Early Experience With Transcatheter Mitral Valve Replacement: A Systematic Review

Background Transcatheter mitral valve replacement (TMVR) has emerged as an alternative therapeutic option for the treatment of severe mitral regurgitation in patients with prohibitive or high surgical risk. The aim of this systematic review is to evaluate the clinical procedural characteristics and outcomes associated with the early TMVR experience. Methods and Results Published studies and international conference presentations reporting data on TMVR systems were identified. Only records including clinical characteristics, procedural results, and 30‐day and midterm outcomes were analyzed. A total of 16 publications describing 308 patients were analyzed. Most patients (65.9%) were men, with a mean age of 75 years (range: 69–81 years) and Society for Thoracic Surgery Predicted Risk of Mortality score of 7.7% (range: 6.1–8.6%). The etiology of mitral regurgitation was predominantly secondary or mixed (87.1%), and 81.5% of the patients were in New York Heart Association class III or IV. A transapical approach was used in 81.5% of patients, and overall technical success was high (91.7%). Postprocedural mean transmitral gradient was 3.5 mm Hg (range: 3–5.5 mm Hg), and only 4 cases (1.5%) presented residual moderate to severe mitral regurgitation. Procedural and all‐cause 30‐day mortality were 4.6% and 13.6%, respectively. Left ventricular outflow obstruction and conversion to open heart surgery were reported in 0.3% and 4% of patients, respectively. All‐cause and cardiovascular‐related mortality rates were 27.6% and 23.3%, respectively, after a mean follow‐up of 10 (range: 3 to 24) months. Conclusions TMVR was a feasible, less invasive alternative for treating severe mitral regurgitation in patients with high or prohibitive surgical risk. TMVR was associated with a high rate of successful valve implantation and excellent hemodynamic results. However, periprocedural complications and all‐cause mortality were relatively high.

M itral regurgitation (MR) is the leading cause of heart valve disease in Western countries and affects %10% of people aged >75 years. 1 Conventional mitral valve surgery (either repair or replacement) remains the standard of care for patients with symptomatic severe MR, but close to half of such patients are not referred to conventional surgery because of potential comorbidities and high surgical risk. 2 In recent years, several transcatheter mitral valve technologies have emerged as alternatives to surgery for the treatment of MR in patients deemed to be at increased surgical risk. Edge-to-edge leaflet repair (MitraClip; Abbott) is the transcatheter mitral valve repair (TMVr) system with the most experience and the only one approved by the US Food and Drug Administration to date. However, a percentage of patients remain suboptimal candidates for this technology, and residual moderate or severe MR after edge-to-edge leaflet repair has been reported in %10% of patients in real-world practice. 3,4 Transcatheter mitral valve replacement (TMVR) has emerged as an alternative to TMVr for treating severe MR. 5 A limited number of TMVR systems are under clinical evaluation, and others have started preclinical development programs. The objective of this systematic review is to evaluate the clinical and procedural characteristics and (early and midterm) clinical outcomes associated with TMVR.

Methods
The data that support the findings of this study are available from the corresponding author on reasonable request.
A comprehensive systematic review of published data describing outcomes from different TMVR systems was performed in agreement with the guidance and the reporting items specified the Preferred Reported Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. 6 A computerized search was performed to identify all relevant studies from the PubMed and Embase databases. Further data were sought by manual search of secondary sources, including references from primary papers (backward snowballing) and data reported in expert international conferences (Transcatheter Cardiovascular Therapeutics, Transcatheter Valve Therapies, Cardiovascular Research Technologies, EuroPCR, and PCR London Valves). The following keyword terms were used: TMVR, TMVI (transcatheter mitral valve implantation), transcatheter/percutaneous mitral valve replacement/implantation. Databases were last accessed January 3, 2019, and studies were included if they were published in English. Transcatheter aortic valve systems used in patients with mitral surgery bioprosthetic or annuloplasty ring dysfunction (valve-in-valve and valve-in-ring procedures) or patients with severely mitral annular calcification (MAC) were beyond the focus of this systematic review.
The data were extracted using a standardized data abstraction sheet. Clinical characteristics, procedural results, and 30-day and midterm outcomes were collected as reported by the authors. Two investigators (D.d.V. and A.N.F.-N.) conducted the literature search selection and data extraction in duplicate. Any discrepancies were resolved by consensus, when needed, with a third investigator (J.R.-C.). Gathered data included (when available) baseline clinical characteristics and relevant comorbidities, echocardiographic results, procedural details, procedure-related complications, and follow-up outcomes. Any TMVR system with at least 1 source (either published or reported in an international congress) describing a clinical experience was included. We excluded studies (1) that included patients using transcatheter aortic valve devices for valve-in-valve, valve-in-ring, or valve-in-MAC procedures; (2) that reported data from preclinical device evaluations; or (3) that reported results only on specialized news websites. When more than 1 reference provided data from the same cohort of patients, only the most recent or the one that provided more detailed data was included.

Statistical Analysis
Continuous variables were expressed as meanAESD. Global cohort values were reported as weighted mean (range) or frequency (percentage). Weighted mean was calculated according to the total number of patients for each device (weight=n). When needed, the method devised by Hozo et al. 7 was used for estimating the standard deviation of the sample. Data analyses were performed using the STATA software (v15.1; StataCorp).

Baseline Characteristics
The main baseline clinical characteristics of TMVR recipients are described in Table 2. The mean age of the patients was 75 years (range: 69-81 years), and 65.9% of patients were men. Most patients (81.5%) were in New York Heart Association (NYHA) class III or IV, and almost half (47.2%) exhibited at least 1 episode of heart failure hospitalization within the year before the TMVR procedure. The mean Society for Thoracic Surgery Predicted Risk of Mortality (STS-PROM) score was 7.7AE0.8%, ranging from 6.14% to 8.6%. Severe comorbidities were frequent, including coronary artery disease (70.3%), prior coronary artery bypass grafting (44.2%), chronic renal insufficiency (60.3%), and atrial fibrillation (55.2%). Mean left

Clinical Perspective
What Is New?
• Early experience with transcatheter mitral valve replacement supports its feasibility, with a high rate of technically successful valve implantation in selected patients.
• Transcatheter mitral valve replacement shows excellent hemodynamic results with a low rate of residual mitral regurgitation and low transvalvular gradients. • Procedure-related complications and midterm mortality remain relatively high.
What Are the Clinical Implications?
• Transcatheter mitral valve replacement has emerged as an alternative treatment option for patients with prohibitive or high surgical risk. • Further iterations of transcatheter mitral valve replacement systems, a gradual increase in use of the transfemoraltranseptal approach, and improved patient selection will be essential for a widespread adoption of this technology as an alternative to conventional surgery. ventricular (LV) ejection fraction was 42AE4% (range: 30-46%). The indication for TMVR was predominantly secondary (functional) or mixed severe MR (87.1%), and 36 patients (12.9%) were diagnosed with primary MR.

Procedural and 30-Day Results
Procedural details and 30-day outcomes are shown in

Midterm Follow-Up
Follow-up (>30-day) data were available for 7 of 11 TMVR systems. Mean follow-up was 10.1AE0.3 months, ranging from 3 to 24 months. The main clinical outcomes during the followup period are summarized in Table 4. The all-cause mortality

Discussion
The main findings of this systematic review on the initial TMVR experience in patients with severe MR can be summarized as follows. First, the data support the feasibility of TMVR, with a high rate of successful valve implantation. Second, TMVR was associated with excellent hemodynamic results, with a very low rate of significant residual MR and low transvalvular mitral gradients after the procedure. Third, the rates of periprocedural complications and early mortality were relatively high. Fourth, most patients improved their functional   Table 3.

Patient Selection Considerations
This review showed that patients selected for TMVR were elderly and exhibited a high comorbidity burden, leading to high to prohibitive surgical risk. In addition, most patients had secondary MR, with reduced LV ejection fraction. Appropriate patient selection for TMVR may be challenging and requires a global assessment including patient comorbidities, mechanisms of MR, and structural/anatomical features. Unfortunately, limited data were provided on inclusion and exclusion criteria and screen failure rates in most TMVR series. Although these details were formally reported in only 2 registries, the global rate of screen failure was presumably high. In the Tendyne Global Feasibility Study, only 100 of 332 patients screened were finally included (screen failure %70%). 23 Similarly, in the Global Pilot Study with the Intrepid TMVR system, only 50 of 166 patients screened were selected. The most common exclusion criteria were severe LV dysfunction, large annulus dimensions, high risk of LV outflow tract obstruction, severe mitral annular or leaflet calcification, previous mitral or aortic valve surgery, intracardiac thrombus, severe pulmonary hypertension, severe tricuspid valve regurgitation, and severe right ventricular dysfunction. Moreover, patient selection was limited by valve size availability in some cases. The mitral valve apparatus is a complex dynamic structure and multiple important anatomical aspects should be considered. Unlike transcatheter aortic valve replacement, TMVR must address challenges such as (1) noncircular saddle-shape dynamic annulus of large dimensions, (2) lack of calcified or rigid mitral annulus, (3) irregular leaflets geometry, (4) proximity of LV outflow tract, and (5) the presence of the subvalvular apparatus. Thus, the use of imaging techniques like 3-dimensional computed tomography is key for evaluating patient eligibility, and anatomical issues remain the most important factor determining TMVR feasibility. 30

Procedural Aspects and Early Outcomes
The vast majority of procedures (>80%) were performed through a transapical approach, with only 4 devices implanted through a transfemoral-transeptal approach Sapien M3 (Edwards Lifesciences, Irvine, CA, USA), Caisson (LivaNova PLC, London, UK), CardiAQ (Edwards Lifesciences, Irvine, CA, USA) and CardioValve (Cardiovalve Ltd., Or Yehuda, Israel). This choice is related to the large size of the valve-delivery catheters along with the location of the mitral valve, which makes the appropriate alignment of the transcatheter valve more difficult when using the antegrade transeptal approach. Although this  study represented the initial experience with different TMVR platforms, technical success was high, and successful valve implantation was achieved in up to 92% of cases (range: 73-100%). In addition, significant LV outflow tract obstruction was reported in only 1 case, probably reflecting the appropriateness of preprocedural imaging workup along with conservative eligibility criteria. However, conversion to open heart surgery was required in 4% of patients. The causes were chordal entanglement (2 cases), valve malposition (4 cases), and the presence of multiple papillary muscles, a septal bulge, and a thickened LV posterior wall impeding the proper placement of a wire after apical puncture (1 case). While these complications may be part of the learning curve process, it highlights the importance of heart teams and specialized centers with high surgical experience dedicated to these procedures. Importantly, the results regarding valve performance showed a very low rate of significant residual MR (moderate or severe: 1.5%) and low transvalvular gradients (mean: <4 mm Hg) following the procedure. These results appear to be similar to those associated with surgical mitral valve repair and replacement 3 and superior to those reported in transcatheter TMVr series, including the most recent studies with the MitraClip device. [31][32][33][34][35] Despite the good results regarding procedural success and valve performance, the 30-day mortality rate after TMVR was as high as 13.6% (varying from 0% to 60%), which exceeded the estimated surgical risk (mean STS-PROM of the study population: %8%) and was much higher than that reported in TMVr series including patients with a similar risk profile. 31,36 The causes of such high periprocedural mortality are probably multifactorial. First, in addition to the significant comorbidity burden, the fact that most patients had secondary MR as the underlying disease may have contributed. 37,38 Second, the rate of periprocedural complications like major or life-threatening bleeding or acute kidney injury-both associated with poorer outcomes-was high (>10%). This may be partially related to the use of the transapical approach in most patients, which has also been associated per se with a negative clinical impact, particularly in elderly and frail patients. 39,40 Third, the myocardial injury secondary to the transapical approach may be particularly deleterious in patients with already reduced ventricular function. 41 Similar to the transcatheter aortic valve replacement field, a progressive transition toward increasing use of transfemoral systems will likely occur in the near future and may translate into improved outcomes. Finally, the learning curve process probably contributed to the high mortality rate observed in this initial TMVR experience.

Midterm Outcomes
Although the results were highly heterogeneous among different TMVR systems, the mean mortality rate was as high as 28% after a mean follow-up close to 1 year. This rate is similar to that reported by the STS/ACC TVT Registry (Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy) including 2952 patients (mean STS-PROM: %6%) with secondary MR treated with the MitraClip system. 31 Although the high noncardiac comorbidity burden of TMVR recipients may have contributed, it has to be noted that about half of the deaths were related to cardiovascular causes. In addition, a significant proportion of patients were hospitalized for heart failure decompensation within the months following the procedure. Importantly, no deaths specifically related to transcatheter valve dysfunction were reported. Two recent trials evaluating the efficacy of TMVr with the MitraClip system for treating secondary MR provided contradictory results, 34,35 highlighting the importance of adequate patient selection to avoid treatment futility in this population. Future studies are needed to determine which patients may benefit the most from TMVR.
Although the follow-up duration was limited, no signs of early valve degeneration were detected following TMVR (up to 1-year follow-up). Future studies with longer follow-up should provide extended valve durability data. However, device thrombosis was reported in 3% of patients, highlighting the importance of appropriate antithrombotic treatment following these procedures. Anticoagulation therapy for a minimum of 3 months was recommended in most TMVR studies, probably mimicking the recommendations from current guidelines regarding conventional surgical mitral valve replacement. Future studies will need to evaluate the optimal antithrombotic strategy in these patients.  35 However, the COAPT (Clinical Outcomes Assessment of the MitraClip Percutaneous Therapy) trial demonstrated significantly lower all-cause mortality and rehospitalization for heart failure in patients who underwent the MitraClip procedure. 34 Main patient baseline characteristic and results comparing the TMVR population with the COAPT device group are summarized in Table 5.

TMVR Versus TMVr
Although both techniques have shown promising results, they have some potential theoretical advantages and limitations. TMVr may be technically more challenging, and mitral anatomy is not suitable in all patients. In addition, hemodynamic results with TMVr devices are less predictable, and the rates of at least moderate residual MR are %10%. 3,4 Safety and procedure-related complications seem to favor TMVr, probably because of the widely used transfemoral approach, lower profile catheters, and consistent hemodynamic stability during the procedure. Moreover, some concerns have been raised about TMVR platforms. It is well known in the surgical field that in patients <65 years, bioprosthetic valves degenerate earlier, driving increased reoperation rates and shorter long-term survival. 42 However, to date, evidence regarding efficacy and long-term durability with TMVR devices remain unclear. Furthermore, antithrombotic therapy in TMVR patients has yet to be formally established, and evidence is limited regarding the risk of valve thrombosis. Most platforms recommended a minimal anticoagulation treatment duration of 3 months postoperatively, usually based on current guidelines for surgical bioprosthetic valves. Further data are needed to determine the best antithrombotic strategy in this scenario. Consequently, both TMVR and TMVr systems should be considered as complementary treatments in patients with high surgical risk and severe MR.

Study Limitations
This study has the limitations inherent to a systematic review that collects only information described in the publications or reported in international conferences; thus, relevant information might be omitted in the review that could shed some more light on this topic. In addition, this systematic review analyzed a limited series of patients for whom, in some cases, only collective data were available. Indeed, incomplete individual data regarding some patient baseline characteristics, procedure-related aspects, and follow-up may have prevented complete and accurate clinical evaluation. Finally, the reported patients might have had better outcomes than those who were not published (ie, selection bias).
In conclusion, TMVR has emerged as a less invasive alternative to conventional surgery for treatment of severe MR in patients with high or prohibitive surgical risk. The early experience with TMVR showed a high rate of technically successful valve implantations and excellent hemodynamic results with a low rate of residual MR. However, despite the heterogeneity of the results, procedure-related complications and midterm mortality remained high. Improvement of patient selection, further iterations of TMVR systems, and a gradual increase in use of the transfemoral-transeptal approach might be necessary before the widespread adoption of this technology as an alternative to conventional surgery. The confirmation of TMVR as an option complementary to TMVr would drastically increase therapeutic options for patients with severe MR and increased surgical risk.

Sources of Funding
Dr del Val is supported by a research grant from the Fundaci on Alfonso Mart ın Escudero (Spain). Dr Rod es-Cabau holds the Research Chair "Fondation Famille Jacques Larivi ere" for the Development of Structural Heart Disease Interventions.