BACKGROUND

Mitral Regurgitation
Epidemiology and Classification

Mitral Regurgitation (MR) is the second most common valvular heart disease, occurring in 7% of people older than age 75 years and accounting for 24% of all patients with valvular heart disease.^1,2, MR with accompanying valvular incompetence leads to left ventricular (LV) volume overload with secondary ventricular remodeling, myocardial dysfunction, and left heart failure. Clinical signs and symptoms of dyspnea and orthopnea may also be present in patients with valvular dysfunction.^3,MR severity is classified as mild, moderate, or severe disease on the basis of echocardiographic and/or angiographic findings (1+, 2+, and 3-4+ angiographic grade, respectively).

Patients with MR generally fall into two categories¾primary (also called degenerative) and secondary (also called functional) MR. Primary MR results from a primary structural abnormality in the valve, which causes it to leak. This leak may result from a floppy leaflet (called prolapse) or a ruptured cord that caused the leaflet to detach partially (called flail).^4, Because the primary cause is a structural abnormality, most cases of primary MR are surgically corrected. Secondary MR results from LV dilatation due to ischemic or dilated cardiomyopathy. This causes the mitral value (MV) leaflets not to coapt or meet in the center.^3, Because the valves are structurally normal in secondary MR, correcting the dilated LV using medical therapy is the primary treatment strategy used in the U. S.

Standard Management
Surgical Management

In symptomatic patients with primary MR, surgery is the main therapy. In most cases, MV repair is preferred over replacement, as long as the valve is suitable for repair and personnel with appropriate surgical expertise are available. The American College of Cardiology and the American Heart Association have issued joint guidelines on the surgical management of MV, which are outlined in Table 1.^4,

Table 1. Guidelines on Mitral Value Surgery

Recommendation	COR	LOE
MV surgery is recommended for the symptomatic patient with acute severe MR.	I	B
MV surgery is beneficial for patients with chronic severe MR and NYHA functional class II, III, or IV symptoms in the absence of severe LV dysfunction (severe LV dysfunction is defined as ejection fraction less than 0.30) and/or end-systolic dimension greater than 55 mm.	I	B
MV surgery is beneficial for asymptomatic patients with chronic severe MR and mild-to-moderate LV dysfunction, ejection fraction 0.30 to 0.60, and/or end systolic dimension greater than or equal to 40 mm.	I	B
MV repair is recommended over MV replacement in the majority of patients with severe chronic MR who require surgery, and patients should be referred to surgical centers experienced in MV repair.	I	C
MV repair is also reasonable for asymptomatic patients with chronic severe MR with preserved LV function … in whom the high likelihood of successful MV repair without residual MR is greater than 90%.	IIa	B
MV surgery is reasonable for asymptomatic patients with chronic severe MR, preserved LV function, and new onset of atrial fibrillation	IIa	C
MV surgery is reasonable for asymptomatic patients with chronic severe MR, preserved LV function, and pulmonary hypertension….	IIa	C
MV surgery is reasonable for patients with chronic severe MR due to a primary abnormality of the mitral apparatus and NYHA functional class III-IV symptoms and severe LV dysfunction … in whom MV repair is highly likely	IIa	C

COR: class of recommendation; LOE: level of evidence; LV: left ventricular; MR: mitral regurgitation; MV: mitral valve; NYHA: New York Heart Association.

The use of standard open MV repair is limited by the requirement for thoracotomy and cardiopulmonary bypass, which may not be tolerated by elderly or debilitated patients due to their underlying cardiac disease or other conditions. In a single-center evaluation of 5737 patients with severe MR in the U. S., Goel et al (2014) found that 53% of patients did not have MV surgery performed, suggesting an unmet need for such patients.^5,
Isolated MV surgery (repair or replacement) for severe chronic secondary MR is not generally recommended because there is no proven mortality reduction and an uncertain durable effect on symptoms. Recommendations from major societies^6,7, regarding MV surgery in conjunction with coronary artery bypass graft surgery or surgical aortic valve replacement are weak because the current evidence is inconsistent on whether MV surgery produces a clinical benefit.^8,9,10,11,

Transcatheter Mitral Valve Repair

Transcatheter approaches have been investigated to address the unmet need for less invasive MV repair, particularly among inoperable patients who face prohibitively high surgical risks due to age or comorbidities. MV repair devices under development address various components of the MV complex and generally are performed on the beating heart without the need for cardiopulmonary bypass.^1,12, Approaches to MV repair include direct leaflet repair,^13, repair of the mitral annulus via direct annuloplasty, or indirect repair based on the annulus’s proximity to the coronary sinus. There are also devices in development to counteract ventricular remodeling, and systems designed for complete MV replacement via catheter.

Direct Leaflet Approximation

One device that undertakes direct leaflet repair, the MitraClip Clip Delivery System (Abbott Vascular), has been approved through the premarket approval process by the U.S. Food and Drug Administration (FDA) for use in certain patients with symptomatic primary MR (see Regulatory Status section). Of the transcatheter MV repair devices under investigation, MitraClip has the largest body of evidence evaluating its use; it has been in use in Europe since 2008.^13, The MitraClip system is deployed percutaneously and approximates the open Alfieri edge-to-edge repair approach to treating MR. The delivery system consists of a catheter, a steerable sleeve, and the MitraClip device, which is a 4-mm wide clip fabricated from a cobalt-chromium alloy and polypropylene fabric. MitraClip is deployed via a transfemoral approach, with transseptal puncture used to access the left side of the heart and the MV. Placement of MitraClip leads to coapting of the mitral leaflets, thus creating a double-orifice valve.

Other Mitral Valve Repair Devices

Devices for transcatheter MV repair that use different approaches are in development. Techniques to repair the mitral annulus include those that target the annulus itself (direct annuloplasty) and those that tighten the mitral annulus via manipulation of the adjacent coronary sinus (indirect annuloplasty). Indirect annuloplasty devices include the Carillon® Mitral Contour System (Cardiac Dimension) and the Monarc™ device (Edwards Lifesciences). The CE-marked Carillon Mitral Contour System is comprised of self-expanding proximal and distal anchors connected with a nitinol bridge, with the proximal end coronary sinus ostium and the distal anchor in the great cardiac vein. The size of the connection is controlled by manual pullback on the catheter (CE-marked). The Carillon system was evaluated in the Carillon Mitral Annuloplasty Device European Union Study and the follow-up Tighten the Annulus Now study, with further studies planned.^14,The Monarc system also involves two self-expanding stents connected by a nitinol bridge, with one end implanted in the coronary sinus via internal jugular vein and the other in the great cardiac vein. Several weeks after implantation, the biologically degradable coating over the nitinol bridge degrades, allowing the bridge to shrink and the system to shorten. It has been evaluated in the Clinical Evaluation of the Edwards Lifesciences Percutaneous Mitral Annuloplasty System for the Treatment of Mitral Regurgitation trial.^15,

Direct annuloplasty devices include the Mitralign Percutaneous Annuloplasty System (Mitralign) and the AccuCinch® System (Guided Delivery Systems), both of which involve transcatheter placement of anchors in the MV; they are cinched or connected to narrow the mitral annulus. Other transcutaneous direct annuloplasty devices under investigation include the enCorTC™ device (MiCardia), which involves a percutaneously insertable annuloplasty ring that is adjustable using radiofrequency energy, a variation on its CE-marked enCor_sq™ Mitral Valve Repair System, and the Cardioband™ Annuloplasty System (Valtech Cardio), an implantable annuloplasty band with a transfemoral venous delivery system.

Transcatheter Mitral Valve Replacement

Permavalve™ (Micro Interventional Devices), under investigation in the U.S., is a transcatheter MV replacement device that is delivered via the transapical approach. On June 5, 2017, the SAPIEN 3 Transcatheter Heart Valve (Edwards Lifesciences) was approved by the FDA as MV replacement device. These replacement valves are outside the scope of this policy.

Medical Management

The standard treatment for patients with chronic secondary MR is medical management. Patients with chronic secondary MR should receive standard therapy for heart failure with reduced ejection fraction; standard management includes angiotensin converting enzyme inhibitor (or angiotensin II receptor blocker or angiotensin receptor-neprilysin inhibitor), b-blocker and mineralocorticoid receptor antagonist, and diuretic therapy as needed to treat volume overload.^4,3, Resynchronization therapy may provide symptomatic relief, improve LV function, and in some patients, lessen the severity of MR.

Regulatory Status

In October 2013, the MitraClip® Clip Delivery System (Abbott Vascular) was approved by the FDA through the premarket approval process for treatment of “significant symptomatic mitral regurgitation (MR ≥3+) due to primary abnormality of the mitral apparatus (degenerative MR) in patients who have been determined to be at a prohibitive risk for mitral valve surgery by a heart team.”^16, FDA product code: NKM.

In March 2019, the FDA approved a new indication for MitraClip, for "treatment of patients with normal mitral valves who develop heart failure symptoms and moderate-to-severe or severe mitral regurgitation because of diminished left heart function (commonly known as secondary or functional mitral regurgitation) despite being treated with optimal medical therapy. Optimal medical therapy includes combinations of different heart failure medications along with, in certain patients, cardiac resynchronization therapy and implantation of cardioverter defibrillators."

RELATED POLICIES

• Transcatheter Pulmonary Valve Implantation (Policy #132 in the Surgery Section)
• Transcatheter Aortic Valve Implantation for Aortic Stenosis (Policy #131 in the Surgery Section)

• Medical office notes with a complete history, physical exam and assessment supporting determination of the patient being at a prohibitive risk for open mitral valve surgery.

• Presence of a Society for Thoracic Surgeons predicted mortality risk of 12% or greater and/or
• Presence of a logistic EuroSCORE of 20% or greater.

• Grade 3+ (moderate) or 4+ (severe) MR confirmed by echocardiography
• New York Heart Association (NYHA) functional class II, III, or IVa (ambulatory) despite the use of stable maximal doses of guideline-directed medical therapy and cardiac resynchronization therapy (if appropriate) administered in accordance with guidelines of professional societies.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function - including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.
To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

MitraClip
Primary Mitral Valve Regurgitation at Prohibitive Surgical Risk
Clinical Context and Therapy Purpose
The purpose of TMVR using MitraClip in patients who have primary MR and are at prohibitive risk for open surgery.is to provide a treatment option that is an alternative to or an improvement on existing therapies.
The question addressed in this policy is: Does TMVR using MitraClip improve the net health outcome in patients with symptomatic primary MR and at prohibitive risk for open surgery?
The following PICO was used to select literature to inform this policy.

Patients
The relevant population of interest is patients with symptomatic primary MR and at prohibitive risk for open surgery.
MR severity is classified as mild, moderate, or severe disease on the basis of echocardiographic and/or angiographic findings (1+, 2+, and 3-4+ angiographic grade, respectively). MR with accompanying valvular incompetence leads to left ventricular (LV) volume overload with secondary ventricular remodeling, myocardial dysfunction, and left heart failure. Clinical signs and symptoms of dyspnea and orthopnea may also present in patients with valvular dysfunction.

Intervention
The therapy being considered is TMVR using MitraClip.

Comparators
The following therapies are currently being used to make decisions about TMVR using MitraClip. Comparators of interest are medical management. Given that primary MR is a mechanical problem and there is no effective medical therapy, an RCT comparing MitraClip with medical management is not feasible or ethical.

Outcomes
The general outcomes of interest are overall survival (OS), morbid events, functional outcomes, and treatment-related morbidity.

No RCTs have been published evaluating MitraClip in prohibitive surgical risk populations.

A TEC Assessment (2014) evaluated the evidence on the use of MitraClip for primary MR, a U.S. Food and Drug Administration (FDA) approved indication.^17, The Assessment included five case series reporting outcomes of patients with primary MR considered at high-risk of surgical mortality who underwent MitraClip placement. Three of the 5 case series were rated as poor because of low or unknown follow-up rates and are not discussed further. Tables 2 and 3 summarize patient characteristics and health outcomes of the case series by Reichenspurner et al (2013)^18, and Lim et al (2013),^19, which were considered higher quality. The Reichenspurner et al (2013) study reported data on 117 primary MR patients who were enrolled in a European postmarketing registry. The Lim et al (2013) study reported data on 127 patients enrolled in the Endovascular Valve Edge-to-Edge REpair STudy (EVEREST II) High Risk Registry (HRR) and the Real World Expanded Multicenter Study of the MitraClip System (REALISM) registry and then retrospectively identified as meeting the definition of prohibitive risk and were followed for 1 year. The 30-day mortality rates were 6.0% and 6.3%, and 12- and 25-month mortality rates were 17.1% and 23.6%, respectively.^18,20, In evaluable patients at 12 months, the percentages of patients who had an MR severity grade of 2 or less were 83.3% and 74.6% in the 2 studies; the percentages with New York Heart Association (NYHA) class I or II functional status were 81% and 87%; and the percentages who improved at least 1 NYHA class level were 68% and 88%, respectively.

Table 2. Key Case Series Characteristics

Study; Trial	Country	Participants	Treatment Delivery	Follow-Up
Reichenspurner et al (2013)18,;ACCESS-EU	Europe	N=117 EF <40% or mean EF: 9.4% NYHA class ≥3: 74% MR severity ≥3+: 96.6% Mean EuroSCORE: 15.5%	MitraClip	71 had 1-y follow-up data
Lim et al (2014)20,; subset of patients at prohibitive risk of open surgery from EVEREST II HRR and REALISM	U.S.	N: 127 EF <40% or Mean EF: 61% NYHA class ≥3: 87% MR severity ≥3+: 100% Mean STS score: 13.2%	MitraClip	1.47 y

Adapted from the TEC Assessment (2014).^17,
EF: ejection fraction; MR: mitral regurgitation; NYHA: New York Heart Association; STS: Society of Thoracic Surgeons surgical risk score.

Table 3. 12-Month Outcomes for Key Case Series of MitraClip for Primary Mitral Valve Disease

Study; Trial	Original N	MR Grade at 12 Months, % (n/N)	NYHA Class at 12 Months, % (n/N)	Other Pertinent Outcomes at 12 Months
Reichenspurner et al (2013)18,; ACCESS-EU	117	MR severity ≤2+: 74.6% (53/71)	Class I/II: 81% (63/78) Improved ≥1 class: 68% (53/78)	Change in MLHFQ from baseline, 13.3 points (p=0.03), n=44 Change in 6MWT from baseline, 77.4 m (p<0.001), n=52
Lim et al (2014)20,; subset of patients at prohibitive risk of open surgery from EVEREST II HRR and REALISM	127	MR severity ≤2+: 83.3% (70/84)	Class I/II: 86.9% (73/84) Improved ≥1 class: 86.9% (73/84)	SF-36 PCS score change, 6.0 (95% CI, 4.0 to 8.0), n=76 SF-36 MCS score change, 5.6 (95% CI, 2.3 to 8.9), n=76

Adapted from the TEC Assessment (2014).^17,
CI: confidence interval; MCS: Mental Component Summary; MLHFQ: Minnesota Living with Heart Failure 10 Questionnaire; MR: mitral regurgitation; NYHA: New York Heart Association; PCS: Physical Component Summary; 6MWT: 6-minute walk test; SF-36: 36-Item Short-Form Health Survey.

The FDA compared the cohort reported by Lim et al (2014; discussed above) with a historical cohort (n=65) generated from the patient-level data Duke Registry of primary MR patients with MR of 3+ or more. The Duke cohort of 65 patients with primary MR was derived from a dataset of 953 patients with an MR severity grade of 3+ or 4+ who were retrospectively identified as being at a prohibitively high-risk for surgery based on the same high-risk criteria as those in the EVEREST II HRR and REALISM studies (ie, Society of Thoracic Surgeons (STS) mortality risk calculation of 12% or higher or protocol-specified surgical risk factors). For the cohort described by Lim et al (2014), compliance to follow-up visits in continuing patients was 98%, 98%, and 95% at 30 days, 12 months, and 2 years, respectively. Cohort characteristics and results are summarized in Tables 4 and 5. There were no intraprocedural deaths and the MitraClip was implanted successfully in 95% of patients. Eight patients died within 30 days of the procedure or discharge postprocedure, resulting in a procedural mortality rate of 6.4% that increased to 24.8% at 12 months. Comparative mortality rates in the Duke cohort at 30 days and 12 months were 10.9% and 30.6%, respectively.

The TEC Assessment identified multiple limitations with use of historical controls. Specifically, patients in the Duke group did not appear to have been evaluated specifically for the MitraClip procedure (ie, their anatomic eligibility to receive the device). Data were not available on patient status at beginning of follow-up, which could have had a critical impact on short-term mortality. These control groups are therefore likely to have higher mortality rates than MitraClip groups. In comparing the clinical characteristics of Duke group with patients receiving MitraClip, although mean predicted surgical mortality risks were similar, subjects differed greatly in NYHA functional class and ejection fraction, among other characteristics. Neither of these control groups provides unbiased or precise estimates of the natural history of patients eligible to receive MitraClip. Due to the lack of an appropriate control group and clear evidence about the natural history of patients with primary MR considered at high-risk for surgery, the TEC Assessment concluded that a determination whether MitraClip improved, had no effect, or worsened mortality than nonsurgical management could not be made.

The FDA, on the contrary, concluded that totality of the evidence demonstrated reasonable assurance of safety and effectiveness of MitraClip to reduce MR and provide patient benefit in this discreet and specific patient population based on the following^16,:

• It is broadly accepted that primary MR is a mechanical problem in which there is a primary abnormality of the mitral apparatus and the “leaflets are broken”. There is no medical therapy for reducing primary MR, which must be treated with mechanical correction of the MV.
• The observed procedural mortality rate with MitraClip was 6.4% (95% CI, 2.8% to 12.0%) at 30 days. This rate was lower than the predicted mortality rate of 13.2% (95% CI, 11.9% to 14.5%) using STS Replacement Risk Score or 9.5% (95% CI, 11.3% to 13.7%) using STS Repair Score for the Lim et al (2014) cohort.
• While acknowledging the pitfalls of using historical controls from the Duke Registry, the FDA found no elevated risk of mortality in MitraClip cohort patients over nonsurgical management and both immediate and long-term improvement in MR severity. MR severity grade of 2+ or less and of 1+ or less was observed in 82% and 54% of surviving patients at discharge, respectively. This improvement was sustained at 12 months, with the majority (83.3%) of surviving patients reporting MR severity grade of 2+ or less and 36.9% reporting MR severity grade of 1+ or less. At 12 months, freedom from death and MR severity grade greater than 2+ was 61.4%, and freedom from death and MR severity grade greater than 1+ was 27.2%.
• Quality of life was assessed using the SF-36. The mean difference in the Physical Component Summary and Mental Component Summary scores from baseline to 12 months improved by 6 and 5.6 points, respectively, which is above the 2- to 3-point minimally important difference threshold reported in the literature.^21, Sensitivity analyses showed that these effectiveness results were robust to missing data.
• The commercial postregistry data of over 8300 patients (one-third primary MR and two-thirds secondary MR) outside the U.S. suggests that mortality rates reported in patients at prohibitive risk of surgery undergoing the MitraClip procedure do not appear to be elevated and are not unexpected given the age and burden of comorbidities of the patients treated. Reported mortality ranges were: in-hospital mortality, 0% to 4%; 30-day mortality, 0% to 9.1%; and 6- to 12-month mortality, 8% to 24%. Reported clinical benefits were: improvement in MR severity grade of 2+ or less after MitraClip in more than 75% of patients; improvement in 6-minute walk distance of 60 to >100 meters (the generally accepted threshold is >40 m), and percentages of patients who improved to a NYHA class of I or II ranged from 48% to 97%.
• The probable adverse event risks of the MitraClip included procedure-related complications such as death (6.3%), stroke (3.4%), prolonged ventilation (3.1%), and transfusion greater than 2 units (12.6%), major vascular complications (5.4%), noncerebral thromboembolism (1.6%), new onset of atrial fibrillation (3.9%), and atrial septal defect (1.6%).

	Percent Event Free (95% CI), %
Study	At 30 Days	At 6 Months	At 12 Months	Freedom From Death and MR >2+	Freedom From Death and NYHA Class III/IV
FDA (2013)16,	N=192	N=192	N=192	N range, 114-124	N range, 114-124
MitraClip	93.6 (87.6 to 96.8)	84.8 (77.2 to 90.0)	75.2 (66.1 to 82.1)	Baseline: 10% 30 d: 82% 12 mo: 61%	Baseline: 13% 30 d: 76% 12 mo: 64%
Duke cohort	89.1 (78.5 to 94.7)	79.6 (67.4 to 87.6)	69.4 (56.3 to 79.3)

Subsequent to the FDA approval of MitraClip in 2013, patients who received MitraClip under Medicare coverage were required to enroll in the joint STS and American College of Cardiology Transcatheter Valve Therapy Registry as part of coverage under evidence development (see the Medicare National Coverage section). Initial results from this U.S.-based registry were reported in 2016 (short-term outcomes) and in 2017 (long-term outcomes) and summarized in Table 6.^22,23, In the initial results of 564 patients enrolled between 2013 to 2014 from 561 U.S. centers, the median STS predicted risk of mortality scores for MV repair and replacement were 7.9% (range, 4.7%-12.2%) and 10.0% (range, 6.3%-14.5%), respectively.^22, The in-hospital mortality rate was 2.3% and the 30-day mortality rate was 5.8%. These results are consistent with those reported in the cohort by Lim et al (2014) used by the FDA for approval^20, and supports that a favorable benefit-risk ratio is attainable outside a clinical trial setting in appropriately selected patients. At 1 year, the proportion of patients who died was 25.8%, had a repeat hospitalization for heart failure was 20.2%, and cumulative incidence of mortality or rehospitalization for heart failure was 37.9%.^23, Higher age, lower baseline LV ejection fraction, worse postprocedural MR, moderate or severe lung disease, dialysis, and severe tricuspid regurgitation were associated with higher mortality or rehospitalization for heart failure. The persistency of mortality (25.8%) and heart failure rehospitalization (20.2%) at 1 year despite of the effectiveness of MitraClip remains a concern. However, the results observed in the Transcatheter Valve Therapy Registry at 1 year were comparable with the 1-year rates observed in the analysis of high-risk patients in the EVEREST II (23.8%) and REALISM (18.0%) studies.^24,

Table 6. Summary of U.S.-Based TVT Registry Data

	No. of Patients	Primary MR, %	Secondary MR, %Study	Postimplantation MR Grade ≤ 2, %	In-Hospital Death, %	30-Day Death, %	1-Year Death, %
Sorajja et al (2016)22,	564	86	14	93	2.3	5.8	-
Sorajja et al (2017)23,	2952	86	9	92	2.7	5.2	25.8

MR: mitral regurgitation; TVT: Transcatheter Valve Therapy.

Other multiple subgroup analyses and systematic reviews have been reported using the EVEREST II HRR, REALISM, and other European/Non-European studies/registries but are not discussed further because they did not report results stratified by MR etiology (primary MR or secondary MR) or were of poor quality or did not add substantial clarity to the evidence already discussed herein.^{24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,}

Section Summary: Primary Mitral Valve Regurgitation at Prohibitive Surgical Risk

The evidence for the use of MitraClip among patients in patients with primary MR at prohibitive surgical risk consists primarily of single-arm prospective cohort and registry studies. Included are the pivotal EVEREST II HRR and EVEREST II REALISM studies and the Transcatheter Valve Therapy Registry studies. These studies have demonstrated that MitraClip implantation is feasible, with procedural success rate greater than 90%, 30-day mortality rates ranging from 2.3% to 6.4% (less than predicted STS mortality score for MR repair or replacement [range, 9.5%-13.2%]), MR severity of 2+ or less in 82% to 93% patients, and clinically meaningful gains in quality of life (5- to 6-point gain in SF-36 scores). However, the 1-year mortality or heart failure hospitalization rates remained considerably high (38%) compared with U.S.-based registry data thereby raising uncertainty about the long-term benefits.

Heart Failure and Secondary Mitral Valve Regurgitation
Clinical Context and Therapy Purpose

The purpose of TMVR using MitraClip in patients who have heart failure and moderate-to-severe or severe symptomatic secondary mitral regurgitation (SMR) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is: Does TMVR using MitraClip improve the net health outcome in patients who have heart failure and moderate-to-severe or severe symptomatic SMRitral regurgitation despite the use of maximally tolerated guideline-directed medical therapy?
The following PICO was used to select literature to inform this policy.

Patients
The relevant population of interest is patients with heart failure and moderate-to-severe or severe symptomatic SMR despite the use of maximally tolerated guideline-directed medical therapy.
Symptomatic SMR occurs when coronary disease with myocardial infarction or primary dilated cardiomyopathy cause a combination of LV wall motion abnormalities, mitral annular dilatation, papillary muscle displacement and reduced closing force that prevent the MV from coapting (to bring together) normally. This results in regurgitation, or backflow, of the MV. Symptoms include shortness of breath, fatigue, and swelling. MR severity is classified as mild, moderate, or severe disease on the basis of echocardiographic and/or angiographic findings (1+, 2+, and 3-4+ angiographic grade, respectively).

Intervention
The therapy being considered is TMVR using MitraClip. TMVR with MitraClip uses an implanted clip to perform the edge-to‐ edge repair technique on the MV to reduce MR.

Comparators
The following therapies are currently being used to make decisions about TMVR in patients with heart failure and SMR.
Comparators of interest are medical management. First‐line treatment is guideline‐directed medical therapy. Resynchronization therapy may provide symptomatic relief, improve LV function, and in some patients, lessen the severity of MR.

Outcomes
The general outcomes of interest are OS, morbid events, functional outcomes, and treatment-related morbidity. Function in patients with heart failure is measured by the NYHA Class. The NYHA Class is based on a four‐step grading scale from Class I, which is no limitation of physical activity to Class IV, which is unable to carry on any physical activity without discomfort.

Review of Evidence
Systematic Reviews

A systematic review and meta-analysis by Kumar et al (2020)^39, evaluated the comparison of MitraClip plus medical therapy to medical therapy alone in patients with SMR (total N=1130) using data from the COAPT and MITRA HF RCT’s discussed below, as well as 2 preceding small propensity score-matched observational studies. Pooled analyses that included the RCT’s and the observational studies found that compared to medical therapy alone, at 2 years of follow-up, MitraClip plus medical therapy significantly reduced the risk of all-cause mortality (relative risk, 0.72; 95% CI, 0.55 to 0.95; I²=55%), readmission events for heart failure (relative risk, 0.62; 95% CI, 0.42-0.92, I²=90%), but not cardiovascular mortality (relative risk, 0.69; 95% CI, 0.47-1.02, I²=68%). Further, results of fixed-effect meta-regression suggest that baseline left ventricular end diastolic volume and age are associated with all-cause mortality and cardiovascular mortality outcomes. However, interpretation of these pooled analyses are limited by their considerable heterogeneity and the potential for increased risk of selection bias due to the inclusion of the nonrandomized studies.

Randomized Controlled Trials

The evidence for the use of MitraClip in patients with SMR consists of 2 RCTs, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT)^40, and the Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR)^41,42, (Tables 7 and 8). Both trials compared MitraClip plus medical therapy to medical therapy alone in patients with SMR and heart failure, but they differed in their eligibility criteria, and primary outcome measures. COAPT enrolled 614 patients at 78 centers in the U.S. and Canada.^40, MITRA-FR enrolled 304 patients at 37 centers in France.^41,42,

COAPT found a significant benefit for Mitraclip on the primary efficacy outcome (all HF hospitalizations within 24 months) and the primary safety outcome (freedom from device-related complications at 12 months). In contrast, the MITRA-FR investigators found no significant differences between Mitra-Clip plus medical therapy and medical therapy alone on the composite primary outcome (death from any cause or unplanned HF hospitalization at 12 months) or any secondary outcome, including all-cause mortality at 12 and 24 months and cardiovascular death at 12 and 24 months (See Table 8).

Although the reasons for these discrepant results are not entirely clear, differences in the studies' design and conduct have been proposed as possible explanations.^43,44, The severity of MR and heart failure among the patients in the trials differed. COAPT participants had more severe MR at baseline (effective regurgitant orifice area 41 vs 31 mm²) and remained symptomatic despite the use of maximal doses of guideline-directed medical therapy.^6,45,44, In both trials, eligible patients had to be symptomatic despite the use of optimal medical therapy. In COAPT, however, a central eligibility committee confirmed that the patient was using maximal doses of guideline-directed medical therapy prior to enrollment, and patients who improved with medical therapy were excluded. MITRA-FR had less stringent eligibility criteria and patients had more changes in medical therapy during the trial, indicating their treatment might not have been optimized. Additionally, patients in MITRA-FR had further progressed heart failure as indicated by LV dilation, and may have been less likely to benefit from MR treatment.

There is some evidence that technical success and procedural safety differed between the trials.^44, Procedural complications were higher in MITRA-FR than in COAPT, and more patients in MITRA-FR experienced residual MR class >3+ post-procedure (both acutely and at 12 months).

Table 7. Summary of Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Stone et al (2018);40,COAPT	US and Canada	78	2012 - 2017	Ischemic or nonischemic cardiomyopathy with LVEF 20% to 50%; moderate-to-severe (grade 3+) or severe (grade 4+) secondary MR; symptomatic (NYHA functional class II, III, or IVa) despite the use of stable maximal doses of guideline-directed medical therapy and cardiac resynchronization therapy	N=302 MitraClip plus medical therapy	N=312 Medical therapy alone
Obadia et al (2018);41, MITRA-FR	France	37	2013 - 2017	Severe SMR with a regurgitant volume of greater than 30ml per beat or an EROA ≥20 mm2 ; NYHA functional class II, III, or IV despite optimal standard of care therapy for heart failure according to investigator LVEF between 15% and 40%; not appropriate for MV surgery by local heart team assessment	N=152 MitraClip plus medical therapy	N=152 Medical therapy alone

RCT: randomized controlled trial; LVEF: left ventricular ejection fraction; SMR: secondary mitral regurgitation; EROA: effective regurgitant orifice area; NYHA: New York Heart Association; MR: mitral regurgitation; MV: mitral valve.

Table 8. Summary of Key RCT Results

Study	Primary Outcome: HF hospitalizations within 24 months	Primary Outcome: Death from any cause or unplanned HF hospitalization at 12 months	All-cause mortality at 12 months	Cardiovascular death at 12 months	All-cause mortality at 24 months	Cardiovascular death at 24 months	MR grade 2+ or lower at 12 months	NYHA functional class I or II at 12 months	Primary Safety Outcome: Freedom from device-related complications at 12 months1 Kaplan-Meier estimate of event-free rate (lower 95% confidence limit)	Serious Adverse events at 1 year	Periprocedural complications during device implantation
Stone (2018);40, COAPT
Sample size	612		612		612	612	385	469	302
Medical therapy alone	283/416.8 (67.9%)		57 (19.1%)		121/312 (46.1%)	97 (38.2%)	82/175 (46.9%)	115/232 (49.6%)
MitraClip + medical therapy	160/446.5 (35.8%)		70 (23.2%)		80/302 (29.1%)	61 (23.5%)		171/237 (72.2%)	96.6% (94.8%)
HR (95% CI) ; p-value	0.53 (0.40 to 0.70); p<0.001		0.81 (95% CI 0.57 to 1.15); <0.001 for noninferiority		0.62 (0.46 to 0.82); p<0.001	0.59 (90.43 to 0.81); p=0.001	p<0.001	p<0.001
NNT	3.1
Obadia (2018); 12-month results41,Iung (2019) 24-month results 42,MITRA-FR
Sample size	304	304	304	304	304	304				304
Medical therapy alone	94/152 (62.3%)	78/152 (51.3%)	34/152 (22.4%)	31/152 (20.4%)	52/152 (22.8%)	48/152 (21.1%)				121/152 (79.6%)
MitraClip + medical therapy	85/152 (55.9%)	83/152 (54.6%)	37/152 (24.3%)	33/152 (21.7%)	53/152 (23.1%)	47/152 (20.5%)				125/152 (82.2%)	21/144 (14.6%)
HR (95% CI); p-value	0.97 (0.72-1.30)	1.16 (0.73 to 1.84); p=0.53	1.11 (0.69 to 1.77)	1.09 (0.67 to 1.78)	1.02 (0.70-1.50)	0.99 (0.66-1.48)				p=values not reported because no adjustment was made for multiple testing

HF: heart failure; NYHA: New York Heart Association; MR: mitral regurgitation; CI: confidence interval; HR: hazard ratio; NNT: number needed to treat; RCT: randomized controlled trial.

¹ Composite of single leaflet device attachment, device embolization, endocarditis requiring surgery, mitral stenosis requiring surgery, eft ventricular assist device implant, heart transplant, or any device related complication requiring non-elective cardiovascular surgery
² includes prespecified adverse events heart transplantation or mechanical cardiac assistance, ischemic or hemorrhagic stroke, myocardial infarction, need for renal-replacement therapy, severe hemorrhage, and infections

Table 9. Study Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Stone (2018);40, COAPT
Obadia (2018);41, MITRA-FR	4		2		1

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.

a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Allocationa	Blindingb	Selective Reportingc	Data Completenessd	Powere	Statisticalf
Stone (2018);40, COAPT	3	1,2
Obadia (2018);41, MITRA-FR	3	1,2

a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

The evidence for the use of MitraClip in patients with SMR consists of a systematic review, 2 RCTs, and observational studies. The trials had discrepant results, but the larger trial, with patients selected for nonresponse to maximally tolerated therapy, found a significant benefit for MitraClip after 2 years compared to medical therapy alone. The systematic review confirmed the benefit of MitraClip found in the larger RCT, but had important methodological limitations.

Primary or Secondary Mitral Regurgitation in Surgical Candidates
Clinical Context and Therapy Purpose

The purpose of TMVR using MitraClip in patients who have symptomatic primary or SMR and are surgical candidates is to provide a treatment option that is an alternative to or an improvement on existing therapies.
The question addressed in this policy is: Does TMVR using MitraClip improve the net health outcome in patients who have symptomatic primary or SMR and are surgical candidates?
The following PICO was used to select literature to inform this policy.

Patients
The relevant population of interest is patients who have symptomatic primary or SMR and are surgical candidates.

Interventions
The therapy being considered is TMVR using MitraClip

Comparators
The following therapies practices are currently being used to make decisions about TMVR.
Relevant comparators are open MV repair and open MV replacement.
In symptomatic patients with primary MR, surgery is the main therapy. In most cases, MV repair is preferred over replacement, as long as the valve is suitable for repair and personnel with appropriate surgical expertise are available.
Isolated MV surgery (repair or replacement) for severe chronic SMR is not generally recommended because there is no proven mortality reduction and an uncertain durable effect on symptoms. Recommendations from major societies regarding MV surgery in conjunction with coronary artery bypass graft surgery or surgical aortic valve replacement are weak because the current evidence is inconsistent on whether MV surgery produces a clinical benefit.

Outcomes
The general outcomes of interest are overall survival, morbid events, functional outcomes, and treatment-related morbidity.

Review of Evidence
Systematic Review

A systematic review by Takagi et al (2017) identified 1 RCT and 6 nonrandomized comparative studies evaluating MitraClip and surgery.^46, The RCT (EVEREST II) is described below. The systematic review conducted several pooled analyses. The meta-analysis did not detect a statistically significant difference in early (30-day or in-hospital) mortality between the MitraClip and surgery groups (pooled odds ratio, 0.54; 95% CI, 0.27 to 1.08; p=0.08). Similarly, a pooled analysis of late survival (≥6 months) did not find a statistically significant difference between the MitraClip and surgery groups (pooled odds ratio /hazard ratio, 1.17; 95% CI, 0.77 to 1.78; p=0.46). However, there was a significantly higher incidence of recurrent MR in the MitraClip than in the surgery group (pooled odds ratio /hazard ratio, 4.80; 95% CI, 2.58 to 8.93; p<0.001).

Randomized Controlled Trial

Feldman et al (2011) reported on the results of EVEREST II, an RCT that evaluated symptomatic or asymptomatic patients with grade 3+ or 4+ chronic MR who had SMR or primary MR etiology to TMVR; patients were randomized to MitraClip or open MV repair/replacement (see Table 11).^47,48, Most patients (73%) had primary MR. Patients were excluded if they had an MV orifice area less than 4.0 cm or leaflet anatomy that precluded MitraClip device implantation, proper MitraClip positioning, or sufficient reduction in MR. MitraClip was considered to have acute procedural success if the clip deployed and MR grade was reduced to less than 3+.

Trial results are summarized in Table 12. In the intention-to-treat (ITT) analysis, for patients who did not have acute procedural success with MitraClip and subsequently underwent open MV repair, the efficacy endpoint was considered met for MitraClip group subjects if they were free from death, reoperation for MR, and MR grade greater than 2+ at 12 months. The trial had a predetermined efficacy endpoint of noninferiority of the MitraClip strategy, with a margin of 25% for the ITT analysis and 31% for prespecified per-protocol analyses. This implies that the MitraClip strategy would be noninferior to surgery at 12 months if the upper bound of difference in the proportion of patients achieving the primary efficacy endpoint between the 2 groups did not exceed 25 percentage points for the ITT analysis and 31% percentage points for the per-protocol analysis. Results showed that TMVR was less effective at reducing MR than conventional surgery before hospital discharge. MitraClip group subjects were more likely to require surgery for MV dysfunction, either immediately post-MitraClip implantation or in the 12 months following. Twenty percent (37/181) of the MitraClip group and 2% (2/89) of the surgery group required reoperation for MV dysfunction (p<0.001). Although in the ITT analysis rates of MR severity grades of 3+ or 4+ at 12 months were similar between groups, in the published per-protocol analysis, patients in the MitraClip group were more likely to have severity grades of 3+ or 4+ (17.2% [23/134] vs 4.1% [3/74], p=0.01), which would suggest that a larger proportion of patients with grade 1+ or 2+ MR in the MitraClip group had had surgical repair. As expected, rates of major adverse events at 30 days were lower in the MitraClip group (15% [27/181]) than in the surgery group (48% [45/89]; p<0.001). Rates of transfusion of more than 2 units of blood were the largest component of major adverse events in both groups, occurring in 13% (24/181) of the MitraClip group and 45% (42/89; p<0.001) of the surgery group. Long-term follow-up at four years^49, and five years^50, showed that significantly more MitraClip patients required surgery for MV dysfunction during the follow-up period.

In the FDA per protocol analysis, MitraClip did not reduce MR as often or as completely as the surgical control, although it could be safely implanted and reduced MR severity in most patients. The FDA concluded that the data did not demonstrate an appropriate benefit-risk profile when compared with standard MV surgery and were inadequate to support device approval for the surgical candidate population.

Table 11. Key RCT Characteristics

Study; Trial	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Feldman et al (2011)47,; EVEREST II	U.S., Canada	37	2005-2008	N=279 Grade 3+ or 4+ chronic MR Symptomatic (LVEF ≥25% and LVESD ≤55 mm) or asymptomatic (LVEF 25%-60% or LVESD 40-55 mm or new AF or pulmonary hypertension)	TMVR (n=184)	Open MV repair or replacement (n=95)

AF: atrial fibrillation; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameter; MR: mitral regurgitation; MV: mitral valve; RCT: randomized controlled trial; TMVR: transcatheter mitral valve repair.

Table 12. Key RCT Results

Study; Trial	Freedom From Death, Surgery for MR Dysfunction, and Grade 3+ or 4+ MR	Major AE at 30 Daysa	Surgery for MV Dysfunctionb	Death	Grade 3+ or 4+ MR
Feldman et al (2011)47,; EVEREST IIc (1 year)	270	274	270	270	270
TMVR	100/181 (55%)	27/180 (15%)	37/181 (20%)	11/181 (6%)	38/181 (21%)
Open repair	65/89 (73%)	45/94 (48%)	2/94 (2%)	5/94 (6%)	18/94 (20%)
p	0.007	<0.001	<0.001	1.00	1.00
FDA (2013)16,; EVEREST II (1 year)	Range, 156-208	274	-	-	-
TMVR	97/134 (72%)d 37/82 (45%)e	27/180 (15%)	Not reported	Not reported	Not reported
Open repair	65/74 (88%)d 51/74 (69%)e	45/94 (48%)	Not reported	Not reported	Not reported
p	0.001d,f 0.169e,f	<0.001	Not reported	Not reported	Not reported
Mauri et al (2013)49,; EVEREST II (4 years)	NR	NR	234	234	234
TMVR	NR	NR	40/161 (25%)	28/161 (17%)	35/161 (22%)
Open repair	NR	NR	4/73 (6%)	13/73 (18%)	18/73 (25%)
p	NR	NR	<0.001	0.914	0.745
Feldman et al (2015)50,; EVEREST II(5 years)			197	197	197
TMVR	NR	NR	43/154 (28%)	32/154 (21%)	19/154 (19%)
Open repair	NR	NR	5/56 (9%)	15/56 (27%)	1/56 (2%)
p	NR	NR	0.003	0.36	0.02

Values are n/N (%) unless otherwise noted.
AE: adverse event; FDA: Food and Drug Administration; MR: mitral regurgitation; MV: mitral valve; NR: not reported; RCT: randomized controlled trial; TMVR: transcatheter mitral valve repair.

^a The composite primary safety endpoint was major AEs at 30 days, defined as freedom from death, myocardial infarction, nonelective cardiac surgery for AEs, renal failure, transfusion of ≥2 units of blood, reoperation for failed surgery, stroke, gastrointestinal complications requiring surgery, ventilation for ≥48 hours, deep wound infection, septicemia, and new onset of permanent atrial fibrillation.
^b The rate of the first MV surgery in the percutaneous repair group and the rate of reoperation for MV dysfunction in the surgery group
^c Crossover to surgery in the immediate postprocedure period if MitraClip failed to adequately reduce MR was considered a successful treatment strategy.
^d Freedom from death, MV surgery, or reoperation and MR severity grade of >2+.
^e Freedom from death, MV surgery, or reoperation and MR severity grade of >1+.
^f As per FDA, noninferiority statistical methods were used to calculate this p value, however, noninferiority was not implied due to the large margin. Therefore, this test shows whether the results show decreased effectiveness by the margin specified of -31%.

Buzzatti et al (2019) reported on the results of a retrospective, propensity-weighted analysis that compared 5-year outcomes between low-intermediate risk individuals aged ≥ 75 years with degenerative MR who underwent treatment with MitraClip or surgical mitral repair (see Tables 12 and 13).^51, Preoperative variables included in the model were age at operation, sex, body mass index categorized as normal (20-30) or not normal (<20 or >30), serum creatinine, atrial fibrillation, New York Heart Association class III, ejection fraction, systolic pulmonary artery pressure, isolate P2 prolapse, and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM). Although MitraClip was associated with improved 1-year survival and a lower rate of all acute complications, longer-term survival and MR recurrence was significant worse with MitraClip.

Table 13. Summary of Observational Comparative Study Characteristics

Study	Study Type	Country	Dates	Participants	Treatment	Treatment	Follow-Up
Buzzatti (2019)51,	Retrospective Cohort	Italy, Switzerland	2005-2017	Individuals aged 75 years and older with degenerative mitral regurgitation and STS-PROM < 8%	MitraClip (N=100)	Surgical repair (N=206)	5 years

STS-PROM: Society of Thoracic Surgeons Predicted Risk of Mortality

Table 14. Summary of Observational Comparative Study Results

Study	Survival at 1 year	Survival at 5 years	All Postoperative complications	MR > 3+ recurrence at 5 years
Buzzatti (2019)51,
MitraClip	97.6%	34.5%	NR	36.9%
Surgical Repair	95.3%	82.2%	NR	3.9%
HR or OR (95% CI)	HR 0.09 (0.02-0.37)	HR 4.12 (2.31-7.34)	"Risk significantly reduced, but data NR"	OR 11.4 (4.40-29.68)

CI: confidence interval; HR: hazard ratio; OR: Odds Ratio; MR: Mitral Regurgitation; NR: Not Reported

Section Summary: MitraClip in Surgical Candidates

The evidence for the use of MitraClip in patients considered candidates for open MV repair surgery includes an RCT (EVEREST II) and a systematic review. The RCT found that MitraClip did not reduce MR as often or as completely as the surgical control, although it could be safely implanted and was associated with fewer adverse events at one year. Long-term follow-up of the RCT showed that significantly more MitraClip patients required surgery for MV dysfunction than conventional surgery. EVEREST II had some methodologic limitations. The noninferiority margin of 25% (ITT) or 31% (per-protocol) was large, indicating that MitraClip could be somewhat inferior to surgery and, yet, the test for noninferiority margin would be met. Crossover to surgery was allowed for patients who had an MR severity grade of 3+ or higher prior to discharge, and 23% of patients assigned to MitraClip met this criterion. This large crossover rate would bias results toward the null on ITT analysis, thus increasing the likelihood of meeting the noninferiority margin. In an analysis by treatment received, this crossover would result in a less severely ill population in the MitraClip group and bias the results in favor of MitraClip. A high proportion of patients required open MV replacement or repair during the first year postprocedure, thus limiting the number of patients who had long-term success without surgical intervention. For these reasons, this single trial is not definitive in demonstrating improved clinical outcomes using MitraClip compared with surgery. Further RCTs are needed to corroborate these results. Similarly, in the retrospective study that compared 5-year propensity-weighted outcomes between low-intermediate risk individuals aged ≥ 75 years with degenerative MR who underwent treatment with MitraClip or surgical mitral repair, although MitraClip was associated with improved 1-year survival and a lower rate of all acute complications, it had lower longer-term survival and greater MR recurrence.

Other Transcatheter Mitral Valve Repair Devices
Clinical Context and Therapy Purpose

The purpose of TMVR using devices other than MitraClip in patients with symptomatic primary or SMR is to provide a treatment option that is an alternative to or an improvement on existing therapies.
The question addressed in this policy is: Does TMVR using devices other than MitraClip improve the net health outcome in patients with symptomatic primary or SMR?
The following PICO was used to select literature to inform this policy.

Patients
The relevant population of interest is patients with symptomatic primary or SMR.

Interventions
The therapy being considered is TMVR with devices other than MitraClip.

Comparators
The following therapies/tools/rules/practices are currently being used to make decisions about TMVR.

Relevant comparators are open MV repair, open MV replacement, and medical management.

Outcomes
The general outcomes of interest are OS, morbid events, functional outcomes, and treatment-related morbidity.

Several devices other than MitraClip are being investigated for TMVR, although none is FDA approved for use in the U.S.

Several indirect annuloplasty devices, the Carillon Mitral Contour System (Cardiac Dimension) and the Monarc device (Edwards Lifesciences), have been evaluated. A case series evaluating use of the Carillon device in 53 patients with a SMR severity grade of 2+ at 7 European centers was reported by Siminiak et al (2012).^14, Of the 53 patients who underwent attempted device implantation, 36 underwent permanent implantation and 17 had the device removed due to transient coronary compromise in 8 patients and less than 1 severity grade reduction in SMR in 9 patients. Echocardiographic measures of secondary MR improved in the implanted groups through 12-month follow-up, along with improvements in 6-minute walk distance. An earlier feasibility study of the Carillon device reported by Schoder et al (2009) who evaluated 48 patients with moderate-to-severe secondary MR; it demonstrated successful device placement in 30 patients, with 18 patients unable to be implanted due to access issues, insufficient acute secondary MR reduction, or coronary artery compromise.^52, The Monarc device has been evaluated in a phase 1 safety trial at 8 European centers, as reported by Harnek et al (2011).^15, Among 72 patients enrolled, the device was successfully implanted in 59 (82%) patients. The primary safety endpoint (freedom from death, tamponade, or myocardial infarction at 30 days) was met by 91% of patients at 30 days and by 82% at 1 year.

Section Summary: Other Transcatheter Mitral Valve Repair Devices

The evidence for the use of TMVR devices other than the MitraClip for patients with MR includes only small case series and case reports. Collectively, these data are insufficient to determine the effects of these technologies on health outcomes.

Summary of Evidence

For individuals who have symptomatic primary MR and at prohibitive risk for open surgery who receive TMVR using MitraClip, the evidence includes a single-arm prospective cohort with historical cohort and registry studies. Relevant outcomes are overall survival (OS), morbid events, functional outcomes, and treatment-related morbidity. The primary evidence includes the pivotal EVEREST II HRR and EVEREST II REALISM studies and Transcatheter Valve Therapy Registry studies. These studies have demonstrated that MitraClip implantation is feasible with a procedural success rate greater than 90%, 30-day mortality ranging from 2.3% to 6.4% (less than predicted Society of Thoracic Surgeons mortality risk score for MR repair or replacement; range, 9.5%-13.2%), postimplantation MR severity grade of 2+ or less in 82% to 93% of patients, and a clinically meaningful gain in quality of life (5- to 6-point gains in 36-Item Short-Form Health Survey scores). At 1 year, freedom from death and MR more than 2+ was achieved in 61% of patients but the 1-year mortality or heart failure hospitalization rates remain considerably high (38%). Conclusions related to the treatment effect on mortality based on historical controls cannot be made because the control groups did not provide unbiased or precise estimates of the natural history of patients eligible to receive MitraClip. Given that primary MR is a mechanical problem and there is no effective medical therapy, a randomized controlled trial (RCT) comparing MitraClip with medical management is not feasible or ethical. The postmarketing data from the U.S. is supportive that MitraClip surgery is being performed with short-term effectiveness and safety in select patient population. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have heart failure and symptomatic secondary MR despite the use of maximally tolerated guideline-directed medical therapy who receive TMVR using MitraClip, the evidence includes a systematic review, two RCTS as well as multiple observational studies. Relevant outcomes are OS, morbid events, functional outcomes, and treatment-related morbidity. The trials had discrepant results potentially related to differences in primary outcomes. The larger trial, with patients selected for nonresponse to maximally tolerated therapy, found a significant benefit for MitraClip after two years compared to medical therapy alone. The systematic review confirmed the benefit of MitraClip found in the larger RCT, but had important methodological limitations. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have symptomatic primary or SMR and are surgical candidates who receive TMVR using MitraClip, the evidence includes a systematic review, 1 RCT and a retrospective comparative observational study in individuals aged ≥ 75 years. Relevant outcomes are OS, morbid events, functional outcomes, and treatment-related morbidity. The RCT found that MitraClip did not reduce MR as often or as completely as the surgical control, although it could be safely implanted and was associated with fewer adverse events at one year. Long-term follow-up from the RCT showed that significantly more MitraClip patients required surgery for MV dysfunction than conventional surgery patients. For these reasons, this single trial is not definitive in demonstrating improved clinical outcomes with MitraClip compared with surgery. Additional RCTs are needed to corroborate these results. The observational study in individuals aged ≥ 75 years found that although MitraClip was associated with improved 1-year survival and a lower rate of all acute complications compared with surgical repair, it had lower 5-year survival and greater MR recurrence. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have symptomatic primary or secondary MR who receive TMVR using devices other than MitraClip, the evidence includes primarily noncomparative feasibility studies. Relevant outcomes are OS, morbid events, functional outcomes, and treatment-related morbidity. The body of evidence consists only of very small case series and case reports. Controlled studies, preferably RCTs, are needed to draw conclusions about the net health benefit. The evidence is insufficient to determine the effects of the technology on health outcomes

SUPPLEMENTAL INFORMATION
Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 4 academic medical centers, one of which provided 4 responses, for a total of 7 responses, while this policy was under review in 2015. Input supported the use of transcatheter mitral valve repair in patients with primary (degenerative) mitral regurgitation at prohibitive risk of open surgery. The greatest consensus for selection criteria to determine “prohibitive risk” was for the use of the Society of Thoracic Surgeons predictive operative risk of 12% or higher, or a logistic EuroSCORE of 20% or higher.

Practice Guidelines and Position Statements
American College of Cardiology

The American College of Cardiology and American Heart Association (2017) released guidelines on the management of valvular heart disease.^6, Table 15 provides the relevant recommendations..

Table 15. Recommendations on Primary and Secondary MR

Recommendation	SOR	LOE
Primary MR
Transcatheter mitral valve repair may be considered for severely symptomatic patients (NYHA class III to IV) with chronic severe primary MR (stage D) who have favorable anatomy for the repair procedure and a reasonable life expectancy but who have a prohibitive surgical risk because of severe comorbidities and remain severely symptomatic despite optimal guideline-directed medical therapy for heart failure	IIb	B
Secondary MR
Mitral valve surgery is reasonable for patients with chronic severe secondary MR (stages C and D) who are undergoing CABG or AVR.	IIb	B
Mitral valve repair or replacement may be considered for severely symptomatic patients (NYHA class III to IV) with chronic severe secondary MR (stage D) who have persistent symptoms despite optimal GDMT for HF.	IIb	B-R

AVR: aortic valve replacement; B-R: moderate-quality evidence; CABG: coronary artery bypass grafting; GDMT: guideline-directed medical therapy; HF: heart failure; MR: mitral regurgitation; NYHA: New York Heart Association; LOE: level of evidence; SOR: strength of recommendation.

The American College of Cardiology, American Association for Thoracic Surgery, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons (2014) issued a position statement on transcatheter therapies for mitral regurgitation (MR).^53, This statement outlined critical components for successful transcatheter MR therapies and recommended ongoing research and inclusion of all patients treated with transcatheter MR therapies in a disease registry.

European Society of Cardiology and European Association for Cardio-Thoracic Surgery

The European Society of Cardiology and the European Association for Cardio-Thoracic Surgery (2017) released joint guidelines on the management of valvular heart disease (see Table 16).^45,.

Table 16. Recommendations on Management of Valvular Heart Disease

Recommendation	SOR	LOE
Primary MR
Percutaneous edge-to-edge procedure may be considered in patients with symptomatic severe primary mitral regurgitation who fulfill the echocardiographic criteria of eligibility and are judged inoperable or at high surgical risk by the Heart Team, avoiding futility.	IIb	C
Secondary MR
“Percutaneous edge-to-edge repair for secondary mitral regurgitation is a low risk option, but its efficacy to reduce mitral regurgitation remains inferior to surgery. It can improve symptoms, functional capacity and quality of life and may induce reverse LV remodelling. Similar to surgery, a survival benefit compared with ‘optimal’ medical therapy according to current guidelines has not yet been proven.”	a	a

LOE: level of evidence; LV: left ventricular; SOR: strength of recommendation.
^a No specific recommendations.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this policy are listed in Table 17.

Table 17. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01920698	Multicentre Randomized Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR)	288	Apr 2019
NCT03521921	GIse Registry Of Transcatheter Treatment of Mitral Valve regurgitaTiOn (GIOTTO)	1100	Feb 2021
NCT02444338	A Clinical Evaluation of the Safety and Effectiveness of the MitraClip System in the Treatment of Clinically Significant Functional Mitral Regurgitation (RESHAPE-HF)	420	Mar 2021
NCT04009434	Treatment of Concomitant Mitral Regurgitation by Mitral Valve Clipping in Patients With Successful Transcatheter Aortic Valve Implantation	1162	Aug 2023
NCT01626079	Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (The COAPT Trial)	610	July 2024 (5-year follow-up per protocol)
NCT04198870	Percutaneous MitraClip Device or Surgical Mitral Valve REpair in PAtients With PrImaRy MItral Regurgitation Who Are Candidates for Surgery (REPAIR MR)	500	Feb 2027

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Transcatheter Mitral Valve Repair
Mitral Valve Repair
MitraClip
MitraClip Clip Delivery Systeml
Carillon Mitral Contour System
Monarc
Mitralign Percutaneous Annuloplasty System
Accucinch System
enCorTC
CardiAQ
Cardiovalve

References:
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38. Hayashida K, Yasuda S, Matsumoto T, et al. AVJ-514 Trial - Baseline Characteristics and 30-Day Outcomes Following MitraClip (R) Treatment in a Japanese Cohort. Circ J. Jul 25 2017; 81(8): 1116-1122. PMID 28321004

39. Kumar A, Al-Khafaji J, Shariff M, et al. Percutaneous mitral valve repair for secondary mitral valve regurgitation: A systematic review and meta-analysis. Eur J Intern Med. Feb 21 2020. PMID 32094019

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49. Mauri L, Foster E, Glower DD, et al. 4-year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation. J Am Coll Cardiol. Jul 23 2013; 62(4): 317-28. PMID 23665364

50. Feldman T, Kar S, Elmariah S, et al. Randomized Comparison of Percutaneous Repair and Surgery for Mitral Regurgitation: 5-Year Results of EVEREST II. J Am Coll Cardiol. Dec 29 2015; 66(25): 2844-2854. PMID 26718672

51. Buzzatti N, Van Hemelrijck M, Denti P, et al. Transcatheter or surgical repair for degenerative mitral regurgitation in elderly patients: A propensity-weighted analysis. J Thorac Cardiovasc Surg. Jul 2019; 158(1): 86-94.e1. PMID 30797588

52. Schofer J, Siminiak T, Haude M, et al. Percutaneous mitral annuloplasty for functional mitral regurgitation: results of the CARILLON Mitral Annuloplasty Device European Union Study. Circulation. Jul 28 2009; 120(4): 326-33. PMID 19597051

53. O'Gara PT, Calhoon JH, Moon MR, et al. Transcatheter therapies for mitral regurgitation: a professional society overview from the American College of Cardiology, The American Association for Thoracic Surgery, Society for Cardiovascular Angiography and Interventions Foundation, and The Society of Thoracic Surgeons. J Thorac Cardiovasc Surg. Mar 2014; 147(3): 837-49. PMID 24529172

54. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Transcatheter MITRAL Valve Repair (TMVR) (20.33). 2015; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?NCDId=363&ncdver=1&CoverageSelection=National&KeyWord=mitral&KeyWordLookUp=Title&Ke yWordSearchType=And&bc=gAAAABAAAAAAAA%3d%3d&. Accessed April 6, 2020.

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