Surgical versus Interventional Mitral Valve Repair: Analysis of 1,100 Propensity Score-Matched Patients

Amabile, Andrea; Muncan, Brandon; Geirsson, Arnar; Kalogeropoulos, Andreas P.; Krane, Markus

doi:https://doi.org/10.1155/2023/8838005

Journal of Cardiac Surgery

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Abstract Introduction Methods Results Discussion Conclusion Data Availability Ethical Approval Disclosure Conflicts of Interest Authors’ Contributions References Copyright Related Articles

Research Article | Open Access

Volume 2023 | Article ID 8838005 | https://doi.org/10.1155/2023/8838005

Surgical versus Interventional Mitral Valve Repair: Analysis of 1,100 Propensity Score-Matched Patients

Andrea Amabile,¹Brandon Muncan,²Arnar Geirsson,^1,3Andreas P. Kalogeropoulos,²and Markus Krane^1,4

Academic Editor: Amanda Dianne Saab

Received02 May 2023

Revised25 Jun 2023

Accepted25 Sept 2023

Published06 Oct 2023

Abstract

Objective. We aimed to investigate outcomes in transcatheter versus surgical mitral valve repair in patients with secondary mitral regurgitation (MR) by leveraging a global, multi-institutional federated network database. Methods. Using validated ICD-10 and CPT codes, the TriNetX Analytics Research Data Network (a global federated database of electronic health records from 58 healthcare organizations) was queried to identify patients diagnosed with chronic, severe, ischemic MR and undergoing either transcatheter mitral valve repair (TMVr) or surgical mitral valve repair (SMVr) between January 1, 2015 and December 31, 2020. To adjust for baseline differences, 1 : 1 propensity score matching was performed via logistic regression using the nearest-neighbor approach and matching for 29 covariates including demographics, comorbidities, surgical history, preoperative medications, left ventricular function and heart failure status. We compared 1- and 3-year mortality rates and 1- and 3-year mitral valve reoperation rates in the matched cohorts using Kaplan-Meier estimates and adjusted Cox proportional hazards models. Results. A total of 2,352 patients met inclusion criteria (1,392 in the surgical mitral valve repair group and 960 in the TMVr group). After 1 : 1 propensity score matching, a total of 550 patients undergoing surgical mitral valve repair (SMVr) were compared to 550 patients undergoing TMVr. All characteristics were adequately matched between the cohorts (standardized mean difference <0.1). At 1- and 3-years respectively, mortality rate was 13.4% and 20.7% for surgical patients and 19.8% and 40.3% for TMVr patients. When compared to TMVr, patients undergoing SMVr were significantly less likely to face mortality at 3 years (HR: 0.42, 95% CI: 0.31–0.56, ). At 1- and 3-years respectively, mitral valve reoperation was 2.2%, and 2.4% for surgical patients and 6.6% and 7.8% for TMVr patients. When compared to TMVr, patients undergoing SMVr were significantly less likely to undergo mitral valve reintervention at 3 years (HR: 0.29, 95% CI: 0.14–0.58, p = 0.0002). Conclusion. In a real-world, propensity score matching analysis of a large cohort of patients with chronic ischemic MR, surgical mitral valve repair had significantly better survival rates and significantly lower reintervention rates at 1- and 3-years compared to TMVr.

1. Introduction

What the best treatment for secondary mitral regurgitation (MR) is remains debated. Surgical randomized controlled trials (RCTs) comparing mitral valve replacement to mitral valve repair are in favor for the replacement of the mitral valve in patients with secondary MR [1]. In that frame, adequately powered, randomized controlled trials comparing outcomes of transcatheter mitral valve repair (TMVr) versus surgical mitral valve repair (SMVr) are currently lacking. The results of the only RCT comparing mitral valve surgery versus TMVr [2] were in favor of a surgical approach in terms of freedom from mitral valve reintervention and recurrent MR. Unfortunately, the trial was limited by the inclusion of patients with both primary and secondary MR, as well as by the different surgical approaches which also included mitral valve replacement.

Nevertheless, the 2020 ACC/AHA valve guidelines provided a class 2a recommendation for the use of TMVr in patients with chronic, severe, secondary MR related to left ventricular systolic dysfunction who remain symptomatic after optimization of guidelines-directed medical therapy (GDMT) and have proper anatomy [3]. The recommendation for TMVr in these patients is predominantly a byproduct of the conflicting results between the MITRA-FR [4] and the COAPT [5] trials. The COAPT trial showed improvement in survival, hospitalization, symptoms, and quality of life in patients with persistent symptoms despite optimization of GDMT, whereas the MITRA-FR trial was not able to demonstrate a difference in reducing the composite endpoint of death or hospitalization as compared with medical therapy. Although both studies included different patient populations (which is most likely responsible for the different results), both studies compared TMVr with medical therapy. Accordingly, it remains unclear which interventional approach (TMVr or SMVr) is superior in the treatment of secondary mitral regurgitation.

Differently than TMVr, surgical mitral valve intervention received a 2a indication only in patients undergoing concomitant coronary artery bypass grafting, and in this patients population the mitral valve was recommended to be replaced rather than repaired (2b recommendation).

In this frame, high-powered and well-controlled studies directly comparing survival and freedom from reoperation in TMVr versus SMVr in patients with secondary MR are lacking. We aimed to investigate these outcomes in a large study population of more than 1,000 matched patients by leveraging a global, multi-institutional federated network database.

2. Methods

2.1. Study Design and Data Source

This study was a retrospective cohort study with data sourced from the TriNetX Analytics Research Network, Cambridge MA (TriNetX). TriNetX is a global federated database containing electronic health records from over 80 million patients from 58 healthcare organizations (community and academic hospital centers, and physician networks) worldwide; however, we use data exclusively from the United States. Detailed descriptions of the TriNetX network have previously been published [6, 7]. The network database complies with the Health Insurance Portability and Accountability Act (HIPAA), a United States national law which protects the integrity and confidentiality of health information. As such, data for research purposes are available without the need for institutional review board approval only in aggregate, fully-deidentified form. Furthermore, the TriNetX platform uses standardized coding systems like International Classification of Diseases, Tenth Revision (ICD-10) and Current Procedural Terminology (CPT) to index data including patient demographics, vital signs, medications, lab results, diagnoses, and procedures. Within the TriNetX network database, internal validity is maintained in real-time by monitoring temporal data trends, and several external validation studies were performed using TriNetX data which confirmed its reliability as a source for retrospective studies.

2.2. Sample

We searched the TriNetX database for patients ≥18 years with ischemic mitral valve regurgitation between 1 January 2015 and 31 December 2020 who exclusively underwent either surgical mitral valve repair (CPT: 33425, 33426, 33427) or transcatheter mitral valve repair, TMVr (CPT: 33418, 0345T). Since there is univocal ICD-10 code for the diagnosis of “ischemic mitral regurgitation,” we queried the database for patients who had nonrheumatic mitral insufficiency (I34.0) who had a previously documented diagnosis of chronic ischemic heart disease (I25). We elected to exclude patients with acute myocardial infarction or papillary muscle rupture in the periprocedural period, as mitral valve regurgitation is an acute onset impairing outcomes in this specific patient population. Additionally, we excluded patients who underwent mitral valve replacement and transcatheter mitral valve implantation, as the indications and outcomes of these are considerably different than in valve repair and are outside the scope of this paper.

2.3. Outcomes

Selected baseline characteristics were identified and matched for by propensity score matching (please see “statistical analysis”). The primary outcomes were mortality and mitral valve reintervention (i.e., open repair, replacement and transcatheter procedures) at 1- and 3-postoperative years from the index procedure.

2.4. Statistical Analysis

Categorical variables are presented as percentage of the total cohort and were compared using the chi-squared test; continuous variables are presented as mean ± standard deviation and were comparedwith the Student’s t-test. After initial database querying and generation of cohorts, we performed 1 : 1 propensity score matching to control for differences in preoperative characteristics between cohorts. More specifically we matched for 29 unique variables including demographics, preoperative comorbidities, surgical history, use of cardiovascular medications, anti-platelet medications, anticoagulants, preoperative B-type natriuretic peptide, and preoperative left ventricular ejection fraction (Table 1) using logistic regression and the nearest-neighbor approach with a caliper of 0.1 pooled standard deviations. The proportionality assumption was assessed using the Schoenfeld residuals. Furthermore, Kaplan-Meier survival analyses with log-rank test, and corresponding Cox proportional hazards models were generated to 1- and 3-year cumulative incidence of outcomes of interest. All the estimates (and corresponding Kaplan-Meier curves) were therefore converted into failure rates. All statistical analyses were performed using the TriNetX Analytics platform (Cambridge, MA) which leverages R v. 3.2–12 and SAS v. 9.4 to perform statistical tests. Of note, the R Survival library uses a robust (sandwich) estimator of variance, which produces conservative estimates of standard errors and minimizes bias. Unless otherwise stated, statistical significance was set to a two-tailed p value of 0.05.

3. Results

3.1. Baseline Characteristics

Before matching, our cohorts consisted of 1,392 SMVr and 960 TMVr patients across 30 healthcare organizations in the United States. TMVr patients tended to be older (76.1 ± 9.7 vs. 66.6 ± 1.11 years; ; SMD = 0.921) and were more likely to have several cardiovascular and non-cardiovascular comorbidities (see Table 1). SMVr was more common amongst male patients (69.0% vs. 63.1%; p = 0.003, SMD: 0.125). After propensity score matching, baseline characteristics were comparable between cohorts (standardized mean difference <0.1) and 550 open repair patients were compared to a corresponding cohort 550 TMVr patients.

3.2. Mortality

In the unmatched analysis, mortality rate was 11.9% in SMVr patients versus 22.7% in TMVr patients (HR: 0.512; 95% CI: 0.418–0.626; log-rank ) at 1 postoperative year. Mortality rate at 3 years postoperatively remained significantly lower in SMVr patients: 18.6% vs. 44.8%; HR: 0.382; 95% CI: 0.33–0.45; .

In the matched analysis, mortality rate in SMVr patients was 13.4% versus 19.8% in TMVr (HR: 0.69; 95% CI: 0.50–0.94; log-rank p = 0.018) at 1 postoperative year. Mortality rate at 3 years postoperatively remained significantly lower in SMVr patients: 20.7% vs. 40.3%; HR: 0.53; 95% CI: 0.41–0.67; . See Figures 1 and 2.

(a)

(b)

(a)

(b)

3.3. Mitral Valve Reintervention

In the unmatched analysis, 1-year mitral valve reintervention rate was 0.8% in initial SMVr patients and 4.8% in initial TMVr patients, representing a statistically significant difference (log-rank ; HR: 0.152; 95% CI: 0.075–0.309). Similarly, at 3 postoperative years, reintervention rate remained lower in SMVr patients (1.1% vs. 6.4%; ; HR: 0.158; 95% CI: 0.085–0.293).

In the matched analysis, 1-year reintervention rate on the mitral valve was 2.2% in initial SMVr patients and 6.6% in initial TMVr patients, representing a statistically significant difference (log-rank p = 0.006; HR: 0.32; 95% CI: 0.16–0.64). Similarly, at 3 postoperative years, reintervention rate remained lower in SMVr patients (2.4% vs. 7.8%; p = 0.002; HR: 31; 95% CI: 0.16–0.60). Reintervention is further outlined in Figures 1 and 2.

4. Discussion

In March 2019, the Food and Drug Administration has approved MitraClip for the treatment of secondary mitral regurgitation as a result of the COAPT trial [8], and the 2020 ACC/AHA valve guidelines have provided a Class 2A recommendation for TMVr in patients with severe, secondary mitral regurgitation who remain symptomatic after optimization of guidelines-directed medical therapy [3]. In this frame, the number of transcatheter mitral valve procedure performed in the United States has been steadily growing over time, both in general and in particular for each subtype of mitral regurgitation [9].

Our study is the first in its nature to probe clinical outcomes in patients of any ages with ischemic mitral regurgitation undergoing SMVr versus TMVr after propensity score matching: we uniquely gathered real-world data from >50 institutions across the United States by leveraging the TriNetX Analytics Research Data Network. The role of this dataset has been recently started to be validated in the cardiac surgery literature [7, 10] and the online, continuously updated, interactive platform of the data network allowed us to query data from 80 million electronic medical records and design a propensity score matching model accounting for an extensive number of variables. As such, we were able to demonstrate that SMVr in ischemic mitral regurgitation holds both a survival advantage as well as lower hazards of reoperation at short- and mid-term compared to TMVr.

Malik et al. have performed a retrospective, observational evaluation of outcomes in octogenarians undergoing SMVr versus TMVr by leveraging the National Inpatient Sample database [11]. They demonstrated a 4-fold higher mortality rate in SMVr versus TMVr as well as an overall higher rate of cardiac, vascular, hemorrhagic, and respiratory complications. Even though the Authors performed propensity score matching between the two cohorts, they also stated not to have stratified results by the etiology and type of mitral regurgitation or to have matched for preoperative left ventricular function. Our group has previously elaborated on the limitations of the National Inpatient Sample data when used for outcome-based clinical research [12]. In a different setting, De Bonis et al. have reported their institutional mid-term results of TMVr versus surgical edge-to-edge repair in patients with severe left ventricular dysfunction and secondary mitral regurgitation [13]. They reported that residual (≥2+) MR at hospital discharge was significantly higher in the TMVr than in the surgical group (29% versus 7.6%, respectively; p = 0.002) and that at 4-year follow-up, freedom from MR ≥2+ was significantly higher in the surgical group than in the TMVr group (74.9% versus 51.4%, respectively; p = 0.01). Interestingly, the use of TMVr was identified as an independent predictor of recurrence of MR ≥2+ at multivariate analysis. Other studies have been published with neutral results, likely as a result of their limited sample sizes [14–17].

In this frame, our study showed a statistically significant lower reintervention rate as a surrogate marker for valvular function in the SMVr group compared to patients undergoing TVMr (2.4% vs. 7.8%, respectively; p = 0.002). This difference in reoperation rates are in line with the results of the EVEREST II (Endovascular Valve Edge-to-Edge Repair Study) RCT trial, which showed significantly higher rates for mitral valve reintervention and recurrent mitral valve regurgitation (3+ or 4+) in patients with TMVr compared to mitral valve surgery at 5 years.

Furthermore, both TMVr and SMVr showed a comparable 5-year mortality without underlying any statistically significant difference [18]. However, the conclusiveness of the EVEREST II trial is limited by the mixed population in terms of underlying mitral valve pathology (26% secondary MR) and different surgical treatment modalities (14% mitral valve replacement) [18, 19].

Interestingly, Vinciguerra et al. have defined ischemic mitral regurgitation as a “multifaceted syndrome” [20] to underline the multiple components in its pathophysiology. From a mechanistic standpoint, the transcatheter option can only address the component of mitral regurgitation caused by lack of valvular leaflet coaptation–without the ability to fully address the mitral annular component or the underlying myocardial ischemia. Indeed, Cimino et al. have demonstrated that patients with more severely dilated left ventricles and mitral valve annulus, or higher pulmonary pressure values, have lower benefits from transcatheter options [21, 22].

4.1. Limitations

In spite of its solid methodology, with propensity score matching allowing to nullify confounding bias, our study have some limitations. First, its retrospective nature. Second, the classification of diseases and comorbidities based on available CPT and ICD-10 codes only. Third, the inability to access patients’ electronic medical records at a granular level which would have allowed as to perform more advanced, stratified analysis. Finally, lack of data on the symptomatic classification of diseases and on center-level adherence to current guidelines.

5. Conclusion

Our analysis of real-world data including a large cohort of propensity score-matched patients with chronic ischemic MR, surgical mitral valve repair had significantly better survival rates and significantly lower reintervention rates at 1- and 3-years when compared to TMVr.

Data Availability

The data used in this study were collected from the TriNetX Network, which provided access to electronic medical records (diagnoses, procedures, medications, laboratory values, genomic information). TriNetX, LLC, is compliant with the Health Insurance Portability and Accountability Act (HIPAA), the US federal law which protects the privacy and security of healthcare data, and any additional data privacy regulations applicable to the contributing HCO. TriNetX is certified to the ISO 27001:2013 standard and maintains an Information Security Management System (ISMS) to ensure the protection of the healthcare data it has access to and to meet the requirements of the HIPAA Security Rule. Any data displayed on the TriNetX Platform in aggregate form, or any patient level data provided in a data set generated by the TriNetX Platform, only contain de-identified data as per the de-identification standard defined in Section §164.514(a) of the HIPAA Privacy Rule. The process by which the data are de-identified is attested to through a formal determination by a qualified expert as defined in Section §164.514(b)(1) of the HIPAA Privacy Rule.

Ethical Approval

Because this study used only de-identified patient records and did not involve the collection, use, or transmittal of individually identifiable data, this study was exempted from Institutional Review Board approval.

Disclosure

The study was performed as part of the employment of the Authors at Yale University School of Medicine.

Conflicts of Interest

Dr. Amabile receives consulting fees from JOMDD. Dr. Krane is a physician proctor and a member of the medical advisory board for JOMDD; Peter Duschek is a medical consultant for EVOTEC and Moderna and has received speakers’ honoraria from Medtronic and Terumo. Dr. Geirsson receives consulting fees for being a member of the Medtronic Strategic Surgical Advisory Board and from Edwards Lifesciences. The authors declare that they have no conflicts of interest.

Authors’ Contributions

Andrea Amabile and Brandon Muncan contributed equally to the study.

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Copyright

Copyright © 2023 Andrea Amabile et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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