Mitral surgical redo versus transapical transcatheter mitral valve implantation.

BACKGROUND: Transcatheter methods have been rapidly evolving to provide an alternative less invasive therapeutic option, mainly because redo patients often present with multiple comorbidities and high operative risk. We sought to evaluate and compare our experience with transapical transcatheter mitral valve replacement (TA-TMVR) to conventional redo mitral valve replacement in patients presenting with degenerated biological mitral valve prostheses or failed valve annuloplasty. METHODS AND MATERIAL: Between March 2012 and November 2020, 74 consecutive high-risk patients underwent surgical redo mitral valve replacement (n = 33) or TA-TMVR (n = 41) at our institution. All patients presented with a history of a surgical mitral valve procedure. All transcatheter procedures were performed using the SAPIEN XT/3™ prostheses. Data collection was prospectively according to MVARC criteria.
RESULTS: The mean logistic EuroSCORE-II of the whole cohort was 19.9±16.7%, and the median STS-score was 11.1±12.5%. The mean age in the SMVR group was 63.7±12.8 years and in the TMVR group 73.6±9.7 years. Patients undergoing TA-TMVR presented with significantly higher risk scores. Echocardiography at follow up showed no obstruction of the left ventricular outflow tract, no paravalvular leakage and excellent transvalvular gradients in both groups (3.9±1.2 mmHg and 4.2±0.8 mmHg in the surgical and transcatheter arm respectively). There was no difference in postoperative major adverse events between the groups with no strokes in the whole cohort. Both methods showed similar survival rates at one year and a 30-day mortality of 15.2% and 9.8% in SAVR and TMVR group, respectively. Despite using contrast dye in the transcatheter group, the rate of postoperative acute kidney failure was similar between the groups.
CONCLUSION: Despite several contraindications for surgery, we showed the non-inferiority of TA-TMVR compared to conventional surgical redo procedures in high-risk patients. With its excellent hemodynamic and similar survival rate, TA-TMVR offers a feasible alternative to the conventional surgical redo procedure in selected patients.

Introduction

Redo surgical mitral valve replacement (SMVR) remains the gold standard treatment in patients who previously underwent a surgical mitral valve (MV) procedure and are presenting with recurrent mitral valve pathologies. Current literature indicates that surgical redo procedures might be required in up to 35% of patients who have undergone MV surgery [1]. Over the past decades, transcatheter methods have been rapidly evolving to provide an alternative less invasive therapeutic option, mainly owing to the fact that redo patients often present with multiple comorbidities and a high operative risk. Although, recent studies have demonstrated the feasibility of transcatheter methods in redo valve procedures, there are only few large studies comparing surgical and interventional methods [2]. The aim of this study is to evaluate our experience with surgical redo SMVR and transapical transcatheter mitral valve replacement (TA-TMVR).

Methods and materials

Study design and populations

Between March 2012 and November 2020, 74 consecutive patients underwent a surgical redo SMVR or TA-TMVR at our institution. We analyzed and compared the outcomes and postoperative complications in patients undergoing a surgical redo SMVR operation or TA-TMVR using the SAPIEN XT™ or SAPIEN 3™ transcatheter heart valve (Edwards Lifesciences, Irvine, CA, USA). Patients were included, if they required a redo mitral valve procedure, presenting either with dysfunctional biological mitral valve prosthesis or with failed ring-annuloplasty with semirigid continuous annuloplasty rings. Patients were excluded, if the underlying disease was infective endocarditis of the mitral valve, and if concomitant coronary artery bypass CABG procedure was needed.

Our interdisciplinary Heart Team discussed all patients. Postoperative echocardiographic evaluation of the implanted valve prosthesis function was performed at our institution at hospital discharge and during follow-up. Data was collected prospectively as a part of our institutional database, including detailed information on patients’ demographics; baseline clinical characteristics; laboratory, echocardiographic, and hemodynamic parameters; intraoperative variables; and postoperative outcomes. The study was conducted according to the Declaration of Helsinki, as revised in 2013. The ethical board of our institution approved the study protocol and data gathering (Ethics committee University Duisburg-Essen, approval number: 21-9937-BO) and waived the patients’ individual informed consent. All patients signed the informed consent on follow-up at hospital admission.

Operative techniques

All transcatheter procedures were performed via transapical access, under general anesthesia in the presence of our institutional Heart Team in a special equipped hybrid operating room. The standard access route for valve-in-valve and valve-in-ring mitral valve procedures at our institution is the direct transapical approach. Therefore, in all of our patients in the TMVR group, transapical approach was used. The transapical access was performed as previously described by our group [3] using 4 pledged-armed U-stiches (Prolene 3–0, MH needle). In brief, access to the left ventricular apex was obtained by a 4–6 cm anterolateral minithoracotomy in the fourth, fifth or sixth intercostal space. Heparin was administered with an intended activated clotting time (ACT) > 250s [3, 4]. After puncturing the apex, a soft guidewire was advanced under fluoroscopic guidance into the right pulmonary vein across the diseased mitral valve. Then, via a Pigtail catheter, an Extra-Stiff wire for further guidance exchanged the soft wire, and a transapical sheath was advanced. The reversely crimped transcatheter valve was finally deployed under ventricular overpacing (120 bpm) [5]. The landing zone was identified mainly with fluoroscopic guidance. Device function was evaluated by transesophageal echocardiography.

For SMVR, the heart was accessed via redo median sternotomy. Cardiopulmonary bypass (CPB) was initiated with the direct cannulation of the ascending aorta and bicaval cannulation of the right atrium. Moderate hypothermic cardiac arrest at 32°C was performed for all procedures. Myocardial protection was achieved with cold crystalloid cardioplegia. The mitral valve was exposed through left atriotomy via the Waterson’s groove or through the right atriotomy and atrial septostomy if any tricuspid valve procedure had to be performed. Extensive debridement of the mitral annulus was performed under preservation of the chords if possible. The MV prosthesis (mechanical or biological) was inserted with single horizontal 4–0 Ethibond pledgeted sutures directed from the left ventricle into the left atrium. After assessment of the valve performance and careful de-airing, the patient was weaned from CPB.

Concomitant aortic valve procedures were performed prior to the MV implantation and tricuspid valve procedures were performed after the MV procedure on the beating heart.

ViV and ViR sizing

The ‘valve-in-valve app’, developed by Bapat et al. and the company UBQO was used for design and sizing information of the pre-existing specific mitral bioprosthesis or annuloplasty ring [6]. Multidetector computed tomography (MDCT) was performed on a Somatom™ dual-source force CT (2x192 slices, Siemens Medical Systems, Erlangen, Germany) with a contrast dose of 40 ml and a spatial resolution of 0.6 mm. Finally, 3D reconstructions of mitral valve were obtained using OsiriX MD™ (Pixmeo, Geneva, Switerland) and the mitral valve and LVOT were evaluated.

Outcomes and definitions

The primary endpoints were 30-day mortality, 1-year mortality, and mortality at follow-up. The secondary endpoint was the development of any complications according to Mitral Valve Academic Research Consortium (MVARC) [6].

Statistical analysis

Statistical analysis, including regression analysis, was performed using IBM SPSS version 27 (IBM Corp., Chicago, IL, USA) and R software v.3.4.3 (R Foundation for Statistical Computing, Vienna, Austria). Data were tested for normality using the Shapiro-Wilk test. Continuous variables were expressed as medians (interquartile range, IQR) or as mean±standard deviation. Categorical variables were expressed as frequencies and percentages. We compared the distributions of the categorical variables using Chi-Square Test or Fischer Exact Test if the assumptions for the first one, were not met. The distributions of the continuous variables were compared between the groups with the t-test in cases of normal distributions and with the Mann-Whitney test if the distributions were not normal. Univariate and multivariable logistic regression analyses were performed to identify independent preoperative risk factors for 30-day mortality. Variables identified by the univariate analysis with a P-value <0.05 were included in the multivariable model. Cox proportional hazards regression models were used to determine factors associated with overall survival. The model was verified by the Schoenfeld individual test. A P-value of less than 0.05 was considered to indicate statistical significance. For plotting the survival curves and for computing the mid-term mortality we used the Kaplan-Meier method. The cumulative survivals of both methods were analysed and compared with the log rank test.

Results

Baseline characteristics

The data on the patients’ baseline characteristics are presented in The mean age at surgery was 69.2±12.2 and male/female ratio was 33/41 (55.4% were female). The SMVR group included 33 patients and the TA-TMVR group consisted of 41 patients. All patients had previously undergone a mitral valve surgery via median sternotomy. The mean time-interval between index surgery and redo surgery (SMVR of TMVR) was 3.62 (IQR 0.74–12.3) years for all patients. The patients in the transcatheter group presented more severe comorbidities, which are reflected by significantly higher risk scores (. Additionally, patients in the transcatheter group had a significantly higher mean systolic pulmonary arterial pressure (63.4±16.5 mmHg vs. 49.9±13.0 mmHg, p<0.001) and presented with significantly lower left-ventricular ejection fraction 45.5±13.1% vs. 52.2±9.1%, p = 0.03).

Procedure

Intraoperative data is presented in . The overall operating time averaged 148.7 minutes. The mean operating time in the transcatheter group was significantly shorter than in the surgical group (82.8±26.1 vs. 230.6±94.0, p<0.001). Also, significantly more patients in the transcatheter group underwent an urgent procedure (. Most of the TA-TMVR procedures were performed under fluoroscopic guidance using a small amount of contrast dye. With our growing experience on the field of transcatheter valve interventions, we have drastically reduced or have completely skipped the use of contrast dye in patients undergoing transcatheter mitral valve interventions. In the present cohort, in 41.5% of the TMVR group the procedure was completely performed with no contrast dye (. All surgical procedures were performed via median re-sternotomy on cardiopulmonary bypass. A total of 5 patients (6.8%) required re-exploration for bleeding (one patient in the transcatheter group) and another three patients (4.1%, all in the SMVR group) suffered from postoperative AV-Block III°, requiring permanent pacemaker implantation. None of these complications occurred significantly more often in either of the groups. We observed no postoperative myocardial infarction or stroke in our cohort (.

Survival

Postoperative outcomes’ data is presented in Within the entire patient cohort, the in-hospital, 30-day, and one-year mortality, were 10.8%, 12.2%, and 22.2%, respectively (. In patients who underwent a surgical redo mitral valve replacement, the in-hospital, 30-day, and one-year mortality was 15.2%, 15.2%, and 18.3%, respectively. In patients with TA-TMVR, the in-hospital, 30-day, and one-year mortality were 7.3%, 9.9%, and 25.4%, respectively (. At one year, mortality did not significantly differ between the groups (p = 0.19) (. The Kaplan-Meier overall survival curve is given in . shows the regression model with significant impact of pulmonary hypertension on `mid-term´ survival.

Overall survival.

The figure shows overall survival of all patients from the cohort presented with a Kaplan- Meier Curve.

Survival of patients undergoing redo SMVR and TA-TMVR.

The figure presents the survivals of patients undergoing a redo SMVR and TA-TMVR presented with Kaplan-Meier curves. The survival rates have been analysed and compared with the log rank test and show no statistical difference (p>0.05).

Discussion

In the present study, a total of 74 high-risk patients presenting with failed mitral valve bioprosthesis or mitral valve annuloplasty rings were treated either by conventional surgical redo mitral valve replacement or a transapical transcatheter mitral valve-in-valve or valve-in-ring implantation. This study provides a number of interesting findings:

TA-TMVR is a feasible and uncomplicated treatment option that is at least a non-inferior alternative to conventional surgical redo procedures in selected high-risk candidates.

Both methods offer a high technical procedural success, nonetheless, TA-TMVR offers significantly shorter operating times and shorter intensive care unit stay.

Although not reaching significance, only SMVR patients needed postoperative pacemaker implantations.

Despite the use of contrast medium in the TA-TMVR group, there was no significant difference in postoperative new onset dialysis rate between the groups.

There was no significant difference in the hemodynamic performance between the groups. Both methods provided low transvalvular gradients at `mid-term´ and a low risk of LVOT obstruction.

There was no significant difference in 30-days and one-year mortality.

Following the great success of transcatheter technologies in aortic valve replacement, transcatheter mitral valve-in-valve (TMViV) or valve-in-ring (TMViR) implantation has also recently been rapidly developing as an alternative to conventional surgical MV redo procedures. Therefore, we sought to evaluate our results with transapical transcatheter mitral valve replacement in high-risk patients with prohibitive surgical risk and to compare them to the conventional redo SMVR. The observational period in the present study was 8 years.

In the transcatheter group, patients were significantly older and presented more comorbidities, which is reflected by higher EuroSCORE-II and STS-Scores compared to the surgical group. Nonetheless, there was no difference in the survival between the groups. While redo SMVR is known to carry a high periprocedural and postoperative mortality risk, mortality rates of the present study are in line with those reported in previous studies [2, 7, 8]. A study published by Kamioka et al. evaluating the results of 59 patients undergoing either TMVR of SMVR reported no significant difference in the survival of both procedures [9], which was proven by our results.

It is our philosophy to replace the mitral valve during reoperation, if re-repair prognostic success was deemed low, which is common sense: Trumello et al. suggested that, as far as long-term durability is concerned, re-repair of the failed mitral annuloplasty ring should only be pursued in cases where the intraoperative findings and immediate results were very reassuring [10]. In the case of TMVR within a failed annuloplasty ring, obstruction of the LVOT might be a concern [11]. Regueiro et al. clearly showed, that the expansion of the transcatheter valve prosthesis could result in displacement of the anterior mitral leaflet into the LVOT leading to potential obstruction [12]. The incidence of the LVOT obstruction after TMVR is reported to be higher than after redo SMVR [13, 14]. Therefore, extensive CT-based evaluation of the LVOT prior to TMVR is essential. By doing so, neither in our transcatheter arm, nor in our surgical group, any relevant LVOT obstruction occurred. In our study, LVOT was defined according to the MVARC criteria described by Stone et al [15].

The current guidelines on valvular heart disease recommend concomitant tricuspid valve (TV) repair in patients presenting with more than moderate tricuspid valve regurgitation [16]. As this concomitant procedure is known not to influence peri-procedural mortality [17, 18], we did not exclude concomitant TV procedures from the present analysis. However, by nature, only in the SMVR group concomitant tricuspid valve repair was performed. Although current guidelines recommend concomitant TV repair, long-term or mid-term outcomes of concomitant TV repair in redo cases remains controversial. Kamioka et al. reported no significant difference in one-year mortality in patients undergoing redo SMVR with or without TV repair [9]. Similarly, we did not discover any significant difference in the mortality between the groups, even though 39.4% (n = 13) of patients in the surgical arm received concomitant TV repair. The rate of more than moderate preoperative tricuspid valve regurgitation was similar between the groups. As the current analysis reflects a 5-year observation period, the “late” impact of tricuspid regurgitation might be underestimated. Nevertheless, we could show, that severe pulmonary hypertension, as an indirect parameter of right heart function, has a significant impact at least on mid-term survival (P = 0.043) as shown in .

In our cohort, we found no significant difference in postoperative major adverse events between the surgical and transcatheter cohort. Kidney function is known to be an independent predictive factor of mortality in patients undergoing transcatheter aortic valve procedures [19, 20]. The correlation between the contrast dye dose used and post-procedural acute kidney injury was reported by Yamamoto et al. [21]. Although, most of the TA-TMVR in our cohort were performed with a very small amount of contrast dye or even none at all, no significant difference was noted in postoperative new onset dialysis between the groups. Similar outcomes have also been reported by Simonetto et al. [22]. We believe that thanks to the fluoroscopic qualities of prior implanted surgical mitral valve prostheses and mitral rings, the amount of contrast dye could be further reduced or completely excluded [5].

Although, a high proportion of our patients underwent a valve-in-ring procedure, we observed no specific valve related complications such as valve embolization of LVOT obstruction. It is known, that patients undergoing transcatheter mitral valve-in-ring procedures might present with `paravalvular´ leakage between the transcatheter heart valve and the annuloplasty ring [23]. This was not the case in the present analysis. A small number of patients (17%) showed mild mitral regurgitation, coming from a small central leakage of the SAPIEN prosthesis. As the transcatheter heart valve during TMVR is implanted in a pre-shaped `docking´-station of known size (, the risk of postoperative pacemaker implantation in inherently lower. Although not reaching statistical significance, none of the patients of the transcatheter group needed postoperative pacemaker implantation.

Transapical transcatheter mitral valve implantation valve-in-valve in a pre-shaped `docking´-station of known size.

A–Positioning of the valve prosthesis in the annuloplasty ring. B–Deployment of the transcatheter valve prosthesis in the mitral position. C–Fully deployed valve prosthesis in the annuloplasty ring.

In accordance with the findings of previous studies, we discovered that both procedures provide comparable and excellent hemodynamic results with low transvalvular gradients at follow-up [9, 11, 22]. Follow-up echocardiography showed mean transvalvular gradients in the transcatheter arm of 4.2±0.8mmHg, compared to 3.9±1.2 mmHg in the surgical group.

All COPD patients within the present analysis were on all inhalative bronchodilatator therapy preoperatively. Our institutional concept is, that patients presenting with a FEV1> 1L were deemed to be operable, for both the transcatheter or conventional surgical approach. Nevertheless, we modified our anesthetic strategy for the transapical approach in the end of 2019: for the transapical approach, we moved from endotracheal intubation towards the use of a laryngeal mask, and only short-acting opioids (remifentanil) were used. With this concept, all patients could be transferred spontaneously breathing to the ICU. All surgical treated patients received an additional epidural anesthetic support.

Despite all the benefits of transcatheter mitral valve procedures, there are several conditions which make the patients ineligible for this therapeutic option. Patients presenting with infective endocarditis, failed annuloplasty treated with an open annuloplasty band or closed rings larger than 34mm present a problem for transcatheter valve replacement and should undergo conventional redo surgery. Moreover, long-term durability of transcatheter valves are still under investigation especially in the mitral valve-in-valve or valve-in-ring position.

Conclusion

Whilst surgical redo mitral valve replacement remains the gold standard of care in patients presenting with degenerated biological mitral valve prostheses or failed mitral valve annuloplasty, transcatheter options have been rapidly evolving as a valid alternative, especially in patients presenting with high operative risk. Although, there are several contraindications for transcatheter mitral valve replacement, in our study we demonstrated the non-inferiority of the transapical transcatheter mitral valve replacement compared to conventional surgical redo procedures in a high-risk cohort. TA-TMVR offers excellent hemodynamic results and similar survival compared to the conventional surgical method. Although not significant, early mortality is nearly doubled in the SMVR group. Additionally, TA-TMVR comes with shorter procedure duration and shorter ICU stay, which also lowers the costs of the procedure. Table 4 summarizes the potential inclusion or exclusion criteria to guide decision-making for TA-TMVR.

Table 4

Inclusion / exclusion criteria for the transapical TMVinV/TMVinR approach.

Inclusion	Exclusion
eligibility for transapical access	mechanical mitral valve prosthesis
prohibitive risk for the conventional surgical approach	hostile anatomy of the left thorax
“heart-team” decision	thrombus within the left apex
patients wish	Large annuloplasty rings (>34mm)
Pre-existing ASD Amplatzer device with no possibility for the transseptal approach	High-risk for LVOT obstruction

Study limitations

The retrospective non-randomized nature of the study coming from a single center with a limited number of patients may have an impact on the outcomes and the study power, and can leave room for bias. So far, only few studies with smaller single-center cohorts on this topic have been published. Further prospective studies on larger cohorts should be conducted to validate the safety and efficiency of this method.

(XLSX)

Click here for additional data file.

1 Jul 2021

PONE-D-21-18022

Mitral Surgical Redo versus Transapical Transcatheter Mitral Valve Implantation

PLOS ONE

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Reviewer #1: This is a mono-centric, retrospective study. The Authors described their experience about redo mitral valve treatment in a period of 8 years. They compared 74 patients underwent to mitral valve replacement or a mitral valve repair that come back for either with dysfunctional biological mitral valve prosthesis or with failed ring-annuloplasty; (33 pt-> SMVR; 41 pt TA-TMVR).

The analysis, and after the conclusion, clearly showed, in this center, the non-inferiority of transapical mitral valvular replacement compared to convention surgical redo procedure.

Please explain:

Table 2

Operating time: what do you mean? In surgical approach usually we may distingue cross clamp time and CBP time

Table 3

A total of 9 patients had shock: 7 in MVR group and 2 in TAMVR; tot 9

7 patient had cardiogenic shock: 4 in MVR and 3 in TAMVR; tot 7

4 patient had a septic shock: 3 in MVR and 1 in TAMVR; tot 4

7 patient (cardiogenic shock)+ 4 patient (septic shock) ; tot 11????? You describe a total of 9 patient with shock;

2 patient in TAMVR but 3+1-> 4

My impression about this manuscript is that the colleagues write a good paper, they correctly described the center experience and critically analyze the results.

Reviewer #2: I read with great interest the paper of the Essen group, comparing surgery and TMVR in a cohort of patients with failing MV procedures. The authors collected a consecutive series of 74 patients, which is a quite huge population and they are to be congratulated for their excellent results. I have some comments that, in my opinion, should be addressed to better clarify the indications and strengthen the manuscript’s message:

1) Patients in TMVR group have significant incidence of comorbidities compared to the MVR group. Among them, COPD is present in 40% of patients. Generally, severe COPD is a risk factor for open surgery, but it is also a contraindication for left thoracotomy (even if with small incision). Among this 40% of COPD patients, how many presented with inhalators therapy or severe pulmonary dysfunction? In the authors’ experience, which are the pulmonary or LV dysfunction condition that are considered high risk or frank contra-indication for TA-TMVR?

2) In TMVR group, 70% of patients presented with CAD, even if only 31% with previous PCI. In the other 40% of patients, was CAD a chronic situation without any indication for concomitant myocardial revascularization? In your practice, the concomitant need of myocardial revascularization influences the decision in favor of MVR vs TMVR? In case of TMVR plus PCI, which is your strategy? A concomitant procedure in hybrid suit or a staged one?

3) I am not sure that the issue of TR is to be considered irrelevant. Several surgical literature clearly showed that even moderate TR secondary to MV pathology, especially in the presence of pulmonary hypertension, should be aggressively addressed. You stated that you did not see any difference in the follow-up in both group, according to TR repair. However, I think that three years of FU is a limited time-frame to assess TR impact. Furthermore (I’ll discuss this issue later) a multivariable analysis, including TV repair, should be performed on early and late mortality, to really assess the prognostic value of any preoperative or intraoperative risk factor.

4) In nearly 50% of both group a MV replacement (or a Mitral ViV) was performed, I presume for bioprosthesis failure. I think that an important missing data is the time between previous surgery and MVR/TMVR, or, in other world, the duration of the previously implanted bioprostheses. Which is the age criteria for bioprosthesis implant according to the authors?

5) In the postoperative data, mild MR is reported in 17% of TMVR patients, but without evident PVL. Which is the mechanism of residual MR in the authors’ opinion?

6) If I look to the risk profile of both population, all patients presented with high risk for surgery (STS 10% vs 12%), even if TMVR patients are older and with more comorbidities. Which are the selection criteria used by the authors in proposing redo surgery vs TA TMVR? Perhaps a brief algorithm or a brief list of inclusion/exclusion criteria would be extremely useful

7) Finally, even if mortality is not statistically significant, there are in my mind two clear facts: early mortality is 15% vs 7-9% in surgery Vs TMVR respectively, which is nearly double anyway, despite patients in TMVR group are more risky. On the contrary at 1-3 years, mortality in TMVR group is higher than the surgical group. In order to better clarify the role of the procedural choice and the impact of the comorbidities, a multivariable analysis for early mortality (logistic regression) and late mortality (Cox regression) should be performed.

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9 Jul 2021

Dr. Emily Chenette

Editor-in-Chief

PLOS ONE

Essen, July 9th 2021

Dear Dr. Chenette,

Please find enclosed our revised manuscript ID PONE-D-21-18022 entitled: “Mitral Surgical Redo versus Transapical Transcatheter Mitral Valve-in-Valve and Valve-in-Ring Implantation” originally submitted for the category “Research Article” to PLOS ONE.

The authors would like to thank you for your interest in publishing the article in your journal. We have considered all reviewers’ remarks and hope that we could sufficiently improve the article in light of the comments. We also provided a point-to-point answer to the reviews (see below). We highlighted all changes in the revised manuscript with a yellow color.

Yours sincerely and respectfully,

Alina Zubarevich, MD

West German Heart and Vascular Center, Essen/ Germany

Reviewer Comments

Reviewer 1

This is a mono-centric, retrospective study. The Authors described their experience about redo mitral valve treatment in a period of 8 years. They compared 74 patients underwent to mitral valve replacement or a mitral valve repair that come back for either with dysfunctional biological mitral valve prosthesis or with failed ring-annuloplasty; (33 pt->SMVR;41ptTA-TMVR).

The analysis, and after the conclusion, clearly showed, in this center, the non-inferiority of transapical mitral valvular replacement compared to convention surgical redo procedure.

Comment 1:

Table2

Operating time: what do you mean? In surgical approach usually we may distingue cross clamp time and CBP time

My impression about this manuscript is that the colleagues write a good paper, they correctly described the center experience and critically analyze the results.

Reply:

Thank you for your valid comment. In our manuscript, “Operating time” is equal to “Incision to skin closure” time. As the transcatheter mitral valve implantation naturally has no CPB and Cross-Clamp time, we decided to compare both techniques only by the operating time. Nevertheless, we calculated the mean CPB- and ACC-time for the surgical group, which was a CPB-time of 138.3±61.7 minutes and mean Cross-clamp-time was 83.2±42.3 minutes, respectively. We added these values into the Table 2.

Comment 2:

A total of 9 patients had shock: 7 in MVR group and 2 in TAMVR; tot 9

7 patient had cardiogenic shock: 4 in MVR and 3 in TAMVR; tot 7

4 patient had a septic shock: 3 in MVR and 1 in TAMVR; tot 4

7 patient (cardiogenic shock)+ 4 patient (septic shock) ; tot 11????? You describe a total of 9 patient with shock;

2 patient in TAMVR but 3+1-> 4

Reply:

Thank you for your comment. You are right about the inconsistency of the numbers. There was a typing error in Table 3, which is now corrected.

Changes in text:

Table 3, the changes are highlighted in color.

Reviewer 2

I read with great interest the paper of the Essen group, comparing surgery and TMVR in a cohort of patients with failing MV procedures. The authors collected a consecutive series of 74 patients, which is a quite huge population and they are to be congratulated for their excellent results. I have some comments that, in my opinion, should be addressed to better clarify the indications and strengthen the manuscript’s message:

Comment 1:

Patients in TMVR group have significant incidence of comorbidities compared to the MVR group. Among them, COPD is present in 40% of patients. Generally, severe COPD is a risk factor for open surgery, but it is also a contraindication for left thoracotomy (even if with small incision). Among this 40% of COPD patients, how many presented with inhalators therapy or severe pulmonary dysfunction? In the authors’ experience, which are the pulmonary or LV dysfunction condition that are considered high risk or frank contra-indication for TA-TMVR?

Reply:

We are grateful for this remark. First, Essen is located within the so called “Ruhrgebiet”, which was famous in the past for coal-mining (during the 70s/80s the largest coal-mining area in Europe), and therefore, still many patients present with COPD or other lung diseases. This explains indeed, the high incidence of COPD in our cohort. All COPD patients within the present analysis were on inhalative bronchodilatator therapy. Our institutional concept is, that patients presenting with a FEV1> 1L were deemed to be operable, for both the transcatheter or conventional surgical approach. However, we modified our anesthetic strategy for the transapical approach in the end of 2019: for the transapical approach, we moved from endotracheal intubation towards the use of a laryngeal mask, and only short-acting opioids (remifentanil) were used. With this concept, all patients could be transferred spontaneously breathing on the ICU. In our experience, COPD or severe lung disease would not count for exclusion for the transapical approach. Moreover, as even in the transpical TMViV or TMViR situation, it still represents a redo-situation and in most cases, only the apex was exposed without opening of the left pleural space.

The following was therefore added in to the revised manuscript:

All COPD patients within the present analysis were on all inhalative bronchodilatator therapy preoperatively. Our institutional concept is, that patients presenting with a FiV1> 1L were deemed to be operable, for both the transcatheter or conventional surgical approach. Nevertheless, we modified our anesthetic strategy for the transapical approach in the end of 2019: for the transapical approach, we moved from endotracheal intubation towards the use of a laryngeal mask, and only short-acting opioids (remifentanil) were used. With this concept, all patients could be transferred spontaneously breathing on the ICU. All surgical treated patients received an additional epidural anesthetic support.

Comment 2:

In TMVR group, 70% of patients presented with CAD, even if only 31% with previous PCI. In the other 40% of patients, was CAD a chronic situation without any indication for concomitant myocardial revascularization? In your practice, the concomitant need of myocardial revascularization influences the decision in favor of MVR vs TMVR? In case of TMVR plus PCI, which is your strategy? A concomitant procedure in hybrid suit or a staged one?

Reply:

Thank you for your excellent comment. Concomitant CAD in patients presenting with a recurrent valve pathology is very common. In our cohort 40% of patients, who did not undergo a PCI, did not require coronary revascularization, but present with non-significant CAD.

In our daily practice, if the patient is eligible for a conventional procedure and requires concomitant coronary revascularization as defined by the guidelines, CABG will be definitively revascularization being performed simultaneously.

If the patient is planned for the transcatheter approach, each patient will be discussed in our institutional Heart Team according to each patients’ specific needs including CAD. Our group has already analyzed patients undergoing TAVR presenting with concomitant CAD (Wendt D, Kahlert P, Lenze T, et al. Management of high-risk patients with aortic stenosis and coronary artery disease. Ann Thorac Surg. 2013;95(2):599-605. doi:10.1016/j.athoracsur.2012.07.075.). Within this previous publication, we could show, that patients who were treated by PCI prior to TAVR had similar results in a propensity score adjusted analysis compared to patients treated by AVR and CABG. Therefore, severe CAD should be treated by PCI prior to TAVR. On the other hand, we also know that concomitant CAD and staged revascularization is a significant mortality predictor in patients undergoing TAVR. Therefore and according to the above-mentioned study, we try to treat all significant CAD prior to each interventional approach (at least 4 weeks prior to TAVR intervention).

On the other hand, in some pathologies, were we aim to perform a transaortic TAVR, and during this procedure (in contrast to the transapical TMVinV / TMVinR), CAD can easily be treated by the addition of an OPCAB-procedure. This concept has been just recently published by our group (Zubarevich A, Zhigalov K, Szczechowicz M, et al. Simultaneous transaortic transcatheter aortic valve implantation and off-pump coronary artery bypass: An effective hybrid approach. J Card Surg. 2021;36(4):1226-1231. doi:10.1111/jocs.15351).

We hope, this answers your question and if wanted, we can add a short comment into the discussion part.

Comment 3:

I am not sure that the issue of TR is to be considered irrelevant. Several surgical literatures clearly showed that even moderate TR secondary to MV pathology, especially in the presence of pulmonary hypertension, should be aggressively addressed. You stated that you did not see any difference in the follow-up in both groups, according to TR repair. However, I think that three years of FU is a limited time-frame to assess TR impact. Furthermore (I’ll discuss this issue later) a multivariable analysis, including TV repair, should be performed on early and late mortality, to really assess the prognostic value of any preoperative or intraoperative risk factor.

Reply:

Thank you for your well-taken comment. Indeed, TR reflects a major factor affecting survival and especially in the long-term. In our present analysis, we evaluated “mid-term” survival over a 5 years period, which is indeed a limited time-frame. As suggested by the reviewer, we went back into our dataset and we constructed (as requested) a regression analysis. Within the univariate analysis, we evaluated TR (I-II°), TR III-III+°concomitant TR surgery and severe pulmonary hypertension in regard to 30-day mortality, but none of these parameters showed any significant impact.

TR I-II°: OR 0.402 (95% CI 0.056-1.818), P=0.278

TR III-III+°: OR 1.714 (95% CI 0.414-8.673), P=0.472

Concomitant TR-surgery: OR 1.402 (95% CI 0.191-6.800), P=0.696

sPAP: OR 1.021 (95% CI 0.979-1.062), P=0.294

In a next step, we performed the same regression analysis in regard to “mid-term” survival for the COX-regression analysis. This model also showed no significant impact the tricuspid valve. TR could not be included into the final model, as the proportional Hazard assumption of the model could not be full-filled. Nevertheless, as the reviewer requested, we constructed the model (without TR) and in this model, at least severe pulmonary hypertension, as an indirect parameter of right heart function showed a significant impact on “mid-term” survival.

TR I-II°: HR 0.896 (95% CI 0.376-2.132), P=0.804

TR III-III+°: HR 1.377 (95% CI 0.595-3.186), P=0.454

Concomitant TR-surgery: HR 0.820 (95% CI 0.277-2.424), P=0.720

sPAP: HR 1.024 (95% CI 1.001-1.047), P=0.04

This final regression model fulfilled the Hazard proportion assumption as was verified by the Schoenfeld residual test with an AUC of 0.94.

Therefore, the following part was added into the stastistical section of the material and methods part:

Univariate and multivariable logistic regression analyses were performed to identify independent preoperative risk factors for 30-day mortality. Variables identified by the univariate analysis with a P-value <0.05 were included in the multivariable model. Cox proportional hazards regression models were used to determine factors associated with overall survival. The model was verified by the Schoenfeld individual test.

Another figure #3 with a corresponding text passage were added into the results part, displaying the results of the COX regression analysis, with emphasis on pulmonary hypertension:

Figure 3 shows the regression model with significant impact of pulmonary hypertension on `mid-term´ survival.

Moreover, these new results were also discussed in the revised discussion part:

As the current analysis reflects a 5-year observation period, the “late” impact of tricuspid regurgitation might be underestimated. Nevertheless, we could show, that severe pulmonary hypertension, as an indirect parameter of right heart function, has a significant impact at least on mid-term survival.

Comment 4:

In nearly 50% of both group a MV replacement (or a Mitral ViV) was performed, I presume for bioprosthesis failure. I think that an important missing data is the time between previous surgery and MVR/TMVR, or, in other world, the duration of the previously implanted bioprostheses. Which is the age criteria for bioprosthesis implant according to the authors?

Reply:

Thank you for your valid comment. First of all, in our center, the percentage of mitral valve repair is >90%. Most of the included patients were operated elsewhere, and were referred to our center for redo surgery, whether due to failed mitral valve repair or early-generated mitral valve bioprosthesis. As asked by the reviewer, the median time between previous surgery and MVR/TMVR was 3.62(IQR 0.74-12.3) years. Our institutional age criteria are reflected by the current guidelines, where mechanical mitral valve prostheses should be considered for patients younger than 60-65 years, if these is no contraindication for warfarin therapy. Nevertheless, individual patients’ comorbidities and the ability to manage warfarin-therapy must be taken into consideration. Moreover, as the transcatheter mitral valve implantation techniques are rapidly developing, biological valve implantation in the mitral position does not necessarily mean a risky re-operation anymore and is at least in Germany steadily increasing.

We added the following into the revised results part:

The mean time-interval between index surgery and redo surgery (SMVR of TMVR) was 3.62 (IQR 0.74-12.3) years for all patients.

Comment 5:

In the postoperative data, mild MR is reported in 17% of TMVR patients, but without evident PVL. Which is the mechanism of residual MR in the authors’ opinion?

Reply:

We are thankful for this remark. Indeed, the residual MR in these patients comes from a small proportion of central leakage coming from the SAPIEN prosthesis.

The following was added into the revised discussion:

A small number of patients (17%) showed mild mitral regurgitation, coming from a small central leakage of the SAPIEN prosthesis.

Comment 6:

If I look to the risk profile of both populations, all patients presented with high risk for surgery (STS 10% vs 12%), even if TMVR patients are older and with more comorbidities. Which are the selection criteria used by the authors in proposing redo surgery vs TA TMVR? Perhaps a brief algorithm or a brief list of inclusion/exclusion criteria would be extremely useful

Reply:

Thank you for your well-taken comment. The high-risk nature of the redo procedure itself represents the main driving factor to go for an interventional approach. In detail, if the patient comes with several comorbidities, requires no further concomitant procedures and is technical feasible (e.g. annuloplasty ring max. 34mm, biological prosthesis in the mitral position) we would aim to treat the patient interventionally. Moreover, all decisions were made by the interdisciplinary institutional “heart-team”.

We like your suggestion to implement a short inclusion/exclusion manual, and therefore added the following table into the revised manuscript, to give the reader some useful tips.

Inclusion Exclusion

eligibility for transapical access mechanical mitral valve prosthesis

prohibitive risk for the conventional surgical approach hostile anatomy of the left thorax

“heart-team” decision thrombus within the left apex

patients wish Large annuloplasty rings (>34mm)

Pre-existing ASD Amplatzer device with no possibility for the transseptal approach High-risk for LVOT obstruction

Comment 7:

Finally, even if mortality is not statistically significant, there are in my mind two clear facts: early mortality is 15% vs 7-9% in surgery Vs TMVR respectively, which is nearly double anyway, despite patients in TMVR group are riskier. On the contrary at 1-3 years, mortality in TMVR group is higher than the surgical group. In order to better clarify the role of the procedural choice and the impact of the comorbidities, a multivariable analysis for early mortality (logistic regression) and late mortality (Cox regression) should be performed.

Reply:

Thank you for your comment, which was answered partly above about the regression analysis. We totally agree with your excellent comment, that early mortality is nearly doubled (although not significant) in the SMVR group. By nature, as the TMVR patients are older and showed more comorbidities (reflected by higher risk-scores), long-term/mid-term survival of the interventional group is worse compared to the younger SMVR group.

Therefore, to emphasis this important point, the following was added into the conclusion part:

Although not significant, early mortality is nearly doubled in the SMVR group.

Submitted filename: Response to reviewers.docx

Click here for additional data file.

10 Aug 2021

Mitral Surgical Redo versus Transapical Transcatheter Mitral Valve Implantation

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16 Aug 2021

PONE-D-21-18022R1

Mitral Surgical Redo versus Transapical Transcatheter Mitral Valve Implantation

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Table 1

Baseline characteristics.

Characteristics	All patients, %(n)	SMVR, %(n)	TA-TMVI, %(n)	P-value
Female gender	55.4(41)	66.7(22)	46.3(19)	0.1
Age, years	69.2±12.2	63.7±12.8	73.6±9.7	0.001
Body Mass Index, kg/m2	26.4±4.6	26.3±4.3	26.4±4.8	0.59
NYHA III	58.1(43)	42.4(14)	70.7(29)	0.02
NYHA IV	29.7(22)	30.3(10)	29.3(12)	1.0
Arterial hypertension	97.3(72)	93.9(31)	100(41)	0.2
Pulmonary hypertension	85.1(63)	66.7(22)	100(41)	<0.001
Diabetes	24.3(18)	12.1(4)	34.1(14)	0.03
Chronic obstructive lung disease	29.7(22)	15.2(5)	41.5(17)	0.02
Coronary artery disease	48.6(36)	21.2(7)	70.7(29)	<0.001
Prior percutaneous coronary intervention	20.3(15)	6.1(2)	31.7(13)	0.008
Peripheral arterial disease	21.6(16)	3.0(1)	36.6(15)	<0.001
Cerebral arterial disease	14.9(11)	6.1(2)	22.0(9)	0.1
Prior stroke	16.2(12)	24.2(8)	9.8(4)	0.1
Sinusrhythmus	35.1(26)	39.2(13)	31.7(13)	0.62
Atrial fibrillation	64.9(48)	60.6(20)	68.3(28)	0.62
Aortic regurgitation >II°	5.4(4)	9.1(3)	2.4(1)	0.32
Aortic stenosis >II°	9.5(7)	6.1(2)	12.2(5)	0.45
Mitral regurgitation	91.9(68)	87.9(29)	95.1(39)	0.4
Mitral regurgitation I°	16.2(12)	9.1(3)	22.0(9)	0.2
Mitral regurgitation II-III°	77.0(57)	81.8(27)	73.2(30)	0.42
Mitral stenosis >II°	45.9(34)	42.4(14)	48.8(20)	0.64
Tricuspid regurgitation <II°	39.2(29)	39.4(13)	39.0(16)	1.0
Tricuspid regurgitation>II°	55.4(41)	48.5(16)	61.0(25)	0.35
Transvalvular mean gradient, mmHg	9.1±6.7	9.7±8.1	8.8±5.4	0.7
Prior sternotomy	100(74)	-	-	-
Prior mitral valve replacement	55.4(41)	48.5(16)	61.0(25)	0.35
Prior mitral valve repair	44.6(33)	51.5(17)	39.0(16)	0.35
Prior coronary artery bypass grafting	40.5(30)	15.2(5)	61.0(25)	<0.001
Prior surgical aortic valve replacement	18.9(14)	9.1(3)	26.8(11)	0.05
Prior pacemaker implantation	18.9(14)	9.1(3)	26.8(11)	0.07
Systolic pulmonary arterial pressure, mmHg	57.4±16.4	49.9±13.0	63.4±16.5	<0.001
Ejection fraction, %	48.5±11.9	52.2±9.1	45.5±13.1	0.03
Chronic kidney injury	59.5(44)	48.5(16)	68.3(28)	0.1
Dialysis	9.5(7)	9.1(3)	9.8(4)	1.0
Creatinine, mg/dL	1.6±1.0	1.4±0.9	1.7±1.1	0.16
GFR (mL/min/1.73m2)	48.1±19.7	52.4±19.6	44.6±19.3	0.075
Preoperative anticoagulation
Aspirin	44.6(33)	21.2(7)	63.4(26)	<0.001
Clopidogrel	10.8(8)	6.1(2)	14.6(6)	0.3
Ticagrelor	1.4(1)	0	2.4(1)	1.0
Apixaban	6.8(5)	0	12.2(5)	0.06
Procoumaron	36.5(27)	48.5(16)	26.8(11)	0.09
Logistic EuroSCORE, %	38.0±23.4	32.6±25.9	42.3±20.5	0.018
EuroSCORE II, %	19.9±16.7	18.2±18.9	21.2±14.8	0.024
STS-Score, %	11.1±12.5	10.2±14.3	11.9±10.8	0.003

GFR–glomerular filtration rate, NYHA–New-York Heart Association Class, STS Score–Society of Thoracic Surgeons

Table 2

Intraoperative characteristics.

Characteristics	All patients, %(n)	SMVR, %(n)	TA-TMVI, %(n)	P-value
elective	58.1(43)	66.7(22)	51.2(21)	0.24
urgent	32.4(24)	18.2(6)	43.9(18)	0.02
emergent	9.5(7)	15.2(5)	4.9(2)	0.23
Transapical access	-	0	100(41)	-
Valve-in-valve	-	0	61(25)	-
Valve-in-ring	-	0	39(16)	-
Concomitant SAVR	5.4(4)	12.1(4)	0	0.04
Concomitant TA-TAVI	10.8(8)	0	19.5(8)	0.007
Operating time, min	148.7±98.6	230.6±94.0	82.8±26.1	<0.001
CPB-time, min	-	138.3±61.7	-	-
Cross-clamp time, min	-	83.2±42.3	-	-
Constrast dye, mL	-	0	40.0(IQR 0–75.0)	-
No contrast dye	67.6(50)	44.6(33)	23(17)	-
Fluoroscopy time, min	-	0	14.1±11.8	-
Valve prosthesis size		28.6±2.4	28.07±1.5	0.32
biological prosthesis	90.5(67)	78.8(26)	100(41)	0.002
mechanical prosthesis	9.5(7)	21.2(7)	0	0.002

CPB–cardiopulmonary bypass, SAVR–surgical aortic valve replacement, TA-TAVI–transapical transcatheter aortic valve implantation

Table 3

Postoperative outcomes.

Characteristics	All patients, %(n)	SMVR, %(n)	TA-TMVI, %(n)	P-value
Paravalvular leakage	0	0	0	-
Postoperative mitral regurgitation>trace	9.5(7)	0	17.1(7)	0.15
Mean gradient at follow-up	4.0±1.0	3.9±1.2	4.2±0.8	0.08
Device success	100%	100%	100%	-
Dislocation	0	0	0	-
Conversion to conventional procedure	-	-	0	-
New onset atrial fibrillation	18.9(14)	27.3(9)	12.2(5)	0.13
Acute kidney failure with dialysis	17.6(13)	27.3(9)	9.8(4)	0.07
Exploration for bleeding	6.8(5)	12.1(4)	2.4(1)	0.16
Stroke	0	0	0	-
Vascular complications	0	0	0	-
Pacemaker implantation	4.1(3)	9.1(3)	0	0.08
Deep wound infection	1.4(1)	3.0(1)	0	0.4
Myocardial infarction	0	0	0	-
Re-intubation	2.7(2)	3.0(1)	2.4(1)	1.0
Shock	14.9(11)	21.2(7)	9.7(4)	0.5
cardiogenic	9.5(7)	12.1(4)	7.3(3)	0.7
septic	5.4(4)	9.1(3)	2.4(1)	0.3
Time on respirator, days	1.0(IQR 1.0–3.1)	1.0(1.4–4.3)	1.0(IQR 0.55–2.4)	0.21
Time on ICU, days	2.0(IQR 1.0–5.2)	4.0(IQR 3.6–6.3)	2.0(IQR 1.6–4.6)	<0.001
In-hospital stay, days	9.0(IQR 7.0–13.25)	11.0 (IQR 8.4–18.4)	9.7±5.4	0.06
In-hospital mortality	10.8(8)	15.2(5)	7.3(3)	0.45
30-day mortality	12.2(9)	15.2(5)	9.8(4)	0.501
Follow-up time, days	997.3(IQR 203.25–1443.25)	1163.0(IQR 928.5–1733.5)	728.6(IQR 510.6–946.6.0)	0.052
1-year mortality	22.2	18.3	25.4	0.19
3-year mortality	27.1	27.1	37.4	-

ICU–Intensive Care Unit