*2.2.1. Percutaneous edge-to-edge mitral valve repair (PMVR): MitraClip®*

The MitraClip® system (Abbott Vascular, IL, USA) is thus far the first device that received regulatory approval and gained widespread clinical application. This device consists of two clip arms and opposing grippers, which can be opened and closed against each other in order to grasp and gain cooptation of MV leaflets at the origin of the regurgitant jet. The procedure is carried out under general anesthesia and using fluoroscopic and transesophageal echo guidance. Once the transseptal access is obtained, the system is advanced across the MV into the LV. Once the device is below the leaflets the two arms are opened and the device is retracted to capture and subsequently closed to increase the coaptation surface of the MV leaflets. The clip can be reopened and repositioned if the obtained result is not acceptable. Further clips can be placed as needed for optimal MR reduction. The amount of remainder MV tissue and resulting increase in transmitral pressure gradient are the main procedural limitations for further clip deployment. A second-generation device with improved maneuverability is now available.

Transcatheter edge-to-edge MV repair has proven to be a safe and effective technique in selected patients with either functional or degenerative MR. Feasibility of the therapy with MitraClip® was first demonstrated in the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) I trial [25] and subsequently compared with conventional surgery in the randomized controlled trial (RCT) EVEREST II [26]. In these studies, stringent echo criteria were used to guide the feasibility of device insertion and deployment. However, with increasing experience more complex valve pathologies can be treated with excellent results [27].

The vast majority of clinical evidence in PMVR is related to MitraClip® and it is currently the most advanced available technology for clinical use. In the EVEREST II trial, 184 patients were randomized (2:1) to receive MitraClip® therapy and 95 patients to undergo surgical MV repair or replacement. Included study population was older than reported surgical series of MV repair (mean age 67 years old) and presented higher rates of comorbidities. The device proved to be safer than surgery with a significant reduction of major adverse events (9.6% versus 57% with surgery, *p* < 0.0001), although this difference was mainly driven by a greater need for blood transfusion with surgery. Conversely, in the intent to treat analysis, survival free from the primary endpoint (death, MV surgery and MR > 2+) was lower with MitraClip® as compared with surgery (55% vs 73%, *p* = 0.0007) [26]. Results of this trial at 5 years follow-up confirmed the initial results of the study. In those patients with an initial successful repair, no differences in mortality or reoperation were found in the PMVR arm compared to surgery. The proportion of patients with MR grade 3+ or 4+ at 5-year follow-up was 19%, just the same observed at 1 year, reassuring the durability of the PMVR [28].

#### *2.2.1.1. Real-world candidates for percutaneous edge-to-edge mitral repair*

Although most patients included in the EVEREST II trial had degenerative MR, in the subgroup of patients with LVD and/or FMR, no differences in outcomes were observed between MV surgery and MitraClip®, opening a new niche for PMVR. In fact, subsequent observational studies, have mainly recruited patients with FMR, especially in Europe (**Table 2**) [29–36]. Beyond the learning curve, real-world reported results showed increasing rates of procedural success over 90–95%, compared to initial experience in the EVEREST I and II trials. Furthermore, observational published registries have reported very low shortterm adverse events and consistent improvements in symptoms, quality of life and MR reduction. Cohorts included in the main European registries may draw the profile of the current prototype of patient candidate for PMVR: advanced age, high-surgical risk, FMR and frequent history of ischemic heart disease, LVD and implantable stimulation device therapies (**Table 3**).


**Table 2.** Main multicenter trials and registries of PMVR.

to capture and subsequently closed to increase the coaptation surface of the MV leaflets. The clip can be reopened and repositioned if the obtained result is not acceptable. Further clips can be placed as needed for optimal MR reduction. The amount of remainder MV tissue and resulting increase in transmitral pressure gradient are the main procedural limitations for further clip deployment. A second-generation device with improved maneuverability is now

Transcatheter edge-to-edge MV repair has proven to be a safe and effective technique in selected patients with either functional or degenerative MR. Feasibility of the therapy with MitraClip® was first demonstrated in the Endovascular Valve Edge-to-Edge Repair Study (EVEREST) I trial [25] and subsequently compared with conventional surgery in the randomized controlled trial (RCT) EVEREST II [26]. In these studies, stringent echo criteria were used to guide the feasibility of device insertion and deployment. However, with increasing experi-

The vast majority of clinical evidence in PMVR is related to MitraClip® and it is currently the most advanced available technology for clinical use. In the EVEREST II trial, 184 patients were randomized (2:1) to receive MitraClip® therapy and 95 patients to undergo surgical MV repair or replacement. Included study population was older than reported surgical series of MV repair (mean age 67 years old) and presented higher rates of comorbidities. The device proved to be safer than surgery with a significant reduction of major adverse events (9.6% versus 57% with surgery, *p* < 0.0001), although this difference was mainly driven by a greater need for blood transfusion with surgery. Conversely, in the intent to treat analysis, survival free from the primary endpoint (death, MV surgery and MR > 2+) was lower with MitraClip® as compared with surgery (55% vs 73%, *p* = 0.0007) [26]. Results of this trial at 5 years follow-up confirmed the initial results of the study. In those patients with an initial successful repair, no differences in mortality or reoperation were found in the PMVR arm compared to surgery. The proportion of patients with MR grade 3+ or 4+ at 5-year follow-up was 19%, just the same observed at 1 year, reassuring the durability of the

Although most patients included in the EVEREST II trial had degenerative MR, in the subgroup of patients with LVD and/or FMR, no differences in outcomes were observed between MV surgery and MitraClip®, opening a new niche for PMVR. In fact, subsequent observational studies, have mainly recruited patients with FMR, especially in Europe (**Table 2**) [29–36]. Beyond the learning curve, real-world reported results showed increasing rates of procedural success over 90–95%, compared to initial experience in the EVEREST I and II trials. Furthermore, observational published registries have reported very low shortterm adverse events and consistent improvements in symptoms, quality of life and MR reduction. Cohorts included in the main European registries may draw the profile of the current prototype of patient candidate for PMVR: advanced age, high-surgical risk, FMR and frequent history of ischemic heart disease, LVD and implantable stimulation device

ence more complex valve pathologies can be treated with excellent results [27].

*2.2.1.1. Real-world candidates for percutaneous edge-to-edge mitral repair*

available.

120 Interventional Cardiology

PMVR [28].

therapies (**Table 3**).

#### *2.2.1.2. Special subsects of patients candidates for MitraClip*

#### *2.2.1.2.1. Non-responders to cardiac resynchronization therapy*

MitraClip® has also been proved to be a useful tool for those patients with HF not responding to cardiac resynchronization therapy (CRT) [37]. Auricchio et al. reported their experience with 51 patients who were severely symptomatic despite CRT therapy. In this cohort, PMVR was associated with a significant reduction in MR, clinical improvement and favorable remodeling echocardiographic parameters during a median follow-up of 14 months.


**Table 3.** Profile of patients that should be considered for PMVR.

#### *2.2.1.2.2. End-stage heart failure*

The effect of MitraClip® in patients with end-stage HF was reported by Franzen et al., analyzing the treatment of 50 patients with LV ejection fraction (LVEF) ≤ 25%, MR ≥ 3+ and severely symptomatic (NYHA III–IV) [38]. The acute procedural success was 94%, and 92% of patients were discharged with MR ≤ 2+. One month mortality was 6% (predicted by EuroScore 34%). At 6-month follow-up, 72% patients were in functional class NYHA I or II; there was inverse remodeling on echo follow-up and a relevant reduction in BNP levels. Several reasons may account for these results: first, the positive hemodynamic changes observed after treatment with reductions in pulmonary pressure, capillary wedge pressure and increase in cardiac output (CO). Second, the avoidance of the low CO post MV surgery; and third, the favorable remodeling in LV [39–41]. However, patients with very poor LVEF are at high-risk of mortality even with this thearpy. Careful selection of these candidates based on operators' experience, probability of success and expected benefits is strongly advisable [34].

#### *2.2.1.2.3. Acute ischemic mitral regurgitation*

Acute ischemic MR is a severe complication associated with high rates of morbimortality even when surgically corrected [42]. MitraClip® has proved to be a safe and effective alternative to surgical intervention in these unstable patients [43, 44]. Acute MR usually develops in a previously normal MV and therefore anatomical features are optimal for PMVR. Rapid improvement in patient's hemodynamics and the avoidance of the systemic inflammatory response associated with cardiopulmonary bypass are potential advantages of transcatheter approach [45]. MitraClip® implantation could be considered as an urgent therapy during admission in patients with recurrent pulmonary edema and/or cardiogenic shock in which MR is deemed to be the main cause of decompensation [46].

#### *2.2.1.2.4. Failing annuloplasty rings*

Undersized annuloplasty is currently the standard approach for MV surgical repair [47]. Even with the modern prosthetic mitral rings, long-term durability is a major concern in patients with FMR, in which the risk for recurrence can be over 50% at 2 years [48]. These patients are frequently symptomatic, with an increased number of hospitalizations, and present often significant LVD. Series from Italy and Spain have proved that the use of the device is safe and produces a persistent reduction in MR, hemodynamic improvement and symptom relief [49, 50]. Therefore, MitraClip® should be considered as an alternative therapy in this sort of patients, given the unacceptable high-risk that may carry reoperation.

#### *2.2.1.3. Expected benefits from percutaneous edge-to-edge repair*

#### *2.2.1.3.1. Persistent reduction in mitral regurgitation*

Persistent MR reduction is one of the main goals of PMVR. The target proposed since the EVEREST trials is to achieve a reduction of mitral insufficiency to a degree ≤2+ and this has been considered as a definition for procedural success (PS) and an acceptable result during follow-up [25]. Interestingly, the EVERST II trial was the one with the lower PS reported (77%) [26]. The use of a single clip in almost all the patients and the fact that the trial was conducted in the beginning of the learning curve of most centers may explain the lower efficacy of the device compared to surgery. With increasing following experience, PS has raised to over 90% of cases in most series, highly impacting the prognosis of patients [29, 32–34, 51, 52]. A persistent MR reduction is linked to better outcomes and "the less MR possible" should be the target of all procedures [53]. Conversely, inability to reduce MR is an independent marker of adverse prognosis [32, 34]. The mechanisms supporting this observation are likely to be related to the hemodynamic changes observed after MR correction [39, 40]. Recurrence of significant MR is around 6–21.1% at 1 year [29, 32]; notably similar figures are reported with surgical repair for ischemic FMR [18].

#### *2.2.1.3.2. Symptoms improvement*

*2.2.1.2.2. End-stage heart failure*

122 Interventional Cardiology

*2.2.1.2.3. Acute ischemic mitral regurgitation*

to be the main cause of decompensation [46].

*2.2.1.2.4. Failing annuloplasty rings*

The effect of MitraClip® in patients with end-stage HF was reported by Franzen et al., analyzing the treatment of 50 patients with LV ejection fraction (LVEF) ≤ 25%, MR ≥ 3+ and severely symptomatic (NYHA III–IV) [38]. The acute procedural success was 94%, and 92% of patients were discharged with MR ≤ 2+. One month mortality was 6% (predicted by EuroScore 34%). At 6-month follow-up, 72% patients were in functional class NYHA I or II; there was inverse remodeling on echo follow-up and a relevant reduction in BNP levels. Several reasons may account for these results: first, the positive hemodynamic changes observed after treatment with reductions in pulmonary pressure, capillary wedge pressure and increase in cardiac output (CO). Second, the avoidance of the low CO post MV surgery; and third, the favorable remodeling in LV [39–41]. However, patients with very poor LVEF are at high-risk of mortality even with this thearpy. Careful selection of these candidates based on operators' experi-

Acute ischemic MR is a severe complication associated with high rates of morbimortality even when surgically corrected [42]. MitraClip® has proved to be a safe and effective alternative to surgical intervention in these unstable patients [43, 44]. Acute MR usually develops in a previously normal MV and therefore anatomical features are optimal for PMVR. Rapid improvement in patient's hemodynamics and the avoidance of the systemic inflammatory response associated with cardiopulmonary bypass are potential advantages of transcatheter approach [45]. MitraClip® implantation could be considered as an urgent therapy during admission in patients with recurrent pulmonary edema and/or cardiogenic shock in which MR is deemed

Undersized annuloplasty is currently the standard approach for MV surgical repair [47]. Even with the modern prosthetic mitral rings, long-term durability is a major concern in patients with FMR, in which the risk for recurrence can be over 50% at 2 years [48]. These patients are frequently symptomatic, with an increased number of hospitalizations, and present often significant LVD. Series from Italy and Spain have proved that the use of the device is safe and produces a persistent reduction in MR, hemodynamic improvement and symptom relief [49, 50]. Therefore, MitraClip® should be considered as an alternative therapy in this sort of

Persistent MR reduction is one of the main goals of PMVR. The target proposed since the EVEREST trials is to achieve a reduction of mitral insufficiency to a degree ≤2+ and this has been considered as a definition for procedural success (PS) and an acceptable result during follow-up [25]. Interestingly, the EVERST II trial was the one with the lower PS reported (77%)

patients, given the unacceptable high-risk that may carry reoperation.

*2.2.1.3. Expected benefits from percutaneous edge-to-edge repair*

*2.2.1.3.1. Persistent reduction in mitral regurgitation*

ence, probability of success and expected benefits is strongly advisable [34].

Symptomatic improvement is one of the most reported benefits of this therapy. Preprocedure patients are usually highly symptomatic with proportions of NYHA functional class III–IV over 85% in published series. After treatment with MitraClip®, there is a significant recovery in the functional capacity with patients presenting on NYHA functional class I–II in a range of 63.3–86% [29, 32, 34, 54, 55]. Furthermore, patients as well experience improvement in 6 minutes-walk test [29] and quality of life [54, 56], and a significant reduction in serum BNP levels [38]. Clinical improvement does also lead to a significant reduction in readmissions for HF, which reduces costs of patients' health care and might probably turn into better prognosis [55].

#### *2.2.1.3.3. Survival advantage*

Survival of patients with FMR treated with MitraClip® is in the range of 15.3–20.3% within the first year [29, 32, 34]. The largest follow-up reported showed an actuarial survival at 3 years of 74.5% [55].

The available evidence to date regarding this issue relies mainly on retrospective studies. The first published was the EVEREST high-risk study [57], where 78 patients with high-surgical risk (STS ≥ 12%) were treated with MitraClip® and compared with a cohort of 36 patients managed medically. At 1 year, MitraClip® patients have significant higher survival rates (76% PMVR vs. 55% medical therapy, *p* = 0.045). In a study by Swaans et al. [58], 139 patients treated percutaneously were compared to 59 patients medically treated. After controlling by propensity score matching, MitraClip® was associated with a relative reduction in the risk of mortality of 59%. In another paper, Velazquez et al. [59] compared the outcomes of 351 patients included in the EVEREST high-risk registry with a historic comparator cohort. Two-hundred and thirty-nine propensity-matched patients in each group were analyzed and MitraClip® was associated with a 1 year improved survival (mortality 22.4% MitraClip® vs. 32% medical therapy, *p* = 0.043). The relative risk reduction in mortality associated with the device was 34%. Finally, Giannini et al. [60] included 60 patients treated with MitraClip® and propensity matched with 60 patients with OMT. After a median follow-up of 515 days, patients treated with PMVR showed less mortality, less cardiac mortality and less readmissions due to heart failure (log-rank test *p* = 0.007, *p* = 0.002 and *p* = 0.04, respectively). While we wait for the final confirmation of these results in currently ongoing RCTs, this information encourages the application of the therapy.

### *2.2.1.3.4. Effect on heart remodeling: mitral annulus and left ventricle*

Reverse LV remodeling is the 'holy grail' of PMVR. Reported results from surgical series of primary MR have been linked to better prognosis [61]. Echo reports from EVEREST trial have demonstrated that there is an inverse remodeling after a successful MitraClip® procedure involving both the left chambers (ventricle and atrium) [62]. Interestingly, the magnitude of the reverse remodeling is greater with greater reduction in MR and this positive effect is maintained at 5 years follow-up [28]. Similar findings were reported in the EVEREST highrisk cohort [55, 57], although, in these series, patients with LVEF below 25% and severe LV dilation (LV end-systolic diameter > 55 mm) were excluded. By contrast, real-world FMR patients treated with MitraClip® tend to exhibit poor or no remodeling at all [32]. One possible explanation for these conflicting results is that real-world patients are treated too late in the natural history of the chronic HF disease, when the LV is largely dilated and LVEF is severely depressed. These patients are less likely to show reverse remodeling and this is a hint for the best timing for PMVR.

Although PMVR with MitraClip® reproduces somehow the Alfieri procedure, traction forces within MV may also favor MA remodeling. Recent studies have demonstrated that in FMR, the MA size (anteroposterior diameter), the MA area and the tenting area are significantly reduced after device implantation [63]. Furthermore, this reduction is associated with an improved functional status at 6 month after the procedure [64]. Conversely, in primary MR, MA parameters remain stable after clipping. Therefore, the potential association of an indirect annuloplasty-like effect may improve mid-term results of this therapy in patients with FMR.

#### *2.2.2. Percutaneous chordal replacement: Neochord®*

Neochord® (Neochord, Minnesota, MN) are the first ePTFE chordal loops conceived to be implanted on the MV leaflets to correct flail or prolapse [65]. Colli et al. reported the results of transapical off-pump mitral valve implantation of Neochord in 62 patients with MV prolapse [66]. Thirty-day major adverse events included one acute myocardial infarction (2%) and two cases of sepsis (3%). MR at 30 days was grade 1+ or 2+ in 55 patients (88.7%).

#### *2.2.3. Transcatheter mitral valve annuloplasty (TMVA): Carillon®, Cardioband®, Mitralign®*

Annuloplasty is the most common surgical repair performed to treat MR [47]. This technique is widely used as a stand-alone procedure to enhance MV coaptation in FMR or added to leaflet repair in degenerative MR in order to improve durability [67]. Based on prior large surgical experience, some percutaneous novel devices have tried to reproduce undersized MV annuloplasty to address dilatation of the MA. A reliable TMVA has the potential to improve outcomes in combination with edge-to-edge repair in selected patients and to increase therapeutic alternatives in patients with anatomic ineligibility for MitraClip®. As a further potential advantage, unlike the MitraClip®, this approach preserves the native valve anatomy, thus keeping the option for future valve implantation open. In fact, some of the annuloplasty rings may actually serve as a dock for the anchoring of available transcatheter aortic valves ("valve-in-ring" procedure).
