Long-term impact of renin-angiotensin system inhibitors for secondary prevention in patients with chronic kidney disease who underwent percutaneous coronary intervention

doi:10.21203/rs.3.rs-1999555/v1

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Long-term impact of renin-angiotensin system inhibitors for secondary prevention in patients with chronic kidney disease who underwent percutaneous coronary intervention

https://doi.org/10.21203/rs.3.rs-1999555/v1

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The impact of renin-angiotensin system (RAS) inhibitors for secondary prevention in patients with coronary artery disease and coexisting chronic kidney disease (CKD) in the long-term remains unclear. Therefore, we investigated how RAS inhibitor use affects long-term clinical outcomes in patients with CKD who underwent percutaneous coronary intervention (PCI). A total of 1190 patients with CKD who underwent their first PCI between 2000 and 2018 were included in this study, and were divided into two groups based on the presence or absence of RAS inhibitor use. In total, 293 patients (24.6%) developed 3-point major adverse cardiovascular events (3P-MACE), including cardiovascular death, non-fatal acute coronary syndrome and non-fatal stroke, and 136 patients (11.4%) developed heart failure (HF). The cumulative incidence rate of 3P-MACE in the RAS inhibitor group was significantly lower than in the non-RAS inhibitor group (31.7% vs. 40.2%, log-rank test, p = 0.034). However, the cumulative incidence rate of admission for HF in the RAS inhibitor group was significantly higher than in the non-RAS inhibitor group (28.2% vs. 13.8%, log-rank test, p < 0.001). In conclusion, the long-term RAS inhibitor use in patients with CKD after PCI could contribute to prevention of cardiovascular events but may increase the risk of HF.

Renin-angiotensin system inhibitor

Chronic kidney disease

Cardiovascular events

Heart failure

Percutaneous coronary intervention

Long-term.

In the renin-angiotensin system (RAS), angiotensin-II activation results in harmful effects and targeted organ damage due to tissue remodeling, endothelial dysfunction, and fibrosis¹. RAS inhibitors, such as angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers, act by decreased the generation of angiotensin-II or blocking angiotensin-II from binding to its receptors. These medications are widely used to treat hypertension, myocardial infarction (MI), and congestive heart failure (HF) in the field of cardiology^2–4. Regarding MI, RAS inhibitors are indicated for patients with reduced ejection fraction (rEF) or HF in order to reduce the risk of hospitalization and death⁵. The guidelines also recommend that RAS inhibitors for patients with coronary artery disease (CAD) except for MI should be considered even in the case of coexisting hypertension, rEF, diabetes, or chronic kidney disease (CKD), unless contraindicated^{6, 7}. Nevertheless, the long-term impact of RAS inhibitor for patients with CAD and CKD are largely unknown, especially in those without MI or rEF. A recent study investigated RAS inhibitors and CKD from a nephrological perspective⁸. In this study, patients who stopped using RAS inhibitors had a better renal prognosis but more cardiovascular events than those who continued using RAS inhibitors. However, the CAD patients in this study accounted for only one-third of the total patients, and the effects of RAS inhibitors on CAD patients with CKD remain unclear. Thus, we investigated how RAS inhibitor use for secondary prevention affects long-term clinical outcomes in patients with CAD and CKD who underwent percutaneous coronary intervention (PCI).

Study population

We conducted a single-center, observational, retrospective cohort study at our institution, identifying 1676 patients with CKD out of 4840 patients who underwent their first PCI between January 2000 and February 2018. The included patients were divided into two groups based on their RAS inhibitor use. Patients with an unknown ejection fraction (EF) and those receiving hemodialysis were excluded.

We defined CAD as acute coronary syndrome (ACS) or chronic coronary syndrome (CCS). We diagnosed ACS (e.g., ST-segment elevation MI, non-ST-segment elevation MI, and unstable angina) based on electrocardiographic abnormalities, positivity for deviant myocardial enzymes or cardiac troponin T, and impaired left ventricular systolic function by echocardiography, in addition to signs and symptoms of cardiac ischemia. Patients with ACS were hospitalized immediately, and emergency PCI was performed. Conversely, CCS was diagnosed on the basis of the following clinical scenarios: classical history of anginal symptoms, new onset of HF or left ventricular dysfunction suggested CAD, and detection of CAD at screening even if asymptomatic. Patients with CCS were initially treated with lifestyle management (e.g., smoking cessation, a healthy diet, physical activity, and maintaining a healthy weight), and pharmacological management. Pharmacological management included treatment of ischemia through anti-ischemic drugs, such as nitrates, β-blockers, calcium channel blockers, or nicorandil, and prevention of ischemic events through antiplatelet drugs, anticoagulant drugs, statins, other lipid-lowering drugs, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

Ethics

The ethics committee of our institution approved this study, and all participants provided written informed consent. The study conformed to the “Declaration of Helsinki”⁹.

Data collection and definitions

We collected patients’ characteristic data from an institutional database. Blood samples were collected in the morning, one day before the intervention, and after an overnight fast. All blood tests were performed in the same laboratory.

CKD was defined as an estimated glomerular filtration rate (GFR) of <60 mL/min/1.73 m² based on the Modification of the Diet in Renal Disease equation modified using the baseline serum creatinine level¹⁰. Patients with a blood pressure of >140/90 mmHg or those receiving antihypertensive drugs were considered hypertensive¹¹. Dyslipidemia was defined as a triglyceride level of ≥150 mg/dL, a low-density lipoprotein cholesterol level of ≥140 mg/dL, a high-density lipoprotein cholesterol level of <40 mg/dL, or lipid-lowering therapy administration¹². Diabetes mellitus was defined as a hemoglobin A1c level of ≥6.5 % or oral hypoglycemic agents administration or insulin injection¹³. Anemia was defined based on the hemoglobin level recommended by the World Health Organization (<12.0 g/dL in women and <13.0 g/dL in men)¹⁴. A family history of premature CAD was defined as the presence of any first-degree relative with premature cardiovascular disease (age <55 years for men and <65 years for women)¹⁵. The coronary artery lesion type (A, B1, B2, or C) was defined based on the American Heart Association/American College of Cardiology classification¹⁶.

Study endpoint

The endpoints of this study were 3-point major adverse cardiovascular events (3P-MACE), defined as a composite of cardiovascular death, non-fatal ACS, and non-fatal stroke, admission for HF, target vessel revascularization (TVR), and all-cause death. Cardiovascular death was defined as death resulting from MI, sudden cardiac death, HF, stroke, cardiovascular procedures, cardiovascular hemorrhage, and other cardiovascular causes. Stroke was defined as ischemic stroke, symptomatic intracerebral hemorrhage, symptomatic subarachnoid hemorrhage, and not otherwise specified according to the classification proposed by Neurologic Academic Research Consortium, because we considered it important to clearly distinguish between clinically meaningful and incidental findings in clinical practice. Patients requiring unscheduled hospital admission for a primary diagnosis of HF with typical signs, symptoms, and diagnostic testing results of HF for a length of stay exceeded 24 hours or crossing one calendar day were classified as being admitted for HF. Any admission for HF was defined as the first onset of HF in each patient. TVR was defined as any repeated PCI or surgical bypass of any segment of the target vessel, including the target lesion^17-19.

Clinical follow-up data were collected from the patients’ medical records or by contacting the patients or their families if the follow-up did not occur at our institution. Information about the circumstances and date of death was obtained from the families of the patients who died at home and by the staff of other hospitals or clinics where the patient had been admitted. Blinded investigators collected all the data.

Statistical analysis

Categorical data were presented as numbers and percentages and were compared using the chi-square test. Continuous variables were expressed as means±standard deviations or as medians and interquartile ranges (IQR), and were compared using a one-way analysis of variance or the Kruskal-Wallis test. The Kolmogorov-Smirnov test was used to determine if the scores were likely to follow a specific distribution in all patients, If the p-value <0.05, then the variable did not follow a normal distribution. Kaplan-Meier analyses for the cumulative incidence of 3P-MACE, admission for HF, TVR, and all-cause death were used to compare the two groups based on the presence or absence of RAS inhibitor, between-group differences were assessed using the log-rank test. Furthermore, the multivariable analysis was performed using a Cox proportional hazard model, and showed the prognostic impacts of RAS inhibitors for 3P-MACE and admission for HF after adjusting for risk factors, comorbidities, and medications related to cardiovascular disease.

All probabilities were expressed as two-tailed values, with statistical significance at p <0.05. All confidence intervals (CIs) were computed at 95% level. All data were analyzed using JMP version 14.2 for Macintosh (SAS Institute, Cary, NC, USA).

Study population

We included 1190 CAD patients with CKD after PCI, excluding 444 patients with an unknown EF and 273 patients receiving hemodialysis. In total, 656 patients (55%) were allocated to the RAS inhibitor group, and 534 (45%) were allocated to the non-RAS inhibitor group (Fig.1). Of those taking RAS inhibitors, 28% took angiotensin-converting enzyme inhibitors, 70% took angiotensin-II receptor blockers, and 2% received dual therapy.

Baseline clinical and procedural characteristics

Baseline clinical characteristics are summarized in Table 1. The mean age was 70±9 years, and 78% of the patients were men. Overall, the prevalence of hypertension, dyslipidemia, diabetes mellitus, current smoker, a family history of premature CAD, and atrial fibrillation was 84%, 85%, 31%, 17%, 26%, and 11%, respectively. The median estimated GFR was 54.3 [IQR, 47.4-57.8] mL/min/1.73 m², and the proportion of mild, moderate, and severe renal impairment was 80%, 17%, and 4%, respectively. The RAS inhibitor group had a significantly higher body mass index, systolic blood pressure, and proportion of hypertension, statin use, calcium channel blockers use, diuretics use and oral hypoglycemic agent use, as well as a lower proportion of male, and EF than the non-RAS inhibitor group (all p <0.05).

Regarding baseline lesion and procedural characteristics, the RAS inhibitor group had a significantly longer stent and lesion length, and a higher proportion of drug-eluting stent use, as well as a lower proportion of bare metal stent use than the non-RAS inhibitor group (all p <0.05).

Clinical outcomes

The median follow-up duration was 7.6 [IQR, 3.5-12.3] years, and the prognostic data were fully documented during the entire follow-up period. During the follow-up, 293 patients (24.6%) developed 3P-MACE, there were 154 cardiovascular deaths, 98 non-fatal ACSs, and 72 non-fatal strokes. In addition, 136 patients (11.4%) developed HF, 171 patients (14.4%) underwent TVR, and 366 patients (30.8%) died of any cause. Compared to the non-RAS inhibitor group, the RAS inhibitor group had a higher proportion of admission for HF (14.3% vs. 7.9%, p<0.001), and a lower proportion of 3P-MACE and cardiovascular death (21.8% vs. 28.1%, p=0.012, 10.2% vs. 16.3%, p=0.002, respectively).

Comparison of long-term prognosis with and without RAS inhibitor

Kaplan-Meier analysis showed that the cumulative incidence rate of 3P-MACE in the RAS inhibitor group was significantly lower than in the non-RAS inhibitor group (31.7% vs. 40.2%, log-rank test, p=0.034, Fig.2(A)). Regarding specific 3P-MACE, the cumulative incidence rate of cardiovascular death and non-fatal ACS in the RAS inhibitor group was significantly lower than in the non-RAS inhibitor group, respectively (16.3% vs. 26.2%, log-rank test, p=0.003), (9.1% vs. 14.2%, log-rank test, p=0.043), but the Kaplan-Meier curves for non-fatal stroke between both groups were not significantly different (11.3% vs. 7.9%, log-rank test, p=0.145). In addition, the cumulative incidence rate of admission for HF in the RAS inhibitor group was significantly higher than in the non-RAS inhibitor group by Kaplan-Meier analysis (28.2% vs. 13.8%, log-rank test, p<0.001, Fig.2(B)). However, the analysis showed that there was no significant difference between both groups for TVR (21.5% vs. 21.1%, log-rank test, p=0.981, Fig.2(C)) and all-cause death (42.2% vs. 45.9%, log-rank test, p=0.257, Fig.2(D)). When the analysis was limited to patients without MI or rEF, the cumulative incidence of admission for HF in the RAS inhibitor group was significantly higher than in the non-RAS inhibitor group, but that of 3P-MACE did not differ (Fig.3 (A)-(D)).

Impacts of RAS inhibitor on major adverse cardiovascular events and admission for HF

Furthermore, Table 2 shows the impact of RAS inhibitor by multivariable Cox proportional hazard analysis after adjustment for various confounders. As results, the RAS inhibitor group was significantly associated with a reduced risk of 3P-MACE (hazard ratio [HR] 0.58, 95% CIs: 0.44-0.78, p<0.001), while an increased risk of admission for HF (HR: 1.84, 95% CIs: 1.08-3.15, p=0.026), compared with the non-RAS inhibitor group (Table 2).

The major findings of this study are as follows: 1) RAS inhibitor group was significantly associated with a lower incidence of adverse cardiovascular events, while a higher incidence of hospitalization for HF, compared to the non-RAS inhibitor group in CAD patients with CKD. In addition, 2) except for MI or rEF, the RAS inhibitor group had a higher rate of admission for HF than non-RAS inhibitor group, despite there was no significant difference for 3P-MACE between both groups. Finally, 3) even after adjustments for pertinent covariates, long-term oral administration of RAS inhibitors also was strongly associated with a reduced risk of 3P-MACE and an increased risk of admission for HF.

As previously reported, RAS inhibitors suppress renal dysfunction in the early to middle stages of CKD²⁰, and are often prescribed to patients with CKD, including those with impaired renal function due to diabetes. In addition, the prescription frequency for patients with HF and cardiovascular disease is high. However, the long-term efficacy and safety of CAD patients with CKD remain controversial. Additionally, the side effects of RAS inhibitors are sometimes clinically problematic; causing hypotension, reduced GFR, hyperkalemia, and coughing. In particular, the progression of renal dysfunction is directly related to long-term prognosis. A report on the association between CKD progression based on the estimated GFR slope per year and the risk of cardiovascular disease has shown that a greater decline in estimated GFR slope was strongly associated with an increase in cardiovascular events, including hospitalization for HF and developing MI²¹. Our study evaluated estimated GFR at baseline, and after one, three, and five years. The baseline estimated GFR did not differ between both groups (54.0 [IQR, 47.8–57.7] mL/min/1.73 m² vs. 54.5 [IQR, 47.0-57.9] mL/min/1.73 m², p = 0.701), however, the estimated GFR in the RAS inhibitor group was significantly lower than in the non-RAS inhibitor group after five years (46.1 [IQR, 35.2–54.0] mL/min/1.73 m² vs. 49.5 [IQR, 40.7–56.6] mL/min/1.73 m², p < 0.001; Fig. 4).

Considering the long-term progression of renal dysfunction, we expected that RAS inhibitors would increase CAD recurrence, stroke development, and hospitalization for HF. However, the RAS inhibitor group was significantly associated with a reduced risk of 3P-MACE, compared with the non-RAS inhibitor group. Other studies have also reported on this paradoxical relationship between renal dysfunction exacerbation and cardiovascular events^{8, 22}. RAS inhibitors have actions that enhance the nitric oxide concentration, decrease oxidants/antioxidants imbalance, and inhibit RAS-induced inflammation. These biochemical alterations eventually improve the endothelium activities and vascular system pathophysiology in atherosclerosis²³. Furthermore, several studies have showed vascular benefits beyond antihypertensive action which was most important in renal dysfunction^{24, 25}, the preventive effects of RAS inhibitor beyond exacerbation factor for cardiovascular events could be explained.

Whereas, there are several possible reasons why hospitalization for HF correlated with oral administration of RAS inhibitors. A previous study included patients with estimated GFR between 30 and 59 mL/min/1.73 m², and demonstrated that the accelerated progression of renal dysfunction within 2 years affected approximately 1 in 4 patients with diabetes and 1 in 7 without diabetes, and hospitalization for HF significantly strongly correlates the CKD progression ²⁶. In our study, estimated GFR in the RAS inhibitor group decreased more over time than in the non-RAS inhibitor group. Furthermore, more patients taking RAS inhibitors were hospitalized for HF than patients not taking RAS inhibitors. This difference in hospitalization for HF between both groups gradually widened over time (shown in Fig. 2(B)), perhaps partly due to the long-term prognosis of renal dysfunction^{24, 26}.

In addition, some studies found that RAS inhibitors suppressed hospitalization for HF, and improved prognosis for patients with symptomatic HF with rEF and asymptomatic left ventricular dysfunction^{27, 28}. However, less than 10% of the patients in our study had an EF < 40%, which classified as rEF. RAS inhibitors have also been effective in patients with MI^{29, 30}, but the prevalence of MI was as low as 20% or less in our study. Therefore, it was challenging to demonstrate the benefits of RAS inhibitors, and no significant results were found in the subgroup corresponding to rEF or MI. Conversely, in the subgroup excluding rEF and MI, long-term RAS inhibitor use had little benefit in a reduced risk of 3P-MACE, and also strongly affected hospitalization for HF. Thus, we should be paid close attention to prescription of RAS inhibitors for CKD patients without MI or rEF who underwent PCI, after considering the risk of HF involved in renal dysfunction exacerbation.

This study had several limitations that require consideration. First, as this was a single-center, retrospective, observational study, and unknown confounding factors might have affected the outcomes, regardless of the analytical adjustments. Also, the relatively small number of enrolled patients limited the statistical power of the study. Second, this study included only patients in their own country. Thus, the RAS inhibitor dose used in other countries may differ. Third, because this study is retrospective, we could not follow up on changes in estimated GFR over time for all enrolled patients. Thus, the change in renal dysfunction was not included as a variable in the multivariable analysis. Overall, our findings warrant further investigation.

In conclusion, the long-term RAS inhibitor use was significantly associated with a reduced risk of adverse cardiovascular events but an increased risk of hospitalization for HF in patients with CKD after PCI. In addition, RAS inhibitors might be more harmful than beneficial for patients without MI or rEF. Thus, we should perform personalized evaluations to weigh the protective effect on the cardiovascular system versus the potential risk to the kidneys rather than uniformly starting or continuing RAS inhibitors for patients with CKD after catheterization.

Acknowledgments: The authors are grateful to the staff of the Department of Cardiovascular Medicine at Juntendo University. The authors also appreciate the secretarial assistance of Ms. Yumi Nozawa.

Authors’ contributions: Analysis: T Fukase. Concept and design: T Fukase, and T Dohi. Interpretation of the data: T Fukase, T Dohi, R Nishio, M Takeuchi, N Takahashi, Y Chikata, H Endo, S Doi, H Nishiyama, I Okai, H Iwata, S Okazaki, K Miyauchi, H Daida, and T Minamino. Drafting of the manuscript: T Fukase. Clinical data acquisition: T Fukase, R Nishio, M Takeuchi, N Takahashi, Y Chikata, H Endo, and S Doi. Writing-editing: T Dohi. Writing-review and editing: T Minamino. Supervision: T Dohi, and T Minamino.

Availability of data and materials: The datasets during and/or analyzed during the current study are available from the corresponding author with reasonable request.

Competing interests: The authors declare no conflicts of interest.

Funding: Not applicable.

Ethics approval and consent to participate: The ethics committee of Juntendo Clinical Research and Trial Center approved this study (reference number 17-0206), and this study was conducted in accordance with the Declaration of Helsinki.

Consent for publication: A written informed consent to participate was obtained from all patients.

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Table 1. Patients’ baseline clinical characteristics

	Overall n=1190	RAS inhibitor group n=656	Non-RAS inhibitor group n=534	p value
Clinical characteristics
Age, years	70±9	71±10	70±9	0.778
Male, n (%)	930 (78)	492 (75)	438 (82)	0.003
Body mass index, kg/m²	24.2±3.4	24.4±3.5	23.9±3.4	0.013
Systolic BP, mmHg	134±24	136±24	131±25	<0.001
Diastolic BP, mmHg	72±14	72±14	71±14	0.259
Total cholesterol level, mg/dL	178±38	177±39	179±38	0.431
Triglyceride level, mg/dL	130±75	131±72	128±77	0.484
HDL-C level, mg/dL	44±13	44±12	44±13	0.811
LDL-C level, mg/dL	108±32	107±33	109±32	0.248
Estimated GFR, mL/min/1.73m²	54.3 (47.4-57.8)	54.0 (47.8-57.7)	54.5 (47.0-57.9)	0.701
45≤ estimated GFR <60, n (%)	948 (80)	525 (80)	423 (79)	0.669
30≤ estimated GFR <45, n (%)	197 (17)	109 (17)	88 (16)	0.981
Estimated GFR <30, n (%)	45 (4)	22 (3)	23 (4)	0.393
Hemoglobin level, g/dL	12.8±1.8	12.7±1.8	12.9±1.8	0.122
FBG level, mg/dL	115±52	116±47	115±58	0.868
HbA1c level, %	6.3±1.0	6.3±1.1	6.2±1.0	0.067
Hs-CRP level, mg/dL	0.14 (0.06-0.40)	0.14 (0.06-0.40)	0.13 (0.06-0.40)	0.644
Ejection fraction, %	60.3±13.7	59.4±14.0	61.6±13.3	0.005
Ejection fraction <40%, n (%)	95 (8)	57 (9)	38 (7)	0.318
Acute coronary syndrome, n (%)	278 (23)	163 (25)	115 (22)	0.178
Comorbidity
Hypertension, n (%)	1003 (84)	656 (100)	347 (65)	<0.001
Dyslipidemia, n (%)	1013 (85)	566 (86)	447 (84)	0.216
Diabetes mellitus, n (%)	371 (31)	216 (33)	153 (29)	0.089
Current smoker, n (%)	200 (17)	111 (17)	89 (17)	0.902
Family history of premature CAD, n (%)	314 (26)	173 (26)	141 (26)	0.990
Atrial fibrillation, n (%)	126 (11)	77 (12)	49 (9)	0.151
Medication
RAS inhibitor, n (%)	656 (55)	656 (100)	0 (0)	<0.001
ACE inhibitor, n (%)	198 (17)	198 (30)	0 (0)
ARB, n (%)	472 (40)	472 (72)	0 (0)
Statin, n (%)	755 (63)	441 (67)	314 (59)	0.003
Aspirin, n (%)	1122 (95)	622 (95)	500 (95)	0.876
Calcium channel blocker, n (%)	528 (44)	329 (50)	199 (37)	<0.001
β-blocker, n (%)	607 (51)	337 (51)	270 (51)	0.781
MRA, n (%)	93 (8)	56 (9)	37 (7)	0.302
Diuretics, n (%)	190 (16)	118 (18)	72 (13)	0.034
Oral hypoglycemic agent, n (%)	357 (30)	217 (33)	140 (26)	0.010
Insulin, n (%)	74 (6)	46 (7)	28 (5)	0.206
Lesion characteristics
Lesion site
Right coronary artery, n (%)	357 (30)	194 (30)	163 (31)	0.722
Left main coronary trunk, n (%)	50 (4)	27 (4)	23 (4)	0.870
Left anterior descending artery, n (%)	522 (44)	298 (45)	224 (42)	0.229
Left circumflex artery, n (%)	232 (20)	128 (20)	104 (19)	0.987
Lesion classification				0.469
Type A, n (%)	71 (6)	34 (5)	37 (7)
Type B1, n (%)	168 (14)	88 (13)	80 (15)
Type B2, n (%)	343 (29)	190 (29)	153 (29)
Type C, n (%)	608 (51)	344 (52)	264 (49)
CTO lesion, n (%)	60 (5)	28 (5)	32 (6)	0.201
Multi vessel disease, n (%)	735 (63)	414 (63)	321 (61)	0.423
Lesion length, mm	17.5±8.7	18.1±8.9	16.9±8.4	0.045
Lesion reference diameter, mm	2.90±0.49	2.88±0.50	2.93±0.48	0.075
procedural characteristics
Use of BMS, n (%)	433 (34)	216 (34)	217 (41)	0.015
Use of DES, n (%)	615 (52)	359 (55)	256 (48)	0.020
Stent length, mm	20.2±7.0	20.8±7.1	19.4±6.8	0.001
Stent diameter, mm	3.02±0.42	3.01±0.43	3.04±0.41	0.153

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMS, bare metal stent; BP, blood pressure; CAD, coronary artery disease; CTO, chronic total occlusion; DES, drug-eluting stent; FBG, fasting blood glucose; GFR, glomerular filtration rate; HbA1c, Hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; Hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; MRA, mineralocorticoid receptor antagonist; RAS, renin-angiotensin system.

Table 2. Impacts of RAS inhibitor on 3P-MACE and admission for heart failure

	3P-MACE		Admission for HF
	Hazard ratio (95% confidence interval)	p value	Hazard ratio (95% confidence interval)	p value
RAS inhibitor group vs. non-RAS inhibitor group
Model 1	0.77 (0.61-0.98)	0.031	1.78 (1.21-2.61)	0.002
Model 2	0.70 (0.54-0.91)	0.007	1.90 (1.20-3.02)	0.007
Model 3	0.58 (0.44-0.78)	<0.001	1.84 (1.08-3.15)	0.026

RAS inhibitor group (n=656).

Non-RAS inhibitor group (n=534).

Model 1 was adjusted for age, sex, and BMI.

Model 2 was adjusted for age, sex, BMI, hypertension, diabetes mellitus, statin use, current smoker, family history of premature CAD, and baseline estimated GFR <45 mL/min/1.73 m².

Model 3 was adjusted for age, sex, BMI, hypertension, diabetes mellitus, statin use, current smoker, family history of premature CAD, baseline estimated GFR <45 mL/min/1.73 m², reduced EF, AMI, atrial fibrillation, anemia, MRA use, and diuretics use.

3P-MACE, 3-point major adverse cardiovascular events; AMI, acute myocardial infarction; BMI, body mass index; CAD, coronary artery disease; EF, ejection fraction; GFR, glomerular filtration rate; HF, heart failure; MRA, mineralocorticoid receptor antagonist; RAS, renin-angiotensin system.

No competing interests reported.

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Long-term impact of renin-angiotensin system inhibitors for secondary prevention in patients with chronic kidney disease who underwent percutaneous coronary intervention

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