary) 38 (67.9)

Mixed: 10 (17.9)

Pacer related: 1 (1.8)

Indeterminate: 1 (1.8)

Comorbidities, n (%):

Atrial fibrillation: 51 (91.1)

Systemic hypertension (treated): 49 (87.5) Pulmonary hypertension (sPAP ≥30 mmHg) in last 12 months: 45 (80.4)

Dyslipidemia or hyperlipidemia: 39 (69.6)

Chronic kidney disease (eGFR 15-89 mL/min/1.73 m2): 37 (66.1)

Cerebrovascular disease (stroke or TIA): 15 (26.8) Diabetes: 12 (21.4)

Ascites: 12 (21.4)

Gastrointestinal or esophageal bleeding: 11 (19.6) RBBB: 11 (19.6)

COPD: 10 (17.9)

CAD (≥ 50% stenosis): 8 (14.3)

LBBB: 6 (10.7)

Peripheral arterial disease: 1 (1.8)

Prior MI: 2 (3.6)

Prior HF hospitalization in last 12 months: 20 (35.7)

Diabetes: 12 (21.4)

Prior cardiac treatments

Prior valve surgery/intervention (mitral/aortic/tricuspid): 22 (39.3)

Pacemaker: 19 (33.9)

CABG: 9 (16.1)

Prior PCI/stent: 8 (14.3)

Prior carotid stenting/surgery: 1 (1.8)

Other clinical parameters, mean (SD):

Albumin, g/dL: 4.0 (0.6)

GFR, ml/min/1.73m2: 49.0 (12.9)

BNP: 678.8 (1,813.8)

AST, U/L: 29.0 (10.1)

ALT, U/L: 22.2 (11.7)

ALKP, U/L: 115.7 (62.5)

GGT, U/L: 86.5 (76.3)

Prothrombin time, s: 18.8 (8.2)

INR: 1.6 (0.74)

Creatinine, mg/dL: 1.2 (0.3)

Uric acid, mg/dL: 7.4 (2.9)

Inclusion criteria: Patients at least 18 years of age, with at least moderate functional or degenerative TR despite medical therapy.

Exclusion criteria: Unsuitable anatomy for device placement, prior TV repair or replacement that would interfere with EVOQUE valve implantation, severe pulmonary hypertension (sPAP>70 mmHg or >2/3 systemic with pulmonary vascular resistance >5 WU after vasodilator challenge), or severe RV dysfunction. Additional exclusion criteria were LVEF <25%, severe renal insufficiency with eGFR ≤25 mL/min/1.73 m2 or requiring chronic renal replacement therapy, along with comorbid condition(s) that, in the opinion of the investigator, could limit patient participation.

TR severity:

BL vs. 30-days, n (%) (N=52):

None/trace (Grade 0): 0 (0) vs. 38 NR (73.1)

Mild (Grade 1): 0 (0) vs. NR (25.0) Moderate (Grade 2): NR (9.6) vs. NR (1.9)

Severe (Grade 3): NR (50.0) vs. 0 (0) Massive (Grade 4): NR (25.0) vs. 0 (0) Torrential (Grade 5): NR (15.4) vs. 0 (0) p<0.001 for change from Grade 2+ to </= Grade 1***, favoring 30-days

BL vs. discharge, n (%) (N=55):

None/trace: (Grade 0) 0 (0) vs. 35 (64) Mild (Grade 1): 0 (0) vs. 18 (33) Moderate (Grade 2): 5 (9.1) vs. 2 (4)

Severe (Grade 3): 25 (45.5) vs. 0 (0)

Massive (Grade 4): 15 (27.3) vs. 0 (0) Torrential (Grade 5):10 (18.2) vs. 0 (0) p<0.001 for BL vs. discharge***, favoring discharge

Reduction in TR grade severity:

At 30 days (N=52):

By number of grades reduced, %:

Reduction of 1 TR grade severity: 1.9

Reduction of 2 TR grades severity: 17.3

Reduction of 3 TR grades severity: 53.8

Reduction of 4 TR grades severity: 15.4

Reduction of 5 TR grades severity: 11.5

By ≥ number of grades reduced, n (%):

Reduction of ≥ 1 grade: 52 (100)

Reduction of ≥ 2 grades: NR (98.1)

Reduction of ≥ 3 grades: NR (80.7)

Reduction of ≥ 4 grades: NR (26.9)

Reduction of 5 grades: NR (11.5)

At discharge, % (N=55, echo endpoint):

Reduction of ≥ 1 TR grade severity: 100

Reduction of ≥ 2 TR grades severity: 98.1 p<0.001*** BL vs. discharge, favoring discharge

NYHA functional class, BL vs. 30-days, n/N (%):

I/II: (78.8) N=52 at 30-days

III/IV: 49/56 (87.5) N=56 at BL p<0.001***, favoring 30-days

6MWD, mean (SD) m: (n=46)

BL vs. 30-days: 199.1 (128.6) vs. 248.9 (127.5)

Difference at 30-days: +49.8 (80.5), p<0.001***, favoring 30-days

QoL, KCCQ score, mean (SD) points: (n=51)

BL vs. 30-days: 46.5 (23.1) vs. 65.6 (21.6) Difference at 30-days: +19.0 (20.5), p<0.001***, favoring 30-days

Improvement in edema:

Ankle swelling via patient edema questionnaire (with moderate to extreme activity limitations),

BL vs. 30-days, %: 35.7 vs. 13.7

Edema via standard pitting test, BL vs. 30-days, p<0.001***, favoring 30-days

Ankle circumference, mean (SD) cm,

BL vs. 30-days:

Left: 23.0 (3.8) vs. 21.8 (4.6), p=0.003**, favoring 30-days

Right: 23.1 (3.7) vs. 21.9 (4.5), p=0.002**, favoring 30-days

Body weight, mean (SD) kg,

BL vs. 30-days: 73.7 (18.6) vs. 71.6 (19.4), p = 0.008**, favoring 30-days

Echocardiographic parameters, mean (SD), BL vs. 30-days:

sPAP, mmHg (n=31): 40.1 (10.5) vs. 32.2 (10.2), p=0.002**, favoring 30 days

RV end-diastolic area, cm2 (n=45): 33.1 (7.2) vs. 23.4 (7.1), p<0.001***, favoring 30 days

RV end-systolic area, cm2 (n=45): 20.5 (5.1) vs. 17.6 (5.8), p=0.001**, favoring 30 days

RV FAC, % (n=45): 37.6 (9.3) vs. 24.8 (9.9), p<0.001***, favoring BL

IVC diameter, expiration, mm (n=48): 27.0 (7.1) vs. 21.3 (5.6), p<0.001***, favoring 30 days

RA volume systolic, mL (n=52): 154.1 (66.1) vs. 138.2 (61.8), p=0.009**, favoring 30 days

TAPSE, mm (n=24): 14.9 (3.9) vs. 13.0 (3.2), p=0.035*, favoring BL

TV mean gradient, mmHg (n=49): 1.8 (1.1) vs. 3.4 (1.5), p<0.001***, favoring 30 days

LVEF, % (n=47): 53.4 (10.2) vs. 58.2 (10.4), p=0.014*, favoring 30 days

Performance endpoints, n (%):

Device success: 55 (98.2)

Procedural success: 54 (96.4)

Clinical success: 41 (73.2)

Note: Device success = device is deployed, and delivery system successfully retrieved as intended at the time of the patient’s exit from the cardiac catheterization laboratory.

Procedural success = device success and no clinically significant paravalvular leak on TTE (assessed by the echocardiographic core laboratory) at the time of discharge.

Clinical success = procedural success and no MAEs in 30 days.

All-cause mortality, 30 days, n (%): 2 (3.6%)

Note: Among the two deaths, one was cardiovascular death (related to the device and procedure) and the other non-cardiovascular death (due to carcinoid syndrome)

Safety endpoint:

Composite MAE rate, through 30-days, n (%):

15 (26.8)

Cardiovascular mortality: 1 (1.8)

Severe bleeding (per Mitral Valve Academic Research Consortium criteria): 15 (26.8)

Major: 8 (14.3)

Extensive: 7 (12.5)

Fatal/life-threatening: 0 (0)

Requiring transfusion of at least 1 unit of RBCs: 9 (60)

Nonelective TV reintervention (due to device embolization): 2 (3.6)

Major access site and vascular complications requiring intervention (due to device migration): 1 (1.8)

MI: 0 (0)

Stroke: 0 (0)

Renal complications requiring dialysis or renal replacement therapy: 0 (0)

New need for renal replacement therapy: 0 (0)

Major cardiac structural complications: 0 (0)

Device-related pulmonary embolism: 0 (0)

New conduction disturbances requiring PPM implantation in patients without a PPM prior to enrollment, n/N (%): 4/36 (11.1)

Note: One patient required 25-days of hospitalization caused by valve embolization, subsequent emergent redo sternotomy, and notable post-surgical bleeding from the chest tube.

Compassionate Use

Reference: Webb et al. 2022

Country: US, Canada, Europe

Study Design: Multicenter (7 sites), prospective, nonrandomized, observational, single-arm, first-in-human; compassionate use population

Purpose: To report 1-year outcomes in the expanded first-in-human experience with the transfemoral EVOQUE system for TR

Funding Source: Funding for study unspecified; however, authors received various sources of funding from multiple entities that included Edwards Lifesciences

Quality: NA. No formal quality assessment performed due to observational, single-arm study design.

Notes: Study took place between May 2019 and Jul 2020. This compassionate use experience describes the durability of TR reduction and symptomatic improvement and explores implications in terms of right heart remodeling.

Intervention: EVOQUE TTVR

Valve size: available in 44 mm, 48 mm, or 52 mm (specific sizes implanted in study were not provided); 28-F EVOQUE tricuspid delivery system

Comparator: NA

Length of follow-up, median (IQR): 379 (197-468) days.

Clinical follow-up & TTE at 30-days & 1 year

Patients (N): 27

Age, years, mean (SD): 77 (8)

Age ≥ 65, n (%): NR

Sex, female, n (%): 24 (89)

Race, n (%): NR

Diagnosis:

NYHA Functional Class, n (%):

II: 3 (11)

III: 21 (78)

IV: 3 (11)

TR etiology, n (%):

Functional: 19 (70)

Degenerative: 3 (11)

Mixed: 5 (19)

TR severity, n (%):

Torrential (Grade 5): 15 (56)

Massive (Grade 4): 7 (26)

Severe (Grade 3): 5 (18)

≤Moderate (≤Grade 2): 0 (0)

LVEF, mean (SD) %: 58.1 (8.5)

EuroSCORE II, mean (SD) %: 7.4 (5.1)

STS score, mean (SD) %: 8.6 (5.5)

Comorbidities, n (%):

CAD: 8 (30)

Previous CABG: 5 (19)

Previous PCI: 3 (11)

Previous valve intervention: 11 (40)

Previous mitral valve intervention: 7 (26)

Other concomitant moderate or severe valvular pathology: 0 (0)

Transtricuspid PPM/ICD lead: 9 (33)

Renal impairment: 15 (56)

COPD: 3 (11)

Atrial fibrillation/flutter: 23 (85)

Previous TIA/stroke: 6 (22)

Hypertension: 19 (70)

Diabetes: 8 (30)

Peripheral edema: 19 (73)

Ascites: 14 (54)

Concomitant medications, n (%):

Loop diuretic: 27 (100)

Aldosterone antagonist: 19 (70)

Oral or other anticoagulant agent: 25 (93)

Other clinical parameters, mean (SD):

GFR, ml/min/1.73m2: 52 (20)

NT-BNP, pg/mL: 2,303 (445)

AST, U/L: 31 (12)

ALT, U/L: 26 (25)

GGT, U/L: 135 (9)

Bilirubin, mg/dL: 1.2 (0.7)

Inclusion criteria: No formal pre-specified criteria due to compassionate use experience. Note: All patients had NYHA Class II-IV symptoms with peripheral edema or ascites with persistent diuretic requirement despite OMT with diuretics; deemed inoperable or high surgical risk by local heart team (tricuspid anatomy unsuitable for optimal TEER [i.e., >10mm coaptation gaps, severe leaflet tethering, and/or pacemaker-induced TR]); suitable anatomy for EVOQUE based on echocardiography and CT analysis.

Exclusion criteria: No formal pre-specified criteria due to compassionate use experience. Note: Excluded patients had severe RV dysfunction or significant pulmonary arterial hypertension (pulmonary artery systolic pressure >60 mmHg).

Co-primary outcomes:

TR severity, BL (N=27) vs. 30 days (N=24) vs. 1 year (N=23), n (%):

Torrential (Grade 5): 15 (56) vs. 1 (4) vs. 1 (4)

Massive (Grade 4): 7 (26) vs. 0 (0) vs. 0 (0)

Severe (Grade 3): 5 (18) vs. 0 (0) vs. 0 (0)

Moderate (Grade 2): 0 (0) vs. 3 (13) vs. 2 (9)

Mild (Grade 1): 0 (0) vs. 8 (33) vs. 11 (48)

None (No TR): 0 (0) vs. 12 (50) vs. 9 (39)

Sustained TR reduction observed w/ TR Grade </=2+ in 96% & </=1+ in 87% at 1 yr

> moderate (Grade 2) vs. ≤ moderate (Grade 2):

BL vs. 1 year: p<0.001***, favoring 1 year

30 days vs. 1 year: <0.001***

favoring 1 year

NYHA functional class, n (%):

BL (N=27) vs. 30 days (N=24) vs. 1 year (N=23):

I: NR (0) vs. NR (15) vs. NR (26)

II: NR (11) vs. NR (54) vs. NR (43)

III: NR (81) vs. NR (15) vs. NR (26)

IV: NR (11) vs. NR (8) vs. NR (4)

NYHA Class I/II:

BL vs. 1 year: 3 (11) vs. 16 (70), p<0.001***, favoring 1 year

30 days vs. 1 year: 18 (69) vs. 16 (70)

Secondary outcomes:

Echocardiographic parameters, BL (N=27) vs. 30 days (N=24) vs. 1 year (N=23), mean (SD):

LVEF, %: 58.1 (8.5) vs. 54.9 (13.3) vs. 58.5 (8.7)

BL vs. 1 year: p=0.663

30 days vs. 1 year: p=0.674

RV end diastolic diameter base, mm: 50.7 (7.3) vs. 46.4 (6.2) vs. 44.7 (7.7)

BL vs. 1 year: p=0.013*, favoring 1 year

30 days vs. 1 year: p=0.189

RV end diastolic diameter mid, mm: 40.0 (7.4) vs. 34.7 (5.9) vs. 33.3 (6.9)

BL vs. 1 year: p=0.005**, favoring 1 year 30 days vs. 1 year: p=0.193

TAPSE, mm: 15.8 (5.7) vs. 13.9 (3.5) vs. 14.4 (5.4)

BL vs. 1 year: p=0.040*, favoring BL

30 days vs. 1 year: p=0.528

RV FAC, %: 37.6 (11.5) vs. 29.6 (7.6) vs. 33.0 (6.9)

BL vs. 1 year: p=0.002**, favoring BL

30 days vs. 1 year: p=0.481

TV mean gradient, mmHg: 1.5 (0.9) vs. 3.2 (1.3) vs. 2.8 (1.2)

BL vs 1 year: p=0.0003***

30 days vs 1 year p=0.651

RV systolic pressure, mmHg: 34.9 (10.0) vs. 42.9 (11.1) vs. 43.6 (11.8)

BL vs 1 year: p=0.059

30 days vs 1 year: p=0.188

IVC, mm: 27.7 (5.0) vs. 20.4 (5.8) vs. 17.5 (4.0)

BL vs 1 year: p<0.001***, favoring 1 year

30 days vs 1 year: p=0.165

Clinical signs of right HF

BL (N=27) vs. 30 days (N=26) vs. 1 year (N=23), n (%):

Peripheral edema: 19 (70) vs. 6 (23) vs. 6 (26), p=0.050 BL vs. 1 year

Ascites: 14 (52) vs. 2 (8) vs. 2 (9), p<0.001*** BL vs. 1 year, favoring 1 year

Diuretic dose reduction

BL (N=27) vs. 30 days (N=26) vs. 1 year (N=23), n (%):

NA vs. 7 (27) vs. 12 (52)

Biomarkers of hepatic congestion

BL (N=27) vs. 1 year (N=23), mean (SD):

AST, U/L: 28 (12) vs. 29 (14), p=0.387

ALT, U/L: 20 (9) vs. 22 (8), p=0.359

GGT, U/L: 109.5 (36) vs. 81 (27), p=0.063

Bilirubin, mg/dL: 1.9 (1.8) vs. 1.0 (0.7), p=0.121

GFR, mL/min/1.73 m2: 52 (20) vs. 53 (18), p=0.496

6MWD

BL (N=27) vs. 30 days (N=26) vs. 1 year (N=23), mean (SD) m:

258 (105) vs. 273 (104) vs. 299 (115), p=0.005*** BL vs. 1 year, favoring 1 year

Note: No deaths were device related. Deaths resulted from multiorgan failure/gastric bleeding (45 days post procedure) and previously undiagnosed malignancy (238 days post procedure).

Secondary outcomes:

Cardiac mortality, n (%):

At 30 days: 0 (0)

Between 30 days and 1 year: 0 (0)

At 1 year: 0 (0)

MI, n (%):

At 30 days: 0 (0)

Between 30 days and 1 year: 0 (0)

At 1 year: 0 (0)

CT-detected HALT, n (%):

At 30 days: 1 (4)

Between 30 days and 1 year: 3 (11)

At 1 year: 4 (15)

Stroke, n (%):

At 30 days: 0 (0)

Between 30 days and 1 year: 0 (0)

At 1 year: 0 (0)

Conversion to surgery, n (%):

At 30 days: 0 (0)

Between 30 days and 1 year: 0 (0)

At 1 year: 0 (0)

Reintervention, n (%):

At 30 days: 0 (0)

Between 30 days and 1 year: 0 (0)

At 1 year: 0 (0)

HF hospitalization, n (%):

At 30 days: 0 (0)

Between 30 days and 1 year: 2 (7)

At 1 year: 2 (7)

Major bleeding, n (%):

At 30 days: 3 (11)

Between 30 days and 1 year: 1 (4)

At 1 year: 4 (15) - 2 procedural / 2 non-procedural

Pulmonary embolism, n (%):

At 30 days: 0 (0)

Between 30 days and 1 year: 0 (0)

At 1 year: 0 (0)

Conduction abnormality requiring new pacemaker, n (%):

At 30 days: 2 (7)

Between 30 days and 1 year: 1 (4)

At 1 year: 3 (11)

New onset renal failure requiring dialysis, n (%):

At 30 days: 1 (4)

Between 30 days and 1 year: 0 (0)

At 1 year: 2 (7)

Reference: Fam et al. 2021

Country: US, Canada, Europe

Study Design: Multicenter (6 sites), prospective, nonrandomized, observational, single-arm, first-in-human; compassionate use population

Purpose: To investigate the feasibility and safety of the EVOQUE TV replacement system and its impact on short-term clinical outcomes

Funding Source: Funding for study unspecified; authors received various sources of funding from Edwards Lifesciences, Abbott Vascular, JC Medical, CryoLife, VDyne, CardioMech, Atricure, MitreMedical, Neptune Medical, W.L. Gore, Boston Scientific, Medtronic, BD, and/or ViVitro Medical

Quality: NA; No formal quality assessment performed due to observational, single-arm study design.

Notes: Study took place between May 2019 and Feb 2020. The proportion of patients in each NYHA Class at BL is not consistent with what is reported in the paper’s Results section. Table 1 reports 22/25 (88%) were NYHA Class III/IV at BL. However, Results state that 24/25 (96%) were Class III/IV at BL. Though this is unable to be reconciled from the text, it is more likely that Table 1 is erroneous.

Intervention: EVOQUE TTVR

Valve size: 44 mm (n=8, 32%) or 48 mm (n=16, 64%); 28-F EVOQUE tricuspid delivery system

Comparator: NA

Length of follow-up, mean: NR

Note: Patients followed for 30 days.

Patients (N): 25

Age, years, mean (SD): 76 (3)

Age ≥ 65, n (%): NR

Sex, female, n (%): 22 (88)

Race, n (%): NR

Diagnosis:

NYHA Functional Class, n (%):

II: 3 (12)

III: 19 (76)

IV: 3 (12)

TR etiology, n (%):

Functional: 19 (76)

Degenerative: 1 (4)

Mixed: 5 (20)

TR severity, n (%):

Torrential (Grade 5): 14 (56)

Massive (Grade 4): 7 (28)

Severe (Grade 3): 4 (16)

EuroSCORE II, mean (SD) %: 7.7 (2.2)

STS score, mean (SD) %: 9.1 (2.3)

LVEF, mean % (SD): 58.3 (3.6)

Comorbidities, n (%):

CAD: 7 (28)

Previous MI: 1 (4)

Previous CABG: 5 (20)

Previous PCI: 2 (8)

Previous valve intervention: 11 (44)

Aortic valve replacement: 7 (28)

Mitral valve replacement: 6 (24)

TV DeVega annuloplasty: 1 (4)

Transtricuspid PPM/ICD lead: 9 (36)

Renal impairment: 15 (60)

Chronic kidney disease: NR (71)

COPD: 3 (12)

Atrial fibrillation: 21 (84)

Previous TIA/stroke: 6 (24)

Hypertension: 17 (68)

Diabetes: 8 (32)

Peripheral edema: 18 (72)

Ascites: 14 (56)

Concomitant medications, n (%):

Loop diuretic: 25 (100)

Aldosterone antagonist: 19 (68)

Oral or other anticoagulant agent:

23 (92)

warfarin 11(44)

DOAC 12 (48)

Other clinical parameters, mean (SD):

GFR, ml/min/1.73m2: 52 (8)

NT-BNP, pg/mL: 3,106 (2,028)

AST, U/L: 30 (4)

ALT, U/L: 25 (10)

GGT, U/L: 137 (7)

Bilirubin, mg/dL: 1.9 (1.7)

Inclusion criteria: No formal pre-specified criteria due to compassionate use experience. Note: Included patients had right-sided HF (NYHA class II-IV) despite OMT and deemed at high surgical risk/inoperable by local heart team and if transcatheter leaflet repair would not be feasible (i.e., large [>10-mm] coaptation gaps, severe leaflet tethering, and/or pacemaker-induced TR). Patients were deemed anatomically suitable for EVOQUE TTVR (i.e., adequate screening TEE imaging of the TV leaflets for procedural guidance and computed tomography-derived TV annular dimensions compatible with 44- or 48-mm valves).

Exclusion criteria: No formal pre-specified criteria due to compassionate use experience

Note: Excluded patients had severe RV dysfunction or significant pulmonary arterial hypertension (pulmonary artery systolic pressure >60 mmHg).

Primary outcome:

Technical success, procedurally, n (%): 23 (92)

Note: Primary outcome = Technical success defined as absence of procedural mortality; successful access, delivery, and retrieval of the device delivery system; successful deployment and correct positioning of the first intended device; and freedom from emergency surgery or reintervention related to the device or access procedure.

Major outcomes:

NYHA Functional Class,

BL vs. 30 days, n (%): ≥Class III: 24 (96) vs. 6 (24), p<0.001***, favoring 30 days

TR severity:

≤ mild (Grade 1), n (%):

Procedurally: 23 (92)

30 days: NR (88)

≤ moderate (Grade 2), 30 days, n (%):

NR (96)

TR grade, BL vs. 30 days, mean (SD):

4.4 (0.3) vs. 0.8 (0.5), p<0.001***, favoring 30 days

Other outcomes:

Clinical signs of right HF, BL vs. 30 days, n (%):

Peripheral edema: NR (72) vs. NR (24), p<0.001***, favoring 30 days

Ascites: NR (56) vs. NR (8), p<0.001***, favoring 30 days

Reduction in diuretic agent doses, 30 days: 28% of patients

Renal function,

BL vs. 30 days:

GFR, mean (SD) mL/min: 52 (8) vs. 58 (9), p=0.14

Hepatic function,

BL vs. 30 days, mean (SD):

Bilirubin, mg/dL: 1.9 (1.7) vs. 0.9 (0.2), p=0.01*, favoring 30 days

GGT, U/L: 137 (7) vs. 99 (58), p=0.08

Echocardiographic parameters,

BL vs. 30 days, mean (SD):

TV gradient, mmHg: 1.5 (0.4) vs. 3.2 (0.6)

TAPSE, mm: 15.6 (2.5) vs. 14 (3), p=0.11

RV FAC, %: 37.6 (5.1) vs. 30 (8), p=0.01*, favoring BL

IVC diameter, mm: 28.4 (2.1) vs. 20 (3), p<0.001***, favoring 30 days

RV systolic pressure, mmHg: 34.6 (4.3) vs. 42 (5.5), p=0.21

RV basal diastolic diameter, mm: 50.8 (7.2) vs. 46.4 (6.3), p=0.009**, favoring 30 days

Note: Selected patients also underwent follow-up CT assessment, which demonstrated reductions in RV volume with RV reverse remodeling and no instances of hypoattenuating leaflet thickening.

MAEs, n (%):

Mortality:

Procedurally: 0 (0)

30 days: 0 (0)

MI:

Procedurally: 0 (0) 30 days: 0 (0)

Stroke: Procedurally: 0 (0) 30 days: 0 (0)

Device embolization:

Procedurally: 0 (0) 30 days:

Major bleeding: Procedurally: 0 (0) 30 days: 3 (12) [Note: 1 GI bleed, 1 spontaneous thigh IM hematoma, 1 retroperitoneal bleed from non access site, all in context of anticoagulant therapy + aspirin]

Conversion to surgery:

Procedurally: 0 (0)

30 days: 0 (0)

Valve reintervention:

Procedurally: 1 (4)

30 days: 0 (0)

HF hospitalization, 30 days: 0 (0)

Conduction abnormality requiring pacemaker, 30 days: 2 (8)

Progressive renal failure requiring dialysis, 30 days: 1 (4) [Note: patient started with stage IV renal impairment]

Afterload mismatch with worsening RV function requiring short-term inotropic support: 2 (8) [Note: patients had baseline mod-severe RV dysfunction]

Asymptomatic leaflet thickening with increased valve gradient: 1 (4) [Note: event was in context of subtherapeutic anticoagulation, which completely resolved

once therapeutic anticoagulation was achieved]

Retrospective Studies Based on Compassionate Use Cohort

Reference: Stolz et al. 2023

Country: US, Canada, Europe

Study Design: Retrospective analysis of a multicenter (8 sites), observational, single-arm, compassionate use study

Purpose: To evaluate survival, symptomatic, and echocardiographic outcomes and AEs at 2-year follow-up in patients who underwent transfemoral TTVR using EVOQUE in a compassionate use setting between 2019 and 2021

Funding Source: Funding for study unspecified; however, authors received various sources of funding from multiple entities that included Edwards Lifesciences

Quality: NA; No formal quality assessment performed due to observational, single-arm study design.

Notes: Appears to be an analysis of the compassionate use study reported in two publications captured in this table (Fam et al. 2021 and Webb et al. 2022).

Intervention: EVOQUE TTVR

Valve size: NR

Comparator: NA

Length of follow-up, median (IQR, max): 520 (360-730,1074) days

Patients (N): 38

Age, years, mean (SD): 77 (12)

Age ≥ 65, n (%): NR

Sex, female, n (%): 28 (74)

Race, n (%): NR

Diagnosis:

TR severity, n (%):

Torrential: 21 (55)

Massive: 13 (34)

Severe: 4 (11)

NYHA Class, n (%): ≥III: NR (92)

EuroSCORE II, mean (SD) %: 7.9 (6.5)

Comorbidities, n (%):

Peripheral edema: NR (71)

Ascites: NR (50)

Inclusion criteria: NR

Exclusion criteria: NR

Echocardiographic parameters, at 2 years:

TAPSE, mean (SD) mm: 18 (11)

TAPSE <17mm, n (%): NR (53)

RV mid-ventricular diameter, BL to latest follow-up, mean change: -6.8 mm, p<0.001***, favoring latest follow-up

RV FAC, BL to latest follow-up, mean change:

-9.1%, p<0.001***, favoring BL

LV forward stroke volume, BL to latest follow-up, mean change: +37%

TR severity:

Reduction to ≤ mild, n (%):

Procedurally: NR (97)

At latest follow-up: NR (94)

TR grade, BL vs. postprocedural vs. latest follow-up, %:

None/Trace: 0 vs. 47 vs. 26

Mild: 0 vs. 50 vs. 63

Moderate: 0 vs. 3 vs. 3

Severe: 11 vs. 0 vs. 0

Massive: 34 vs. 0 vs. 0

Torrential: 55 vs. 0 vs. 0

No follow-up: NA vs. NA vs. 8

NYHA Functional Class:

≥ Class III, BL vs. 2 years, n (%):

NR (92) vs. NR (20)

Clinical signs of right HF, BL vs. latest follow-up, n (%):

Peripheral edema:

NR (71) vs. NR (37)

Ascites:

NR (50) vs. NR (14) p<0.001***, favoring latest follow-up

Diuretic dosage,

BL vs. discharge vs. latest follow-up, mean mg/d: 85 vs. 56 vs. 60

Renal function: “Remained unchanged” (no data provided)

Hepatic congestion,

BL to latest follow-up, mean change:

Bilirubin: -0.5 mg/dL

GGT: -42 U/L p=0.001**, favoring latest follow-up

Survival, n (%):

At 1 year: 27 (86)

At 2 years: 19 (71)

Mortality:

At 1 year: 14%

At 2 years: 29%

Note: 6 of 10 patients died of cardiac causes.

MI, at latest follow-up, n (%): 0 (0)

Stroke, at latest follow-up, n (%): 0 (0)

Pulmonary embolism, at latest follow-up, n (%): 0 (0)

Surgical TV replacement after early device migration (5 days post-TTVR), n (%): 1 (2.6)

Conduction disturbance (within 1-week post-TTVR), n (%): 4 (10.5)

Requiring PPM: 3 (7.9)

Major bleeding, at latest follow-up, n (%): 4 (11)

HALT, 17-552 days post-TTVR, n/N (%): 9/25 (36)

Note: 2 cases were classified as clinically relevant valve thrombosis. TV inflow gradient was 5.5 mmHg vs. 2.9 (SD: 1.2) mmHg in remaining patients.

Reference: Weckbach et al. 2023

Country: NR

Study Design: Research Letter (retrospective analysis of Fam et al. 2021, conducted at 6 sites)

Purpose: To assess impact of TTVR on RV reverse remodeling

Funding Source: Authors received funding from various sources, including Edwards Lifesciences, Abbott, Cardiovalve, AstraZeneca, and Bayer.

Quality: NA; No formal quality assessment was performed due to observational, single-arm study design.

Notes:

Appears to be an analysis of the compassionate use study reported in two publications captured in this table (Fam et al. 2021 and Webb et al. 2022).

BL demographics do not match Fam et al. 2021 re: TR grade and NYHA Functional Class.

Intervention: EVOQUE TTVR

Valve size: NR

Comparator: NA

Length of follow-up, median (IQR): 64 (45-267) days

Patients (N): 25

Age, years, median (IQR): 82 (77- 84) years

Age ≥ 65, n (%): 25 (100)

Sex, female, n (%): 88

Race, n (%): NR

Diagnosis:

Right-sided heart failure

NYHA functional class: ≥III

NT-proBNP level, pg/mL, median (IQR): 1,393 (739-2,453)

TR severity, %:

Torrential: 56.0

Massive: 32.0

Severe: 12.0

RV function:

TAPSE, mm, median (IQR): 17 (14-22)

14/25 (56%) of patients were >16 mm

FAC, %, median (IQR): 37 (29-46)

13/19 (68%) of patients were >35%

CT findings:

RV EF, %, median, IQR: 52 (46-56)

Patients with ≥50% RV EF, n/N, %: 15/25, 60

RV-EDV, mL, median (IQR): 225 (187-297)

Echocardiographic findings:

RV mid diameter, mm, median (IQR): 40 (35-47)

LVEF, %, median (IQR): 58 (55-64)

23/25 (92%) of patients had LVEF preserved

Comorbidities, n (%): NR

Inclusion criteria: Patients were selected for TTVR if they were judged to be inoperable because of high surgical risk and if the TV was considered unsuitable for T-TEER because of large coaptation gaps or complex anatomy by the local heart team.

Exclusion criteria: NR

NYHA functional class,

BL vs. last follow-up, %:

I/II: 0 vs. 76

III/IV: 100 vs. 24

Echocardiographic findings:

TR severity, n (%):

Grade ≤1+: 25 (100)

LV forward stroke volume, BL vs. follow-up, mean (SEM) mL: 39 (3) vs. 52 (4), p<0.0001***, favoring last follow-up

Difference: +30%

CT findings:

RV-EDV, BL vs. last follow-up, mean:

-35%, p<0.0001***, favoring last follow-up

Correlation between decrease in RV-EDV with BL RV-EDV, Spearman r: 0.09, p=0.69

Correlation between decrease in RV-EDV with BL TR severity, Spearman r:

-0.03, p=0.88

RV-EF, BL vs. last follow-up, median (IQR) %: 34 (21-39), p<0.0001***, favoring last follow-up

End-systolic volume, at last follow-up: “slight decrease” (data NR), p=0.049*

Symptomatic valvular thrombosis in all leaflets, n (%): 3 (12)

Case Reports

Reference: Cuko et al. 2023

Country: France

Study Design: Case report

Purpose: Report the practicality, safety, and effectiveness of the EVOQUE valve system in clinical practice.

Funding Source: All authors declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Quality: NA; No formal quality assessment performed due to study design.

Notes: NA

Intervention: EVOQUE TTVR

Valve size: 52 mm

Comparator: NA

Length of follow-up: 18 months

Patients (N): 1

Age, years: 82

Age ≥ 65, n (%): 1 (100)

Sex, female, n (%): 1 (100)

Race, n (%): NR

Diagnosis:

Severe TR

Hepatomegaly

Ascites

Tricuspid annular dilatation

Right and left atrial dilatation

Right ventricular dilatation

Mild right ventricular dysfunction

Comorbidities:

Permanent atrial fibrillation

History of breast cancer

History of hypothyroidism

Inclusion criteria:

Surgery ineligible

TEER ineligible

Post-procedure TR severity: “immediate elimination of severe TR”

Post-procedure echocardiographic parameters: “mean gradient 2mmHg”

18-month TR severity: No residual TR

18-month NYHA Class: NYHA I

“Postprocedural recovery was uneventful with good hemodynamic response”

Reference: Wild et al. 2021

Country: Germany

Study Design: Case report

Purpose: To demonstrate the potential of TTVR after failed leaflet repair of TR

Funding Source: Funding for study unspecified; authors received funding from Edwards Lifesciences, Abbott Vascular

Quality: NA; No formal quality assessment performed due to study design.

Notes: Two patients were discussed in this paper. However, no relevant outcomes data was reported for the second patient. Thus, data was extracted only for the first patient.

Intervention: EVOQUE TTVR

Valve size: 52 mm

Comparator: NA

Length of follow-up: 4 months

Patients (N): 1

Age, years: 84

Age ≥ 65, n (%): 1 (100)

Sex, female, n (%): 1 (100)

Race, n (%): NR

Diagnosis (post-PASCAL / pre-EVOQUE):

TR severity: Torrential (grade 5+)

NYHA Class: Class IV

Prominent peripheral edema

Comorbidities:

Prior transcatheter leaflet repair (PASCAL) for treatment of severe symptomatic TR (TR 3+) with EuroSCORE II = 31.9% & STS-PROM 11.3% resulting in good TR reduction (TR 1+)

Single leaflet device attachment 1-month post-PASCAL

Inclusion criteria: NA

Exclusion criteria: NA

NYHA Class (4 months): Class II

Clinical signs of right HF (4 months): “Resolution of peripheral edema” "Weight loss of 15 kg"

6MWD,

BL to 4 months, mean change: +190 m

Echocardiographic parameters:

(Post-procedure): "residual trace TR, no paravalvular leakage and a mean transprosthetic gradient of 3 mmHg"

(4 months): “good positioning of the prosthesis without valvular or paravalvular residual TR, and stable gradient"

Reference: Fam et al. 2020

Country: Canada

Study Design: Case report

Purpose: To report a case treated with transfemoral TTVR

Funding Source: Abbott Vascular and Edwards Lifesciences

Quality: NA; No formal quality assessment performed due to case report study design.

Notes: NA

Intervention: EVOQUE TTVR

Valve size: 48-mm diameter; 28-F percutaneous delivery system

Comparator: NA

Length of follow-up: 6 months

Patients (N): 1

Age, years: 75

Age ≥ 65, n (%): 1 (100)

Sex, female, n (%): 0

Race, n (%): NR

Diagnosis:

NYHA functional class III (with dyspnea, edema, and fatigue)

Torrential TR with leaflet tethering and a 15 mm coaptation gap

Dilated RV with mild dysfunction, and LV function preserved

Computed tomography: tricuspid annulus measured 49 mm

Comorbidities, n (%): AF, history of CABG surgery

Inclusion criteria: NA

Exclusion criteria: NA

Primary endpoint:

NYHA Functional Class, at 6 months:

Observed reduction from Class III to Class I, with reduced diuretic requirements (details NR).

Change in 6MWD: +200 m

QoL, change in MLHFQ: +45 points

Echocardiographic parameters:

Normal RV function

Mild paravalvular TR

Mean gradient: 2 mmHg

CT findings:

“Significant reduction” in RV diastolic volume from 230 to 168-cm3 (p-value NR)

*p<0.05; **p<0.01; ***p<0.001

Abbreviations: 6MWD: 6-minute walk distance; AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BL: baseline; CABG: coronary artery bypass graft; CAD: coronary artery disease; CI: confidence interval; COPD: chronic obstructive pulmonary disease; CT: computed tomography; EuroSCORE II: European System for Cardiac Operative Risk Evaluation II; FAC: fractional area change; GFR: glomerular filtration rate; GGT: gamma-glutamyl transferase; HALT: hypoattenuated leaflet thickening; HF: heart failure; HR: hazard ratio; HRQoL: health-related QoL; ICD: implantable cardioverter-defibrillator; IQR: interquartile range; IVC: inferior vena cava; LBBB: left bundle branch block; LV: left ventricular; LVEF: LV ejection fraction; MAE: major AE; MI: myocardial infarction; MLHFQ: Minnesota Living With Heart Failure Questionnaire; NA: not applicable; NR: not reported; NYHA: New York Heart Association; OMT: optimal medical therapy; OR: odds ratio; PCI: percutaneous coronary intervention; PPM: permanent pacemaker; QoL: quality of life; RBBB: right bundle branch block; RV: right ventricular; RVEDD: RV end diastolic dimension; RV-EDV: RV end diastolic volume; SAE: serious AE; SD: standard deviation; SEM: standard error of the mean; sPAP: systolic pulmonary artery pressure; STS: Society of Thoracic Surgeons; TAPSE: tricuspid annular plane systolic excursion; TEE: transesophageal echocardiogram; TIA: transient ischemic attack; TTE: transthoracic echocardiogram; TTVR: transcatheter tricuspid valve replacement; TR: tricuspid regurgitation; TV: tricuspid valve; US: United States

Appendix C: Heart Failure Quality of Life and Functional Measures

Measure	Description	References
New York Heart Association (NYHA) classification	Class and Patient Symptoms I: No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation or shortness of breath. II: Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, shortness of breath or chest pain. III: Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, shortness of breath or chest pain. IV: Symptoms of heart failure at rest. Any physical activity causes further discomfort.	https://doi.org/10.1161/CIR.0b013e31829e8807 (see Table 4) https://www.heart.org/en/health-topics/heart-failure/what-is-heart-failure/classes-of-heart-failure The Criteria Committee of the New York Heart Association. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, Mass: Little & Brown; 1994.
Kansas City Cardiomyopathy Questionnaire (KCCQ)	The KCCQ captures how heart failure affects patients’ lives. The KCCQ has a 2-week recall period and includes 23 items that map to 7 domains: symptom frequency; symptom burden; symptom stability; physical limitations; social limitations; quality of life; and self-efficacy.	https://doi.org/10.1016/S0735-1097(00)00531-3 https://doi.org/10.1016/j.jacc.2020.09.542
Short Form Health Survey (SF-36)	The SF-36 is a self-reported outcome measure assessing the impact of health on an individual's everyday life. Also, the survey can be administered by a trained interviewer in person or by telephone. The SF-36 evolved from the Medical Outcomes Study. Eight domains: 1. Limitations in physical activities because of health problems. 2. Limitations in social activities because of physical or emotional problems 3. Limitations in usual role activities because of physical health problems 4. Bodily pain 5. General mental health (psychological distress and well-being) 6. Limitations in usual role activities because of emotional problems 7. Vitality (energy and fatigue) 8. General health perceptions	https://doi.org/10.1097/00005650-199303000-00006 https://www.rand.org/health-care/surveys_tools/mos/36-item-short-form/survey-instrument.html Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992 Jun;30(6):473-83. PMID: 1593914. https://doi.org/10.1136/bmj.305.6846.160
6-minute walk distance (6MWD)	The six-minute walk test is a simple cardiopulmonary functional testing modality. Its results can help ascertain the degree of functional impairment.	https://doi.org/10.1177%2F1753944719870084 https://www.ncbi.nlm.nih.gov/books/NBK576420/
EuroQuol 5 dimension, 5 level survey (EQ-5D-5L)	The EQ-5D-5L assesses health status in terms of five dimensions of health. These dimensions are not specific to any one patient group or health condition.	https://euroqol.org/information-and-support/euroqol-instruments/eq-5d-5l/ https://doi.org/10.1186/s12955-015-0356-8 https://doi.org/10.1016/j.jval.2021.02.003
Canadian Study of Health and Aging Clinical Frailty Scale	The Clinical Frailty Scale (CFS) summarizes the overall level of fitness or frailty of an older adult after they had been evaluated by an experienced clinician.	https://doi.org/10.1503/cmaj.050051 https://doi.org/10.1371/journal.pone.0216166
Katz Index of Independence in Activities of Daily Living	The Katz Index of Independence in Activities of Daily Living assesses functional status as a measurement of the patient’s ability to perform activities of daily living (ADL) independently. It quantifies ADL across a wide range of patient populations.	https://doi.org/10.1002/acr.20638

[1] CMS’ CED Guidance Document (2024), 2, 3.

[2] CMS’ CED Guidance Document (2024), 4

[3] CMS’ CED Guidance Document (2024), 6. This document also contains information on the purpose, principles, and process of CED.

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Transcatheter Tricuspid Valve Replacement (TTVR)

Decision Summary

Proposed Decision Memo

I. Proposed Decision

II. Clinical Review

III. Evidence

IV. CMS Coverage Analysis

V. History of Medicare Coverage

VI. Appendices

Bibliography

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