Prevalence and Impact of Renal Insufficiency on Clinical Outcomes of Patients Undergoing Coronary Revascularization

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1 Circ J 2007; 71: Prevalence and Impact of Renal Insufficiency on Clinical Outcomes of Patients Undergoing Coronary Revascularization Qiang Zhang; Chang-Sheng Ma; Shao-Ping Nie; Xin Du; Qiang Lv; Jun-Ping Kang; Yin Zhang; Rong Hu; Chang-Qi Jia; Xin-Min Liu; Xiao-Hui Liu; Jian-Zeng Dong; Fang Chen; Yu-Jie Zhou; Shu-Zheng Lv; Fang-Jiong Huang; Cheng-Xiong Gu; Xue-Si Wu Background Patients with renal insufficiency are more likely to die after coronary revascularization, but mild renal insufficiency is neglected and little is known about its clinical effects. Methods and Results In the present study 3,025 patients grouped by estimated creatinine clearance (CrCl) were analyzed to evaluate the association between CrCl and clinical outcome. The mean serum creatinine was 1.0± 0.4 mg/dl, with 4.3% above normal; in 65.8% CrCl was <90 ml/min. During hospitalization, there were significant differences in mortality among the groups stratified by CrCl (p<0.0001). During follow-up after hospital discharge, there were significant differences in mortality (p<0.0001), new-onset myocardial infarction (p=0.007), and stroke (p=0.032). In patients with severe renal insufficiency, the in-hospital and follow-up mortality reached 15.4% and 31.3%, respectively. The independent risk factors for all-cause death after revascularization were the mode of revascularization, age and the CrCl level. In patients with mild renal insufficiency or normal renal function, the all-cause mortality after percutaneous coronary intervention was significantly lower than that after CABG. Conclusions Renal insufficiency is not rare in patients undergoing coronary revascularization and in the present study even mild renal insufficiency correlated with adverse clinical outcomes after revascularization. In patients with normal renal function or mild renal insufficiency, the mode of revascularization might lead to a prognostic difference. (Circ J 2007; 71: ) Key Words: Chronic kidney disease; Creatinine clearance; End-stage renal disease; Mortality; Revascularization There is little doubt that the global incidence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) is increasing. The major cause of morbidity and mortality in these patients is cardiovascular disease. According to recent data, 45% of all deaths in patients with ESRD are cardiac related, with approximately 20% of these deaths caused by acute myocardial infarction (AMI). 1 However, to the best of our knowledge, there is a paucity of study results regarding patients with CKD treated by coronary revascularization because of the exclusion of such patients from major trials. In some small, mostly nonrandomized trials comparing medical therapy with revascularization, revascularization appeared to offer symptom relief and mortality benefit. 2 The retrospective study based on the database of the United States Renal Data System also indicates a benefit, but compared with patients without renal insufficiency, patients with CKD have an increased risk of death and other major adverse events. Renal dysfunction is independently associated in a linear relationship with mortality and other adverse cardiac events during and after coronary revascularization. The increased risk occurs (Received February 22, 2007; revised manuscript received April 15, 2007; accepted May 8, 2007) Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China Mailing address: Chang-Sheng Ma, Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing , China. chshma@vip.sina.com.cn even when renal insufficiency is mild, with a doubling of mortality at 1 year. 3 The pathophysiology is multifactorial, but still unclear. In the present study, we determined the major adverse cardiac cerebral events (MACCE) in patients with mild, moderate and severe renal insufficiency following coronary revascularization, and examined the factors that could be associated with clinic outcome in patients with renal insufficiency. Methods Study Samples In the study, 3,763 patients were enrolled from a singlecenter registry of coronary revascularization at Beijing Anzhen Hospital between July 2001 and June 2002, and between July 2003 and June The mode of revascularization included percutaneous coronary intervention (PCI) (patients were treated with 1 or more stents, excluding coronary angioplasty only with balloon), coronary artery bypass graft (CABG) and hybrid coronary revascularization (including emergency CABG following the failure of PCI). Patients were excluded if revascularization was within 48 h of the onset of AMI, if there was severe anaemia or liver function abnormality. In total, 3,025 formed the study sample (2,377 men, 648 women; mean age 60.0±10.2 [range 14 85] years). Baseline demographic, clinical and angiographic features were recorded for each patient. For patients who had more than 1 revascularization procedure

2 1300 ZHANG Q et al. Table 1 Demographic Data for the Renal Insufficiency Groups and Control Group Age (years) 67.5± ± ± ±9.3 <0.001 Male (%) <0.001 Hemoglobin (g/l) ± ± ± ±15.98 <0.001 WBC ( 10 9 /L) 9.04± ± ± ± Diabetes mellitus (%) Hypertension (%) <0.001 History of ischemic stroke (%) <0.001 History of hemorrhagic stroke (%) Valvular heart disease (%) Prior MI (%) Prior renal disease (%) <0.001 Peripheral vascular disease (%) Prior revascularization (%) Current smoking history (%) <0.001 Indications for revascularization Unstable angina (%) NSTEMI (%) STEMI (%) LVEF<40% (%) CrCl, creatinine clearance; WBC, white blood cells; MI, myocardial infarction; NSTEMI, non-st-elevation MI; STEMI, ST-elevation MI; LVEF, left ventricular ejection fraction. during the study period, the intervention during the index hospitalization was included for analysis, with previous as past history and following as repeat revascularization. The study was approved by the Institutional Review Board of Beijing Anzhen Hospital. Group-Based Creatinine Clearance (CrCl) Serum creatinine level was determined h before coronary revascularization, and renal function was assessed by the CrCl estimated using the Cockroft-Gault formula: = [(140 age) weight (kg)]/72 serum creatinine (mg/dl) ( 1 for men, 0.85 for women). 4 Patients were divided into 4 CrCl groups: <30 ml/min (n=26), ml/min (n=592), ml/min (n=1,372) and 90 ml/min (n=1,035). Follow-up and Endpoints All patients who underwent revascularization were observed in hospital for at least 3 days after the procedure. Inhospital data was collected by reviewing medical records. Of all discharged patients 2,430 (2,430/2,936, 82.8%) were successfully followed up, with a median follow-up time of 664 (182 1,530) days. Follow-up data after discharge was collected by telephone inquiry or interview in the outpatient clinic. MACCE, including all-cause of death, new-onset myocardial infarction (MI), stroke and repeat revascularization, were also recorded. The number of diseased vessels was defined as the number of the coronary arteries with luminal diameter narrowing 70%, and main left main coronary arteries stenosis 50% were considered to be 2-vessel disease. Complete revascularization was achieved if there was no remaining stenosis 70% in the coronary artery luminal diameter 2 mm. Left anterior descending (LAD) proximal lesion was defined as stenosis 70% in the proximal half of the LAD. Long lesion was defined as being >20 mm. MI after revascularization was defined by serum cardiac enzyme (CK-MB) elevation at least 3-fold the upper limit of the normal range; symptoms and ECG changes were not necessary. Statistical Analysis Data are expressed as mean ± standard deviation or percentage. Comparisons among groups were made by the Pearson chi-square test for discrete numerical measurements and ANOVA test for continuous numerical parameters. Comparisons between 2 groups were made by Student s t-test for continuous numerical parameters. We then used multiple logistic regression analyses to examine factors, including the demographic, clinical, and revascularization characteristics, associated with the outcomes of patients after revascularization. All tests of significance were 2- tailed and p<0.05 was considered significant. All statistical analysis was made using SPSS 13.0 software (Chicago, IL, USA). Results Baseline Patient Characteristics Patients in the renal insufficiency groups were older and more were women, had hypertension and a history of ischemia stroke, renal disease and peripheral vascular disease than those in the normal renal function group. Patients in the renal insufficiency groups had lower levels of hemoglobin and higher white blood cell counts than normal renal function group. In the lowest CrCl group, 2 (7.7%) patients were undergoing long-term hemodialysis. No patient in the other groups had undergone hemodialysis before revascularization. Diabetes mellitus, history of hemorrhagic stroke, valvular heart disease, prior MI, prior revascularization, indications for revascularization and left ventricular ejection fraction <40% were not significantly different among the 4 groups (Table 1). Angiographic and Revascularization Characteristics The lowest CrCl group had a greater number of diseased coronary vessels than the higher CrCl groups, but the inci-

3 Renal Insufficiency and Coronary Revascularization 1301 Table 2 Angiographic and Procedural Data No. of diseased vessels 2.50± ± ± ±0.84 <0.001 Multivessel disease (%) <0.001 LM lesion (%) LAD proximal lesion (%) Ostial lesion (%) CTO (%) ISR (%) Long lesion (%) Complex lesion (%) Revascularization PCI (%) CABG (%) Complete Revascularization(%) Failed PCI (%) LAD, left anterior descending; CTO, chronic total occlusion; ISR, in-stent restenosis; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft. Other abbreviation see in Table 1. Table 3 In-Hospital Medical Therapy Statin (%) ASA (%) Clopidogrel (%) ACEI (%) blocker (%) ASA, aspirin; ACEI, angiotensin-converting enzyme inhibitors. Other abbreviation see in Table 1. Table 4 Medical Therapy After Discharge (n=16) (n=472) (n=1,103) (n=839) Statin (%) ASA (%) Clopidogrel (%) ACEI (%) blocker (%) Abbreviations see in Tables 1,3. dence of left main lesion, LAD proximal lesion, ostial lesion, chronic total occlusion, in-stent restenosis lesion, long lesion or complex lesion was similar among the 4 groups. In the lowest CrCl group, more patients underwent CABG, whereas in the normal renal function group and the mild renal insufficiency group more patients underwent PCI. The rates of complete revascularization and failed PCI were similar among the 4 groups (Table 2). Medical Therapy Characteristics The rates of in-hospital usage of statins and clopidogrel in the lowest CrCl group were lower than in the higher CrCl groups, but were not significantly different among the 4 groups during follow-up after hospital discharge. The usage of aspirin, angiotensin-converting enzyme inhibitors and -blockers were similar among the 4 groups both during hospitalization and after hospital discharge (Tables 3,4). Clinical Outcomes During hospitalization, mortality in the lowest CrCl group was 15.4% (3 (11.5%) cardiogenic deaths, 1 (3.8%) noncardiogenic death), which were much higher than in the highest CrCl group (1.0%, 0.7%, 0.3%, respectively; all p<0.001). The difference in the incidences of stroke and MACCE among the 4 groups was also significant (Table 5). In particular, there was a significant difference between the CrCl ml/min group and the CrCl 90 ml/min group in MACCE (3.4% vs 1.4%, p=0.002), mortality (2.3% vs 1.0%, p=0.016), cardiogenic death (1.6% vs 0.7%, p=0.018) and new-onset MI (1.0% vs 0.2%, p=0.019). In addition, 7 (26.9%) patients in the lowest CrCl group underwent continuous renal replacement therapy after the procedure for 3 10 days; 2 of them died from cardiogenic causes later during hospitalization, and none of the other 5 patients had to undergo hemodialysis after discharge.

4 1302 ZHANG Q et al. Table 5 Adverse In-Hospital Clinical Outcomes After Revascularization Death (%) <0.001 Cardiogenic death (%) <0.001 Noncardiogenic death (%) <0.001 MI (%) Stroke (%) Repeat revascularization (%) MACCE (%) <0.001 MACCE, major adverse cardiac cerebral events. Other abbreviations see in Table 1. Table 6 Adverse Clinical Outcomes During Follow-up After Discharge (n=16) (n=472) (n=1,103) (n=839) Death (%) <0.001 Cardiogenic death (%) <0.001 Noncardiogenic death (%) <0.001 MI (%) Stroke (%) Repeat revascularization (%) MACCE (%) Abbreviations see in Tables 1,5. Table 7 Multivariate Analysis of Risk Factors for All-Cause Death After Revascularization All-cause death OR (95%CI) p value Male (0.159, 1.367) Age (1.040, 1.171) Diabetes mellitus (0.125, 1.495) Hypertension (0.392, 2.050) Current smoking (0.330, 1.935) Indication for revascularization (0.598, 1.733) LVEF (0.944, 1.013) Statin therapy during hospitalization (0.224, 1.259) SCr (0.686, 3.634) CrCl (0.213, 0.988) Mode of revascularization (PCI/CABG) (2.261, ) No. of diseased vessels (0.595, 1.920) OR, odds ratio; CI, confidence interval; SCr, serum creatinine. Other abbreviations see in Tables 1,2. During follow-up after discharge (median 664 days), mortality in the lowest CrCl group was 31.3% (4 (25.0%) cardiogenic deaths, 1 (6.3%) noncardiogenic death), which were also much higher than in the highest CrCl group (2.0%, 1.5%, 0.5% respectively; all p<0.001). There were also significant differences among the 4 groups in rates of new-onset MI, stroke, and MACCE, but no difference in repeat revascularization (Table 6). Predictors of All-Cause Mortality At present, a statistically significant center effect regarding the all-cause death of patients after revascularization has not been found. In the present study, 12 potential risk factors for all-cause death were tested in the multivariate analysis (Table 7) and the mode of revascularization, age and the degree of CrCl proved to be independent risk factors (odds ratio (OR) 7.487, 95% confidence interval (CI) , p=0.001; OR 1.104, 95% CI , p=0.001; OR 0.458, 95%CI , p=0.047, respectively). Interaction With Mode of Revascularization Both the in-hospital and after discharge follow-up outcomes were analyzed across the choice of mode of revascularization (PCI or CABG). The interaction terms between the PCI and CABG groups in patients with normal renal function (CrCl 90 ml/min) or mild renal insufficiency (CrCl ml/min) were significant different in the outcomes (1.8% vs 5.2%, p=0.008; 2.3% vs 9.4%, p<0.001 respectively). But in the moderate (CrCl ml/min) and severe renal sufficiency patients (CrCl <30 ml/min), there was no significant difference between the PCI and CABG groups (Table 8). These results suggest that the effect of the mode of the revascularization on all-cause death did differ in patients with CrCl 60 ml/min.

5 Renal Insufficiency and Coronary Revascularization 1303 Table 8 Mortality After Revascularization in the Subgroup Analysis Mode of revascularization Mortality (%) p value <30 PCI 37.5 CABG PCI 6.8 CABG PCI 2.3 CABG 9.4 < PCI 1.8 CABG Abbreviations see in Table 2. Discussion In our study of 3,025 patients (mean age 60±10 (14 85) years), 2,377 (78.6%) of them were male and the indications for revascularization were ST-elevation MI (321, 10.6%), non-st-elevation MI (83, 2.7%), unstable angina (1,938, 64.1%) and stable angina (596, 19.7%). The mode of revascularization was PCI (1,639, 54.2%), CABG (1,379, 45.6%) or a hybrid (7, 0.2%). These data reflect the real world of revascularization treatment in China at present. We found that in patients with renal insufficiency, the rate of repeat revascularization is not increased after producer in follow-up, but patients with severe renal insufficiency had a approximately 15-fold increased risk of death, nearly 80% from cardiogenic causes, and an approximately 9-fold increased risk of MI during follow-up compared with the normal renal function patients. It has been determined that cardiovascular events are fold greater in dialysisdependent CKD patients than in the general population. 5,6 Recently, some investigators turned their attention to the prognosis of patients with mild renal insufficiency after revascularization. 3,7,8 Those studies have demonstrated that mild renal insufficiency is associated with a doubling of mortality. In our study, there were only 4.3% of patients with a serum creatinine 1.5 mg/dl and 2 (0.07%) patients undergoing hemodialysis, but approximately 65.8% of the patients had renal insufficiency (CrCl <90 ml/min), and 45.4% in particular had mild renal insufficiency (CrCl ml/min). In the present mild renal insufficiency group, the risk of in-hospital death and cardiogenic death were both 2.3-fold greater than in the normal renal function group, and the risk of new-onset MI was 5-fold greater. These results remind us not to neglect patients with a normal serum creatinine level, especially older females and lower weight patients. Using the Cockroft-Gault formula, these patients CrCl would be lower than that for younger males and normal weight patients in the same level of serum creatinine. Not surprisingly, in the present study patients with renal insufficiency were older, and more had hypertension and prior ischemic stroke that those with normal renal function. It will improve patient outcomes if those with mild renal insufficiency are identified before revascularization. To date there has not been a meta-analysis or pooled analysis of the data from trials of revascularization in patients with renal insufficiency, although in general it appears that PCI provides excellent angiographic success despite being associated with increased restenosis and the need for repeat revascularization, and that CABG, while associated with higher in-hospital morbidity and mortality, provides better overall long-term results and freedom from angina. 9 In a series from the New York registry, Szczech et al found the adjusted estimated 2-year survival to be 51.9% after PCI and 77.4% after CABG in patients with renal insufficiency. 10 Similarly, Reddan et al found that CABG provided a survival benefit in comparison with both PCI and medical management across the entire spectrum of renal insufficiency. Contrarily, PCI provided a survival benefit in comparison with medical management only in patients with mild or moderate renal dysfunction. 11 However, a more recent study of 350 patients by Rubenstein et al found more promising short- and long-term outcomes using advances in interventional cardiology such as stents and debulking devices. 12 In addition, a retrospective analysis of 1,654 patients with a glomerular filtration rate of <60 ml/min revealed that PCI yielded better results than medical therapy and CABG in renal insufficiency patients with acute coronary syndromes. 13 There is still debate about the optimal treatment for CVD patients with renal insufficiency. In the current study, the independent risk factors of all-cause of death after procedure were the mode of revascularization, age and the degree of CrCl. In total the patients undergoing CABG had a higher mortality than those undergoing PCI. When we investigated further, we found that in both the normal renal function group and the mild renal insufficiency group the mortality of patients undergoing PCI was significantly lower than for those undergoing CABG, whereas in the moderate to severe renal insufficiency groups, there was no significant difference between those undergoing PCI or CABG. Remarkably, the patients undergoing CABG in the current study usually had complex coronary lesion and many complications, and some of them were failed prior PCI cases, so there is not strange that the patients undergoing CABG had poor prognoses, especially during hospitalization after procedure. Our results suggest that patients with moderate or severe renal insufficiency would not get a benefit from PCI. Although therapy with aspirin, -blockers, angiotensin-converting enzyme inhibitors and statins is effective and safe in patients with coronary heart disease and renal insufficiency, studies have determined that their usage is still lower than in patients with normal renal function, and this is thought to be associated with the higher mortality in the former group of patients. 14,15 In our retrospective study, there was hardly any difference among the normal renal function, mild to severe renal insufficiency groups. A deficiency in medical therapy was not an important influencing factor on the mortality of patients with renal insufficiency and coronary heart disease, and the patients with renal insufficiency had a higher mortality rate even though they were treated with almost the same medical therapy as those with normal renal function. Despite the debate regarding the relative merits of revascularization and medical therapy, the number of coronary

6 1304 ZHANG Q et al. revascularization procedures in patients with severe renal insufficiency is certain to increase. Based on the database of the United States Renal Data System, the benefits of CABG and PCI in dialysis patients have been identified. The in-hospital mortality was 8.6% for 6,668 CABG patients and 4.1% for 4,280 stent patients, which was lower than that of the medicine therapy patients. The 2-year allcause survival was 56.4% for CABG patients and 48.4% for stent patients, which was higher than that of medicine therapy patients. 16 In the present CrCl <30 ml/min group, the all-cause survival was 50% for CABG patients and 62.5% for PCI patients. The use of off-pump CABG, antithrombotic and antiplatelet therapies, new thrombectomy devices, chronic total occlusion technology, and distal protection devices may also be of benefit. In a word, patients with severe renal insufficiency have a very poor prognosis, and whether they could also benefit from revascularization merits further investigation. Study Limitations First, the renal function in the study was assessed by the estimated CrCl using the Cockroft-Gault formula, not using fractional uptake of 99m TC-DTAP. Second, there is difference in the mean age among the 4 CrCl groups, as well as for gender. Further prospective studies are needed to elucidate the coronary revascularization risk associated with renal insufficiency. References 1. National Institute of Diabetes and Digestive and Kidney Diseases. Renal Data System: USRDS 2000 Annual Data Report. (NIH publication no ). Bethesda, MD: National Institutes of Health, 2000; Manske CL, Wang Y, Rector T, Wilson RF, White CW. Coronary revascularisation in insulin-dependent diabetic patients with chronic renal failure. Lancet 1992; 340: Best PJ, Lennon R, Ting HH, Bell MR, Rihal CS, Holmes DR, et al. The impact of renal insufficiency on clinical outcomes in patients undergoing percutaneous coronary interventions. J Am Coll Cardiol 2002; 39: Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: Brunner FP, Selwood NH. Profile of patients on RRT in Europe and death rates due to major causes of death groups: The EDTA Registration Committee. Kidney Int Suppl 1992; 38: S4 S Parekh RS, Carroll CE, Wolfe RA, Port FK. Cardiovascular mortality in children and young adults with end-stage kidney disease. J Pediatr 2002; 141: Szczech LA, Best PJ, Crowley E, Brooks MM, Berger PB, Bittner V, et al; Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Outcomes of patients with chronic renal insufficiency in the bypass angioplasty revascularization investigation. Circulation 2002; 105: Zhang RY, Ni JW, Zhang JS, Hu J, Yang ZK, Zhang Q, et al. Long term clinical outcomes in patients with moderate renal insufficiency undergoing stent based percutaneous coronary intervention. Chin Med J 2006; 119: Ivens K, Gradaus F, Heering P, Schoebel FC, Klein M, Schulte HD, et al. Myocardial revascularization in patients with end-stage renal disease: Comparison of percutaneous transluminal coronary angioplasty and coronary artery bypass grafting. Int Urol Nephrol 2001; 32: Szczech LA, Reddan DN, Owen WF, Califf R, Racz M, Jones RH, et al. Differential survival after coronary revascularization procedures among patients with renal insufficiency. Kidney Int 2001; 60: Reddan DN, Szczech LA, Tuttle RH, Shaw LK, Jones RH, Schwab SJ, et al. Chronic kidney disease, mortality, and treatment strategies among patients with clinically significant coronary artery disease. J Am Soc Nephrol 2003; 14: Rubenstein MH, Harrell LC, Sheynberg BV, Schunkert H, Bazari H, Palacios IF. Are patients with renal failure good candidates for percutaneous coronary revascularization in the new device era? Circulation 2000; 102: Keeley EC, Kadakia R, Soman S, Borzak S, McCullough PA. Analysis of long-term survival after revascularization in patients with chronic kidney disease presenting with acute coronary syndromes. Am J Cardiol 2003; 92: Berger AK, Duval S, Krumholz HM. Aspirin, beta-blocker, and angiotensin-converting enzyme inhibitor therapy in patients with endstage renal disease and an acute myocardial infarction. J Am Coll Cardiol 2003; 42: Yigit F, Muderrisoglu H, Guz GP, Bozbas H, Korkmaz ME, Ozin MB, et al. Comparison of intermittent with continuous simvastatin treatment in hypercholesterolemic patients with end stage renal failure. Jpn Heart J 2004; 45: Herzog CA, Ma JZ, Collins AJ. Comparative survival of dialysis patients in the United States after coronary angioplasty, coronary artery stenting, and coronary artery bypass surgery and impact of diabetes. Circulation 2002; 106: