Dose‐dependent effect of impaired renal function on all‐cause mortality in patients following percutaneous coronary intervention

Abstract Objective To determine the risk prediction of various degrees of impaired renal function on all‐cause mortality in patients following percutaneous coronary intervention (PCI). Background Patients with chronic kidney disease (CKD) are at high risk of all‐cause mortality after PCI. However, there are less data of various degrees of impaired renal function to predict those risks. Methods This was a subgroup analysis of nationwide PCI registry of 22 045 patients. Patients were classified into six CKD stages according to preprocedure estimated glomerular filtration rate (eGFR) (ml/min/1.73 m2): I (≥90), II (60−89), III (30−59), IV (15−29), or V (<15) without or with dialysis. Baseline clinical and angiographic characteristics were compared among patients in each stage. One‐year all‐cause mortality was reported with risk prediction based on CKD stages and other risk factors. Results Patients with CKD stage I−V without and with on dialysis were found in 26.9%, 40.8%, 23.2%, 3.9%, 1.5%, and 3.7%, respectively. PCI procedural success and complication rates ranged from 94.0% to 96.2% and 2.8% to 6.1%, respectively. One‐year overall survival among CKD stages I−V was 96.3%, 93.1%, 84.4%, 65.2%, 68.0%, and 69.4%, respectively (p < .001 by log‐rank test). After adjusting covariables, the hazard ratios of all‐cause mortality for CKD stages II−V as compared to stage I by multivariate Cox regression analysis were 1.5, 2.6, 5.3, 5.9, and 7.0, respectively, (p < .001). Conclusion Among patients undergoing PCI, lower preprocedure eGFR is associated in a dose‐dependent effect with decreased 1‐year survival. This finding may be useful for risk classification and to guide decision‐making.


| INTRODUCTION
Coronary artery disease (CAD) is the leading cause of morbidity and mortality in chronic kidney disease (CKD) patients, accounting for almost half of their deaths. 1,2 In addition to traditional atherosclerotic risk factors, several uremia-related risk factors have been associated with accelerated atherosclerosis and aggravated symptoms. 3,4 Moreover, the survival in those CKD patients is limited by other comorbid diseases that shorten their life-expectancies. [5][6][7] There has been controversy regarding how aggressively percutaneous coronary intervention (PCI) should be performed in CKD patients, especially in end-stage renal disease (ESRD) with dialysis. 8,9 PCI treatment aims to relieve symptoms, and importantly, to prolong survival. With the advance in new generations of drug-eluting stents and adjunctive equipment for PCI, the immediate outcomes of PCI have been significantly improved. 10,11 Nevertheless, previous studies have shown that a lower estimated glomerular filtration rate (eGFR) was associated with decreased long-term survival. 12,13 In Thailand, with an increasing burden of CKD, rising PCI costs, and limited healthcare resources, it is necessary to select suitable patients having a better life expectancy.
Although PCI in advanced CKD patients has been studied extensively since the past decade, little is known about the impact of PCI on patients with varying degrees of renal failure. It is well known that CAD and its severity increase as renal function deteriorates. 14,15 Patients with advanced CKD usually have severe coronary calcification, 16 extensive CAD disease, and poor LV systolic function, which adversely affects outcomes after revascularization by PCI or even coronary artery bypass grafting (CABG). [17][18][19] Moreover, PCI in this high-risk population without renal replacement therapy is associated with a higher risk of contrast-induced nephropathy and worsening renal function. 20 In the Asian population, limited published data are existing on quantifying risk and assessment of long-term outcomes after PCI's treatment in impaired renal function patients, especially with ESRD patients on dialysis. Identifying the poor prognostic factors might help reduce morbidity and mortality, especially in the first year of patients undergoing PCI. Furthermore, if the procedural risk associated with each stage of CKD can be predicted, an operator would be able to weigh the risks and benefits properly, as well as informing PCI decision-making. Therefore, the objective of this study was to distinguish the risk prediction of various degrees of impaired renal function on all-cause mortality in patients after undergoing PCI.

| MATERIALS AND METHODS
This study utilized a nationwide prospective multicenter Thai PCI registry, initiated by the Cardiac Intervention Association of Thailand.
The registry protocol was published previously 21   of new loss of viable myocardium or new regional wall motion abnormality. Stroke was defined as a new neurological deficit during the first 24 h following PCI secondary to cerebral ischemia or cerebral hemorrhage detected by computed tomography or magnetic resonance imaging. Unplanned revascularization was defined as unplanned repeated PCI or CABG. MI during the first 48 h following revascularization was defined as an increase in cTn to >5 × 99th percentile of the upper reference limit (in patients with general baseline cTn concentrations) or an increase of 20% (in patients with elevated cTn before PCI or CABG). All of those adverse outcomes were adjudicated for accuracy by the study committee.

| Data collection
Data were initially collected and recorded in the case record forms.
Then, it was computerized by well-trained research assistants. All

| Statistical analysis
Baseline characteristics were described among CKD groups using means ± SD for continuous variables or as percentages for categorical variables. Continuous data were analyzed using analysis of variance or the Kruskal−Wallis test as appropriate and presented as mean values ± SD. Categorical data were analyzed using the χ 2 or Fisher's exact test. All tests of significance were two tailed. Hence, Kaplan-Meier overall survival curves were applied to describe survival probabilities by CKD stages I-V with and without dialysis and compared by log-rank test. Each of the above variables was examined for its association with mortality using a univariate Cox regression analysis. Associated variables with mortality (p ≤ .1) in the univariate analysis were also included in the multivariate Cox regression model. The proportionality-of-hazards assumption was assessed using the Schoenfeld test, and the assumption was met for all variables included. Adjusted hazard ratios (HR) along with 95% confidence interval (CI) were then estimated.   Table 1. In brief, patients with stages III−V were more likely to be older, female, never smokers, and have smaller BMIs and more cardiovascular risk factors (i.e., hypertension, dyslipidemia, and DM).
Patients with stage V with dialysis were more likely to have a previous history of CVD, PAD, prior MI, heart failure, PCI, or CABG, and have a lower LVEF.
The most common indication for PCI was stable angina, except CKD stages IV and V without dialysis, where NSTEMI/UA was more common. Patients with CKD stage V with dialysis were more likely to present with stable angina and NSTEMI/UA with infrequent STEMI.

| Angiographic and procedural characteristics
There were group differences of nearly all lesion characteristics and adjunctive devices used (

| In-hospital major adverse cardiac event (MACE) in overall population
In-hospital outcomes of PCI procedures are described in

| Long-term follow-up results
About 97% of the study patients were followed up to 18 months with a median of 12 ± 3.7 months. All-cause mortality rates were highest in patients with CKD stages IV and V with/or without dialysis (34.8%, 32.0%, and 30.6%, respectively) followed by stage III, II, and I (15.6%, 6.9%, and 3.7%, respectively) (

| Predictors of all-causes of death
Using a univariate analysis (   As known, patients with CKD stage V with regular dialysis are at high risk for CV mortality and morbidity. 24,25 They have been largely excluded from all randomized trials evaluating outcomes of revascularization. In general, PCI in these advanced CKD patients, especially stage V on dialysis, is more complex and difficult to perform because of greater calcification and lesion complexity, requiring plaque modification devices such as atherectomy. 26 However, our findings showed that the angiographic success rate was acceptably as high as other CKD stages whereas the complication rate was unexpectedly the lowest in CKD with dialysis than the other groups. There are several possible explanations for these findings, including younger age patients, less STEMI presentation, less cardiogenic shock and mostly of the PCI procedure were planned. Our study supported the previous studies that contemporary PCI is feasible and safe in appropriated selected patients with higher technical success and acceptable complication rates, even though they require more complex PCI procedure. 27 However, it needs to be emphasize that the 1-year all-cause mortality in these patients was still high after adjustment for other risk factors which mostly was driven by CV death or sudden death (56.5%) and additional unplanned revascularization.
Antecedently, there was no single eGFR cutoff value that was a strong predictor of in-hospital and long-term mortality after PCI.
Recently, Nozari, et al. 28  would be a suitable cutoff for using to consider early invasive management. Importantly, only culprit-PCI may be a better reperfusion option for CKD patients with STEMI or NSTEMI with the multivessel disease rather than multivessel-PCI, concerning the procedure time and the risk of contrast-induced nephropathy. To answer these uncertainties, further well-designed, large-scale prospective studies, and randomized controlled trials are warranted to substantiate these findings and to assess the best revascularization strategies in each sub-group of this high-risk population.

| Limitation of the study
Though this was a well-designed, and prospective cohort study, some limitations need to be mentioned. First, this was only one eGFR result from before the procedure to use for stratification of patients. The subsequent effect on renal function, whether it deteriorated or improved, was not known. Second, we assessed direct effect of CKD on mortality but CKD might be a surrogate marker for other comorbidities that are also causes of mortality. To prove this, a mediation analysis should be further applied. Third, some data were incomplete and not included for analysis such as a syntax score, bleeding risk, which can be important for decision making. Forth, the efficacy of the treatment in each group could not be evaluated because of the lack of randomization and compliance of treatment.
Fifth, the different treatment effect and prognoses of patients in each CKD group were not compared because these were out of scopes of this study and they depended on various uncontrolled factors, including clinical profile and anatomical differences. A randomized controlled trial or a real-world data with propensity score analysis comparing long-term survival after different treatment modalities in these CKD stages should be further conducted.

| CONCLUSION
CKD is a common comorbid disease in CAD patients who undergo elective or urgent/emergency PCI. Various stages of CKD are independently associated with 1-year mortality even after F I G U R E 1 Kaplan−Meier survival for 1-year mortality by CKD stages. CKD, chronic kidney disease.
adjustment for other risk factors. Deterioration of renal function, even to a mild degree, was a strong independent risk predictor of inhospital MACEs and 1-year all-cause mortality in a dose-dependent effect after successful PCI. Currently, the choice of coronary revascularization in these high-risk patients is individualized. This finding may be advantageous for risk classification and to guide decision-making. Whether this risk prediction of the CKD stage can help to reduce the long-term all-cause mortality is a question requiring further study.