Transcatheter Edge-to-Edge Repair for Tricuspid Valve Regurgitation (T-TEER)

The Centers for Medicare & Medicaid Services (CMS) proposes to cover tricuspid transcatheter edge-to-edge repair (T-TEER) 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.

We propose that T-TEER is covered when furnished according to a Food and Drug Administration (FDA) market-authorized indication and all the following conditions are met:

Despite optimal medical therapy (OMT), patients must have symptomatic TR with tricuspid valve repair being considered as appropriate by a heart team.

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

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

The T-TEER 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:

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”). 

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

1)      Tricuspid transcatheter edge-to-edge repair (T-TEER) is not covered for patients outside of a CMS-approved study.

2)      Nothing in this proposed NCD would preclude coverage of T-TEER 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.

Table of Contents

1. Proposed Decision
1. Proposed Decision
2. Coverage Criteria
   1. Patient Criteria
   2. Physician Criteria
   3. CED Study Criteria
3. Other Uses of T-TEER
2. Clinical Review
   1. Background
   2. Food and Drug Administration Status
3. Evidence
   1. Evidence Questions
   2. Technology Assessments
   3. Medicare Evidence Development and Coverage Advisory Committee (MEDCAC)
   4. Clinical Literature Search
      Summary of Evidence
   5. Assessment of the Evidence
      1. Trial Design and Enrollment Criteria
      2. Study Populations
      3. Background Therapy
      4. Intervention Setting
      5. Endpoints
      6. RCT Study Quality and Risk of Bias
      7. Synthesizing the Clinical Trial Evidence
      8. Evidence from observational studies and relevance to Medicare beneficiaries
      9. Limitations of Evidence
      10. Considerations for Further Research
   6. Evidence-Based Guidelines
   7. Professional Society Recommendations / Consensus Statements / Other Expert Opinion
   8. Appropriate Use Criteria
   9. Public Comment
4. CMS Coverage Analysis
   1. CMS Coverage Authority
   2. CMS Analysis for Coverage of T-TEER for TR
      1. Rationale for Coverage Requirements for T-TEER for TR (Patient, Physician, and CED Study Criteria)
      2. Evidence Questions – Answered
   3. Benefit Category
   4. Shared-Decision Making
5. History of Medicare Coverage
   1. Current National Coverage Request
   2. Timeline of NCA Milestones
6. Appendices
   Appendix A: Proposed Medicare National Coverage Determinations Manual Language
   1. Proposed Decision
   2. Coverage Criteria
      1. Patient Criteria
      2. Physician Criteria
      3. CED Study Criteria
   3. Other Uses of T-TEER
   Appendix B: Referenced Materials
   Appendix C: Heart Failure Quality of Life and Functional Measures

Abbreviations used throughout the Proposed Decision Memorandum for Transcatheter Edge-to-Edge Repair for Tricuspid Valve Regurgitation (T-TEER)

6MWD – Six-Minute Walk Distance
6MWT – Six-Minute Walk Test
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
ASTR - Atrial Secondary Tricuspid Regurgitation
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 – Cardiac Implantable Electronic Device
CMS – Centers for Medicare & Medicaid Services
COPD – Chronic Obstructive Pulmonary Disease
CT – Computed Tomography
CV – Cardiovascular
DVT – Deep Vein Thrombosis
EACTS – European Association for Cardio-Thoracic Surgery
EAPCI – European Association of Percutaneous Cardiovascular Interventions
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
HFA – Heart Failure Association
HR – Hazard Ratio
ICD – Implantable Cardioverter Defibrillator
IDE – Investigational Device Exemption
IQR – Interquartile Range
ITT – Intention-to-Treat
IVC – Inferior Vena Cava
KCCQ – Kansas City Cardiomyopathy Questionnaire
LVEF – Left Ventricular Ejection Fraction
MAC – Medicare Administrative Contractor
MAE – Major Adverse Event
MCID – Minimal Clinically Important Difference
MEDCAC – Medicare Evidence Development & Coverage Advisory Committee
MI – Myocardial Infarction
MLHFQ – Minnesota Living with Heart Failure Questionnaire
MR – Mitral Regurgitation
M-TEER – Mitral Transcatheter Edge-To-Edge Repair
NCA – National Coverage Analysis
NCD – National Coverage Determination
NYHA – New York Heart Association
OMT – Optimal Medical Therapy
OR – Odds Ratio
PA – Pulmonary Artery
PAP – Pulmonary Artery Pressure
PASP – Pulmonary Artery Systolic Pressure
PCI – Percutaneous Coronary Intervention
PE – Pulmonary Embolism
PH – Pulmonary Hypertension
PM – Pacemaker
PMA – Premarket Approval
PPM – Permanent Pacemaker
PH – Pulmonary Hypertension
QoL – Quality of Life
RA – Right Atrium
RCT – Randomized Controlled Trial
RHC – Right Heart Catheterization
RHF – Right Heart Failure
RVCPi – Right Ventricular Cardiac Power Index
RV – Right Ventricle/Ventricular
RVEDD – Right Ventricular End Diastolic Diameter
RVFAC – Right Ventricular Fractional Area Change
SCAI – Society for Cardiovascular Angiography and Interventions
SD – Standard Deviation
SDM – Shared Decision Making
SF-36 – Short Form Health Survey
STS – Society of Thoracic Surgeons
SPAP – Systolic Pulmonary Artery Pressure
SSED – Summary of Safety and Effectiveness Data
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
TTE – Transthoracic Echocardiography
T-TEER – Tricuspid Transcatheter Edge-to-Edge Repair
TR – Tricuspid Regurgitation
TV – Tricuspid Valve
US – United States
USPSTF – United States Preventive Services Task Force
VHD – Valvular Heart Disease
VSTR – Ventricular Secondary Tricuspid Regurgitation
WR – Win Ratio

I.                 Proposed Decision

The Centers for Medicare & Medicaid Services (CMS) proposes to cover tricuspid transcatheter edge-to-edge repair (T-TEER) 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.

We propose that T-TEER is covered when furnished according to a Food and Drug Administration (FDA) market-authorized indication and all the following conditions are met:

Despite optimal medical therapy (OMT), patients must have symptomatic TR with tricuspid valve repair being considered as appropriate by a heart team.

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

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

The T-TEER 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:

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”). 

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

1)      Tricuspid transcatheter edge-to-edge repair (T-TEER) is not covered for patients outside of a CMS-approved study.

2)      Nothing in this proposed NCD would preclude coverage of T-TEER 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

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 typically 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 exerciseintolerance, 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 (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 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.

Concurrent TV surgery is advised as a Class 1 recommendation for patients undergoing left-sided valve surgery who have severe TR per the 2020 ACC/AHA Guideline for the Management of Patients with Valvular Heart Disease Class of Recommendations (Otto et al., 2021).  With progressive TR in the setting of tricuspid annular dilation or signs and symptoms of right HF, TV repair concurrent with left-sided valve surgery is given a 2a recommendation, as is isolated TV surgery in patients with right HF and severe primary TR or in those with severe secondary TR due to annular dilation without PH or left-sided disease (Otto et al., 2021).  These same guidelines provide a Class 2b recommendation for surgery in asymptomatic patients with severe primary TR in whom RV dilation or systolic dysfunction develop.  Similarly, these guidelines include a class 2b recommendation for isolated TV surgery in patients with symptomatic, severe TR and prior left-sided valve surgery if PH and severe RV systolic dysfunction are absent.

Transcatheter Tricuspid Valve Devices:

A minimally-invasive, percutaneous, transvenous, catheter-based approach to TV repair has emerged as a potential treatment for TR.  The Abbott TriClip System is the first FDA cleared tricuspid transcatheter edge-to-edge repair (T-TEER) device in the U.S.

On April 1, 2024, the FDA approved the TriClip G4 System premarket approval (PMA) application (P230007 ).  This device is indicated for improving quality of life and functional status in patients with symptomatic severe TR despite optimal medical therapy, who are at intermediate or greater risk for surgery and in whom TEER is clinically appropriate and is expected to reduce TR severity to moderate or less, as determined by a multidisciplinary 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 T-TEER for TR.  This proposed NCD addresses a family of devices that employ the “edge-to-edge” technique of reducing TR by clamping and apposing the tricuspid leaflets for the purpose of treating tricuspid regurgitation.  This assessment does not address non-TEER devices for addressing TR, nor does it address devices deployed outside of the tricuspid valve.

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.

The following questions guide our review and analysis of the evidence on the clinical utility of T-TEER for symptomatic severe TR:

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

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

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

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

A MEDCAC meeting was not convened on this topic.

A systematic literature review focused on T-TEER for TR was undertaken to address the evidence questions defined above.  Literature searches were conducted in PubMed and Embase on three occasions, ultimately inclusive of studies through May 18, 2024, with the following search terms: (1) “tricuspid regurgitation” or “tricuspid valve insufficiency,” and (2) “tricuspid edge-to-edge,” (3) “TriClip,” and (4) “tricuspid transcatheter clip.”  The review included peer-reviewed English-language medical literature and excluded observational reports with fewer than 30 patients, editorials, and conference abstracts.  The focus of the search was on clinical outcomes and safety factors associated with T-TEER.

Of the references identified in the searches, 14 publications were deemed eligible for inclusion.  Priority was given to the pivotal trial for this analysis.

One RCT, TRILUMINATE Pivotal, as reported in three publications and in publicly available reports to the FDA, was reviewed.  We primarily reviewed the results that supported the FDA premarket approval of the TriClip G4 System.  We note that additional results were published shortly prior to publication of this proposed decision memorandum.  While they have not been summarized in detail here, we will add those results in the final decision memorandum.  The results of recent publications do not change our proposed decision.

An overview of the studies included in the systematic review with at least one year of follow-up is provided in Table 1.  For a more detailed summary of these and other studies, see Appendix B.

Table 1. Studies Reviewed to Assess Tricuspid Transcatheter Edge-to-Edge Repair (T-TEER) for Tricuspid Regurgitation, arranged by Device and Length of Follow-up

Legend: y = years; ^aThe lowest level of TR severity patients included in the publication, as reported by the authors; ^bevents per person-year; ^cEligible = patients who met the eligibility criteria for the TRILUMINATE Pivotal randomized controlled trial.
Abbreviations: ASTR = atrial secondary tricuspid regurgitation; GDMT = guide-directed medical therapy; HF = heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; MLHFQ = Minnesota Living with Heart Failure Questionnaire; PTR = primary tricuspid regurgitation; RCT=randomized controlled trial; RV = right ventricular; SF-36: Short-Form Health Survey; STR = secondary tricuspid regurgitation; TEER = transcatheter edge-to-edge repair; TR = tricuspid regurgitation; VSTR = ventricular secondary tricuspid regurgitation

Only significant results are designated by an asterisk; *p<0.05; **p<0.01; ***p<0.001.

TRILUMINATE Pivotal

The Trial to Evaluate Cardiovascular Outcomes in Patients Treated with the Tricuspid Valve Repair System Pivotal (TRILUMINATE Pivotal) was a prospective, multi-center, open-label RCT evaluating tricuspid valve edge-to-edge repair (T-TEER) using the TriClip Transcatheter Tricuspid Valve Repair system (Sorajja et al., 2023; Arnold et al., 2024).  Patients with severe symptomatic TR were enrolled, then assigned to one of two groups (randomized cohort: likely that TR could be reduced to moderate or less; single-arm cohort: likely to reduce TR by ≥ 1 grade but unlikely to reduce to moderate or less).  Those in the randomized cohort were randomized 1:1 to receive either T-TEER using the TriClip/TriClip G4 system or medical therapy alone.  The randomization goal was up to 550 subjects and up to 200 patients were to be included in the single-arm cohort.  TRILUMINATE Pivotal included the first 350 patients randomized, with device patients undergoing procedure within 14 days of randomization.  After completion of the 12 month visit, control group participants were eligible to cross over to device.

Patients with NYHA functional class II-IV heart failure secondary to TR were eligible if the local heart team determined that they had been adequately treated per standard of care therapy and stable for at least 30 days, having undergone guideline-directed medical therapy (GDMT), such as diuretics, had undergone device therapy, if appropriate, and were confirmed by a heart team cardiac surgeon to be at intermediate or greater risk for mortality or morbidity with TV surgery.  Transesophageal echocardiography (TEE) was required for confirmation of TR etiology.  Exclusion criteria were numerous and included pulmonary hypertension, severe uncontrolled systemic hypertension, prior TV procedure that may interfere, current indication for left-sided or pulmonic valve correction, CIED leads that may interfere, TV stenosis, LVEF ≤ 20%, TV not evaluable by echocardiography, or certain TV anatomic features.  Other notable exclusions were recent myocardial infarction (MI), percutaneous coronary intervention (PCI), or stroke, hemodynamic instability, chronic dialysis, bleeding disorder/hypercoagulability, peptic ulcer or gastrointestinal (GI) bleeding, infection, or life expectancy of less than 12 months.  Trial visits occurred at 30 days, six months, and one year, to continue through 5 years.

TRILUMINATE Single Arm

TRILUMINATE Single-Arm was a prospective, multi-center, single-arm, interventional study conducted across 21 sites in the US and Europe (Nickenig et al., 2019, Lurz et al., 2021; von Bardeleben et al., 2023) in which 85 trial subjects underwent T-TEER using the TriClip system.  Results were reported at 6 months in Nickenig et al., one year in Lurz et al., and two years in von Bardeleben et al.  Subjects had an average age of 77.8 years (SD: 7.9) and the majority were female (66%), had functional TR (84%), and were in NYHA Class III/IV (75%).

TRILUMINATE Pivotal

Baseline characteristics of the device and control groups are shown in Table 2.  All patients had symptomatic TR, and over 95% had a TR severity of severe or greater on the 5-grade scale described by Hahn and Zamorano (2017).  Baseline echocardiographic grading of TR was achieved in 173/175 of the randomized T-TEER patients, and 165/175 controls.  Most patients were NYHA functional class III or IV.  The mean age was approximately 78 years, and both the T-TEER and GDMT groups were mostly female (56% vs. 54%, respectively).  As reported in the Summary of Safety and Effectiveness Data (SSED), patients had a wide range of co-morbidities.  Most prominent of these in device (D) and controls (C), respectively, were atrial fibrillation (87.4%, 93.1%), hypertension (81.1%, 80.6%), and dyslipidemia (66.9%, 52.6%) (FDA, 2024a).  Renal disease was present in 35.4% in both groups.  Pulmonary artery systolic pressure ranged from 30-50 mmHg in both groups.  At baseline, 37% had undergone mitral or aortic valve intervention, including 15.4% aortic valve intervention, 11.4% transcatheter mitral valve repair, 6.6% surgical mitral valve repair, 5.4% mitral valve replacement, and one prior TV repair (T-TEER group).

Table 2. Comparison of baseline patient characteristics in TRILUMINATE Pivotal

Legend: NYHA = New York Heart Association; TR = Tricuspid regurgitation

TRILUMINATE Single Arm

Baseline characteristics of patients are shown in Table 3.  TR severity was severe or greater in 94% of patients.  The mean age was approximately 78 years, and the majority of patients were female (66%).  Comorbidities included atrial fibrillation (92%), hypertension (86%), and renal disease (46%).  Mean pulmonary artery systolic pressure was 38.9 (SD 16.0) mmHg.  At baseline, 11% had undergone previous aortic intervention and 33% had undergone previous mitral intervention, including 32.1% percutaneous repair, 28.6% surgical repair, 25% surgical replacement, and 7.1% percutaneous replacement.

Table 3. Baseline patient characteristics in TRILUMINATE Single Arm

Legend: NYHA = New York Heart Association; TR = Tricuspid regurgitation

As shown in Table 4, the vast majority of patients in TRILUMINATE Pivotal received diuretics, a majority received β-receptor antagonists, 37-39% received ACE-I, ARB, or ARNI, and fewer than 10% received vasodilators.  Patients were required to receive stable GDMT for HF for 30 days or more prior to the beginning of the study.

Table 4. Baseline rates of guideline-directed medical therapy in the TRILUMINATE Pivotal RCT.

Legend: ACE-I: angiotensin-converting enzyme inhibitors; ARB: angiotensin II receptor blocker; ARNI: Angiotensin Receptor-Neprilysin Inhibitor.

The TRILUMINATE Pivotal trial was conducted across 65 sites, randomizing 350 subjects in the US (N=296), Canada (N=38), and Europe (N=16).  Patients were adjudicated as eligible by a local heart team that consisted of specialists board-certified in cardiac surgery, interventional cardiology, echocardiology, and heart failure.  Severity of tricuspid regurgitation was confirmed by an independent echocardiography laboratory to confirm eligibility.  All sites were required to have experience in transcatheter edge-to-edge repair of the mitral valve (M-TEER) of at least 50 procedures (FDA, 2024b).  Up to three roll-in patients were allowed per implanter with no prior TriClip experience prior to randomization (FDA, 2024a).  Outcomes in the roll-in cohort (n=141) were presented to the FDA.  Nearly 30% of all subjects were enrolled at the top 5 high-volume sites.

TRILUMINATE Pivotal

The primary endpoint was a composite of all-cause mortality or TV surgery, HF hospitalization, and quality of life assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ) at one year, analyzed on an intent to treat (ITT) basis as a Finkelstein-Schoenfeld win ratio using unmatched pairs.  Secondary endpoints, evaluated in a hierarchical order if results for the primary endpoint were significant, included freedom from major adverse events (MAE) at 30 days post procedure in the attempted-procedure group, change in KCCQ at one year (ITT), TR reduction to moderate or less at 30 days (ITT), and change in 6-minute walk distance (6MWD) at 1 year (ITT).

Procedural endpoints analyzed were Technical Success (exit from procedure room alive with successful access, delivery, and retrieval of the device delivery system, completed deployment and correct positioning of a clip, and no need for additional unplanned surgery or intervention related to the procedure); Device Success (alive with original intended clips in place, no additional surgery or intervention related to the index procedure, at least one grade improvement in TR severity, no embolization or single leaflet attachment, and absence of device-related complications at 30 days post-procedure); and Procedural Success (device success with no device- or procedure-related SAEs at 30 days post-procedure).

Two-year secondary endpoints to be reported in the future are recurrent HF hospitalizations (ITT), and freedom from all-cause mortality, TV surgery or intervention (ITT).  MAE was inclusive of cardiovascular death, new-onset kidney failure, endocarditis treated with surgery, and nonelective CV surgery for device-related adverse event.

In the second publication on TRILUMINATE Pivotal, the primary endpoint was the one-year change in QoL, as measured by the score on the KCCQ (Arnold et al., 2024).

TRILUMINATE Single Arm

The primary efficacy endpoint in TRILUMINATE Single-Arm was a TR reduction of ≥1 grade at 30 days, which was achieved by 86% of 83 patients and exceeded the performance goal of 35% (Nickenig et al., 2019).  The percentage of patients who met the endpoint was sustained from 30 days to the two-year follow-up (86% vs. 85%, respectively; Nickenig et al., 2019; von Bardeleben et al., 2023) and the percentage of patients with a TR severity ≤ moderate increased from baseline to 2 years (4% vs. 60%, respectively, p<0.0001), and the improvement remained unchanged from 30 days to the two-year follow-up (63% vs. 60%, p=0.90; von Bardeleben et al., 2023).  Of the 39 patients with the greatest TR severity (torrential or massive) at baseline, 90% experienced a TR reduction of ≥1 grade after one year (Nickenig et al., 2019, Lurz et al., 2021; von Bardeleben et al., 2023).

The primary safety endpoint in TRILUMINATE Single-Arm was the proportion of patients with MAEs at 6 months, which was 4% of 84 patients and significantly below the 39% performance goal (p<0.0001; Nickenig et al., 2019).  The percentage of patients who experienced MAEs was driven by CV mortality (n=2) and new onset renal failure (n=1).  At one year, the rates for MAEs remained relatively low, with 7% of 84 patients experiencing CV mortality (n=4), stroke (n=1), or new onset renal failure (n=1) (Lurz et al., 2021).  Single-leaflet device attachment was reported in 7% without clinical findings or worsening of TR.  At two years, 18% of patients experienced MAEs, which was over twice the rate at one year (von Bardeleben et al., 2023).  All-cause mortality was relatively low at 6 months (5% of 84) and 1 year (7% of 84), but more than doubled at 2 years (17%).  Other than all-cause mortality, the most common AE at 6 months, 1 year, and 2 years was major bleeding (6 months: 11% of 84, 1 year: 12% of 84, 2 years: 12%).  Hospitalization for HF was significantly lower for 1-year post-TEER vs. 1-year pre-TEER (0.78 events/P-Y vs. 1.30 events/P-Y, p=0.003) and 2 years post-TEER vs. 1-year pre-TEER (0.66 events/P-Y vs. 1.30 events/P-Y, p<0.0001).  An analysis of mortality/HF hospitalization at 1 year stratified by TR severity among 70 patients revealed that patients with a reduction to ≤ moderate severity at 30 days post-TEER had a 60% lower rate of mortality/HF hospitalization compared to those with ≥ severity at 30 days (HR: 0.40, p=0.034).  This finding suggests a correlation between mortality/HF hospitalization and reduction of TR severity after two years.

A formal quality assessment using the US Preventive Services Task Force’s (USPSTF) Criteria for Assessing Internal Validity of Individual Studies tool was performed for the TRILUMINATE Pivotal study, which received a rating of “Good”.  Factors contributing to this rating included adequate randomization, comparable treatment groups at BL, an acceptable overall completion rate (86%), and a <10% difference in attrition between treatment groups.  Intention-to-treat analysis was used for all endpoints except freedom from MAEs.  While patient blinding was not inherently possible due to the nature of treatment, efforts were made to mitigate the risk of performance and detection biases by independent adjudication of AEs and blinded QoL assessors.  However, echocardiogram assessors were not blinded to treatment assignment and thus, could serve as a potential source of bias.  Notably, patients were assessed for final study eligibility by a Heart Team and were excluded if deemed unlikely to show sufficient reduction in TR severity.  Moreover, patients underwent mandated right heart catheterization to confirm appropriate medical management and TR as the likely source of their symptoms.  Aside from the rigorous selection of patients, another limitation acknowledged by the authors was the enrollment of patients with fewer overall comorbidities compared to prior studies.  This might have contributed to the favorable early survivorship observed.

A formal quality assessment was not performed on the remaining studies due to either their observational and/or single-arm study design.  These study types tend to have low internal/external validity with inherent biases and thus, would likely render the overall evidence as poor quality.  Additionally, single-center studies may have introduced various forms of bias (e.g., patient selection), enrolled potentially homogenous populations that affect their applicability to the US population, and may not be representative of providers’ varying levels of skill in performing T-TEER.  Studies with smaller sample sizes may not have been adequately powered, and follow-up periods were relatively short for the majority of studies.

TRILUMINATE Pivotal Results

Trial results are reported in Table 1 and baseline characteristics of the study groups are provided in Table 2.

Of 175 subjects randomized to the device arm, three patients withdrew before the procedure was attempted.  Device implantation was attempted in 172 patients and was successful in 170 patients (97.1%).  A single clip was deployed in 10.5%, two clips were deployed in 61.0%, three were deployed in 24.4%, and four were deployed in 2.9% of device patients.

At one-year follow-up, the primary endpoint win ratio favored the T-TEER group (WR 1.48, 95% CI: 1.06 to 2.13, p=0.02), primarily driven by performance on the KCCQ-Overall Summary score.  Approximately 50% vs. 26% of patients in the T-TEER and GDMT groups, respectively, reported overall QoL improvement on the KCCQ measure at one year (p<0.0001).  The remaining components of the primary endpoint—all-cause mortality or TV surgery (9.4% vs. 10.6%, p=0.75) and HF hospitalization (0.21 vs. 0.17 events/P-Y, p=0.41) for the T-TEER and GDMT groups, respectively—did not significantly differ between groups at one year.  Sensitivity analyses conducted for the as-treated (WR: 1.59, 95% CI: 1.13 to 2.31), per-protocol (win ratio: 1.44, 95% CI: 1.00 to 2.11), and post-COVID diagnosis (win ratio: 1.43, 95% CI: 1.02 to 2.04) groups were relatively consistent with the intention-to-treat findings.

Technical success was 98.8%, with 88.9% 30-day device success reported in the 162 patients for whom all relevant data were available.  Single-leaflet device attachment occurred in 11 patients, three had no reduction in TR, and three required surgery or intervention within 30 days.  One death occurred within 30 days in the device group.  Procedural success was further diminished by the three subjects with device- or procedure-related SAEs, including single leaflet attachment, ruptured chordae, and an access site complication.

In the device vs. control groups, respectively, through 12 months, adverse events included all-cause mortality (8.6 vs. 7.4%), CV mortality (6.3 vs 4.6%), hospitalizations (36.0 vs. 34.3%), non-CV hospitalization (21.7 vs. 21.1%), and major bleeding (5.7 vs. 1.7%).  There was one TV surgery due to an unsuccessful T-TEER procedure.  At the 30-day follow-up, 169 patients in the attempted-procedure population (98.3%) were free from MAEs, compared with a 90% performance goal (Sorajja et al., 2023).

As reported in Sorajja et al., 2023, 161 device patients and 146 control patients had echocardiography available at 30 days, and tricuspid regurgitation was reported as moderate or less in 87.0% of device and 4.8% of control patients studied.  This difference persisted at one-year post-procedure (88% vs. 6%, respectively).

Diuretic dosages did not decline at one year in the device group, and IV diuretic usage was higher in the device group at one year, confounding understanding of the impact of the intervention relative to medication management.

Analysis of the KCCQ-Overall Summary scores showed an improvement in QoL for the T-TEER group exceeding that of the medical therapy group by an average of 11.7 points (95% CI: 6.8 to 16.6, p<0.001).  Change in 6MWD was -8.1±10.5 m in the device group, compared with -25.2±10.3 in the control group, a non-significant difference (p=0.25).  In a post-hoc analysis, improvements in QoL were correlated with residual TR severity, with greater increases in KCCQ score with reduced TR severity.  However, as shown in the SSED analysis, large standard deviations were observed in each category assessed (FDA, 2024a).

In the most recent analysis of TRILUMINATE Pivotal focused on QoL, the KCCQ-Overall Summary score improvement reported in the T-TEER group exceeded that in the control group by 10.4 points (95% CI: 6.3-14.6, p<0.001) at the one-year follow-up (Arnold et al., 2024).  The analysis highlighted device vs. control group outcomes for all KCCQ domain scores except for mental health (physical limitations, 7.3 points, p=0.003; total symptoms, 6.8 points, p=0.004; quality of life, 14.1 points, p<0.001; social limitation, 14.0 points, p<0.001; and the physical component summary, 5.2, p<0.001).

In summary, the results of TRILUMINATE Pivotal suggest that TriClip implantation improves TR severity and QoL but not all-cause mortality/TV surgery or HF hospitalization for patients with severe TR who are receiving GDMT and are at intermediate or greater risk for surgery. TR severity and QoL were significantly improved in the T-TEER group vs. the GDMT group at 30 days and the improvements were sustained one-year post-procedure. For QoL, the difference between the two groups exceeded 10 points, which is greater than the estimated minimal clinically important difference (MCID) in the KCCQ of 5 points or less (Butler et al., 2020). However, all-cause mortality/TV surgery and HF hospitalization were comparable for the two groups. It was also unclear if improvement in functional capacity was greater for the T-TEER group than the GDMT group because no significance testing was performed.

TRILUMINATE Single-Arm Results

Trial results are reported in Table 1 and baseline characteristics of the study group are provided in Table 3.

Evaluable TR severity was available for 48 of the 85 subjects at 2 years.  Attrition was due to 14 deaths, 6 withdrawals, 3 missed visits, and unreadable echocardiographic imaging in 14 subjects.  Reduction to ≤ moderate TR was achieved in 29 at 2 years, with TR reduction of at least one grade in 41.  Thirty-day TR reduction was sustained in 36 of evaluable subjects, 12 of whom demonstrated further reduction in TR at 2 years.  Increase in TR at 2 years was observed in 12 subjects, with 6 exceeding moderate.  The percentage of patients in NYHA Class I/II increased from 33% to 85% from baseline to 30 days and was 81% at 2 years (von Bardeleben et al., 2023).  The average distance for the 6MWT increased by 60 meters (p<0.01), and the average KCCQ-HF score increased by 13 points (p<0.0001) from baseline to 2 years (von Bardeleben et al., 2023).

Some echocardiographic parameters, such as right ventricular end diastolic diameter (RVEDD), tricuspid annular plane systolic excursion (TAPSE), and fractional area change (FAC), suggested favorable remodeling of the right heart following T-TEER, with changes occurring predominantly during the first 30 days post-procedure.  However, tricuspid annular diameter septal-lateral, right atrial volume, RV fractional area change (RVFAC), RV systolic pressure, RV global longitudinal strain, and left ventricular ejection fraction (LVEF) did not significantly change between baseline and two years.

Uncontrolled observational studies, including registry-based studies, were identified in this analysis. An overview of the studies with at least one year of follow-up is provided in Table 1. Detailed study characteristics and outcomes are provided in Appendix B.

Publications reporting solely on TriClip

bRIGHT PAS

bRIGHT PAS, a large registry study, was examined in a total of three publications.  The study began in 2020 and was designed as a real-world, post-market registry to satisfy European CE Mark requirements for the safety and effectiveness of TriClip.  Two publications that utilized data from the bRIGHT registry evaluated the short-term outcomes of TriClip implantation at 30 days post-procedure, and the latest publication examined outcomes at the one-year follow-up.

Lurz et al. (2024) examined the one-year outcomes for the 511 patients from the bRIGHT registry.  The percentage of patients with a TR grade of moderate or less did not change significantly from 30 days to one year (85% vs. 81%, respectively, p=0.69).  HF hospitalization rate for the one-year pre- vs. post-device was significantly reduced (events/person-years: 0.57 vs. 0.28, respectively, p<0.0001).  There was no device embolization at one year, but the number of single leaflet device attachments increased from 3.5% at 30 days to 3.9% at 1 year, as did the number of reinterventions (30 days, 0.2% vs. 1 year, 3.3%), all-cause mortality (30 days, 1.0% vs. 1 year, 15.1%) and cardiovascular mortality (30 days, 0.8% vs. 1 year, 8.8%).  Significant predictors of survival at one year using Kaplan-Meier estimation included aspartate transaminase (OR [95% CI]: 1.26 [1.00, 1.58], p=0.047), female sex (OR [95% CI]: 0.55 [0.33, 0.91], p=0.02), moderate or less residual TR (OR [95% CI]: 0.32 [0.19, 0.55], p=0.02), serum creatinine (OR [95% CI]: 1.85[1.42, 2.39], p<0.001), LVEF (OR [95% CI]: 0.71 [0.56, 0.91], p=0.007), and baseline KCCQ Overall Summary, OR [95% CI]: 0.73 [0.55, 0.96], p=0.007).  Site experience with performing T-TEER, RV TAPSE, alanine transaminase, and Systolic Pulmonary Artery Pressure (sPAP) were not significant predictors of survival at one year (all p > 0.05).

Publications reporting on the combined use of TriClip and PASCAL (Edward Lifesciences; Irvine, CA)

Hanses et al. conducted a single-arm study in Germany with 102 patients implanted with TriClip or PASCAL.  A subgroup analysis was performed for patients with a low vs. high right ventricular cardiac power index (RVCPi).  At 30 days, there were no differences between the low and high groups for all-cause mortality (12% vs. 7%, p=0.5), the rehospitalization of patients with congestive heart failure (9% vs. 1%, p=0.09), or any of the safety events.  However, one-year all-cause mortality was lower in the low RVCPi group than the high RVCPi group (18% vs. 38%, log-rank p=0.024) (Hanses et al., 2023).

TriValve Registry

The TriValve registry was a large, international registry with patients at 24 centers in Europe and North America.  Two included publications examined outcomes from the TriValve registry at the one-year follow-up.

Coisne et al. conducted a study of the TriValve registry with a total of 308 patients who were implanted with MitraClip, TriClip, or PASCAL.  The study sought to determine if the clinical outcomes were associated with the TV gradient at discharge.  The highest quartile of the TV gradient had the highest residual TR≥3 at discharge (Q1=10.5%, Q2=10.5%, Q3=23.1%, and Q4=28.0%; p<0.01) and the lowest procedural success rate (defined as the patient was alive, the device successfully implanted, and residual TR ≤ 2) (Q1=89.5%, Q2=86.8%, Q3=76.9%, and Q4=72%, p=0.02).  However, the TV gradient was not related to the primary or secondary endpoints.  The primary composite endpoint of all-cause mortality or HF hospitalization occurred in 20.4% of patients, and the secondary endpoints of all-cause mortality and HF hospitalization occurred in 11.0% and 15.6%, respectively, of patients.  In addition, no differences were revealed by TV gradient for the NYHA functional class before T-TEER (p=0.78), at 30 days (p=0.84), or at the last follow-up (p=0.63) (Coisne et al., 2023).

Russo et al. conducted a TriValve registry study to compare the clinical characteristics and outcomes of patients with atrial secondary TR (ASTR) and ventricular secondary TR (VSTR).  A total of 298 patients (n: ASTR 65, VSTR 233) implanted with MitraClip, TriClip, or PASCAL were followed through 12 months.  There were no differences between the ASTR and VSTR groups for procedural success, which was the primary endpoint (80% vs. 83%, respectively; p=0.56).  However, the survival rate, which was defined as the time from the date of T-TEER until death due to any cause, was higher for the ASTR group than the VSTR group (91% vs. 72%, log-rank p=0.02).  However, in a multivariate analysis to predict mortality risk, the only significant predictor was acute procedural risk (HR [95% CI]: 0.41 [0.17–0.96], p=0.04); VSTR vs. ASTR, age of 75 or above, elevated NT-proBNP, TAPSE < 17 mm, and high-dose diuretics were all insignificant (all p > 0.05).  For safety outcomes, there were also no differences between the two groups (Russo et al., 2023).

Bonn Registry

The Bonn registry was a large, international registry at the Heart Centre in Bonn. Two included publications examined outcomes from the Bonn registry at the one-year follow-up.

Tanaka et al. conducted a study of the Bonn registry that included 204 patients implanted with MitraClip, TriClip, or PASCAL.  The study examined post-procedural changes in RV function and its association with clinical outcomes.  Overall, procedural success occurred in 78% of patients, with success defined as successful implantation combined with a reduction in TR severity to 2 or less upon discharge.  For the study’s primary composite outcome, which was mortality or hospitalization due to HF at the one-year follow-up, the endpoint was more likely to occur for patients with RV dysfunction at baseline (defined as RVFAC < 35%) than those with normal RV function (46.8% vs. 23.8%, p=0.006).  Among patients with RV dysfunction at baseline, an increased RVFAC at the three-month follow-up was associated with a significantly lower risk of the endpoint (aHR [95% CI], 0.35 [0.14-0.89], p=0.028).  However, for patients with normal RV function at baseline, an increase in the RVFAC did not alter the likelihood of mortality or hospitalization for HF.  In addition, patients with a low RV–pulmonary artery coupling (defined as TAPSE/sPAP<0.317 mm/mmHg) and reduction in the TAPSE at the three-month follow-up had the highest risk of the endpoint (aHR, [95% CI]: 5.37 [2.12-13.61], p<0.001).  A logistic regression analysis was conducted to identify predictors of RV responders.  In a small sample of patients with RV dysfunction at baseline (n=45), RV responder was predicted by a smaller RV diameter and a greater reduction of TR severity (aOR [95% CI]: 0.89 [0.80–0.99], p=0.038; and 1.75 [1.07–7.68], p=0.037; respectively) (Tanaka et al., 2024).

Vogelhuber et al. conducted a Bonn registry study of 262 patients to compare outcomes for patients with normal RV function and RV dysfunction.  No differences were revealed between the two groups for the primary endpoint, which was 30-day mortality (RV function, [3.2%] vs. RV dysfunction, [2.3%], p=0.99).  There were also no differences between the two groups for the secondary endpoints of implant success, procedural success, TR reduction of 2 or more grades, in-hospital mortality, or complications (all p > 0.05).  However, at two years, the normal RV function group had improved outcomes in comparison to the RV dysfunction group for mortality (27.0% vs. 56.3%, respectively, p<0.001), cardiovascular death (14.1% vs. 39.0%, p<0.001), and rehospitalization for HF (29.9% vs. 49.1%, p=0.007).  Following T-TEER, RV function declined in the normal RV function group (RVFAC mean [SD], n=205: 46.2 [8.1] vs. 40.3 [9.7], p<0.001), but not in the RV dysfunction group (RVFAC mean [SD], n=41: 29.6 [4.1] vs. 31.6 [8.3], p=0.14) (Vogelhuber et al., 2024).

Stolz et al. conducted a multi-center registry study of 962 patients in Germany.  The authors examined the generalizability of TRILUMINATE Pivotal by applying the trial’s inclusion/exclusion criteria to a real-world cohort and examining the outcomes after one-year post-procedure.  Overall, 54.8% of the patients met the inclusion/exclusion criteria; those meeting the criteria had better left ventricular function and fewer comorbidities than the ineligible group.  For the primary endpoint of one-year survival, the results were significantly higher for the eligible group than the ineligible group (84.7% vs. 74.9%, log-rank p<0.001).  Regarding the secondary endpoint, the eligible group was also significantly more likely to be free from TV surgery, repeat intervention, and hospitalization for HF (72.9% vs. 58.0%, p<0.001) (Stolz et al., 2024).

Publications reporting on the use of PASCAL

Kodali et al. reported the 1-year results from the CLASP TR EFS (Edwards PASCAL Transcatheter valve repair system in tricuspid regurgitation Early Feasibility Study).  This study enrolled 65 U.S. patients in a prospective, multicenter, single-arm registry to evaluate the performance and safety of the PASCAL and PASCAL Ace T-TEER systems (Edwards Life Science, Irvine CA). Thirty-day clinical outcomes were favorable (death, 3.1%; stroke, 1.5%; and no device-related reinterventions), and single leaflet device detachment occurred in 3 patients (4.6%) within the first month. At 1 year, freedom from all-cause mortality and HF hospitalization were 88% and 78%, respectively.  Major bleeding was noted in six patients (9.2%), unplanned reintervention was required in one patient (1.5%), and stroke occurred in three patients (4.6%).  Treatment with T-TEER was associated with improvements in 1-year NYHA functional class (92% achieved NYHA functional class I or II; p<0.001 vs baseline), 6MWD (+94 m; p=0.014), and health status or QOL (KCCQ, +18 points; p<0.001).  HF hospitalizations were reduced by 56% in the year following treatment vs. the year before treatment.  Reductions in TR were durable at 1 year, with 86% of patients having moderate TR or less and all patients achieving at least a 1-grade reduction from baseline.  Despite evidence of favorable RV remodeling (i.e., reduced RVEDD and volume), measures of RV systolic function remained unchanged (Kodali et al., 2023).

The literature for T-TEER is limited and largely represents the European experience.  The pivotal RCT, TRILUMINATE Pivotal, along with the TRILUMINATE Single Arm, uncontrolled observational studies, and registry-based analyses from Europe represent the extent of the literature on this technology.

The evidence reviewed had several important limitations.  The evidence is inadequate to fully assess which characteristics of the patient, practitioner, or facility predict the most successful patient outcomes from the T-TEER device.

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 medical therapy in the trials was partially an artifact of the many underlying causes of TR.  Improvement in health outcomes following T-TEER for each phenotype cannot be assessed in comparison to optimal medical therapy for TR in this circumstance.

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 T-TEER 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 are needed to identify and reliably demonstrate which Medicare beneficiaries are likely to benefit from T-TEER and how that benefit varies by subgroup.  Specifically, more evidence is needed for:
  • Patients with greater than mild RV dysfunction and those with advanced hepatic or renal dysfunction;
  • Subpopulations defined by sex, age, other demographic characteristics, and important comorbidities;
• Durability and treatment benefit for hospitalization, total hospitalizations, or survival should be demonstrated for at least two years;
• One or more objective clinical outcomes, especially mortality, should be demonstrated for at least two years;
• More evidence is needed to identify which implant size of the TriClip device is most appropriate for specific patients;
• More evidence is needed to define the optimal coaptation gap for successful T-TEER;
• More evidence is needed to define the treatment conditions (e.g., implanting physician experience/training, echocardiographer experience/training, heart team, facility characteristics) necessary to achieve optimal T-TEER outcomes;
• Given the high risk of bias inherent in unblinded studies, T-TEER studies should pre-specify both subjective (e.g., QoL, functional outcomes) and objective (e.g., heart failure hospitalization, heart failure hospitalization or heart failure hospitalization equivalent events, total hospitalizations, survival) outcome criteria;
• In composite outcome measures all outcomes comprising the composite outcome should demonstrate movement in the same direction (e.g., physiologic, patient-reported, and other relevant health outcomes).

Other trials of tricuspid TEER are under way (TRICI-HF [NCT04634266] and TRI-FR [NCT04646811]); with sufficient follow-up, the combined results of these trials may inform us about the potential prognostic effects of tricuspid TEER in general and about the sub-groups of patients that derive the greatest benefit from this procedure.

Patients enrolled in TRILUMINATE Pivotal had a mean age of 78 years; however, there are limits in extrapolating trial results to the broader pool of Medicare beneficiaries eligible for T-TEER.  TRILUMINATE Pivotal and TRILUMINATE Single Arm were trials conducted on select populations with stringent inclusion and exclusion criteria and patients were assessed, treated, and managed in highly controlled settings.  This is a common limitation of RCTs, and larger, real-world, registry-based studies can provide the generalizability we seek to Medicare beneficiaries in their usual care settings.

The reviewed observational studies included a broader diversity of patient characteristics and treatment settings.  The mean age of the observational studies ranged from 75 to 82 years.  Single-center studies included in this review may not adequately represent the varied experience levels of providers conducting T-TEER procedures in general use.  Additionally, many of the included studies were conducted outside of the US, which limits the applicability of outcomes such as hospitalization that may be influenced by differences in insurance and health system factors.

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 T-TEER is considered for the treatment of symptomatic tricuspid regurgitation.

To better serve Medicare beneficiaries, additional evidence should address:

1. Sufficient patient enrollment to have confidence that expected outcomes will be reliably achieved in real-world use;
2. Sufficient representation of Medicare beneficiaries, disease subgroups, and demographic groups in clinical studies of the TriClip device to demonstrate generalizability to those populations;
3. Clinical studies of sufficient duration to demonstrate that observed outcomes demonstrate clinically meaningful differences and are durable to an extent appropriate for treatment of tricuspid regurgitation;
4. Clinical studies clarifying the site of service, clinical staffing, and experience profiles associated with expected outcomes in real-world use of transcatheter edge-to-edge repair of the tricuspid valve.

Based on the evidence review, we believe that evidence published in the peer reviewed literature should critically evaluate the following outcomes through a minimum of 1 year:

• 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.

We identified two professional society guidelines relevant to the contemporary care of patients with TR.  Both guidelines focus on appropriate medical and surgical care of the TR patient.

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 medical 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.

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.”
• “For patients with large annuli due to RV failure, atrial fibrillation, or a combination, tricuspid TEER may be difficult, if not impossible, because of large coaptation gaps.  These patients may be better suited for transcatheter TV replacement or transcatheter annuloplasty.”
• Severity of pulmonary hypertension (PH) should be considered in treatment choice due to risks of “complete and sudden elimination of TR in patients with severe PH leading to acute RV failure and hemodynamic instability.”
• The presence of CIED leads may inform choices about transcatheter TV therapy.  The location of leads may interfere with device placement and device choice may impact future pacemaker options.

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 medical 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 medical 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.

There are no relevant, published appropriate use criteria.

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: October 3, 2024 – November 2, 2024

During the first 30-day public comment period CMS received 64 comments.  The majority of commenters spoke positively of the use T-TEER.  A few commenters did not support coverage of T-TEER 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=316&fromTracking=Y& .

The majority of comments were anecdotes provided by physicians who utilized T-TEER among their patients.  Three comments were received from medical technology manufacturers, including Abbott, Boston Scientific, and Edwards Lifesciences.  We received one joint comment from the American Association for Thoracic Surgery (AATS), the American College of Cardiology (ACC), the American Society of Echocardiography (ASE), the Heart Rhythm Society (HRS), the Society for Cardiovascular Angiography and Interventions (SCAI), and the Society of Thoracic Surgeons (STS).  One comment was received from a trade association, the Medical Device Manufacturers Association (MDMA).  One comment was received from a patient advocacy organization, Heart Valve Voice US.  One comment was received from a group of clinician and patient advocacy organizations, the Heart Valve Disease Policy Task Force.

Second Comment Period: April 3, 2025 – May 3, 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.

IV.         CMS Coverage Analysis

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]

The Centers for Medicare & Medicaid Services (CMS) proposes to cover transcatheter edge-to-edge repair of the TV (T-TEER) under Coverage with Evidence Development (CED) for the treatment of symptomatic tricuspid regurgitation according to the provisions in sections I.B (Coverage Criteria) and I.C (Other Uses of T-TEER) under the Proposed Decision section of this document, which are explained below.

Context of care:

Coverage Criteria

T-TEER is covered when furnished according to a Food and Drug Administration (FDA) market-authorized indication.

1.     Patient Criteria:

Despite optimal medical therapy (OMT), patients must have symptomatic TR with tricuspid valve repair being considered as appropriate by a heart team.

These criteria are consistent with the TRILUMINATE Pivotal trial inclusion criteria and FDA-approved label indications.

2.     Physician Criteria

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

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

T-TEER Heart Team Composition:  The multi-disciplinary heart team is a patient-centered concept that supports evidence-based medical decision making and promotes the best possible outcomes.  We 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 T-TEER, allowing for transition to a community cardiologist for routine care.  This requirement is consistent with the FDA-approved label for the TriClip 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 state, “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.  In the TRILUMINATE Pivotal trial, the cardiac surgeon on the site heart team was required to “concur that the patient is at intermediate or greater estimated risk for mortality or morbidity with tricuspid valve surgery” as an inclusion criterion.  FDA labeling for TriClip G4 specifies that “The TriClip G4 System should be implanted … in a facility with immediate access to cardiovascular surgery.”  Potential need for rescue procedures mandates 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.”

Cardiologist with training and experience in heart failure management:  The TRILUMINATE Pivotal trial required participation of a heart failure cardiologist in the heart team.  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 cardiologists with training and experience in heart failure management as part of comprehensive management of patients with complex heart failure.  These recommendations underscore the importance of attentive, expert medical 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 T-TEER is based on the frequency of interaction between the TV and CIEDs and unanswered questions related to this relationship.  The TRILUMINATE Pivotal trial excluded patients in whom, “Pacemaker or implantable cardioverter-defibrillator (ICD) leads that would prevent appropriate placement of the TriClip™ Clip.”  The TriClip G4 instructions for use require that “Patients with pre-existing cardiac leads should be assessed to ensure placement of the TriClip Implant is possible.”  As such, and in the absence of evidence-based guidance for appropriate use in the setting of a CIED, 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.

Multimodality cardiac imaging specialists:  Multimodality cardiac imaging specialists are also necessary to the success of a T-TEER 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 medical 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.

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 that “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 TriClip G4 specifies that “The TriClip G4 System should be implanted … using fluoroscopy and transoesophageal echocardiography” and that “Echocardiographic images should be carefully assessed to ensure they are of adequate quality to allow successful implantation of the TriClip G4 Implant.”

3.      Coverage with Evidence Development

CMS acknowledges limitations in the published evidence available to assist the heart team in optimal patient selection for T-TEER.  Because evidentiary gaps remain relative to optimization of patient selection for T-TEER, 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 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.

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 T-TEER.

Rationale for (c):
The trials that generated the promising evidence for T-TEER were performed in highly-specialized medical centers with expertise at transcatheter valve intervention.  Insufficient 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.

Rationale for (d):
More evidence is needed about the above subgroups to determine which patients will clinically benefit from, or be harmed by, T-TEER, and under what treatment conditions and the practitioner and facility level variables.  Note that patients with LVEF ≤ 20%, any prior TV procedure that would interfere with placement of the device, indication for mitral, aortic or pulmonary valve correction (untreated), CIED leads that would interfere with placement of the device, and patients on dialysis were excluded from the RCT.  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 T-TEER is necessary to guide appropriate therapy in this group of patients with TR.  Recent observational evidence suggests that, as with mitral valve repair, degree of residual TR after repair is associated with survival (Stolz et al., 2024).  The TRILUMINATE Pivotal investigators have also asserted the importance of the degree of valve regurgitation for long-term event-free survival.  Therefore, subgroup analysis based on TR residual is relevant.

A CED study would be considered successful if it demonstrated all of the following:

•         Clinically meaningful improvement in health outcomes in Medicare beneficiaries following T-TEER for treatment of symptomatic TR, in comparison to optimal medical therapy.
•         Satisfactory risk/benefit profile of T-TEER compared with tricuspid valve surgery in Medicare beneficiaries with symptomatic TR.
•         Specific patient and disease phenotype subgroups likely to benefit from T-TEER.
•         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 T-TEER programs.  Further, there are minimal data on treatment conditions that support outcomes comparable to those in the published RCT on T-TEER.  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 T-TEER.

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

Q1: Is the evidence sufficient to conclude that T-TEER 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 T-TEER 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 TRILUMINATE Pivotal trial did not show differences between groups in mortality, nor in the rate of heart failure hospitalization at one year.  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.  The investigators emphasized the importance of longitudinal study follow up for survival and hospitalizations (Sorajja et al., 2023).  It is noted that the FDA-approved label indicates that information provided to the patient should include that “Patients on average are unlikely to experience any survival benefit or a reduced rate of heart failure-related hospitalization.”

Because OMT was not standardized and because of the lack of analysis of disease subgroups, improvement in health outcomes following T-TEER is not yet thoroughly understood in comparison to optimal medical therapy for TR.  It is notable that a percentage of patients in the medical arm improved, suggesting that there was benefit from optimizing medical 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 and no statistically significant difference on these measures was shown between groups.  Expected longitudinal outcomes of TRILUMINATE Pivotal beyond one year will be helpful to further understanding of the benefits of this intervention.

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

Uncertain – Evidence is lacking.

As noted by the TRILUMINATE Pivotal investigators, patients in the pivotal trial were highly selected with few comorbidities.  A high percentage of enrolled patients were NYHA class II, and HF hospitalizations in the year preceding randomization were low.  Patients with HF with reduced ejection fraction, a major cause of secondary tricuspid regurgitation, were underrepresented in the trial.  It remains unknown whether a population with a higher-risk profile would derive a benefit from T-TEER over medical therapy alone.  Further, patients with a good quality of life were not shown to benefit from T-TEER.  It is noted that the FDA label indicates that information provided to the patient should include that “Patients who have good baseline quality of life and functional status may not experience further improvement in these attributes following treatment with the TriClip G4 System.”

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.

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

Uncertain – As noted by the trial investigators, degree of residual valve regurgitation has implications for long-term event-free survival.  The RCT for TriClip was performed in specialized centers with selected procedural operators with experience in performance of percutaneous structural heart procedures and the study authors have indicated that high rates of attaining moderate-or-less tricuspid regurgitation in the TRILUMINATE Pivotal trial were likely related to operator experience.  No stratification nor subgroup analysis is available based on treatment conditions and there are no published studies or guidelines that address the impact of the qualifications of procedural operators on patient outcomes during and after T-TEER.  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).

There is little evidence to date that outcomes achieved in rigorous trials at highly selected sites can be replicated in the real world.  Treatment conditions that provide an appropriate balance of satisfactory health outcomes and optimal patient access are currently unknown for this technology.

Based on the totality of the evidence, CMS finds further justification that coverage under CED is appropriate.  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 T-TEER.

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 Medical and Other Health Services) of the Act.

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

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 T-TEER 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

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

This is CMS’ first NCA on T-TEER.  This request was externally initiated.  CMS received a complete, formal request to open an NCA on the topic of transcatheter edge-to-edge repair for tricuspid valve regurgitation from Abbott.  The request letter is available at https://www.cms.gov/files/document/id316.pdf . Abbott is participating in the Transitional Coverage for Emerging Technologies (TCET) pilot program and tested the processes and concepts of TCET.

VI.         Appendices

Appendix A: Proposed Medicare National Coverage Determinations Manual Language

The Centers for Medicare & Medicaid Services (CMS) proposes to cover tricuspid transcatheter edge-to-edge repair (T-TEER) 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.

We propose that T-TEER is covered when furnished according to a Food and Drug Administration (FDA) market-authorized indication and all the following conditions are met:

Despite optimal medical therapy (OMT), patients must have symptomatic TR with tricuspid valve repair being considered as appropriate by a heart team.

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

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

The T-TEER 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:

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”).

1)      Tricuspid transcatheter edge-to-edge repair (T-TEER) is not covered for patients outside of a CMS-approved study.

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

Appendix B: Referenced Materials

^αStudy quality assessed using the US Preventive Services Task Force’s Criteria for Assessing Internal Validity of Individual Studies tool
*p<0.05; **p<0.01; ***p<0.001

Abbreviations: 6MWT: 6-minute walk test; AE: adverse event; AST: aspartate transaminase; BL: baseline; CABG: coronary artery bypass graft; CAD: coronary artery disease; CI: confidence interval; CIED: cardiac implantable electronic device; COPD: chronic obstructive pulmonary disease; CRT: cardiac resynchronization therapy; CRT-D: CRT defibrillator; CV: cardiovascular; CVA: cerebrovascular accident; DBP: diastolic blood pressure; EQ-5D: EuroQol-5-dimension questionnaire; EROA: effective regurgitant orifice area; FAC: fractional area change; GFR: glomerular filtration rate; GI: gastrointestinal; HF: heart failure; HR: hazard ratio; HRQoL: health-related QoL; ICD: implantable cardioverter-defibrillator; ICU: intensive care unit; IQR: interquartile range; ITT: intention-to-treat; IVC: inferior vena cava; KCCQ: Kansas City Cardiomyopathy Questionnaire; LV: left ventricular; LVEF: LV ejection fraction; LVOT: LV outflow tract; MAE: major AE; MI: myocardial infarction; MT: medical therapy; NA: not applicable; NR: not reported; NTproBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association; OMT: optimal medical therapy; OR: odds ratio; PCI: percutaneous coronary intervention; PISA: proximal isovelocity surface area; PPM: permanent pacemaker; P-Y: patient-year; QoL: quality of life; RCT: randomized controlled trial; RV: right ventricular; RVCPi: right ventricular cardiac power index; RVFAC: right vent RVEDD: RV end diastolic dimension; SAE: serious AE; SBP: systolic blood pressure; SD: standard deviation; SF-36: 36-item Short Form Health Survey; SLDA: single leaflet device attachment; sPAP: systolic pulmonary artery pressure; TA: tricuspid valve annulus; TAPSE: tricuspid annular plane systolic excursion; TAVI: transcatheter aortic valve implantation; TDI: tissue Doppler imaging; TEE: transesophageal echocardiogram; TIA: transient ischemic attack; TTE: transthoracic echocardiogram; T-TEER: tricuspid valve transcatheter edge-to-edge repair; TR: tricuspid regurgitation; TV: tricuspid valve; VTI: velocity time integral; WR: win ratio

Appendix C: Heart Failure Quality of Life and Functional Measures

[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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