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10.1080/0886022X.2024.2398189
2398189
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Research Article
Critical Care Nephrology and Continuous Kidney Replacement Therapy
Association of ACEI/ARB therapy with total and cardiovascular death in coronary artery disease patients with advanced chronic kidney disease: a large multi-center longitudinal study
W. Lai et al.
Running Head: Acei/Arb Therapy and Cad Patients with Advanced Ckd
Lai Wenguang a*
Zhao Xiaoli b*
Zhang Tingting a*
Huang Donghui a
Liang Guoxiao cd
Zhou Yang cd
Liu Jin cd
Chen Shiqun cd
Liu Yong cd
a Heyuan People’s Hospital, Guangdong Provincial People’s Hospital, Heyuan Hospital, Heyuan, China
b Department of Cardiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
c Department of Cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
d Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
* These authors contributed equally to this work.

Supplemental data for this article can be accessed online at https://doi.org/10.1080/0886022X.2024.2398189.

CONTACT Jin Liu ljaw397017568@163.com
Shiqun Chen shiqunchen@126.com
Yong Liu liuyong@gdph.org.cn Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
4 9 2024
2024
4 9 2024
46 2 239818924 4 2024
25 6 2024
25 8 2024
KnowledgeWorks Global Ltd.30 8 2024
published online in a building issue30 8 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
The Author(s)
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Abstract

Introduction

Advanced chronic kidney disease (CKD) is common among patients with coronary artery disease (CAD), and angiotensin‑converting enzyme inhibitors (ACEI) or angiotensin‑receptor blockers (ARB) can improve cardiac and renal function, but whether ACEI/ARB therapy improves long-term prognosis remains unclear among these high-risk patients. Therefore, this research aimed to investigate the relationship between ACEI/ARB therapy and long-term prognosis among CAD patients with advanced CKD.

Methods

CAD patients with advanced CKD were included in five hospitals. Advanced CKD was defined as estimated glomerular filtration rate (eGFR)<30 ml/min per 1.73 m2. Cox regression models and competing risk Fine and Gray models were used to examine the relationship between ACEI/ARB therapy and all-cause and cardiovascular death, respectively.

Results

Of 2527 patients, 47.6% population of our cohort was discharged on ACEI/ARB. The overall all-cause and cardiovascular mortality were 38.6% and 24.7%, respectively. Multivariate Cox regression analyses indicated that ACEI/ARB therapy was found to be associated with lower rates of both all-cause mortality (hazard ratio (HR)=0.836, 95% confidence interval (CI): 0.738–0.948, p = 0.005) and cardiovascular mortality (HR = 0.817, 95%CI: 0.699–0.956, p = 0.011). In the propensity-matched cohort, the survival benefit was consistent, and significantly better survival was observed for all-cause mortality (HR = 0.856, 95%CI: 0.752–0.974, p = 0.019) and cardiovascular mortality (HR = 0.830, 95%CI: 0.707–0.974, p = 0.023) among patients treated with ACEI/ARB.

Conclusion

ACEI/ARB therapy showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up, which manifested that strategies to maintain ACEI/ARB treatment may improve clinical outcomes among these high-risk populations.

STUDY HIGHLIGHTS

What is the current knowledge on the topic?

Advanced CKD is highly prevalent and strongly associated with higher mortality risk and worse outcomes among CAD patients, and patients with advanced CKD have often been excluded from randomized controlled trials, creating an evidence gap for these high-risk CAD patients. ACEI/ARB are beneficial for greater survival among CAD patients, but the effect of ACEI/ARB therapy on long-term prognosis is unclear among CAD patients with advanced CKD.

What does this study add to our knowledge?

ACEI/ARB treatment showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up.

How might this change clinical pharmacology or translational science?

CAD patients with advanced CKD are not only have worse outcomes but also limited in their choice of therapy strategies. Our study may prompt an important reference for the subsequent improvement of long-term prognosis among these high-risk populations.

Keywords

Coronary artery disease
advanced chronic kidney disease
mortality
angiotensin-converting enzyme inhibitors
angiotensin receptor blockers
Guangdong Provincial science and technology 2020B1111170011 Guangdong Provincial science and technology KJ022021049 National Science Foundation for Young Scientist of China 82070360 This research was funded and supported by Guangdong Medical Science and Technology Research Foundation (A2024142); Guangdong Provincial science and technology project (2020B1111170011); Guangdong Provincial science and technology project (KJ022021049).
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pmcIntroduction

Numerous risk factors are related to coronary artery disease (CAD), of which renal dysfunction and proteinuria[1] are both common and of particular importance due to their impact on mortality [2]. Impaired renal function is independently associated with poor prognosis, especially for stage 4 - 5 chronic kidney disease (CKD) [3,4]. Although common in clinical practice, patients with advanced CKD have often been excluded from randomized controlled trials, creating an evidence gap for these high-risk CAD patients [5,6].

Randomized clinical trials have shown that angiotensin‑converting enzyme inhibitors (ACEI) or angiotensin‑receptor blockers (ARB) is beneficial for greater survival among CAD patients [7–9]. However, there is still insufficient clinical evidence as to whether ACEI/ARB therapy should be used in CAD patients with advanced CKD (estimated glomerular filtration rates (eGFR) <30 mL/min/1.73m2). Importantly, the renal function of these patients may further decline [10,11]. In addition, ACEI/ARB treatment can also potentially cause acute kidney injury (AKI) and hyperkalemia, which are more common among subjects with renal insufficiency, preventing clinicians from treating them with these drugs [12,13]. However, recent research revealed that ACEI/ARB administration for any indication was related to greater survival among non-dialysis-dependent patients with CKD [14]. Previous multicenter randomized controlled trial, that assigned patients with advanced CKD either to discontinue or to continue therapy with ACEI/ARB, also indicated that the discontinuation of ACEI/ARB was not related to a significant between-group difference in the long-term rate of decrease in the eGFR among patients with advanced CKD [15,16]. Despite a gradual improvement in optimal medical therapy for CAD, there is still a gap between guidelines and practices in terms of using ACEI/ARB among CAD patients with advanced CKD.

Therefore, our research aimed to assess the association of ACEI/ARB therapy with long-term prognosis among CAD patients with advanced CKD.

Methods

Data sources and patient selection

Patients from five large tertiary hospitals were included in our research (Cardiorenal Improvement II, ClinicalTrials.gov NCT05050877) in China, during the period 2007–2020. 2527 CAD patients with advanced CKD on initial admission were included in the analysis. The exclusion criteria were as follows: a) patients missing information on ACEI or ARB; b) patients were discharged with medication for angiotensin receptor-neprilysin inhibitor; c) patients lacking survival information; d) patients aged < 18 years (Figure 1). The Ethics Committee of the Guangdong Provincial People’s Hospital approved the study (No.GDREC2019-555H-2). This research was conducted in accordance with the principles expressed in the Declaration of Helsinki.

Figure 1. Subgroup analyses of ACEI/ARB therapy on the risk of all-cause mortality in the whole cohort.

Data collection

All clinical data were extracted from the electronic clinical management system (ECMS). The collected baseline information included demographic characteristics, coexisting conditions, procedures, laboratory examinations, and medications at discharge. Survival information was obtained by cause-specific surveillance data at the regional Center for Disease Control and Prevention and public security system, recorded and matched with the ECMS.

Clinical definition and endpoint

The endpoints were all-cause and cardiovascular death (the median follow-up period was 3.0 years (interquartile range: 1.4–5.6)). The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation [17], and advanced CKD was defined as eGFR <30mL/min/1.73m2 [18]. Anemia was defined as a hematocrit ≤ 39% for males or ≤ 36% for females. CAD is defined as stenosis above 50% in at least one main coronary vessel at coronary angiography, and the definition of CAD is consistent across all participating centers. Acute myocardial infarction (AMI), diabetes mellitus (DM), and hypertension (HT) were defined according to the 10th Revision Codes of the International Classification of Diseases (ICD-10).

Statistical analysis

For descriptive analysis, means ± standard deviations or median and interquartile ranges depending on the distribution of data for continuous variables and frequency and proportions for categorical variables were estimated. To reduce heterogeneity and selection bias, we undertook further sensitivity analyses matching on propensity scores using the following covariates: age, gender, acute myocardial infarction (AMI), atrial fibrillation (AF), hypertension (HT), diabetes (DM), chronic heart failure (CHF), anemia, stroke, chronic obstructive pulmonary disease (COPD), eGFR, left ventricular ejection fraction (LVEF), statins, β-blocker, calcium channel blockers (CCB), antiplatelet, and diuretics. A 1:1 nearest-neighbor matching was used. To estimate the balance of the baseline characteristics before and after propensity score matching (PSM), a standardized mean difference (SMD) was used, with SMD less than 0.1 indicating adequate balance between the groups [19].

Multivariable Cox proportional hazard models were developed to predict all-cause mortality. Patients with an unknown cause of mortality were excluded from analyses involving cardiovascular mortality, and the relationship between cardiovascular mortality and ACEI/ARB treatment was tested by competing risk Fine and Gray models. Two types of Cox models were performed: (a) in the whole cohort, the multivariable Cox model was adjusted according to age, gender, HT, DM, CHF, anemia, stroke, COPD, AMI, AF, eGFR, LVEF, statins, β-blocker, CCB, antiplatelet, and diuretics; The heterogeneity was assessed, and subgroup analyses according to dialysis, age, gender, HT, and DM were performed among whole cohort; (b) univariable Cox proportional hazards model stratified on PS matched cohort related to ACEI/ARB treatment. We used Kaplan-Meier survival analysis to generate plots for all-cause death by ACEI/ARB treatment in the matched cohort. To better visually depict the influence of the competing risk, we generated cumulative incidence function (CIF) curves for cardiovascular death, and Gray’s tests were used to assess differences for cardiovascular mortality.

All data processing and statistical analyses were conducted using the statistical software R version 4.0.3. All p values are two-sided, and p = 0.05 was considered the cutoff for statistical significance.

Results

Patient characteristics in the whole and propensity-matched cohorts

The final study population included 2527 CAD patients with advanced CKD, and 520 (20.6%) received dialysis treatment. A total of 1205(47.6%) patients were discharged with ACEI/ARB, of which 231(44.4%) patients in the dialysis group and 974 (48.5%) patients in the non-dialysis group received ACEI/ARB. The mean age of all the participants was 68.10 ± 10.59 years and 32.2% were women, and they had an average left ventricular ejection fraction (LVEF) of 52.33 ± 13.41, and eGFR of 17.37 ± 8.57. Characteristics of the cohort as stratified by the use of ACEI/ARB at discharge are described in Table 1. Patients with ACEI/ARB treatment were older, had a higher percentage of females, and were also less likely to have HT and DM.

Table 1. Baseline characteristics according to ACEI/ARB use in coronary artery disease patients with advanced CKD before and after propensity matching.

Characteristic	Before matching	 	 	After matching	 	 	
ACEI/ARB use	 	 	ACEI/ARB use	 	 	
No	Yes	p-value	SMD	No	Yes	p-value	SMD	
1322	1205	1090	1090	
Demographic characteristics	
Age, years	67.67 ± 10.75	68.57 ± 10.39	0.034	0.085	68.14 ± 10.59	68.35 ± 10.38	0.637	0.020	
Age > 60, n(%)	991 (75.0)	946 (78.5)	0.040	0.084	835 (76.6)	846 (77.6)	0.610	0.024	
Female, n (%)	373 (28.2)	441 (36.6)	<0.001	0.180	344 (31.6)	370 (33.9)	0.254	0.051	
Complication	
HT, n (%)	1026 (77.6)	996 (82.7)	0.002	0.127	895 (82.1)	894 (82.0)	1.000	0.002	
Anemia, n (%)	1054 (82.2)	883 (75.6)	<0.001	0.161	872 (80.0)	850 (78.0)	0.270	0.050	
AF, n (%)	90 (7.0)	90 (7.7)	0.564	0.026	75 (6.9)	76 (7.0)	1.000	0.004	
AMI, n (%)	449 (34.0)	365 (30.3)	0.053	0.079	350 (32.1)	341 (31.3)	0.713	0.018	
CHF, n (%)	526 (39.8)	489 (40.6)	0.715	0.016	439 (40.3)	443 (40.6)	0.896	0.007	
Stroke, n (%)	127 (9.6)	126 (10.5)	0.519	0.028	115 (10.6)	117 (10.7)	0.945	0.006	
DM, n (%)	726 (54.9)	742 (61.6)	0.001	0.135	636 (58.3)	660 (60.6)	0.316	0.045	
COPD, n (%)	52 (3.9)	45 (3.7)	0.876	0.010	45 (4.1)	43 (3.9)	0.913	0.009	
Operation	
PCI, n (%)	1040 (78.7)	913 (75.8)	0.091	0.069	850 (78.0)	838 (76.9)	0.573	0.026	
IABP, n (%)	88 (6.7)	62 (5.1)	0.128	0.064	71 (6.5)	60 (5.5)	0.367	0.042	
Physical examination	
eGFR, mL/min/1.73m2	16.80 ± 8.18	18.24 ± 8.80	0.023	0.287	16.84 ± 8.12	17.20 ± 8.84	0.175	0.027	
LVEF, %	52.00 ± 13.16	52.72 ± 13.71	0.297	0.053	52.42 ± 13.20	52.63 ± 13.51	0.777	0.016	
K+, mmol/L	4.32 ± 0.73	4.26 ± 0.72	0.045	0.081	4.32 ± 0.75	4.27 ± 0.73	0.119	0.067	
HDLC, mmol/L	0.95 ± 0.28	0.97 ± 0.28	0.037	0.094	0.95 ± 0.27	0.97 ± 0.27	0.155	0.068	
Medication at discharge	
β-Blocker, n (%)	1021 (77.2)	1000 (83.0)	<0.001	0.145	894 (82.0)	896 (82.2)	0.955	0.005	
Statins, n (%)	1191 (90.1)	1120 (92.9)	0.013	0.103	1009 (92.6)	1009 (92.6)	1.000	<0.001	
Antiplatelet, n (%)	1274 (96.4)	1181 (98.0)	0.019	0.099	1066 (97.8)	1067 (97.9)	1.000	0.006	
Diuretics, n (%)	615 (46.5)	555 (46.1)	0.847	0.008	501 (46.0)	500 (45.9)	1.000	0.002	
CCB, n (%)	582 (44.0)	536 (44.5)	0.849	0.009	505 (46.3)	486 (44.6)	0.439	0.035	
Abbreviations: AMI: acute myocardial infarction; AF: atrial fibrillation; HT: hypertension; DM: diabetes mellitus; CAD: coronary artery disease; PCI: percutaneous interventions; COPD: chronic obstructive pulmonary disease; CHF: congestive heart failure; IABP: intra-aortic balloon pump; HDL-C: high-density lipoprotein; eGFR: estimated glomerular filtration rate; LVEF: left ventricular ejection fraction; CCB: calcium channel blocker; ACEI/ARB: angiotensin-converting enzyme inhibitor/angiotensin receptor blocker.

We then used the propensity scores to assemble a matched cohort of 1090 pairs of patients receiving or not receiving ACEI/ARB at discharge. We assessed the baseline characteristic differences between ACEI/ARB users and nonusers using SMD. SMD was reduced to less than 10% for all 17 matching variables, which demonstrated that no significant differences were observed between groups in the balancing variables. Generally, patients in the matched cohort were 32.8% female, with a mean age of 68.24 ± 10.49 years, and had an average eGFR of 17.02 ± 8.57 (Table 1).

Impact of ACEI/ARB on long-term prognosis in the whole cohort

With a median duration of 3.0 years follow-up, there were 977 (38.6%) all-cause deaths and 625 (24.7%) cardiovascular deaths (n = 2527). All-cause death occurred in 427 patients (35.4%) in the ACEI/ARB group (n = 1205), 550 patients (41.6%) in the untreated group (n = 1322); similarly, cardiovascular death was observed in 274 patients (22.7%) among the ACEI/ARB population and in 351 patients (26.5%) among the untreated patients. Under the multivariate Cox models analysis, CAD patients with advanced CKD receiving ACEI/ARB consistently showed a lower risk of all-cause mortality (hazard ratio (HR)=0.836, 95% confidence interval (CI): 0.738–0.948, p = 0.005) and cardiovascular mortality (HR = 0.817, 95%CI: 0.699–0.956, p = 0.011) than those not receiving ACEI/ARB. Subsequently, to further analyze the relationship between the ACEI/ARB treatment and long-term prognosis, patients were grouped according to whether to receive dialysis treatment: dialysis group and non-dialysis group. In the non-dialysis group, patients receiving ACEI/ARB still consistently showed a lower risk of all-cause mortality (HR = 0.799, 95%CI: 0.688–0.927, p = 0.003) and cardiovascular mortality (HR = 0.764, 95%CI: 0.634–0.921, p = 0.005) than those not receiving ACEI/ARB. However, the use of ACEI/ARB did not show significant benefit among dialysis patients in both all-cause mortality (HR = 1.037, 95%CI: 0.810–1.328, p = 0.772) and cardiovascular mortality (HR = 1.027, 95%CI: 0.763–1.383, p = 0.860) (Table 2).

Table 2. Multivariable cox regression analysis of the relationship between ACEI/ARB therapy at discharge and death in the whole cohort and in the PS-matched cohort.

 	All-cause mortality HR (95% CI)	p-value	Cardiovascular mortality HR (95% CI)	p-value	
Whole cohorta	0.836(0.738–0.948)	0.005	0.817(0.699–0.956)	0.011	
 Dialysis patient	1.037(0.810–1.328)	0.772	1.027(0.763–1.383)	0.860	
 non-Dialysis patient	0.799(0.688–0.927)	0.003	0.764(0.634–0.921)	0.005	
PS-matched cohortb	0.856(0.752–0.974)	0.019	0.830(0.707–0.974)	0.023	
 Dialysis patient	1.023(0.797–1.313)	0.860	1.050(0.784–1.406)	0.745	
 non-Dialysis patient	0.815(0.697–0.953)	0.010	0.801(0.658–0.976)	0.028	
ACEI/ARB: angiotensin‑converting enzyme inhibitors or angiotensin‑receptor blockers; PS: propensity score; CI: confidence interval; HR: hazard ratio.

a Model in whole cohort: adjusted for age, gender, HT, DM, CHF, anemia, stroke, COPD, AMI, AF, eGFR, LVEF, statins, β-blocker, CCB, antiplatelet, and diuretics.

b Model in PS-matched cohort: crude analysis.

We further explored heterogeneity in subgroup analyses, there is a similar effect among these patients (elderly, male, HT, and DM) for both all-cause and cardiovascular mortality. Interaction analyses indicated the relationship between ACEI/ARB treatment and all-cause mortality was evident in gender (P for interaction = 0.023), and patients with DM (P for interaction = 0.033), while the association of ACEI/ARB treatment with cardiovascular death was evident among patients with DM (p for interaction = 0.034) (Figures 1and 2).

Figure 2. Subgroup analyses of ACEI/ARB therapy on the risk of cardiovascular mortality in the whole cohort.

Impact of ACEI/ARB on long-term prognosis in the propensity-matched cohort

All-cause mortality occurred in 390 (35.8%) as compared to 456 (41.8%) of subjects taking and not taking ACEI/ARB at discharge among propensity-matched cohorts, respectively. Cox regression analysis showed that ACEI/ARB therapy was related to better survival (HR = 0.856, 95%CI: 0.752–0.974, p = 0.019). Similarly, as for cardiovascular death, there were 245 (22.5%) cardiovascular deaths among subjects on ACEI/ARB as opposed to 297 (27.2%) cardiovascular deaths among subjects not receiving ACEI/ARB therapy; Consistently, patients on ACEI/ARB also showed better survival (crude analysis: HR = 0.830, 95%CI: 0.707–0.974, p = 0.023). However, further research also demonstrated that the use of ACEI/ARB did not show significant benefit in dialysis populations in both all-cause (HR = 1.023, 95%CI: 0.797–1.313, p = 0.860) and cardiovascular mortality (HR = 1.050, 95%CI: 0.784–1.406, p = 0.745) (Table 2).

Kaplan–Meier curves for all-cause mortality and CIF curves for cardiovascular mortality manifested that patients on ACEI/ARB at discharge have a lower all-cause and cardiovascular mortality among CAD patients with advanced CKD in the propensity-matched cohort. Consistently, further analysis also found ACEI/ARB therapy has a better survival benefit among non-dialysis-dependent patients, while did not show significant benefits for both all-cause and cardiovascular mortality in dialysis-dependent populations (Figures 3 and 4).

Figure 3. ACEI/ARB therapy at discharge and risk of all-cause mortality in the PS-matched cohort.

Figure 4. ACEI/ARB therapy at discharge and risk of cardiovascular mortality in the PS-matched cohort.

Discussion

This is the large multicenter, longitudinal cohort research to explore the relationship between ACEI/ARB therapy and all-cause, as well as cardiovascular mortality among CAD patients with advanced CKD. The main finding of our research was that ACEI/ARB treatment was related to a 17% reduced risk for all-cause mortality and 19% for cardiovascular mortality in the analysis of the whole cohort. The survival benefit was consistent after propensity-score matched analysis, there were 15% and 17% reduced risk for all-cause and cardiovascular mortality, respectively. Therefore, our study manifested that strategies to maintain ACEI/ARB treatment may improve clinical outcomes among these high-risk population.

Advanced CKD is highly prevalent and strongly associated with higher mortality risk and worse outcomes among CAD patients [20,21]. ACEI/ARB can inhibit the activation of renin-angiotensin-aldosterone system to exert the cardio- and nephroprotective effect. In a large contemporary cohort of non-dialysis-dependent CKD patients, ACEI/ARB treatment was related to better survival [14]. In addition, the nationwide observational research of patients with advanced CKD showed that stopping renin-angiotensin system inhibition was related to higher absolute risks of mortality and major adverse cardiovascular events, but also to a lower absolute risk of initiating kidney replacement therapy [22]. Yao Qiao et al. also reported that continuing ACEI/ARB therapy may be related to cardiovascular benefits without excessive harm of end-stage kidney disease among patients with low eGFR [23]. Moreover, a body of studies have proved that ACEI/ARB treatment could reduce poor outcomes for patients with CAD [8,24] and be recommended for the treatment [25]. Solomon et al. reported, ACEI/ARB therapy increased prognostic benefit on cardiovascular mortality among stable CAD patients with reduced eGFR in the PEACE trial, with increasing benefit seen with decreasing baseline renal function [26]. In the study of Evans et al. found that AMI patients on ACEI/ARB was related to greater long-term survival, regardless of underlying renal function in a cohort of 64,442 patients, and a similar survival benefit was observed across all kidney function strata [27]. Consistent with these previous studies, our study also demonstrated the survival benefit of ACEI/ARB treatment among CAD patients with advanced CKD.

In our subgroup analysis, ACEI/ARB treatment reduced the risk of mortality in non-dialysis population, but showed no survival benefit in the dialysis group. This may be attributed to some potential reasons for the discrepancy in the dialysis group. There are a number of risk factors observed in dialysis patients, like disorders of hormone, fluid volume overload, as well as chronic inflammation, which could tend to suffer a higher risk of adverse events. These risk factors may modify the survival benefit of ACEI/ARB treatment [28,29]. Meanwhile, blood concentrations of ACEI may be reduced due to dialysis clearance, which has some influence on the therapeutic effect of ACEI [30]. Besides, dialysis session may induce myocardial ischemia and myocardial damage, which is related to higher mortality among CAD patients [31]. Moreover, a meta-analysis also showed that there was no significant improvement in all-cause and cardiovascular mortality among dialysis patients with ACEI/ARB treatment [32]. At the same time, our subgroup analysis also suggested that there was a survival benefit among patients who were combined with HT or DM, and these two comorbidities are well-known as strong risk factors in determining the progression of end-stage renal disease and cardiovascular complications among CKD patients [33]. Randomized trials indicated that ACEI/ARB treatment was effective in preventing the progression of renal insufficiency and reducing cardiovascular adverse outcomes among DM patients [34]. Moreover, a meta-analysis also showed that ACEI was proved to be significant in reducing the risk of all-cause and cardiovascular death among patients with HT. Although ARB therapy did not show a reduction in total deaths or cardiovascular deaths, the reductions were significant for both classes for AMI, stroke, and heart failure [35].

Our research provided some important clinical implications in therapy among CAD patients with advanced CKD. Firstly. our findings suggested that ACEI/ARB treatment may represent a useful therapeutic option, which reduced the long-term all-cause and cardiovascular death. Secondly, ACEI/ARB use has the potential risk of some adverse events, like hyperkalemia and AKI, so there is a continued need for close monitoring of blood potassium and eGFR. According to the previous study, hyperkalemia was found only in 8.3% and 11.6% of patients with CKD stages 4 and 5, respectively [36]. However, there are some measures to solve this problem, such as dietary K restriction, and using some drugs that could eliminate K from the intestinal tract [37]. Meanwhile, Brar et al. reported that ACEI/ARB was related to an increased hospitalization rate caused by acute renal failure and hyperkalemia, but no difference was found for ESRD. Moreover, patients with AKI accepted an ACEI/ARB in the hospital had a lower mortality compared to those with no ACEI/ARB therapy, which may encourage clinicians to prescribe ACEI/ARB [38]. Finally, management of comorbidities, such as DM and HT, may be helpful to improve the outcomes of these high-risk patients.

Limitations

Nevertheless, the present research has some limitations that should be considered. Firstly, this was a retrospective study, some confounders could not be excluded. However, our study is a large multicenter population-based study, which can be a good representative of these high-risk population. Secondly, we failed to collect information on adverse events such as hyperkalemia after discharge, which may affect patients’ compliance issues, so we could not guarantee whether they would continue to use ACEI/ARB after discharge. Thirdly, we could not systematically collect information on proteinuria, which is a significant risk factor for both renal progression and cardiac disease. In addition, there may be a selection bias from the clinician in choosing who went on an ACEI/ARB, and some clinicians may be based on blood potassium levels, urine volume, and the patient’s condition. Finally, more high-quality randomized controlled trials are needed to confirm the therapeutic option to improve the outcomes of these high-risk populations.

Conclusions

ACEI/ARB treatment showed a better survival benefit among high-risk CAD patients with advanced CKD at long-term follow-up, but long-term careful monitoring of severe adverse events is needed in clinical practice. Our study may prompt an important reference for the subsequent improvement of long-term prognosis among these high-risk populations, and future randomized controlled trials are essential to verify these findings.

Supplementary Material

study highlights.docx

Supplemental Figure 1.tif

Acknowledgement

None.

Ethical approval

All traceable personal identifiers were removed from the analytic dataset to protect patients’ privacy. The study protocol was approved by the Guangdong Provincial People’s Hospital ethics committee(No.GDREC2019-555H-2), and all participating sites received institutional review board approval from their own ethics committees. The study was performed according to the World Medical Association Declaration of Helsinki. Since our research included retrospective cases, there was no additional intervention, and information of all patients was desensitized, and no informed consent was required.

Authors’ contributions

The authors’ responsibilities were as follows—(I) Research idea and study design: Wenguang Lai, Xiaoli Zhao, and Tingting Zhang. (II) Data acquisition: Wenguang Lai, Xiaoli Zhao, Tingting Zhang, Donghui Huang, and Yang Zhou; (III) Data analysis/interpretation: Wenguang Lai, and Xiaoli Zhao; (IV) Statistical analysis: Wenguang Lai, Guoxiao Liang; (V) Supervision and mentorship: Jin Liu, Shiqun Chen, and Yong Liu; (VI) Writing guidance: Jin Liu, Shiqun Chen, and Yong Liu.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets generated and analyzed during the current study are not publicly available due to the institution policy but are available from the corresponding author on reasonable request.
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