Continuous Direct Left Atrial Pressure During Mitraclip Therapy One Key to Clinical Success

Mitral regurgitation (MR) affects ≈4 million Americans and is the leading cause of valvular heart disease in the United States.^1–5 The prevalence of MR increases with age and affects ≈10% of people over the age of 75 years.^3,6,7 Moderate-to-severe MR is associated with a 20% 1-year mortality and a 50% 5-year mortality.^8,9 There are 3 major subtypes of MR; degenerative (primary), functional (secondary), and an overlap between degenerative and functional. Degenerative (primary) MR results from dysfunction within the mitral valve apparatus. Functional (secondary) MR results from left ventricular (LV) dysfunction and remodeling leading to displacement of the mitral valve apparatus. Surgical mitral valve repair or replacement for functional mitral valve regurgitation is currently a class IIb recommendation based on the current American Heart Association/American College of Cardiology guidelines.¹⁰ Percutaneous transcatheter mitral repair and replacement is a promising new option for the management of functional MR, with a growing body of research showing benefit. In this review, we will discuss new developments in transcatheter therapies for functional MR.

Anatomy

The healthy mitral valve is a complex apparatus that functions as a 1-way conduit from the left atrium to the LV. The mitral apparatus is composed of the mitral annulus, leaflets, commissures, chordae tendinae, posterior left atrium, LV free wall, and papillary muscles, which work in a coordinated fashion to allow frictionless passage of blood through the left side of the heart.^11,12 Dysfunction of any component can lead to mitral valve pathology, including MR (Figure 1).^11,13

**Figure 1.** **Atrial and sagittal views of mitral valve**. A, Schematic representation of the mitral valve and surrounding structures from the atrial view. Note the 2 fibrous trigones and structures posterior to the mitral valve (coronary sinus and left circumflex artery). Note the mitral leaflet scallops; P1-A1 is anterolateral, P3-A3 is posteromedial. B, Sagittal view showing subvalvular supporting structures. A indicates anterior; P, posterior; and PM, papillary muscle. Reprinted from Maréchaux et al¹³ with permission. Copyright ©2017, Elsevier.

Pathophysiology and Natural History

MR is classified based upon the acuity and the underlying mitral valve structure. The Carpentier classification is a helpful tool to standardize the mitral valve pathologies (Figure 2).^9–11,14,15 Functional MR differs from degenerative (primary) MR in that the mitral valve apparatus is normal, but ventricular remodeling provides the substrate for mitral valve dysfunction. Ventricular remodeling from any cause (ischemic cardiomyopathy or nonischemic cardiomyopathy), as well as left atrial dilatation due to AF (and subsequent annular dilatation), leads to progressive annular dilatation and leaflet malapposition. This begins a cycle of further LV pressure and volume overload from the regurgitant volume, leading to further LV remodeling with progressive LV dilation and dysfunction. Functional MR is an independent predictor of adverse prognosis and mortality.^10,11,14,15 The sequelae of LV remodeling includes a cycle of neurohormonal activation and irreversible damage and fibrosis, resulting in poor cardiac output, heart failure, and ultimately death.^11,12,16 Furthermore, invasive hemodynamic studies had shown an elevation in left atrial mean pressure, left atrial V-wave pressure, left atrial mean pressure index, left atrial V-wave pressure index, increased pulmonary capillary wedge pressure, pulmonary arterial pressures, and right atrial and tricuspid annular dilatation, all of which are risk factors of recurrent hospitalizations (Figure 3).^17,18

**Figure 2.** **Carpentier classification.** PM indicates papillary muscle; and RF, regurgitant fraction.

**Figure 3.** **Freedom from rehospitalization due to heart failure (HF) according to hemodynamic changes.** LAmP indicates left atrial mean pressure; and LAmPI, left atrial mean pressure index. Reprinted from Kuwata et al¹⁸ with permission. Copyright ©2019, Elsevier.

Chronic MR can be divided further into 3 stages. In stage 1 (compensated phase), long-standing MR results in LV volume overload/enlargement, eccentric hypertrophy with normal systolic function. Enlargement of left atrium due to compliance keeps the left atrial pressures and thus pulmonary arterial pressures within normal limits in the initial compensatory phase (stage 1) of MR.¹⁹ Left atrial enlargement is the first sign that MR is worsening. In stage 2 (transitional phase), there is mild LV dysfunction; however, it is reversible following correction of the regurgitant lesion. In stage 3 (decompensated phase), the LV dilates, wall stress increases, and may cause irreversible myocardial damage. As this occurs, LV contractility may decline, with a reduction in LV stroke volume and ejection fraction (Figure 4).^10,11,14,20

**Figure 4.** **Left ventricular (LV) stress-volume loops in the 3 stages of chronic mitral regurgitation (MR).** As the ventricle adapts to the chronic hemodynamic burden, a progressive increase in LV end-diastolic volume and systolic wall stress occurs. Ejection fraction progressively declines from 65% in compensated MR to 55% during the transitional stage and finally to 45% (or lower) in decompensated MR. Reprinted from Gaasch and Meyer²⁰ with permission. Copyright ©2008, Wolters Kluwer Health, Inc.

Diagnosis

Transthoracic echocardiography remains the cornerstone in the initial assessment of MR. Transesophageal echocardiography is often necessary to define the mitral valve anatomy and mechanism of MR. Additionally, transesophageal echocardiography is a useful tool to evaluate the optimal percutaneous intervention by elucidating the leaflet characteristics (leaflet length, degree of coaptation, calcification, and degree of prolapse), the subvalvular apparatus, and the annulus diameter.³ The severity of MR can be estimated using echocardiographic parameters including the vena contracta, proximal isovelocity surface area, effective regurgitant orifice area, and thereby the regurgitant volume and regurgitant fraction. The American Society of Echocardiography defines severe MR by a vena contracta >0.7 cm, regurgitant volume of >60 mL, regurgitant fraction >50%, effective regurgitant orifice area >0.4 cm², and a dilated LV (Figure 5).²¹ The European guideline differs slightly, defining severe MR as having an effective regurgitant orifice area of >0.2 cm² and regurgitant volume of 30 mL.²²

**Figure 5.** **Algorithm for assessment of mitral regurgitation (MR) severity by the American Society of Echocardiography.** CMR indicates cardiac magnetic resonance; CW, continuous wave; EROA, effective regurgitant orifice area; LA, left atria; LV, left ventricle; PISA, proximal isovelocity surface area; RF, regurgitant fraction; RVol, regurgitant volume; TEE, transesophageal echocardiography; TTE, transthoracic echocardiography; and VCW, vena contracta width. Reprinted from Zoghbi et al²¹ with permission. Copyright ©2017, Elsevier.

Newer imaging modalities are emerging to best assess the severity and etiology of MR. Cardiac magnetic resonance imaging is one of the emerging modalities, giving a precise assessment of mitral valve anatomy, LV parameters (dimensions, volumes, and function), and left atrial volumes. Specific criteria to determine regurgitant volumes and regurgitant fraction on cardiac magnetic resonance are lacking.¹⁷ Multidetector row computed tomography is another emerging imaging modality in the assessment of MR. The benefit of multidetector row computed tomography is the accurate demonstration of the mitral apparatus morphology and relationship of the mitral apparatus to other cardiac structures, both of which are critical for successful percutaneous interventions.^23–25

Percutaneous Intervention

Catheter-based mitral interventions target mitral valve pathologies ranging from leaflet dysfunction (prolapse and rupture) to annulus dilation to subvalvular problems (ventricular dilation, ruptured chordae, or papillary muscles). Mitral valve replacement focuses on all these pathologies. Alternatively, repair options focus on each individual pathology, resulting in a nuanced approach. Various catheter-based mitral interventions are summarized in Figure 6.

**Figure 6.** **Transcatheter mitral devices.** ACCESS-EU indicates MitraClip Therapy Economic and Clinical Outcomes Study Europe; CE, Conformité Européenne; CINCH-2, A Study of Percutaneous Repair of Functional Mitral Regurgitation Using the Ancora Heart, Inc, AccuCinch Ventricular Repair System - COAPT, Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation; DMR, degenrative mitral regurgitation; EF, ejection fraction; EVEREST, Endovascular Valve Edge-to-Edge Repair Study; FDA, Food and Drug Administration; FMR, functional mitral regurgitation; INTERLUDE, Clinical Investigation of the Caisson Transcatheter Mitral Valve Replacement (TMVR) System for Percutaneous Mitral Valve Replacement in Patients With Symptomatic Mitral Regurgitation; LV, left ventricular; MAC, mitral annular calcification; MITRA-FR, Percutaneous Repair With the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation; MR, mitral regurgitation; MS, mitral stenosis; PML, posterior mitral leaflet; PRELUDE, Percutaneous Mitral Valve Replacement Evaluation Utilizing IDE Early Feasibility Study; RELIEF, Reduction or Elimination of Mitral Regurgitation in Degenerative or Functional Mitral Regurgitation With the CardiAQ-Edwards Transcatheter Mitral Valve; ReChord, Randomized Trial of NeoChord Versus Open Surgical Repair; REDUCE-FMR, Reducing Functional Mitral Regurgitation Associated With Heart Failure; TA, trans-apical; TACT, Transapical Artificial Chordae Tendinae; TAVR, transcatheter aortic valve replacement; TF, transfemoral; TITAN, Transcatheter Implantation of Carillon Mitral Annuloplasty Device; TOP-MINI, Transapical Off-Pump Mitral Valve Repair With Neochord Implantation; TRAMI, Transcatheter Mitral Valve Interventions; and TS, transseptal.

Transcatheter Mitral Valve Repair

The most common transcatheter mitral valve intervention is leaflet repair with the MitraClip edge-to-edge system that is based on the surgical Alfieri double-orifice technique/Alfieri stitch.^26,27 MitraClip was initially approved for degenerative (primary) MR and has subsequently been approved for functional (secondary) MR based on results of the COAPT trial (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation). The EVEREST II trial (Endovascular Valve Edge-to-Edge Repair Study) randomly assigned 258 patients with grade 3+ or 4+ in a 2:1 ratio (178:80) to percutaneous mitral valve repair with MitraClip versus conventional surgery.²⁷ Although there was no difference in mortality for either group, MitraClip was safer with fewer side effects but less effective in reducing the severity of MR² The increased risk for residual MR with MitraClip resulted in these patients more commonly requiring surgery for residual MR during the first year after treatment than patients who were initially treated with surgery. However, between 1- and 5-year follow-up, there were comparably low rates of surgery for residual mitral valve dysfunction observed for both treatments consistent with durable MR reduction with both percutaneous and surgical repair techniques.²⁷ Further, real-world results were shown in the 2-phase observational ACCESS-EU study (MitraClip Therapy Economic and Clinical Outcomes Study Europe), which evaluated high-risk elderly patients predominantly with functional MR. MitraClip was safe with a 30-day mortality of 3.4% and was effective in significantly improving MR grade at 12 months.²⁸ There was also a significant improvement in 6-minute walk from baseline to 6 months with a continued trend at 12 months.²⁸

Importantly, there was an initial learning curve for MitraClip, which was influenced by lack of prior experience in left atrial navigation for mitral interventions, as well as the absence of 3-dimensional echocardiography. One of the factors associated with poor outcomes, recurrent MR, or need for recurrent intervention was detachment of the clip, alternatively referred to as single leaflet device attachment or loss of leaflet insertion. This was reported to have an incidence of 6.3% in the EVEREST II trial, which reduced to 4.8% in the ACCESS-EU trial with improved operator experience.^27,28 Further work by Chhatriwalla et al²⁹ examining 14 923 cases out of the TVT registry (Transcatheter Valve Therapies) has also shown improved procedural success and decreased complications with increasing operator experience.

The multicenter German Transcatheter Mitral Valve Interventions registry enrolled 828 real-world patients, the majority of whom had functional MR (70%) with New York Heart Association (NYHA) grade ≥III symptoms (89%). The vast majority of these patients underwent MitraClip implantation. This registry revealed a correlation between procedural safety and higher center volumes.³⁰ The most common major complication of bleeding requiring blood transfusion was postulated to be related to large-bore venous access.³⁰ Improved operator experience and technical prowess has led to improved clinical outcomes and the application of the technology beyond classic EVEREST trial inclusion criteria to clinically challenging cases (ie, emergency, papillary ruptures, extreme LV dysfunction).^26,27

Two landmark trials evaluated the efficacy of MitraClip in symptomatic heart failure patients with secondary MR. The MITRA-FR trial (Percutaneous Repair With the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) was a multicenter, open-label, randomized controlled trial that compared MitraClip plus guideline-driven medical therapy (GDMT) versus GDMT alone. A total of 307 patients were randomized, of whom 152 were assigned to MitraClip+GDMT. Although the MitraClip group had a significant reduction of MR, there was no statistically significant difference in primary outcomes of 1-year mortality or unplanned hospitalization (hazard ratio, 1.16 [95% CI, 0.73–1.84]; P=0.53).³¹ The COAPT trial was a multicenter, randomized, controlled, parallel-group trial that enrolled 614 patients with heart failure and secondary MR. The majority of patients had NYHA class III-IV symptoms. A total of 302 patients were randomized to MitraClip+GDMT group while 312 patients to GDMT alone. The MitraClip+GDMT group had statistically significant reductions in all-cause mortality (29.1% of the patients in the device group versus 46.1% in the control group; hazard ratio, 0.62 [95% CI, 0.46–0.82]; P<0.001), hospitalization (35.8% per patient-year in the device group versus 67.9% per patient-year in the control group; hazard ratio, 0.53 [95% CI, 0.40–0.70]; P<0.001), and MR (P<0.001). There was also a significant improvement in quality of life and functional capacity at 24-month follow-up in patients treated with the MitraClip.⁴

There are several possible explanations for the apparent discordant clinical outcomes between these studies. The patients in COAPT trial were required to be on optimized medical therapy at baseline before consideration of enrollment. Only symptomatic patients refractory to maximum tolerated medical therapy were included in the COAPT trial compared with the MITRA-FR trial, which allowed variable medication adjustments in each group during follow-up. It is possible that the more aggressive medical therapy in COAPT versus MITRA-FR accounted for the improved survival in the COAPT trial. The second possible explanation is related to the degree of MR in context of LV volumes.³² Patients in COAPT had larger effective regurgitant orifice area than MITRA-FR trial (41+15 versus 31+10 mm²), thus had more severe MR, and relatively smaller LV end-diastolic volumes (101+34 versus 135+35 mL/m²). Thus, the degree of MR was disproportionately greater than would have been expected from the LV chamber enlargement (disproportionate MR). In contrast, the patients in Mitra-FR had proportionate MR, in that the degree of their MR was predicted by the degree of ventricular dysfunction. This finding lead to the hypothesis that the use of proportionate versus disproportionate MR echo findings can help better select patients who respond favorably to MitraClip.³³ Lastly, procedural success rates also differed between the 2 trials and could also explain the difference in outcomes. The COAPT trial group had more clips per patient on average, less procedural complications (8.5% versus 14.6%), and had more sustained reduction of MR at 1 year compared with MITRA-FR patients (5% versus 17%, respectively).^4,31–34 Regardless of the differences in the trials, both trials emphasized medical optimization of the patient with secondary MR before consideration for mitral valve repair, and even in those patients assigned to medical therapy, there was improvement in functional status. Based on the COAPT trial results, the Food and Drug Administration approved MitraClip for symptomatic heart failure due to secondary MR.³⁰ A meta-analysis including 2121 patients with heart failure and severe secondary MR comparing MitraClip+GDMT (n=833) versus GDMT alone (n=1288) also demonstrated that MitraClip (plus GDMT) was superior to GDMT alone and was associated with a significant survival benefit, with consistent findings across all subgroups.³⁵ MitraClip efficacy and complication data in major observational studies, registries, and randomized trials are summarized in Table 1.^{4,27,28,30,31,36–46} Furthermore, major differences between the newer generation MitraClip XTR and NTR are summarized in Table 2. Upcoming iterations in the MitraClip platform continue with the newest being the G4 platform that allows for 4 different clip sizes, independently articulated gripper elements, and continuous left atrial monitoring during the case.

**Table 1.** Mitraclip Efficacy and Complication Data
Registry/Study/ Trial Name	N	Mean Age (yrs)	Male	Mean or Median Risk	NYHA Functional Class III/IV	Mean LVEF	Severe or 3+ or 4 MR	FMR Etiology	≤2+ MR Post Procedure	≥2 Mitraclips	Procedural Success	Stroke/TIA	Bleeding Complications Requiring Transfusion	Early Surgical Repair	Intra-Procedural & Inhospital death	LVEF at 1, 6, 12 mo	Mortality at 1, 6, 12 mo	NHYA Class at 1, 6, 12 mo	Rehospitalization due to HF at 1 - 6 - 12 mo
TRAMI^30,36	1,064	75	62%	10%*	87%	‡	94.6%	76%	96%	1.5 mean	95%	1.8%	7.4%	0.9%	0 & 2.8%	#	4.5%, #, #	66% (median f/u 75-84 days)	12% (median f/u 75-84 days)
ACCESS-EU²⁸	567	78	64%	23%†	85%		97.7%	77%	91%	40%	99.6%	0.7%	3.9%	1%	0 & 3.4%	#	3.4, #, 17%	#, #, 74%	3.4%, - #, 17.3%
European Sentinel³⁷	628	74	63%	20%†	86%	43%		72%	98%	39%	95%	0.2%	10%	#	# & 2.9%	No change	#, #, 15.3%	75, #, 74%	#, #, 22.8%
EVEREST II and REALISM²⁷	351	76	61%	11%*	85%	48%	86%	70%	86%	39%	97%	2.6%	13.4%	0.9%	0 & 2.6%	#, #, 48%	4.8%, #, 22.8%	#, #, 83%	#, #, 19.8%
GRASP³⁸	171	71	62%	7%*	81%	37%†† 42%‡‡	97%	78%	93%	43%	99%	0.6%	1.2%	0	0 & #	42% †† 45% ‡‡	1.8%, #, 11%	77, #, 82%	1.8%, #, 7%
MARS³⁹	142	71	64%	17%†	68%	47%	100%	54%	77%	51%	94%	0	3.5%	0.7%	n.g. & 5.6%	45%, #, #	5.6%, #, #	82%, #,#	0.7%, #, #
Taramasso et al⁴⁰	109	69	84%	22%†	82%	28%	100%	100%	87%	70%	99%	0	#	1%	0 & 1.8%	#, #, 35%	1.8%, -, 10% (75% alive 3 years)	#, #, 86%	#, #, #
MitraSwiss⁴¹	100	77	67%	17%†	82%	48%	100%	62%	85%	44%	85%	1%	6%	3%	1% & 4%	#, #, 48%, 48%	#, 10, 15%	#, 80%, 80%	#, #, #
French multicenter⁴²	62	73	72%	19%†	81%	40%	93%	74%	88%	17%	95%	0	8.1%	3.2%	0 & 3.2%	# (36% at discharge)	#, 17, #	#, 91, #	#, #, #
Treede et al⁴³	202	75	63%	44%†	98%	44%	99%	65%	92%	35%	92%	#	#	5.4%	& 3.5%	#	#, #, 10%	#, #, 72%	#, #, #
Bozdag-Turan et al⁴⁴	121	77	69%	11%*	96%	42%	100	59%	99%	28%	97%	0	5.8%	#	0 & 2.5%	#, #, 46%	3.3%, #, 23%	#, #, 99%	#, #, 22%
Rudolph et al⁴⁵	104	74	62%	36%†	100%	43%	99	66%	92%	38%	92%	#	9%	7%	- & 3.3%	#, 43%	#, #, 22%	#, #, 69%	#, #, 31%
Neuss et al⁴⁶	157	74	67%	22%†	100%	40%	100%	73%	100%	16%	98%	#	6%	6%	#	#, 44%, 44%	7%, 13%, 20%	#, 62%, 45%	#, #, 31%
MITRA-FR³¹**	152 (302)	70	79%	6.6*	63%	33%	100%	100%	92%%	54%	96%	4.6%	3.5%	0	0 & 0	#	#, #, 24.3%	#	#, #, 48.7%
COAPT⁴**	302 (614)	72	67%	7.8%*	57%	31%	100%	100%	95%	64%	98%	0.7% (4.4% in 2 years)	#	0	#	#	2.3%, #, 18.8% (29% at 2 yrs)	76%, 72%, 72%	13%,#, # (70% at 2 years)

**Table 2.** MitraClip XTR Versus NTR
	Anatomic Considerations	Favored XTR	Favored NTR
Leaflet insertion	Longer leaflet*	+
	A2-P2	+
	Large flail†	+
	Redundant leaflet	+
	Restricted leaflet‡		+
Tissue quality	Calcification of annulus and leaflet§		+
Gradient	Smaller MV area∥		+
Cordial entrapment	Mitral valve commissures¶		+

The Edwards PASCAL transcatheter mitral valve repair system targets the mitral leaflets with a similar edge-to-edge technique. Unlike MitraClip, PASCAL has larger paddles that can grasp a large amount of leaflet surface, independent articulation of both arms, and the presence of a spacer that theoretically could allow for better coaptation. A multicenter, prospective, observational, first-in-man study involving 23 patients established feasibility of PASCAL device with a high rate of technical success and reduction of MR.⁴⁷ Twenty-two (96%) patients with NYHA class III or IV underwent successful implantation of PASCAL device, resulting in procedural residual MR of grade ≤2+ in 22 (96%) patients. Technical success rate was achieved in 22 (96%) patients. Periprocedural complications occurred in 2 (9%) of 23 patients (1 minor bleeding event and 1 transient ischemic attack). Mortality at 30 days was 13% (3 of 23 patients).⁴⁷ The CLASP trial is enrolling patients and is designed to assess safety and major adverse events defined as cardiovascular mortality, stroke, myocardial infarction, need for renal replacement therapy, severe bleeding, and reintervention for study device–related complications at 30 days.

Transcatheter Mitral Valve Chordal System

Neochord involves off-pump artificial chordal implantation via the transapical approach. Initial safety and efficacy experience was evaluated in the TACT trial (Transapical Artificial Chordae Tendinae). Thirty patients with severe MR due to isolated Carpentier type II prolapse of the posterior mitral valve leaflet and without annulus dilation were included in this study, and patients with secondary MR were excluded.^48–50 TACT concluded that off-pump transapical implantation of artificial chordae to correct MR is technically safe and feasible. The TOP-MINI early feasibility trial (Transapical Off-Pump Mitral Valve Repair With Neochord Implantation) evaluated 49 patients with severe symptomatic degenerative MR (89.8% with posterior leaflet prolapse, 8.2% with anterior leaflet prolapse, and 2% with combined disease). Early results from TOP-MINI suggest that Neochord is feasible and safe with acute procedure success (defined as successful placement of at least 3 neochords with reduction of residual MR to less than grade 2+) achieved in all patients and in-hospital mortality observed in 2%. At 3-month follow-up, survival was 98% and MR was absent in 16 patients (33.4%), grade 1+ in 15 (31.2%), and grade 2+ in 12 (25%) patients. Five patients (10.4%) developed recurrent severe MR due to anterior native chordae rupture.^26,48,49 A prospective ReChord trial (Randomized Trial of NeoChord Versus Open Surgical Repair) is ongoing with plans to enroll 585 patients and is expected to finish in 2020.

The Harpoon system is a polytetrafluoroethylene chordal implantation device that is similar to Neochord and has completed an early feasibility study in 11 patients with posterior mitral leaflet prolapse and normal ejection fraction. Procedural success was 100% with trace MR observed immediately after the procedure and mild MR at 1 month.⁵¹ The safety profile of the Harpoon system was confirmed in a prospective trial of 30 patients where 27 of 30 patients (90%) met the primary efficacy end point but 10% (3 of 30) required conversion to open mitral surgery. There were no deaths, strokes, or permanent pacemaker implantations. MR was mild or less in 89% (24 of 27) at 1 month and was moderate in 11% (3 of 27).^26,51,52

Transcatheter Mitral Valve Annuloplasty

Direct Annuloplasty

Although conventional mitral annuloplasty can be done surgically, surgical intervention is a class IIb recommendation in patients with secondary MR and may be associated with increased mortality and morbidity.^10,14 Patients who are undergoing cardiac surgery for other reasons, such as coronary artery bypass grafting or aortic valve disease, may have mitral annuloplasty performed as well. Percutaneous direct annuloplasty concepts have been conceptualized based on surgical annuloplasty. Several direct annuloplasty systems are currently under development and include the Cardioband, Mitralign, and Millipede systems.

Cardioband uses transseptal access to the annulus and is implanted on the posterior annulus from the anterior-lateral to the posterior-medial mitral valve commissure on the atrial side of the valve.^40,53,54 The early feasibility study enrolled 31 patients with secondary MR and reduced LV function (LV ejection fraction, 34+11%).⁵⁵ At 6-month follow-up, Cardioband was effective in reducing MR, improving heart failure symptoms, and had a favorable safety profile.⁵⁴ Per data presented at polymerase chain reaction London valve 2018, the Cardioband CE trial in 61 patients demonstrated a survival rate of 79% with 96% of patients having an MR grade of ≤2 at 2-year follow-up. There was a 9% reduction in mitral annular area and 83% of patients were NYHA class I or II, which translate to improved 6-minute walk tests at 2-year follow-up.

Mitralign is a transarterial system that reduces annulus size by delivering paired pledgeted sutures to the posterior mitral annulus coming from the ventricular to the atrial side of the valve. Early feasibility evaluation in 71 patients demonstrated a 70.4% device success rate with 8.9% of patients developing cardiac tamponade. At 30 days (n=45) and 6 months (n=41), rates for all-cause mortality, stroke, and myocardial infarction were 4.4%, 4.4%, 0.0% and 12.2%, 4.9%, 0%, respectively. Further, a 50% reduction in MR and a significant reduction in annular size were noted at 6 months.^55–57

The Millipede IRIS system is a semirigid annuloplasty ring with 8 anchors placed directly into the mitral annulus using a transseptal catheter. The primary end point of the initial first-in-human use trials was the change in septal-lateral diameter of the mitral annulus, which decreased from a baseline of 38.0±4.1 to 25.9±4.9 mm at 30 days (n=7).⁵⁸ An ongoing Annular Reshaping of the Mitral Valve for Patients With Mitral Regurgitation Using the Millipede IRIS System multicenter trial aims to complete enrollment of 50 patients by January 2020, will provide further insight into this device.

Indirect Annuloplasty

Indirect mitral annuloplasty may be accomplished through the coronary sinus or by altering the dimensions of the LV chamber (ventriculoplasty). At least 2 systems are being developed to address the coronary sinus approach: Carillon Mitral Contour System and Mitral Valve cerclage.

The Carillon device was evaluated in the AMADEUS trial (CARILLON Mitral Annuloplasty Device European Union Study), which enrolled 48 patients with symptomatic heart failure, LV ejection fraction <40%, and moderate-to-severe MR. Eighteen patients did not undergo device deployment because of access issues, insufficient functional mitral regurgitation (FMR) reduction, or risk of coronary artery compromise. The rate of major adverse events (death, myocardial infarction, coronary sinus dissection/perforation, device embolization, and surgery of percutaneous coronary intervention related to device) was 13% at 30 days. These included 1 reported death, 3 myocardial infarctions, and 3 coronary sinus dissection/perforation. At 6-month follow-up, FMR reduction ranged from 22% to 32%, and 6-minute walk distance improved from 307+87 m at baseline to 403+137 m (P<0.001).^59,60 Carillon was also evaluated in the TITAN trial (Transcatheter Implantation of Carillon Mitral Annuloplasty Device). Although 36 patients initially received an implant, the device was recaptured in 17 patients (who subsequently served as control group) for various reasons including coronary compromise. The successfully implanted group demonstrated significant reductions in FMR (baseline, 34.5±11.5 to 17.4+12.4 mL at 12 months; P<0.001) and LV volumes (baseline LV diastolic volume, 208.5±62.0 to 178.9±48.0 mL at 12 months; P=0.015 and baseline systolic volume, 151.8±57.1 to 120.7±43.2 mL at 12 months; P=0.015).⁶⁰ In comparison, patients in the control group had progressive LV dilation. Further, the 6 minute walk distance test markedly improved in the implanted patients.^60,61 However, wire fractures were observed next to the proximal anchor locking mechanism, at high-strain locations on the Carillon devices, in both AMADEUS and TITAN, which prompted a subsequent device iteration.⁶¹ A modified Carillion system was evaluated in the subsequent TITAN II trial, which enrolled 36 patients with symptomatic congestive heart failure, LV ejection fraction <40, and moderate or greater FMR. TITAN II demonstrated a reduction in FMR, improvement in functional class, and 6-minute walk. There was 1 non–device-related death 17 days post-device implant and no device wire fractures.^61,62 The Safety and Efficacy of the CARILLON Mitral Contour System in Initial results on REDUCE-FMR trial (Reducing Functional Mitral Regurgitation Associated With Heart Failure) demonstrated the Carillon device significantly reduced the degree of MR along with LV volumes in symptomatic patients with FMR receiving optimal medial therapy at 1-year follow-up in 73 of 87 (84%) in the device-implanted group.⁶³

Coronary sinus annuloplasty Cerclage is an investigational device undergoing preclinical evaluation for indirect annuloplasty, which also involves the coronary sinus. Animal studies have been performed, but human feasibility studies are yet to be done.^64,65

Transcatheter Mitral Valve Replacement

The Tendyne transcatheter mitral valve is the most widely studied transcatheter mitral valve replacement (TMVR) system with >100 valves implanted to date.⁶⁶ It is a D-shaped porcine pericardial trileaflet valve with 2 nitinol stents, adjustable tether and apical fixation/sealing pad, that is delivered transapically.⁶⁷ The Global feasibility trial reported 30-day outcomes on the first 30 high-surgical-risk patients with grade 3 or 4 MR. The device was successfully implanted in 28 patients (93.3%). One patient died on day 13 following device deployment due to pneumonia, and another patient developed leaflet thrombosis, which resolved with warfarin treatment. At 30 days, 1 patient had mild MR, and no MR was observed in remaining 26 patients. An improvement in LV end-diastolic volume index (90.1+28.2 at baseline versus 72.1+19.3 mL/m² at follow-up) and LV end-systolic volume index (48.4+19.7 versus 43.1+16.2 mL/m²) was reported. Most patients (75%) reported mild or no symptoms at follow-up (NYHA class I or II).^66,68,69 The results of the first 100 high-surgical-risk patients, with The Society of Thoracic Surgeons-predicted mortality of 7.9%, and predominant severe MR enrolled in the international CE mark study revealed a high procedural success rate without significant complications. There was a 97% procedural success rate, no procedural mortality, surgical conversion, or need for mechanical circulatory support. A majority of the patients (98.7%) had no or trace MR at 30 days among the 76 patients with complete 30-day data.⁶⁶ The ongoing SUMMIT trial is comparing Tendyne TMVR versus conventional surgical mitral valve replacement.

The Intrepid TMVR system is a self-expanding bovine pericardial trileaflet valve, which is placed using a transapical delivery system. A global multicenter, multinational study enrolled 50 high-surgical- risk patients (mean high The Society of Thoracic Surgeons scores, 6.4+5.5%). The device was successfully implanted in 48 patients, and 30-day mortality was 14%. There were no disabling strokes or repeat interventions. At median follow-up of 173 days, there was no or mild MR and significant improvement in NYHA functional class in 79% of patients. No valve thrombosis events were observed, and ≈4 (8%) patients were admitted with heart failure within 30 days.^70,71 The ongoing APOLLO trial consists of 2 arms, with 1 arm randomizing Intrepid TMVR versus traditional surgery (n=650) and a second arm that will treat patients with Intrepid TMVR who are ineligible for surgery as a single arm cohort (n=550).⁷²

The TIARA system was implanted for compassionate use in 2 patients with severe MR, depressed LV function, and NYHA class IV symptoms. The procedure was technically successful with hemodynamic NYHA class improvement in both patients without major complication.⁷³ An early feasibility study enrolled 8 patients, with procedural success in 7 patients, and 1 patient was converted to open surgery. There was no mortality or major complications at 30 days in successfully implanted patients.⁷⁴ TIARA-I—an early feasibility—and TIARA-II—European CE Mark Study—are ongoing. More than 50 high-risk patients with moderate-to-severe LV systolic dysfunction and secondary MR have received TIARA valve with 95% device implant success rate and 8.5% mortality rate.⁷⁵

Other TMVR systems are either in early feasibility clinical trials or yet to start feasibility trials. These include Edwards EVOQUE, Sapien 3, HighLife TMVR, and CAISSON TMVR (https://www.clinicaltrials.gov; unique identifier: NCT02718001, NCT03193801, NCT02974881, and NCT02768402).^76–79

Transcatheter Ventricular Restoration

AccuCinch is a novel concept of treating MR that targets the LV free wall. Instead of focusing on the mitral annulus, the AccuCinch system focuses on the ventricle—the presumed cause of secondary MR. The AccuCinch system is an arterial system that is advanced retrograde through the aortic valve into the LV that places several anchors in the LV and then cinches the LV, thus allowing for a reduction in LV end-diastolic diameter. By decreasing LV diameter, the stress of the LV wall should be decreased (LaPlace law), and subsequent LV dilation could be prevented. Fourteen of 16 patients underwent successful implantation of AccuCinch, and preliminary promising findings show a significant reduction in LV volumes. The LV ejection fraction improved from a baseline of 30% to 42% and 47% while FMR was reduced from baseline grade 3⁺or 4⁺ to 1⁺ or 2⁺ in data available from 9 and 4 patients at 30 days and 6 months, respectively. Mortality at 30 days was reported at 6.3%.⁸⁰ The early feasibility and CE mark studies (CorCinch-FMR study, the CINCH-2 study, and the CorCinch-EU study) are underway.

Clinical Practice Guidelines

The COAPT and MITRA-FR trials were published in 2018 and in March 2019, the Food and Drug Administration approved the use of the MitraClip for the treatment of functional MR. An American College of Cardiology expert consensus decision pathway was released in 2020 emphasizing the appropriate evaluation and management of the patients with secondary MR that incorporates the findings of these trials and recommends the use of edge-to-edge percutaneous mitral valve repair in high-risk patients who have had their medical therapy optimized.⁸¹ Unfortunately, the American College of Cardiology valvular guidelines have not been updated with the recent trial findings and make no comment about percutaneous options for the treatment of secondary MR.¹⁰ The European Society of Cardiology published its latest guidelines on management of valvular heart disease in 2017, where it provided a class IIb recommendation for percutaneous edge-to-edge repair of mitral valve for patients with severe secondary MR who remain symptomatic despite optimal medical therapy (including CRT if indicated).⁸² Hopefully, these guidelines will soon be updated, and in the setting of multiple additional therapies that are being developed, a system of rapid and possibly continuous iterations of guidelines might be considered.

Conclusions

Functional MR is common among patients with heart failure and is increasing in prevalence with the aging population. When left untreated, MR often progresses and is associated with hospitalization, high mortality, and high costs to the healthcare system. Percutaneous catheter-based interventions provide novel therapeutic options. There is now robust evidence from COAPT trial for mortality reduction in functional MR when adhering to the strict inclusion criteria of COAPT trial. MitraClip—the most frequent catheter-based intervention done worldwide—effectively reduces the severity of MR and has been associated with improved mortality and reduced morbidity, as well as with a consistent and reproducible safety profile. Not surprisingly, considering the complexity of the mitral valve apparatus, multiple catheter-based treatment options are currently under development and are in clinical trials. Indeed, the optimal catheter-based treatment for a specific patient may, in the future, require a combination of devices, each with a specific focus (leaflet, annulus, ventricular free wall, etc) to achieve the best, most durable result. The percutaneous interventional devices discussed herein will most likely rapidly iterate and evolve as clinical experience builds.

Nonstandard Abbreviations and Acronyms

ACCESS-EU	MitraClip Therapy Economic and Clinical Outcomes Study Europe
AMADEUS	CARILLON Mitral Annuloplasty Device European Union Study
COAPT	Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation
EVEREST II	Endovascular Valve Edge-to-Edge Repair Study
GDMT	guideline-driven medical therapy
LV	left ventricular
MITRA-FR	Percutaneous Repair With the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation
MR	mitral regurgitation
NYHA	New York Heart Association
ReChord	Randomized Trial of NeoChord Versus Open Surgical Repair
REDUCE-FMR	Reducing Functional Mitral Regurgitation Associated With Heart Failure
TACT	Transapical Artificial Chordae Tendinae
TITAN	Transcatheter Implantation of Carillon Mitral Annuloplasty Device
TMVR	transcatheter mitral valve replacement
TOP-MINI	Transapical Off-Pump Mitral Valve Repair With Neochord Implantation

Footnotes

For Sources of Funding and Disclosures, see page 12.

Correspondence to: Mahboob Ali, MD, University of Cincinnati, 231 Albert Sabin Way, ML 0542, Cincinnati, OH 45267. Email mahboob. [email protected] com

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Source: https://www.ahajournals.org/doi/10.1161/CIRCINTERVENTIONS.120.008998