Original Contribution

Characteristics and Outcomes of Patients Ineligible for Transcatheter Mitral Valve Replacement (TMVR): Implications for Future Device Innovation

Sebastian Ludwig, MD1;  Benedikt Koell, MD1;  Roya Sedighian, MD1;  Jessica Weimann, MD1;  Niklas Schofer, MD1;  Andreas Schäfer, MD2;  Lisa Voigtländer, MD1;  Lara Waldschmidt, MD1;  Johannes Schirmer, MD2;  Moritz Seiffert, MD1;  Simon Pecha, MD2;  Dirk Westermann, MD1;  Hermann Reichenspurner, MD2;  Stefan Blankenberg, MD1;  Edith Lubos, MD1;  Lenard Conradi, MD2;  Daniel Kalbacher, MD1

Sebastian Ludwig, MD1;  Benedikt Koell, MD1;  Roya Sedighian, MD1;  Jessica Weimann, MD1;  Niklas Schofer, MD1;  Andreas Schäfer, MD2;  Lisa Voigtländer, MD1;  Lara Waldschmidt, MD1;  Johannes Schirmer, MD2;  Moritz Seiffert, MD1;  Simon Pecha, MD2;  Dirk Westermann, MD1;  Hermann Reichenspurner, MD2;  Stefan Blankenberg, MD1;  Edith Lubos, MD1;  Lenard Conradi, MD2;  Daniel Kalbacher, MD1


Objectives. Due to high rates of transcatheter mitral valve replacement (TMVR) screening failure, a substantial proportion of patients with severe mitral regurgitation (MR) remain on optimal medical treatment (OMT) only. Data on outcomes of these patients ineligible for mitral interventions are scarce. This study aimed to assess characteristics and outcomes of severe MR patients treated medically following TMVR screening failure. Methods. From 2016-2020, a total of 111 patients with severe MR underwent screening for TMVR. Screening failure occurred in 66 cases. Among these, 30 patients were treated with OMT only. Characteristics of these patients were analyzed, Kaplan-Meier estimates calculated, and univariate regression analysis performed. Median follow-up time was 2.26 years (95% confidence interval, 1.24-3.25). Results. Anatomical reasons for screening failure in the study cohort (n = 30) were left ventricular (LV) restraints, risk of LV outflow tract obstruction, mitral annulus calcification, and sizing issues. Median ejection fraction was 56.0% (interquartile range, 38.8%-60.0%). Concomitant tricuspid regurgitation and severe pulmonary hypertension were present in 36.7% and 46.2%, respectively. Intercommissural diameters ranged from 22.5-52.0 mm. Mortality was 23.6% after 6 months and 35.7% after 1 year. Factors associated with mortality were female sex, MR severity, ischemic MR, high N-terminal pro-brain natriuretic peptide levels, and small annulus diameters. Conclusions. Despite growing experience with TMVR, the subset of MR patients anatomically eligible for TMVR is small and many patients are treated medically. Mortality in these patients remains high, underlining an unmet need for adequate therapeutic alternatives. TMVR devices adapting to broader annular size ranges with smaller ventricular profiles might fill this gap.

J INVASIVE CARDIOL 2021 February 18 (Ahead of Issue). 

Key words: cardiac computed tomography, cardiac imaging, mitral valve replacement 

Transcatheter mitral valve replacement (TMVR) is a promising therapy for surgical high-risk patients suffering from severe mitral regurgitation (MR) with unfavorable anatomy for endovascular edge-to-edge repair.1,2 Recently, several studies have shown the feasibility of TMVR with different dedicated devices.3,4 However, after a thorough screening process including echocardiography and full cardiac cycle multislice computed tomography (MSCT), only a minority of screened patients is anatomically amenable to TMVR valve deployment and high screening failure rates have been reported.5,6 

As a consequence of ineligibility for any given interventional or surgical therapy, a significant number of patients is forced to continue with medical therapy despite clinically relevant MR.7 Although an optimal medical therapy (OMT) is recommended in all patients with secondary MR prior to any invasive treatment,8 interventional treatment has proven to increase functional outcomes and improve survival in selected patients with an established indication for MR therapy.9,10 Consequently, severe MR patients declined for any form of interventional or surgical therapy suffer from poor prognosis and a high burden of heart failure symptoms and recurrent hospitalizations.7 However, data on characteristics and outcomes of these patients are scarce.

The present study sought to investigate clinical and anatomic characteristics as well as outcomes of this neglected subset of patients ineligible for interventional (ie, edge-to-edge repair and TMVR) and surgical treatment. The primary aim of this study was the identification of factors associated with adverse outcomes in these patients, thereby targeting potential future device innovations.


Study population and data aquisition. From May 2016 to May 2020 a total of 111 high-risk patients with clinically relevant MR who were considered ineligible for both surgery and endovascular edge-to-edge repair underwent screening for TMVR at our institution. The screening process comprised MSCT and both transthoracic and transesophageal echocardiography. A detailed description of the interdisciplinary screening process has been given elsewhere.6 After thorough clinical and anatomical evaluation, a total of 66 patients (59.5%) were deemed ineligible for available TMVR prostheses: Tiara (Neovasc), Tendyne (Abbott Vascular), CardiAQ (Edwards Lifesciences), HighLife Valve (HighLife Medical), Caisson (LivaNova) and Cardiovalve (Cardiovalve). Among these patients, 25 (22.5%) were treated with percutaneous edge-to-edge repair and 2 patients (1.8%) received percutaneous mitral valve annuloplasty. High-risk surgery was performed in 5 patients (4.5%). After exclusion of 4 patients with non-severe MR, 30 severe MR patients (27.0%) were subsequently left on OMT only and formed the study population (Figure 1). We investigated baseline characteristics as well as outcomes of these patients who were ineligible for mitral valve repair and replacement. Survival data were obtained from in-house information as part of clinical routine. All patients provided written informed consent for device screening and data acquisition. The study was conducted in accordance with the Declaration of Helsinki.

Echocardiography. Transthoracic and transesophageal echocardiography were performed in every patient for assessment of MR severity and etiology. Evaluation of MR was performed according to the 2017 European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines for the management of valvular heart disease and documented according to a standardized protocol. 

Full cardiac cycle MSCT analyses. Full cardiac cycle MSCT was performed in every patient who underwent the TMVR screening process. A dedicated software (3mensio Structural Heart, version 9.1; Pie Medical Imaging) was used to assess dimensions of the mitral valve annulus and the left ventricle (LV) at 30% (end-systole) and 75% (mid-to-end diastole) of the cardiac cycle. The mitral valve annulus was sized according to the D-shaped annulus concept. Routine measurements of the mitral valve annulus are demonstrated in Figure 2. 

Statistical analysis. Continuous variables are shown as median with interquartile range (IQR); binary variables are shown as counts (frequencies). Histograms were used to assess distributions of systolic intercommissural (IC) diameters and systolic annulus areas. Frequencies of observations per 2 or 1 units are plotted. The median follow-up time was estimated by the reverse Kaplan-Meier estimator. To examine the primary endpoint of all-cause mortality after 1-year survival, probabilities of patients were estimated using the Kaplan–Meier method. Several groups were compared using the log-rank test. To assess the association of baseline characteristics, laboratory, echocardiography, and MSCT variables with the primary endpoint, an unadjusted Cox regression model was fitted. Change in continuous variables was modeled as change per standard deviation. A P-value of <.05 was considered statistically significant. All analyses were performed with R statistical software, version 3.6.0 (R Foundation for Statistical Computing).


Clinical baseline characteristics. Detailed clinical baseline characteristics are shown in Table 1. Patients in the study population had a median age of 78.5 years (IQR, 75.0-81.1 years), were more frequently female (60%), and had a high estimated surgical risk as assessed by EuroScore II (5.8%;  IQR, 2.8%-9.6%) and STS PROM (10.7%; IQR, 4.0%-14.0%). The median body mass index (BMI) was 26.7 kg/m2 (IQR, 24.3-28.7 kg/m2), diabetes mellitus was present in one-half (50.0%), and chronic renal impairment was present in more than two-thirds (70.0%) of the study population. Regarding cardiac comorbidities, atrial fibrillation and coronary artery disease were present in more than one-half of the study population (each 56.7%). Five patients (16.7%) had myocardial infarction in the past and 2 patients (6.7%) required coronary artery bypass graft surgery. The rate of previous transcatheter or surgical aortic valve replacement (AVR) was 30.0% (13.3% surgical and 20.0% transcatheter, including 1 patient with valve-in-valve replacement of a surgical bioprosthesis). No patient received mitral valve surgery prior to TMVR screening initiation. 

The study population was highly symptomatic, with New York Heart Association (NYHA) class III or IV in 89.7% (NYHA III, 69.0%; NYHA IV, 20.7%) and high median N-terminal pro-brain natriuretic peptide (NT-proBNP) levels at baseline (5422 ng/L; IQR, 3,092-15,926 ng/L). Moreover, 76.7% of the patients were admitted to a hospital for decompensated heart failure during the last year. Almost every patient (93.3%) required at least 1 heart failure medication at the time of screening. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor-1 (AT-1) antagonists and beta-blockers were each prescribed in 76.7% of the patients, whereas aldosterone antagonists were recommended in only 16.7%. The intake of angiotensin-receptor neprilysin inhibitor (ARNI) was recommended in only 1 patient (3.3%). Loop diuretics were given to 83.3% of the patients.

Echocardiographic parameters. Anatomical characteristics of the study population as assessed by echocardiography and MSCT are given in detail in Table 2. One-half of the patients (50.0%) had secondary MR, whereas primary MR etiology was present in 40.0% of the patients. Mixed primary and secondary MR was found in 3 patients (10.0%). Severity of MR was diagnosed as moderate-to-severe in 33.3% and severe in 66.7% of the study population, with a median effective regurgitant orifice area (EROA) of 0.2 cm2 (IQR, 0.2-0.4 cm2) and a median regurgitation volume of 43.8 mL (IQR, 27.9-63.6 mL). Median ejection fraction (EF) of the investigated patients was preserved, with 56.0% (IQR, 38.8%-60.0%) having a high-normal median left ventricular end-diastolic diameter (LVEDD) of 52.0 mm (IQR, 45.9-61.1 mm). Concomitant moderate-to-severe or severe tricuspid regurgitation (TR) was present in 36.7% of the study population. Severe pulmonary hypertension (defined as a systolic pulmonary artery pressure [sPAP] of ≥55 mm Hg) was found in 46.2% of the patients; median sPAP was 52.0 mm Hg (IQR, 44.9-63.2 mm Hg). 

MSCT parameters. Detailed results of mid-to-end diastolic and end-systolic MSCT measurements in the study population are presented in Table 2. Median diastolic and systolic IC diameters were 35.8 mm (IQR, 31.9-39.9 mm) and 34.9 mm (IQR, 31.4-40.4 mm), respectively. Median mitral annulus area was assessed as 9.4 cm2 (IQR, 8.4-15.1 cm2) diastolic and 8.8 cm2 (IQR, 8.2-13.3 cm2) systolic. The ranges of all MSCT-derived mitral annular parameters are given in Supplemental Table S1. Additionally, Figure 3 demonstrates the spectrum of annular dimensions for the study population, as assessed by systolic IC diameters (Figure 3A) and systolic annulus area (Figure 3B). Any mitral annular calcification (MAC) was found in 53.3% of all patients. Of these, 36.7% presented with severe circumferential MAC. 

Reasons for TMVR screening failure. A total of 83 device screenings for 6 different TMVR devices were performed. The mean number of device screenings performed per patient was 2.53. According to internal anatomical evaluation and to available statements of device manufacturers, 5 reasons for TMVR screening failure were found. The most common reasons resulting in TMVR ineligibility were small LV dimensions (26.7%) and a high predicted risk of LV outflow tract obstruction (21.7%). Severe MAC was the cause of screening failure in 23.3% of patients. Annular dimensions led to screening failure, with 10.0% considered too small and 18.3% considered too large. The distribution of reasons for TMVR screening failure is summarized in Figure 4.

Mortality and predictors of outcome. After the median follow-up time of 2.26 years (95% confidence interval [CI], 1.24-3.25) all-cause mortality occurred in 12 cases, resulting in an overall mortality rate of 40%. Figure 5 shows Kaplan-Meier analysis for the endpoint of all-cause mortality performed for 1 year after TMVR screening initiation. All-cause mortality for patients ineligible for TMVR receiving OMT, as assessed by Kaplan-Meier estimates, was 23.6% after 6 months and 35.7% after 1 year.

Univariate Cox regression analysis for the hazard of all-cause mortality was performed for a selected subset of clinical and anatomical baseline parameters. The results are given in Supplemental Table S2. Factors significantly associated with mortality were female sex, previous myocardial infarction, high EROA, and high baseline NT-proBNP. Non-significant trends toward an association with mortality were found for previous coronary artery bypass graft surgery, high regurgitation volume, and NYHA class IV. On the other hand, significant associations with survival were found for wider IC diameters and higher trigon distance, as assessed by MSCT in both systole and diastole. Moreover, non-significant trends for an association with survival were found for other diametric parameters (ie, mean mitral annulus diameter [Dmean]) as well as for high hemoglobin and high serum albumin. 

Kaplan-Meier analyses for 1-year all-cause mortality were generated for symptomatic status stratified by NYHA stage and NT-proBNP levels (Figure 6A), MR severity according to EROA (Figure 6B), anemia (hemoglobin levels) (Figure 6C), and annulus dimensions as assessed by systolic IC diameter (Figure 6D). All-cause mortality after 1 year in symptomatic patients with highest NT-proBNP levels in NYHA class IV was significantly higher than in those with low NT-proBNP levels and NYHA class I-III. Patients in the highest EROA tertile had significantly higher all-cause mortality after 1 year compared with lower EROA tertiles. Anemia, as assessed by low hemoglobin levels, was associated with higher 1-year mortality rates compared with those who had higher hemoglobin levels. Lastly, patients with smallest IC diameters had the highest mortality rates after 1 year as compared with patients who had wider IC diameters.


The present study investigated clinical and anatomical characteristics of severe MR patients who were screened but rejected for TMVR therapy and ineligible for interventional mitral valve repair, who were subsequently treated with OMT only. The key findings of this study were: (1) despite rapidly evolving interventional therapies addressing MR, a substantial number of patients still remain unsuitable for any form of interventional MR therapy, including TMVR, and thus, these patients are left to medical treatment only; (2) this subset of patients is characterized by high surgical risk, high rates of cardiovascular comorbidities, and high prevalence of moderate or severe TR and pulmonary hypertension; (3) despite sufficient OMT medication, all-cause mortality rates after both 6 months and 1 year were high (23.6% and 35.7%, respectively); and (4) factors associated with poor outcomes in these patients were MR severity, small mitral annular dimensions, female sex, history of myocardial infarction, and high NT-proBNP level. 

For the present study cohort of patients ineligible for any MR therapy who underwent OMT after TMVR screening failure, the most common anatomical reasons for screening failure were small LV dimensions, predicted risk of LV outflow tract obstruction, severe MAC, and too-small or too-large annular diameters. This is reflected by our echocardiographic and MSCT findings, with severe MAC in 36.6%, a preserved LV ejection fraction in more than one-half of the study population, as well as the wide range of mitral annular dimensions (Figure 3 and Supplemental Table S1). Moreover, the prevalence or primary MR was high (40.0%) compared with the patients included in a recently published TMVR study, which mainly included secondary MR patients.4 As primary MR is often (but not necessarily) associated with preserved ejection fraction compared with secondary MR, this finding additionally implies that LV dimensions in the present study population may not have been favorable for the deployment of current TMVR devices. Our results are in line with previous studies reporting ventricular restraints, risk of LV outflow tract obstruction, severe MAC, and annular dimensions as the most frequent reasons for screening failure.5-7 Regarding clinical characteristics, we found high rates of relevant TR, pulmonary hypertension, and renal impairment, as well as a high proportion of patients with a history of AVR. Of note, both anatomical and clinical characteristics of this medically treated study population may have been driven by TMVR study exclusion criteria. In particular, severe MAC, severe TR, severe pulmonary hypertension, renal impairment, and prior AVR represent some of the most common exclusion criteria of ongoing TMVR trials and have led to study exclusion of some of our patients.3,4,7,11 However, as experience with TMVR is rapidly growing and devices become further developed, the proportion of patients receiving TMVR despite these anatomical and clinical features will certainly increase. At this point, several studies with small sample sizes already support the treatment of patients with severe MAC and with prior AVR with selected TMVR devices.12,13 By the time these TMVR devices become commercially available, such patients are expected to be treated more frequently. 

Mortality rates of patients treated for severe MR have been reported by several TMVR and edge-to-edge studies in recent years. The Tendyne global feasibility trial reported an all-cause mortality rate of 26% after 1 year for 100 patients treated with the Tendyne valve (Abbott Vascular),4 while 22.0% of 50 treated patients died after a median follow-up of 7.04 months after TMVR with the Intrepid valve (Medtronic) according to the Intrepid global pilot study.3 Recently published randomized edge-to-edge repair vs OMT trials reported diverging 1-year mortality rates of 24.3% and 19.1% in the interventionally treated cohorts, but similar mortality rates for those treated with OMT of 22.4% and 23.2%.10,14 In a similar approach to our study, Niikura et al analyzed 76 patients undergoing medical treatment after TMVR screening failure and described a 1-year rate of death or heart failure rehospitalization of 22.4%.7 Compared with these data, the present study found a notably higher rate of all-cause mortality of 23.6% already after 6 months and 35.7% after 1 year for the study subset of patients ineligible for TMVR undergoing OMT. One factor that might explain this particularly high mortality rate is the relatively high proportion of primary MR. In contrast with secondary MR, patients with primary MR do not necessarily benefit from medical therapy due to structural alterations of the mitral valve apparatus instead of LV heart failure.15 However, we did not find associations of primary or secondary MR etiology (with the exception of ischemic MR) with mortality in the present study. Our findings emphasize that there is indeed an unmet need for adequate treatment options for this subset of patients with severe MR suffering from particularly poor prognosis.

We further aimed to define subgroups of currently untreatable patients in whom the treatment of MR may be the most urgent. First, we found that patients with ischemic MR suffer from higher mortality, a finding in line with current knowledge that has been demonstrated repeatedly.16-18 Second, as expected, highly symptomatic patients presenting with NYHA class IV and high NT-proBNP levels as well as those with very severe MR were found to have particularly poor outcomes.16,18-20 Third, patients with low hemoglobin suffered from the highest mortality rates. A strong association between decreased levels of circulating hemoglobin with patient frailty has been described by several studies.21,22 Accordingly, frailty might represent another essential risk factor in patients with severe MR ineligible for TMVR. Fourth, a finding that has not been described yet is a higher mortality rate of patients with small annulus diameters compared with those who have larger diameters. An explanation for this result might be that TMVR ineligibility due to small annulus diameters is frequently associated with the presence of severe MAC, which has proven to be independently predictive of mortality in previous studies with different patient populations.23,24 However, the presence of severe MAC itself was not associated with mortality in the current study population. 

The findings of our study on a cohort of severe MR patients ineligible for TMVR emphasize that there is a clear need for routine treatment of patients with approved TMVR devices beyond highly selective feasibility studies. Protracted screening processes and conservative study exclusion criteria (ie, severe MAC, prevalent TR or pulmonary hypertension, previous AVR, etc) primarily affect highly symptomatic and frail patients, who are in need of timely interventional MR treatment. Moreover, adjustments in TMVR device designs will have to focus on smaller ventricular profiles and a larger range of mitral annulus diameters in order to meet real-world patient conditions. According to the present study, patients with small mitral annuli in particular seem to suffer from poor prognosis and might profit from adequate MR treatment.

Study limitations. The present study has several potential limitations. First, due to the retrospective study design and its single-center character, the presented results can only be hypothesis generating. Second, the small sample size may have biased the results and hampers the drawn conclusions. In this regard, larger-scale investigations of severe MR patients ineligible for interventional therapy are warranted. Third, due to the relatively small sample size, we were not able to perform a multivariable analysis of outcome predictors with sufficient statistical power. Thus, the presented results of univariable analysis might be influenced by confounding factors. However, we are convinced that our results provide valuable information on the unmet needs for treatment of severe MR.


Despite growing experience with TMVR, only a small subset of patients is anatomically amenable to TMVR, leaving a substantial number of patients on medical treatment only. We found a high 1-year mortality rate in these patients, underlining an unmet need for adequate therapeutic alternatives in this substantial portion of patients with severe MR. TMVR devices adapting to broader annular size ranges with smaller ventricular profiles might fill this gap in the future.


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From the 1Department of Cardiology, University Heart and Vascular Center Hamburg, Hamburg, Germany; and 2Department of Cardiovascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Blankenberg reports grants and personal fees from Abbott Diagnostics, Bayer, and Thermo Fisher; grants from Siemens and Singulex; personal fees from Abbott, Astra Zeneca, Amgen, Medtronic, Pfizer, Roche, Novartis, and Siemens Diagnostics.

Dr Conradi is an advisor and proctor for Abbott, Edwards Lifesciences, Neovasc, Boston Scientific, and Medtronic. Dr Kalbacher reports speaker honoraria and travel compensation from Abbott; proctor for Edwards Lifesciences (travel compensation). Dr Lubos reports grants and personal fees from Abbott Vascular; personal fees from Edwards Lifesciences, Abiomed, Astra Zeneca, Bayer, New Valve Technology, and Novartis. Dr Ludwig reports travel compensation from Edwards Lifesciences. Dr Reichenspurner is on the European Advisory Board for Medtronic; reports speaker honoraria from Abbott. Dr Schofer reports personal fees from Boston Scientific; travel compensation from Abbott and Edwards Lifesciences. Dr Seiffert reports personal fees from AstraZeneca, Bayer Healthcare, Abiomed, Boehringer Ingelheim, Bristol-Myers Squibb, Medtronic, Amgen, and Shockwave Medical; travel compensation from Abbott Vascular, Biotronik, Boston Scientific, Edwards Lifesciences, Nicolai Medizintechnik, and OrbusNeich Medical; grants and personal fees from Philips. Dr Westermann reports personal fees from AstraZeneca, Bayer, Berlin-Chemie, and Novartis. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript accepted June 22, 2020.

Address for correspondence: Sebastian Ludwig, MD, Department of Cardiology, University Heart and Vascular Center Hamburg, Martinistrasse 52, 20246 Hamburg, Germany. Email: se.ludwig@uke.de