The Impact of Renal Dysfunction on the Long Term Clinical Outcomes of Diabetic Patients Undergoing Percutaneous Coronary Intervention in the Drug-Eluting Stent Era

Background Limited data are available regarding the association between renal dysfunction and clinical outcomes in diabetic patients undergoing percutaneous coronary intervention (PCI) in the drug-eluting stent (DES) era. Methods Between March 2003 and December 2010, 2,181 diabetic patients were enrolled in a single-center registry. We divided diabetic patients into a renal dysfunction group (n = 518) and a non-renal dysfunction group (n = 1,663) according to a baseline estimated glomerular filtration rate <60 mL/min/1.73 m2. Propensity score matching analysis was also performed. The primary outcome was cardiac death. Results The median follow-up duration was 48 months. The rate of cardiac death was higher in the renal dysfunction group than in the non-renal dysfunction group (14.3% vs. 3.0%, adjusted hazard ratio [HR] 3.63, 95% confidence interval [CI] 2.47 to 5.35, p<0.001). Similarly, the incidence of stent thrombosis was significantly higher in the renal dysfunction group than in the non-renal dysfunction group (4.1% vs. 1.4%, adjusted HR 1.90, 95% CI 1.02 to 3.56, p = 0.04). After 1:1 propensity score matching (502 pairs), patients with renal dysfunction still had a higher rate of cardiac death (13.3% vs. 4.8%, HR 2.58, 95% CI 1.52 to 4.38, p<0.001) although there was no significant difference in the rate of stent thrombosis (4.0% vs. 2.8%, HR 1.31, 95% CI 0.64 to 2.69, p = 0.47). Conclusions Renal dysfunction is associated with long-term mortality for diabetic patients undergoing PCI in the DES era.


Introduction
Diabetes mellitus is regarded as a coronary heart disease risk equivalent as defined by the US National Cholesterol Education Program Adult Treatment Panel III guidelines and is the leading cause of chronic kidney disease (CKD) [1][2][3]. Several studies have demonstrated that patients with renal dysfunction have an increased risk of adverse clinical outcomes after percutaneous coronary intervention (PCI), including stent thrombosis [4][5][6][7][8][9]. Renal dysfunction was shown to be an independent predictor of adverse cardiovascular events among diabetic patients undergoing PCI before the introduction of drug-eluting stents (DES) [10][11][12][13]. After the development of DES, PCI was expected to improve survival rates in patients with renal dysfunction and prevent restenosis, which is accelerated by atherosclerosis [14]. However, the association between renal dysfunction and long-term cardiovascular outcomes of diabetic patients has not been fully elucidated in the DES era. Therefore, the aim of this study was to determine the association between renal dysfunction and long-term clinical outcomes for diabetic patients who undergo PCI with DES.

Study population
This was a retrospective, single-center, observational study. Between March 2003 and December 2010, a total of 2,187 consecutive diabetic patients who underwent PCI with DES were recruited from the cardiovascular catheterization databases of Samsung Medical Center, Seoul, Korea. Six patients who did not have data on creatinine levels were excluded. Baseline characteristics, angiographic and procedural data, and outcome data were prospectively recorded by PCI registry research coordinators. Additional information was obtained from medical records and telephone interviews if necessary. The requirement for informed consent of the individual patients was waived given the retrospective nature of the study by the Institutional Review Board of the Samsung Medical Center.

Percutaneous coronary intervention procedure
Coronary interventions were performed according to current standard procedural guidelines. All patients received loading doses of aspirin (300 mg) and clopidogrel (300-600 mg) before coronary intervention unless they had previously received these antiplatelet medications. Anticoagulation therapy during PCI was performed according to the current practice guidelines stipulated by the Korean Society of Interventional Cardiology. The treatment strategy, duration of clopidogrel use, and the use of glycoprotein IIb/IIIa receptor inhibitors or intravascular ultrasound were all performed according to the operator's discretion. Drug-eluting stents were used without restriction.
hypoglycemic agents or insulin. Renal dysfunction was assessed based on a baseline estimated glomerular filtration rate <60 mL/min/1.73m 2 according to the Modification of Diet in Renal Disease (MDRD) equation [15,16]. All-cause death was defined as any post-procedure death during follow up and was considered cardiac unless a definite non-cardiac cause was established. Recurrent myocardial infarction (MI) was defined as the recurrence of ischemic symptoms or electrocardiographic changes accompanied by elevated cardiac enzymes. Any revascularization was defined as revascularization of either target or non-target vessels with PCI or bypass graft surgery. Stent thrombosis (ST) was defined using the definitions of the Academic Research Consortium as definite, probable, or possible stent thrombosis [17]. The timing of ST was stratified as early (within 1 month after index procedure), late (between 1 month and 1 year), or very late (after 1 year).
Diabetic patients were divided into two groups according to their baseline estimated glomerular filtration rate (GFR) (<60 or 60 ml/min/1.73m 2 ). The primary outcome was cardiac death during follow-up. Secondary outcomes included all-cause death, myocardial infarction, ST, and major adverse cardiac and cerebrovascular events (MACCE) consisting of cardiac death, MI, ST, any revascularization, and cerebrovascular events (CVA). Among diabetic patients with renal dysfunction, additional analysis was performed to determine whether duration of dual antiplatelet therapy affects the incidence of ST.

Statistical analysis
Continuous variables were compared using the t-test or Wilcoxon rank-sum test when applicable. Categorical data were tested using the chi-squared test or Fisher's exact test, as appropriate. Event-free survival was evaluated by Kaplan-Meier analyses and significance level was assessed with the log-rank test. In multivariable models, covariates that were either statistically significant on univariate analysis or clinically relevant were considered candidate variables. To assess the association of renal dysfunction with clinical outcomes, we used a Cox proportional hazards model adjusted for age, sex, hypertension, smoking status, history of PCI, previous MI, history of CVA, multi-vessel disease, left anterior descending artery involvement, and presence of acute coronary syndrome. Propensity score matching was performed in order to reduce selection bias and potential confounding factors. A full nonparsimonious model was developed that included all variables listed in Table 1 with the exception of creatinine level. After propensity score matching, model fit and predictive power were assessed using the Hosmer-Lemeshow test and c-statistic. Cox regression analysis using pairs matched by a greedy algorithm and the nearest available pair-matching method among patients with an individual propensity score was also performed to evaluate the reduction in outcomes risk. The covariate balance achieved by matching was assessed by calculating the absolute standardized mean differences between two groups. Continuous variables were compared with the paired t test or Wilcoxon signedranked test, as appropriate. Categorical variables were compared with the McNemar's or Bowker's test of symmetry, as appropriate. Cumulative incidence rates of individual clinical outcomes and composite outcomes were estimated by the Kaplan-Meier method and compared by the paired Prentice-Wilcoxon test. Statistical analyses were performed with SAS 9.2 (SAS Institute Inc., Cary, NC, USA). All tests were two-tailed and p <0.05 was considered statistically significant.

Baseline and angiographic characteristics
Overall population. A total of 2,181 consecutive diabetic patients who underwent PCI with DES were analyzed in this study. Among the patients, 518 (23.8%) had renal dysfunction and 1,663 (76.2%) had preserved renal function. Baseline clinical and angiographic characteristics according to estimated GFR are described in Table 1. Patients with renal dysfunction were more likely to be women, older, and have a lower body mass index, lower prevalence of smoking, and a higher prevalence of hypertension, insulin treatment rates, prior PCI or bypass surgery, previous MI, CVA, peripheral vascular disease, and higher serum creatinine level. There were no significant differences in clinical presentation and glycated hemoglobin A 1c . Multi-vessel disease was more common in the renal dysfunction group, but the vessel involved and the number of treated vessels was similar between the two groups.
Propensity-matched population. After performing propensity score matching for the entire population, a total of 502 matched pairs of patients were obtained ( Table 1). The c-statistic for the propensity score model was 0.73, which indicates good discrimination (Hosmer-Lemeshow goodness of fit p = 0.98). There were no significant differences in baseline clinical  and angiographic characteristics for the propensity-matched subjects, with the exception of creatinine level. All variables had acceptable standardized mean differences.

Duration of dual antiplatelet and stent thrombosis
Diabetic patients with renal dysfunction were analyzed based on whether they had undergone less or greater than 12 months of dual antiplatelet therapy. Patients who died within a year of undergoing PCI were excluded from the analysis. Among those included, there were 124 patients who had been on less than 12 months of dual antiplatelet therapy of whom 4 had definitive or probable ST (3.2%), whereas there were 339 patients who had been on greater than 12 months of therapy of whom 8 had ST (2.4%). The difference between the two groups was not statistically significant (HR 1.20, 95% CI 0.36 to 4.00, p = 0.768).

Clinical outcomes according to the grade of renal insufficiency
We performed additional analyses to evaluate the association of a decrease in GFR with the rates of cardiac death and stent thrombosis. Study patients were divided into four groups according to their baseline estimated GFR (>90, 89-60, 59-30, and <30 ml/min/1.73m2). Table 4 shows cumulative clinical outcomes according to the level of GFR. There were no significant differences in the rates of cardiac death and ST between normal renal function (GFR > 90) and mild renal insufficiency (GFR 89 to 60) groups. However, moderate or severe renal insufficiency groups (GFR 59 to 30 and <30) had higher rates of cardiac death compared with normal renal function group. Severe renal insufficiency group (GFR <30) had a trend toward a high incidence in ST (6.9%) compared with normal renal function group (2.0%).

Discussion
In the present study, we investigated the association between renal dysfunction and long-term cardiovascular outcomes in diabetic patients undergoing PCI with DES using a single-center registry. The major findings of this study were that renal dysfunction was associated with higher rates of cardiovascular events in diabetes patients after PCI with DES. In particular, the association of renal dysfunction with a higher incidence of cardiac death was maintained in propensity-matched populations. In addition, definite or probable stent thrombosis was numerically higher in the renal dysfunction group than the non-renal dysfunction group, there was no statistically difference between the two groups.
For the pre-DES era, a previous study showed that diabetic patients with CKD had an almost 2-fold higher rate of all-cause death and 1.5-fold higher rate of MACCE (death, MI, bypass surgery, or target lesion PCI) compared with those without CKD [10]. Similarly, in our study of patients undergoing PCI with DES, patients with renal dysfunction had a 2-to 3-fold higher rate of cardiac death, all-cause death, and MI compared with those without renal dysfunction after performing propensity-score matching; and the rate of MACCE was almost 1.5-fold higher in the renal dysfunction group compared with the non-renal dysfunction group. These findings suggest that the association of renal dysfunction with worse clinical outcomes in diabetic patients undergoing PCI was maintained in the DES era even though the introduction of DES has dramatically reduced the restenosis rate. CKD is not defined as a coronary risk equivalent in the current guideline due to insufficient data [18]. However, a recent large cohort study showed that the diabetes and CKD group had a greater relative risk of MI and all-cause death than the previous MI group [19]. In addition, CKD is associated with an increased bleeding risk and a greater risk of thrombotic  complications, including stent thrombosis [7][8][9][20][21][22]. Moreover, the presence of a low platelet response to clopidogrel is related to worse cardiovascular outcomes after PCI in patients with CKD [23]. However, comparison of ST between renal dysfunction and non-renal dysfunction groups among diabetic patients has been not fully evaluated in the DES era. In this study, we demonstrated that the risk of ST (definitive or probable) in the DES era is increased almost 2-fold in diabetic patients with renal dysfunction (4.1%) compared with those without renal dysfunction (1.4%). This finding is in agreement with a previous study indicating that impaired renal function is related to the reduced anti-platelet effects of clopidogrel in diabetes patients undergoing PCI [24]. After performing propensity-score matching, although the absolute incidence of stent thrombosis was higher in the renal dysfunction group than in the non-renal dysfunction group, no statistically significant difference was found between the two groups. The discrepancy between multivariate analysis and propensity score matching may be due to the very low incidence of ST. Further prospective multi-center studies with a large study population would be helpful to confirm the results of our study. Dual antiplatelet therapy improves clinical outcomes after PCI through reductions in both ST and MI not related to ST [25]. Current practice guidelines recommend at least 12 months of dual antiplatelet therapy in patients with acute coronary syndrome undergoing PCI with DES [26]. However, optimal duration of dual antiplatelet use has been subject to debate. Though it seems logical to presume benefit to longer duration of dual antiplatelet therapy in diabetic patients with renal dysfunction due to their increased risk of thrombosis and resistance to P2Y12 inhibitors, among diabetic patients with renal dysfunction in the present study, dual antiplatelet therapy duration after PCI (less than 12 months vs. more than 12 months) did not show any statistically significant difference on the incidence of ST. It is uncertain why there were no significant differences between the two groups in the incidences of ST. Accordingly, a large randomized controlled trial is needed to further elucidate the optimal duration of dual antiplatelet therapy in diabetic patients with renal dysfunction.

Study limitations
This study had several limitations. First, it was an observational study, which may have affected the results because of confounding factors. In addition, the selection of treatment strategies was based on the doctor's preference. Although we performed various risk adjustments for potential confounding factors, including propensity score matching, we were not able to correct for unmeasured variables. Second, in particular, due to the limitations of our data base, we did not have information on why physicians discontinued dual antiplatelet therapy. Third, estimated GFR was assessed by laboratory data from a single time-point and the influence of contrast toxicity on clinical outcomes or laboratory data was not investigated. However, the earliest measured serum creatinine before PCI, which should most accurately represented the patients' baseline kidney function, was recorded. Finally, our results must be interpreted with caution considering the relatively small sample size and the lack of power to detect differences in ST.

Conclusion
Renal dysfunction was associated with worse long-term clinical outcomes in diabetic patients undergoing PCI despite the introduction of DES.
Supporting Information S1 Dataset. Minimal relevant dataset of this study. (CSV)