Author + information
- Received November 15, 2016
- Revision received February 12, 2017
- Accepted February 12, 2017
- Published online April 24, 2017.
- aQuebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada
- bCardiovascular Research Foundation, Skirball Center for Innovation, Orangeburg, New York
- ↵∗Address for correspondence:
Dr. Josep Rodés-Cabau, Quebec Heart and Lung Institute, Laval University, 2725 Chemin Ste-Foy, G1V 4GS Quebec City, Quebec, Canada.
Transcatheter mitral valve repair, particularly edge-to-edge leaflet repair, is a well-established alternative for patients with severe primary mitral regurgitation (MR) considered at high or prohibitive surgical risk. More recently, transcatheter mitral valve replacement (TMVR) has emerged as a potential therapeutic option for the treatment of severe MR. TMVR may offer some advantages over transcatheter repair by providing a more complete and reproducible MR reduction. Several devices are under preclinical and clinical evaluation, and the early experience with more than 100 patients has demonstrated the feasibility of TMVR. In this review, we describe the TMVR systems currently in development and the results obtained from early clinical experiences. We also discuss the main challenges in and future perspectives on this emerging field. Future studies with a much larger number of patients are needed to provide consistent safety and efficacy data on each of the TMVR systems.
Mitral regurgitation (MR) is the most prevalent form of valve disease in developed countries, affecting ∼10% of people older than 75 years of age (1,2). MR management is dependent on the cause, pathophysiology, natural history, and expected treatment efficacy. Mitral valve repair or replacement is the gold standard treatment for MR, but some studies have shown that up to one-half of the patients with severe symptomatic MR are not referred for surgery (3,4). The mortality rate in such patients reaches 50% at 5 years of follow-up, and up to 90% of surviving patients had at least 1 hospitalization for heart failure within the 5 years after the diagnosis of severe MR (3,4). Lack of surgical referral is related, in part, to the perceived risk of the procedure, and an alternative, less invasive approach in vulnerable patients would be desirable. It should be noted, however, that a significant proportion of patients with severe MR suffer from secondary MR, and no strong evidence exists yet for the efficacy of any valve intervention in terms of survival or improvement in quality of life in such patients (5).
Over the last decade, several transcatheter mitral valve repair technologies adapted from different surgical techniques have emerged for treating MR in patients at high or prohibitive surgical risk. The transcatheter mitral valve repair “tool box” is rapidly expanding, with up to 5 devices already approved in Europe, including the MitraClip (Abbott Vascular, Inc., Santa Clara, California), the DS1000 device (NeoChord, Inc., St. Luis Park, Minnesota), the Carillon (Cardiac Dimensions, Inc., Kirkland, Washington), the CardioBand (Valtech Cardio, Or Yehuda, Israel), and the Mitralign device (Mitralign, Inc., Tewksbury, Massachusetts). In current practice, transcatheter mitral valve repair is mainly limited to the MitraClip device, which mimics the edge-to-edge leaflet repair described by Alfieri et al. (6). Since the introduction of MitraClip in 2003, more than 35,000 patients have been treated (7) with high success and safety rates, translating into some degree of functional improvement in most patients (8–11).
Transcatheter mitral valve replacement (TMVR) may offer several theoretical advantages over transcatheter repair. Considering the complexity and heterogeneity of mitral valve disease, the development of a transcatheter mitral valve repair device to target all anatomic variations and patient risk profiles will be difficult and presents several challenges. TMVR could offer a more universal concept for treating mitral valve disease, with a more predictable decrease in MR severity, in a procedure that could potentially be less invasive compared with current surgical techniques (12). Additionally, the utility of TMVR will need to be further assessed due to the fact that surgical mitral valve repair has excellent results in patients with severe primary MR (5), and it is unknown whether intervention will result in any changes in outcome in patients with severe secondary MR.
The objectives of this review were to provide an overview of the main technical characteristics of different TMVR devices under preclinical and clinical evaluation and to analyze the main clinical results and challenges experienced in the initial phases of clinical validation. TMVR using transcatheter aortic valve systems in patients with severely calcified mitral annuli (13) and valve-in-valve procedures for the treatment of mitral surgical bioprosthetic dysfunction (14) are beyond the focus of this review.
Challenges for TMVR Development
Target valve and/or disease
One of the main challenges presented by TMVR relates to the position and complex anatomy of the mitral valve. Transseptal access and a delivery catheter with high-flexure capabilities are needed in order to reach the native mitral valve with a fully percutaneous approach. Also, several aspects of the valve anatomy may increase the difficulty of TMVR: asymmetrical annulus and irregular geometry of valve leaflets; large dimensions; no calcified structure in most cases; and a complex subvalvular anatomy (which should be preserved).
MR is a very heterogeneous disease resulting from the dysfunction of any of the components of the mitral valve apparatus or surrounding structures. MR has multiple causes with different stages of severity. As MR evolves, there are changes to the ventricle associated with geometrical distortion, which have a wide range of variations as the disease progresses over time. Due to this extensive variability, it is challenging to develop a “universal device concept” tailored to target all potential anatomic variations seen in all MR types and patient risk profiles.
Similar to the transcatheter aortic valve replacement (TAVR) experience, a fully percutaneous transfemoral (venous) procedure would be the less invasive and preferred approach for TMVR. However, that approach faces the challenges of a high-profile delivery system (to accommodate a large valve prosthesis) that has to negotiate an extreme angle within a relatively small space (through the transseptal approach) to reach the mitral valve. This is partially the reason why most TMVR systems to date have been developed to deliver the valve prosthesis transapically, following a puncture of the ventricular apex. The transapical approach has been a common alternative in TAVR for patients without iliofemoral access and has the advantage of a very short distance between the access and the target valve, also allowing good alignment of the valve prosthesis with small movements of the delivery system. However, many studies have reported poorer outcomes associated with transapical TAVR (compared with transfemoral access), likely related to a higher degree of myocardial injury, along with the negative effects of a thoracotomy in a high-risk and frail population (15–17). The transition from transapical to transseptal delivery of clinically available TMVR devices will require important engineering modifications in size and possible valve designs and anchoring mechanisms.
Valve prosthesis anchoring and sealing
The pathophysiology and anatomic substrate of MR is complex and heterogeneous. One of the main challenges in the development of TMVR is trying to obtain prosthesis stability similar to that of surgical mitral valve replacement. In contrast to TAVR, where the landing zone for the prosthesis is a tubular calcified structure, the valve prostheses used to treat MR in native valves need to be anchored into a dynamic, D-shaped noncalcified structure. To tackle this issue, several mechanisms have been proposed (18,19), including: 1) application of counteracting axial forces, tensioning the device between a proximal and a distal constraint (apical tether; Tendyne valve; Abbott Vascular, Abbott Park, Illinois); 2) ventricular anchors to grasp the free margins of the native leaflets (native leaflet engagement; Tiara valve; Neovasc, Richmond, British Columbia, Canada); 3) atrial and ventricular flanges that engage the mitral annulus and mitral leaflets/chordae (mitral annulus clamping; CardiAQ-Edwards; Edwards Lifesciences, Irvine, California); 4) a series of anchors around the edge of the valve that either pierce the mitral valve tissue or provides friction with radial interference (annular winglets; NaviGate valves; NaviGate Cardiac Structures, Lake Forest, California); 5) a “champagne cork-like” effect produced by a radial force along the valve stent (radial force; Intrepid valve; Medtronic, Minneapolis, Minnesota); and 6) simultaneous creation of a landing zone by implanting a ring or a docking system (external anchor; Caisson [anchor is fixed by mitral annulus clamping]; Maple Grove, Minnesota), MValve (subannular mitral ring; Herzliya, Tel Aviv, Israel), and HighLife valves (dock is anchored by mitral annulus clamping; HighLife Medical, Irvine, California) (Central Illustration).
Valve sealing is also a major challenge in TMVR. The complex 3-dimensional (3D) anatomy with a dynamic morphology of the mitral annulus, along with the high-pressure gradient generated by the ventricle during systole, may contribute to the occurrence of significant paravalvular leakage following valve implantation.
Left ventricular outflow tract obstruction
Left ventricular outflow tract (LVOT) area is decreased following mitral surgery with annuloplasty rings and prostheses (20), and LVOT obstruction after surgical mitral valve procedures has also been described (21). This phenomenon has not been limited to the use of surgical prostheses, and it has also been described following transcatheter mitral procedures with nondedicated devices. The reported rate of acute LVOT obstruction with transcatheter mitral valve-in-ring procedures is 8.2% (14), and it increases up to 9.3% following TMVR in the presence of severe mitral annular calcification (13). Multiple factors should be evaluated when determining the risk of LVOT obstruction after TMVR (22,23): the aortomitral-annular angle, which is the angle between the annular planes of these 2 valves (if the angle is obtuse, there may be a higher risk of obstruction, as the struts of the prosthesis will encroach on the LVOT); degree of septal hypertrophy; left ventricle size; and device protrusion and flaring into the LVOT.
Pre-procedural planning and multimodality imaging
Pre-procedural multimodality imaging is essential for TMVR planning. Pre-procedural imaging is used to define the presence, type, and severity of MR; to confirm patient eligibility according to the anatomic characteristics and the prosthetic valve designs; to identify patients at risk for possible specific TMVR complications (e.g., LVOT obstruction); and to determine pre-operative prediction of fluoroscopic angulation and access location.
Echocardiography remains the gold standard for diagnosing MR (5). A comprehensive echocardiographic examination helps to establish the cause, mechanism, and severity of MR and the impact of MR on myocardial function. Additionally, echocardiography with 3D segmentation of the mitral annulus can be used as the initial screening imaging modality for TMVR in patients with impaired renal function who are at risk for acute kidney injury with contrast computed tomography (CT).
Although echocardiography is the primary imaging modality for the diagnosis and quantification of MR, CT is the preferred imaging modality for pre-procedural TMVR evaluation. However, with improving 3D technology, transesophageal echocardiography could assume a more important role over time. Electrocardiogram (ECG)-gated cardiac CT offers 3D volumetric data sets with submillimeter spatial resolution, enabling a comprehensive assessment by providing an exact characterization of the anatomy of the subvalvular apparatus and the geometry of the mitral valve (24). This process has also been shown to be highly reproducible (25,26). In addition to ECG-gated cardiac CT, non–ECG-gated CT data acquisition of the thorax may be performed to evaluate thoracic wall anatomy for device deployment in transapical approaches and of the pelvis to evaluate the iliofemoral venous diameter in patients undergoing transfemoral TMVR. Three-dimensional CT reconstruction data are used during the screening process to assess mitral valve anatomy and determine the appropriateness of different devices for each individual patient. Although it is currently the preferred modality for pre-procedural TMVR evaluation, there is still uncertainty about the most important variables, as many of the measurements are empirical, requiring validation (Figure 1). It is anticipated that the ideal means of measuring mitral valve anatomy to guide device and patient selection will be refined with increasing clinical experience. The most important information that should be included in a pre-procedural TMVR comprehensive systematic CT analysis is described in Table 1. The definitions and methodology for each measurement are beyond the scope of this paper. More information can be found elsewhere (18,25–31).
Prosthetic valve structural degeneration
Although no long-term durability data exist for TMVR, there are some factors that should be considered regarding the possibility of bioprosthesis degeneration. First, surgical mitral bioprosthetic valves are more likely to suffer from early structural degeneration than surgical aortic bioprostheses. Also, surgical bioprostheses tend to degenerate more rapidly in younger patients (32). Although this may be of lesser concern in patients with a relatively short life expectancy, young patients with MR may have a longer life expectancy, which raises concerns about long-term durability. A systematic clinical and echocardiographic follow-up of patients undergoing TMVR will be critical to provide consistent data for valve durability and structural valve failure in the coming years.
TMVR Devices Under Clinical Evaluation
CardiAQ-Edwards transcatheter mitral valve
The CardiAQ-Edwards transcatheter mitral valve is a self-expanding trileaflet valve composed of bovine pericardial tissue (Table 2, Figure 2). The nitinol frame is composed of 2 sets of circumference-oriented, opposing anchors which secure the device to the mitral annulus. The ventricular anchors rest behind the mitral leaflets and subvalvular apparatus, preserving the chords and using native leaflets as support. The symmetrical design requires no rotational alignment. The frame is covered by a polyester fabric skirt designed to reduce the risk of paraprosthetic leakage. The valve has a supra-annular position intended to minimize the ventricular profile and, therefore, the risk of LVOT obstruction. The valve can be implanted using a transapical or transfemoral approach.
The procedure can be summarized in 5 steps: 1) the delivery system is advanced across the interatrial septum in the transseptal approach or using the apex in the transapical access approach; 2) after crossing the mitral valve, a ventriculogram is obtained to reassess the mitral plane and correct the height of the system (above the papillary muscles); 3) the left ventricular anchors are released by turning the retraction wheel to initiate leaflet capture; 4) the valve is expanded to finalize leaflet capture; and 5) after a correct position is confirmed, the valve is released (33).
The first-in-human implantation of the first-generation CardiAQ was done in 2012 (34). Since then, 13 cases have been reported, including 1 additional patient treated through a transfemoral approach with the second-generation valve (35,36). The main clinical results of this initial clinical experience are summarized in Table 3. An early feasibility study, which plans to enroll 28 patients, using the transfemoral and transapical delivery systems is currently enrolling patients, and a larger prospective registry including 200 patients started in 2016 (Table 4).
Neovasc Tiara mitral transcatheter heart valve
The Tiara valve is a self-expanding trileaflet valve made of bovine pericardium and a nitinol frame (Table 2, Figure 3). The valve is designed to fit the D-shaped mitral annulus. The atrial portion helps to seat the prosthesis into the atrial portion of the mitral annulus and has a full atrial skirt. The ventricular anchors (2 anterior and 1 posterior) fix the valve onto the fibrous trigon and the posterior part of the annulus. There are 2 valve dimensions: the 35-mm valve has internal dimensions of 30 mm and 35 mm (area ranges: 6.3 cm2 to 9.0 cm2), and the 40-mm valve has internal dimensions of 34.2 mm and 40 mm (area ranges: 9.0 cm2 to 12.0 cm2) (37). The valve is implanted using the transapical approach (38).
The procedure can be summarized in 4 steps: 1) the left ventricular apex is exposed through a left mini-thoracotomy, a needle puncture is performed, and a J-tip wire is introduced across the mitral valve; 2) the Tiara delivery system is introduced directly and across the mitral valve, and the atrial portion of the prosthesis is unsheathed, oriented, and aligned with the D-shaped mitral annulus to allow proper fit; 3) the delivery system is then pulled back to seat the atrial part of the valve; and 4) the ventricular anchors are released to secure and release the prosthetic valve (39).
The first cases using the Tiara mitral valve system implants were performed in January 2014 in Vancouver (38). Since then, 19 cases have been reported, 5 patients in the TIARA-1 early feasibility study and 14 patients under a special access program (Table 3) (40). An early feasibility trial is currently enrolling patients and plans to include a total of 30 patients (Table 4).
Tendyne bioprosthetic mitral valve system
The Tendyne mitral valve system is composed of a trileaflet porcine pericardial valve on a self-expanding nitinol double-frame stent, an adjustable tether, and an apical fixation/sealing pad (Table 2, Figure 4). The valve is designed to fit the mitral annulus and can accommodate a wide range of sizes. The inner stent is one size and circular to maintain an effective orifice area of >3.2 cm2. There is an atrial cuff designed to provide sealing (prevention of diastolic paravalvular leak) and anchoring (preventing valve from pulling into the ventricle when force is applied to the tether). A left ventricular apical tethering system with an apical pad anchors the device and assists with apical closure. The device is implanted using a transapical approach and can be fully retrieved or repositioned even after full deployment (41).
The procedure can be summarized in 4 steps: 1) Standard transapical approach through a left mini-thoracotomy and left ventricle access. 2) A balloon-tipped catheter is advanced into the left atrium to deliver a standard 0.035-inch guidewire. The 36-F delivery system is advanced over the guidewire. The valve is brought into the left atrium and positioned above the mitral annulus and allowed to partially expand. 3) The valve’s rotational orientation is verified and corrected if necessary to assure the D-shaped outer stent is oriented so that the straight side is aligned with the anterior aspect of the mitral orifice. The valve is deployed into the mitral orifice. 4) The apical pad is threaded over the tether and positioned on the epicardium at the left ventricular access; a tension tool is used to adjust the tether length from the valve to the ventricular apex to provide valve stability. The apical pad is secured and assists with closure of the apex (42).
The first-in-human implantation of the Tendyne valve was performed in October 2014 (41). The results of the first 30 patients treated with this valve have been reported and are summarized in Table 3 (43). An early feasibility study of the Tendyne mitral valve system is currently recruiting patients (Table 4).
Medtronic Intrepid TMVR
The Intrepid TMVR is a tri-leaflet bovine pericardial valve contained in a self-expanding nitinol frame, which has dual structure design consisting of a circular inner stent to house the valve and a conformable outer fixation ring to engage the mitral anatomy. The outer fixation ring is designed to accommodate the variability of the native mitral annulus while isolating the inner valve assembly throughout the cardiac cycle. A flexible brim is attached to the atrial end of the fixation ring, which facilitates imaging during the procedure (44). The outer stent is being investigated in 3 sizes of 43, 46, and 50 mm. The circular inner stent houses a 27-mm valve across the 3 outer stent sizes (Table 2, Figure 5). There is no need for rotational alignment or to search for leaflets. Fixation and sealing are achieved through a combination of design features: 1) the outer fixation ring is larger in circumference than the native mitral valve annulus with varying degrees of radial stiffness along its axial length; 2) the flexible atrial portion deflects inward while the stiff ventricular mid-section resists compression and maintains its shape, producing a final ‘champagne cork-like’ conformation (narrow neck and wider body) to resist migration under systolic pressures and; 3) 3 circumferential rings of frictional elements on the outer stent further help fixation. The prosthesis is designed to preserve the native leaflets and chordae and leverage them to seal around the device (44).
The Intrepid TMVR delivery system is currently designed for transapical access only and consists of an apical introducer sheath (with dilator) and a hydraulically actuated delivery catheter. The procedure can be summarized in 5 steps: 1) after standard transapical access, the system is advanced across the mitral valve; 2) the valve is expanded until the brim is completely deployed; 3) the system is retracted into the desired position on the annulus; 4) the fixation ring is expanded; and 5) the valve is released, the sheath is removed, and the incision is closed. Steps 3 through 5 are performed under rapid ventricular pacing. Duration of rapid pacing has averaged at 30 s during deployment (45).
The first case to use an Intrepid TMVR in a human was performed in September 2014. Since then, 27 patients have been treated, and the main clinical results are summarized in Table 3 (44,46,47). A prospective registry is ongoing (Table 4).
Caisson TMVR system
The Caisson TMVR system consists of 2 main components, an anchor and a valve (Table 2, Figure 6). The anchor is a D-shaped, self-expanding nitinol structure. It serves as a foundation that grips the native valve annulus. The anchor is implanted onto the mitral valve such that the tips of the ventricular feet engage under the mitral valve annulus, and the atrial holding features engage with the atrial surface of the mitral valve annulus. The valve is composed of a self-expanding nitinol frame with a trileaflet porcine pericardial valve and is designed to nest in the anchor. Both the valve and the anchoring system are retrievable (48). The valve is delivered completely percutaneously, using the transfemoral approach with a 31-F delivery system (49).
Five patients were treated through October 2016, 4 in a U.S. early feasibility study and 1 patient under the Canadian special access program (49). The main clinical results of this initial experience are summarized in Table 3. The first-in-human early feasibility study is ongoing and plans to include 20 patients in 5 centers (Table 4).
HighLife TMVR device
The HighLife device is composed of 2 components: a ring that is placed around the native leaflets (subannular implant) and a prosthetic valve that is placed inside the ring (Table 2, Figure 7). The valve prosthesis is composed of a 31-mm nitinol frame and a trileaflet bovine pericardial valve that has a pre-formed groove in the annular region. The subannular implant consists of a polymer tube with nitinol hooks for ring closure that is placed around the prosthesis to avoid displacement of the valve into the left ventricle. In its final position, the native leaflets are trapped between the subannular implant and the prosthetic valve (50).
The procedure can be summarized in 3 steps: 1) a guidewire is introduced through the femoral artery and is looped around the native mitral valve leaflets; 2) the subannular implant ring is placed over the guidewire loop; and 3) the prosthetic valve is implanted through a transapical approach similar to a valve-in-ring implant. A single-center early feasibility and safety study is ongoing. Results from the first 6 patients treated with this device have been reported and are summarized in Table 3 (51).
The MValve system is not a valve but a docking device designed to fit other transcatheter prostheses that are anchored within the docking system (Table 2, Figure 8). The MValve system can be implanted using a transapical approach and is designed to be compatible with a variety of commercially available transcatheter valves. The anchoring of the docking system is designed to allow preservation of the native leaflet function, offering a true chord-sparing approach. The MValve system enables positioning due to its fluoroscopic visibility, atrioventricular positioning, and a sealing element that is intended to minimize the risk of paravalvular leak. The docking system can be recaptured and retrieved after full deployment (52).
The first-in-human implantation was performed in September 2015. There were no major periprocedural complications, and immediate post-operative echocardiography revealed no residual MR and good valve position. The patient died 20 days after the procedure due to pneumonia. The early feasibility and safety study of the MValve in conjunction with the Lotus transcatheter heart valve (Boston Scientific, Marlborough, Massachusetts) is planned to start by the second quarter of 2017 (Table 4). The company is currently also working on the design of the next-generation MValve device. The goal for this new-generation device is implantation in a single-step procedure, and it will have a proprietary valve built and secured within the MValve dock. It will be adaptable for transseptal implantation with a profile of 24-F (53).
NCSI NaviGate mitral valve
The NaviGate valve is a self-expandable TMVR system composed of a nitinol stent-frame with a truncated cone 21 mm in height (Table 2, Figure 9). Several annular winglets anchor the valve within the mitral annulus. The valve can be delivered using transatrial, transapical, or transseptal access. The delivery system has a diameter of 30-F at the distal part and 18-F at the level of the catheter shaft (54). The first-in-human implantation of the NaviGate valve was performed in October 2015. According to the manufacturer’s information, the early feasibility and safety study with a transatrial approach is planned to start during 2017 and will include 30 patients in 2 centers (55). Further information regarding this trial has is not yet available.
Technologies Under Preclinical Evaluation
AccuFit TMVR system
The AccuFit TMVR system (Sino Medical Science Technology, Inc., Tianjin, China) is composed of a circular, self-expanding, self-centering frame device that has an atrial flange, a ventricular flange, and an annulus support (Figure 10). It has a supra-annular design and is self-centering. The valve is made of 3 bovine pericardial leaflets. The valve is anchored mainly through sandwiching the annulus and native valve leaflets between the atrial and ventricular flanges. The prosthetic valve is implanted using a transapical approach with a 38-F caliber system (56). The first-in-human study will be initiated in the first quarter of 2017 (57).
Cardiovalve TMVR system
The Cardiovalve TMVR is a self-expandable trileafleat valve (Figure 10). The system is advanced using the transfemoral approach with a 28-F introducer. The height of the crimped valve is 32 mm. Once the valve is deployed, the protrusion into the left ventricle is approximately 12 mm. The valve is anchored into the mitral annulus over 24 focal “sandwiching” points, with a symmetrical design that does not require rotational positioning. There are 3 differently sized valves with diameters that range from 40 to 50 mm. The system is under preclinical evaluation, and the first-in-human implantations are planned for 2017 (58).
Cephea TMVR system
The Cephea TMVR system (Cephea Valve Technologies, San Jose, California) consists of a self-expanding double-disk structure and a bovine trileaflet valve (Figure 10). The prosthesis has a multilevel conformability design, making the valve capable of adapting to various anatomies. The atrial disc rests on the floor of the left atrium, the center column provides a stable platform for leaflet support, and the ventricular disc anchors to the subannular region. This modular architecture isolates the prosthesis from external annular and myocardial deformation. The prosthesis can be deployed using an antegrade approach (transatrial or transseptal) and can be fully recaptured. There is a 2-step deployment that uses multiple redundant mechanism to anchor the valve. During the first step, the frame aligns and self-orients to the subannular plane, and anchors using the native annulus as a support, and during the second step, the frame self-centers and seals by supra-annular fixation (59,60). The first-in-human implantations are planned for 2017.
Saturn TMVR technology
The Saturn technology (InnovHeart Srl, Milan, Italy) is composed of an annular structure that encircles the mitral valve and provides support for the valve prosthesis (Figure 10). Both parts are designed to be connected by means of guidewires. The transapical procedure has already been preclinically validated. The procedure using a transseptal approach is under development. The first part of the procedure consists of positioning a pair of guidewires to embrace the mitral leaflets at a level immediately below the mitral annulus. The annular structure is then introduced over-the-wire in the left ventricle. The second part consists of introducing onto the left ventricle the collapsed central stent engaged over the connecting guidewires to reconnect the component to the annular structure, followed by the final positioning and release of the central stent (61).
The Abbott TMVR system (Abbott Vascular, Abbott Park, Illinois) is a self-expanding bovine trileaflet valve with 2 components: a nitinol annular portion and a braided nitinol atrial section (Figure 10). The atrial section is intended to avoid paravalvular leakage. Fixation of the valve is accomplished by leaflet capture and atrial sealing. The procedure is done using the transapical approach (62). A transfemoral delivery system is in development.
There are several other devices under preclinical evaluation. However, design features of and preclinical results using these devices are very limited at the present time.
Insights From TMVR Early Clinical Experience
Patient clinical characteristics and selection
According to early observations reported with various systems, patients currently selected for TMVR are those considered at high or prohibitive surgical risk, as determined by surgical risk scores and evaluation by the heart team. To date, most patients have been treated on the basis of compassionate clinical use programs. There are, however, scarce data for the reasons for selecting TMVR over other approved transcatheter therapies, such as the MitraClip device. In fact, no data exist as to whether or not the patients selected for TMVR were considered suboptimal candidates for MitraClip therapy.
The main clinical characteristics of the patients undergoing TMVR are summarized in Table 5. Patients who have undergone TVMR were in their mid-70s, and most of them (74%) were male. Most patients (76%) had low left ventricular ejection fractions (LVEF), and MR was of ischemic origin in the majority. Comorbidities such as chronic kidney disease and chronic pulmonary obstructive disease were among the most frequently reported. Of note, secondary MR was diagnosed in most patients who underwent TMVR, despite the lack of definite evidence supporting a clinical benefit with this clinical approach.
Unfortunately, scarce data exist for patient inclusion and/or exclusion criteria and patient screening. Although there are no definite data on the number of patients screened versus those finally undergoing the procedure for the different transcatheter valve platforms, the screening failure rate at this stage seems to be high. It will be very important to collect this information in future studies in order to better determine the subset of patients who may potentially benefit from this technology.
A total of 115 cases with 9 different dedicated transcatheter mitral valve prosthetic devices have been reported to date. The majority of procedures (94%) were performed using a transapical approach under general anesthesia and fluoroscopic and transesophageal echocardiographic guidance. One device in particular was used exclusively in the transfemoral approach (Caisson prosthesis), whereas another could be implanted using transapical or transfemoral approach (CardiAQ device).
Although these were the very early and/or first-in-human phase experiences with different TMVR devices, the average technical success (valve successfully implanted with a normally functioning valve post-procedure) was high (88%; ranging from 75% to 100%). The main technical issues were related to: 1) transcatheter valve instability or inappropriate valve fixation due to incomplete capture of the posterior mitral leaflet; 2) issues with the subvalvular mitral apparatus; 3) problems with the hemostasis of the transapical access (usually due to myocardial tears); 4) leaflet malfunction following valve implantation; and 5) interaction with a previously implanted aortic valve. Of note, the fact that most current TMVR systems are not fully retrievable led to conversion to open heart surgery and valve explantation in most patients experiencing technical issues during the TMVR procedure.
This life-threatening complication occurred in a single case (<1%) in these initial series of TMVR. This probably reflects appropriate patient selection criteria using 3D CT, excluding those patients with very small LVOTs that would predict excessive risk. Also, the fact that several TMVR platforms involve capturing the anterior leaflet among the mechanisms for valve anchoring might have decreased the risk of this complication.
Valve performance: hemodynamic results
Results of valve performance associated with the different transcatheter valve platforms have been very good, with mean transvalvular gradients of ≤3 mm Hg in all cases and a very low rate (<2%) of significant paravalvular leakage. These results compare favorably with those obtained with transcatheter mitral valve repair systems and are close to those reported following surgical mitral valve repair and/or replacement. However, the presence of mitral annular calcification has been an exclusion criterion for all TMVR systems, and there are no data on how these devices would perform in the setting of severe annular calcification, where paravalvular leakage and anchoring could be issues.
To date, the average 30-day mortality rate following TMVR has been 23%, ranging from 0% to 53%. Approximately one-half of the deaths occurred periprocedurally and were mainly related to unsuccessful TMVR, frequently leading to conversion to open-heart surgery. Also, access site management issues were responsible for some episodes of death in this initial experience, mainly secondary to myocardial tears. The other half of in-hospital and/or 30-day deaths occurred later on, following the initial periprocedural period. In these cases, multiorgan failure was the most commonly reported cause of death. Although procedural complications and failure to achieve technical success contributed to these deaths in many cases, other patients died within the weeks following a successful, uncomplicated TMVR procedure. In these cases, the reasons explaining post-TMVR mortality are probably multifactorial. First, patients’ comorbidities, including noncardiac diseases and frailty issues, might have played a role. Second, the transapical approach has been associated with a higher rate of periprocedural complications (particularly major and/or life-threatening bleeding) and mortality in the TAVR field (63). In addition to the negative effects of thoracotomy in an elderly and frail population, the higher degree of myocardial injury associated with the transapical approach may be particularly deleterious in patients with reduced LVEF pre-procedurally, such as those harboring severe functional MR. Finally, acute abolishment of the volume overload associated with severe MR in patients with severely depressed (<30%) LVEF may have temporary negative effects, including a further reduction in LVEF that may complicate the post-operative period. This is well known in the surgical field (64) and should be considered when evaluating these patients for TMVR.
Intermediate term data for outcomes after TMVR are limited to only 2 platforms (Intrepid and Fortis [Edward Lifescience). There have been no reports of structural valve degeneration, valve dislocation requiring reintervention, or new or worsening paravalvular leakage over 6 to 12 months of follow-up.
Concerns have arisen regarding the risk of valve thrombosis after TAVR (65). There is, however, scarce information about the risk of valve thrombosis after TMVR. The TMVR program with the Fortis valve was temporarily halted due to issues of valve thrombosis (66). No details about this complication were provided, but 1 of the patients in the current series had a clinically relevant episode of valve thrombosis a few weeks after TMVR with the Fortis valve. One episode of valve thrombosis was reported following implantation of the Tendyne valve. The patient, whose anticoagulation therapy was subtherapeutic (INR = 1.5), had an increased mitral gradient at the 30-day follow-up and evidence of leaflet thrombosis on CT imaging. Complete resolution of the thrombus with normalization of the prosthetic valve function was documented by echography and CT following intensification of oral anticoagulation therapy (43). Anticoagulation is recommended for at least the first 3 months after surgical mitral valve replacement (67,68). While waiting for more data on antithrombotic therapy post-TMVR, anticoagulation therapy for the first months following the procedure should probably be used. Future studies should also determine the risk and efficacy of adding antiplatelet therapy in addition to anticoagulation in such patients.
TMVR is evolving to become a potentially new alternative for treating patients with severe MR who are at very high or prohibitive surgical risk. The complexity of the mitral valve apparatus and the heterogeneity of the disease have limited the implementation of this therapy to date. Several devices are under clinical evaluation, and the early experience with more than 100 patients has demonstrated the feasibility of TMVR. Presently, multiple TMVR systems are being evaluated in several centers in an overall small number of highly selected patients. Future studies with a much larger number of patients are needed to provide consistent safety and efficacy data for each of the TMVR systems. This will determine whether or not TMVR could become a real alternative for the increasing number of patients with severe MR for whom more aggressive approaches are not suitable.
Drs. Rodés-Cabau and Dagenais have received research grants from Edwards Lifesciences. The CRF Skirball Center for Innovation has received research support from Edwards Lifesciences, Neovasc, Abbott Vascular, Sinomed, and Cephea. Dr. Granada is a cofounder of Cephea. Dr. Regueiro was supported by a grant from the Fundacion Alfonso Martin Escudero (Madrid, Spain). Deepak L. Bhatt, MD, MPH, served as Guest Editor-in-Chief for this paper. Patrick O’Gara, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- computed tomography
- left ventricular ejection fraction
- left ventricular outflow tract
- mitral regurgitation
- transcatheter aortic valve replacement
- transcatheter mitral valve replacement
- Received November 15, 2016.
- Revision received February 12, 2017.
- Accepted February 12, 2017.
- 2017 American College of Cardiology Foundation
- Coffey S.,
- Cairns B.J.,
- Iung B.
- Mirabel M.,
- Iung B.,
- Baron G.,
- et al.
- Goel S.S.,
- Bajaj N.,
- Aggarwal B.,
- et al.
- ↵Maisano F. Transcatheter mitral valve repair outcomes after 30,000 treated patients. Paper presented at: Transcatheter valve therapies (TVT): a multidisciplinary heart team approach; June 18, 2016; Chicago, IL.
- Feldman T.,
- Kar S.,
- Rinaldi M.,
- et al.,
- for the EVEREST investigators
- Feldman T.,
- Kar S.,
- Elmariah S.,
- et al.,
- for the EVEREST II investigators
- Maisano F.,
- Franzen O.,
- Baldus S.,
- et al.
- Maisano F.,
- Alfieri O.,
- Banai S.,
- et al.
- Guerrero M.,
- Dvir D.,
- Himbert D.,
- et al.
- Paradis J.M.,
- Del Trigo M.,
- Puri R.,
- Rodés-Cabau J.
- Ribeiro H.B.,
- Nombela-Franco L.,
- Muñoz-García A.J.,
- et al.
- Urena M.,
- Webb J.G.,
- Eltchaninoff H.,
- et al.
- Fröhlich G.M.,
- Baxter P.D.,
- Malkin C.J.,
- et al.,
- for the National Institute for Cardiovascular Outcomes Research
- Blanke P.,
- Naoum C.,
- Webb J.,
- et al.
- Wu Q.,
- Zhang L.,
- Zhu R.
- Blanke P.,
- Naoum C.,
- Dvir D.,
- et al.
- Delgado V.,
- Tops L.F.,
- Schuijf J.D.,
- et al.
- Abdelghani M.,
- Spitzer E.,
- Soliman O.I.,
- et al.
- Thériault-Lauzier P.,
- Mylotte D.,
- Dorfmeister M.,
- et al.
- Blanke P.,
- Dvir D.,
- Cheung A.,
- et al.
- Thériault-Lauzier P.,
- Dorfmeister M.,
- Mylotte D.,
- et al.
- Natarajan N.,
- Patel P.,
- Bartel T.,
- et al.
- Pibarot P.,
- Dumesnil J.G.
- Sondergaard L.,
- Ussia G.P.,
- Dumonteil N.,
- Quadri A.
- Søndergaard L.,
- De Backer O.,
- Franzen O.W.,
- et al.
- Ussia G.P.,
- Quadri A.,
- Cammalleri V.,
- et al.
- ↵Sondergaard L. CardiAQ-Edwards TMVR. Paper presented at: PCR London Valves; September 19, 2016; London, United Kingdom.
- ↵Cheung A. Transcatheter mitral valve replacement Neovasc Tiara: design and clinical trial updates. Paper presented at: Transcatheter cardiovascular therapeutics (TCT); October 31, 2016; Washington, DC.
- Cheung A.,
- Webb J.,
- Verheye S.,
- et al.
- ↵Cheung A. Neovasc TIARA. Paper presented at: PCR London Valves; September 19, 2016; London, UK.
- Quarto C.,
- Davies S.,
- Duncan A.,
- et al.
- Muller D.,
- Farivar R.S.,
- Jansz P.,
- et al.,
- for the Tendyne Global Feasibility Trial investigators
- Meredith I.,
- Bapat V.,
- Morriss J.,
- McLean M.,
- Prendergast B.
- ↵Bapat V. Intrepid Taped Case. Paper presented at: Transcatheter Valve Therapies (TVT): a multidisciplinary heart team approach; June 16, 2016; Chicago, IL.
- ↵Meredith IT. Medtronic Intrepid TMVR. Paper presented at: PCR London Valves. September 19, 2016; London, UK.
- ↵Bapat V. Intrepid design and clinical trial update. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); October 29, 2016; Washington, DC.
- ↵Williams M. The Caisson transcatheter mitral valve replacement system. Paper presented at: PCR London Valves; September 18, 2016; London, UK.
- ↵Williams M. Caisson: design and clinical trial updates. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); October 31, 2016; Washington, DC.
- Lange R.,
- Piazza N.
- ↵Lange R. A two-component, self-centering TMV system. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); October 31, 2016; Washington, DC. Available at: https://www.tctmd.com/slide/highlife-design-and-clinical-trial-updates. Accessed March 6, 2017.
- ↵Buchbinder M. MValve: design highlights and clinical update. Paper presented at: Transcatheter Valve Therapies (TVT): a multidisciplinary heart team approach; June 16, 2016; Chicago, IL.
- ↵Buchbinder M. M-Dock: design and clinical trial update. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); October 31, 2016; Washington, DC. Available at: https://www.tctmd.com/slide/m-dock-design-and-clinical-trial-updates. Accessed March 6, 2017.
- ↵Navia JL. My choice for percutaneous mitral valve replacement. Paper presented at: American Association for Thoracic Surgery Annual Meeting; April 25, 2015; Baltimore, MD. Available at: http://webcast.aats.org/2015/Detail.php?d=Saturday&s=1. Accessed March 6, 2017.
- ↵NaviGate Cardiac Structures, Inc. First Navigate patient at 8 months shows excellent mitral valve function and has returned to work. Navigate Cardiac Structures, Inc. June 23, 2016. Available at: http://www.navigatecsi.com/announcement/first-navi-patient-at-8-months-shows-excellent-mitral-valve-function-and-has-returned-to-work/. Accessed March 1, 2017.
- ↵Serruys PW. AccuFit transapical mitral valve replacement system: a technical update. Paper presented at: EuroPCR; May 19, 2016; Paris, France.
- ↵Maisano F. Valtech TMVR: design highlights and clinical update. Presented at: Transcatheter Valve Therapies (TVT): a multidisciplinary heart team approach; June 16, 2016; Chicago, IL.
- ↵Granada JF. Transcatheter mitral valve therapies: new rings, anchors and techniques. Cephea. Paper presented at: EuroPCR; May 21, 2015; Paris, France.
- ↵Leon MB. The Cephea transcatheter mitral valve replacement system. Paper presented at: PCR London; September 18, 2016; London, UK.
- ↵Denti P. Saturn Project: a novel approach to transcatheter replacement. Paper presented at: Mitral Valve Meeting (MVM); February 7, 2017; Zurich, Switzerland.
- ↵Cheung A. St. Jude TMVR: design development update. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); October 31, 2016; Washington, DC.
- Gaasch W.H.,
- Meyer T.E.
- Hansson N.C.,
- Grove E.L.,
- Andersen H.R.,
- et al.
- ↵Edwards Life Sciences, Corp. Edwards pauses enrollment in early stage mitral program. Edwards Lifesciences Corp. May 19, 2016. Available at: http://www.edwards.com/fr/newsroom/Pages/ShowPR.aspx?PageGuid=%7B61d40c10-d690-45fa-b541-ab1f4806b975%7D. Accessed March 1, 2017.
- Nishimura R.A.,
- Otto C.M.,
- Bonow R.O.,
- et al.
- Vahanian A.,
- Alfieri O.,
- et al.,
- for the taskforce members
- De Backer O.,
- Piazza N.,
- Banai S.,
- et al.