Mild Renal Insufficiency and Attributable Risk of Adverse In-hospital Outcomes in Patients with ACS from the Improving Care for Cardiovascular Disease in China (CCC) Project


 Background: Renal insufficiency (RI) is a frequent comorbidity among patients with acute coronary syndrome (ACS). We aimed to evaluate the attributable risk associated with mild RI for the in-hospital outcomes in patients with ACS. Methods: The Improving Care for Cardiovascular Disease in China-ACS (CCC-ACS) Project was a collaborative study of the American Heart Association and the Chinese Society of Cardiology. A total of 92509 inpatients with a discharge diagnosis of ACS were included. The attributable risk was calculated to investigate the effect of mild RI (eGFR 60-89 ml / min · 1.73 m2) on major adverse cardiovascular events (MACE) during hospitalization. Results: The average age of these ACS patients was 63 years, and 73.9% were men. The proportion of patients with mild RI was 36.17%. After adjusting for other possible risk factors, mild RI was still an independent risk factor for MACE in ACS patients. In the ACS patients, the attributable risk of eGFR 60-89ml/min·1.73m2 to MACE was 8.96%, 5.59% of eGFR 45-59 ml/min·1.73m2 ,5.31% of eGFR 30-44 ml/min·1.73m2, and 4.03% of eGFR＜30 ml/min·1.73m2. Conclusion: Compared with moderate to severe RI, mild RI has higher attributable risk to MACE during hospitalization in Chinese ACS population.


Background
In 2018, an estimated 11 million Chinese were affected by coronary heart disease (CHD) [1]. The aging population and increasing prevalence of cardiovascular disease risk factors [2,3] will lead to a growing burden of CHD [4,5]. The population affected by CHD is predicted to increase to 22.6 million by 2030 [6]. The mortality rate of CHD in China reached 1.39 million in 2013 [7].
It is generally believed that hypertension, diabetes, smoking and hyperlipidemia are the risk factors for CHD [8][9][10]. In addition, renal insu ciency (RI) is also one of the important risk factors for CHD [11]. Many studies had shown that in the patients with CHD, worse renal function was an independent predictor for short-and long-term prognosis [12][13][14]. However, the impact of mild RI on adverse in-hospital outcomes is not clear, and there are few studies about it. The information about the attributable risk associated to mild RI in patients with ACS for MACE is scarce too. Therefore, the purpose of the present study is to evaluate the in uence of mild RI on the in-hospital outcomes in patients with ACS.

Research design
Details of the design and methodology of the CCC-ACS project have been published [15]. Brie y, it is a national, hospital-based quality improvement project with an ongoing database, aiming to increase adherence to ACS guidelines in China and to improve patient outcomes. It was launched in 2014 as a collaborative initiative of the American Heart Association (AHA) and Chinese Society of Cardiology (CSC). 240 hospitals were recruited representing the diversity of ACS care in hospitals in China, including 160 tertiary hospitals and 80 secondary hospitals. Clinical data were collected via a web-based data collection platform (Oracle Clinical Remote Data Capture, Oracle Corporation). Trained data abstractors entered the data elements abstracted from medical charts. Eligible patients were consecutively reported to the CCC-ACS database for each month before the middle of the following month. Around 5% of reported cases were randomly selected and compared with the original medical records. An audit by a third party was performed to ensure that cases were reported consecutively rather than selectively. This research has been registered in https://clinicaltrials.gov (NCT02306616).

Research population
A total of 92509 inpatients with ACS, identi ed based on their principal diagnosis at discharge, were enrolled from 240 hospitals across China from November 2014 to December 2019. Based on the eGFR, all the patients were further divided into ≥90 ml/min·1.73m 2 group, 60-89 ml/min·1.73m 2 group, 45-59 ml/min 1.73 m 2 group, 30-44 ml/min 1.73 m 2 group and < 30 ml/min 1.73 m 2 group. Institutional review board approval was granted for the aggregate data set for research and quality improvement by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University. No informed consent was required.

Di nition of mild RI
Mild RI is de ned as eGFR 60-89 ml / min · 1.73m 2 .
De nition of in-hospital outcomes Major adverse cardiovascular events (MACE) were de ned as a combination of death, heart failure, cardiac arrest, and cardiac shock.

De nition of other Variables
The ACS classi cation was based on the primary diagnosis at discharge in the medical record. Non-ST-segment elevation ACS was de ned as non-STsegment elevation myocardial infarction (STEMI) or unstable angina. Hypertension was de ned as having a history of hypertension, receiving antihypertensive therapy, or having a systolic blood pressure≥140mmHg or diastolic blood pressure≥90mmHg at admission. Diabetes mellitus was de ned as having a previous or new diagnosis of diabetes mellitus, receiving oral hypoglycemic drug therapy or insulin therapy, or having a HBA1C≥6.5%. Hyperlipidemia was de ned as having a history of hyperlipidemia, receiving lipid-lowering drugs, or having a serum LDL-C≥1.8mmol/L at admission. Current smoking was de ned as smoking in the preceding 1 year according to the medical records of the patients.
All the laboratory testing values were the values tested the rst time after admission.

Statistical methods
Continuous variables with normal distribution were presented as mean±standard deviation, and ANOVA analysis was used for univariate comparison. On the other hand, those with non-normal distribution were represented as median and interquartile range, and Wilcoxon-Mann-Whitney test was used for univariate comparison. The categorical variables were reported as number of cases and percentages, and the chi-square test was used for univariate comparison. A multivariate logistic regression model was used to determine the association between the eGFR and in-hospital outcomes by controlling for potential confounders. Candidate adjustment factors included age, history of hypertension, diabetes mellitus, heart failure, atrial brillation, stroke, previous PCI or CABG ACS type, heart failure at admission, cardiogenic shock at admission, cardiac arrest at admission, Killip class at admission, systolic pressure at admission, taking antiplatelet drugs before admission, taking β-blocker before admission and taking ACEI/ARB before admission, HB at admission, LDL-C at admission. The attributable risk (AR) was calculated using the method described by Bruzzi P [17] to investigate the effect of mild RI on MACE during hospitalization.
PE= probability of exposure of disease For data with missing values lower than 15%, the sequential regression multiple imputation method implemented by IVEware software version 0.2(Survey Research Center, University of Michigan, Ann Arbor, MI, USA) was used to imputed the missing values.
SPSS software version 22.0 (IBM Inc, Armonk, NY, USA) was used to analyze the data. For all analyses, P 0.05 was considered as statistically signi cant.

Patients' characteristics
This study included 92509 ACS patients from 240 hospitals across China. The clinical characteristics of these patients are summarized in Table 1. The average age of these ACS patients was 63 years, and 73.9% of them were men.
The percentages of patients with eGFR≥90 ml/min·1.73m 2 , 60-89 ml/min·1.73m 2 , 45-59 ml/min 1.73 m 2 , 30-44 ml/min 1.73 m 2 and < 30 ml/min 1.73 m 2 were 45.95%, 36.17%, 9.06%, 5.38% and 3.43%, respectively. The comparison results were shown in Table 1. With the decrease of eGFR, the proportion of STEMI decreased gradually, while the proportion of NSTE-ACS increased gradually. The proportion of patients with hypertension, diabetes mellitus, heart failure, previous heart myocardial and previous stroke increased gradually, while the proportion of patients with hyperlipidemia and LDL-C level decreased gradually. With the decrease of eGFR, the proportion of patients with taking β-blockers, antiplatelet drugs and statins before admission increased, while the proportion of patients with taking ACEI/ARB decreased when the eGFR 60 ml/min·1.73m 2 . With the decrease of eGFR, the proportion of patients undergoing coronary angiography and PCI decreased signi cantly after admission, while the severity of coronary artery lesions in patients undergoing angiography increased gradually.

Discussion
In this large, hospital-based registry for patients with ACS, eGFR was signi cantly associated with the risk of MACE during hospitalization. Moreover, the attributable risk of mild RI to MACE was higher than that of moderate to severe RI, which is especially obvious in patients with NSTE-ACS.
The subjects of this study were patients with ACS. In the present study, we found the proportion of patients with eGFR < 90 ml / min · 1.73m 2 was 54.05%, and the proportion of patients with mild RI (eGFR 60-89 ml / min · 1.73m 2 ) was 36.17%. This was similar to the foreign literature report: in a study including 20604 patients with ACS in New Zealand, 53.3%, 23.3%, 1.7% and 1.4% of patients combined with CKD stages 2, 3, 4 and 5 respectively [18]. In other studies with relative small sample size, the proportion of ACS patients with RI is also similar [19,20]. It can be seen that the proportion of patients with RI is large in ACS population and which is mainly mild RI.
The present study also found that RI was an independent risk factor for MACE during hospitalization, and there was a gradual correlation between them. In the multivariate regression analysis, the odds ratio(95% CI) of MACE in the patients with 60-89 ml/min·1.73m 2 ,45-59 ml/min·1.73m 2 , 30-44 ml/min·1.73m 2 and 30 ml/min·1.73m 2 were 1.27, 1.65, 2.04 and 2.23. We can see from this data that the worse the renal function in the patients with ACS, the higher risk of MACE during hospitalization, which is consistent with the foreign literature reports [13,21]. Therefore, we always pay more attention to the ASC patients with severe RI in clinical work, while often ignore the ACS patients with mild RI.
However, it also can be seen from the data of the present study that only the slightly decrease of eGFR (60-89 ml / min·1.73m 2 ) in the patients with ACS, the risk of MACE increased 1.272 times compared to those with normal renal function (eGFR ≥ 90ml / min·1.73m 2 ). Smith GL et al. followed up 118753 patients with AMI for 10 years. They found that even mild impairment of renal function (eGFR66-74 ml/min.1.73 m 2 ) could increase 10-year mortality risk of patients to 10% compared to patients with normal renal function [22]. Other studies with relatively small sample size also found that mild RI was related to the short-term and long-term prognosis in ACS patients [22][23][24]. However, only regression analysis was used to analyze the relationship between mild RI and prognosis of ACS patients in these studies. And this was not be reported in previous literature that used attributable risk to reveal the relationship between mild RI and hospital outcomes in ACS population. Attributable risk is re ected in the total chance of a disease (or death) in the population exposed to a certain factor, the part that really attributable to the exposure factor. The public health signi cance of this index is that for the exposed population, if the exposure factors are eliminated, the number of morbidity (or death) per unit population can be reduced. In the present study, the attributable risk of eGFR 60-89ml/min·1.73m 2 was 8.96%, eGFR 45-59 ml/min·1.73m 2 was 5.59%, eGFR 30-44 ml/min·1.73m 2 was 5.31% and eGFR 30 ml/min·1.73m 2 was 4.03%. That is to say, among the ACS patients, 8.96% of MACE during hospitalization was caused by mild RI. It can be seen that in the ACS population in the present study, although the risk of MACE during hospitalization with mild RI was lower than that of moderate and severe RI, its attributable risk is far greater than that of moderate and severe RI. The occurrence of this phenomenon is attributed to the proportion of patients with mild RI far greater than that of patients with moderate and severe RI. This suggests that we should pay more attention to ACS patients and their prognosis even with mild RI.
We even found that in the NSTE-ACS population, the attributable risk of eGFR 60-90 ml/min·1.73m 2 to MACE during hospitalization was as high as 15.5%. While that is 8% in patients with STEMI. This is related to the relatively high percentage of mild RI and a higher OR value of mild RI to MACE in NSTE-ACS population. In the present study, the proportion of STEMI patients with RI compared with NST-ACS patients with RI was 51.14% vs 58.43%. Moreover, 34.95% of patients with STEMI had mild RI, while that of NST-ACS patients was 38%. It can be seen that patients with NSTE-ACS are more likely to have a poor basic renal function than patients with STEMI. In other words, once ACS occurs in patients with chronic kidney disease (CKD), the type of ACS is more likely to be NSTE-ACS than STEMI, which is similar to Gupta's conclusion [13]. They analyzed 3187404 patients. In the ACS subgroup, the percentages of STEMI in non CKD, CKD and ESRD patients were 34.5%, 22.3% and 16.6% respectively, while the percentages of NSTE-ACS were 65.5%, 77.7% and 83.4%. The occurrence of this phenomenon may be related to the presence of microin ammation,vascular calci cation caused by abnormal bone metabolism, etc in patients with RI, which leads to the progression of chronic invasive plaque of coronary artery and eventually lead to chronic obstruction [25,26].
The current study has the following limitations: (1) Because cardiologists usually avoid to do coronary angiography in patients with RI because of a high risk. Therefore, the population for assessing the severity of coronary artery lesions in our study, may not be represented all the ACS patients. (2) Because the data in our study are obtained from CCC-ACS database, which does not be included the data of calcium and phosphorus metabolism, in ammation, the current study couldn't adjust the impact of the above factors on the short-term outcomes in patients with ACS. (3) The outcome of our study was limited to hospital events and follow-up data were not available.

Conclusion
In conclusion, the present study is the largest sample study for the ACS population in China. It is suggested that the mild decline of eGFR is an independent risk factor for the poor short-term prognosis in ACS patients. Moreover, the attributable risk of mild RI is far greater than that of moderate and severe RI in ACS patients with short prognosis during hospitalization, which is especially in NSTE-ACS patients. Therefore, in clinical work, the prevention of cardiovascular disease is not only limited to moderate and severe RI, but also start from those with early RI.  antiplatelet drugs before admission, taking β-blocker before admission and taking ACEI/ARB before admission, HB at admission, LDL-C at admission.  Figure 1 Percentage of different renal function in STEMI and NSTE-ACS patients eGFR: estimated glomerular ltration rate STEMI ST-elevation myocardial infarction NSTE-ACS Non-ST elevation acute coronary syndrome