Temporal Trends and Early Outcomes of Transcatheter versus Surgical Mitral Valve Repair in Atrial Fibrillation Patients

Objectives To study trends of utilization, in-hospital outcomes, and short outcomes in patients undergoing transcatheter mitral valve repair (TMVR) vs. surgical mitral valve repair (SMVR) in atrial fibrillation (AF). Background TMVR is a treatment option in inoperable or high-risk patients with mitral regurgitation (MR). AF is a common comorbidity of MR. Data comparing between TMVR and SMVR in MR patients with AF is lacking. Methods The National Readmission Database from 2016 to 2019 was utilized to identify hospitalizations undergoing TMVR or SMVR with AF. Outcomes of interest included mortality, postoperative complications, length of stay, and 30-day readmission rate. Results A total of 9,195 patients underwent TMVR and 16,972 patients underwent SMVR with AF; the number of AF undergoing TMVR was increasing from 1,342 in 2016 to 4,215 in 2019 and SMVR. The incidence of in-hospital mortality decreased from 2.6% in 2016 to 1.8% in 2019. We identified length of stay>5 days, dyslipidemia, cerebrovascular disease, heart failure with reduced ejection fraction, and urgent/emergent admissions as independent risk factors for in-hospital mortality. After matching, we included 4,680 patients in each group; the in-hospital death, transfusion, acute kidney injury, sepsis, stroke, and mechanical ventilation were lower in TMVR compared with SMVR. TMVR was associated with a similar rate of all-cause readmission at 30 days compared with SMVR. Conclusion Patients with AF receiving TMVR have been increasing along with progressive improvement in in-hospital death and length of stay. Compared to SMVR, AF patients receiving TMVR had a lower rate of in-hospital death and postoperative complications.


Introduction
Mitral regurgitation (MR) is a common heart valve disease that afects approximately 10% of people over the age of 75 in the general population [1].Severe MR can lead to left ventricular failure, pulmonary hypertension, atrial fbrillation, and even death, and in patients with a New York Heart Association (NYHA) class III or IV, the mortality rate is 34% yearly [2].Surgical mitral valve repair (SMVR) used to be the only treatment option for patients with MR that was poorly controlled by medications [3,4].In 2003, the frst MitraClip procedure was performed and received European CE certifcation in 2008.Based on the results of the EVEREST II and COAPT clinical trials, transcatheter mitral valve repair (TMVR) for primary and secondary MR has been updated to class 2a in the latest guidelines.
Atrial fbrillation (AF) is often associated with valvular heart disease (VHD), and up to 60% of the patients with AF have some form of valvular abnormality [5].Previous research has revealed poor outcomes in AF patients treated with SMVR [6].Patients with AF who undergo TMVR have higher risks of postoperative bleeding and stroke as well as a higher risk of mortality during follow-up.As TMVR is being increasingly performed, its safety in specifc patient populations needs further clarifcation.However, there is very little published research specifcally comparing the outcomes of TMVR and SMVR in AF patients [7].Tis study compared utilization trends and outcomes of TMVR and SMVR using nationally representative real-world population data.

Methods
2.1.Data Source.Te National Readmission Database (NRD) from January 2016 to December 2019 was used for this analysis.Te NRD is a part of administrative databases developed by federal support of Healthcare Research and Quality (AHRQ) agency.Te NRD has over 16 million admissions, which represents a 57% stratifed sample of all discharges from community hospitals in the United States excluding rehabilitation and long-term acute care hospitals [8].As an administrative database, the NRD used the International Classifcation of Diseases, 10th Revision (ICD-10) code, to identify patient diagnosis and operation.Tis article was approved by the Ethics Committee of the Affliated Hospital of Qingdao University (ethics number: QYFY WZLL 27354).

Study Design and Data Selection.
We searched the 2016-2019 NRD for patients with AF who underwent SMVR or TMVR using the ICD-10 (TMVR: 02UG3JZ; SMVR: 02QG0ZE or 02QG0ZZ).Patients with less than 18 -year-old and missing data were excluded.Meanwhile, we also excluded patients with CABG to reduce the likelihood of selection in favor of SMVR.To calculate the estimated cost of hospitalization, the NRD data were merged with cost-tocharge ratios available from the Healthcare Cost and Utilization Project.We estimated the cost of each inpatient stay by multiplying the total hospital charge with cost-to-charge ratios.Cost was also adjusted for infation (December 2021).

2.3.
Outcomes.Our study's primary outcome was inhospital outcomes including the in-hospital death, length of stay, cost, transfusion, acute kidney injury, sepsis, mechanical ventilation, and stroke.Te secondary outcomes were the 30-day outcomes including all-cause readmission, cardiovascular (CV) readmission, and heart failure readmission.CV readmission was defned as hospitalization due to myocardial infarction, heart failure, or arrhythmia.Te primary diagnosis in the frst readmission after TMVR or SMVR was a reason for readmission.In the case of multiple postoperative readmissions, only the frst hospitalization after admission was counted.All ICD-10 codes used for cohort screening, baseline characteristics, and outcomes are presented in Supplementary Table 1.

Statistical Analysis
Normally distributed measures are expressed as the mean ± variance using Student's t test; nonnormally distributed measures are expressed as the median (interquartile range (IQR)) using the Wilcoxon rank-sum test.Categorical variables are expressed as percentages, and comparisons between the groups were made using the X 2 test or the Fisher's exact test.A nearest neighbor 1 : 1 variable ratio, parallel, balanced, propensity-matching model was made using a caliper width of 0.2.Te Cochran-Armitage trend test was used for categorical variables and linear regression for continuous ones' trend analysis.We entered variables with P < 0.05 in the univariate analysis into a multivariate regression model and selected the entry method to identify independent predictors of in-hospital death and 30-day readmission and compute the odds ratio (OR) and 95% confdence interval (CI).
We chose two sides' P value of <0.05 as statistically signifcant.We used univariate Cox proportional hazards regression for the 30-day outcomes to calculate the hazard ratio (HR) and 95% CI.Kaplan-Meier curves for 30-day allcause readmissions were constructed.Statistical analyses and propensity-matched analysis were performed using R version 3.5.  1 illustrates the patient selection process.Before matching, patients in the TMVR group were older (mean age of 79.3 years vs. 66.6 years; P < 0.001) and had more women (44.7 vs. 41.2%;P < 0.001) compared with those in the SMVR group.Te TMVR group associated more comorbidities including the prior PCI, prior CABG, smoke, myocardial infarction, congestive heart failure, chronic pulmonary disease, diabetes, renal disease, cerebrovascular disease, peripheral vascular disease, and metastatic solid tumor compared with the SMVR group.Conversely, more obesity was associated in the SMVR group.Te detailed diferences between TMVR and SMVR are summarized in Table 1.

Temporal Trends.
Over the study period, the number of AF undergoing TMVR was increasing from 1,342 in 2016 to 4,215 in 2019 (P � 0.049 for trend) and with SMVR remained unchanged from 4,323 in 2016 to 4,084 in 2019.In the TMVR group, we reported the in-hospital mortality in the range of 2% (2.6 vs. 1.8%;P � 0.049 for trend), while in SAVR, the mortality rate also declined (2.2 vs. 1.7%;P � 0.037 for trend).In terms of postoperative complications in the SMVR group, transfusion, sepsis, acute kidney injury, mechanical ventilation, and stroke all remained unchanged.However, in the TMVR group, the sepsis rate declined (2.7 vs. 1.0%;P � 0.037 for trend) and transfusion, acute kidney injury, mechanical ventilation, and stroke all remained unchanged.
In the 30-day readmission rate, the all-cause and CV reason remained stable, but there was a trend towards a decreased admissions for heart failure (2.7 vs. 1.0%;P = 0.037 for trend) in the TMVR group.However, in the SMVR group, the all-cause, CV, and heart failure reason rate all declined during 2016-2019.Te TMVR and SMVR groups' temporal trends between 2016 and 2019 patients are summarized in Tables 2 and 3.In the TMVR group, among the univariate logistic regression analyses of risk factors for 30-day readmission, we determined that LOS >5 days, female, chronic pulmonary disease, dementia, heart failure with reduced ejection fraction, renal disease, urgent/emergent admission, heart failure with preserved ejection fraction, and Charlson comorbidity index had statistically signifcant diferences.After adjusting for these confounding factors, we identifed LOS >5 days, female, chronic pulmonary disease, dementia, heart failure with reduced ejection fraction, and renal disease as a risk factor for 30-day readmission.Tables 4 and 5 summarize the odds ratio and 95% CI both the univariate and multivariate logistic regression.We have also shown the data distribution before and after propensity matching in the Supplementary Figure 1.
After matching, a total of 4,680 TMVR patients were matched with 4,680 SMVR patients with AF.All the baseline characters were equally balanced between the two groups (Table 1).TMVR was associated with a lower risk in the hospital death (2.3 vs. 3.3%; OR: 0.69; 95% CI: 0.53-0.88;P � 0.003).Meanwhile, TMVR had fewer surgical complications, including transfusion, acute kidney injury, sepsis, stroke, and mechanical ventilation.Te TMVR group had shorter hospital stay and less cost.All the matching cohort outcomes are detailed in Tables 6 and 7.

Subgroup Analysis.
According to the AF type, we divided the patients into paroxysmal AF and nonparoxysmal AF groups in the matching cohort.In the paroxysmal AF group, TMVR and SMVR had the similar risk in the hospital death and stroke.TMVR was associated with a lower rate in the transfusion, acute kidney injury, sepsis, and mechanical ventilation.
In the nonparoxysmal AF group, the TMVR and SMVR had the similar risk in sepsis and stroke.TMVR was associated with a lower rate in the hospital death, transfusion, acute kidney injury, and mechanical ventilation.. Te paroxysmal AF detail outcomes are shown in Table 8, and the nonparoxysmal AF group outcomes are shown in Table 9.

MR Etiology.
According to the diferent causes of mitral regurgitation, we classify them into rheumatic mitral valve, mitral valve prolapse, congenital heart disease, and other cause groups.In the rheumatic mitral valve group, TMVR and SMVR had the similar risk in the hospital death, sepsis, cardiogenic shock, and stroke.TMVR was associated with a lower rate in transfusion, acute kidney injury, and mechanical ventilation.Missing mortality data (N=32)

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In the mitral prolapse group, TMVR and SMVR had the similar risk in the hospital death, mechanical ventilation, acute kidney injury, sepsis, and stroke.TMVR was associated with a lower rate in transfusion and cardiogenic shock.
In the congenital valvular heart disease group, TMVR and SMVR had the similar risk in the hospital death, mechanical ventilation, acute kidney injury, sepsis, transfusion, and cardiogenic shock.
In the other reason group, TMVR was associated with a lower rate in hospital death, mechanical ventilation, acute kidney injury, sepsis, transfusion, and cardiogenic shock.Te diferent etiologies of mitral regurgitation outcomes are shown in Table 10.

Discussion
We report the following main fndings in our contemporary real-world population study of TMVR and SMVR outcomes in patients with AF. (1) Patients with AF receiving TMVR have been increasing since 2016 and SMVR has remained stable.(2) Te incidence of in-hospital mortality decreased from 2.6% in 2016 to 1.8% in 2019, and 30-day all-cause readmission remains stable in the TMVR group.(3) In AF receiving TMVR, LOS>5 days, dyslipidemia, cerebrovascular disease, heart failure with reduced ejection fraction, and urgent/emergent admission were associated with in-hospital mortality.LOS >5 days, female, chronic pulmonary disease, TMVR is being increasingly performed because of its expanding real-world application and growing popularity.MR and AF are closely related.MR can lead to atrial enlargement, possibly resulting in an increased incidence of AF [9].In a retrospective study in which echocardiographic characteristics were collected, researchers observed that the annual incidence of new-onset AF was approximately 5% in primary MR patients [10].In previous trials and registry studies in which NRD was consulted, approximately 32 to 68% of AF patients underwent TMVR [11][12][13][14].Using NRD, we identifed in the real world about 57.1% of patients with MR who underwent mitral valve repair coexisting with AF.We identifed independent risk factors for in-hospital mortality in patients with atrial fbrillation receiving TMVR, including the importance of urgent/emergent admissions and prior cardiovascular events.AF is an important risk factor for ischemic stroke, and these patients tend to have higher rates of embolism and bleeding.Tese patients tend to have a higher rate of perioperative bleeding.So, enhanced management of anticoagulants in patients with AF helps reduce in-hospital mortality in those patients receiving TMVR.
Similar to previous studies, our TMVR cohort was older (mean age 79.4) and had a higher prevalence of pre-existing comorbidities.Before matching, the patients in the TMVR group were generally in poor condition and the in-hospital mortality was slightly higher comparing the SMVR group, but not statistically diferent.After matching, TMVR demonstrated a lower in-hospital death and multiple inhospital outcomes, as shown in the current study, including blood transfusion, acute kidney injury, sepsis, mechanical ventilation, cardiogenic shock, and stroke.Tis result is  probably related to the fact that transcatheter manipulation is less invasive to the body.Fewer in-hospital complications were also refected in the lower length of stay and cost of hospitalization in the TMVR group.
During the study period, we reported that the in-hospital mortality rate was 2% in AF patients who underwent TMVR.Te in-hospital mortality rate found in our study was similar to that found in Alkhouli et al.'s study, which reported an inhospital mortality of 2.47% for patients who underwent TMVR and were identifed using the NRD database from 2014 to 2018 [15].Although the diference in the incidence of postoperative complications was not signifcant, the gradual decrease in incidence indicates a gradual improvement in the safety of TMVR.Tis improvement in the safety of TMVR is also refected in a gradual decrease in the length of stay over the study period.By using the STS/ACC TVT Registry, we found that as TMVR became more frequently performed and as operators became more experienced in performing TMVR, the procedural success improved and the complication rate decreased [16,17].Early all-cause readmission correlates to a poor prognosis.AF patients who underwent TMVR had a high 30-day readmission rate.
Previous studies have shown that heart failure is the most common reason for readmission of TMVR patients [18].We found that the 30-day readmission heart failure rate declined from 2016 to 2019 in AF patients who underwent TMVR.Tis decreased rate is associated with reduced mitral regurgitation and relief of heart failure symptoms in AF patients with TMVR.However, we also note that the heart failure rate did not change signifcantly from 2017 to 2019.Whether this is related to the loose extension of TMVR indications to patients with functional MR, especially atrial functional MR, still needs further investigation in the future.
Whether AF has adverse efects on patients receiving mitral valve repair remains unclear.Alexiou et al.'s and Kessler et al.'s studies concluded that AF has a major negative impact in the long-term follow-up in patients undergoing SMVR [5,6].However, other reports have shown that the outcomes of SMVR are similar in patients with AF and those without AF [19,20].For patients who underwent TMVR, AF was not an independent risk factor for in-hospital death [21,22], but it was an independent risk factor for 30-day readmission [18].Terefore, it is important to identify risk factors for readmission of AF patients to

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Journal of Interventional Cardiology reduce readmission after TMVR.Te longer length of stay may be associated with the patients' poorer general condition, more comorbidities, and a higher probability of in-hospital complications, which are also associated with an increased 30-day readmission rate [23].Strategies such as increased collaboration between pulmonologists and      According to the well-known EVEREST II trial subgroup analysis, the AF patients in the TMVR and SMVR groups had similar in-hospital death rates and 1-year survival outcomes [24].Our results were consistent with those of previous studies, and no signifcant diferences were observed between TMVR and SMVR in terms of 30-day readmission after matching.However, before matching, the SMVR group had a lower 30-day readmission rate.In fact, after matching, the SMVR patients we matched were older, frailer, and had more comorbidities.As a result, the prognosis of SMVR was poorer.

Journal of Interventional Cardiology
We evaluated the impact of diferent AF types on outcomes, and we found that the paroxysmal AF group had similar risk in hospital death compared to SMVR, but the nonparoxysmal AF group had a lower in-hospital mortality rate.Generally, the prognosis of patients with paroxysmal AF tends to be positively correlated with the presentation of the frequency of AF.
Patients with nonparoxysmal AF have worsening heart failure symptoms, frailty, and a higher burden of noncardiovascular disease.Tis is also refected in a metaanalysis by Ganesan et al. including approximately 100,000 patients receiving SMVR, where all-cause mortality was higher in nonparoxysmal AF than in paroxysmal AF [25].However, in our univariate logistic regression analyses, the paroxysmal AF is not a protective factor for in-hospital death in AF patients undergoing TMVR and this is consistent with Gangani et al.'s study [26].Also, in our subgroup analysis, we found that in the nonparoxysmal AF patients, TMVR appears to be more benefcial for patients compared to SMVR.However, this result still needs to be further demonstrated in a randomized trial.In a subgroup analysis by etiology, we found no signifcant diference in in-hospital death between the two groups in the comparison of rheumatic mitral valve, mitral valve prolapse, and congenital Journal of Interventional Cardiology heart disease.We found that TMVR was more favorable than SMVR in patients with mitral regurgitation due to other causes (including left atrium enlargement for various reasons and mitral valve degeneration).We think that this is due to part of the group of small sample size.
5.1.Limitations.Our study has the following limitations.NRD used for this analysis is an administrative database, and we used the ICD-10 code to identify the patients and outcomes, so it may sufer from coding errors.However, the procedure code was used to recognize our cohort, and we expect the errors in the coding to be negligible.Meanwhile, our study cannot calculate the Society of Toracic Surgeons (STS) score.However, in our study, we found that the TMVR group had a high burden of comorbidity; it refects the current guideline that TMVR patients are at intermediate or high surgical risk.Whether the STS score can be an indicator of patient prognosis factor is unclear.
Meanwhile, the RCT study should be conducted to analyze whether there is a diference between TMVR and SMVR in intermediate or high surgical risk patients in the future.Second, although we performed subgroup analyses based on diferent MR causes, including rheumatic heart disease, congenital valvular heart disease, and mitral valve prolapse, other causes including the search for secondary mitral regurgitation due to enlargement cannot be analyzed.Meanwhile, we also can get the echocardiography data (including the efective aortic valve orifce area, ejection fraction, pulmonary artery pressure, left ventricular diameter, left ventricular end-diastolic volume, and MR degree).Tese unmeasured factors may infuence the results of the analysis as confounding factors.
Tird, our study is a retrospective analysis with the inherent disadvantages of retrospective analysis.However, randomized grouping cannot be done as in randomized controlled studies although we used propensity score matching to reduce the diference between the two groups.
Fourth, the NRD database does not include emergency and out-of-hospital deaths.It can only count patients admitted to the hospital in the same state.However, we expect such readmissions to be uncommon in patients undergoing aortic valve replacement.Meanwhile, we used the ICD-10 code to identify outcomes, like others studies used [27,28].Te possibility exists that some patients were coded incorrectly; however, the frequency of a given outcome being miscoded is similar in a particular group.Te strength of this study is the large sample and the multicenter retrospective study.

. Conclusion
We report real-world data on in-hospital outcomes of TMVR and SMVR in AF patient.Te number of AF undergoing TMVR was increasing.We also found that the incidence of in-hospital mortality and sepsis decreased but the 30-day all-cause readmission remained stable.LOS >5 days, cerebrovascular disease, urgent/emergent admission, prior stroke, and smoke were considered as risk factors for in-hospital mortality; female, chronic pulmonary disease, and renal disease were considered as risk factors for 30-day readmission.After matching, TMVR had a low risk in hospital death, transfusion, acute kidney injury, sepsis, stroke, and mechanical ventilation.However, TMVR had a similar 30-day all-cause readmission incidence compared to SMVR in AF patients.

4. 4 .
Outcomes in Matching Cohort.Te variables used in the matching model are shown in the Supplementary Table
4.1.Population Characteristics and Outcomes.Tere were 26,037 patients of TMVR and 45,619 patients of SMVR performed in the NRD between 2016 and 2019.After screening, we fnally included 9,195 patients of TMVR and 16,972 patients of SMVR. Figure

Table 1 :
Baseline characteristics for SMVR versus TMVR in patients with AF in unmatched and matched cohorts.
Normally distributed continuous variables expressed as the mean value ± standard deviation and categorical variables were expressed as percentages.AF: atrial fbrillation; SMVR: surgical mitral valve repair; TMVR, transcatheter mitral valve repair; PPM: permanent pacemaker implant; ICD:

Table 2 :
Early outcomes of AF patients undergoing TMVR between 2016 and 2019.

Table 3 :
Early outcomes of AF patients undergoing SMVR between 2016 and 2019.

Table 4 :
Factors associated with in-hospital death undergoing TMVR.

Table 6 :
In-hospital and 30-day outcomes for SMVR versus TMVR in patients with AF in unmatched and matched cohorts.

Table 7 :
In-hospital outcomes in SMVR versus TMVR in atrial fbrillation in the propensity score matched cohort.

Table 8 :
In-hospital outcomes in SMVR versus TMVR in paroxysmal AF in the propensity score matched cohort.

Table 9 :
In-hospital outcomes in SMVR versus TMVR in nonparoxysmal AF in the propensity score matched cohort.

Table 10 :
In-hospital outcomes in SMVR versus TMVR in the propensity score matched cohort with diferent etiologies of mitral regurgitation.