Transcatheter Tricuspid Valve Replacement (TTVR)

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The Centers for Medicare & Medicaid Services (CMS) covers transcatheter tricuspid valve replacement (TTVR) for the treatment of symptomatic tricuspid regurgitation (TR) under Coverage with Evidence Development (CED) according to the provisions in sections I.B. and I.C. below. B. Coverage Criteria TTVR is covered when furnished according to a Food and Drug Administration (FDA) market-authorized indication and all the following conditions are met: 1. Patient Criteria Despite optimal medical therapy (OMT), patients must have symptomatic TR 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) Cardiologist with training and experience in heart failure management; 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. 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; 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 CED studies must adhere to the following scientific standards (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, sex, 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 relat

Decision Memo: Table of Contents Decision 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 Support for Medicare Coverage for TTVR Non-Coverage for TTVR Coverage Indications Physician Criteria Institutional Criteria Volume Criteria CED Criteria for TTVR Accessibility Miscellaneous Comments 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: Medicare National Coverage Determinations Manual Language 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 Abbreviations used throughout the 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 Medical 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 Medical 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 TEER – Transcatheter Edge-to-Edge Repair 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 US – United States VHD – Valvular Heart Disease I. Decision A. Decision The Centers for Medicare & Medicaid Services (CMS) covers transcatheter tricuspid valve replacement (TTVR) for the treatment of symptomatic tricuspid regurgitation (TR) under Coverage with Evidence Development (CED) according to the provisions in sections I.B. and I.C. below. B. Coverage Criteria TTVR is covered when furnished according to a Food and Drug Administration (FDA) market-authorized indication and all the following conditions are met: 1. Patient Criteria Despite optimal medical therapy (OMT), patients must have symptomatic TR 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) Cardiologist with training and experience in heart failure management; 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. 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; 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 CED studies must adhere to the following scientific standards (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, sex, 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 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 Medicare National Coverage Determinations Manual language. 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/m 2 ), and female (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 medical 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, 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 medical 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 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. 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 medical 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 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 . 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 medical 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 medical therapy were eligible and medical 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 m 2 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 medical 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 medical 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 medical therapy as per investigator discretion. Enrollment in TRISCEND II was limited to patients with symptomatic TR despite medical 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 medical 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 medical 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 medical 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 medical 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