`
`Complexities of transcatheter mitral valve replacement (TMVR)
`and why it is not transcatheter aortic valve replacement (TAVR)
`
`Moritz C. Wyler von Ballmoos1,2, Ankur Kalra3, Michael J. Reardon1,2
`
`1Department of Cardiovascular Surgery, Houston Methodist Hospital, Houston, Texas, USA; 2Weill Cornell Medicine, New York, NY, USA;
`3Division of Cardiovascular Medicine, Department of Medicine, Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical
`Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
`Correspondence to: Moritz C. Wyler von Ballmoos, MD, PhD, MPH, FACC, FAHA. Department of Cardiovascular Surgery, Houston Methodist
`DeBakey Heart & Vascular Center, Houston, TX 77030, USA. Email: mcwylervonballmoos@houstonmethodist.org.
`
`Transcatheter mitral valve replacement (TMVR) is currently being investigated as a procedural alternative
`to surgical mitral valve repair or replacement (SMVR). Early data from first-in-man trials with current
`devices suggest that TMVR is technically feasible but carries a high mortality. This is substantially different
`from the early success transcatheter aortic valve replacement (TAVR) has seen and is related to complexities
`of the mitral valve anatomy, differences in pathology that require mitral valve replacement as well as the
`impact that mitral valve replacement has on physiology and cardiac function, irrespective of the modality
`by which the mitral valve is replaced. Importantly, in the case of TAVR, a less invasive method is offered to
`accomplish the same as the traditional surgical intervention. On the other hand, valve replacement is not
`the recommended treatment option for the majority of mitral valve disease, and in fact is avoided whenever
`possible during surgery given the shortened life expectancy and increased morbidity with mitral valve
`replacement. Another distinction between TAVR and TMVR is the etiology and natural progression of the
`underlying disease and driving factors for intervention that are vastly different between aortic and mitral
`valve disease. The primary aortic disease treated has been aortic stenosis, which has several etiologic factors
`that cause a similar physiologic dysfunction and risk. Aortic valve replacement leads to improved survival and
`quality of life. The primary mitral valve disease targeted is regurgitation, which occurs as a primary valve
`defect and as a secondary consequence of ventricular dysfunction. Primary mitral regurgitation is treated by
`valve repair with excellent long-term outcomes. Secondary regurgitation has poor long-term outcomes with
`current commonly used repair techniques and limited data exists showing that correction of the regurgitation
`improves survival. Adoption of TMVR will require overcoming the anatomic challenges as well as generating
`data that supports improved survival and/or quality of life.
`
`Keywords: Mitral valve; transcatheter mitral valve replacement (TMVR); transcatheter aortic valve replacement
`(TAVR); transcatheter therapy; device development
`
`Submitted Aug 07, 2018. Accepted for publication Oct 04, 2018.
`doi: 10.21037/acs.2018.10.06
`View this article at: http://dx.doi.org/10.21037/acs.2018.10.06
`
`Introduction
`
`Following the success and rapid adoption of transcatheter
`aortic valve replacement (TAVR), a procedural, catheter-
`based approach to mitral valve pathology and options for
`replacement of the mitral valve quickly became an obvious
`target for investigators and industry. Whilst TAVR has
`
`become commonplace for aortic stenosis in patients that
`present with an increased surgical risk, transcatheter mitral
`valve replacement (TMVR) is still very much in its infancy.
`To date, only about 250 TMVR cases with a dedicated
`mitral valve system have been performed worldwide. The
`only randomized trial for a transcatheter mitral valve
`device in the United States is currently the TMVR with
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`Epidemiology of mitral valve disease
`
`Figure 1 Epidemiology of mitral valve pathology. DMR, degenerative mitral valve regurgitation; PCI, percutaneous coronary intervention;
`CAD, coronary artery disease; FMR, functional mitral regurgitation.
`
`the Medtronic IntrepidTM TMVR System in Patients with
`Severe Symptomatic Mitral Regurgitation (APOLLO) trial
`(NCT03242642), investigating the Intrepid valve. Initial
`results from this study are expected to be available in 2021.
`In 2015 alone, the total investments made by industry in
`mitral valve technology exceeded 2.5 billion U.S. dollars (1).
`This is consistent with the much higher incidence of
`mitral valve pathology in the general population. It is
`estimated that in the United States, 1.7 percent of the adult
`population are living with mitral regurgitation and a small
`percentage with mitral stenosis (2).
`
`Different patient characteristics affecting the
`need for TMVR and its feasibility
`
`Over the last several decades, there has been a dramatic
`reduction in the prevalence of rheumatic heart disease
`in developed countries. The aging of our population
`combined, with the advent of advanced medical and
`interventional therapy for ischemic heart disease, have led
`ischemic functional secondary mitral regurgitation (MR)
`and degenerative primary MR to become the most common
`mitral valve pathologies (2,3). Mitral regurgitation is now
`the most common valve pathology overall (Figure 1). With
`the shift from mitral stenosis to MR over time, the needs for
`therapeutic interventions in the mitral space have morphed
`away from valve replacement and towards valve repair (see
`also next section ‘Challenges with mitral valve replacement
`in general’).
`The demographics of patients presenting with
`degenerative aortic valve disease and mitral valve disease
`are also distinctively different. A review of the Society of
`
`Thoracic Surgeons (STS) database shows that patients
`undergoing surgical aortic valve replacement are on
`average are 70 years old, with 20% of all patients being
`octogenarians or older (4). Contrary to that, patients
`requiring mitral valve replacement are 10 years younger
`on an average and only 8% are 80 years old or older (5).
`This is a critically important context for the durability
`of bioprosthetic valves and the resulting need for future
`interventions. It is well established that bioprosthetic valves
`have a shortened lifespan in younger patients, arguably
`due to a more robust immune response, and heightened
`hemodynamic stress in younger patients. Both the
`shortened durability of valves and longer life expectancy
`in younger patients will contribute to a higher incidence
`of subsequent valve replacement. It is well known from
`surgical valve replacements that mitral valves have a higher
`rate of degeneration than aortic valves. This is likely
`because the mitral valve is exposed to a systolic pressure
`gradient and the aortic valve to a diastolic pressure gradient.
`Additionally, valve-in-valve procedures create a tube graft
`by the second valve continuously holding open the first
`valve. In the aortic position, the structure at risk is the
`coronary circulation; the likelihood of an occlusion can be
`predicted relatively reliably from CT scans based on the
`size of the Sinuses of Valsalva. In the mitral position, the
`‘tube graft’ will interfere with the left ventricular outflow
`track (LVOT) and the extent of this obstruction is much
`more difficult to predict. Additionally, the consequences of
`complications, e.g., the need for a permanent pacemaker
`and suboptimal hemodynamic results, such as residual
`gradients or paravalvular leaks, are more impactful, again
`due to the longer life expectancy of younger patients.
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`Additionally, the changes in valve morphology requiring
`replacement are quite different between the aortic and
`mitral position. TAVR has become a tremendous success
`for treatment of the most common aortic valve pathology,
`degenerative sclerotic aortic stenosis. Bicuspid aortic
`valves [about 10% of aortic stenosis (AS) cases in Western
`countries; roughly 20% in Asian countries] and predominant
`aortic insufficiency (13% of AVR cases) (6) continue to
`pose a challenge for good outcomes with TAVR. In case of
`the mitral valve, the underlying pathology that will require
`valve replacement comes in many more variations. The
`mitral valve forms a complex, functional unit with its sub-
`valvular apparatus. The varying degree of excessive tissue
`or scarring of leaflets, chordal rupture, annular dilatation,
`leaflet and/or annular calcification create a sheer unlimited
`number of substrates in which a transcatheter valve will
`have to be deployed successfully.
`Learning from the TAVR experience, implantation of
`an aortic transcatheter heart valve (THV) in the mitral
`position has been performed successfully in cases of severe
`mitral annular calcification (MAC) (7). Because the valves
`used were not specifically designed for the mitral position,
`the success of these cases can be attributed in part to the
`annular calcification, a condition that is uncommon in most
`patients with mitral valve disease.
`
`Challenges with mitral valve replacement in
`general
`
`The predominant presenting pathology in mitral valve
`disease is regurgitation, either due to primary degenerative
`valve disease or with ischemic functional secondary MR.
`Other than with AS, mitral valve disease is rarely associated
`with sudden or rapid progression to death, and the need
`for intervention is mostly driven by symptoms. Although
`MR does shorten life expectancy, this effect is more
`indolent, occurring over years, as opposed to months as
`seen in AS patients. Guideline-directed medical therapy
`has high 1-year survival in mitral valve patients. It is widely
`accepted and emphasized in guidelines that surgical repair
`is the preferred approach over replacement in primary MR
`because of superior outcomes, both in terms of morbidity
`and mortality (8). Today, over 60% of patients in the U.S.
`undergoing mitral valve surgery have a valve repair (4) and
`for primary degenerative mitral valve disease, the need
`for valve replacement in experienced centers is nearly
`nonexistent (9). On the other hand, the most appropriate
`approach to secondary MR remains controversial in the
`
`light of recent evidence that puts the durability of surgical
`repair in this group of patients into question (10,11). High-
`risk patients with functional secondary MR may therefore
`become the most likely first demographic in which TMVR
`could be successful and prove useful. The trouble with this
`growing group of patients is that the mitral valve is not
`actually the problem and any intervention on it will not
`treat the underlying ventricular pathology.
`Aortic stenosis often occurs in isolation and can result in
`reduced ventricular contractility, which commonly returns
`to normal once the outflow obstruction is removed, such
`as by TAVR. On the other hand, rendering the mitral
`valve competent again will require more work from the
`left ventricle (LV); this results in a well-described dip of
`the ventricular function and increased morbidity/mortality
`following intervention for MR. MR is also commonly
`associated with tricuspid regurgitation (TR) and atrial
`fibrillation, both of which impact morbidity and mortality
`independently. A tricuspid repair and anti-arrhythmia
`surgery are therefore routinely performed in patients
`undergoing mitral valve surgery. TMVR will not be a
`sufficient intervention in many patients that present with
`more than mild TR and/or atrial fibrillation. In fact, any
`TR is an exclusion criterion for all current clinical trials
`of TMVR. Transcatheter therapies for either TR or atrial
`fibrillation have not been able to reproduce the results seen
`with surgical intervention.
`Paravalvular leak (PVL) has certainly remained as
`one of the Achilles’ heels of THV implantation. In the
`case of TAVR, this has been greatly mitigated with new
`devices that have fabric coverage at the annular level and
`during procedures with post-implantation dilation of the
`prosthesis. The latter will prove much more problematic
`with the mitral valve, given the challenging combination
`of little anatomic support and proximity to the conduction
`system, circumflex coronary artery and aortic valve. Even if
`design of TMVR devices continues to improve, the slightest
`bit of PVL will be problematic in patients with long-term
`survival, given the high systolic pressure the prosthesis is
`exposed to. This is evidenced by the much higher mortality
`of mitral PVL compared with aortic PVL (12).
`
`TMVR device issues
`
`Multiple device-specific considerations distinguish TMVR
`from TAVR. The mitral valve annulus is significantly larger
`than the aortic annulus, and therefore will require larger
`valve mounted on larger delivery system. A substantial part
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`Figure 2 Progressive LVOT obstruction resulting from mitral valve prosthesis extending into LV cavity. Cardiac computed tomography
`showing a left ventricular (LV) long axis, mitral valve and LVOT. Blue color: LVOT and aortic root; green color: low profile mitral
`prosthesis; red color: high profile mitral prosthesis. LVOT, left ventricular outflow track.
`
`of the success and rapid adoption seen with TAVR is related
`to the high success rate with extra-thoracic access used,
`such as transfemoral, transaxillary and transcarotid delivery.
`Several of the TMVR systems currently under investigation
`require transapical access and the larger system certainly
`makes any transseptal approach more challenging. The next
`challenge is the specific configuration of the mitral annulus
`and surrounding structures. While the aortic valve is
`situated in a complete fibrous ring, the mitral valve annulus
`is much more delicate and more or less supported along its
`circumference. Posteriorly, it is embedded in the junction
`of the left atrium and left ventricle, while the anterior
`portion essentially consists of the aorto-mitral curtain, a
`dynamic structure with limited rigidity. This poses multiple
`challenges for both securing a device, but also bares the risk
`of compression and distortion of other structures such as
`the aortic valve. If the mitral valve cannot be secured safely,
`the cyclic high systolic pressures it will be exposed to can
`easily lead to early or late device migration.
`Furthermore, the D-shaped configuration of the mitral
`valve annulus poses a unique challenge. Firstly, appropriate
`sizing may prove difficult even with multimodality and
`fusion imaging, which have accomplished remarkable
`advances recently, and with the early lessons learned from
`TAVR. Early difficulties with TAVR and device sizing were
`related to the assumption that the aortic valve is round,
`while in fact it has an elliptical shape. Yet, the aortic annulus
`can be conformed to a relatively symmetrical round shape
`without much impact on surrounding structures, valve or
`cardiac function. This is not likely the case for the mitral
`valve. Secondly, the asymmetrical configuration of the
`
`mitral valve makes it difficult to achieve uniform radial
`force with any implant. This may lead to a higher incidence
`of device migration and PVL.
`The proximity, and more importantly, the angle of
`the mitral valve annulus in relation to the LVOT further
`complicate TMVR. The device itself poses a risk of
`obstructing the LVOT. Additionally, the native anterior
`leaflet may cause obstruction being pushed anteriorly.
`This is akin to the obstruction of coronary ostia seen with
`TAVR, which is also gaining more recognition in the
`literature, and is particularly challenging if future access
`to the coronaries is needed. Several software packages and
`algorithms are currently available to obtain mitral annular
`sizing from cardiac computed tomography (CT) scans and
`to predict the extent to which a prosthesis will protrude into
`the LVOT (Figure 2). However, this is currently limited to
`making various assumptions and cannot reliably predict the
`extent of LVOT obstruction that will occur under dynamic
`conditions, potentially resulting in severe complications.
`Finally, the requirements for approval of TMVR
`devices and the likely population for early trials is the
`same as for TAVR. This is problematic for various reasons.
`The landmark trials for TAVR were completed with two
`competing TAVR devices, meanwhile, there are currently
`at least 10 TMVR devices under investigation and another
`20 devices are in the pipeline. Such competition will
`unquestionably dilute trial enrollment. More importantly,
`the frail, comorbid, high-risk or inoperable patient is a
`common scenario among individuals with degenerative
`aortic disease. On the other hand, this kind of demographic
`is rare in the larger pool of patients with mitral valve disease,
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`that consists of mostly younger patients with degenerative
`MR. All this is reflected by the slow recruitment TMVR
`trials have seen across the board.
`
`Current status of TMVR trials
`
`In 2014, a conceptual milestone was reached when
`percutaneous implantation of a transcatheter valve in a
`surgical ring was first reported using the Edwards Sapien
`XT prosthesis (13). Several sporadic reports and anecdotal
`evidence suggest Sapien valves have been used occasionally
`to deliver a transcatheter aortic valve in the mitral position
`within a surgical valve, ring or in cases of severe MAC
`(14-16). The number of TMVRs with a dedicated mitral
`prosthesis and in a native mitral valve have remained
`relatively small to date with less than 150 human implants
`worldwide. The first such replacement was successfully
`completed in Denmark in 2012, using the CardiAQ
`prosthesis. Since then, the CardiAQ device has been used in
`several trials in an attempt to achieve CE mark approval in
`Europe; but most recently a trial was stopped by Edwards
`Lifesciences given concerns with the design of the valve. In
`the U.S., there are several centers that have participated in
`early TMVR trials. The Tendyne experience was recently
`reported as part of an international feasibility trial, in which
`30 patients with a high surgical risk (STS 7.3%) successfully
`had the transapically tethered TMVR valve implanted (17).
`Other valves that have entered clinical trials at various stages
`include the Neovasc Tiara, Medtronic Intrepid and Boston
`Scientific MValve devices, all competing with Tendyne to
`become the first commercially approved TMVR in Europe
`and then in the U.S. In addition, there is a large number of
`ongoing preclinical trials for several different devices (1).
`The Intrepid study enrolled 50 patients who had severe,
`symptomatic mitral regurgitation and were at high or
`extreme risk for conventional mitral valve replacement (18).
`The device was successfully implanted in 48 patients.
`At 30 days, there were no disabling strokes or repeat
`interventions, while the mortality rate was 14 percent. In
`addition, 74 percent of patients had no mitral regurgitation
`at 30 days and the remaining 26 percent had mild disease.
`The Tendyne study enrolled 30 patients with severe,
`asymptomatic mitral regurgitation who were deemed by the
`heart team to be poor candidates for surgery. The device
`was successfully implanted in 28 patients. At one year, five
`patients had died and three had been re-hospitalized for
`heart failure. None of the deaths were attributed to the
`
`procedure and no patients suffered a stroke. Of the other
`22 patients, 21 had no mitral regurgitation at one year. At
`30 days, transthoracic echocardiography showed mild
`central MR in one patient and no residual MR in the
`remaining 26 patients with valves in-situ. The left
`ventricular (LV) end-diastolic volume index decreased from
`mean 90.1 mL/m2 at baseline to 72.1 mL/m2. The Tendyne
`device is an apically tethered tri-leaflet porcine pericardial
`valve sewn onto a nitinol frame. It is specifically designed
`to address the complex mitral anatomy of functional,
`degenerative and mixed etiology mitral regurgitation. One
`of the major advantages of this device system is the fact that
`if the function of the prosthesis is not acceptable or LVOT
`obstruction occurs, it can be recaptured, repositioned, or
`fully retrieved, even after full deployment in the mitral
`annulus. The CardiAQ-Edwards Transcatheter Mitral Valve
`Replacement System (Edwards LifeSciences) is also being
`tested in an early feasibility study. In early 2017, Edwards
`paused enrollment of the trial to evaluate one of the valve’s
`features. The company resumed the trial a few months later,
`announcing a decision to pursue a transseptal, rather than
`transapical, delivery approach. Finally, a small series has
`been reported on three patients suffering from functional
`mitral regurgitation with a severe reduction of LV function
`who received the Fortis TMVR device from Edwards under
`compassionate clinical use program because they were
`thought to be at very high risk for surgery (19).
`The APOLLO trial using Medtronic’s Intrepid valve
`is expected to enroll up to 1,200 patients with severe,
`symptomatic mitral regurgitation. A cohort of 650 patients
`who are candidates for surgery and not eligible for mitral
`repair will be randomized to receive the Intrepid or undergo
`surgery, while another cohort of up to 550, deemed too
`high risk for surgery, will receive the Intrepid. All patients
`will be evaluated before and after the procedure, upon
`hospital discharge, and at 30 days, six months and on an
`annual basis for the next five years. All exclusion criteria
`(e.g., LV end-diastolic diameter >70 mm, severe mitral
`annular or leaflet calcification, left atrial or LV thrombus,
`prior mitral or aortic valve surgery, prior transcatheter
`mitral intervention, pulmonary artery systolic pressure
`>70 mmHg, severe tricuspid regurgitation and severe
`right ventricular dysfunction) are quite common clinical,
`anatomic or hemodynamic characteristics of so-called
`inoperable or high-risk patients scheduled for mitral valve
`surgery, complicating the enrolment of patients in these
`trials.
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`Table 1 Specific challenges with TMVR
`
`Domain
`
`Epidemiology
`
`TAVR
`
`TMVR
`
`Single: degenerative sclerotic AS
`
`Complex: non-rheumatic DMR & ischemic FMR
`
`Existing gold-standard of treatment
`
`SAVR; TAVR accomplishes the
`same thing
`
`Mostly mitral valve repair; TMVR equivalent of
`surgical replacement only
`
`Unmet need & high-risk patients
`
`Common
`
`Uncommon in overall MR population
`
`Durability of bioprosthetic valve
`
`Good in aortic position
`
`Poor in mitral position
`
`Impact of suboptimal results (PVL, PPM,
`risk of obstruction)
`
`Low (in older patients; higher in
`younger patients)
`
`High (generally younger patients; LVOT obstruction;
`systolic pressure gradient)
`
`Heterogeneity of substrate for implant
`
`Low
`
`High
`
`Other pathologies that need to be
`addressed
`
`Trial enrollment & progress
`
`Uncommon
`
`Common (Afib, TR)
`
`Fast (prohibitive risk: previously
`untreated population)
`
`Slow (strict inclusion criteria; uncommon
`demographic; competing devices)
`
`TMVR, transcatheter mitral valve replacement; TAVR, transcatheter aortic valve replacement; DMR, degenerative mitral valve regurgitation;
`FMR, functional mitral regurgitation; SAVR, surgical aortic valve replacement; PVL, paravalvular leak; PPM, permanent pacemaker; LVOT,
`left ventricular outflow track; TR, tricuspid regurgitation.
`
`Summary
`
`There are several important aspects that make the
`development and successful commercialization of TMVR
`devices challenging. These can be divided into several
`categories: the epidemiology and current treatment
`options for MR, the incidence and prevalence of different
`pathologies, anatomic and device challenges, as well as
`the trials currently underway for TMVR (Table 1). As
`less invasive methods will always be the preferred option,
`provided that outcomes are comparable with existing
`techniques and technology, TMVR will most certainly
`become a successful alternative treatment strategy in the
`long run. The current gold-standard for the management
`of patients with mitral valve disease consists of guideline-
`directed medical management and open heart surgery.
`Contemporary results of mitral valve surgery demonstrate a
`very high repair rate in non-rheumatic degenerative mitral
`valve disease with excellent long-term outcomes and low
`mortality (1.1%) (20). Review of the STS database and
`cases performed at the US Veterans Administration Health
`System also clearly show the increased mortality that is
`associated with mitral valve replacement in patients with
`degenerative MR (21). For ischemic functional MR, recent
`randomized clinical trials have shown comparable results
`between mitral valve repair and replacement in terms of
`mortality and somewhat favorable results for replacement
`
`with regards to residual MR. As TMVR tries to make its
`way into clinical practice, these surgical standards will
`provide the benchmark. Simultaneously, the devices will
`be expected to be safe, reliable and provide durable results
`consistent with the current surgical experience of mitral
`valve replacement using a bioprosthetic valve. In order
`to offer a truly minimally-invasive alternative to surgery,
`delivery will also have to be delivered by a trans-septal
`approach. Efforts to this extent are well underway and
`TMVR can be expected to be commercially available for
`select patient groups within the next few years.
`
`Acknowledgements
`
`Dr. Wyler von Ballmoos received grant support from the
`Thoracic Surgery Foundation for Research and Education
`via the Michael J. Davidson Fellowship Award.
`
`Footnote
`
`Conflicts of Interest: The authors have no conflicts of interest
`to declare.
`
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`© Annals of Cardiothoracic Surgery. All rights reserved.
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`www.annalscts.com
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`Cite this article as: Wyler von Ballmoos MC, Kalra A,
`Reardon MJ. Complexities of transcatheter mitral valve
`replacement (TMVR) and why it is not transcatheter
`aortic valve replacement (TAVR). Ann Cardiothorac Surg
`2018;7(6):724-730. doi: 10.21037/acs.2018.10.06
`
`© Annals of Cardiothoracic Surgery. All rights reserved.
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`Ann Cardiothorac Surg 2018;7(6):724-730
`
`Colibri Heart Valve LLC, Exhibit 2033, Page 7 of 7
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