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Valvular heart disease
Original research
Guideline-directed medical therapy after transcatheter edge-to-edge mitral valve repair
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  1. Tetsu Tanaka1,
  2. Refik Kavsur1,
  3. Maximilian Spieker2,
  4. Christos Iliadis3,
  5. Clemens Metze3,
  6. Birthe M Brachtendorf1,
  7. Patrick Horn2,
  8. Christian Zachoval1,
  9. Atsushi Sugiura1,
  10. Malte Kelm2,
  11. Stephan Baldus3,
  12. Georg Nickenig1,
  13. Ralf Westenfeld2,
  14. Roman Pfister3,
  15. Marc Ulrich Becher1
  1. 1 Heart Center Bonn, Department of Medicine II, University Hospital Bonn, Bonn, Germany
  2. 2 Heart Center, Department of Cardiology, University Hospital of Düsseldorf, Düsseldorf, Germany
  3. 3 Heart Center, Department of Cardiology, University Hospital Cologne, Cologne, Germany
  1. Correspondence to Dr. Marc Ulrich Becher, Heart Center Bonn, Department of Medicine II, University Hospital Bonn, Venusberg-Campus 1, 53127 Bonn, Germany; ubecher{at}uni-bonn.de

Abstract

Objective A sizeable proportion of patients with secondary mitral regurgitation (SMR) do not receive guideline-directed medical therapy (GDMT) for heart failure (HF). We investigated the association between the use of GDMT and mortality in patients with SMR who underwent transcatheter edge-to-edge repair (TEER).

Methods We retrospectively analysed patients with SMR and a left ventricular ejection fraction of <50% who underwent TEER at three centres. According to current HF guidelines, GDMT was defined as triple therapy consisting of beta-blockers, renin–angiotensin system (RAS) inhibitors and mineralocorticoid receptor antagonists (MRAs). Patients were divided into two groups: GDMT and non-GDMT groups. We calculated the propensity scores and carried out inverse probability of treatment weighting (IPTW) analyses to compare 2-year mortality between the two groups.

Results Of 463 patients, 228 (49.2%) were treated with GDMT upon discharge. IPTW-adjusted Kaplan-Meier curve showed patients with GDMT had a lower incidence of mortality than those without GDMT (19.8% vs 31.1%, p=0.011). In IPTW-adjusted Cox proportional hazards analysis, GDMT was associated with a reduced risk of 2-year mortality (HR: 0.58; 95% CI: 0.35 to 0.95; p=0.030), which was consistent among clinical subgroups. Moreover, patients with GDMT had a higher rate of left ventricular reverse remodelling at 1 year after TEER than those without GDMT.

Conclusion GDMT, defined as triple therapy consisting of beta-blockers, RAS inhibitors and MRAs, was associated with a reduced risk of 2-year mortality after TEER for SMR. Optimisation of medical therapy is crucial to improve clinical outcomes in patients undergoing TEER for SMR.

  • Mitral Valve Insufficiency

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/heartjnl-2022-320826

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Guideline-directed medical therapy (GDMT) is an essential treatment for secondary mitral regurgitation (SMR) and impaired left ventricular systolic function; however, in clinical practice, there is a sizeable proportion of patients with SMR who do not receive GDMT.

    WHAT THIS STUDY ADDS

    • In this study including 463 patients with SMR and a left ventricular ejection fraction of <50% who underwent transcatheter edge-to-edge repair (TEER), we used inverse probability of treatment weighting methodology and showed that use of GDMT, defined as triple therapy consisting of beta-blockers, renin–angiotensin system inhibitors, and mineralocorticoid receptor antagonists, was associated with a reduced risk of 2-year mortality after TEER. Furthermore, patients with GDMT had a higher rate of left ventricular reverse remodelling following TEER compared with those without GDMT.

    HOW THIS STUDY MIGHTTHIS AFFECT RESEARCH, PRACTICE OR POLICY

    • Our findings underline that there is a crucial need for using optimal GDMT to improve clinical outcomes after TEER in patients with SMR.

    Introduction

    Secondary mitral regurgitation (SMR) is associated with an impaired prognosis in patients with heart failure (HF).1 SMR is mainly attributed to underlying left ventricular (LV) systolic dysfunction,2 3 and the use of neurohormonal antagonists based on the HF guidelines is an initial treatment for SMR. Recently, transcatheter edge-to-edge mitral valve repair (TEER) is an emerging treatment option for symptomatic SMR. Based on the results of the COAPT trial,4 the current guidelines recommend TEER for patients with SMR and LV ejection fraction (LVEF) of 20%–50% who continued to be symptomatic despite the maximally tolerated medical therapy.5 However, in clinical practice, there is a sizeable proportion of patients with SMR who do not receive optimal medical therapy as recommended by the HF guidelines.6 7 Beneath these observations, the clinical relevance of guideline-directed medical therapy (GDMT) after TEER needs to be elucidated.

    We sought to evaluate the association between the use of GDMT and all-cause mortality after TEER in patients with SMR and an LVEF of <50%.

    Methods

    Study population

    This study was designed as a retrospective analysis of data from a multicentre, prospective, observational registry of symptomatic patients with MR who underwent a MitraClip procedure (Abbott Vascular, Santa Clara, California, USA) from October 2011 to September 2018 at three German high-volume centres (University Hospitals of Bonn, Cologne and Düsseldorf). The patients all agreed to participate in our registry.

    Consecutive patients with an LVEF of <50% and SMR who underwent TEER were enrolled in this study. All patients had moderate-to-severe or severe MR accompanied by symptomatic HF despite medical therapy and were considered as inoperable or at high surgical risk. Patients who died during the index hospitalisation (n=22) and those without available information about their medical therapy (n=19) were excluded from the present analysis. The final study population consisted of 463 patients (online supplemental figure 1).

    Supplemental material

    The indication for TEER was evaluated by the interdisciplinary heart team of each centre, including HF specialists. The heart teams optimised medical therapy based on the guidelines and decided to perform TEER, considering MR severity, cardiac function, symptoms, comorbidity and life expectancy of the patient. A titration of the medical therapy was performed by the heart team during the index hospitalisation and was left up to the discretion of the treating physicians after discharge.

    The medical therapy of each patient was evaluated at discharge after TEER. Based on the 2021 European Society of Cardiology (ESC) HF guidelines,8 GDMT was defined as triple therapy consisting of beta-blockers, renin–angiotensin system (RAS) inhibitors (ACE inhibitors, angiotensin receptor blockers, or angiotensin receptor/neprilysin inhibitor) and mineralocorticoid receptor antagonists (MRAs). In contrast, patients with a lack of the triple therapy were recognised as non-GDMT group. Sodium-glucose co-transporter 2 (SGLT2) inhibitors were not included in the definition of GDMT, because the use of SGLT2 inhibitors was still rare in this registry. For each patient, the percentage of the optimal dosage of beta-blockers and RAS inhibitors was calculated and stratified based on the recommended target dose in the 2021 ESC HF guidelines (0%, 1%–24%, 25%–49%, 50%–99% and 100%), and the dose of loop diuretics was expressed as a standardised furosemide equivalent.9

    Echocardiographic parameters

    We assessed the echocardiographic parameters that were collected at baseline and discharge, according to the current guidelines.10 The severity of MR was graded as follows: grade 0, none; 1+, mild; 2+, moderate; 3+, moderate to severe; 4+, severe. LV volumes and ejection fraction were calculated using the apical biplane views, including two-chamber and four-chamber views. Also, post-procedural echocardiographic assessments were collected at 1 year after TEER. LV reverse remodelling was defined as a reduction in the LV end-systolic volume of ≥10% from baseline to the 1-year follow-up.11 All measurements were reviewed by an independent cardiologist dedicated to echocardiographic evaluation at each centre.

    Clinical follow-up

    The primary endpoint was all-cause mortality within 2 years after TEER. Follow-up data and the occurrence of clinical events were collected from admission and outpatient medical records or telephone interviews with the patients’ general practitioners or families.

    Patient and public involvement

    Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    Statistical analysis

    Continuous variables are presented as the mean±SD or medians with an IQR for normally and non-normally distributed variables, respectively. Continuous variables were compared using t-tests or the Mann-Whitney test. Proportions of categorical data were presented as percentages and compared using the Χ2 test or Fisher’s exact test.

    Treatment effects were examined in two ways. First, to minimise confounding by patient factors for GDMT, we calculated propensity scores and carried out inverse probability of treatment weighting (IPTW)-adjusted analyses.12 Multiple imputation using chained equations was performed to handle missing values in baseline variables that were required for estimation of the propensity score and subsequent analyses, and we generated 20 imputed data sets by using a sequential regression model.13 The number of missing records per baseline variable is summarised in online supplemental table 1. In all subsequent analyses, Ruben’s rules were applied to unify the effect estimates and variances from the 20 different analyses across multiple imputed data sets. A propensity score was separately calculated in each imputed data set using multiple logistic regression that estimated the propensity toward belonging to GDMT. The dependent variables were age, sex, body mass index, prior myocardial infarction, coronary artery disease, diabetes mellitus, atrial fibrillation, estimated glomerular filtration rate (eGFR), haemodialysis, New York Heart Association class, cardiac implantable electronic device, cardiac resynchronisation therapy, chronic obstructive pulmonary disease, N-terminal pro-B-type natriuretic peptide, Logistic European System for Cardiac Operative Risk Evaluation, systolic blood pressure, heart rate, site of intervention, LVEF, LV end-diastolic volume, MR severity grade, effective regurgitation orifice area, systolic pulmonary artery pressure, tricuspid annular plane systolic excursion (TAPSE), severity of tricuspid regurgitation and dose of loop diuretics. Each patient was weighted by the inverse probability of treatment: patients who received GDMT were weighted by the reciprocal of the propensity score, and those who did not receive GDMT were weighted by the reciprocal of 1 minus the propensity score; the weights were then stabilised by the proportion of patients in each group.14 Covariate balance was evaluated by using the standardised differences approach and Kernel density plots. Absolute standardised differences ≤10% were considered acceptable. IPTW-adjusted Kaplan-Meier curves were depicted to compare 2-year mortality between groups. We further conducted an IPTW-adjusted Cox proportional hazards regression model to calculate the weighted HRs, which allowed for adjustment for any covariate that remained unbalanced after IPTW. In addition, we conducted a stratified analysis to examine heterogenicity of treatment effects according to age, eGFR, site of intervention, LVEF, TAPSE, residual MR and post-procedural LVEF by testing the interaction terms within the IPTW-adjusted Cox proportional hazards models.

    Second, as a sensitivity analysis, we fitted multivariable Cox proportional hazards regression models to assess the effect of GDMT on 2-year mortality in the non-weighted population, in which covariates that showed significance (p<0.10) in the univariate analysis were included. We tested for collinearity in the multivariable models using a variance inflation factor, and the variables had low variance inflation factors (<2).

    Statistical significance was set as a two-sided p<0.05. All analyses were conducted using Stata V.15.1 (StataCorp, College Station, Texas, USA).

    Results

    Baseline characteristics

    Among 463 included patients, the mean age was 74±9 years and 72.6% were of male sex (table 1). The median LVEF was 32.2% (IQR: 26.0–39.7), and 23.3% of the patients had an LVEF between 40% and 50%. Technical success was achieved in 98.7%, and the rate of reduction in MR to 2+ or less was 94.6% (online supplemental table 2).

    View this table:
    Table 1

    Baseline patient characteristics

    Of these, 228 patients (49.2%) were treated with GDMT at discharge (figure 1). The use of beta-blockers, RAS inhibitors, and MRAs was 92.0%, 79.9%, and 60.5%, respectively. Between sites of intervention (ie, University Hospitals of Bonn, Düsseldorf and Cologne), the proportion of GDMT was comparable (45.3%, 47.2% and 57.4%, respectively; p=0.089). The detailed dose of each drug is summarised in table 2. In addition, medical therapy before the procedure is shown in online supplemental table 3.

    Figure 1
    Figure 1

    Prevalence of medical therapy in the study population. Venn diagram indicating the prevalence of medical therapy in the study population. GDMT, guideline-directed medical therapy; MRA, mineralocorticoid receptor antagonist; RAS, renin–angiotensin system.

    View this table:
    Table 2

    Medical therapy for heart failure upon discharge

    Also, GDMT based on the 2016 ESC HF guidelines (ie, both RAS inhibitors and beta-blockers and, in patients with an LVEF of ≤35%, MRAs) was achieved in 292 patients (63.1%).

    Baseline characteristics of patients with or without GDMT are shown in table 1. Patients with GDMT were younger, more likely to be male, had lower LVEF, larger LV volumes and different patterns of comorbidities, compared with those without GDMT. In contrast, the rates of implantation success and reduction in MR to 2+ or less were comparable between the groups (online supplemental table 2). Consequently, propensity scores were differently distributed between patients with and without GDMT (online supplemental figure 2).

    After IPTW adjustment, all variables were well balanced, with all absolute standardised differences less than 10% (table 3 and online supplemental figure 3), and propensity score distribution between the two groups achieved adequate balance (online supplemental figure 2).

    View this table:
    Table 3

    Baseline characteristics after inverse probability of treatment weighting

    Clinical outcomes

    The median follow-up period was 528 days (IQR: 348–842). Within 2 years, 92 patients (19.7%) died from all causes, including 76 due to cardiovascular causes. Two-year clinical follow-up was complete in 249 patients. IPTW-adjusted Kaplan-Meier curves showed that patients with GDMT had a lower incidence of all-cause mortality within 2 years after TEER, compared with those without GDMT (19.8% vs 31.1%, p=0.011; figure 2). In the IPTW-adjusted Cox proportional hazards analysis, GDMT was associated with a reduced risk of all-cause mortality within 2 years after TEER (weighted HR: 0.58; 95% CI: 0.35 to 0.95; p=0.030; figure 2). The association between GDMT and 2-year mortality was consistent across the subgroups, including pre-procedural LVEF (≤40% or >40%: p for interaction=0.835; figure 3).

    Figure 2
    Figure 2

    Inverse probability of treatment weighting-adjusted Kaplan-Meier analysis of all-cause mortality. An inverse probability of treatment weighting-adjusted Kaplan-Meier curve of all-cause mortality within 2 years after transcatheter edge-to-edge mitral valve repair for patients with guideline-directed medical therapy (GDMT) versus those without GDMT.

    Figure 3
    Figure 3

    Subgroup analysis of the association between guideline-directed medical therapy (GDMT) and all-cause mortality within the inverse probability of treatment weighting-adjusted population. A forest plot illustrates the association between GDMT and all-cause mortality for prespecified subgroups within the inverse probability of treatment weighting-adjusted population. eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; MR, mitral regurgitation; TAPSE, tricuspid annular plane systolic excursion.

    In the sensitivity analysis, the association between GDMT and all-cause mortality was consistent (non-weighted HR: 0.52; 95% CI: 0.33 to 0.81; p=0.004: online supplemental table 4).

    Echocardiographic follow-up

    Echocardiographic assessments at 1 year after TEER were available in 192 patients (41.5%) (online supplemental table 5). The median LVEF was 33.2% (IQR: 25.8–41.6), and the median LV end-systolic volume was 117 mL (IQR: 79–172). LV reverse remodelling was observed in 64 patients (33.9%). Patients with GDMT had a higher rate of LV reverse remodelling than those without GDMT (40.2% vs 26.8%; p=0.038).

    Medication follow-up

    Detailed information about medical therapy at 3 months and 1 year after TEER is shown in online supplemental table 6. In both groups, the dose of beta-blockers and RAS inhibitors was comparable between baseline and follow-up, while the proportion of MRAs in patients with GDMT decreased at 3-month and 1-year follow-ups from baseline.

    Discussion

    In the present study using a multicentre cohort of patients with SMR with LVEF <50% who underwent TEER, we investigated the prognostic benefit of GDMT, defined as triple therapy consisting of beta-blockers, RAS inhibitors and MRAs, using the IPTW analysis. The main findings can be summarised as follows:

    1. Approximately half of patients with SMR who underwent TEER were treated with GDMT at discharge based on the 2021 ESC HF guidelines.

    2. GDMT was associated with a reduced risk of mortality within 2 years after TEER, which was consistent among all predefined clinical subgroups, including pre-procedural LVEF (≤40% or >40%).

    3. Patients with a GDMT were likely to have LV reverse remodelling at 1 year after TEER.

    Optimisation of medical therapy is the first-line therapy for patients with SMR.3 Numerous studies have demonstrated that medical therapy plays a pivotal role in the global range of patients with HF. Nevertheless, there is still a sizeable proportion of patients with SMR who do not receive optimal medical therapy in clinical practice, due to age, blood pressure, renal function and comorbidities.6 7 In the present cohort, approximately half of patients undergoing TEER for SMR were not treated with GDMT upon discharge, which was comparable with the COAPT trial and other previous studies.4 6 7 15 Nevertheless, it has been little known about the clinical relevance of GDMT after TEER.

    We tested the hypothesis whether the optimisation of medical therapy based on the HF guidelines improves clinical outcomes of patients undergoing TEER for SMR. Since the adherence to GDMT is affected by various patient factors, the effects of optimising medical therapy have multiple potential confounders. To overcome the bias related to these potential confounders, we used IPTW analysis, which is a statistical approach to infer a causal association and allows increasing the weight of under-represented observations to reduce the imbalances related to treatment allocation, thereby mimicking the effect of randomisation on baseline characteristics.16 In the IPTW analysis, GDMT based on the 2021 ESC HF guidelines was associated with a reduced risk of 2-year mortality after TEER. Furthermore, this association was consistent with the subgroup analysis that was stratified by patient characteristics and post-procedural findings. Our findings collectively indicate the causal association of GDMT with mortality after TEER in patients with SMR.

    The potential explanations for the association of GDMT with mortality are multifactorial. A plausible reason may be related to the higher rate of LV reverse remodelling in patients with GDMT. Reduction in MR by TEER can improve LV function and reduce LV volumes, which itself consequently might lead to improved clinical prognosis.11 Furthermore, owing to the positive effects on LV reverse remodelling, GDMT may further ameliorate MR even after the initial reduction of MR and potentially reduce the risk of recurrent MR, thereby improving clinical outcomes.17–19

    The reduction in MR and the optimisation of medical therapy are two pivotal managements in patients with SMR. There might be synergistic benefits of TEER and medical therapy on clinical outcomes. Besides the GDMT upon discharge, we showed that patients with residual MR <2+ had a lower risk of mortality (unadjusted HR: 1.58; 95% CI: 1.04 to 2.41; p=0.034), indicating that the reduction of MR by TEER also plays a key role in clinical outcomes in patients with SMR. Our findings emphasise that TEER and GDMT should go ‘hand in hand’, and GDMT should not be neglected after TEER for SMR.

    Owing to multiple options of neurohormonal antagonists for HF, there are various possible combinations of medical therapy, which have different prognostic benefits.20 In the present study, the lack of RAS inhibitors or MRAs accounted for the majority of patients without GDMT, while the proportion of use of beta-blockers was relatively high (85%). The lack of RAS inhibitors or MRAs might be due to renal dysfunction, hyperkalaemia or hypotension; however, the association between GDMT and mortality was consistent after adjustment for the potential confounders. These findings may collectively indicate a possibility that the inferior results in the non-GDMT group were mainly driven by the lack of RAS inhibitors or MRAs. Nevertheless, larger studies are needed to investigate the clinical benefits of each neurohormonal antagonist and their combination in patients undergoing TEER for SMR.

    There are limited data about the effect of neurohormonal antagonists on HF with an LVEF between 40% and 50%, which is referred to as ‘mildly reduced EF’. Recent retrospective analyses revealed the clinical benefits of neurohormonal antagonists for HF with mildly reduced EF as well as for that with reduced EF (ie, LVEF <40%).21–23 Accordingly, the 2021 ESC HF guidelines now provide recommendations on medical therapy for patients with mildly reduced EF, including beta-blockers, RAS inhibitors and MRAs. The present study revealed no significant interaction between the clinical benefits of GDMT and pre-procedural LVEF (≤40% or >40%). In settings of MR, due to the afterload-reducing effect of MR, LV systolic dysfunction is likely underestimated. Therefore, the severity of the underlying LV dysfunction in patients with SMR and mildly reduced EF may resemble that of patients with reduced EF but without MR. Thus, GDMT may have prognostic benefits in patients with mildly reduced EF who underwent TEER for SMR, as well as those with reduced EF.

    Limitations

    First, our results need to be interpreted within the limitations of a retrospective, observational study. The present analyses are subject to a selection bias, which we attempted to correct by using an IPTW-adjusted approach. Nonetheless, several unmeasured confounders may have affected our results. Second, the management of medical therapy was not adjudicated by a core laboratory, and we could not assess the patient compliance to the prescribed medical therapy. In the present analysis, approximately half of patients were not treated with GDMT, and the number of patients treated with medical therapy at the target dose was small, which might be partially explained by the ineligibility of medical therapy. Among patients without GDMT, 41.8% had any of the factors related to the ineligibility (ie, systolic blood pressure <100 mm Hg, heart rate <60 beats/min or eGFR <30 mL/min/m2),8 although detailed reasons for the intolerance of GDMT were not recorded. The present study was the analysis of data from the multicentre, real-world registry, and therefore, we believe that our findings are generalisable to the clinical practice in the real-world setting. Third, the present study did not have a control arm consisting of patients treated with medical therapy alone. Therefore, we could not evaluate the relative improvements in prognosis with TEER compared with medical therapy only. Fourth, we did not assess the effects of novel HF drugs, including SGLT2 inhibitors, although SGLT2 inhibitors have a class I indication for patients with HF with reduced EF in the current guidelines.8 Therefore, further investigation is necessary to examine the beneficial effects of the new drugs in patients undergoing TEER. Finally, approximately 45% of patients were lost to clinical follow-up within 2 years, and information about echocardiographic assessments and medications at follow-up was not fully available. However, the selection bias due to the loss to clinical follow-up might be limited since patient characteristics were comparable between patients with completed and lost follow-up (online supplemental table 7).

    Conclusion

    GDMT, defined as triple therapy consisting of beta-blockers, RAS inhibitors and MRAs, was associated with a reduced risk of all-cause mortality within 2 years after TEER for SMR. Furthermore, GDMT was linked to a greater LV reverse remodelling after TEER. Our findings suggest that optimisation of medical therapy is crucial to improve clinical outcomes in patients undergoing TEER for SMR.

    Data availability statement

    Data are available upon reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by the ethical committees of the individual centres (University Hospital Bonn, University Hospital Cologne and University Hospital Düsseldorf) in accordance with the Declaration of Helsinki. Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We thank Dr Meghan Lucas (scientific coordinator for the Heart Center Bonn, Bonn, Germany) for proofreading the manuscript.

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • TT and RK are joint first authors.

    • Twitter @TETSUTANAKA5

    • Contributors TT and MUB conceived the study and were responsible for the design of the study. TT performed formal analysis. TT and RK wrote the first draft and revised the manuscript. MS, CI, CM, BMB, PH and CZ were involved in data collection and contributed to manuscript review. AS was involved in manuscript review and editing. MUB, MK, SB, GN, RW and RP were involved in supervision and manuscript review and editing. TT and MUB are guarantors for the study.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests RP has received speaker and consultant honoraria from Abbott and Edwards Lifesciences, outside the submitted work. GN has received research funding from the Deutsche Forschungsgemeinschaft, the German Federal Ministry of Education and Research, the European Union, Abbott, Edwards Lifesciences, Medtronic and St Jude Medical; and has honoraria for lectures or advisory boards from Abbott, Edwards Lifesciences, Medtronic and St Jude Medical. SB has received lecture honoraria from Edwards Lifesciences, Bayer Vital, CVRx, MSD Sharp&Dome, JenaValve Technology and Abbott; and research grants from IcoVifor, Symetis SA, Pfizer, JenaValve Technology, Valtech, OptumInsight, Biotronik and Abbott, outside the submitted work. CI has received travel support from Abbott and speaker and consultant honoraria from Abbott and Edwards Lifesciences, outside the submitted work. TT has been financially supported in part by a fellowship from the Japanese College of Cardiology. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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