Medical Policy

Policy Num:      02.002.031
Policy Name:    Transcatheter Mitral Valve Repair
Policy ID:          [2.002.031]  [Ac / B / M+ / P+]  [2.02.30]

Last Review:      September 24, 2024
Next Review:      August 20, 2025
 

Related Policies:

07.001.104 Transcatheter Pulmonary Valve Implantation

07.001.103 Transcatheter Aortic Valve Implantation for Aortic Stenosis

Transcatheter Mitral Valve Repair

Summary

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. Two devices, MitraClip™ and PASCAL™, have 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. MitraClip is also approved for patients with heart failure and moderate-to-severe or severe symptomatic secondary MR despite the use of maximally tolerated guideline-directed medical therapy. The Edwards SAPIEN 3 transcatheter heart valve has been approved by the U.S. Food and Drug Administration for transcatheter mitral valve-in-valve replacement (TMViVR) in patients with a failing surgical bioprosthetic mitral valve who are at high or greater risk for repeat surgery.

Summary of Evidence

For individuals who have symptomatic primary mitral regurgitation (MR) and are at prohibitive risk for open surgery who receive transcatheter mitral valve repair (TMVR) using MitraClip or PASCAL, the evidence includes a noninferiority randomized controlled trial (RCT) and 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, the Transcatheter Valve Therapy Registry study, and the CLASP IID/IIF study. Studies evaluating MitraClip 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 [STS] 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 SF-36 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 (HF) 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, an RCT comparing TMVR 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 CLASP IID/IIF randomized cohort demonstrated that PASCAL is noninferior to MitraClip in safety and effectiveness for patients with primary MR at prohibitive surgical risk, and the single-arm registry cohort demonstrated that PASCAL is safe and effective in patients with complex mitral valve (MV) anatomy precluding the use of MitraClip. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have HF and symptomatic secondary mitral regurgitation (SMR) despite the use of maximally tolerated guideline-directed medical therapy who receive TMVR using MitraClip, the evidence includes a systematic review, 2 RCTs, and 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 up to 5 years compared to medical therapy alone, including benefits in overall survival and hospitalization for heart failure. 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 an improvement in the net health outcome.

For individuals who have symptomatic primary or secondary MR 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 or more. 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 or more 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 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 or PASCAL, the evidence includes a randomized study, nonrandomized prospective studies, and noncomparative feasibility studies. Relevant outcomes are OS, morbid events, functional outcomes, and treatment-related morbidity. The randomized, sham-controlled trial for the indirect annuloplasty device Carillon offers promising safety data; however, further studies are needed to determine efficacy and long-term outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have valve dysfunction and mitral stenosis or regurgitation after prior bioprosthetic mitral valve replacement, who are at a high or prohibitive risk for redo surgical mitral valve replacement (rSMVR), and who receive a transcatheter mitral valve-in-valve replacement (TMViVR) using an FDA-approved device, the evidence includes 2 meta-analyses, 8 comparative retrospective cohort studies, and 9 observational studies. Relevant outcomes are OS, morbid events, functional outcomes, and treatment-related morbidity. The meta-analyses had mixed early-term findings, with one observing a benefit for in-hospital mortality favoring TMViVR over rSMVR, but at 30 days, 1-year, and 2-year follow-up, no difference between groups in OS was observed in either review. Both analyses found that complications of stroke, renal dysfunction, vascular complications, pacemaker implantation, and bleeding were more common in the rSMVR group. The comparative studies generally found that mortality was equivalent or favored TMViVR through 1-year follow-up; however, several studies that reported longer-term outcomes observed that the trend in mortality was reversed with numerically higher rates in the TMViVR group. TMViVR was associated with a shorter hospital or ICU stay than rSMVR. Several adverse events (acute kidney injury, cardiac arrest, cardiogenic shock, major bleeding, pacemaker implantation, pneumonia, sepsis, stroke, and vascular complications) were more commonly reported in the rSMVR group compared to TMViVR. These results were supported by observational data, which provided data on mortality, functional outcomes, and complications through up to 7 years post-implantation. The evidence base is limited primarily by the lack of experimental studies, but assigning patients who are at high or prohibitive risk for open surgery to rSMVR is ethically prohibitive so retrospective comparisons will likely continue to represent the best available evidence for this intervention. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether transcatheter mitral valve repair improves the net health outcome in patients with primary (degenerative) or secondary (functional) mitral regurgitation.

Policy Statements

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

TMVR with a device approved by the U.S. FDA may be considered medically necessary for individuals with heart failure and moderate-to-severe or severe symptomatic secondary MR despite the use of maximally tolerated guideline-directed medical therapy (see Policy Guidelines section).

TMVR is considered investigational in all other situations.

Transcatheter mitral valve-in-valve replacement (TMViVR) with a device approved by the U.S. FDA is considered medically necessary for individuals when all of the following conditions are present:

• Failure (stenosed, insufficient, or combined) of a surgical bioprosthetic mitral valve; AND

• New York Heart Association heart failure class II, III, or IV symptoms; AND

• Individual is not an operable candidate for open surgery, as documented by at least 2 cardiovascular specialists (including a cardiac surgeon); OR individual is an operable candidate but is considered at increased surgical risk for open surgery, as documented by at least 2 cardiac specialists (including a cardiac surgeon); OR individual is considered at increased surgical risk for open surgery (eg, repeat sternotomy) due to a history of congenital vascular anomalies AND/OR has a complex intrathoracic surgical history, as documented by at least 2 cardiovascular specialists (including a cardiac surgeon) (see Policy Guidelines section).

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.

The FDA definition of high risk for open surgery is:

• Society of Thoracic Surgeons (STS) predicted operative risk score of 8% or higher; or

• Judged by a heart team, which includes an experienced cardiac surgeon and a cardiologist, to have an expected mortality risk of 15% or higher for open surgery.

Moderate to severe or severe mitral regurgitation (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]).

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

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+ to 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 MR (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 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.^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 societies^7,8, 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.^9,10,11,12,

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

Devices currently approved by the FDA for transcatheter mitral valve repair (TMVR) undergo direct mitral leaflet repair (also referred to as transcatheter edge-to-edge repair). Of the TMVR 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.

The PASCAL (PAddles Spacer Clasps ALfieri) Mitral Repair System (Edwards Lifesciences) is also a direct coaptation device and works in a similar manner to the MitraClip system.^15, PASCAL has been in clinical use since 2016 and was approved for use in Europe in 2019.^16, The delivery system consists of a 10-mm central spacer that attaches to the MV leaflets by 2 paddles and clasps.

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. 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.^17,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.^18,

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-in-Valve Replacement

Mitral valve-in-valve replacement is a minimally invasive procedure designed to treat patients with failing surgical bioprosthetic mitral valves who are at high risk for complications with repeat open-heart surgery. The Edwards SAPIEN 3 Transcatheter Heart Valve received FDA approval in June 2017 (PMA #P140031) for patients with a failing surgical bioprosthetic mitral valve who are at high or prohibitive risk for repeat surgery. The procedure involves deploying the replacement valve within the failing bioprosthetic valve using a catheter-based transapical or transseptal approach. Once in position, the replacement valve is expanded, pushing the leaflets of the failing bioprosthetic valve aside and taking over the valve function.

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), beta-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.”^19,

In June 2017, the Edwards SAPIEN 3 Transcatheter Heart Valve received FDA approval through the premarket approval process for the treatment of patients with a "failing surgical bioprosthetic mitral valve who have been determined to be at high or greater risk for open-heart surgery by a heart team."

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."

In September 2022, the FDA approved the PASCAL Precision Transcatheter Valve Repair System 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 prohibitive risk for mitral valve surgery by a heart team."^20,

FDA product code for MitraClip and PASCAL: NKM.
FDA product code for Edwards SAPIEN 3: NPV

Rationale

This evidence review was created in July 2014 with searches of the PubMed database. The most recent literature update was performed through March 4 , 2024.

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 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

MitraClip and PASCAL

Population Reference No. 1

Primary Mitral Valve Regurgitation at Prohibitive Surgical Risk

Clinical Context and Therapy Purpose

The purpose of TMVR using MitraClip or PASCAL in individuals who have primary mitral regurgitation (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 following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals 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+ to 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 individuals with valvular dysfunction.

Intervention

The therapy being considered is TMVR using MitraClip or PASCAL.

Comparators

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 or PASCAL 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

Randomized Controlled Trials

The ongoing CLASP IID/IIF pivotal trial for the PASCAL device is enrolling adults with MR (3+ to 4+) into 1 of 3 cohorts, 2 of which have undergone interim analyses and were evaluated by the FDA for pre-marketing approval. The main cohort constituted a randomized, multicenter noninferiority study comparing PASCAL and MitraClip in patients with primary MR. The second cohort constituted a single-arm registry study (the PASCAL IID registry, described in the Non-Randomized Studies section) that enrolled patients with primary MR who were eligible for treatment in the study with PASCAL but were ineligible for randomization due to complex mitral valve anatomy (rendering them unsuitable for treatment with MitraClip).^20,21, The third cohort constituted a randomized, multicenter study comparing PASCAL and MitraClip in patients with functional (secondary) MR receiving guideline-directed medical therapy, results of which have not yet been reported.^22,

In the main CLASP IID cohort, eligible patients were randomized 2:1 to TMVR with PASCAL or MitraClip.^20, The primary safety endpoint was a composite of major adverse events at 30-day follow-up, including cardiovascular death, stroke, myocardial infarction, new need for renal replacement therapy, severe bleeding, and/or non-elective mitral valve re-intervention. The primary effectiveness endpoint was the proportion of patients with MR ≤2+ at 6-month follow-up. The noninferiority margins for the primary safety and effectiveness endpoints were absolute differences between groups of 15% and 18%, respectively. The first planned interim analysis was performed after 180 patients were randomized and had undergone the study procedure attempt. Mean age was approximately 81 years; most participants were male (67% of PASCAL and 68% of MitraClip patients) and White (72% and 76% of PASCAL and MitraClip patients, respectively; 4.3% and 1.6% were Asian and 2.6% and 3.2% were Black or African American, respectively). All 180 patients randomized at the time of analysis underwent the procedure attempt. No differences between groups in New York Heart Association (NYHA) functional class, operative risk scores, or other baseline characteristics were identified. The most common reasons for prohibitive surgical risk were frailty (>84% in both groups) and a predicted mortality risk for mitral valve replacement ≥8% (>14% in both groups). In the primary analyses, PASCAL was noninferior to MitraClip for safety and effectiveness. The proportion of patients in the PASCAL (n=117) and MitraClip groups (n=63) who experienced a major adverse event at 30 days was 3.4% and 4.8% (upper bound of 95% confidence interval [CI] for between-group difference, 5.1%), respectively. The most common major adverse event was severe bleeding in both PASCAL and MitraClip groups (2.6% and 3.2%, respectively). In the PASCAL group, 2 patients died prior to 30-day follow-up and 1 patient had missing 30-day and 6-month data. In the MitraClip group, 1 patient died prior to 30-day follow-up. The proportion of patients in the PASCAL (n=114) and MitraClip groups (n=62) with MR ≤2+ at 6 months was 96.5% and 96.8%, respectively (lower bound of 95% CI for between-group difference, -6.2%). At 6 months, 6.1% of PASCAL recipients and 11.1% of MitraClip recipients had experienced a major adverse event, and all-cause mortality was 5.1% and 6.3%, respectively. Functional status, exercise capacity, and quality-of-life measures improved from baseline at comparable rates in both groups. No interactions between the primary outcomes and sex or age were identified in either group.

Zahr et al (2023) reported 1-year outcomes of the CLASP IID trial, which compared the safety and effectiveness of the PASCAL device (n=204) with the MitraClip device (n=96) for the treatment of MR in the full cohort of 300 patients.^23, The study population was well-balanced between the 2 groups, with the majority of participants in each group deemed to be at prohibitive surgical risk due to frailty. At 1-year follow-up, data were available for 91.5% and 94.3% of participants in the PASCAL and MitraClip groups, respectively. The primary safety endpoint, the proportion of patients experiencing a major adverse event at 30 days, was similar between the PASCAL (4.6%) and MitraClip (5.4%) groups (upper bound of 95% CI for between-group difference, 4.6%). Severe bleeding was the most common major adverse event in both groups (PASCAL: 3.6%; MitraClip: 2.2%), with 1 cardiovascular death (0.5%) in the PASCAL group and 2 (2.2%) in the MitraClip group. Freedom from major adverse events remained comparable between groups at 1 year (PASCAL: 84.7%; MitraClip: 88.3%; p=.471). The primary effectiveness endpoint, the proportion of patients with MR ≤2+ at 6 months, was achieved by 97.9% and 95.7% of patients in the PASCAL and MitraClip groups, respectively (absolute difference, 2.2%), meeting the prespecified noninferiority margin. At 1 year, MR reduction to ≤2+ was sustained in both groups (PASCAL: 95.8%; MitraClip: 93.8%), with no significant differences observed. Both groups experienced significant improvements in functional (NYHA functional class) and quality of life (Kansas City Cardiomyopathy Questionnaire Score, EQ-5D-5L, mean 6-minute walk distance) from baseline to 1 year (p<.05 for all), with no differences between groups. Study limitations included unblinded treatment allocation, the use of multiple generations of PASCAL and MitraClip devices, and loss to follow-up for time-to-event outcomes. The findings suggest that the PASCAL device is non-inferior to the MitraClip device for the reduction of MR severity and the rate of major adverse events at 1 year, consistent with the interim analysis.

Non-Randomized Studies

Tables 1 and 2 summarize patient characteristics and health outcomes of the case series by Reichenspurner et al (2013)^24, and Lim et al (2013),^25, which were considered higher quality. The Reichenspurner et al (2013) study reported data on 117 patients with primary MR 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.^24,26, 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 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 MitraClip Case Series Characteristics

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

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.

In reviewing data for MitraClip, 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 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 in evaluating MitraClip. 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 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 following^19,:

• 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 mitral valve (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 36-Item Short-Form Health Survey (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.^27, Sensitivity analyses showed that these effectiveness results were robust to missing data.

• The commercial post registry 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 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 3. Key Observational Comparative Study Characteristics

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

Table 4. Key Observational Comparative Study Results

CI: confidence interval; 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.^28,29, 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% to 12.2%) and 10.0% (range, 6.3% to 14.5%), respectively.^28, 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^26, 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 (HF) was 20.2%, and cumulative incidence of mortality or rehospitalization for HF was 37.9%.^29, 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 HF. The persistency of mortality (25.8%) and heart failure rehospitalization (20.2%) at 1 year despite 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.^30,

An open-label head-to-head trial by Gercek et al (2021) evaluated the efficacy of the PASCAL system versus the MitraClip system in patients with severe primary MR.^31, During the study time frame, 38 patients with primary MR underwent percutaneous edge-to-edge MV repair; 22 received the PASCAL device and 16 received MitraClip intervention. The decision of the device used was made at the discretion of the interventionalist. All patients were in NYHA functional class III or IV and had MR severity scores of 3+ or 4+. Procedural success was achieved in 95.5% of patients who had PASCAL implantation versus 87.5% of patients with MitraClip implantation. In 86.4% of patients who received the PASCAL device, a residual MR severity grade <1+ was achieved, whereas, reduction to MR severity grade <1+ with MitraClip was achieved in 62.5% of patients (p=.039). No patients in either group had any periprocedural major adverse events.

The second cohort of patients who were enrolled in the single-arm PASCAL IID registry cohort included: patients with primary MR enrolled in the CLASP IID/IIF trial comparing PASCAL and MitraClip who were eligible for use of PASCAL but ineligible to undergo randomization due to complex mitral valve anatomy precluding use of MitraClip.^20,32, Outcomes of the initial analysis of this registry study are summarized in Table 5. Among 92 patients who underwent successful PASCAL implantation (6 patients did not receive the device due to inability to grasp leaflets, increased transmitral valve gradient, or insufficient MR reduction), mean age was 81 years; most were male (62%) and White (73%; 3.3% were Asian and 4.3% were Black or African American). At 30-day follow-up, 8.7% of patients in the registry cohort had experienced a major adverse event, the most common of which was severe bleeding (4.3%); at 6-month follow-up, 12% had experienced a major adverse event and all-cause mortality was 6.5%. Severity of MR was ≤2+ in 91% of patients at 6 months.

Table 5. Summary of U.S.-Based Transcatheter Valve Therapy Registry Data

MR: mitral regurgitation; NR: not reported 

Other multiple subgroup analyses and systematic reviews have been reported using the EVEREST II HRR, REALISM, CLASP IID/IIF, 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.^{30,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,}

Section Summary: Primary Mitral Valve Regurgitation at Prohibitive Surgical Risk

The evidence for the use of MitraClip and PASCAL in patients with primary MR at prohibitive surgical risk consists of 1 RCT, and otherwise 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% to 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 HF hospitalization rates remained considerably high (38%) compared with U.S.-based registry data thereby raising uncertainty about the long-term benefits. The randomized cohort of the CLASP IID/IIF trial demonstrated noninferiority of PASCAL to MitraClip for safety and effectiveness in reducing MR severity to 2+ or less, and findings from the single-arm PASCAL IID registry cohort of this study further indicate that PASCAL is safe and effective in patients with complex mitral valve anatomy precluding the use of MitraClip.

For individuals who have symptomatic primary mitral regurgitation (MR) and are at prohibitive risk for open surgery who receive transcatheter mitral valve repair (TMVR) using MitraClip or PASCAL, the evidence includes a noninferiority randomized controlled trial (RCT) and 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, the Transcatheter Valve Therapy Registry study, and the CLASP IID/IIF study. Studies evaluating MitraClip 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 [STS] 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 SF-36 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 (HF) 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, an RCT comparing TMVR 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 CLASP IID/IIF randomized cohort demonstrated that PASCAL is noninferior to MitraClip in safety and effectiveness for patients with primary MR at prohibitive surgical risk, and the single-arm registry cohort demonstrated that PASCAL is safe and effective in patients with complex mitral valve (MV) anatomy precluding the use of MitraClip. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Heart Failure and Secondary Mitral Valve Regurgitation

Clinical Context and Therapy Purpose

The purpose of TMVR using MitraClip in individuals who have HF 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 following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with HF 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+ to 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

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 individuals , 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 HF 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)^48, evaluated the comparison of MitraClip plus medical therapy to medical therapy alone in patients with SMR (N=1130) using data from the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) and the Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) 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 HF (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 LV 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

Limited experience using PASCAL in patients with SMR has been reported.^49, This use is being investigated in a randomized cohort of the CLASP IID/IIF trial; analysis of this cohort has not yet been reported.^22,

The evidence for the use of MitraClip in patients with SMR consists of 2 RCTs, the COAPT ^50,51, and the MITRA-FR ^52,53, (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.^50, MITRA-FR enrolled 304 patients at 37 centers in France.^52,53,

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).^50, Improvements in MR severity, quality-of-life measures, and functional capacity persisted to 36 months in patients who received TMVR.^51, In the final analysis of COAPT through 5-year follow-up, rates of all-cause death (hazard ratio [HR], 0.72; 95% CI, 0.58 to 0.89) and cardiovascular death (HR, 0.71; 95% CI, 0.56 to 0.90), hospitalization for any reason (HR, 0.75; 95% CI, 0.63 to 0.89) and for cardiovascular reason (HR, 0.64; 95% CI, 0.53 to 0.77), death or hospitalization for heart failure (HR, 0.53; 95% CI, 0.44 to 0.64), and unplanned mitral valve intervention or surgery (HR, 0.09; 95% CI, 0.05 to 0.17) were significantly lower in the MitraClip arm.^54, The 5-year rate of freedom from device-related complications was 89.2%; severe mitral stenosis was reported in 7.6% of MitraClip patients, none of whom underwent surgery for severe mitral stenosis. No patients in the control group developed mitral stenosis. Crossover TMVR had been performed in 21.5% of patients in the control group at median 26 months after randomization; in a post hoc analysis, crossover TMVR was independently associated with lower risk of subsequent death or hospitalization for heart failure (HR, 0.53; 95% CI, 0.36 to 0.78).

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).^52,53,

Although the reasons for these discrepant results are not entirely clear, differences in the studies' design and conduct have been proposed as possible explanations.^55,56,57, The severity of MR and HF 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.^7,58,57, 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 HF 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.^57, 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

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

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 HF 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

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

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.

Non-Randomized Studies

EXPAND was a prospective, multicenter, post-marketing observational study designed to evaluate safety outcomes (as a composite of major adverse events, including all-cause death, myocardial infarction, stroke, or non-elective surgery for device-related complications, at 30 days) in patients treated with MitraClip.^59, A total of 1041 patients from 22 sites in the U.S. and 35 sites in Europe were enrolled in EXPAND, 413 of whom received MitraClip for SMR. Among these patients, mean age was 75 years and most were male (58%) with class III NYHA functional status (66%). The acute procedural success rate was 97%, and 99% had MR ≤2+ at hospital discharge. At 30-day follow-up, 3.6% of patients had experienced a major adverse event, most of which were cardiovascular deaths (2.7%). At 1-year follow-up, 99.6% of patients had MR maintained at ≤2+ and 1-year rates of all-cause death and hospitalization for heart failure were 17.7% and 26% (representing a 65% reduction from baseline in annualized heart failure hospitalizations; p<.001), respectively; repeat MV intervention and MV replacement each occurred in 1.4% of patients.

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 up to 5 years compared to medical therapy alone, including improvements in OS and hospitalization for heart failure. 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.

For individuals who have HF and symptomatic secondary mitral regurgitation (SMR) despite the use of maximally tolerated guideline-directed medical therapy who receive TMVR using MitraClip, the evidence includes a systematic review, 2 RCTs, and 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 up to 5 years compared to medical therapy alone, including benefits in overall survival and hospitalization for heart failure. 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 an improvement in the net health outcome.

Population Reference No. 3

Primary or Secondary Mitral Regurgitation in Surgical Candidates

Clinical Context and Therapy Purpose

The purpose of TMVR using MitraClip in individuals 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 following PICO was used to select literature to inform this review.

Populations

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

Interventions

The therapy being considered is TMVR using MitraClip

Comparators

Relevant comparators are open MV repair and open MV replacement.

In symptomatic individuals 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.^60, 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/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; patients were randomized to MitraClip or open MV repair/replacement (see Table 10).^61,62, 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 years^63, and 5 years^64, 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.

The REPAIR MR RCT is comparing TMVR with MitraClip to surgical MV repair in surgical candidates who are older (age ≥75 years) or at moderate surgical risk; results have not yet been reported.^65,

Table 10. Key Randomized Controlled Trial Characteristics

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

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 or older with degenerative MR who underwent treatment with MitraClip or surgical mitral repair (see Tables 12 and 13).^66, Preoperative variables included in the model were age at operation, sex, body mass index categorized as normal (20 to 30) or not normal (<20 or >30), serum creatinine, atrial fibrillation, NYHA class III, ejection fraction, systolic pulmonary artery pressure, isolate P2 prolapse, and STS 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

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

Table 13. Summary of Observational Comparative Study Results

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

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.

For individuals who have symptomatic primary or secondary MR 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 or more. 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 or more 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 that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Other Transcatheter Mitral Valve Repair Devices

Clinical Context and Therapy Purpose

The purpose of TMVR using devices other than MitraClip and PASCAL in individuals with symptomatic primary or SMR is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

Populations

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

Interventions

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

Comparators

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 and PASCAL are being investigated for TMVR, although none is FDA approved for use in the U.S.

Indirect Annuloplasty Devices

Randomized Controlled Trial

Several indirect annuloplasty devices, including the Carillon Mitral Contour System (Cardiac Dimension) and the Monarc device (Edwards Lifesciences), have been evaluated. The Carillon Mitral Contour System for Reducing Functional Mitral Regurgitation (REDUCE-FMR) study by Witte et al (2019) was a multicenter, double-blind, sham-controlled randomized trial to report outcomes with the Carillon device in patients with functional SMR.^67, Patients included were taking optimally tolerated doses of guideline-directed medication therapy. Of note, 29.7% of patients included were classified as having mild MR (severity class 1+) based on echocardiographic evaluation. Patients were randomized to Carillon device (n=87) or sham (n=33). In the treatment group, 73 (84%) of patients had the device implanted. At 1 year, patients with the Carillon device had a statistically significant reduction in MR volume (decrease of 7.1 mL/beat; 95% CI, -11.7 to -2.5) compared to the sham group (decrease of 3.3 mL/beat; 95% CI, -6.0 to 12.6; p=.049). Additionally, the Carillon device significantly reduced LV volumes in symptomatic patients with MR receiving optimal medical therapy (LV end-diastolic volume decrease of 10.4 mL; 95% CI, -18.5 to -2.4; LV end-systolic volume decrease of 6.2 mL; 95% CI, -12.8 to 0.4) compared to sham (LV end-diastolic volume increase of 6.5 mL; 95% CI, -5.1 to 18.2; p=.03; LV end-systolic volume increase of 6.1 mL; 95% CI, -1.42 to 13.6; p=.04). Patient-centered outcomes, including 6-minute walk test and quality of life scores, did not differ between groups. A post-hoc analysis by Khan et al (2021) assessed patient-centered outcomes only in patients with SMR severity 2+ to 4+.^68, Of the 83 patients included in this analysis, 62 (75%) were randomized to the Carillon device group and 21 (25%) were randomized to sham procedure. A minimally clinically important difference for the outcomes was defined as a >30 m increase in 6-minute walk test, an NYHA decrease in >1 class, and a >3 point increase in KCCQ score at 1 year follow-up. All outcomes at 1 year favored the Carillon group over sham, but the only significant difference was in the 6-minute walk test scores (59% vs. 23%; p=.029; number needed to treat, 2.8). This analysis was not adequately powered to evaluate clinical endpoints. Further studies are needed to determine actual benefit and long-term outcomes beyond 1 year.

Case Series

A case series evaluating the use of the Carillon device in 53 patients with an SMR severity grade of 2+ at 7 European centers was reported by Siminiak et al (2012).^17, 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 SMR 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 SMR; it demonstrated successful device placement in 30 patients, with 18 patients unable to be implanted due to access issues, insufficient acute SMR reduction, or coronary artery compromise.^69, The Monarc device has been evaluated in a phase 1 safety trial at 8 European centers, as reported by Harnek et al (2011).^18, 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.

The CINCH post-market registry evaluated the outcomes of percutaneous mitral valve repair using the Carillon Mitral Contour System in patients with functional mitral regurgitation and symptomatic heart failure from 2012 to 2022.^70, The single-arm study enrolled 101 patients at 13 sites in Germany, with a mean age of 75 years and primarily NYHA class III (69%) and MR grade 3 (68%). Over 5 years, all-cause mortality was 40.1%, heart failure hospitalization incidence was 53.9%, and the composite outcome of hospitalization or death was 66.4%. The annualized rate of cumulative heart failure hospitalization through 2 years was 28.8%. Statistically significant reductions in NYHA class and MR grade were reported at each follow-up interval through 5 years; at the 5-year follow-up, 100% of participants had an improvement or maintained their NYHA class, and none had a mitral regurgitation score of 3+ or greater. There were no device-related serious adverse events reported, and 2 (2%) procedure-related serious adverse events, both of which were minor vascular access complications.

The retrospective TENDER (Tendyne European Experience) registry evaluated the Tendyne transcatheter mitral valve replacement (TMVR) system at 31 high-volume heart valve centers (Germany, Austria, Belgium, France, Italy, Spain, Switzerland, and the United Kingdom).^71, The study included 195 patients eligible for 1-year follow-up, with a median age of 77 years and a median Society of Thoracic Surgeons Predicted Risk of Mortality of 5.6%. Technical success was achieved in 94.9% of patients. Cardiovascular mortality rates were 6.7% at 30 days and 16.9% at 1 year, while all-cause mortality rates were 9.3% at 30 days and 28.6% at 1 year. The rate of heart failure hospitalization significantly decreased from 68.1% in the year prior to the procedure to 25.4% in the 1-year post-procedure period. At 1-year follow-up, a reduction of mitral regurgitation to mild or less (≤1+) was achieved in 97.9% of patients, and 82.5% of patients were in NYHA functional class I or II, compared to 22.6% at baseline. Within the 1-year post-discharge follow-up, major adverse events included disabling stroke (2.4%), myocardial infarction (1.3%), new-onset atrial fibrillation (5.4%), and new conduction disturbances (1.2%). Device-specific events comprised valve thrombosis (3.0%), valve migration (0.6%), and paravalvular leak >1+ inch (5.2%).

Section Summary: Other Transcatheter Mitral Valve Repair Devices

The evidence for the use of TMVR devices other than MitraClip and PASCAL for patients with MR includes a randomized study, nonrandomized prospective studies, and small case series and case reports. The randomized, sham-controlled trial for the indirect annuloplasty device Carillon offers promising safety data, however further studies are needed to determine efficacy and long-term outcomes.

For individuals who have symptomatic primary or secondary MR who receive TMVR using devices other than MitraClip or PASCAL, the evidence includes a randomized study, nonrandomized prospective studies, and noncomparative feasibility studies. Relevant outcomes are OS, morbid events, functional outcomes, and treatment-related morbidity. The randomized, sham-controlled trial for the indirect annuloplasty device Carillon offers promising safety data; however, further studies are needed to determine efficacy and long-term outcomes. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5

Transcatheter Mitral Valve-in-Valve Replacement

Clinical Context and Therapy Purpose

The purpose of transcatheter mitral valve-in-valve replacement (TMViVR) implantation is to provide a treatment option that is an alternative to or an improvement on existing therapies, such as surgical mitral valve repair and medical management, in individuals with a degenerated mitral valve bioprosthesis who are at a high or prohibitive risk for redo surgical mitral valve replacement (rSMVR).

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

Populations

The relevant population of interest is individuals with a previously implanted bioprosthetic mitral valve who experience valve stenosis or mitral regurgitation and are determined to be at high surgical risk.

Interventions

The therapy being considered is TMViVR, a minimally invasive surgical procedure that repairs the mitral valve without removing the old, damaged valve by wedging a replacement valve into the place of the mitral valve.

Comparators

The first comparator of interest is surgical mitral valve repair, performed through sternotomy. The decision to repair a damaged mitral valve depends on the severity of the symptomatic mitral stenosis or regurgitation, the patient's age, and overall health. Medical management, including lipid-lowering therapy, anti-hypertensive drugs, and anti-calcific therapy, is the second comparator of interest in this review.

Outcomes

The general outcomes of interest are OS, symptoms, morbid events, treatment-related mortality, and treatment-related morbidity. Symptoms may include heart murmur, angina, dizziness or syncope, shortness of breath, fatigue, and heart palpitations. Morbid events may include stroke, coronary obstruction, vascular complications, conduction disturbance, valve malpositioning and sizing, mitral valve injury, annular rupture, myocardial trauma, low cardiac output, cardiogenic shock, and cardiac arrest.

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 longer-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

Zhou et al (2023) conducted a meta-analysis of TMViVR (n=1464) versus rSMVR (n=1574) for patients who have had mitral bioprosthesis failure.^72, Nine retrospective cohort studies were included in the analysis from a literature search through September 2022. TMViVR was associated with a lower reported in-hospital mortality than rSMVR (3.2% vs. 6.8%; OR, 0.44; 95% CI, 0.30 to 0.64; p<.001; I²=0%) with no observed heterogeneity. However, 30-day (OR, 0.65; 95% CI, 0.36 to 1.17; p=.15) and 1-year mortality (OR, 0.96; 95 %CI, 0.63 to 1.45; p=.84) did not differ significantly between treatment groups. The TMViVR group had a lower rate of reported stroke (OR, 0.44; 95% CI, 0.29 to 0.67), renal dysfunction (OR, 0.52; 95% CI, 0.37 to 0.75), vascular complications (OR, 0.58; 95% CI, 0.43 to 0.78), pacemaker implantation (OR, 0.23; 95% CI, 0.15 to 0.36), and exploration for bleeding (OR, 0.24; 95% CI, 0.06 to 0.96) than the rSMVR group.

Ismayl et al (2023) published a meta-analysis comparing TMViVR (n=338) to rSMVR (n=369) for individuals with degenerated bioprosthetic mitral valves.^73, A total of 6 observational studies with a median follow-up of 2.7 years were included based on a literature search through September 2022; studies with potential overlap from the Nationwide Inpatient Sample and National Readmission Database were excluded from the analysis. Thirty-four patients (9.2%) in the TMViVR group received valve-in-ring rather than TMViVR and could not be separated for outcome assessment. The pooled risk of in-hospital mortality (OR, 0.52; 95% CI, 0.22 to 1.23; p=.14), 30-day mortality (OR 0.65; 95% CI, 0.36 to 1.17; p=.15), 1-year mortality (OR, 0.97, 95% CI, 0.63 to 1.49, p=.89), 2-year mortality (OR, 1.17; 95% CI, 0.65 to 2.13; p=.6) was similar between groups with low heterogeneity (I²= 0%). TMViVR had a lower risk of stroke (OR, 0.31; 95% CI, 0.11 to 0.88; p=.03), bleeding (OR, 0.21; 95% CI, 0.12 to 0.39; p<.00001), acute kidney injury (OR, 0.43; 95% CI, 0.22 to 0.84; p=.01), arrhythmias (OR, 0.17; 95% CI, 0.04 to 0.64; p=.009), and permanent pacemaker insertion (OR, 0.18; 95% CI, 0.05 to 0.60; p=.005).

Comparative Studies

Eight retrospective cohort or registry-based studies were identified, which provided indirect comparisons of TMViVR and rSMVR with follow-up periods from 1 to 5 years (Table 14).^{74,75,76,77,78,79,80,68,80,} Patients included in the TMViVR groups had higher mean ages (range: 74 to 77) compared to rSMVR (range: 63 to 72) as well as worse Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) (range: 11.9% to 12.7% vs. 8.7% to 10.2%) and EuroScore (range: 15.7% to 39% vs. 15% to 23%). Due to this imbalance of patient characteristics between groups, propensity matching was performed in 4 studies.^74,76,68, However, despite efforts to make the treatment groups comparable, 2 of these studies still had baseline imbalances.^74,80, Five of eight studies reported the device used for valve-in-valve replacement, all of which used either SAPIEN, SAPIEN 3, SAPIEN 3 Ultra or SAPIEN XT; 2 studies included a minority of patients with valve-in-ring procedures and did not report outcomes separately for valve-in-valve (ViV).^74,75, Several studies were based on registry data and may have recounted participants from other studies with overlapping enrollment periods.^76,68,80,

Outcomes for studies comparing TMViVR to rSMVR are reported in Table 15. In-hospital mortality was reported by 4 studies (TMViVR range: 2 to 7.3; rSMVR range: 3.2 to 15.2), with 3 finding equivalent in-hospital mortality and 1 finding that TMViVR was favored over rSMVR.^80, At 30 days post-implantation, 1 of 5 studies (TMViVR range: 2.4% to 14%; rSMVR range: 1.3% to 15.2%) found a significant difference in mortality favoring TMViVR over rSMVR.^75, Mortality at one-year follow-up was reported by 6 studies (TMViVR range: <2.8% to 16.7%; rSMVR range: 4.8% to 18.3%), which found a significantly lower rate in TMViVR when compared to rSMVR in 1.^68, Longer-term follow-up was reported by 3 studies, all of which found numerically higher mortality in the TMViVR group, but statistical tests were provided for only 1 study, which found that rates were comparable with rSMVR.^75,79,77, The change in the direction of survival benefit may be due to TMViVR participants having a higher surgical risk and more advanced age, which, despite attempts to control statistically, remained unbalanced in 2 studies or the ability to treat concomitant conditions (e.g. tricuspid regurgitation or atrial fibrillation) during rSMVR which may confer a survival benefit. The length of hospital or intensive care unit (ICU) stay was reported in 6 studies (TMViVR range: 2 to 9.7 days; rSMVR range: 3 to 13 days) 4 of which found fewer in-hospital days amongst valve-in-valve repair patients compared to rSMVR. Complications of acute kidney injury, cardiac arrest, cardiogenic shock, major bleeding, pacemaker implantation, pneumonia, sepsis, stroke, and vascular complications were greater in the rSMVR group; participants treated with TMViVR were more likely to report a residual defect needing closure or an increased likelihood of paravalvular regurgitation.

Table 14. Summary of Observational Comparative Study Characteristics

AF: atrial fibrillation; ASD: atrial septal defect; BL; baseline; CABG: coronary artery bypass graft; CAD: coronary artery disease; CHF: congestive heart failure; GFR; glomerular filtration rate; HTN: hypertension; NR: not reported; NS: non-significant; NYHA: New York Heart Association; PROM: predicted risk of mortality; PS: propensity score; PVD; peripheral vascular disease; rSMVR: redo-surgical mitral valve replacement; SAVR: surgical aortic valve replacement SS: statistically significant; STS: Society of Thoracic Surgeons; TAVR: transcatheter aortic valve replacement; TMViVR: transcatheter mitral valve-in-valve replacement; VSD: ventricular septal defect. 

Table 15. Summary of Observational Comparative Study Results

AF: atrial fibrillation; CI: confidence interval; HR: hazard ratio; LVOT: Left ventricular outflow tract; MR: Mitral Regurgitation; NR: Not Reported; NS: non-significant difference; OR: Odds Ratio; rSMVR: redo surgical mitral valve repair; SD: standard deviation; TMViVR: transcatheter mitral valve-in-valve repair.

Observational Studies

Nine retrospective cohort studies reported outcomes of patients undergoing TMViVR from 30 days to 7 years post-implantation (Table 16).^{81,82,83,84,85,86,87,88,20,} Participants ranged in age from a mean of 72.6 years to 77.5 years. Mean STS scores over 8, which indicates a high risk for surgery, were reported for 7 studies (range: 5.9 to 11.1); EuroScore was reported in 4 studies (range 8.9 to 11.5). All studies reported that SAPIEN, SAPIEN 3, SAPIEN 3 Ultra, or SAPIEN XT were used for ViV procedures, but 2 studies included a minority of patients who were treated with non-US FDA-approved valves (Lotus, Direct Flow, and Melody devices).^86,87,

Observational study outcomes for TMViVR are reported in Table 17. Technical success during TMViVR was reported by 5 studies and ranged from 73.6% to 96.8%, with device success ranging from 28.6% to 88.2% in 3 studies; however, different definitions of technical and device success were applied, which makes comparisons across studies challenging.^{81,85,86,87,88,} Four studies reported an improvement in NYHA functional class from baseline levels.^83,84,85,89, Three studies found improvements from baseline on the Kansas City Cardiomyopathy Questionnaire (KCCQ), with the longest follow-up being 5 years.^84,85,89, Mortality at 30 days post-implantation ranged from 2.5% to 6.8% in 4 studies;^81,82,86,88, at 1 year, this range increased to 3% to 16% in 8 studies.^{81,82,83,84,85,86,87,88,} Mortality at 2 years follow-up was only reported by 2 studies and had a wide range from 6.7% to 29.4%,^84,88, and at 5 years follow-up, mortality increased to a range of 21.4% to 58.1% in 3 studies.^83,84,85, A single observational study reported that at 7 years after TMViVR the mortality rate was 64.3%.^82, Complications reported by more than one author included conversion to open surgery, left ventricular outflow tract obstruction, major vascular complications, new pacemaker implantation, stroke, and transcatheter heart valve thrombosis.

Table 16. Summary of Observational Study Characteristics

MR: mitral regurgitation; MS: mitral stenosis; NR: not reported; NS: non-significant; NYHA: New York Heart Association; STS-PROM: Society of Thoracic Surgeons Predicted Risk of Mortality; TMVR: transcathter mitral valve replacement; TMViVR: transcatheter mitral valve-in-valve replacement;

Table 17. Summary of Observational Study Results

ASD: atrial septal defect; BL: baseline; CI: confidence interval; HF: heart failure; HR: hazard ratio; KCCQ: Kansas City Cardiomyopathy Questionnaire; LVOT: Left ventricular outflow tract; MR: Mitral Regurgitation; MVARC: Mitral Valve Academic Research Consortium; NR: Not Reported; NYHA: New York Heart Association; OR: Odds Ratio; THV: transcathetr heart valve.

Section Summary: Transeptal Mitral Valve-in-Valve Replacement

The evidence for the use of TMViVR in patients who are at a high risk for open surgery includes 8 retrospective cohort or registry studies that compared TMViVR to rSMVR as well as 9 observational studies and 2 meta-analyses. The meta-analyses had mixed early-term findings, with one observing a benefit for in-hospital mortality favoring TMViVR, but at 30 days, 1 year, and 2 year follow-up, no difference between groups was observed in either review. Both analyses found that complications of stroke, renal dysfunction, vascular complications, pacemaker implantation, and bleeding were more common in the rSMVR group. The comparative studies generally found that mortality was equivalent or favored TMViVR through 1-year follow-up; however, several studies observed that at longer durations of follow-up, the trend in mortality was reversed with numerically higher mortality in the TMViVR group. TMViVR was associated with a shorter length of hospital or ICU stay than rSMVR. Several adverse events (acute kidney injury, cardiac arrest, cardiogenic shock, major bleeding, pacemaker implantation, pneumonia, sepsis, stroke, and vascular complications) were more commonly reported in the rSMVR group compared to TMViVR. These results were supported by observational studies which provided data on mortality, functional outcomes and complications through up to 7 years post-implantation. A high level of technical success for TMViVR was also observed in these studies, although the rate of device success, which had multiple definitions across studies, varied. Benefits to NYHA functional class and improvements in Kansas City Cardiomyopathy Questionnaire outcomes were observed in 3 studies with maximum follow-up of 5 years. Despite the potential early benefits in mortality, duration of hospital stay, functional outcomes, and complications, there is uncertainty due to the lack of direct comparisons, imbalanced patient groups, different valve-in-valve approaches used, and concerns that at longer-term follow-up mortality may favor rSMVR. Given that no RCTs are available, selection bias cannot be ruled out. However, randomizing patients who are at high or prohibitive risk for open surgery to rSMVR is ethically prohibitive so retrospective comparisons will likely continue to represent the best available evidence for this intervention. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have valve dysfunction and mitral stenosis or regurgitation after prior bioprosthetic mitral valve replacement, who are at a high or prohibitive risk for redo surgical mitral valve replacement (rSMVR), and who receive a transcatheter mitral valve-in-valve replacement (TMViVR) using an FDA-approved device, the evidence includes 2 meta-analyses, 8 comparative retrospective cohort studies, and 9 observational studies. Relevant outcomes are OS, morbid events, functional outcomes, and treatment-related morbidity. The meta-analyses had mixed early-term findings, with one observing a benefit for in-hospital mortality favoring TMViVR over rSMVR, but at 30 days, 1-year, and 2-year follow-up, no difference between groups in OS was observed in either review. Both analyses found that complications of stroke, renal dysfunction, vascular complications, pacemaker implantation, and bleeding were more common in the rSMVR group. The comparative studies generally found that mortality was equivalent or favored TMViVR through 1-year follow-up; however, several studies that reported longer-term outcomes observed that the trend in mortality was reversed with numerically higher rates in the TMViVR group. TMViVR was associated with a shorter hospital or ICU stay than rSMVR. Several adverse events (acute kidney injury, cardiac arrest, cardiogenic shock, major bleeding, pacemaker implantation, pneumonia, sepsis, stroke, and vascular complications) were more commonly reported in the rSMVR group compared to TMViVR. These results were supported by observational data, which provided data on mortality, functional outcomes, and complications through up to 7 years post-implantation. The evidence base is limited primarily by the lack of experimental studies, but assigning patients who are at high or prohibitive risk for open surgery to rSMVR is ethically prohibitive so retrospective comparisons will likely continue to represent the best available evidence for this intervention. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

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.

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 and American Heart Association

In 2020, the American College of Cardiology and American Heart Association presented updated expert consensus on the management of mitral regurgitation (MR).^92, The recommendations are as follows: "At present, transcatheter mitral repair using an edge-to-edge clip device can be considered for the treatment of patients with primary MR and severe symptoms who are felt to be poor surgical candidates. Surgical or transcatheter treatment for secondary MR is undertaken only after appropriate medical and device therapies have been instituted and optimized, as judged by the multidisciplinary team with input from a cardiologist with experience managing heart failure and MR."

Also 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. Individuals who have prosthetic valve stenosis are recommended to be offered revision surgery, but for severely symptomatic patients who are at high risk for surgery, a transcatheter aortic valve-in-valve procedure may be reasonable (B level of evidence, moderate class of recommendation); no recommendation is given regarding mitral valve-in-valve procedures. Relevant recommendations on interventions for primary and secondary MR, and prosthetic valve stenosis are shown in Table 18.

Table 18. Recommendations on Interventions for Primary and Secondary Mitral Regurgitation

Source: Adatped from Otto et al (2020).^5,
1Moderate, nonrandomized; ²Limited data; ³Moderate, randomized.
AF: atrial fibrillation; CABG: coronary artery bypass graft; CAD: coronary artery disease; COR: class of recommendation; EF: ejection fraction; 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; ViV: valve-in-valve; VKA, vitamin K antagonist.

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 MR.^93, 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.

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

The European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) issued guidelines on the management of valvular heart disease in 2022.^8, A new position on the management of prosthetic valve dysfunction was issued, stating, "Transcatheter valve-in-valve implantation in the mitral and tricuspid position may be considered in selected patients at high risk for surgical intervention." This recommendation was given a class IIb recommendation, indicating that there is conflicting evidence about the usefulness or efficacy of this treatment, with the opinion being supported by less well-established evidence.

National Institute for Health and Care Excellence

The NICE guideline on heart valve disease management (2021) makes the following recommendations related to TMVR:^94,

• "1.5.10 - Consider transcatheter edge-to-edge repair, if suitable, for adults with severe primary mitral regurgitation and symptoms, if surgery is unsuitable.

• 1.5.14 - Consider transcatheter mitral edge-to-edge repair for adults with heart failure and severe secondary mitral regurgitation, if surgery is unsuitable and they remain symptomatic on medical management."

Another NICE guideline was issued in 2021 on the use of transapical transcathter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis:^95,

• "1.1 - Evidence on the safety of transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis is adequate and shows some serious but well‑recognised complications. Evidence on its efficacy is limited in quality. So, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research."

• "1.4 - Patient selection should be done by a multidisciplinary team which must include interventional cardiologists experienced in the procedure, cardiac surgeons, an expert in cardiac imaging, and where appropriate, a cardiac anaesthetist and a specialist in medicine for older people. The multidisciplinary team should determine the risk level for each patient and the device most suitable for them."

• "1.6 - The procedure is technically challenging and should only be done in specialised centres, and only by clinical teams with special training and experience in complex endovascular cardiac interventions, including regular experience in transcatheter valve implantation procedures. Centres doing these procedures should have cardiac surgical support for emergency treatment of complications and subsequent patient care."

• "1.7 - NICE encourages further research into transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis. Studies should include details on patient selection, type and size of valve used, functional outcomes (New York Heart Association functional class, mitral valve regurgitation), quality of life, patient‑reported outcome measures, survival and complications. Studies should report long‑term follow up of clinical outcomes and valve durability. NICE may update this guidance on publication of further evidence."

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

The Centers for Medicare & Medicaid Services issued a national coverage decision for the use of TMVR in 2015, which was updated in 2021.^96,

The Centers for Medicare & Medicaid Services determined that it would cover TMVR under Coverage with Evidence Development for the treatment of symptomatic moderate-to-severe or severe functional (secondary) MR or significant symptomatic degenerative (primary) MR when all of the following conditions are met:

"1. The procedure is furnished with a [TMVR] system that has received FDA [Food and Drug Administration] premarket approval (PMDA).

2. The patient (preoperatively and postoperatively) is under the care of a heart team...

3. Each patient's suitability for surgical mitral valve repair, [TMVR], or palliative therapy must be evaluated, documented...

4. An interventional cardiologist or cardiac surgeon from the heart team must perform the mitral valve [TMVR]...

5. Mitral valve [TMVR] must be furnished in a hosptial with appropriate infrastructure and experience...

6. The heart team and hospital are participating in a prospective, national, audited registry...

7. The registry shall collect all data necessary and have a written executable analysis plan..."

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 19.

Table 19. Summary of Key Trials

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.
^bPrimary results have been published, long-term follow-up ongoing

References

1. Chiam PT, Ruiz CE. Percutaneous transcatheter mitral valve repair: a classification of the technology. JACC Cardiovasc Interv. Jan 2011; 4(1): 1-13. PMID 21251623
2. Fedak PW, McCarthy PM, Bonow RO. Evolving concepts and technologies in mitral valve repair. Circulation. Feb 19 2008; 117(7): 963-74. PMID 18285577
3. Carabello BA. The current therapy for mitral regurgitation. J Am Coll Cardiol. Jul 29 2008; 52(5): 319-26. PMID 18652937
4. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. Sep 23 2008; 52(13): e1-142. PMID 18848134
5. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Feb 02 2021; 143(5): e72-e227. PMID 33332150
6. Goel SS, Bajaj N, Aggarwal B, et al. Prevalence and outcomes of unoperated patients with severe symptomatic mitral regurgitation and heart failure: comprehensive analysis to determine the potential role of MitraClip for this unmet need. J Am Coll Cardiol. Jan 21 2014; 63(2): 185-6. PMID 24036029
7. Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. Jul 11 2017; 70(2): 252-289. PMID 28315732
8. Vahanian A, Alfieri O, Andreotti F, et al. Guidelines on the management of valvular heart disease (version 2012). Eur Heart J. Oct 2012; 33(19): 2451-96. PMID 22922415
9. Diodato MD, Moon MR, Pasque MK, et al. Repair of ischemic mitral regurgitation does not increase mortality or improve long-term survival in patients undergoing coronary artery revascularization: a propensity analysis. Ann Thorac Surg. Sep 2004; 78(3): 794-9; discussion 794-9. PMID 15336993
10. Wong DR, Agnihotri AK, Hung JW, et al. Long-term survival after surgical revascularization for moderate ischemic mitral regurgitation. Ann Thorac Surg. Aug 2005; 80(2): 570-7. PMID 16039207
11. Mihaljevic T, Lam BK, Rajeswaran J, et al. Impact of mitral valve annuloplasty combined with revascularization in patients with functional ischemic mitral regurgitation. J Am Coll Cardiol. Jun 05 2007; 49(22): 2191-201. PMID 17543639
12. Smith PK, Puskas JD, Ascheim DD, et al. Surgical treatment of moderate ischemic mitral regurgitation. N Engl J Med. Dec 04 2014; 371(23): 2178-88. PMID 25405390
13. Young A, Feldman T. Percutaneous mitral valve repair. Curr Cardiol Rep. Jan 2014; 16(1): 443. PMID 24281977
14. Minha S, Torguson R, Waksman R. Overview of the 2013 Food and Drug Administration Circulatory System Devices Panel meeting on the MitraClip Delivery System. Circulation. Aug 20 2013; 128(8): 864-8. PMID 23960257
15. Noack T, Kiefer P, Besler C, et al. Transcatheter mitral valve repair: review of current techniques. Indian J Thorac Cardiovasc Surg. Jan 2020; 36(Suppl 1): 53-63. PMID 33061185
16. Corpataux N, Winkel MG, Kassar M, et al. The PASCAL Device-Early Experience with a Leaflet Approximation Device: What Are the Benefits/Limitations Compared with the MitraClip?. Curr Cardiol Rep. Jun 27 2020; 22(8): 74. PMID 32594261
17. Siminiak T, Wu JC, Haude M, et al. Treatment of functional mitral regurgitation by percutaneous annuloplasty: results of the TITAN Trial. Eur J Heart Fail. Aug 2012; 14(8): 931-8. PMID 22613584
18. Harnek J, Webb JG, Kuck KH, et al. Transcatheter implantation of the MONARC coronary sinus device for mitral regurgitation: 1-year results from the EVOLUTION phase I study (Clinical Evaluation of the Edwards Lifesciences Percutaneous Mitral Annuloplasty System for the Treatment of Mitral Regurgitation). JACC Cardiovasc Interv. Jan 2011; 4(1): 115-22. PMID 21251638
19. Food and Drug Administration. Summary of Safety and Effectiveness Data (SSED): Mitral Valve Repair Device. 2013; https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100009b.pdf. Accessed March 15, 2024.
20. Food and Drug Administration. Summary of Safety and Effectiveness Data (SSED): Mitral Valve Repair Device. 2022; https://www.accessdata.fda.gov/cdrh_docs/pdf22/P220003B.pdf. Accessed March 14, 2024.
21. Lim DS, Smith RL, Gillam LD, et al. Randomized Comparison of Transcatheter Edge-to-Edge Repair for Degenerative Mitral Regurgitation in Prohibitive Surgical Risk Patients. JACC Cardiovasc Interv. Dec 26 2022; 15(24): 2523-2536. PMID 36121247
22. ClinicalTrials.gov. Edwards PASCAL CLASP IID/IIF Pivotal Clinical Trial (CLASP IID/IIF) (NCT03706833). 2023; https://clinicaltrials.gov/ct2/show/NCT03706833. Accessed March 15, 2024.
23. Zahr F, Smith RL, Gillam LD, et al. One-Year Outcomes From the CLASP IID Randomized Trial for Degenerative Mitral Regurgitation. JACC Cardiovasc Interv. Oct 26 2023. PMID 37962288
24. Reichenspurner H, Schillinger W, Baldus S, et al. Clinical outcomes through 12 months in patients with degenerative mitral regurgitation treated with the MitraClip® device in the ACCESS-EUrope Phase I trial. Eur J Cardiothorac Surg. Oct 2013; 44(4): e280-8. PMID 23864216
25. Lim S, Kar S, Fail P, et al. The EVEREST II high surgical risk cohort: effectiveness of transcatheter reduction of significant mitral regurgitation in high surgical risk patients. J Am Coll Cardiol. 2013;61(10 Suppl):E1958.
26. Lim DS, Reynolds MR, Feldman T, et al. Improved functional status and quality of life in prohibitive surgical risk patients with degenerative mitral regurgitation after transcatheter mitral valve repair. J Am Coll Cardiol. Jul 15 2014; 64(2): 182-92. PMID 24184254
27. Ware J, Kosinski M, Bjorner JB, et al. User's Manual for the SF-36v2 Health Survey (2nd Ed). Lincoln, RI: QualityMetric; 2007.
28. Sorajja P, Mack M, Vemulapalli S, et al. Initial Experience With Commercial Transcatheter Mitral Valve Repair in the United States. J Am Coll Cardiol. Mar 15 2016; 67(10): 1129-1140. PMID 26965532
29. Sorajja P, Vemulapalli S, Feldman T, et al. Outcomes With Transcatheter Mitral Valve Repair in the United States: An STS/ACC TVT Registry Report. J Am Coll Cardiol. Nov 07 2017; 70(19): 2315-2327. PMID 29096801
30. Glower DD, Kar S, Trento A, et al. Percutaneous mitral valve repair for mitral regurgitation in high-risk patients: results of the EVEREST II study. J Am Coll Cardiol. Jul 15 2014; 64(2): 172-81. PMID 25011722
31. Gerçek M, Roder F, Rudolph TK, et al. PASCAL mitral valve repair system versus MitraClip: comparison of transcatheter edge-to-edge strategies in complex primary mitral regurgitation. Clin Res Cardiol. Dec 2021; 110(12): 1890-1899. PMID 33837469
32. Hausleiter J, Lim DS, Gillam LD, et al. Transcatheter Edge-to-Edge Repair in Patients With Anatomically Complex Degenerative Mitral Regurgitation. J Am Coll Cardiol. Feb 07 2023; 81(5): 431-442. PMID 36725171
33. Feldman T, Kar S, Rinaldi M, et al. Percutaneous mitral repair with the MitraClip system: safety and midterm durability in the initial EVEREST (Endovascular Valve Edge-to-Edge REpair Study) cohort. J Am Coll Cardiol. Aug 18 2009; 54(8): 686-94. PMID 19679246
34. Chan PH, She HL, Alegria-Barrero E, et al. Real-world experience of MitraClip for treatment of severe mitral regurgitation. Circ J. 2012; 76(10): 2488-93. PMID 22785461
35. Whitlow PL, Feldman T, Pedersen WR, et al. Acute and 12-month results with catheter-based mitral valve leaflet repair: the EVEREST II (Endovascular Valve Edge-to-Edge Repair) High Risk Study. J Am Coll Cardiol. Jan 10 2012; 59(2): 130-9. PMID 22222076
36. Wan B, Rahnavardi M, Tian DH, et al. A meta-analysis of MitraClip system versus surgery for treatment of severe mitral regurgitation. Ann Cardiothorac Surg. Nov 2013; 2(6): 683-92. PMID 24349969
37. Bail DH, Doebler K. The MitraClip System: a systematic review of indications, procedural requirements, and guidelines. Thorac Cardiovasc Surg. Feb 2014; 62(1): 18-25. PMID 24297637
38. Estévez-Loureiro R, Franzen O, Winter R, et al. Echocardiographic and clinical outcomes of central versus noncentral percutaneous edge-to-edge repair of degenerative mitral regurgitation. J Am Coll Cardiol. Dec 24 2013; 62(25): 2370-2377. PMID 24013059
39. Grasso C, Ohno Y, Attizzani GF, et al. Percutaneous mitral valve repair with the MitraClip system for severe mitral regurgitation in patients with surgical mitral valve repair failure. J Am Coll Cardiol. Mar 04 2014; 63(8): 836-8. PMID 24161329
40. Munkholm-Larsen S, Wan B, Tian DH, et al. A systematic review on the safety and efficacy of percutaneous edge-to-edge mitral valve repair with the MitraClip system for high surgical risk candidates. Heart. Mar 2014; 100(6): 473-8. PMID 23813844
41. Swaans MJ, Bakker AL, Alipour A, et al. Survival of transcatheter mitral valve repair compared with surgical and conservative treatment in high-surgical-risk patients. JACC Cardiovasc Interv. Aug 2014; 7(8): 875-81. PMID 25147032
42. Philip F, Athappan G, Tuzcu EM, et al. MitraClip for severe symptomatic mitral regurgitation in patients at high surgical risk: a comprehensive systematic review. Catheter Cardiovasc Interv. Oct 01 2014; 84(4): 581-90. PMID 24905665
43. Vakil K, Roukoz H, Sarraf M, et al. Safety and efficacy of the MitraClip® system for severe mitral regurgitation: a systematic review. Catheter Cardiovasc Interv. Jul 01 2014; 84(1): 129-36. PMID 24323764
44. Bail DH. (Meta)-analysis of safety and efficacy following edge-to-edge mitral valve repair using the MitraClip system. J Interv Cardiol. Feb 2015; 28(1): 69-75. PMID 25689550
45. Velazquez EJ, Samad Z, Al-Khalidi HR, et al. The MitraClip and survival in patients with mitral regurgitation at high risk for surgery: A propensity-matched comparison. Am Heart J. Nov 2015; 170(5): 1050-1059.e3. PMID 26542516
46. Hayashida K, Yasuda S, Matsumoto T, et al. AVJ-514 Trial　- Baseline Characteristics and 30-Day Outcomes Following MitraClip ® Treatment in a Japanese Cohort. Circ J. Jul 25 2017; 81(8): 1116-1122. PMID 28321004
47. Srinivasan A, Brown J, Ahmed H, et al. PASCAL repair system for patients with mitral regurgitation: A systematic review. Int J Cardiol. Apr 01 2023; 376: 108-114. PMID 36681242
48. 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. Aug 2020; 78: 107-112. PMID 32094019
49. Szerlip M, Spargias KS, Makkar R, et al. 2-Year Outcomes for Transcatheter Repair in Patients With Mitral Regurgitation From the CLASP Study. JACC Cardiovasc Interv. Jul 26 2021; 14(14): 1538-1548. PMID 34020928
50. Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter Mitral-Valve Repair in Patients with Heart Failure. N Engl J Med. Dec 13 2018; 379(24): 2307-2318. PMID 30280640
51. Mack MJ, Lindenfeld J, Abraham WT, et al. 3-Year Outcomes of Transcatheter Mitral Valve Repair in Patients With Heart Failure. J Am Coll Cardiol. Mar 02 2021; 77(8): 1029-1040. PMID 33632476
52. Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation. N Engl J Med. Dec 13 2018; 379(24): 2297-2306. PMID 30145927
53. Iung B, Armoiry X, Vahanian A, et al. Percutaneous repair or medical treatment for secondary mitral regurgitation: outcomes at 2 years. Eur J Heart Fail. Dec 2019; 21(12): 1619-1627. PMID 31476260
54. Stone GW, Abraham WT, Lindenfeld J, et al. Five-Year Follow-up after Transcatheter Repair of Secondary Mitral Regurgitation. N Engl J Med. Jun 01 2023; 388(22): 2037-2048. PMID 36876756
55. Atianzar K, Zhang M, Newhart Z, et al. Why Did COAPT Win While MITRA-FR Failed? Defining the Appropriate Patient Population for MitraClip. Interv Cardiol. Feb 2019; 14(1): 45-47. PMID 30858892
56. Nishimura RA, Bonow RO. Percutaneous Repair of Secondary Mitral Regurgitation - A Tale of Two Trials. N Engl J Med. Dec 13 2018; 379(24): 2374-2376. PMID 30575469
57. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Card Fail. Aug 2017; 23(8): 628-651. PMID 28461259
58. Baumgartner H, Falk V, Bax JJ, et al. 2017 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. Sep 21 2017; 38(36): 2739-2791. PMID 28886619
59. Orban M, Rottbauer W, Williams M, et al. Transcatheter edge-to-edge repair for secondary mitral regurgitation with third-generation devices in heart failure patients - results from the Global EXPAND Post-Market study. Eur J Heart Fail. Mar 2023; 25(3): 411-421. PMID 36597850
60. Takagi H, Ando T, Umemoto T. A review of comparative studies of MitraClip versus surgical repair for mitral regurgitation. Int J Cardiol. Feb 01 2017; 228: 289-294. PMID 27865200
61. Feldman T, Foster E, Glower DD, et al. Percutaneous repair or surgery for mitral regurgitation. N Engl J Med. Apr 14 2011; 364(15): 1395-406. PMID 21463154
62. Mauri L, Garg P, Massaro JM, et al. The EVEREST II Trial: design and rationale for a randomized study of the evalve mitraclip system compared with mitral valve surgery for mitral regurgitation. Am Heart J. Jul 2010; 160(1): 23-9. PMID 20598968
63. 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
64. 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
65. McCarthy PM, Whisenant B, Asgar AW, et al. Percutaneous MitraClip Device or Surgical Mitral Valve Repair in Patients With Primary Mitral Regurgitation Who Are Candidates for Surgery: Design and Rationale of the REPAIR MR Trial. J Am Heart Assoc. Feb 21 2023; 12(4): e027504. PMID 36752231
66. 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
67. Witte KK, Lipiecki J, Siminiak T, et al. The REDUCE FMR Trial: A Randomized Sham-Controlled Study of Percutaneous Mitral Annuloplasty in Functional Mitral Regurgitation. JACC Heart Fail. Nov 2019; 7(11): 945-955. PMID 31521683
68. Khan MS, Siddiqi TJ, Butler J, et al. Functional outcomes with Carillon device over 1 year in patients with functional mitral regurgitation of Grades 2+ to 4+: results from the REDUCE-FMR trial. ESC Heart Fail. Apr 2021; 8(2): 872-878. PMID 33619896
69. 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
70. Yildiz M, Haude M, Sievert H, et al. The CINCH-FMR postmarket registry: Real-world long-term outcomes with percutaneous mitral valve repair with the Carillon Mitral Contour System®. Cardiovasc Revasc Med. Mar 2024; 60: 35-40. PMID 37838620
71. Hell MM, Wild MG, Baldus S, et al. Transapical Mitral Valve Replacement: 1-Year Results of the Real-World Tendyne European Experience Registry. JACC Cardiovasc Interv. Mar 11 2024; 17(5): 648-661. PMID 38385922
72. Zhou J, Li Y, Chen Z, et al. Transcatheter mitral valve replacement versus redo surgery for mitral prosthesis failure: A systematic review and meta-analysis. Front Cardiovasc Med. 2022; 9: 1058576. PMID 36741847
73. Ismayl M, Abbasi MA, Mostafa MR, et al. Meta-Analysis Comparing Valve-in-Valve Transcatheter Mitral Valve Replacement Versus Redo Surgical Mitral Valve Replacement in Degenerated Bioprosthetic Mitral Valve. Am J Cardiol. Feb 15 2023; 189: 98-107. PMID 36521415
74. Szlapka M, Hausmann H, Timm J, et al. Transcatheter mitral valve implantation versus conventional redo surgery for degenerated mitral valve prostheses and rings in a multicenter registry. J Thorac Cardiovasc Surg. Mar 2024; 167(3): 957-964. PMID 36088142
75. Simard T, Lloyd J, Crestanello J, et al. Five-year outcomes of transcatheter mitral valve implantation and redo surgery for mitral prosthesis degeneration. Catheter Cardiovasc Interv. Apr 2022; 99(5): 1659-1665. PMID 35019211
76. Gill J, Zahra F, Retzer E. In-Hospital Outcomes and Predictors of Mortality for Redo Surgical Mitral Valve Replacement Versus Transcatheter Mitral Valve-in-Valve Replacement. Am J Cardiol. Aug 01 2022; 176: 89-95. PMID 35644696
77. Murzi M, Cerillo AG, Gasbarri T, et al. Antegrade and retrograde perfusion in minimally invasive mitral valve surgery with transthoracic aortic clamping: a single-institution experience with 1632 patients over 12 years. Interact Cardiovasc Thorac Surg. Mar 01 2017; 24(3): 363-368. PMID 28040754
78. Kamioka N, Babaliaros V, Morse MA, et al. Comparison of Clinical and Echocardiographic Outcomes After Surgical Redo Mitral Valve Replacement and Transcatheter Mitral Valve-in-Valve Therapy. JACC Cardiovasc Interv. Jun 25 2018; 11(12): 1131-1138. PMID 29929633
79. Zubarevich A, Szczechowicz M, Arjomandi Rad A, et al. Mitral surgical redo versus transapical transcatheter mitral valve implantation. PLoS One. 2021; 16(8): e0256569. PMID 34432834
80. Zahid S, Ullah W, Hashem AM, et al. Transcatheter valve-in-valve implantation versus redo surgical mitral valve replacement in patients with failed mitral bioprostheses. EuroIntervention. Nov 18 2022; 18(10): 824-835. PMID 36106346
81. Akodad M, Trpkov C, Cheung A, et al. Valve-in-Valve Transcatheter Mitral Valve Replacement: A Large First-in-Human 13-Year Experience. Can J Cardiol. Dec 2023; 39(12): 1959-1970. PMID 37625668
82. Wilbring M, Petrov A, Arzt S, et al. Long-Term Outcomes after Transcatheter Mitral Valve-in-Valve or Valve-in-Ring Procedures. J Pers Med. May 08 2023; 13(5). PMID 37240973
83. Schamroth Pravda N, Mishaev R, Levi A, et al. Five-Year Outcomes of Patients With Mitral Structural Valve Deterioration Treated With Transcatheter Valve in Valve Implantation - A Single Center Prospective Registry. Front Cardiovasc Med. 2022; 9: 883242. PMID 35557522
84. Guerrero ME, Eleid MF, Wang DD, et al. 5-Year Prospective Evaluation of Mitral Valve-in-Valve, Valve-in-Ring, and Valve-in-MAC Outcomes: MITRAL Trial Final Results. JACC Cardiovasc Interv. Sep 25 2023; 16(18): 2211-2227. PMID 37758379
85. Whisenant B, Kapadia SR, Eleid MF, et al. One-Year Outcomes of Mitral Valve-in-Valve Using the SAPIEN 3 Transcatheter Heart Valve. JAMA Cardiol. Nov 01 2020; 5(11): 1245-1252. PMID 32745164
86. Simonato M, Whisenant B, Ribeiro HB, et al. Transcatheter Mitral Valve Replacement After Surgical Repair or Replacement: Comprehensive Midterm Evaluation of Valve-in-Valve and Valve-in-Ring Implantation From the VIVID Registry. Circulation. Jan 12 2021; 143(2): 104-116. PMID 32975133
87. Yoon SH, Whisenant BK, Bleiziffer S, et al. Outcomes of transcatheter mitral valve replacement for degenerated bioprostheses, failed annuloplasty rings, and mitral annular calcification. Eur Heart J. Feb 01 2019; 40(5): 441-451. PMID 30357365
88. Urena M, Brochet E, Lecomte M, et al. Clinical and haemodynamic outcomes of balloon-expandable transcatheter mitral valve implantation: a 7-year experience. Eur Heart J. Jul 21 2018; 39(28): 2679-2689. PMID 29788044
89. U.S. Food and Drug Administration (FDA). Edwards Sapein 3 Transcatheter Heart Valve, Summary of Safety and Effectiveness Data (SSED). 1997; https://www.accessdata.fda.gov/cdrh_docs/pdf14/P140031S028B.pdf. Accessed March 18, 2024.
90. Eleid MF, Wang DD, Pursnani A, et al. 2-Year Outcomes of Transcatheter Mitral Valve Replacement in Patients With Annular Calcification, Rings, and Bioprostheses. J Am Coll Cardiol. Dec 06 2022; 80(23): 2171-2183. PMID 36456047
91. Guerrero M, Pursnani A, Narang A, et al. Prospective Evaluation of Transseptal TMVR for Failed Surgical Bioprostheses: MITRAL Trial Valve-in-Valve Arm 1-Year Outcomes. JACC Cardiovasc Interv. Apr 26 2021; 14(8): 859-872. PMID 33888231
92. Bonow RO, O'Gara PT, Adams DH, et al. 2020 Focused Update of the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. May 05 2020; 75(17): 2236-2270. PMID 32068084
93. 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
94. National Institute for Health and Care Excellence (NICE). Heart valve disease presenting in adults: investigation and management [NG208]. 2021; https://www.nice.org.uk/guidance/ng208/chapter/Recommendations. Accessed March 15, 2024.
95. National Institute for Health and Care Excellence (NICE). Transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis [IPG706]. 2021; https://www.nice.org.uk/guidance/ipg706. Accessed March 17, 2024.
96. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Transcatheter Edge-to-Edge Repair (TEER) for Mitral Valve Regurgitation (20.33). 2021; https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?ncdid=363&ncdver=2&. Accessed March 15, 2024

Codes

Policy History