Transcatheter Mitral Valve Repair - CAM 20230

Description 
Transcatheter mitral valve repair (TMVR) is an alternative to surgical therapy for mitral regurgitation (MR). MR is a common valvular heart disease that can result from a primary structural abnormality of the mitral valve (MV) complex or a secondary dilatation of an anatomically normal MV due to a dilated left ventricle caused by ischemic or dilated cardiomyopathy. Surgical therapy may be underutilized, particularly in patients with multiple comorbidities, suggesting that there is an unmet need for less invasive procedures for MV repair. One device, MitraClip, has approval from the U.S. Food and Drug Administration for the treatment of severe symptomatic MR due to a primary abnormality of the MV (primary MR) in patients considered at prohibitive risk for surgery and for patients with heart failure and moderate-to-severe or severe symptomatic secondary MR despite the use of maximally tolerated guideline-directed medical therapy.

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% to 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 a select patient population. The evidence is sufficient to determine that the technology results in animprovement 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, 2 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 2 years compared to medical therapy alone. Improvements in MR severity, quality of life measures, and functional capacity persisted to 36 months in patients who received TMVR. 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 animprovement 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 1 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 s that the technology results in an improvement in the net health outcome.

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 s that the technology results in an improvement in the net health outcome.

Additional Information
Not applicable

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 2 categories: primary (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 valve (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 (See Supplemental Information).5

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 5,737 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.6

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 societies7,8 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.9-12

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.1,13  Approaches to MV repair include direct leaflet repair,14, 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 2008.14 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 TMVR 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 a manual pull back 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.15 The Monarc system also involves 2 self-expanding stents connected by a nitinol bridge, with one end implanted in the coronary sinus via the 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.16

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 enCorsq Mitral Valve Repair System, and the Cardioband Annuloplasty System (Valtech Cardio), an implantable annuloplasty band with a transfemoral venous delivery system.

Transcatheter MV 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 a MV replacement device. These replacement valves are outside the scope of this evidence review.

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
701131 Transcatheter Pulmonary Valve Implantation
701132 Transcatheter Aortic Valve Implantation for Aortic Stenosis

Policy
Transcatheter mitral valve repair with a device approved by the U.S. Food and Drug Administration for use in mitral valve repair may be considered MEDICALLY NECESSARY for patients with symptomatic, primary mitral regurgitation who are considered at prohibitive risk for open surgery (see Policy Guidelines section).

Transcatheter mitral valve repair with a device approved by the U.S. Food and Drug Administration may be considered MEDICALLY NECESSARY for patients with heart failure and moderate-to-severe or severe symptomatic secondary mitral regurgitation despite the use of maximally tolerated guideline-directed medical therapy (see Policy Guidelines section).

Transcatheter mitral valve repair is considered investigational and/or unproven and therefore NOT MEDICALLY NECESSARY in all other situations.  

Policy Guidelines
"Prohibitive risk" for open surgery may be determined based on:  

  • 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.

Moderate to severe or severe MR may be determined by:  

  • 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.

Optimal medical therapy may be determined by guidelines from specialty societies (e.g., American Heart Association/American College of Cardiology Guideline for the Management of Patients with Valvular Heart Disease, European Society of Cardiology/European Association for Cardio-Thoracic Surgery Guidelines for the Management of Valvular Heart Disease, American Heart Association/American College of Cardiology/Heart Failure Society of America Guideline for the Management of Heart Failure (refer to supplemental materials for guideline citations).

Please see the Codes table for details.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all devices approved by FDA may not be considered investigational. Therefore, FDA-approved devices may be assessed only on the basis of their medical necessity.

Rationale 
This evidence review was created in July 2014 with searches of the PubMed database. The most recent literature update was performed through March 30, 2021.

This review was informed, in part, by a TEC Assessment (2014) that evaluated the use of transcatheter mitral valve repair (TMVR) in patients with symptomatic primary mitral regurgitation (MR) at prohibitive risk for mortality during open surgery.18

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, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical uses 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 evidence review 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 review.

Populations
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.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
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.18 The Assessment included 5 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 1 and 2 summarize patient characteristics and health outcomes of the case series by Reichenspurner et al. (2013)19 and Lim et al. (2013),20 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.19,21 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 1. Key Case Series Characteristics 

Study; Trial Country Participants Treatment Delivery Follow-Up
Reichenspurner et al (2013)19;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 data
Lim et al (2014)21; 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).18
EF: ejection fraction; MR: mitral regurgitation; NYHA: New York Heart Association; STS: Society of Thoracic Surgeons surgical risk score.

Table 2. 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)19; 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 =.03), n=44

Change in 6MWT from baseline, 77.4 m (p <.001), n=52
Lim et al (2014)21; 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).18
6MWT: 6-minute walk test; 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; 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 (i.e., Society of Thoracic Surgeons 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 3 and 4 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 post-procedure, 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 the use of historical controls. Specifically, patients in the Duke group did not appear to have been evaluated specifically for the MitraClip procedure (i.e., 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 the 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 the 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 following17

  • 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% confidence interval [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.22 Sensitivity analyses showed that these effectiveness results were robust to missing data.

  • The commercial post registry data of over 8,300 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 an 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%).

 Table 34. Key Observational Comparative Study Characteristics

Study Design Country Dates Participants Treatment Treatment Follow-up
FDA (2013)17 Single cohort with historical comparator U.S. Unclear MitraClip cohort
N=127
Age: 82.4 y
>75 y: 84%
NYHA class ≥III: 87%
STS predicted mortality: 13.2%
LVEF: 61%

Duke cohort
N=65
Age: 76.8 y
>75 y: 68%
NYHA class ≥III: 44%
STS predicted mortality: 13.3%
LVEF: 44%
MitraClip Nonsurgical management 1 y

FDA: Food and Drug Administration; FU: follow-up; LVEF: left ventricular ejection fraction; NYHA: New York Heart Association; STS: Society of Thoracic Surgeons.

Table 4. Key Observational Comparative Study Results 

  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)17 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)    

FDA: Food and Drug Administration; MR: mitral regurgitation; NYHA: New York Heart Association. 

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 5.23,24 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.23 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 approval21 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%.24 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.25,

Table 5. Summary of U.S.-Based Transcatheter Valve Therapy 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)23 564 86 14 93 2.3 5.8 -
Sorajja et al (2017)24 2952 86 9 92 2.7 5.2 25.8

MR: mitral regurgitation 

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.25-39

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 a 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 evidence review is: Does TMVR using MitraClip improve the net health outcome in patients who have heart failure and moderate-to-severe or severe symptomatic SMR regurgitation despite the use of maximally tolerated guideline-directed medical therapy?

The following PICO was used to select literature to inform this review.

Populations
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 causes 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.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A systematic review and meta-analysis by Kumar et al. (2020)40 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 RCTs 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 [RR], 0.72; 95% CI, 0.55 to 0.95; I2=55%), readmission events for heart failure (RR, 0.62; 95% CI, 0.42 to 0.92, I2=90%), but not cardiovascular mortality (RR, 0.69; 95% CI, 0.47 to 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, the interpretation of these pooled analyses is 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)41 and the Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR)42,43 (Tables 6 and 7 ). 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.41 MITRA-FR enrolled 304 patients at 37 centers in France.42,43

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).44 Improvements in MR severity, quality-of-life measures, and functional capacity persisted to 36 months in patients who received TMVR. 45

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 7 ).

Although the reasons for these discrepant results are not entirely clear, differences in the studies' design and conduct have been proposed as possible explanations.46,47 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.7,48,47 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.47 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 6. Summary of Key Randomized Controlled Trial Characteristics  

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
Stone et al (2018);41 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);42 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

COAPT: Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation; EROA: effective regurgitant orifice area; LVEF: left ventricular ejection fraction; MITRA-FR: Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation; MR: mitral regurgitation; MV: mitral valve; NYHA: New York Heart Association; SMR: secondary mitral regurgitation 

Table 7. Summary of Key Randomized Controlled Trial 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 year2 Periprocedural complications during device implantation
Stone (2018);41 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 <.001   0.81 (95% CI 0.57 to 1.15); p <.001 for noninferiority   0.62 (0.46 to 0.82); p <.001 0.59 (90.43 to 0.81); p =.001 p <.001 p <.001      
NNT 3.1                    
Obadia (2018); 12-month results42  Iung (2019) 24-month results 43 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 to 1.30) 1.16 (0.73 to 1.84); p =.53 1.11 (0.69 to 1.77) 1.09 (0.67 to 1.78) 1.02 (0.70 to 1.50) 0.99 (0.66 to 1.48)       p=values not reported because no adjustment was made for multiple testing  

CI: confidence interval; COAPT: Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation; HF: heart failure; HR: hazard ratio; MITRA-FR: Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation; MR: mitral regurgitation; NNT: number needed to treat; NYHA: New York Heart Association.
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

Tables 8 and 9 display notable gaps identified in COAPT and MITRA-FR. Patients enrolled in MITRA-FR had less severe MR and more severe heart failure than those who are likely to benefit from MV treatment. Design and conduct gaps in both trials include their open-label design and lack of information on allocation concealment. Lack of blinding is less of a concern with objective outcome measures but could impact the validity of measures of symptoms and quality of life. At baseline, more patients in the intervention group in MITRA-FR had a previous myocardial infarction. Otherwise, there were no significant differences between groups at baseline.

Table 8. Study Relevance Limitations 

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Stone (2018);41 COAPT          
Obadia (2018);42 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.

Table 9. Study Design and Conduct Limitations Gaps 

Study Allocationa Blindingb Selective Reportingc Data Completenessd Powere Statisticalf
Stone (2018);41 COAPT 3 1,2        
Obadia (2018);42 MITRA-FR 3 1,2        

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

Section Summary: Heart Failure and Secondary Mitral Regurgitation
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. Improvements in MR severity, quality of life measures, and functional capacity persisted to 36 months in patients who received TMVR. 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 evidence review 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 review.

Populations
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 OS, morbid events, functional outcomes, and treatment-related morbidity.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

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.49 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 [OR], 0.54; 95% CI, 0.27 to 1.08; p =.08). Similarly, a pooled analysis of late survival (≥6 months) did not find a statistically significant difference between the MitraClip and surgery groups (pooled OR /hazard ratio [HR], 1.17; 95% CI, 0.77 to 1.78; p =.46). However, there was a significantly higher incidence of recurrent MR in the MitraClip than in the surgery group (pooled OR /HR, 4.80; 95% CI, 2.58 to 8.93; p <.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 10 ).50,51 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 11. 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 <.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 =.01), which would suggest that a larger proportion of patients with grade 1+ or 2+ MR in the MitraClip group 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 <.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 <.001) of the surgery group. Long-term follow-up at 4 years52 and 5 years53 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 10. Key Randomized Controlled Trial Characteristics  

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
Feldman et al (2011)50; 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; TMVR: transcatheter mitral valve repair.

Table 11. Key Randomized Controlled Trial 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)50; EVEREST II(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 .007 <.001 <.001 1.00 1.00
FDA (2013)17; 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 .001d,f

.169e,f
<.001 Not reported Not reported Not reported
Mauri et al (2013)52; 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 <.001 .914 .745
Feldman et al (2015)53; 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 .003 .36 .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; 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%.

Observational Studies
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).54 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 were significantly worse with MitraClip. 

Table 12. Summary of Observational Comparative Study Characteristics 

Study Study Type Country Dates Participants Treatment Treatment Follow-Up
Buzzatti (2019)54 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 13. 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)54        
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 to 0.37) HR 4.12 (2.31 to 7.34) "Risk significantly reduced, but data NR" OR 11.4 (4.40 to 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 1 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 of 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 evidence review 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 review.

Populations
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.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

  • Studies with duplicative or overlapping populations were excluded.

Review of Evidence
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 the 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).15 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 inSMR 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.55 The Monarc device has been evaluated in a phase 1 safety trial at 8 European centers, as reported by Harnek et al. (2011).16 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 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 a select patient population. The evidence is sufficient to determine that the technology results in animprovement 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, 2 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 2 years compared to medical therapy alone. Improvements in MR severity, quality of life measures, and functional capacity persisted to 36 months in patients who received TMVR. 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 animprovement 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 1 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 s that the technology results in an improvement in the net health outcome.

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 s that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

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.

2015 Input
In response to requests, input was received from 4 academic medical centers, 1 of which provided 4 responses, for a total of 7 responses, while this policy was under review in 2015. Input supported the use of TMVR in patients with primary (degenerative) mitral regurgitation (MR) 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
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Cardiology andAmerican Heart Association
In 2020, the American College of Cardiology and American Heart Association released updated guidelines on the management of valvular heart disease.5 The guidelines state that TMVR is of benefit to patients with severely symptomatic primary MR who are at high or prohibitive risk for surgery, and to a subset of patients with secondary MR who remain severely symptomatic despite guideline-directed management and therapy for heart failure. Relevant recommendations on interventions for primary and secondary MR are shown in Table 14.

Table 14. Recommendations on Interventions for Primary and Secondary Mitral Regurgitation  

Recommendation COR LOE
Primary MR    
In symptomatic patients with severe primary MR (Stage D), mitral valve intervention is recommended irrespective of LV systolic function 1 (Strong) B-NR1
In asymptomatic patients with severe primary MR and LV systolic dysfunction (LVEF <60%, LVESD >40 mm) (Stage C2), mitral valve surgery is recommended 1 (Strong) B-NR1
In patients with severe primary MR for whom surgery is indicated, mitral valve repair is recommended in preference to mitral valve replacement when the anatomic cause of MR is a degenerative disease, if a successful and durable repair is possible 1 (Strong) B-NR1
In asymptomatic patients with severe primary MR and normal LV systolic function (LVEF >60% and LVESD >40 mm) (Stage C1), mitral valve repair is reasonable when the likelihood of a successful and durable repair without residual MR is >95% with an expected mortality rate of <1% when it can be
performed at a Primary or Comprehensive Valve Center
2a (Moderate) B-NR1
In asymptomatic patients with severe primary MR and normal LV systolic function (LVEF >60% and LVESD <40 mm) (Stage C1) but with a progressive increase in LV size or decrease in EF on >3 serial imaging studies, mitral valve surgery may be considered irrespective of the probability of a successful and durable repair 2b (Weak) C-LD2
In severely symptomatic patients (NYHA class III or IV) with primary severe MR and high or prohibitive surgical risk, TEER is reasonable if mitral valve anatomy is favorable for the repair procedure and patient life expectancy is at least 1 year 2a (Moderate) B-NR1
In symptomatic patients with severe primary MR attributable to rheumatic valve disease, mitral valve repair may be considered at a Comprehensive Valve Center by an experienced team when surgical treatment is indicated, if a durable and successful repair is likely 2b (Weak) B-NR1
In patients with severe primary MR where leaflet pathology is limited to less than one half the posterior leaflet, mitral valve replacement should not be performed unless mitral valve repair has been attempted at a Primary or Comprehensive Valve Center and was unsuccessful 3:Harm (Strong B-NR1
Secondary MR    
In patients with chronic severe secondary MR related to LV systolic dysfunction (LVEF <50%) who have persistent symptoms (NYHA class II, III, or IV) while on optimal GDMT for HF (Stage D), TEER is reasonable in patients with appropriate anatomy as defined on TEE and with LVEF between 20% and 50%,
LVESD <70 mm, and pulmonary artery systolic pressure <70 mmHg
2a (Moderate) B-R3
In patients with severe secondary MR (Stages C and D), mitral valve surgery is reasonable when CABG is undertaken for the treatment of myocardial ischemia 2a (Moderate) B-NR1
In patients with chronic severe secondary MR from atrial annular dilation with preserved LV systolic function (LVEF >50%) who have severe persistent symptoms (NYHA class III or IV) despite therapy for HF and therapy for associated AF or other comorbidities (Stage D), mitral valve surgery may be considered 2b (Weak) B-NR1
In patients with chronic severe secondary MR related to LV systolic dysfunction (LVEF <50%) who have persistent severe symptoms (NYHA class III or IV) while on optimal GDMT for HF (Stage D), mitral valve surgery may be considered 2b (Weak) B-NR1
In patients with CAD and chronic severe secondary MR related to LV systolic dysfunction (LVEF <50%) (Stage D) who are undergoing mitral valve surgery because of severe symptoms (NYHA class III or IV) that persist despite GDMT for HF, chordal-sparing mitral valve replacement may be reasonable to choose over downsized annuloplasty repair 2b (Weak) B-R3

TMVR: transcatheter mitral valve repair. Source: Adapted from Otto et al. (2020)5
1Moderate, nonrandomized; 2Limited data; 3Moderate, randomized.
CABG: coronary artery bypass graft; CAD: coronary artery disease; COR: class of recommendation; GDMT: guideline-directed medical therapy; HF: heart failure; LOE: level of evidence; LV: left ventricular; LVEF: left ventricular ejection fraction; LVESD: left ventricular end-systolic diameters; MR: mitral regurgitation; MV: mitral valve; NYHA: New York Heart Association; TEE: transesophageal echocardiogram; TEER: transcatheter edge-to-edge repair

American College of Cardiology, American Association for Thoracic Surgery, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons
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).56 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.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 15. 

Table 15. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date
Ongoing      
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
NCT01626079a Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation (The COAPT Trial) 614 July 2024
(5-year follow-up per protocol)
NCT04198870a Percutaneous MitraClip Device or Surgical Mitral Valve REpair in PAtients With PrImaRy MItral Regurgitation Who Are Candidates for Surgery (REPAIR MR) 500 Feb 2027
Unpublished      
NCT03521921 GIse Registry Of Transcatheter Treatment of Mitral Valve regurgitaTiOn (GIOTTO) 1500 Feb 2021

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

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Coding Section 

Codes Number Description
CPT  33418 Transcatheter mitral valve repair, percutaneous approach, including transseptal puncture when performed; initial prosthesis
  33419 additional prosthesis(es) during same session (List separately in addition to code for primary procedure)
  0345T  Transcatheter mitral valve repair percutaneous approach via the coronary sinus 
  0544T  Transcatheter mitral valve annulus reconstruction, with implantation of adjustable annulus reconstruction device, percutaneous approach including transseptal puncture (effective 7/1/19) 
ICD-10- CM I01.1; I02.0; I05.1; I05.2; I08.0; I08.1; I08.3  Rheumatic mitral valve insufficiency code list
  I34.0-I34.9  Nonrheumatic mitral valve disorders code range (I34.0 is mitral valve regurgitation) 
ICD-10-PCS   ICD-10-PCS codes are only used for inpatient services.
  02QG4ZZ  Repair, mitral valve, percutaneous endoscopic, no device
  02RG4JZ Replacement, mitral valve, percutaneous endoscopic, synthetic substitute
  02UG4JZ Supplement, mitral valve, percutaneous endoscopic, synthetic substitute
Type of Service     
Place of Service     

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

11/01/2021 

Annual review, no change to policy intent. Updating description, background, guidelines, rationale and references. 

11/02/2020 

Annual review, no change to policy intent. Updating rationale and references. 

11/07/2019 

Annual review, adding medical necessity statement "transcatheter mitral valve repair with an FDA approved device is considered medically necessary for patients with heart failure and secondary mitral regurgitation despite the use of maximally tolerated guideline directed medical therapy". Also updating description, background, guidelines, regulatory status, rationale, references and coding. 

12/03/2018 

Annual review, no change to policy intent. Updating description, background, rationale and references. 

12/05/2017 

Updating policy with 2018 coding. No other changes made to policy. 

11/02/2017 

Annual review, no change to policy intent. Updating background, regulatory status, rationale and references. 

11/01/2016 

Annual review, no change to policy intent. Updating background, description, guidelines, rationale and references. 

11/03/2015 

Annual review, added medical necessity criteria and guidelines for a procedure which was previously considered investigational. Updated background, description, guidelines, coding, rationale,and references. 

12/01/2014

New Policy

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