Coverage Policy Manual
Policy #: 2014017
Category: Medicine
Initiated: September 2014
Last Review: May 2023
  Transcatheter Mitral Valve Repair

Description:
Transcatheter mitral valve repair (TMVR) is an alternative to surgical therapy for mitral regurgitation (MR). MR is a common valvular heart disease that can result from a primary structural abnormality of the mitral valve (MV) complex or a secondary dilatation of an anatomically normal MV due to a dilated left ventricle caused by ischemic or dilated cardiomyopathy. Surgical therapy may be underutilized, particularly in patients with multiple comorbidities, suggesting that there is an unmet need for less invasive procedures for MV repair. One device, MitraClip, has approval from the U.S. Food and Drug Administration for the treatment of severe symptomatic MR due to a primary abnormality of the MV (primary MR) in patients considered at prohibitive risk for surgery and for patients with heart failure and moderate-to-severe or severe symptomatic secondary MR despite the use of maximally tolerated guideline-directed medical therapy.
 
Background
 
MR: Epidemiology and Classification
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 (Chiam, 2011; Fedak, 2008). 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 (Carabello, 2008). MR severity is classified as mild, moderate, or severe disease on the basis of echocardiographic and/or angiographic findings (1+, 2+, and 3-4+ angiographic grade, respectively).
 
Patients with MR generally fall into two 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) (Bonow, 2008). Because the primary cause is a structural abnormality, most cases of primary MR are surgically corrected. Secondary MR results from LV dilatation due to ischemic or dilated cardiomyopathy. This causes the mitral value (MV) leaflets not to coapt or meet in the center (Carabello, 2008). 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.
  
Surgical management
In symptomatic patients with MR, surgery is the main therapy. In most cases, repair of the MV 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 (ACC) and the American Heart Association (AHA) have issued joint guidelines for the surgical management of MV, which are outlined as follows (Otto, 2021):
 
Primary MR
  • In symptomatic patients with severe primary MR (Stage D), mitral valve intervention is recommended irrespective of LV systolic function COR 1 (Strong) LOE B-NR (Moderate, nonrandomized)
  • In asymptomatic patients with severe primary MR and LV systolic dysfunction (LVEF less than or equal to 60%, LVESD greater than or equal to 40 mm) (Stage C2), mitral valve surgery is recommended COR 1 (Strong) LOE B-NR (Moderate, nonrandomized)
  • In patients with severe primary MR for whom surgery is indicated, mitral valve repair is recommended in preference to mitral valve replacement when the anatomic cause of MR is degenerative disease, if a successful and durable repair is possible COR 1 (Strong) LOE B-NR (Moderate, nonrandomized)
  • In asymptomatic patients with severe primary MR and normal LV systolic function (LVEF > or equal to 60% and LVESD > or equal to 40 mm) (Stage C1), mitral valve repair is reasonable when the likelihood of a successful and durable repair without residual MR is >95% with an expected mortality rate of <1%, when it can be performed at a Primary or Comprehensive Valve Center COR 2a (Moderate) LOE B-NR (Moderate, nonrandomized)
  • In asymptomatic patients with severe primary MR and normal LV systolic function (LVEF > 60% and LVESD < 40 mm) (Stage C1) but with a progressive increase in LV size or decrease in EF on > 3 serial imaging studies, mitral valve surgery may be considered irrespective of the probability of a successful and durable repair COR 2b (Weak) LOE C-LD (Limited Data)
  • In severely symptomatic patients (NYHA class III or IV) with primary severe MR and high or prohibitive surgical risk, TEER is reasonable if mitral valve anatomy is favorable for the repair procedure and patient life expectancy is at least 1 year COR 2a (Moderate) LOE B-NR (Moderate, nonrandomized)
  • In symptomatic patients with severe primary MR attributable to rheumatic valve disease, mitral valve repair may be considered at a Comprehensive Valve Center by an experienced team when surgical treatment is indicated, if a durable and successful repair is likely COR 2B (Weak) LOE B-NR (Moderate, nonrandomized)
  • In patients with severe primary MR where leaflet pathology is limited to less than one half the posterior leaflet, mitral valve replacement should not be performed unless mitral valve repair has been attempted at a Primary or Comprehensive Valve Center and was unsuccessful COR 3 Harm (Strong) LOE B-NR (Moderate, nonrandomized)
 
Secondary MR
  • In patients with chronic severe secondary MR related to LV systolic dysfunction (LVEF <50%) who have persistent symptoms (NYHA class II, III, or IV) while on optimal GDMT for HF (Stage D), TEER is reasonable in patients with appropriate anatomy as defined on TEE and with LVEF between 20% and 50%, LVESD <70 mm, and pulmonary artery systolic pressure <70 mmHg COR 2a (Moderate) LOE B-R (Moderate, randomized)
  • In patients with severe secondary MR (Stages C and D), mitral valve surgery is reasonable when CABG is undertaken for the treatment of myocardial ischemia COR 2a (Moderate) LOE B-NR (Moderate, nonrandomized)
  • In patients with chronic severe secondary MR from atrial annular dilation with preserved LV systolic function (LVEF >50%) who have severe persistent symptoms (NYHA class III or IV) despite therapy for HF and therapy for associated AF or other comorbidities (Stage D), mitral valve surgery may be considered COR 2b (Wek) LOE B-NR (Moderate, nonrandomized)
  • In patients with chronic severe secondary MR related to LV systolic dysfunction (LVEF <50%) who have persistent severe symptoms (NYHA class III or IV) while on optimal GDMT for HF (Stage D), mitral valve surgery may be considered COR 2b (Weak) LOE B-NR (Moderate, nonrandomized)
  • In patients with CAD and chronic severe secondary MR related to LV systolic dysfunction (LVEF <50%) (Stage D) who are undergoing mitral valve surgery because of severe symptoms (NYHA class III or IV) that persist despite GDMT for HF, chordal-sparing mitral valve replacement may be reasonable to choose over downsized annuloplasty repair COR 2b (Weak) LOE B-R (Moderate, randomized)
 
The use of standard open MV repair is limited by the requirement for thoracotomy and cardiopulmonary bypass, which may not be tolerated by elderly or debilitated patients due to their underlying cardiac disease or other conditions. In a single-center evaluation of 5,737 patients with severe MR in the U.S., Goel et al found that 53% of patients did not have MV surgery performed, suggesting an unmet need for such patients (Goel, 2013).
 
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 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 (Nishimura, 2017; Vahanian, 2012; Diodato, 2004; Wong, 2005; Mihaljevic, 2007; Smith, 2014).
 
Transcatheter MV Repair
Transcatheter approaches have been investigated to address the unmet need for less invasive MV repair, particularly among patients who face prohibitively high surgical risks due to their ages 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 (Chiam, 2011: Vahanian, 2012). Approaches to MV repair include direct leaflet repair; repair of the mitral annulus via direct annuloplasty or through indirect approaches 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, the MitraClip has the largest body of evidence evaluating its use and has been in use in Europe since 2008 (Minha, 2013). The MitraClip system is a percutaneously deployed device that approximates the open Alfieri edge-to-edge repair approach to treating MR. The delivery system consists of a delivery catheter, a steerable sleeve and the MitraClip device, which is a 4-mm wide clip fabricated from a cobalt-chromium alloy and polypropylene fabric. The MitraClip is deployed via a transfemoral approach, with transseptal puncture used to access the left side of the heart and the MV. Placement of the 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 (Noack, 2020). PASCAL has been in clinical use since 2016 and was approved for use in Europe in 2019 (Corpataux, 2020). The delivery system consists of a 10-mm central spacer that attaches to the MV leaflets by 2 paddles and clasps.
 
Devices for TMRV that use various 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 Inc., Kirkland, WA) and the Monarc™ device (Edwards Lifesciences, Irvine, CA). The CE-marked Carillon Mitral Contour System is comprised of self-expanding proximal and distal anchors connected with a nitinol bridge, with the proximal end coronary sinus ostium and the distal anchor in the great cardiac vein. The size of the connection is controlled by manual pullback on the catheter (CE marked). The Carillon system was evaluated in the Carillon Mitral Annuloplasty Device European Union Study and the follow-up Tighten the Annulus Now study, with further studies planned (Siminiak, 2012). The Monarc system also involves 2 self-expanding stents connected by a nitinol bridge, with one end implanted in the coronary sinus via internal jugular vein and the other end in the great cardiac vein. Several weeks following implantation, a 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 (Hamek, 2011).
 
Direct annuloplasty devices include the Mitralign Percutaneous Annuloplasty System (Mitralign, Tewksury, MA) and the Accucinch® System (Guided Delivery Systems, Santa Clara, CA), both of which involve transcatheter placement of anchors in the MV which are cinched or connected to narrow the mitral annulus. Other transcutaneous direct annuloplasty devices under investigation include the enCorTC™ device (Micardia Corp., Irvine, CA), which involves a percutaneously insertable annuloplasty ring that is adjustable using radiofrequency energy, a variation on its CE-marked enCorsq™ Mitral Valve Repair System, and the Cardioband™ Annuloplasty System (Valtech Cardio Ltd., Or-Yehuda, Israel), an implantable annuloplasty band with a transfemoral venous delivery system.
 
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 (Bonow, 2008; Carabello, 2008). 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 received U.S. Food and Drug Administration (FDA) approval through the premarket approval process. The device received approval 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” (FDA, 2013).
 
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" (FDA, 2022).
 
FDA product code for MitraClip and PASCAL: NKM.
 
Coding
Effective in 2015, there are CPT category I codes for this procedure:
33418 Transcatheter mitral valve repair, percutaneous approach, including transseptal puncture when performed; initial prosthesis
 
33419 additional prosthesis (es) during same session (List separately in addition to code for primary procedure)

Policy/
Coverage:
Effective November 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Transcatheter mitral valve repair with a device approved by the U.S. Food and Drug Administration for use in mitral valve repair (i.e. MitraClip) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for individuals with:
 
        • Heart failure AND moderate to severe symptomatic secondary mitral regurgitation despite the use of maximally tolerated guideline-directed medical therapy; OR  
        • Symptomatic, degenerative mitral regurgitation who are considered at prohibitive risk for open surgery.  “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.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Transcatheter mitral valve repair in all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, transcatheter mitral valve repair in all other situations is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective May 2019 through November 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Transcatheter mitral valve repair with a device approved by the U.S. Food and Drug Administration for use in mitral valve repair (i.e. MitraClip) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for individuals with:
 
        • Heart failure AND moderate to severe symptomatic secondary mitral regurgitation despite the use of maximally tolerated guideline-directed medical therapy; OR  
        • Severe symptomatic secondary mitral regurgitation despite the use of maximally tolerated guideline-directed medical therapy; OR
        • Symptomatic, degenerative mitral regurgitation who are considered at prohibitive risk for open surgery.  “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.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Transcatheter mitral valve repair in all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, transcatheter mitral valve repair in all other situations is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to May 2019
  
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Transcatheter mitral valve repair with a device approved by the U.S. Food and Drug Administration  for use in mitral valve repair meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for patients with symptomatic, degenerative mitral regurgitation who are considered at prohibitive risk for open surgery.
 
“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.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Transcatheter mitral valve repair in all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, transcatheter mitral valve repair in all other situations is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to April 2018
 
Transcatheter mitral valve repair does not meet member benefit certificate primary coverage criteria in any situation.
 
For members with contracts without primary coverage criteria, transcatheter mitral valve repair is considered investigational in all situations. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 

Rationale:
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2018. Following is a summary of the key literature identified.
 
The literature search for this policy focused primarily on studies evaluating the MitraClip, but evidence related to other devices is briefly discussed. Assessment of efficacy for therapeutic interventions such as the MitraClip involves a determination of whether the intervention improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes, but are prone to biases. For the MitraClip, the appropriate comparison group could be either open surgical repair (for surgical candidates) or best medical therapy (among persons at prohibitive surgical risk.
 
There are 2 major categories of patients with mitral regurgitation (MR) who are potential candidates for transcatheter MV repair: those who are considered to be at prohibitively high risk for cardiac surgery and those who are surgical candidates. Studies addressing these 2 subsets of patients are outlined separately. Although outcomes and etiology differ for functional MR (FMR) and DMR, studies on the MitraClip most often evaluate the device in mixed populations.
 
MITRACLIP IN PROHIBITIVE SURGICAL RISK CANDIDATES
The MitraClip device delivery system has FDA approval for use in patients with DMR who are not candidates for open surgery. There are no controlled trials of MitraClip in this population. Available studies include multiple cohort studies and case series, the largest of which are the EVEREST II HRR and the EVEREST II Real World Expanded Multi-center Study of the MitraClip System (REALISM) studies. Systematic reviews of these uncontrolled studies have also been published.
 
Systematic Reviews
A 2014 TEC Assessment evaluated the evidence on the use of MitraClip for DMR, the FDA-approved Indication (BCBSA, TEC, 2014). The Assessment included 5 case series reporting outcomes of patients with DMR considered at high risk of surgical mortality who underwent MitraClip placement. In the 2 studies the Assessment considered higher quality, 30-day mortality rates were 6.0% and 6.3%, and 12- to 25-month mortality rates were 17.1% and 23.6%, respectively. In evaluable patients at 12 months, the percentage of patients who had an MR grade of 2 or less was 83.3% and 74.6% in the 2 studies; the percentage of patients with New York Heart Association (NYHA) class I or II functional status was 81% and 87%; and improvement of at least 1 NYHA class was present in 68% and 88% of patients, respectively.
 
The Assessment reviewed evidence on the natural history of patients with MR who were considered  at high risk for surgery in an attempt to determine an appropriate comparison group for the uncontrolled case series of MitraClip in high surgical risk patients. The evidence included 1 published study by Whitlow et al (2012)  and data presented to FDA as part of the device’s premarket approval application. The TEC Assessment concluded that these control groups may not provide unbiased or precise estimates of the natural history of patients eligible to receive MitraClip because most patients were not evaluated for anatomic eligibility for MitraClip or were ineligible. As such, the control groups likely had higher mortality rates than patients eligible to receive MitraClip.
 
Due to the lack of an appropriate control group or clear evidence about the natural history of patients with DMR considered at high risk for surgery, the Assessment concluded that it cannot be determined whether the mortality rate associated with MitraClip use was improved, equivalent, or worse than medical treatment.
 
Also in 2014, Philip et al reported on results of a systematic review of studies evaluating MitraClip or surgical mitral valve (MV) repair or replacement for severe symptomatic MR in patients at high surgical risk (logistic EuroSCORE >18 or Society for Thoracic Surgeons [STS] score >10).
 
Reviewers included 21 studies that used MitraClip (n=3198 patients) and surgical MV repair (n=490)  or MV replacement (n=2775). MitraClip patients had a mean STS score of 14 and a mean EuroSCORE of 23. Acute procedural success did not differ significantly between groups. However, the 30-day pooled technical failure rate was 3.2% (95% confidence interval [CI], 1.5% to 7%) for    MitraClip patients compared with 0.6% (95% CI, 0.2% to 1.8%) for surgical repair/replacement patients (p=0.002). In pooled analysis, the 30-day mortality rate was 3% (95% CI, 2.6% to 4.2%) among MitraClip patients and 16% (95% CI, 13% to 20%) in surgical repair/replacement patients. Of the total sample, 1-year data were available for 1064 MitraClip patients (1-year data for surgical repair patients, limited to 47 patients, was not reported). Overall, among MitraClip patients, the 1-year mortality rate was 13.0% (95% CI, 9% to 18.3%), the 1-year stroke rate was 1.6% (95% CI, 0.8% to 3.2%), and the need for repeat MV surgery was 1.3% (95% CI, 0.7% to 2.6%).
 
A systematic review by Munkholm-Larsen et al. (2013) summarized safety and efficacy results from  12 publications evaluating the efficacy of the MitraClip in surgically high-risk patients. The authors included studies that evaluated high-risk surgical patients with significant MR who underwent transcatheter MR repair with the MitraClip device, and excluded studies that included surgical candidates. All studies were prospective observational studies from specialized tertiary centers, with   3 multicenter studies and 9 single-institution studies. The 3 largest studies included 202, 117, and 100 patients, while the rest included fewer than 100 patients. Follow-up duration ranged from 1 month to  14 months. Across the studies, 30-day mortality rates ranged from 0% to 7.8%. Most of the high surgical risk patients had successful reduction of MR of grade 2+ or less (73%-100% across studies). In studies that reported follow-up at 6 to 12 months, 61% to 99% of patients demonstrated continued MR reduction of grade 2+ or less, and 50% to 89% of patients demonstrated improvements in NYHA functional class to I to II. This systematic review suggests that the MitraClip is associated with short- term improvements in echocardiographic parameters among high surgical-risk patients, but does not provide evidence on clinical outcomes. Longer term follow-up studies are limited. In addition, most studies included both FMR and DMR, which limits the ability to assess outcomes stratified by etiology.
 
Several systematic reviews have focused on safety of MitraClip. Bail et al (2015) reported results of a systematic review and meta-analysis of the safety and efficacy of MitraClip placement, which included 26 studies (3821 patients). Within the first 30 days postprocedure, 3.5% (95% CI, 2.9% to 4.2%) required open MV repair, 18.3% (95% CI 17.0% to 19.6%) experienced an adverse event, and 2.8% (95% CI, 2.3% to 4.4%) died. At 6 months, 4.5% (95% CI, 15.1% to 24.1%) required open MV repair, 18.9% (95% CI, 15.1% to 24.1%) experienced an adverse event, and the all-cause mortality rate was 11.9% (95% CI, 10.3 to 14.2%). By 12 months, 11.4% (95% CI, 9.6% to 13.5%) required open repair,and the all-cause mortality rate was 17.4% (95% CI, 15.1% to 18.9%).
 
Vakil et al (2014) reported results of a systematic review of the safety and efficacy of the MitraClip system for moderate-to-severe or severe FMR or DMR; it included 16 studies (2980 patients). Based on calculated STS score, EuroSCORE, or the surgeon’s discretion, 2689 patients in 14 studies were considered high risk for surgery and 291 patients in 2 studies were considered low risk for surgery. The pooled 30-day mortality rate (primary safety outcome) was 4.2%. During a mean follow-up of 310 days (range, 80 days to 4 years), 387 of 2457 (15.8%) deaths occurred. In the 8 studies reporting the cause of death, the pooled incidence of cardiac mortality was 3.7%.
 
Randomized Controlled Trials
No RCTs have been published evaluating MitraClip in prohibitive surgical risk populations.
 
Nonrandomized Comparative Studies
Swaans et al (2014) reported results of a study comparing survival for MR patients considered at high surgical risk who underwent MitraClip placement with high-risk patients who had conservative management and with patients who had surgical repair. MitraClip-treated patients (n=139) included those treated at a single institution with MitraClip for symptomatic MR whose high surgical risk was based on a logistic EuroSCORE of at least 20, or who were denied surgery based on additional  factors associated with increased mortality, as judged by the heart team. These patients were compared with a retrospectively defined cohort of patients with MR and indications for MV repair treated at the same institution in the 2 years prior to MitraClip availability who were treated with either conservative management (n=59) or opensurgery (n=38). At baseline, patients treated with MitraClip had a higher logistic EuroSCORE than the other 2 groups (23.9 with MitraClip vs 14.2 with surgical repair vs 18.7 with conservative treatment; p<0.001). Rates of coronary artery disease and previous coronary artery bypass grafting were higher in the MitraClip group as well. At 1-year follow-up, survival rates were 85.8%, 82.2%, and 67.75% in the MitraClip, open surgery, and conservatively treated groups, respectively. Survival rates for the transcatheter MV repair group were 75.5% and 62.3% after 2 and 3 years, respectively.
 
Single-Arm Studies
EVEREST High Risk Registries.
Concurrently with the EVEREST II RCT, described below, investigators enrolled patients into the EVEREST II HRR Study who were deemed ineligible for surgery due to prohibitively high surgical risks. In addition, a continued access study, EVEREST II REALISM, which included a high-risk and a non-high-risk arm, was conducted. For inclusion in the EVEREST II HRR, patients were considered high surgical risk if either their Society of Thoracic Surgeons (STS) predicted operative mortality risk was 12% or higher or the surgeon investigator determined the patient to be high risk (• 12% predicted operative mortality risk) due to the presence of 1 of several prespecified risk factors. Patients were excluded from the registry if they had LVEF less than 20%, left ventricular end-systolic diameter (LVESD) greater than 60 mm, MV orifice area less than 4 cm2, or leaflet anatomy that might preclude MitraClip device implantation and/or proper MitraClip device positioning and/or sufficient reduction in MR. The REALISM registry high-risk arm had the same inclusion criteria as the EVEREST II HRR.
 
In 2014, Lim et al. published outcomes from transcatheter MV repair with the MitraClip among high- surgical-risk patients with DMR who were included in the EVEREST II HRR and REALISM registries. For this analysis, prohibitive risk for surgical repair of DMR was defined as the presence of 1 or more of the following documented surgical risk factors: STS Risk Calculator predicted risk of 30-day mortality for MV replacement of 8% or greater, porcelain aorta or extensively calcified ascending aorta, frailty (assessed by • 2 indices), hostile chest, severe liver disease or cirrhosis, severe pulmonary hypertension, severe pulmonary hypertension, or an “unusual extenuating circumstance” (eg, RV dysfunction with severe tricuspid regurgitation, chemotherapy for malignancy, major bleeding diathesis, AIDS, severe dementia). One hundred forty-one patients with severe (• 3+) DMR who met the definition of prohibitive surgical risk were identified, 127 of whom had follow-up data available at 1 year. Of these, 25 patients were from the EVEREST II HRR, 98 were from the high-risk arm of the REALISM Continued Access study, and 4 were treated under compassionate use and met the definition of prohibitive risk and all MV anatomic criteria for entry. At baseline, patients had poor functional status, with 87% in NYHA functional status class III/IV.
 
The MitraClip was successfully placed in 95.3% of patients. Thirty-day and 12-month mortality rates were 6.3% and 23.6%, respectively. The MitraClip reduced MR to grade 2+ or less in 86.1% of patients with baseline MR of 3+ and in 68.4% of patients with baseline MR of 4+. Fifty-eight percent of   patients with 3+ MR at baseline and 36.8% of patients with 4+ MR at baseline had MR reduced to 1+. Of 91 patients who had procedural reduction of MR to grade 2+ or less, 64 patients (70.3%) had sustained MR 2+ or less at 1 year, 10 (11.0%) experienced worsening MR to 3+ or 4+, and 17 (18.7%) died. Of 59 patients who had a procedural reduction of MR to grade 1 or less, 21 patients (35.6%) had sustained MR • 1+ at 1 year, 20(33.9%) had an increase in MR grade to 2+, 8 (13.6%) had an increase in MR grade to 3+ or 4+, and 10 (16.9%) died. There were no significant differences in 12-month survival between those who were discharged with an MR grade of • 1+ compared with those the with an MR grade of 2+. At 1 year, 30.6% of the 98 patients with baseline NYHA functional class III or IV had an improvement of at least 2 classes. In this high surgical risk population, the MitraClip use was associated with a relatively low rate of procedural complications and a high rate of short-term improvements in MR grade to 2+ or less, along with improvements in functional status.
 
However, a major limitation of this trial is the lack of a control group. In addition, the cohort of high- risk patients with DMR were retrospectively identified, so all analyses were post hoc. There are questions about the validity of combining registry data from 2 separate registries that were collected over different time periods, along with the consistency of the inclusion criteria measures, as the STS surgical risk calculator changed over time.
 
Glower et al (2014), reported 12-month results for MitraClip use in the first 351 patients enrolled in either the Everest HRR (N=78) or high-risk patients in the REALISM study (n=273), which had previously been presented to FDA. Seventy percent of patients had FMR. Following MitraClip implantation, 325 patients (86%) had MR reduced 2+ or less. At 12 months, 225 patients (84%) had MR of 2+ or less. By Kaplan- Meier analysis, survival at 12 months was 77.2%. Patients had improvements in quality of life scores and NYHA functional class.
 
In 2015, Velasquez et al published an industry-sponsored analysis comparing outcomes in patients from the Everest HRR and Everest REALISM registries who were matched with patients who were treated nonsurgically.31 The investigators used propensity score matching to create groups with characteristics as similar as possible. In the optimal matched cohorts (239 high-risk MitraClip   patients, 239 high-risk nonsurgical patients), baseline characteristics were similar for all but 3 variables: MR etiology, LV internal dimensions, and STS score. Among patients in the optimally matched cohorts, Kaplan-Meier 1-year mortality estimates were significantly lower in the MitraClip group (22.4%) than in the nonsurgical control group (32.0%; adjusted hazard ratio [HR], 0.66; 95% CI, 0.45 to 0.99). Thirty-day mortality in the optimally matched cohorts was 4.2% in the MitraClip group and 7.2% in the nonsurgical group (HR and p value not reported).
 
Transcatheter Valve Therapy Registry
STS and American College of Cardiology’s (ACC) Transcatheter Valve Therapy (TVT) registry includes patients who have had TMVR after initial FDA approval of MitraClip. Data on 564 patients, treated between November 2013 and August 2014 in the registry, were published by Sorajja et al in 2016.27 All patients had symptomatic primary MR and were at prohibitive surgical risk. All were treated at 1 of 61 hospitals, 42 of which had experience with the treatment prior to FDA approval. Postimplantation MR grade of 2 or less and no open heart surgery occurred in 514 (93.1%) of 526 patients. There were 13 (2.3%) in-hospital deaths and the 30-day mortality rate was 5.8% (26 deaths). Procedural success, defined as a reduction to MR grade 2 or less in the absence of cardiac surgery or in-hospital mortality, was 90.6%.
 
 
Section Summary: MitraClip in Prohibitive Surgical Risk Candidates
The evidence for the use of MitraClip among patients who are not considered surgical candidates consists primarily of single-arm cohort studies. The available single-arm studies include the pivotal EVEREST II HRR and EVEREST II REALISM trials. These studies demonstrate that MitraClip implantation is feasible, with high rates (on the order of at least 70% to 90%) of short-term reductions in MR grade to 2+ or less, and has a reasonable safety profile. The TVT registry of patients treated in the United States after the MitraClip became commercially available had findings similar to the EVEREST trials. Moreover, an analysis matching patients in the EVEREST registries to similar nonsurgically treated patients found significantly lower 1-year morality rates in MitraClip-treated patients.
 
MITRACLIP IN SURGICAL CANDIDATES
 
Systematic Reviews
A 2017 systematic review by Takagi et al identified 1 RCT and 6 nonrandomized comparative studies evaluating MitraClip and surgery.28 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=0.08). Similarly, a pooled analysis of late survival (• 6 months) did not find a statistically significant difference between the MitraClip and surgery groups (pooled OR/HR, 1.17; 95% CI, 0.77 to 1.78; p=0.46). However, there was a significantly higher incidence of recurrent MR in the MitraClip than in the surgery group (pooled OR/HR, 4.80; 95% CI, 2.58 to 8.93; p<0.001).
 
Randomized Controlled Trials
One RCT evaluating use of MitraClip in surgical candidates has been published. The multicenter EVEREST II trial was designed to evaluate the efficacy of TMVR with MitraClip compared with open MV repair (Feldman, 2011; Mauri, 2010). Eligible patients had grade 3+ or 4+ MR and were all  candidates for MV repair surgery. Symptomatic patients were required to have left ventricular ejection fraction (LVEF) of more than 25% and a LVESD of 55 mm or less; asymptomatic patients were required to have at least 1 of the following: LVEF of 25% to 60%; LVESD of 40 to 55 mm; new atrial fibrillation; or pulmonary hypertension. Patients were excluded if they had a MV orifice area less than 4.0 cm or leaflet anatomy that may have precluded MitraClip device implantation, proper MitraClip positioning, or sufficient reduction in MR. Two hundred seventy-nine patients were randomized in a 2:1 ratio to transcatheter repair (184 patients) or standard MV surgery (95 patients).
 
The composite primary safety end point was major adverse events at 30 days, defined as freedom from death, myocardial infarction, non-elective cardiac surgery for adverse events, renal failure, transfusion of2 or more units of blood, reoperation for failed surgery, stroke, gastrointestinal complications requiring surgery, ventilation for 48 or more hours, deep wound infection, septicemia, and new onset of permanent atrial fibrillation. The composite primary efficacy end point was freedom from MR 2+ or more, freedom from cardiac surgery for valve dysfunction, and freedom from death at 12 months.
 
MitraClip was considered to have acute procedural success if the clip deployed and MR was reduced to less than 3+. The protocol’s safety and efficacy analyses were reported on both an intention-to- treat (ITT) and a per-protocol basis. In the ITT analyses presented in the main manuscript, crossover to surgery in the immediate post-procedure period if the MitraClip failed to adequately reduce MR is considered a successful treatment strategy. Thus, in the ITT analysis, the efficacy end point was considered met for MitraClip group subjects if they were free from death, reoperation for MR, and MR greater than 2+ at 12 months in patients who did not have acute procedural success (and may have undergone open MV repair) and freedom from death, any MV surgery for MR, and MR greater than 2 + at 12 months for patients who did have acute procedural success. The study had a predetermined efficacy end point 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 is noninferior to surgery at 12 months if the rate of the primary efficacy end point for the MitraClip group is not more than 25 percentage points less than that that in the surgery group (for the ITT analysis).
 
The treatment groups were generally similar, except for the fact that a higher proportion of those in  the MitraClip group had congestive heart failure (167/184 [91%] vs 74/95 [78%], p=0.005). Of 178 patients who were randomized to the MitraClip group and who did not withdraw from the study, 41 (23%) had grade 3+ or 4+ MR before hospital discharge and were referred for immediate surgery, which was performed in 28. On an ITT basis, for the study’s primary combined efficacy end point, rates of freedom from death, MV surgery, and grade 3+/4+ MR at 12 months, were 55% in the MitraClip group and 73% in the surgery group (noninferiority, p=0.007). Rates of death and grade 3+ or 4+ MR at 12 months postprocedure were similar between groups; however, MitraClip group subjects were more likely to require surgery for MV dysfunction, either immediately post-MitraClip implantation or in the 12 months following. Twenty percent (37/181) of the MitraClip group and 2% (2/89) of the surgery group required reoperation for MV dysfunction (p<0.001). Although in the ITT analysis, rates of grade 3+ or 4+ MR at 12 months were similar between groups, in the study’s per- protocol analysis, patients in the MitraClip group were more likely to have grade 3+ or 4+ MR (23/134 [17.2%] vs 3/74 [4.1%], p=0.01), which suggests that a larger proportion of patients with grade 1+ or 2 + MR in the MitraClip group had had surgical repair.
 
Rates of major adverse events at 30 days were lower in the MitraClip group compared with the surgery group (27/181 [15%] vs 45/89 [48%], p<0.001). Rates of transfusion of more than 2 units of blood were the largest component of major adverse events in both groups, occurring in 13% (24/181) of the MitraClip group and 45% (42/89, p<0.001) of the surgery group. In subgroup analysis, there  was significant subgroup interaction between those with FMR compared with those with DMR (p= 0.02) in which patients with DMR had more favorable rates of the primary efficacy end point with surgery.
 
In 2013, Mauri et al. reported results from 4-year follow-up of patients enrolled in the EVEREST II trial.  Of patients randomized to the percutaneous repair group, 161 (885) were included in the 4-year efficacy analysis; of those in the surgery group, 73 (77%) were included in the 4-year efficacy  analysis. The study evaluated several end points, including freedom from death, surgery for MV dysfunction, and 3+ and 4+ MR at 4 years; freedom from surgery for MV dysfunction; and freedom from death. The authors also evaluated interactions between treatment groups and 2 additional variables: age 70 years or older and FMR (vs DMR). At 4 years, 39.8% of those in the MitraClip group (64/161) achieved the primary efficacy end point of freedom from death, surgery for MV dysfunction, and 3+ and 4+ MR, compared with 53.4% (39/73) of the surgical group (p=0.070). However, significantly more MitraClip patients required surgery for MV dysfunction during the follow-up period (24.85 [40/161] in the MitraClip group vs 5.5% [4/73], p<0.001); in the MitraClip group, most of the MV surgery occurred before 12 months. Tests of interaction between age and MR etiology were significant. Among those younger than 70, the difference between rates of the primary efficacy end point between the MitraClip and surgery groups was -28.5% (favoring surgery; 95% confidence  interval [CI], -46% to -10.5%). Among those 70 or older, this difference was 3.3% (favoring MitraClip; 95% CI, -16.4 to 23.0). Among those with DMR, the difference between rates of the primary efficacy end point between the MitraClip and surgery groups was -24.85 (favoring surgery; 95% CI, -40.5 to -9.1). Among those with FMR, this difference was 11.4% (favoring MitraClip; 95% CI, -11.1% to 33.8%). These results suggest that outcomes following MitraClip and surgical repair for MR are similar at 4-year follow-up as they are at 1-year follow-up.
 
Five-year results of EVEREST II were reported by Feldman et al in 2015.37 This analysis included patients who completed the 5-year follow-up visit and had data on their MR grade, or who had died or had MV surgery before withdrawing from the trial. As with the 4-year analysis (described above), significantly more patients in the MitraClip group had MV surgery or reoperation during the follow-up period (27.9%) compared to the surgical group (8.9%; p=0.003). In addition, significantly more   patients in the MitraClip group had grade 3+ or 4+ MR (12.3%) compared with the surgical group (1.8%; p=0.02). The primary outcome was a composite of freedom from death, freedom from surgery for MV dysfunction, and freedom from grade 3+ or 4+ MR. The rate of this composite outcome was 44.2% (68/154) in the MitraClip group and 64.3% (36/56) in the surgical group (p=0.01). The mortality rate did not differ significantly between groups (20.8% in the MitraClip group vs 26.8% in the surgical group; p=0.36). As noted in previous analyses of EVEREST II data, most of the additional surgeries in the MitraClip group occurred early, in the first 6 to 12 months postprocedure. Among patients who were event-free at 1 year, there was no significant difference in the composite outcome at 5 years: 69% (60/87) in the MitraClip group and 75% (36/48) in the surgical group (p=0.55).
 
Nonrandomized Comparative Studies
Several nonrandomized cohort studies have compared outcomes for MR treated with either surgical or TMVR using the MitraClip device. Two studies (Conradi et al, 2013 Taramasso et al, 2012)
included patients with only FMR, while Paranskaya et al, 2013 reported results for a mixed DMR and FMR cohort. These 3 studies were included in the 2013 Wan meta-analysis.
 
In 2016, De Bonis et al published a study designed to verify the finding from the EVEREST II trial that, for patients with an initial positive response to MitraClip, results were sustained at long-term follow-up and were similar to surgery.41 The study included 85 patients with FMR and an initial good result after MitraClip implantation (ie, MR grade • 1 at hospital discharge). Findings were compared with 58 consecutive surgical patients, treated before MitraClip was an option, who also had MR grade of 1 or less at discharge. Patients were followed prospectively and data were entered into a dedicated database. Patients in the 2 groups were comparable at baseline on most variables (eg, NYHA functional class, proportion with atrial fibrillation, LV dimensions); however, age and logistic EuroSCORE were significantly higher in the MitraClip group.
 
At 1 year, echocardiographic prevalence of MR grade of 2 or more was 32.5% in the MitraClip group (p<0.001 within group vs hospital discharge). In addition, among patients in the MitraClip group (n=
53) with MR grade of 1 or less at 12 months, 8 (19%) of 42 with follow-up data had MR progression at least 1 grade at 2 years and 9 (33%) of 27 with follow-up data had MR grade 2 or more at 3 years. Compared with the surgery group, the 4-year freedom from grade 3+ MR (94% vs 75%) and freedom from grade 2+ MR (82% vs 37%) were significantly higher in the surgery group. Overall survival at 4 years was similar between groups, 74% in MitraClip patients and 77% in surgical patients. This analysis is limited by missing data and lack of randomization. However, it does suggest that, at least in this group of MitraClip patients, an initially successful outcome did not prevent progression of MR   over time and that surgery may have greater long-term efficacy for MR control.
 
Section Summary: MitraClip in Surgical Candidates
The evidence for the use of MitraClip in patients who are considered candidates for open MV repair surgery includes 1 RCT (EVEREST II), a systemic review and several comparative and noncomparative cohort studies. The RCT found that, MitraClip was noninferior to open surgery in terms of safety and effectiveness at 1-year follow-up. At the 5-year follow-up, efficacy as assessed by a composite outcome, was significantly higher in the surgery group than in the MitraClip group. In EVEREST II, most patients who had persistent MV dysfunction after MitraClip developed it within the first year postprocedure and, among patients event-free at 1 year, 5-year efficacy did not differ significantly in the MitraClip and surgery groups. EVEREST II had some methodologic limitations. The noninferiority margin of 25% was large, indicating that MitraClip could be somewhat inferior to surgery and the noninferiority margin still met. Crossover to surgery was allowed for patients who had grade 3 + or more MR prior to discharge, and 23% of patients assigned to MitraClip met this criterion. This large rate of crossover would bias results toward the null on intention-to-treat analysis, thus increasing the likelihood of meeting the noninferiority margin. In an analysis by treatment received, this crossover would result in a less severely ill population in the MitraClip group and bias the results in favor of MitraClip. A high proportion of patients required open MV replacement or repair during the first year postprocedure, thus limiting the number of patients who had long-term success without surgical intervention. As a result of these factors, this single trial is not definitive in demonstrating improved clinical outcomes with MitraClip compared with surgery and further RCTs are needed to corroborate these results. A subsequent nonrandomized controlled trial that attempted to verify the findings of EVEREST II did not find the same low rates of long-term MR control in MitraClip patients with an initially positive response to treatment.
 
OTHER TRANSCATHETER MV REPAIR DEVICES
Several devices other than the MitraClip are being investigated for transcatheter MV repair, although none are FDA approved for use in the U.S.
 
Several indirect annuloplasty devices, the Carillon® Mitral Contour System™ (Cardiac Dimension Inc., Kirkland, WA) and the Monarc device (Edwards Lifesciences, Irvine, CA), have been evaluated. A case series evaluating use of the Carillon device in 53 patients with 2+ FMR at 7 European centers was reported in 2012 (Siminiak, 2012). Of the 53 patients who underwent attempted device implantation, 36 underwent permanent implantation and 17 had the device recaptured due to transient coronary compromise in 8 patients and less than 1 grade of FMR reduction in 9 patients.
 
Echocardiographic measures of FMR improved in the implanted groups up through 12-month follow- up, along with improvements in 6-minute walk distance. An earlier feasibility study of the Carillon device in 48 patients with moderate-to-severe FMR demonstrated successful device placement in 30 patients, with 18 patients unable to be implanted due to access issues, insufficient acute FMR reduction, or coronary artery compromise (Schofer, 2009). The Monarc device has been evaluated in a phase 1 safety trial at 8 European centers (Harnek, 2011). Among 72 patients enrolled, the device was successfully implanted in 59 patients (82%). The primary safety end point (freedom from death, tamponade, or myocardial infarction at 30 days) was met in 91% of patients at 30 days and in 82% at 1 year.
 
SUMMARY OF EVIDENCE
For individuals who have symptomatic degenerative mitral regurgitation (DMR) or functional mitral regurgitation (FMR) and are at prohibitive risk for open surgery who receive transcatheter mitral valve repair (TMVR) using MitraClip, the evidence includes primarily single-arm cohort studies. Relevant outcomes are overall survival, morbid events, functional outcomes, and treatment-related morbidity. Several single-arm studies have demonstrated that MitraClip implantation is feasible, with high rates (at least 70% to 90%) of short-term reductions in mitral regurgitation(MR) grade to 2+ or less, and a reasonable safety profile. A nonrandomized analysis matching patients in the EVEREST registries to similar non-surgically-treated patients found significantly lower 1-year morality rates in MitraClip- treated patients. However, the lack of concurrent control groups, especially in randomized trials, makes it difficult to draw conclusions on whether there is a net health benefit compared with alternative therapies in this population. There are no strong barriers to conducting controlled trials, including randomized controlled trials (RCTs) comparing MitraClip to continued medical management. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who have symptomatic DMR or FMR and are surgical candidates who receive TMVR using MitraClip, the evidence includes a systematic review, an RCT, and several comparative and noncomparative cohort studies. Relevant outcomes are overall survival, morbid events, functional outcomes, and treatment-related morbidity. The RCT found that MitraClip was noninferior to open surgery in terms of safety and effectiveness at 1-year follow-up. At 5-year follow-up, efficacy, assessed using a composite outcome, was significantly higher in the surgery group than in the MitraClip group. The RCT had some methodologic limitations, including a wide noninferiority margin and permissibility of crossing over to surgery and still considered to have a positive outcome. This single trial does not definitively demonstrate improved clinical outcomes with MitraClip compared with surgery. Additional Other RCTs are needed to corroborate these results. A subsequent nonrandomized controlled trial, which attempted to verify the findings of the RCT, did not find the same low rates of long-term MR control in MitraClip patients with an initially positive response to treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who have DMR or FMR who receive TMVR using devices other than MitraClip, the evidence includes primarily noncomparative feasibility studies. Relevant outcomes are overall survival, morbid events, functional outcomes, and treatment-related morbidity. The body of evidence     consists only of very small case series and case reports. Controlled studies, preferably RCTs, are needed to draw conclusions about the net health benefit. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Clinical Input Received From Physician Specialty Societies and Academic Medical Centers While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty  societies or academic medical centers, unless otherwise noted.
 
In response to requests, input was received from 4 academic medical centers, one of which provided 4 responses, for a total of 7 responses, while this policy was under review in 2015. The input supported the use of transcatheter MV repair in patients with DMR at prohibitive risk of open surgery. The greatest consensus for selection criteria to determine “prohibitive risk” was for the use of the Society of Thoracic Surgeons predictive operative risk of 12% or higher, or a logistic EuroSCORE of 20% or higher.
 
Practice Guidelines and Position Statements American College of Cardiology and American Heart Association
 
The American College of Cardiology (ACC) and American Heart Association (AHA) released guidelines on the management of valvular heart disease in 2014. The guidelines include the following class IIB recommendation related to the use of transcatheter MV repair for MR:
 
Transcatheter mitral valve repair may be considered for severely symptomatic patients (NYHA class III to IV) with chronic severe primary MR (stage D) who have favorable anatomy for the repair procedure and a reasonable life expectancy but who have a prohibitive surgical risk because of severe comorbidities and remain severely symptomatic despite optimal guideline-directed medical therapy for heart failure. (Level of Evidence: B.)
 
American College of Cardiology, American Association for Thoracic Surgery, et al
The ACC, American Association for Thoracic Surgery, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons released a position statement on transcatheter therapies for MR in 2014. This statement outlines critical components for successful transcatheter MR therapies and recommends ongoing research and inclusion of all patients treated with transcatheter MR therapies in a disease registry.
 
In 2012, the Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery released guidelines on the management of valvular heart disease. These guidelines do not address transcatheter MV repair.
 
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed below:
 
· NCT01841554 - Cardioband With Transfemoral Delivery System; planned enrollment 51; completion date July 2016 (ongoing).
· NCT01920698 - Multicentre Study of Percutaneous Mitral Valve Repair MitraClip Device in Patients With Severe Secondary Mitral Regurgitation (MITRA-FR); planned enrollment 288; completion date October 2017.
· NCT02371512 - A Multicenter, Randomized, Controlled Study to Assess Mitral vAlve reconsTrucTion for advancEd Insufficiency of Functional or iscHemic ORigiN (MATTERHORN); planned enrollment 210; completion date December 2017
· NCT02444338 - A Clinical Evaluation of the Safety and Effectiveness of the MitraClip System in the Treatment of Clinically Significant Functional Mitral Regurgitation (Reshape-HF2); planned enrollment 380; completion date September 2019.
  
Regulatory Status
In October 2013, the MitraClip® Clip Delivery System (Abbott Vascular, Menlo Park, CA) was approved by the U.S. Food and Drug Administration (FDA, 2013) 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.” FDA product code: NKM.
 
2019 Update
A literature search was conducted through March 2019.  There was no new information identified that would prompt a change in the coverage statement.  
 
2020 Update
A literature search was conducted through April 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2020, the American College of Cardiology and American Heart Association released updated guidelines on the management of valvular heart disease (Otto, 2021). The guidelines state that TMVR is of benefit to patients with severely symptomatic primary mitral regurgitation who are at high or prohibitive risk for surgery, and to a subset of patients with secondary mitral regurgitation who remain severely symptomatic despite guideline-directed management and therapy for heart failure.
 
A systematic review and meta-analysis by Kumar et al, evaluated the comparison of MitraClip plus medical therapy to medical therapy alone in patients with SMR (total N=1,130) (Kumar, 2020). Pooled analyses that included RCT’s and observational studies found that compared to medical therapy alone, at 2 years of follow-up, MitraClip plus medical therapy significantly reduced the risk of all-cause mortality (relative risk, 0.72; 95% CI, 0.55 to 0.95; I2=55%), readmission events for heart failure (relative risk, 0.62; 95% CI, 0.42-0.92, I2=90%), but not cardiovascular mortality (relative risk, 0.69; 95% CI, 0.47-1.02, I2=68%). Further, results of fixed-effect meta-regression suggest that baseline left ventricular end diastolic volume and age are associated with all-cause mortality and cardiovascular mortality outcomes. However, interpretation of these pooled analyses are limited by their considerable heterogeneity and the potential for increased risk of selection bias due to the inclusion of the nonrandomized studies.
 
The evidence for the use of MitraClip in patients with SMR consists of 2 RCTs, the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT), and the Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) (Obadia, 2018; Atianzar, 2019; Iung, 2019). 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 (Obadia, 2018). MITRA-FR enrolled 304 patients at 37 centers in France (Atianzar, 2019; Iung, 2019). 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) (Stone, 2018). Improvements in MR severity, quality of-life measures, and functional capacity persisted to 36 months in patients who received TMVR (Mack, 2021).
 
Buzzatti et al reported on the results of a retrospective, propensity-weighted analysis that compared 5-year outcomes between low-intermediate risk individuals aged 75 years with degenerative MR who underwent treatment with MitraClip or surgical mitral repair (Buzzatti, 2019). Preoperative variables included in the model were age at operation, sex, body mass index categorized as normal (20-30) or not normal (30), serum creatinine, atrial fibrillation, New York Heart Association class III, ejection fraction, systolic pulmonary artery pressure, isolate P2 prolapse, and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM). Although MitraClip was associated with improved 1-year survival and a lower rate of all acute complications, longer-term survival and MR recurrence was significant worse with MitraClip.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
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 (Noack, 2020). The delivery system consists of a 10-mm central spacer that attaches to the MV leaflets by 2 paddles and clasps (CE marked, which isa status of approval awarded by a quality organization in the European Union). Pivotal trials are ongoing in the U.S.
 
The CLASP trial is an ongoing, multicenter, single-arm, prospective study of the safety and efficacy of the PASCAL system to treat patients with MR severity grade 3+ or 4+. The first report of 30-day outcomes for 62 patients demonstrated reduced MR severity, improved functional status, increased exercise capacity, and improved quality of life, with 98% of participants achieving MR severity grade 2+ or less (Lim, 2019). At 1 year follow-up of the 62 original patients,47 additional patients had been recruited, totaling 109 patients (Webb, 2020). Outcomes for this population were reported by Webb et al. At 30-days post-implantation for the newly included patients, MR severity grade <2+ was achieved in 96% of patients, 88% of patients were in NYHA functional class I or II, 6-minute walk test had improved by 28 m, and Kansas City Cardiomyopathy Questionnaire (KCCQ) score had improved by 16 points (p<.001 for all outcomes). In the 62 original patients at 1-year post-implantation, Kaplan-Meier survival was 92%, with 88% freedom from HF hospitalization. Additionally, MR severity grade was <2+ in 100% of patients, 88% of patients were in NYHA functional class I or II, and KCCQ score had improved by 14 points (p<.001 for all outcomes). By the 2-year follow-up, 124 patients were enrolled (Szerlip, 2021). For the patients 2-years post-implantation, Kaplan-Meier estimates showed 80% survival and 84% freedom from HF hospitalization, with 85% reduction in annualized HF hospitalization rate and MR severity grade <2+ achieved in 97% (all outcomes p<.001). LV end-diastolic volume had decreased at 2 years by 33 mL (p<.001) and 93% of patients were in NYHA functional class I to II (p<.001). Study follow-up for this single-arm study is ongoing and the pivotal head-to-head CLASP IID/IIF RCT, comparing the safety and effectiveness of the PASCAL transcatheter valve repair system to the MitraClip system in patients with clinically significant MR (degenerative or functional), is underway.
 
A small, open-label head-to-head trial by Gercek et al evaluated the efficacy of the PASCAL system versus the MitraClip system in patients with severe primary MR (Gercek, 2021). 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 PASCAL device, a residual MR severity grade <1+ was achieved, where as, 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.
 
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 was a multicenter, double-blind, sham-controlled randomized trial to report outcomes with the Carillon device in patients with functional SMR (Witte, 2019). 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 assessed patient-centered outcomes only in patients with SMR severity 2+ to 4+ (Khan, 2021). 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, a 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.
 
In 2020, the American College of Cardiology and American Heart Association presented updated expert consensus on the management of mitral regurgitation (MR) (Bonow, 2020). 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."
 
The NICE guideline on heart valve disease management (2021) makes the following recommendations related to TMVR (NICE, 2021):
"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."
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
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) (FDA, 2022; Lim, 2022). 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 (ClinicalTrials.gov, 2023).
 
In the main CLASP IID cohort, eligible patients were randomized 2:1 to TMVR with PASCAL or MitraClip (FDA, 2022). 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-monthfollow-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 of95% 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.
 
The second cohort of patients who were enrolled in the single-arm PASCAL IID registry cohort included: patients with primary MR enrolled in the CLASPIID/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 (FDA, 2022; Hausleiter, 2023). 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.
 
The use of PASCAL in patients with SMR is being investigated in a randomized cohort of the CLASP IID/IIF trial; analysis of this cohort has not yet been reported (ClinicalTrials.gov, 2023).
 
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 (Glower, 2014; Feldman, 2009; Chan, 2012; Whitlow, 2012; Wan, 2013; Bail, 2014; Estevez-Loureiro, 2013; Grasso, 2014; Munkholm-Larsen, 2014; Swaans, 2014; Philip, 2014; Vakil, 2014; Bail, 2015; Velazquez, 2015; Hayashida, 2017; Srinivasan, 2023).
 
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 (Stone, 2023). 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 26months 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).
 
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 (Orban, 2023). 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.
 
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 (McCarthy, 2023).
 
The Centers for Medicare & Medicaid Services issued a national coverage decision for the use of TMVR in 2015, which was updated in 2021 (CMS, 2021).
 
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.…

CPT/HCPCS:
33418Transcatheter mitral valve repair, percutaneous approach, including transseptal puncture when performed; initial prosthesis
33419Transcatheter mitral valve repair, percutaneous approach, including transseptal puncture when performed; additional prosthesis(es) during same session (List separately in addition to code for primary procedure)

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