Effects of β-blockers therapy on the 28-day and 3-year survival rates of end-stage renal disease patients with cardiovascular disease: a retrospective cohort study

Introduction

End-stage renal disease (ESRD) refers to a permanent decline in kidney function (1). Cardiovascular diseases (CVDs) are often prevalent in ESRD patients due to the use of dialysis and the shared pathological mechanism and risk factors (2). Approximately 40% of ESRD patients die due to arrhythmias or sudden cardiac death (3). It is estimated that ESRD patients with CVDs experience a high morbidity rate of up to 50% (4), and the relative risk of death is approximately 20 times higher than that of the general population (5). Thus, it is vital to examine therapeutic options for patients with ESRD complicated with CVD.

To date, β-blockers have been recommended in the treatment of ESRD patients (6). In the study of Lin et al., they pointed out that β-blockers have a protective effect on atrial fibrillation in ESRD patients (6). Not only that, β-blockers have also been widely used to treat CVD patients for more than 50 years, due to their role in reducing mortality and morbidity, hypertension (7), sudden cardiac death (8), and heart failure (9,10), and for the secondary prevention of coronary heart disease (11,12). Kotecha et al. conducted a meta-analysis of kidney disease patients with CVDs and found that β-blockers reduced the mortality of moderate stage chronic kidney disease patients with heart failure with preserved ejection fraction (HFrEF) (13). Compared to placebos, β-blockers have been proven to significantly reduce all-cause mortality by 15% and cardiovascular death/heart failure hospitalization by 13% in ESRD patients with HFrEF (13). However, due to the exclusion of ESRD patients with CVDs from many clinical trials, the effects of β-blockers on ESRD patients with CVDs have not been fully investigated. Additionally, β-blockers have been reported to have a potential protective effect for patients during critical illness requiring intensive care (14,15). This may be related to the fact that β-blockers have many beneficial immunomodulatory effects and might improve the prognosis of intensive care unit (ICU) patients (14,15).

In this study, data from the Medical Information Mark for Intensive Care III (MIMIC III) database were collected to investigate the potential association between β-blockers therapy and the short- and long-term survival rates of ESRD patients with CVD who had been admitted to the ICU. We hypothesized that patients with ESRD and CVD who were admitted to the ICU and received beta-blockers were associated with improved 28-day and 3-year survival rates. Our findings may provide a theoretical basis for clinical applications of β-blockers therapy in such patients. We present the following article in accordance with the STROBE reporting checklist (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5317/rc).

Methods

Data sources and study design

All the data in this retrospective cohort study were obtained from the MIMIC III database (16). The MIMIC III database contains the information of 46,520 patients admitted to various ICUs of the Beth Israel Deaconess Medical Center (BIDMC) in Boston from 2001 to 2012, and includes data on patients’ demographics, vital signs, laboratory tests, fluid balance, and survival status. A local ethics committee’s approval was not required for this study, as the disease information of the patients were publicly available, and all the individual information in the database had been anonymized.

To be eligible for this study, patients had to meet the following inclusion criteria: (I) aged ≥20 years; (II) have ESRD; (III) have CVD; (IV) admitted to the ICU; (V) have mortality information. The International Classification of Diseases 9th revision (ICD‐9) of ESRD were: 40301, 40311, 40391, 40403, 40413, 40492, 40493, 5856. The CVDs included congestive heart failure, cardiac dysrhythmia, angina, and myocardial infarction. The following disease codes of the ICD‐9 were used: heart failure congestive = 4280; cardiac dysrhythmia = 42789, 4279; angina = 4130-4131, 4139; myocardial infarction = 41000-41002, 41010-41012, 41020-41022, 41030-41032, 41040-41042, 41050-41052, 41060-41062, 41070-41072, 41080-41080, and 41090-41092. Patients were excluded from the study if they met any of the following exclusion criteria: (I) had received a kidney transplant; (II) had incomplete baseline data. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Exposure

We extracted information from the MIMIC III database about whether patients were using β-blockers or not. Patients were distributed to 2 groups depending on whether they received β-blockers therapy: β-blockers therapy group and non-β-blockers therapy group.

Outcomes and follow-up

The outcomes of this study were the short- and long-term survival rates of ESRD patients with CVD, defined as the 28-day and 3-year survival rates of the patients, respectively. Death information of all patients from the MIMIC III database was recorded through the social security account, and the starting time of follow-up was admission to the ICU, and the end point of follow-up was 28-day or 3-year death after admission to the ICU.

Data collection

The following data were extracted (6,15,17)—age, gender, race, diabetes, hypertension, hyperlipidemia, renal replacement treatment (RRT), simplified acute physiological score II (SAPS II), sequential organ failure assessment (SOFA) score, dialysis, use of statins, glucocorticoids and mycophenolate mofetil (MMF), transferrin, hemoglobin, blood urea nitrogen (BUN), creatinine, and 28-day and 3-year survival status.

Statistical analysis

All the statistical analyses were performed in SAS 9.4 (SAS Institute, Cary, NC, USA) and SPSS 24.0 (IBM Corp., Armonk, NY, USA). The categorical data are presented as the number of cases and percentages, and the χ² test or Fisher’s exact test were used for the intergroup comparisons. The measurement data with normal distribution data are described as mean and standard deviation (mean ± SD), and the t-test was used for the intergroup comparisons. Non-normal measurement data are described as median and interquartile range (IQR), and the comparison between groups was performed by Mann-Whitney U test.

We performed univariate analysis (see Tables S1,S2) to select the potential covariates (P<0.05). A multivariate Cox regression analysis was conducted to explore the effects of β-blockers therapy on the 28-day and 3-year survival rates of ESRD patients with CVD. In addition, subgroup analysis was performed to examine the association between β-blockers therapy and the 28-day and 3-year survival rates in patients stratified by age and gender. A total of 3 models were used for the covariate adjustment: Model 1 was the crude model; Model 2 adjusted for age and gender. Given the small sample size and number of outcomes, the inclusion of too many covariates could lead to model instability and over fitting. Thus, for Model 3, we conducted a stepwise regression to screen the variables that had statistically significant differences in the univariate analysis (P<0.05) Model 3 adjusted for age, race, hyperlipidemia, dialysis, SAPS II, SOFA score, glucocorticoid, hemoglobin, diabetes, hypertension for the outcome of 28-day survival, and adjusted for age, race, hyperlipidemia, dialysis, SAPS II, SOFA score, glucocorticoid, hemoglobin, diabetes, hypertension, creatinine for the outcome of 3-year survival. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. The missing values were deleted in this study due to the proportion of missing values more than 30%. We also performed the sensitivity analysis before and after deletion of missing values (Table S3). The survival curves were presented using the Kaplan-Meier method and estimated by the means method for covariates. The statistical significance levels were all 2-sided. A P value <0.05 was considered statistically significant.

Results

Baseline characteristics

A total of 1,921 ESRD patients were initially obtained from the MIMIC III database. After excluding 676 patients without CVD, 58 patients who had received a kidney transplant, 31 patients were not admitted to the ICU, and 75 patients with missing baseline data, 1,081 participants were ultimately included in the study, of whom, 248 (22.9%) were treated with β-blockers. The flowchart for patient selection is shown in Figure 1. The mean and SD age of the patients was 68 years, and 642 (59.4%) were male. In relation to race distribution, 678 (62.7%) were white, 215 (19.9%) were black, 22 (2.0%) were Asian, and 43 (4.0%) were Hispanic. There were more patients with hyperlipidemia (47.9% vs. 30.73%) and those who underwent dialysis (83.1% vs. 62.6%) in the β-blockers therapy group compared with the non-β-blockers therapy group. The SAPS II (45.5±13.4 vs. 42.5±13.2) and SOFA scores [7 (IQR, 5–10) vs. 6 (IQR, 4–9)] of the patients in the β-blockers therapy group were higher than those of patients in the non-β-blockers therapy group. The baseline characteristics of the patients are detailed in Table 1.

Figure 1 Flowchart for the selection of the ESRD patients with CVD. ESRD, end-stage renal disease; CVD, cardiovascular disease; ICU, intensive care unit.

During the 28 days of ICU hospitalization, 895 (82.8%) patients survived, and the patients had a mean inpatient hospital stay of 24.7 days. At 3 years, 410 (37.9%) patients survived, and the patients had a median survival time of 489.2 days.

Short-term (28-day) survival rate

A total of 220 (88.7%) and 675 (81.0%) patients in the β-blockers and non-β-blockers therapy groups survived to 28 days. The patients who received β-blockers therapy had a higher 28-day survival rate than those who did not (Model 1: HR =0.56, 95% CI: 0.38–0.84). In adjusted analyses, patients with β-blockers therapy had a better short-term survival rate than those who did not (Model 2: HR =0.56, 95% CI: 0.37–0.83, P=0.004; Model 3: HR =0.51, 95% CI: 0.33–0.77, P=0.001). The results of the multivariate Cox regression analysis are shown in Table 2, and cumulative incidence and Kaplan-Meier survival curves are shown in Figures 2,3.

Figure 2 Comparison of 3-year cumulative incidence curves among ESRD patients with CVD who did or did not receive β-blocker therapy. Model 1: crude model; Model 2: adjusted for age and gender; Model 3: adjusted for age, race, hyperlipidemia, dialysis, simplified acute physiological score II, sequential organ failure assessment, glucocorticoid, hemoglobin, diabetes, hypertension and creatinine for the outcome of 28-day survival; Model 3: adjusted for age, race, hyperlipidemia, dialysis, simplified acute physiological score II, sequential organ failure assessment, glucocorticoid, hemoglobin, diabetes, hypertension and creatinine for the outcome of 3-year survival. ESRD, end-stage renal disease; CVD, cardiovascular disease.

Figure 3 The Kaplan-Meier curves of (A) the 28-day survival rate; (B) the 3-year survival rate of the ESRD patients with CVD. ESRD, end-stage renal disease; CVD, cardiovascular disease.

Long-term (3-year) survival rate

A total of 115 (46.4%) and 295 (35.4%) patients in the β-blockers and non-β-blockers therapy groups survived to 3 years. The crude model showed that the patients treated with β-blockers therapy had a higher 3-year survival rate than the untreated patients (Model 1: HR =0.77, 95% CI: 0.64–0.94). In adjusted analyses, the patients who received β-blockers therapy also had a higher long-term survival rate than those who did not (Model 2: HR =0.76, 95% CI: 0.63–0.92, P=0.005; Model 3: HR =0.71, 95% CI: 0.57–0.90, P=0.004). The multivariate Cox regression analysis results are shown in Table 2, and cumulative incidence and Kaplan-Meier survival curves are shown in Figures 2,3.

Subgroup or exploratory analysis

Additionally, we examined the association of β-blockers therapy and short-term, long-term survival rate based on the subgroup analysis of age and gender (Table 3). In adjusted analyses, male patients with β-blockers therapy had a better short-term and long-term survival rate than those who did not (short-term: HR =0.50, 95% CI: 0.30–0.82, P=0.007; long-term: HR =0.73, 95% CI: 0.55–0.98, P=0.038). β-blockers therapy was associated with improved long-term survival rates among female patients (HR =0.67, 95% CI: 0.46–0.98, P=0.037), but not statistically different from short-term survival (HR =0.51, 95% CI: 0.24–1.10, P=0.085). For patients with younger than 65 years, β-blockers therapy was associated with improved short-term and long-term survival rates (short-term: HR =0.20, 95% CI: 0.07–0.60, P=0.004; long-term: HR =0.52, 95% CI: 0.33–0.81, P=0.004); β-blockers therapy was positively related to short-term survival rates for patients with more than 65 years (HR =0.60, 95% CI: 0.38–0.96, P=0.032), but there was no statistically difference in β-blockers therapy and long-term survival (HR =0.78, 95% CI: 0.60–1.03, P=0.076).

Discussion

This study explored the association between β-blockers therapy and the short- and long-term survival of ESRD patients with CVD who were admitted to the ICU, and our results indicated that β-blockers therapy was associated with improved 28-day and 3-year survival rates. In addition, we also found that male patients with β-blockers therapy was related to short-term and long-term survival rates. Among patients younger than 65 years, β-blocker treatment was significantly associated with 3-year survival rates. This finding may provide a theoretical basis for the clinical application of β-blockers therapy in such patients.

A meta-analysis had shown that β-blockers seem to be associated with reduced mortality in patients on dialysis (17). Berger et al. found that β-blocker therapy was associated with a 22% lower mortality rate among ESRD patients with acute myocardial infarction after adjusting for baseline variables (18). Additionally, Pun et al. showed that among the 43,000 outpatients treated with hemodialysis, 729 of suffered cardiac arrest, and the presence of a β-blocker prescription was associated with increased survival at 24 h and 6 months, and there was a positive correlation between the exposure dose and survival (19). Similarly, this study indicated that β-blockers increased the short- and long-term survival rates of ESRD patients with CVD during critical illness requiring intensive care.

Specific to ICU patients, β-blocker may treat different types of CVD and reduce the risk of myocardial reinfarction and its associated mortality (20). Macchia et al. have concluded that β-blockers may be related to a survival advantage for patients who subsequently develop sepsis with organ dysfunction and are admitted to the ICU (21). These findings have suggested a benefit of β-blocker use in ICU patients. Critical illness may also lead to activation of the sympathetic nervous system, which plays a vital role in CVDs in ESRD patients (22). Sympathetic nerve over-activation has been reported to be associated with various CVDs, such as left ventricular hypertrophy (23,24), arrhythmia (25), and poor survival among patients with heart failure (26,27). Due to associations between sympathetic nerve over-activation and CVDs and ESRD, consideration needs to be given to treatments directed at minimizing the effects of sympathetic nerve over-activation in ESRD patients with CVD. Further, β-blockers have been confirmed to weaken the sympathetic overactivity that links kidney disease with cardiovascular sequelae (28,29), which may explain why β-blockers improved the short- and long-term survival rates of the ESRD patients with CVD admitted to the ICU in this study.

Studies on the treatment of ESRD patients with CVD admitted to the ICU are limited. The strengths of the present study: firstly, the inclusion of the varied ethnic representation and the detailed information available in the MIMIC III database. Secondly, complete long-term follow up data was available. However, this study also had several limitations. We were unable to obtain details of the specific β-blockers regimens from the MIMIC III database, which hindered our ability to further examine the effects of dose, duration and timing of β-blockers therapy on the survival of the ESRD patients with CVD. We also were unable to obtain information on how drug adherence the β-blockers during the 3-year follow-up period. Finally, there were missing information about potential confounders such as history of anticoagulant and antithrombotic drug use, the cause of ICU admission, or smoking status. We were also unable to draw further conclusions about the cause of death as this was not available.

Conclusions

β-blocker therapy was associated with increased 28-day and 3-year survival rates of ESRD patients with pre-existing CVD and who were admitted to ICU. Our findings may provide a theoretical basis for the clinical application of β-blocker treatment in such patients. However, randomized control trials need to be conducted to further investigate and confirm the efficacy of β-blocker treatment on ESRD patients with CVD.

Acknowledgments

The authors appreciate the academic support from AME Critical Care Collaborative Group.

Funding: This research was supported by Shanghai 2021 annual “Science and Technology Innovation Action Plan” Natural Science Foundation Project (No. 21ZR1459400) and Shanghai 2019–2022 Annual Medical Key Disciplines (Class A) Project of Yangpu District (No. YP19ZA07).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://atm.amegroups.com/article/view/10.21037/atm-22-5317/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-5317/coif). CD received travel support from Nestlè Italia. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Huleatt)