Author + information
- Received January 16, 2018
- Revision received February 16, 2018
- Accepted February 16, 2018
- Published online April 23, 2018.
- Mayra Guerrero, MDa,∗∗ ( )(, )
- Marina Urena, MDb,∗,
- Dominique Himbert, MDb,
- Dee Dee Wang, MDc,
- Mackram Eleid, MDd,
- Susheel Kodali, MDe,
- Isaac George, MDf,
- Tarun Chakravarty, MDg,
- Moses Mathur, MDh,
- David Holzhey, MD, PhDi,
- Ashish Pershad, MDj,
- H. Kenith Fang, MDk,
- Daniel O’Hair, MDl,
- Noah Jones, MDm,
- Vaikom S. Mahadevan, MBBS, MDn,
- Nicolas Dumonteil, MDo,
- Josep Rodés-Cabau, MDp,
- Nicolo Piazza, MDq,
- Enrico Ferrari, MDr,
- Daniel Ciaburri, MDs,
- Mohammed Nejjari, MDt,
- Augustin DeLago, MDu,
- Paul Sorajja, MDv,
- Firas Zahr, MDw,
- Vivek Rajagopal, MDx,
- Brian Whisenant, MDy,
- Pinak Bipin Shah, MDz,
- Jan-Malte Sinning, MDaa,
- Adam Witkowski, MDbb,
- Helene Eltchaninoff, MDcc,
- Danny Dvir, MDdd,
- Bena Martin, MDee,
- Guilherme F. Attizzani, MDff,
- Diego Gaia, MDgg,
- Nagela S.V. Nunes, MDhh,
- Amir-Ali Fassa, MDii,
- Faraz Kerendi, MDjj,
- Gregory Pavlides, MDkk,
- Vijay Iyer, MDll,
- Georges Kaddissi, MDmm,
- Christian Witzke, MDnn,
- James Wudel, MDoo,
- Gregory Mishkel, MDpp,
- Bryan Raybuck, MDqq,
- Chi Wang, PhDrr,
- Ron Waksman, MDss,
- Igor Palacios, MDtt,
- Alain Cribier, MDcc,
- John Webb, MDdd,
- Vinnie Bapat, MDf,
- Mark Reisman, MDh,
- Raj Makkar, MDg,
- Martin Leon, MDe,
- Charanjit Rihal, MDd,
- Alec Vahanian, MDb,
- William O’Neill, MDc and
- Ted Feldman, MDa
- aDivision of Cardiology, Evanston Hospital, Evanston, Illinois
- bDepartment of Cardiology, Bichat Hospital, Paris, France
- cDivision of Cardiology, Henry Ford Hospital, Detroit, Michigan
- dDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- eDivision of Cardiology, Columbia University Medical Center, New York, New York
- fCardiothoracic Surgery, Columbia University Medical Center, New York, New York
- gDivision of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California
- hDivision of Cardiology, University of Washington Medical Center, Seattle, Washington
- iDivision of Cardiac Surgery, Leipzig Heart Center, Leipzig, Germany
- jDivision of Cardiology, Banner University Medical Center, Phoenix, Arizona
- kDivision of Cardiac Surgery, Banner University Medical Center, Phoenix, Arizona
- lDivision of Cardiac Surgery, Aurora St. Luke’s Medical Center, Milwaukee, Wisconsin
- mDivision of Cardiology, Mount Carmel East Hospital, Columbus, Ohio
- nDivision of Cardiology, University of California San Francisco, San Francisco, California
- oGroupe CardioVasculaire Interventionnel (GCVI), Clinique Pasteur, Toulouse, France
- pDepartment of Cardiology, Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada
- qDivision of Cardiology, Royal Victoria Hospital, Montreal, Quebec, Canada
- rDivision of Cardiac Surgery, Cardiocentro Ticino Foundation, Lugano, Switzerland
- sDivision of Cardiac Surgery, Saint Francis Medical Center, Peoria, Illinois
- tDivision of Cardiology, Centre Cardiologique du Nord, St. Denis, France
- uDivision of Cardiology, Albany Medical Center Hospital, Albany, New York
- vDivision of Cardiology, Abbott Northwestern Hospital, Minneapolis, Minnesota
- wKnight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon
- xDivision of Cardiology, Piedmont Heart Institute, Atlanta, Georgia
- yDivision of Cardiology, Intermountain Heart Institute, Salt Lake City, Utah
- zDivision of Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts
- aaDivision of Cardiology, Heart Center, University Hospital Bonn, Bonn, Germany
- bbDivision of Cardiology, Institute of Cardiology, Warsaw, Poland
- ccDivision of Cardiology, University of Rouen's Charles Nicolle Hospital, Rouen, France
- ddDivision of Cardiology, St. Paul’s Hospital, Vancouver, British Columbia, Canada
- eeDivision of Cardiac Surgery, National Institute of Cardiovascular Diseases, Bratislava, Slovakia
- ffDivision of Cardiology, University Hospitals Case Medical Center, Cleveland, Ohio
- ggDivision of Cardiac Surgery, Escola Paulista de Medicina, São Paulo, Brazil
- hhDivision of Cardiology, Complexo Hospitalar de Niteroi, Niteroi, Brazil
- iiDivision of Cardiology, Hôpital de La Tour, Geneva, Switzerland
- jjDivision of Cardiac Surgery, Heart Hospital of Austin, Austin, Texas
- kkDivision of Cardiology, The Nebraska Medical Center, Omaha, Nebraska
- llDivision of Cardiology, Buffalo General Medical Center, Buffalo, New York
- mmDivision of Cardiology, Cooper University Hospital, Camden, New Jersey
- nnDivision of Cardiology, Einstein Medical Center, Philadelphia, Pennsylvania
- ooDivision of Cardiac Surgery, Nebraska Heart Hospital, Lincoln, Nebraska
- ppDivision of Cardiology, Prairie Heart Institute, Springfield, Illinois
- qqDivision of Cardiology, INOVA Fairfax Hospital, Falls Church, Virginia
- rrDepartment of Biostatistics and Research Informatics, Research Institute, NorthShore University HealthSystem, Evanston, Illinois
- ssDivision of Cardiology, Medstar Washington Hospital Center, Washington, DC
- ttDivision of Cardiology, Massachusetts General Hospital, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Mayra Guerrero, Cardiology Division, Evanston Hospital/NorthShore University Health System, University of Chicago Pritzker School of Medicine, 2650 Ridge Avenue, Walgreen Building, 3rd Floor, Evanston, Illinois 60201.
Background The risk of surgical mitral valve replacement in patients with severe mitral annular calcification (MAC) is high. Several patients worldwide with severe MAC have been treated successfully with transcatheter mitral valve replacement (TMVR) using balloon-expandable aortic transcatheter valves. The TMVR in MAC Global Registry is a multicenter registry that collects data on outcomes of these procedures.
Objectives The goal of this study was to evaluate 1-year outcomes in this registry.
Methods This study was a multicenter retrospective review of clinical outcomes.
Results A total of 116 extreme surgical risk patients with severe MAC underwent TMVR; 106 had a procedure date >1 year before data-lock and were included in the analysis. Their mean age was 73 ± 12 years, and 68% were female. The mean Society of Thoracic Surgeons score was 15.3 ± 11.6%, and 90% were in New York Heart Association functional class III or IV. Thirty-day and 1-year all-cause mortality was 25% and 53.7%, respectively. Most patients who survived 30 days were alive at 1 year (49 of 77 [63.6%]), and the majority (71.8%) were in New York Heart Association functional class I or II. Echocardiography data at 1 year were available in 34 patients. Mean left ventricular ejection fraction was 58.6 ± 11.2%, mean mitral valve area was 1.9 ± 0.5 cm2, mean mitral gradient was 5.8 ± 2.2 mm Hg, and 75% had zero or trace mitral regurgitation.
Conclusions TMVR with balloon-expandable aortic valves in extreme surgical risk patients with severe MAC is feasible but associated with high 30-day and 1-year mortality. Most patients who survive the 30-day post-procedural period are alive at 1 year and have sustained improvement of symptoms and transcatheter valve performance. The role of TMVR in patients with MAC requires further evaluation in clinical trials.
- calcific mitral valve stenosis
- mitral annular calcification
- mitral valve disease
- mitral valve replacement
- transcatheter valve replacement
Patients with mitral annular calcification (MAC) are frequently an elderly high-risk population with multiple comorbidities and a high risk of cardiovascular death and all-cause mortality (1–3). The risk of surgical mitral valve (MV) replacement in this group is high due to comorbidities and technical challenges related to calcium burden, precluding successful surgery in many patients (4,5). There is an unmet clinical need for many who are not treated due to their high surgical risk profile. There have been several reports of successful transcatheter mitral valve replacement (TMVR) with the compassionate use of balloon-expandable transcatheter aortic valves in this population, most with the Sapien family of valves (Edwards Lifesciences, Irvine, California). The first few procedures were performed using a surgical transapical (6,7) or open transatrial (8,9) approach, but subsequent reports described successful implantation with a completely percutaneous transfemoral, transseptal approach (10–12).
We established the TMVR in MAC Global Registry to collect outcomes data from TMVR procedures performed worldwide to better understand safety and efficacy in a larger group. We previously reported the short-term outcomes of the first 64 patients treated in this registry (13). However, the long-term outcomes are unknown. The present study evaluated the clinical results and function of the mitral prosthesis at 1-year follow-up. Our hypothesis was that patients who survive the 30-day procedural period remain stable at 1 year.
The TMVR in MAC Global Registry was initiated in October 2013. Centers around the world with experience in TMVR using balloon-expandable valves in patients with MAC were invited to participate (Online Appendix). A total of 116 patients from 51 centers in 11 countries from North America, Europe, and South America who underwent TMVR with compassionate use of balloon-expandable transcatheter heart valves (THVs) between September 2012 and March 2017 were included. A total of 106 patients had an implant date >1 year before data-lock of this analysis (May 1, 2017) and were included in the 1-year evaluation, whereas 10 are not included due to an implant date <1 year from data-lock (Figure 1). The Institutional Review Board of the NorthShore University HealthSystem Research Institute approved the study.
Inclusion criteria were the presence of symptomatic severe mitral valvular disease with severe MAC in patients not eligible for standard MV surgery due to comorbidities or technical reasons related to calcium burden. A quantitative definition of severe MAC was not specified. However, most operators considered severe MAC to be the presence of diffuse, almost circumferential heavy calcification of the MV ring as seen by using cardiac computed tomographic (CT) imaging (Figure 2). Data were collected retrospectively for the procedures performed before the registry was initiated and prospectively thereafter in the majority of the patients, using a standardized case-report form. These data included:
1) Baseline clinical characteristics and baseline echocardiographic characteristics and CT imaging–based MV annulus diameter and area measurements when available.
2) Procedural characteristics, including type and size of THV implanted, valve delivery approach, and technical success; early post-implantation echocardiographic evaluation, including left ventricular ejection fraction, mean mitral valve gradient (MVG), mitral valve area (MVA), and left ventricular outflow tract (LVOT) gradient.
3) Procedural complications and major adverse events were collected at discharge, 30 days, and 1 year; and New York Heart Association (NYHA) functional class at 30 days and 1 year. The follow-up data were reported according to the lapse of time between the index procedure and data-lock for this analysis (May 1, 2017).
Technical success (measured at exit from the cardiac catheterization/operating room) was defined according to the Mitral Valve Academic Research Consortium (MVARC) criteria (14) as a procedure meeting all of the following: absence of procedural mortality; successful access, delivery, and retrieval of the device delivery system; successful deployment and correct positioning of the first intended device; and freedom from emergent surgery or reintervention related to the device or access. Periprocedural death was defined as death occurring within 30 days of the intervention or beyond 30 days for patients not yet discharged. All clinical endpoints were also defined according to MVARC criteria.
Continuous variables are summarized as mean ± SD or median (range). Categorical variables are summarized as frequency and percentage. The paired Student’s t-test for continuous variables and the McNemar test for categorical variables were used to compare 30-day or 1-year measurements versus the baseline echocardiographic data, and an adjusted p value using Bonferroni correction was reported. Percentages were based on all known values if the missing items were <5%. Missing data items resulted in reduced denominators for several variables. If ≥5% of the values were missing for a particular variable, the number of known values was indicated and included in the denominator. Survival curves for time to event variables were constructed by using Kaplan-Meier estimates. A multivariable Cox proportional hazards regression model was used to determine the potential independent risk factors related to 30-day and 1-year survival. Statistically significant risk factors with a p value <0.05 from the univariate analysis were first selected for the multivariable model. Stepwise variable selection was then used to further reduce the number of risk factors and to reach the final model.
Throughout the report, a p value <0.05 was considered to be statistically significant. Statistical analysis was performed by using SAS version 9.3 (SAS Institute, Inc., Cary, North Carolina).
Patient characteristics and procedural results
Baseline patient characteristics are listed in Table 1. Patients’ mean age was 73 ± 12 years (range: 39 to 96 years), and 68.1% were female. Multiple comorbidities were present, including chronic kidney disease in 53% of the patients. The mean Society of Thoracic Surgeons score was 15.3 ± 11.6% (range: 0.7% to 56%). Left ventricular ejection fraction was preserved in most patients (mean: 60.0 ± 10.3%). The primary MV pathology was stenosis in 94%, and 6% had mitral regurgitation (MR) without stenosis. The mean MVG was 11.5 ± 4.2 mm Hg, and the mean MVA was 1.3 ± 0.7 cm2. The mean pre-existing LVOT gradient was 5.8 ± 15.0 mm Hg (range: 0 to 50 mm Hg). Most patients were in NYHA functional class III or IV (90%).
Table 2 summarizes the procedural results. Technical success according to MVARC criteria was achieved in 89 (76.7%) of 116 patients, primarily limited by the need for a second THV in 17 (14.7%) due to migration in 6 and regurgitation in 11. At the end of the procedure, the mean MVG was 4.37 ± 2.37 mm Hg, and the mean MV orifice area was 2.44 ± 0.95 cm2. Paravalvular regurgitation was mild or absent in 95.1%, and 4.9% had grade 3 or more paravalvular MR. Discharge medication information was available in 67.2% of the patients; 50.0% were discharged on oral anticoagulation with warfarin plus single antiplatelet drug, 16.7% on warfarin alone, 14.1% on aspirin plus clopidogrel, 12.8% on aspirin alone, 3.8% on triple therapy, and 2.6% on non–vitamin K antagonist anticoagulants.
Procedure-related LVOT obstruction
LVOT obstruction with hemodynamic compromise occurred in 13 patients (11.2%). One patient underwent emergency open heart surgery to explant the THV but died during the rescue operation; 1 underwent emergency kissing aortic and mitral balloon valvuloplasty with moderate improvement of LVOT gradient but died of multiorgan failure 2 days later; 5 were treated medically (1 died in the cardiac catheterization laboratory before any additional intervention could be performed, 3 more died during the same hospitalization 1 to 11 days after TMVR, 1 was discharged from the hospital and died 2 months later due to failure to thrive); 6 underwent emergent percutaneous alcohol septal ablation with a significant improvement in LVOT gradient (1 died 4 days later due to complete atrioventricular block; 1 had recurrent LVOT gradient the following day due to septal edema treated with surgical explantation of the THV followed by successful transatrial TMVR with resection of the anterior leaflet but died 3 weeks later due to multiorgan failure; 4 were discharged from the hospital and were alive at 30 days). Of the 4 patients who survived 30 days, 1 died at 45 days post-TMVR due to gastrointestinal bleed and sepsis; 1 died 3 months later of unknown cause; and 2 are alive and stable at 1-year follow-up (Figure 3).
30-day and 1-year outcomes
The median follow-up was 170 days (mean: 355 days; range: 50 to 1,687 days). Clinical outcomes are shown in Table 3. The 30-day all-cause mortality was 25% (cardiovascular 13%; noncardiovascular 12%). There were 28 deaths between 31 days and 1-year post-TMVR, and 49 patients were alive at 1 year. Patient flow is summarized in Figure 1. The 1-year all-cause mortality was 53.7% (cardiovascular 23.5%; noncardiovascular 30.2%). However, landmark analysis after 30 days showed that most patients who survived the 30-day post-procedural period remained alive at 1 year (Central Illustration). Of the 28 deaths after 30 days, 10 were cardiovascular and 18 were noncardiovascular. The causes of the 10 cardiovascular deaths included 3 endocarditis, 3 progression of heart failure, 2 valve thrombosis (both patients were receiving warfarin [the international normalized ratio was 2.2 in 1 patient and <2 in the other patient]), 1 LVOT obstruction (the patient underwent transatrial TMVR for LVOT obstruction 2 months after the index procedure and died of cardiogenic shock after surgery), and 1 stroke (occurred during index hospitalization, and the patient died at a nursing home 3 months later). The cause of the 18 noncardiovascular deaths included noncardiac infection in 5 patients, failure to thrive in 5, gastrointestinal bleed in 2 (1 was receiving warfarin therapy, 1 was not), respiratory failure in 2 (1 due to chronic pulmonary obstructive disease, and 1 due to hemoptysis), 1 cervical fracture, 1 bowel ischemia, 1 liver failure, and the cause was unknown in 1 patient. There was no statistically significant difference in mortality related to access type: transapical = 26.1%, transseptal = 25.5%, and transatrial = 21.7% (p = 0.92) at 30 days versus transapical = 56.5%, transseptal = 62.5%, and transatrial = 35% (p = 0.12) at 1 year.
On univariate Cox regression analysis, several predictors of 1-year mortality were identified, including age, NYHA functional class, transapical or transseptal versus transatrial delivery access, LVOT obstruction, valve embolization, and conversion to open surgery. Technical success defined by using the MVARC criteria was a predictor of lower mortality at 30 days (hazard ratio [HR]: 0.37; 95% CI: 0.14 to 0.98; p = 0.04) and 1 year (HR: 0.23; 95% CI: 0.12 to 0.44; p < 0.0001). On multivariable Cox regression analysis, LVOT obstruction was found to be an independent predictor of mortality at 30 days (HR: 3.16; 95% CI: 1.19 to 8.36; p = 0.02) and 1 year (HR: 3.56; 95% CI: 1.81 to 7.01; p < 0.001) (1-year data in Table 4).
There were 9 MV reinterventions within 30 days from the index TMVR procedure: 4 percutaneous paravalvular leak (PVL) closure, 2 transseptal TMVR valve-in-valve (1 for central MR and 1 for PVL), 2 transatrial TMVR (1 for embolization 2 weeks after the index procedure due to suspected undersized valve and 1 for LVOT obstruction), and 1 surgical MVR for persistent PVL several days after the index procedure. Four additional reinterventions occurred after 30 days from the index procedure: 1 transseptal TMVR valve-in-valve for PVL, 1 PVL closure, 1 transatrial TMVR for persistent symptomatic LVOT obstruction initially treated medically, and 1 surgical MVR 2 months after the index procedure for late migration causing MR suspected to have started on day 28 post-TMVR.
Most patients had sustained improvement of symptoms. At 1 year, 28 of the 39 patients with NYHA functional class data available were in class I or II (71.8%), 10 were in class III (26.6%), and 1 was in class IV (2.6%) (p < 0.001 vs. baseline) (Figure 4).
Thirty-day and 1-year follow-up echocardiographic data are shown in Table 5. Transthoracic echocardiographic follow-up at 1 year was available in 34 (70.8%) of 49 patients alive at the time of the present analysis. There was no difference in mean left ventricular ejection fraction at 1 year compared with baseline. Mean left ventricular ejection fraction was 58.6 ± 11.2% (p < 0.67 vs. baseline). However, there was a significant improvement in mean MVG and MVA. Mean MVG was 5.8 ± 2.2 mm Hg (p < 0.0001 vs. baseline) with an MVA of 1.9 ± 0.5 cm2 (p < 0.011 vs. baseline) (Figure 5). Twenty-four patients (75%) had zero to trace MR, 7 (21.9%) had mild MR (all central), and 1 patient (3.1%) had severe paravalvular MR (p < 0.001 vs. baseline). The average peak LVOT gradient was 7.3 ± 10.8 mm Hg (p = 0.16 vs. baseline). No cases of valve degeneration were observed.
Outcomes relative to experience
Outcomes of the first half of the patients treated in this registry were compared with the second half (Table 6). There was a trend toward lower 30-day mortality in the second half of patients treated (first half = 31% vs. second half = 19%; p = 0.07) and lower need for a second valve (19% vs. 10.3%; p = 0.09). Four patients needed conversion to surgery in the first half of the experience (7.6%) versus no need for conversion to surgery in the second half (0%) (p = 0.04). Forty participating institutions enrolled 1 to 2 patients each, 10 enrolled 3 to 9 patients each, and only 1 institution enrolled >10 (n = 13). There was no statistically significant difference in outcomes among institutions according to number of patients enrolled (1 to 2, 3 to 9, or >10).
TMVR with balloon-expandable aortic valves in extremely high surgical risk patients with severe MAC is feasible but associated with high 30-day and 1-year mortality. However, most patients who survive the 30-day post-procedural period are alive at 1 year and have sustained improvement of symptoms as well as THV performance. LVOT obstruction was the most important and independent predictor of 30-day and 1-year mortality. Efforts should be made to avoid this important complication to improve short-and long-term outcomes.
This study is the first large multicenter evaluation of TMVR with balloon-expandable aortic THVs in patients with severe native MV disease due to severe MAC who were considered poor candidates for traditional surgical mitral replacement. In our initial report of short-term outcomes, we found that TMVR with balloon-expandable valves designed for aortic position is feasible in this extremely high-risk patient population (13). Technical success was achieved in most patients. Although there were important complications and a high 30-day mortality, we interpreted the results as encouraging considering this study represents the first human experience with a THV not designed for the mitral position and used in an extremely high-risk patient population with a mean Society of Thoracic Surgeons risk score much higher than in the PARTNER I (Placement of Aortic Transcatheter Valves) trial (15). In the present analysis of the 1-year outcomes of these patients, we found a high mortality rate of 53.7%. Although two-thirds of the patients who survived the 30-day post-procedural period were alive at 1 year, the overall 53.7% mortality is concerning, and efforts should be made to improve patient selection to achieve better outcomes. Many of the deaths that occurred after 30 days were noncardiovascular, suggesting that these late events are most likely related to the multiple comorbidities, noncardiac frailty, and advanced age of these extremely ill patients who had a baseline Society of Thoracic Surgeons score of 15.3%.
The results we report are similar to the complications and mortality reported in the initial experience with transcatheter valves designed for the MV to treat patients with MR. In the early experience with the CardiAQ valve (Edwards Lifesciences), the FORTIS valve (Edwards Lifesciences), and the Tiara valve (Neovasc Inc., Richmond, British Columbia, Canada), there were complications, and several patients died after a seemingly successful procedure (16–20). These outcomes might have been related to patient selection because some patients had severe left ventricular dysfunction and died of progression of heart failure. Similarly, the late results in our registry are likely related to patient selection as perhaps most patients were treated too late in their disease process similar to the so-called “cohort C” patients in the transcatheter aortic valve replacement experience. There is no good comparison from the surgical literature because these patients rarely undergo open, conventional MV replacement due to the intrinsic high surgical risk.
TMVR-induced LVOT obstruction
We found that TMVR-induced LVOT obstruction is a strong independent predictor of 30-day and 1-year mortality. Strategies to treat and prevent this complication are being evaluated, including alcohol septal ablation as bailout treatment (21), pre-emptive alcohol septal ablation performed several weeks before TMVR, and percutaneous anterior mitral leaflet laceration (22). Another strategy could be the use of self-expandable aortic retrievable devices, which may have the advantage of allowing device retrieval if severe LVOT obstruction occurs after TMVR. The use of the Lotus valve (Boston Scientific Corporation, Marlborough, Massachusetts) and Direct Flow (Direct Flow Medical Inc., Santa Rosa, California) has been reported with success in patients with severe MAC (23,24). Although the option of repositioning or retrieving the valve in the setting of TMVR-induced LVOT obstruction may be an advantage over the balloon-expandable valve technology, an important disadvantage is that these technologies have the transapical route as the only delivery option at this time, and the Direct Flow is no longer available. Similarly, the Tendyne valve (Abbott Vascular, Santa Clara, California), which is a self-expandable, fully retrievable THV designed for the mitral position, has been used successfully in patients with severe MAC (25). This device can also be retrieved if severe LVOT obstruction occurs after TMVR. However, the experience with transcatheter MVs in MAC is limited at this time because none of these new transcatheter valves built for the mitral position was designed to treat calcified valves. Severe MAC is an exclusion criterion in early feasibility TMVR clinical trials.
Sustained improvement of symptoms and valve performance
Patients who survived 1 year experienced significant and sustained improvement of symptoms. This finding is important because it suggests that TMVR in carefully selected patients may be an alternative with the potential to provide significant improvement in symptoms and quality of life. This theory needs to be evaluated in prospective clinical trials. Similarly, adequate valve function was maintained at 1 year. Although we observed lower MVA at 1 year compared with the echocardiogram data at 30 days, the number of patients is too small to draw meaningful conclusions about this difference. Furthermore, the MVG did not change significantly at 1 year, suggesting adequate valve function. Another encouraging finding was that significant MR of moderate severity or greater was absent in all patients except for 1 who had severe PVL after the procedure and moderate to severe PVL at 1 year. Only 7 of the 32 patients with MR severity data at 1 year (21.9%) developed mild central MR. Whether this finding represents a sign of valve leaflet deterioration is unclear at this time. The number of patients is very small, and the echocardiographic data were self-reported and not evaluated by a core laboratory.
Outcomes relative to experience
When outcomes of the first half of the patients treated in this registry were compared with the second half, there was a trend toward lower mortality (31% vs. 19%; p = 0.07) and lower need for a second valve (19.0% vs. 10.3%; p = 0.09). This finding did not reach statistical significance, most likely due to the small sample. However, there was no need for conversion to surgery in the second half of this experience (7.6% vs. 0%; p = 0.04). These findings are encouraging and indicate that as operators gain experience in patient selection and procedural techniques, the outcomes tend to improve. This finding suggests that further improvement in outcomes could be achieved with better patient selection, increase in experience, and refinement of procedure techniques.
Mitral annulus sizing and the role of imaging
In the absence of a validated standard method for mitral annulus sizing, operators have extrapolated from TAVR experience and used a variety of measurement approaches, including echocardiography, three-dimensional transesophageal echocardiography, cardiac CT imaging, and balloon sizing techniques. Only a few patients treated in the early experience were not evaluated with cardiac CT scanning. However, this imaging modality rapidly became the most accepted method for annulus size assessment. As experience has increased, it has been recognized that CT scanning may also provide essential information for pre-procedural planning. CT scanning is excellent for evaluating the amount and distribution of calcium in an attempt to predict valve anchoring and features that may assist in predicting LVOT obstruction, including the aorto-mitral angle, the anterior leaflet length, the size of the left ventricular cavity, the presence of septal hypertrophy, and the change in the residual LVOT space in relation to the depth of valve implantation. We learned to better predict LVOT obstruction based on CT analysis that allows estimates of the new LVOT space after TMVR, the Neo-LVOT area (26–28). This concept was crucial to improve patient selection and reject patients at high risk for LVOT obstruction or consider alternatives such as surgical direct transatrial delivery with resection of the anterior leaflet in patients who can undergo surgery or percutaneous anterior mitral leaflet laceration in patients who are not candidates for any kind of surgery (22). Considering that LVOT obstruction was the most important independent predictor of mortality in this study, we believe that our new knowledge on cardiac CT analysis is the most important progress we have made to improve procedural outcomes. Cardiac CT scanning can also be helpful in planning the site and trajectory of transapical or transseptal access (Figure 6).
This study has important limitations inherent to registries. The total number of patients analyzed is small, and most centers included only 1 or 2 patients. Participating sites were encouraged to submit all cases, successful and unsuccessful. However, complete reporting of all cases per site has not been determined. Therefore, selective reporting cannot be excluded. Multivariate analysis for predictors of poor 1-year outcome is also limited by the sample size. Because this is real-world practice experience, the patient population is not homogeneous. Most of the data were collected retrospectively, and not all data were captured or reported in all centers, resulting in a significant amount of missing data. The clinical outcomes were self-reported. Because the clinical events were not adjudicated, it is possible that the adverse events were underestimated. In addition, there were no core laboratories utilized, which could have resulted in underestimated valve dysfunction and deterioration.
A prospective clinical trial may help overcome the important limitations of this registry. The MITRAL (Mitral Implantation of Transcatheter Valves) trial (NCT02370511) is a U.S. Food and Drug Administration–approved, physician-sponsored, pilot investigational device exemption trial that is currently ongoing in the United States to systematically evaluate the safety and feasibility of this technology in severe native MV disease with severe MAC. We anticipate that the MITRAL trial will help provide insights to further improve technical success, patient selection, and the overall clinical outcomes of this patient population.
TMVR with balloon-expandable aortic THVs in extremely high surgical risk patients with severe MAC is feasible but associated with high 30-day and 1-year mortality. The majority of patients who survive the 30-day post-procedural period are alive at 1 year and have sustained improvement of symptoms as well as THV performance. This strategy might be an alternative for carefully selected high-risk or inoperable patients with limited treatment options but remains off-label at this time, and efforts are required to improve outcomes. The role of TMVR and predictors of outcomes in MAC patients treated with TMVR requires further evaluation in clinical trials.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Early experience with TMVR using a balloon-expandable prosthesis in patients at high surgical risk with severe mitral annular calcification has been associated with high 30-day mortality. However, most patients surviving beyond 30 days post-procedure were alive and exhibited sustained improvement in symptoms and satisfactory valve performance at 1 year.
TRANSLATIONAL OUTLOOK: Further studies are needed to improve patient selection and procedural techniques for TMVR to enhance clinical outcomes.
↵∗ Drs. Guerrero and Urena contributed equally to this work and are joint first authors. Bernard J. Gersh, MBChB, DPhil, served as Guest Editor for this paper.
The TMVR in MAC Global Registry is not supported by external funding. Dr. Guerrero has served as a proctor and consultant and has received research grant support from Edwards Lifesciences. Dr. Himbert has served as a proctor for Edwards Lifesciences and Medtronic; and served as a consultant for Edwards Lifesciences. Dr. Wang has served as a consultant to Edwards Lifesciences. Dr. Kodali has received research grant support from Edwards Lifesciences, Medtronic, Boston Scientific, and Abbott Vascular; and has ownership interest in Dura Biotech, Thubrikar Aortic Valve, and BioTrace Medical. Dr. George has served as a consultant to Edwards Lifesciences. Dr. Holzhey has served as a proctor for Symetis; and has served on the advisory board for Edwards Lifesciences and Medtronic. Dr. Pershad has served as a consultant to Edwards Lifesciences. Dr. Fang has served as a consultant to Edwards Lifesciences. Dr. O’Hair has served as a consultant to Medtronic. Dr. Mahadevan has served as a proctor for Edwards Lifesciences. Dr. Dumonteil has served as a proctor for Edwards Lifesciences, Medtronic, and Boston Scientific; and has served as a consultant to Biotronik. Dr. Rodés-Cabau received institutional research grants from Edwards Lifesciences. Dr. Piazza has served as a consultant to Medtronic and HighLife; and has received research grant support from Medtronic. Dr. Ferrari has served as a proctor and consultant to Edwards Lifesciences. Dr. Sorajja has served as a consultant to Abbott Vascular, Medtronic, Boston Scientific, and Lake Regions Medical; and has received research grant support from Abbott Vascular. Dr. Rajagopal has served as a proctor and consultant to Abbott Vascular, Boston Scientific, and Medtronic. Dr. Whisenant has served as a consultant to Edwards Lifesciences. Dr. Shah has served as a consultant to Edwards Lifesciences and St. Jude Medical. Dr. Witkowski has served as a consultant to Edwards Lifesciences. Dr. Dvir has served as a consultant to Edwards Lifesciences. Dr. Attizzani has served as a proctor for Edwards Lifesciences and Medtronic; is on the Speakers Bureau for Medtronic and Abbott Vascular; and is a consultant to St. Jude Medical. Dr. Cribier has served as a consultant to Edwards Lifesciences. Dr. Webb has served as a consultant to Edwards Lifesciences. Dr. Bapat has served as a consultant to Edwards Lifesciences, Medtronic, Sorin, and Boston Scientific; and has served as a proctor for Edwards Lifesciences. Dr. Rihal has served as a consultant and received research grant support from Edwards Lifesciences. Dr. Vahanian has served as a consultant to Edwards Lifesciences, Medtronic, and Abbott Vascular; and has received research grant support from Valtech. Dr. O’Neill has served as a consultant to Edwards Lifesciences and Medtronic. Dr. Feldman has served as a consultant for and has received research grant support from Abbott Vascular, Boston Scientific, and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- computed tomography
- hazard ratio
- left ventricular outflow tract
- mitral annular calcification
- mitral regurgitation
- mitral valve
- mitral valve area
- Mitral Valve Academic Research Consortium
- mitral valve gradient
- New York Heart Association
- paravalvular leak
- transcatheter heart valve
- transcatheter mitral valve replacement
- Received January 16, 2018.
- Revision received February 16, 2018.
- Accepted February 16, 2018.
- 2018 American College of Cardiology Foundation
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