Transcatheter mitral valve repair with clip for treatment of secondary or functional mitral insufficiency. Literature review

Mitral insufficiency is one of the most common acquired heart valve diseases and a common cause of heart failure, often in response to mitral annulus dilation. In such cases, the condition is referred to as functional or secondary and may be associated with ischemic heart disease or other dilated cardiomyopathies of varying etiology. Mitral valve insufficiency is common among older patients or individuals with several comorbidities, who are often not eligible for conventional mitral valve surgery due to high risk of intraoperative death and complications. Surgical outcomes (valve repair or replacement) may also be limited, particularly in patients with functional mitral insufficiency (class IIb indication according to most international guidelines). Several less invasive clip-based transcatheter mitral valve repair techniques have been developed. These have been addressed in several randomized trials in the last few years, such as the EVEREST-II, the MITRA-FR and the COAPT trials. Positive COAPT trial outcomes supported the indication of mitral clip procedures in functional mitral regurgitation patients with favorable anatomy, who remain symptomatic despite optimal medical treatment. Patients with “disproportionate” mitral insufficiency (i.e., large degree of mitral regurgitation relative to ventricular dysfunction) are those who benefit most from the intervention, with lower rates of hospital readmission and death. These outcomes prompted the incorporation of novel technologies (MitraClip® NTR, MitraClip® XTR and Pascal). Major features of these devices, such as longer clip arms, capability of independent grasping of anterior and posterior leaflets, and wider arm width range are reviewed in detail in this article.


INTRODUCTION
Mitral valve insufficiency (MI) is one of the most common acquired heart valve diseases and may be caused by abnormalities at different sites of the mitral valve apparatus, such as leaflets, annulus, chordae tendinae and papillary muscles. [1][2][3][4] Mitral valve insufficiency may be categorized as primary (degenerative) or secondary (functional). Degenerative MI results from structural valve deformity, whereas secondary MI is associated with annular dilatation, often in response to ischemic heart disease or other dilated cardiomyopathies of varying etiology. 3 MI is the leading cause of heart failure (HF) in response to heart valve disease and may progress to advanced disease if not properly treated. An estimated 80% of patients suffe ring from MI require at least one hospital admission per year, mostly to intensive care units. However, mitral valve disease is more common in older patients and individuals with several comorbidities, who are often not eligible for conventional mitral valve surgery due to high risk of intrao perative death and complications. 2,4,5 Surgical outco mes (valve repair or replacement) may also be limited, particularly in patients who are refractory to medical treatment (class IIb indication according to most international guidelines). [5][6][7][8] Wider access to novel therapeutic modalities are therefore needed, particularly for the large group of patients with limited therapeutic options due to high surgical risk or potentially limited surgical outcomes.

TRANSCATHETER MITRAL VALVE REPAIR
Several less invasive heart valve disease treatment techniques have been developed in the last decade ( Figure 1) 2,9 , including transcatheter mitral valve repair (TMVR), which is a percutaneous procedure for endovascular repair of incompetent mitral valves. 2,9 MitraClip ® is currently the only transcatheter system available for clinical use in Brazil. This system is based on the Alfieri procedure (Figure 2), in which two orifices are created by uniting the anterior and posterior leaflets of the mitral valve. 10 In this procedure, the catheter is introduced through the femoral vein and the right atrium into the left atrium using a standard transseptal approach over a guidewire and dilator. The system has a clip attached to its distal end, which is positioned orthogonally to the mitral valve and over the origin of the regurgitant jet ( Figure 2). Mitral valve leaflets are then held together and coaptation restored, with significant MI reduction. Primary clinical and anatomical criteria for MitraClip ® indication are summarized in table 1.
Data supporting approval of this device for clinical use were derived from several "real world" registry studies -European studies in particular -and the North American randomized trial EVEREST II (Endovascular Valve Edge-to-Edge Repair Study). In the latter study, 279 patients with chronic moderate-severe (3+) or severe (4+) MI secondary to poor anterior and posterior leaflet coaptation were randomized (2:1) to TMVR with MitraClip ® or traditional surgical treatment (valve replacement or repair). The primary efficacy endpoint (defined as survival, need for surgical valve replacement or moderate-severe or severe residual mitral regurgitation at 12 months) was reached by 55% of patients submitted to TMVR versus 73% of surgical patients (p=0.007). Mortality rates at 12 months were similar between groups (6%). However, the need for surgical correction of mitral valve dysfunction was greater in the   Source: copyright Abbott. Figure 2. MitraClip ® system based on the Alfieri procedure. 10 TMVR with clip relative to the surgery arm (20% and 2% respectively; p<0.001). At 1 year, the incidence of 3+ or 4+ MI was higher in the TMVR with clip as compared to the surgery arm (17% and 4%, respectively; p=0.01). At 5-year follow-up, mortality rates were similar between groups. 11 The primary safety endpoint of the study included severe adverse events at 30 days and was in favor of the TMVR with clip arm (TMVR, 15%, and surgery arm, 48%; p<0.001) due to the greater need of transfusion of one or more red blood cell units in surgical patients (13% versus 45%; p=0.01). Surgical morbidity rates as per Society of Thoracic Surgeons (STS) were 9% and 2% (surgical and TMVR patients respectively; p=0.02). The main conclusion of the EVEREST II trial was that, although percutaneous repair with clip was less effective in reducing mitral regurgitation compared to conventional surgery, the procedure was safer and led to similar clinical improvement, in spite of greater need for reintervention, particularly in the first 6 months. 11 Major findings of the EVEREST II trial are summarized in table 2.
The EVEREST II trial and several other global registries have shown that mitral clips can be used effectively in individuals with functional or degenerative MI. Therapeutic benefits of this intervention are reduced mitral regurgitation and improved functional class after implantation, which translate into better quality of life and less need for readmission due to HF. Especially in the functional or secondary MI population, the number of treated patients in the EVEREST II trial was small. Still, a subanalysis of this study revealed similar reduction in mitral regurgitation in a small group of patients with functional MI treated surgically or with MitraClip ® . 12 Specific, well-designed randomized trials comparing TMVR with clip and optimized medical management alone, for example, were still lacking.

RECENT TRIALS ADDRESSING MITRACLIP® USE IN SECONDARY OR FUNCTIONAL MITRAL INSUFFICIENCY
Given the limited outcomes of surgical treatment for secondary/functional MI, 3,13 and the lack of randomized trials comparing TMVR with clip and optimized medical management, findings of two important randomized trials have been recently published.
In the MitraClip® arm, the number needed to treat (NNT) in order to reduce readmission rates at 2 years was only 3.1 (95%CI 1.9-7.9) (Figure 2). All-cause mortality rates at 2 years were also significantly lower in the MitraClip® as compared to the OMT alone group (29.1% versus 46.1%; RR=0.62; 95%CI 0.46-0.82; p<0.001), yielding a NNT of only 5.9 patients treated to prevent one death at 2 years (95%CI 3.9-11.7). The rate of freedom from devicerelated complications at 12 months (primary safety endpoint) was only 96.6%. Significant (p<0.01) improvement in quality of life and functional capacity and significantly (p<0.01) reduced MI and left ventricular diameter (left ventricular end-diastolic diameter) were also reported. 15 The different outcomes between these two important contemporary trials addressing the use of TMVR with MitraClip® in functional or secondary MI are worthy of consideration. Deeper and detailed analysis of each of these studies raises several questions which may help clarify these differences, as summarized in table 3. Firstly, sample size (304 versus 614 patients) and follow-up time to primary endpoint assessment (12 versus 24 months) differed widely, so that the COAPT trial included twice the number of patients followed for twice as long. Also, the primary end point in the COAPT trial accounted for all HF admissions (including recurrent events), whereas the primary endpoint in the MITRA-FR trial comprised all-cause mortality or unplanned HF admission. As for inclusion criteria, different definitions of mitral regurgitation were adopted, the MITRA-FR trial enrolling patients with less severe MI (effective regurgitant orifice area >20mm 2 and/or regurgitant volume >30mL in the MITRA-FR trial versus >30mm 2 and >45mL in the COAPT trial). The MITRA-FR trial also included patients with more advanced HF (LVEF ranging from 15% to 40% and 20% to 50%, MITRA-FR and COAPT trial, respectively) and larger left ventricle. This translated into larger left ventricles (mean end-diastolic volume index of 135mL/m 2 versus 101mL/m 2 ) and less severe MI (effec tive regurgitant orifice area of 31±10mm 2 versus 41±15mm 2 ) in the MITRA-FR compared to the COAPT trial. With regard to implantation techniques, good success rates were reported in the MITRA-FR trial relative to previous observational studies. However, even better rates with less periprocedural complications were reported in the COAPT trail. Enrollment strategies also differed. In the COAPT trial, a central eligibility committee examined the current medical management of each patient prior to enrollment. Medical management was optimized prior to actual enrollment and few changes were made over the course of follow-up. In contrast, a more inclusive enrollment strategy was adopted in the MITRA-FR trial and changes in medical management according to real world practices were accepted. This may have translated into improvements obser ved in the control arm of the latter trial. Whether or not the above-mentioned differences impacted the results of both trials is not completely defined yet. Another recent important concept formulated to explain differences between both trials is the occurrence of disproportionate MI (Figure 4). 16 Patients with severe left ventricle dysfunction may be further categorized according to MI severity, and whether it is proportionate or disproportionate to the degree of ventricular dysfunction ( Figure  4). 17 Medical management aimed at decreasing left ventriclar volume overload (such as neurohormonal blockers) are effective in proportionate MI but no so much in disproportionate MI. In contrast, procedures aimed to improving mitral valve function (such as cardiac resynchronization and mitral valve repair) are effective in patients with disproportionate MI. This is yet another potential partial explanation for outcome differences between the MITRA-FR and COAPT trials.  Figure 2; Relationship between EROA and LVEDV illustrating domains that define disproportionately severe, proportionately severe, and nonsevere functional mitral regurgitation; p. 357. CRT: cardiac resynchronization therapy. Figure 4. Procedures aimed at transcatheter mitral valve repair should be indicated for patients with disproportionate mitral insufficiency relative to ventricular dysfunction severity (orange-colored region) rather than for those with proportionate or non-severe mitral insufficiency (grey and blue regions, respectively). The equation for the proportional relation corresponds to effective regurgitant orifice area divided by left ventricle enddiastolic volume (ratio=0.13-0.14). 16,17 Source: Grasso C, Popolo Rubbio A. The PASCAL transcatheter mitral valve repair system for the treatment of mitral regurgitation: another piece to the puzzle of edge-to-edge technique. J Thorac Dis. 2017;9(12):4856-59. 19    NTR, the MitraClip ® XTR and the Edwards Pascal TMVR systems are being incorporated. The MitraClip ® NTR is a third-generation device incorporating important changes, primarily in the delivery system, for easier navigation and clip positioning in the mitral valve through the left atrium. It also includes grippers made of nitinol wire for easier grasping of valve leaflets. In the XTR version, 3mm longer arms allow leaflet grasping even in cases with more challenging anatomy. A fourth-generation MitraClip ® device (G4 -NT/XT/NTW/XTW) shall be available in the near future. This version offers 9-and 12-mm long arms and wider arm width range (4 to 6mm). 18 This system also allows independent grasping of the anterior and posterior leaflets and continuous left atrial pressure monitoring. The Edwards Pascal system comprises a simplified left atrium navigation system consisting of a 10-mm central spacer to achieve MI reduction. This system also allows independent grasping of mitral leaflets and continuous left atrial pressure monitoring. 19 A recent study investigated MitraClip ® XTR in 107 patients (mean age, 76±9 years; 69% males) with functional (n=53; 50%), primary (n=40; 37%) or mixed etiology (n=14; 13%) MI. Of 102 patients (95.3%) who survived the procedure and were discharged with no need for surgery, 95 (93%) had MI ≤2+ and 79 (77%) MI ≤1+. Mean transmitral gradient increased from 1.9±1.0mmHg to 3.5±1.8mmHg upon hospital discharge (p<0.001). The mean number of clips per patient was 1.5±0.6 and 46 patients (43%) required multiple devices. Clip detachment, leaflet injury and conversion to open surgery were reported in four, two and four cases, respectively. Overall procedural success rate was 93%. 20 Another recent study evaluated the Pascal device in 23 patients (median age of 75 years) with moderate or severe MI. Patients received at least one Pascal device and residual MI <2+ was achieved in 22 (96%) cases. A second clip was required in six (26%) cases. The procedure was technically successful in 22 (96%) patients and successful outcome at 30 days was reported in 18 (78%) cases. 21

COMMENTS
According to guidelines provided by the major national and international societies, transcatheter mitral valve repair with clip is indicated for patients with moderate or severe mitral insufficiency (NYHA functional class III or IV dyspnea) who remain symptomatic in spite of optimized medical management, but are high-risk patients for conventional mitral valve surgery due to comorbidities ( Figure 6). 22,23 Life expectancy >1 year and favorable anatomy are other important criteria. Tridimensional transesophageal echocardiographic monitoring by a specialist is highly recommended to monitor the procedure. This procedure should be carried out by trained interventional cardiologists specialized in transcatheter procedures and the indication should be supported by a multidisciplinary team (clinical cardiologist, cardio vascular imaging specialist, cath lab specialist and surgeon). Recent randomized trials addressing MitraClip ® use in patients with functional mitral insufficiency suggest this therapy is actually effective in reducing mitral insufficiency in properly selected patients, with favorable anatomy, and should be performed by experienced operators and with high levels of precision, in order to control symptoms, improve patient quality of life, enhance left ventricular remodeling and, eventually, decrease mortality. Longterm follow-up on the COAPT and MITRA-FR trials and the ongoing RESHAPE-HF2 and MATTERHORN trials may contribute with additional information to further consolidate this intervention as an important therapeutic alternative for mitral valve disease. Finally, the results obtained with novel mitral clip devices (MitraClip ® NTR, MitraClip ® XTR, MitraClip ® G4 NTW and Edwards-Pascal) offering longer and wider arms, and allowing independent grasping of anterior and posterior leaflets, may translate into improved outcomes and greater benefits for patients.

SOURCE OF FUNDING
None.

DISCLOSURE OF CONFLICTS OF INTEREST
Henrique Barbosa Ribeiro is proctor of MitraClip ® (Abbott Vascular).

CONTRIBUTION OF AUTHORS
Conception and design of the study: HBR, FSBJ and AA; data collection: HBR, FSBJ and AA; data interpretation: HBR, FSBJ and AA; writing of the text: HBR, FSBJ and AA; approval of the final version to be published: HBR, FSBJ and AA.