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Surgical Aortic Valve Replacement for Aortic Stenosis in Dialysis Patients ― Analysis of Japan Cardiovascular Surgery Database ―

Background: Perioperative risk during surgical aortic valve replacement (SAVR) is reportedly high in dialysis patients. We aimed to determine the postoperative mortality and morbidity and identify the perioperative risk factors of mortality during SAVR in dialysis-dependent patients. Methods and Results: From the Japan Adult Cardiovascular Surgery Database, we compared 2,875 dialysis-dependent patients with 18,839 non-dialysis patients who all underwent SAVR between January 2013 and December 2016. The operative mortality was 8.7% vs. 2.0% in the dialysis and non-dialysis groups, respectively. Multivariate stepwise logistic regression analysis for operative mortality revealed 8 independent risk factors including age (odds ratio [OR]=1.2), concomitant coronary artery bypass grafting (OR=1.5), peripheral arterial disease (OR=1.9), atrial fibrillation (OR=2.5), New York Heart Association class IV (OR=2.5), liver dysfunction (OR=5.8), reduced left ventricular function (OR=1.4), and history of previous cardiac surgery (OR=2.1). In addition, 8 postoperative predictors of operative mortality were identified including bleeding deep sternal infection (OR=3.4), prolonged ventilation (OR=5.4) and gastrointestinal complications (OR=10.3). Conclusions: Compared with non-dialysis patients, SAVR in dialysis patients was associated with high rates of mortality and morbidity. An appropriate surgical strategy and careful perioperative assessment and management for prevention of infection, and respiratory and gastrointestinal complications might contribute to improved clinical outcomes after SAVR in these patients. Stability the relationship between operative death and postoperative complications conducted a multivariate stepwise regression model and P<0.2 for operative mortality including postoperative for each In clinical and association interquartile range. We examined differences between 2 groups (SAVR with and without dialysis) using bivariate tests: Fisher’s exact test and the Pearson’s chi-square test for categorical covariates, and the unpaired t-test or Wilcoxon rank sum test for continuous covariates. To investigate the risk factors of SAVR with dialysis, we conducted a multivariate stepwise logistic regression model (P>0.25 for removal, and P<0.2 for entry) for operative mortality including the following

dependent patients has been established to date. [3][4][5] In the past few decades, various studies have reported the clinical outcomes of cardiac surgery in dialysis-dependent patients, but almost all have been from single centers or with relatively small cohorts. 6-8 Moreover, we found few large-scale studies that focused on SAVR in dialysisdependent patients and included multivariate analysis of perioperative risk factors of operative mortality, which has been reported from the USA 2 but does not refer to the effect of postoperative complications on mortality. Therefore, in the present study we examined 21,714 SAVR patients with or without concomitant CABG, including 2,875 dialysis-dependent patients registered in the Japan Adult Cardiovascular Surgery Database (JCVSD) between 2013 and 2016 to determine the contemporary clinical outcomes of SAVR and the pre-and postoperative risk factors for perioperative death following SAVR in patients A ortic stenosis (AS) occurs frequently in patients with chronic renal failure (CRF) and is a major cause of mortality and morbidity in these patients, who often need surgical intervention. Surgical aortic valve replacement (SAVR) has been reported as having satisfactory survival rates in patients with kidney disease; 1 however, the operative mortality and morbidity rates for SAVR are reportedly high compared with those for non-dialysis patients. 2 Therefore, an appropriate surgical strategy and perioperative medical treatment based on identification of perioperative risk factors would lead to an improvement in the clinical outcomes of these surgical procedures. To date, transcatheter aortic valve replacement (TAVR) has shown excellent short-and mid-term clinical outcomes in patients with comorbidities and TAVR is expected to improve the clinical outcome of AVR for dialysis-dependent patients although no algorithm for SAVR or TAVR in dialysis-YAMAUCHI T et al.
hospital electronically submits the data to the central office. The JCVSD Review Board approved the present study.
We examined 21,714 cases of elective SAVR for AS with or without CABG registered in this database between January 1, 2013 and December 31, 2016. Exclusion criteria were as follows: urgent/emergency/salvage surgery, concomitant cardiac surgery other than CABG, aortic regurgitation dominant (grade 3 or 4), rheumatic heart disease, active infective endocarditis, annular abscess, graft infection, Marfan syndrome, aortitis, Behcet's disease, and previous AVR (mechanical or bioprosthesis). Records with missing data or out of range data for age, sex, or 30-day status (see Endpoints section below) were also excluded. After data cleaning, the population for investigating risk factors in the mortality analysis consisted of 21,714 patients.

Statistical Analysis
Descriptive statistics are presented as frequencies with percentage for categorical variables or as median value with with dialysis-dependent CRF in Japan. We hope the data in the present study will contribute to the establishment of an algorithm for SAVR or TAVR in dialysis-dependent patients.

Study Population
The JCVSD was initiated in 2000 to collate the outcomes after cardiovascular procedures in many centers throughout Japan. 9 The JCVSD adult cardiovascular division currently captures clinical information from nearly half of all Japanese hospitals performing cardiovascular surgery. The data collection form has approximately 300 variables (definitions are available online at http://www.jacvsd.umin.jp), and these are almost identical to those in the Society of Thoracic Surgeons (STS) National Database (definitions are available online at http://sts.org). The JCVSD has developed software for a web-based data collection system through which the data manager of each participating

Relationship Between Operative Mortality and Postoperative Complications
Results are summarized in Table 5. Among the complications observed relatively often (incidence >3%), the follow-

Clinical Background and Outcome of SAVR in Dialysis Patients
The clinical outcomes of SAVR, including hemodialysis and/or peritoneal dialysis-dependent patients, have been reported. 6-8 In the present study, the exact number of hemodialysis patients was unclear because the JCVSD does not distinguish between hemodialysis-and peritoneal dialysis-dependent patients among those requiring dialysis. The annual dialysis data report from Japan has revealed that peritoneal dialysis-dependent patients comprised 2.7% (9,021/329,609) of chronic dialysis patients in 2016. 10 The operative mortality rate of dialysis patients after SAVR in this study was 8.7%, which was similar to previous studies reporting an operative mortality of approximately 10%. 2,6-8, 11 The postoperative mortality rate of the dialysis group was 3-4fold higher than that in the non-dialysis group. Interestingly, the mortality rate of TAVR has been reported to be also around 10%. 3,12 As previously reported, dialysis patients have more preoperative comorbidities. 2, 13 Com-between complications, 11 complications (reoperation for bleeding, stroke, perioperative myocardium infarction, cardiac block, cardiac arrest, anticoagulation-related complication (bleeding and thromboembolism), tamponade, gastrointestinal complication, AF, deep sternal infection, prolonged ventilation) were used in the current analysis.
All P values were 2-sided, and P<0.05 was considered statistically significant. All statistical analyses were conducted with STATA 15 software (Stata Corp., College Station, TX, USA).

Patients' Demographics
Baseline characteristics of the study population are summarized in Table 1. Patients in the dialysis group were significantly younger and had lower BMI than the non-dialysis patients. As expected, the dialysis-dependent patients had a significantly greater number of baseline comorbidities than did the non-dialysis patients. Patients in the dialysis group were more likely to have a history of diabetes (42.7% vs. 30.8%; P<0.0001), and PAD (20.1% vs. 7.4%; P<0.0001). A higher rate of current congestive heart failure (40.9% vs. 35.5%; P<0.0001) with a lower EF and lower NYHA status was observed in the dialysis group. As for coronary artery disease (CAD), coronary stenosis (≥2 vessels: 29.3% vs. 18.6%; P<0.0001) and LMT disease (7.6% vs. 5.4%; P<0.0001) were more common in dialysis patients.

Postoperative Outcomes
Transfusion and concomitant CABG were required more often in the dialysis group. Operation time, extracorporeal time and cardiac arrest time were also significantly longer in the dialysis group. In the dialysis group, a mechanical valve was significantly applied compared with the nondialysis group (30.1% vs. 11.9%; P<0.0001) ( Table 2). Inhospital outcomes are summarized in Table 3. The 30-day mortality rate was 5.1% vs. 1.2% (P<0.0001) and the operative mortality rate was 8.7% vs. 2.0% (P<0.0001) in the dialysis and non-dialysis groups, respectively. Both the  Abbreviations as in Tables 1,4.
improving the clinical outcome of SAVR in dialysis patients complicated with CAD. Concomitant CABG should be performed with consideration of the "risks and benefits" and further study will be necessary to elucidate this important issue. Aljohani et al also show that in-hospital mortality after SAVR in dialysis patients remained 2fold higher than in non-dialysis patients in propensity-matched cohorts, 2 suggesting the presence of unrevealed risk factors that affect the mortality rate of SAVR in dialysis patients. Further study is necessary to investigate such risk factors (e.g., porcelain aorta or duration of dialysis) in order to establish benchmarks for selecting the operative procedure (SAVR or TAVR) for these patients.

Effect of Postoperative Complications on Mortality Rate of SAVR in Dialysis-Dependent Patients
Relatively few large-series reports have documented the detailed incidence of postoperative morbidity after SAVR in dialysis-dependent patients. 2 Compared with non-dialysis patients, the incidence of major postoperative complications was high in the dialysis-dependent patients in the present study, as previously reported. 2,13 Postoperative complications could be considered to be closely associated with higher mortality rate. The higher incidence of these complications in dialysis-dependent patients might partly explain their poor clinical outcomes. However, the effect of each complication on mortality after SAVR in dialysisdependent patients has never been demonstrated as far as we know. We have previously reported the effect of postoperative complications on mortality after CABG in 1,300 dialysis-dependent patients, such as stroke (OR=9.85), infection (OR=6.72), prolonged ventilation (OR=3.82), pneumonia (OR=13.15), gastrointestinal complication (OR=5.43) and heart block (OR=12.46). 13 To improve the clinical outcome of SAVR in dialysis patients, it seems important to prevent the 7 complications demonstrated in the present study.

Study Limitations
Frailty and intraoperative values were not evaluated in our study. Some specific factors that may affect the operative results, such as porcelain aorta or small aortic annulus, were not included in the possible factors.

Conclusions
Compared with non-dialysis patients, SAVR in dialysis patients was associated with high rates of mortality and morbidity in the present study. An appropriate surgical strategy and careful perioperative assessment and management for infection, and prevention of respiratory and gastrointestinal complications might contribute to improvements in clinical outcomes after SAVR in dialysis-dependent patients.

Acknowledgments
The authors thank the data managers in each cardiovascular institute participating in the JCVSD for their great effort in registering clinical data, and Shinichi Takamoto who contributed to the establishment of JCVSD. Hiroyuki Yamamoto, and Hiroaki Miyata are affiliated with the Department of Healthcare Quality Assessment at the University of Tokyo. The department is a social collaboration department supported by grants from the National Clinical Database, Johnson & Johnson K.K., and Nipro Co. pared with the clinical outcomes of 2,264 dialysis-dependent patients undergoing SAVR from the National Inpatient Sample from 2005 to 2014, 2 in the present study the rates of hypertension, chronic lung disease, liver disease and AF tended to be low. Sex, DM, PAD, and history of cardiac surgery were comparable. Major postoperative morbidity (stroke, tamponade) was also comparable. Besides the major complications, the prevalence of transient ischemic attack, coma, cardiac arrest, anticoagulant complication, gastrointestinal complications and intensive care unit stay in dialysis patients were also significantly higher than in non-dialysis patients.

Risk Factors of Mortality of SAVR in Dialysis-Dependent Patients
Aljohani et al analyzed 2,264 dialysis patients who underwent SAVR that included valve surgery. They demonstrated male sex, age >75 years, cardiogenic shock, PAD, liver disease, concomitant surgery, intra-aortic balloon pumping/LV assist device as risk factors for perioperative mortality in dialysis-dependent patients, 2 which is almost consistent with our findings.
Among the relatively frequent preoperative comorbidities in the dialysis patients, we also showed that PAD (OR=1.9) and AF (OR=2.5) were strong independent risk factors for mortality. We have previously shown that PAD was an independent risk factor for death among 13,961 patients (including 1,542 (11%) dialysis-dependent patients) undergoing SAVR for AS (OR=2.15). 13 Kim et al also demonstrated that PAD was associated with a higher incidence of major postoperative vascular complications with higher 30-day mortality and PAD was identified as an independent predictor of 1-year mortality after TAVR. 14 PAD might represent the systemic severity of atherosclerotic changes associated with a higher incidence of postoperative major complications and mortality. PAD might be a "troublesome" comorbidity for both SAVR and TAVR.
Regarding AF, it has been reported as a common morbidity in dialysis-dependent patients. 15 The prevalence of AF in the present study was higher among the dialysis-dependent patients than the non-dialysis patients. Interestingly, our abovementioned previous report also demonstrated that AF was an independent risk factor of death (OR=2.08). 16 The STS risk calculator uses the prevalence of AF for risk analysis of isolated AVR. The mechanism by which AF shows an adverse effect on mortality after SAVR remains unclear. AF in patients with reduced LV function has been reported to show an adverse effect on the survival rate. 17 AF might be also associated with perioperative stroke, which increases the postoperative morbidity and mortality.
We also demonstrated that concomitant CABG was an independent risk factor for operative mortality after SAVR in dialysis patients (OR=1.5). The question arises whether CABG should be performed simultaneously with SAVR when coronary disease is complicated. Horst et al report that the risk for perioperative death associated with CABG combined with valve operation is approximately 10-fold that for isolated CABG. 6 Nicolini et al report that valve surgery combined with CABG increases the late mortality rate. 8 The worse operative morbidity in dialysis patients compared with non-dialysis patients might be partially attributed to coronary disease being more severe and concomitant CABG therefore being performed more frequently in dialysis patients (39.0% vs. 26.7%, P<0.0001). Percutaneous coronary intervention might contribute to