Journal of the American College of Cardiology Vol. 50, No. 11, 2007 © 2007 by the American College of Cardiology Foundation ISSN 0735-1097/07/$32.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2007.05.033

CLINICAL RESEARCH Clinical Trial

Renal Protection for Coronary in Advanced Renal Failure Patients by Prophylactic A Randomized Controlled Trial

Po-Tsang Lee, MD,*‡§ Kang-Ju Chou, MD,*‡ Chun-Peng Liu, MD,† Guang-Yuan Mar, MD,† Chien-Liang Chen, MD,*‡ Chih-Yang Hsu, MD,* Hua-Chang Fang, MD,*‡ Hsiao-Min Chung, MD* Kaohsiung, Taipei, and Tainan, Taiwan

Objectives We performed a study to determine whether prophylactic hemodialysis reduces contrast nephropathy (CN) after coronary angiography in advanced renal failure patients.

Background Pre-existing renal failure is the greatest risk factor for CN. Hemodialysis can effectively remove contrast media, but its effect upon preventing CN is still uncertain.

Methods Eighty-two patients with chronic renal failure, referred for coronary angiography, were assigned randomly to re- ceive either normal saline intravenously and prophylactic hemodialysis ( group; n ϭ 42) or fluid supple- ment only (control group; n ϭ 40).

Results Prophylactic hemodialysis lessened the decrease in creatinine clearance within 72 h in the dialysis group (0.4 Ϯ 0.9 ml/min/1.73 m2 vs. 2.2 Ϯ 2.8 ml/min/1.73 m2;pϽ 0.001). Compared with the dialysis group, the serum creatinine concentrations in the control group were significantly higher at day 4 (6.3 Ϯ 2.3 mg/dl vs. 5.1 Ϯ 1.3 mg/dl; p ϭ 0.010) and at peak level (6.7 Ϯ 2.7 mg/dl vs. 5.3 Ϯ 1.5 mg/dl; p ϭ 0.005). Temporary renal re- placement therapy was required in 35% of the control patients and in 2% of the dialysis group (p Ͻ 0.001). Thirteen percent of the control patients, but none of the dialysis patients, required long-term dialysis after dis- charge (p ϭ 0.018). For the patients not requiring chronic dialysis, 13 patients in the control group (37%) and 2 in the dialysis group (5%) had an increase in serum creatinine concentration at discharge of more than 1 mg/dl from baseline (p Ͻ 0.001).

Conclusions Prophylactic hemodialysis is effective in improving renal outcome in chronic renal failure patients undergoing coronary angiography. (J Am Coll Cardiol 2007;50:1015–20) © 2007 by the American College of Cardiology Foundation

Contrast nephropathy (CN) is a major complication after abetic patients (5–7). When CN occurs in these high-risk coronary intervention and is the third leading cause of patients, this could cause temporary renal deterioration or hospital-acquired acute renal failure (1–4). Because pre- lead to permanent end-stage renal disease (ESRD) neces- existing renal dysfunction is the most important risk factor sitating chronic dialysis. (1–4), the incidence of acute renal shutdown after coronary Several interventions have been used to prevent CN, but angiography (CAG) is quite high in patients with chronic only fluid supplements, low-osmolality contrast, a double renal failure. It has been reported that when serum creati- dose of N-acetylcysteine, and reducing the dose of the nine (Cr) levels are Ͼ4.5 mg/dl, the likelihood of CN contrast agent have been shown to be effective (8–15). approaches 100% for diabetic patients and 60% for nondi- These strategies were mainly investigated in the general population or in patients with mild renal insufficiency; methods for preventing CN in advanced renal failure patients remain From the Divisions of * and †Cardiology, Department of Medicine, unknown. Additionally, excessive fluid supplement is barely Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; ‡National Yang-Ming University, School of Medicine, Taipei, Taiwan; and the §Institute of Clinical tolerated in patients with renal failure, especially when they Medicine, National Cheng Kung University Medical College, Tainan, Taiwan. have poor heart function. Supported by grants from Kaohsiung Veterans General Hospital (VGHKS93-31) and Contrast media are excreted mainly by glomerular filtra- the National Science Committee (NSC93-2314-B-075B-012). Manuscript received December 6, 2006; revised manuscript received May 18, 2007, tion. The elimination is slow in patients with chronic renal accepted May 22, 2007. failure; therefore, it would make these vulnerable patients 1016 Lee et al. JACC Vol. 50, No. 11, 2007 Hemodialysis Prevents Contrast Nephropathy September 11, 2007:1015–20

Abbreviations exposed to contrast media longer. Follow-up. Creatinine clearance (CrCl) was measured by and Acronyms It is known that contrast media 24-h urine collection before and on the fourth day after can be effectively removed from coronary angiography. Additional measurements of Cr were coronary ؍ CAG angiography the blood of patients with chronic performed in patients with acute renal failure (defined as an contrast nephropathy renal failure by hemodialysis even increase of Cr on the fourth day of more than 25% from ؍ CN faster than by kidney in normal baseline) every other day until dialysis started or renal serum creatinine ؍ Cr subjects (16). Hemodialysis after function recovered and at discharge in all patients who did ؍ CrCl creatinine clearance contrast media exposure is hy- not need dialysis. Biochemical data were analyzed at a end-stage renal pothesized to be helpful in lessen- central laboratory. The primary end point was the change in ؍ ESRD disease ing CN. Therefore, we performed CrCl between baseline and the fourth day. Secondary end a prospective, randomized control points were the differences in Cr levels on the fourth day trial to examine the efficacy of prophylactic hemodialysis in from baseline, peak Cr level during hospitalization, and Cr the prevention of CN in patients with advanced renal failure level at discharge. The numbers of patients with an increase undergoing coronary procedures. in Cr level at discharge of at least 1.0 mg/dl above baseline and of patients that required emergent and permanent dialysis were also recorded. Emergent dialysis was per- Methods formed if there was oliguria for more than 48 h despite the Participants. The study was performed between August administration of more than 1,000 mg intravenous furo- 2003 and June 2006 in Kaohsiung Veterans General Hos- semide per day or if the level of serum potassium remained pital in Taiwan. Patients were considered eligible for the Ͼ6 mEq/l with or without electrocardiogram change de- study if they were older than 20 years of age, had been spite the administration of oral kayexalate. Hemodialysis referred for coronary angiography, and had a stable Cr was discontinued when there was evidence of recovery of concentration of more than 3.5 mg/dl with a change of renal function, with the restoration of urine amount of Ͻ0.5 mg/dl in 1 month. Criteria for exclusion included Ͼ500 ml/day and improvement of CrCl Ͼ5 ml/min/ pregnancy, lactation, intravascular administration of con- 1.73 m2. The need for permanent dialysis was persistent trast medium within the previous 7 days, treatment with with CrCl Ͻ5 ml/min/1.73 m2. metformin or nonsteroidal anti-inflammatory drugs within Statistical analysis. When calculating sample size, we the previous 48 h, exposure to nephrotoxic drugs within the assumed a baseline CrCl of 12 ml/min/1.73 m2. Assuming previous 7 days, history of serious reactions to the contrast a decrease in the CrCl of 5 percent for the dialysis group, medium, newly diagnosed unstable diabetes, severe con- 20% for the control group and a common standard deviation comitant disease, renal transplantation, and ESRD neces- of the decrease of 2.2 ml/min/1.73m2; the inclusion of 34 sitating chronic dialysis. Acetylcysteine, theophylline, dopa- subjects in each group allowed for a 2-sided significance mine, and mannitol were not used during the study. level of 5% and 90% power. The data are expressed as Angiotensin-converting enzyme inhibitors were allowed but mean Ϯ SD or as proportions. To compare baseline were withheld on the day of radiographic investigation. The variables between the 2 groups, Fisher exact test for cate- ethics committee of Kaohsiung Veterans General Hospital goric variables and Student unpaired t test for continuous approved the study protocol, and all patients gave written, variables were used. Changes in Cr values in the dialysis and informed consent. control groups were assessed using repeated-measures anal- Procedures. All patients were given intravenous normal ysis of covariance. Statistical analysis of the decrease in the saline at 1 ml/kg/h for 6 h before and 12 h after contrast CrCl from baseline to day 4 was performed using multiple medium exposure, and then randomized to receive hemo- regression. The covariates were age, gender, diagnosis of dialysis (dialysis group) or not (control group). In the diabetes mellitus, hypertension, type of procedure, dose of dialysis group, dialysis was started as soon as technically contrast medium, prophylactic dialysis, and baseline CrCl. possible after angiography, and the time interval from Age, contrast medium dose, and baseline CrCl were exam- contrast exposure to initiation of dialysis was recorded. ined as continuous variables. A p value of Ͻ0.05 was Hemodialysis was performed through a double-lumen in- considered to be of statistical significance. All calculations travenous femoral catheter placed before coronary angiog- were computed with the aid of the SPSS 10.0 software raphy. The dialyzer was a high-flux polysulfone membrane package (SPSS Inc., Chicago, Illinois). (BS1.8, Toray Industries, Inc., Tokyo, Japan). The blood flow was 150 ml/min, the duration of dialysis was 4 h, and Results the dialysate flow was 500 ml/min. To lessen the hemody- namic changes, 200 ml normal saline priming was admin- A total of 3,724 patients who received coronary angiography istered before dialysis and no fluid removal was prescribed in were consecutively screened, and 318 patients had chronic the dialysis group. The radiocontrast medium was nonionic renal insufficiency. Eighty-eight patients had ESRD necessi- iohexol (Omnipaque, GE Healthcare Technologies, tating chronic dialysis, 122 patients had Cr Ͻ3.5mg/dl, 18 Waukesha, Wisconsin), and the dose was recorded. patients refused to enter the study, and 90 were enrolled. They JACC Vol. 50, No. 11, 2007 Lee et al. 1017 September 11, 2007:1015–20 Hemodialysis Prevents Contrast Nephropathy

Clinical Characteristics of the Patients Figure 1 shows the time course of renal function in the Table 1 Clinical Characteristics of the Patients 2 groups. In the control group, the mean Cr concentra- Dialysis Group Control Group tion increased significantly after coronary angiography p Value and maintained higher than baseline values at hospital (40 ؍ n) (42 ؍ n) Age (yrs) 65.3 Ϯ 11.1 65.9 Ϯ 11.2 0.780* discharge in those patients who did not need permanent Male 27 (64%) 26 (65%) 0.946† Ϯ Ϯ dialysis. After angiography in the dialysis group, the Cr Body weight (kg) 63.7 10.2 61.0 10.0 0.220* Ϯ Systemic hypertension 40 (95%) 37 (93%) 0.604† concentrations were slightly increased on day 4 (4.9 1.3 Ϯ ϭ Diabetes mellitus 23 (55%) 25 (62%) 0.477† mg/dl vs. 5.1 1.3 mg/dl; p 0.06) but were signifi- Coronary artery disease 0.600† cantly increased only at peak value (5.3 Ϯ 1.5 mg/dl; p ϭ Stenosis Ͻ50% 3 (7%) 1 (3%) 0.008). No significant changes from baseline values in Single-vessel 16 (38%) 12 (30%) renal function were observed at discharge (5.1 Ϯ 1.3 Double-vessel 8 (19%) 10 (25%) mg/dl). The renal function of patients in the dialysis Triple-vessel 15 (36%) 17 (42%) group was better preserved over the whole course after Prior myocardial infarction 10 (24%) 7 (18%) 0.481† CAG compared with the control group. Left ventricular ejection fraction 0.45 Ϯ 0.07 0.42 Ϯ 0.08 0.221* Use of ACE inhibitors 11 (26%) 11 (28%) 0.894† One patient (2%) in the dialysis group and 14 patients Indication for CAG 0.812† (35%) in the control group required temporary dialysis after Stable angina 22 (52%) 22 (53%) CAG (p Ͻ 0.001) (Fig. 2) during hospitalization. The Acute coronary syndrome 20 (48%) 18 (47%) length of time between contrast exposure and initiation of Performed procedure 0.837† dialysis was 5 Ϯ 3 days (range 1 to 13 days). Ten of the Coronary angiography 19 (45%) 19 (47%) patients recovered and stopped hemodialysis within 3 weeks Percutaneous coronary 22 (55%) 21 (53%) (range 1 to 21 days). No patients in the dialysis group, but intervention Volume of contrast medium (ml) 106.8 Ϯ 44.0 108.1 Ϯ 32.6 0.877* 5 in the control group (13%), required maintenance dialysis after discharge (number needed to treat [NNT] 8; p ϭ Data are presented as n (%) or mean Ϯ SD. *Student unpaired t test was used for the comparison 0.018). For the patients who did not require chronic between the groups. †Fisher exact test was used for the comparison between the groups. ACE ϭ angiotensin-converting enzyme; CAG ϭ coronary angiogram. dialysis, the mean Cr level at discharge was higher, but not significantly, in the control group than in the dialysis group were randomized into 2 groups. After excluding patients of (5.9 Ϯ 2.5 mg/dl vs. 5.1 Ϯ 1.4 mg/dl; p ϭ 0.113). However, insufficient follow-up (n ϭ 3), receiving nonsteroid anti- 18 patients in the control group (45%), but only 2 in the inflammatory drugs (n ϭ 2), receiving N-acetylcysteine (n ϭ dialysis group (5%), had permanent renal damage with an 2), and receiving another contrast examination within 48 h increase in Cr concentration greater than 1 mg/dl or (n ϭ 1), 42 receiving prophylactic hemodialysis after coronary required permanent dialysis after discharge (risk ratio 2.80, angiography and 40 receiving fluid supplement only were 95% confidence interval 1.24 to 4.35, NNT 2.5; p Ͻ 0.001). included in the analyses (Table 1). The 2 groups were similar The length of hospital stay was considerably shorter in the with respect to demographic and baseline clinical characteris- dialysis group compared to that in the control group (6 Ϯ 3 tics. Among the patients in the dialysis group, dialysis was days vs. 13 Ϯ 18 days; p ϭ 0.017). initiated at an interval of 81 Ϯ 32 min, ranging from 45 to 180 No major complications were associated with the min, after exposure to the contrast medium. dialysis or the catheter in the dialysis group. Only 1 The baseline CrCl was similar in the dialysis (13.2 patient developed minor bleeding from the puncture site ml/min/1.73 m2) and control (12.6 ml/min/1.73 m2) of the femoral catheter; the bleeding stopped easily after groups; however, the CrCl on the fourth day after coronary removal of catheter and there was no need for a blood angiography in the dialysis group was significantly higher transfusion. ؎ than that in the control group (Table 2). The decrease in 2 ChangesFrom Baseline in Renal to Day Function 4 (Mean SD) CrCl within 72 h after the procedure was 0.4 ml/min/1.73 m Changes in Renal Function 2 Table 2 (in the dialysis group and 2.2 ml/min/1.73 m in the control From Baseline to Day 4 (Mean ؎ SD group (p Ͻ 0.001) (Table 2). Dialysis Control Multiple regression analysis shows that only prophylactic Group Group p Value (40 ؍ n) (42 ؍ dialysis and baseline CrCl were significantly associated with (n a change in CrCl (Table 3). The control group was Baseline plasma creatinine (mg/dl) 4.9 Ϯ 1.3 4.9 Ϯ 1.6 0.936 significantly associated with a decrease in CrCl of 1.938 Baseline creatinine clearance 13.2 Ϯ 3.6 12.6 Ϯ 4.4 0.528 (ml/min/1.73 m2) ml/min/1.73 m2. Every 1-ml/min/1.73 m2 decrease in Day 4 creatinine clearance 12.8 Ϯ 3.5 10.4 Ϯ 4.4 0.008 baseline CrCl was significantly associated with a decrease in (ml/min/1.73 m2) 2 CrCl of 0.324 ml/min/1.73 m . There is no association Change in creatinine clearance Ϫ0.4 Ϯ 0.8 Ϫ2.2 Ϯ 2.8 0.001 between the change in CrCl and other risk factors such as from baseline to day 4 (ml/min/1.73 m2) age, gender, diabetes, hypertension, type of procedure, or dose of contrast medium. Student unpaired t test was used for the comparison between the groups. 1018 Lee et al. JACC Vol. 50, No. 11, 2007 Hemodialysis Prevents Contrast Nephropathy September 11, 2007:1015–20

(0.260 ؍ FactorsClearance Associated From Baseline With Change to Day 4 in for Creatinine All Patients (R2 Factors Associated With Change in Creatinine Table 3 (0.260 ؍ Clearance From Baseline to Day 4 for All Patients (R2

Unstandardized Standardized 95% Confidence Coefficient B Coefficient B Interval p Value Age (1-yr increase) 0.001 0.001 Ϫ0.043 to 0.043 0.991 Male 0.645 0.140 Ϫ0.465 to 1.755 0.251 Diabetes mellitus Ϫ0.169 Ϫ0.038 Ϫ1.206 to 0.868 0.746 Hypertension Ϫ0.241 Ϫ0.026 Ϫ2.310 to 1.827 0.817 PCI 0.203 0.499 Ϫ0.791 to 1.197 0.685 Dose of contrast medium (1-ml increase) Ϫ0.003 Ϫ0.040 Ϫ0.015 to 0.010 0.716 Prophylactic dialysis 1.938 0.440 1.040 to 2.837 Ͻ0.001 Baseline creatinine clearance 0.324 0.180 0.042 to 0.318 0.011 (1-ml/min/1.73 m2 increase)

PCI ϭ percutaneous coronary intervention.

Discussion to improve renal outcome in patients with advanced renal failure who need CAG. Patients with chronic renal failure are prone to atheroscle- Some may argue that either the Cr level or CrCl could rotic cardiovascular diseases (17), and renal dysfunction represent the glomerular filtration rate (GFR) only at a accounts for the greatest risk factor in developing CN after steady state. Because it is the change in GFR rather than the CAG. Once CN occurred, 36% to 60% of these high-risk absolute GFR level that we wanted to measure, and because patients required emergent dialysis, and the hospital stay the change in Cr level reflects the change in GFR faithfully, was prolonged to an average of 17 days (18,19). Of these we chose the changes in Cr level and CrCl to evaluate the patients, 28% to 33% did not recover and needed mainte- nance dialysis. Therefore, the cardiologist usually has to change in renal function after CAG in the present study. make a difficult choice between alleviating coronary syn- The only pitfall was that the Cr level in the dialysis group dromes by coronary intervention and the risk of acute renal would be artificially lower immediately after prophylactic failure in patients with pre-existing renal dysfunction. Based hemodialysis. According to an earlier study (20), Cr levels in on the present results, prophylactic hemodialysis immedi- the dialysis group would catch up with baseline levels and ately after CAG appears to be an effective and safe strategy the levels in the control group within 3 days. Therefore, we used the changes in Cr level or CrCl of day 4 from baseline to express the change in GFR. Besides, using our secondary end points, including the number of patients who needed either temporary or long-term dialysis after CAG and the changes in Cr level at discharge, prophylactic hemodialysis after CAG also showed significantly better results in the dialysis group.

Figure 1 Cr Levels Before Coronary Angiography, on Day 4, at Peak Value, and at Hospital Discharge

Changes in serum creatinine (Cr) values in the dialysis and control groups were assessed using repeated-measures analysis of covariance. Multiple compari- Figure 2 Renal Outcomes of Dialysis and Control Groups sons with the Bonferroni t test were used for the comparisons between and within groups. For the interaction between time and treatment in terms of the The bars show significantly different percentages of dialysis and control Cr level, F statistic ϭ 22.9 (p Ͻ 0.001). Changes from baseline in the Cr level patients who needed subsequent dialysis (2% vs. 35%; p Ͻ 0.001), patients were significant at the peak value in the dialysis group (***p ϭ 0.008) and on who needed permanent dialysis (0 vs. 13%; p ϭ 0.018), and those with an day 4, at the peak value, and at discharge in the control group (*p Ͻ 0.001); increase in serum creatinine level between baseline and discharge of at least the difference between the 2 groups was significant on day 4 and at peak 1.0 mg/dl (5% vs. 37%; p Ͻ 0.001). Fisher exact test was used for the com- value (**p ϭ 0.010 on day 4; p ϭ 0.005 at peak value). parison between the groups. JACC Vol. 50, No. 11, 2007 Lee et al. 1019 September 11, 2007:1015–20 Hemodialysis Prevents Contrast Nephropathy

The underlying mechanism of CN is not clear. A reduction (25), hemodialysis might be more practicable than CVVH in renal perfusion caused by a direct effect of the contrast to prevent CN after CAG. medium on the kidney and toxic effects on the tubular cells are Study limitations. Our study was not blinded. The poten- generally accepted as the main factors in the pathogenesis of tial effective strategies to prevent CN had been imple- CN (21). In patients with renal insufficiency, delayed excretion mented in both groups, including fluid supplement, low- of the contrast medium has led to concerns about increased osmolality contrast media, and a lower dose of contrast toxicity after CAG. Although the concentration of the agents, and there was still shown to be a significant benefit contrast medium can be effectively reduced by hemodialysis of prophylactic hemodialysis. However, the influence of the within short periods (22–25), the effect of prophylactic double dose of N-acetylcysteine and hemodialysis to prevent hemodialysis in preventing CN addressed in earlier studies CN requires further investigation. is still controversial (20,26). Different doses of contrast media, small sample sizes, and variations in residual renal Conclusions function might be causes of bias. Moreover, nephrotoxicity Our findings suggest that prophylactic hemodialysis in due to dialysis per se has been linked with the activation of patients with advanced chronic renal failure undergoing inflammatory reactions by the dialyzer and the induction of coronary angiography reduces the intensity of acute renal hypovolemia and hypotension during dialysis. It is possible deterioration due to contrast medium exposure, shortens that the nephrotoxic effect of hemodialysis might have offset hospital stay, and improves renal outcome. the beneficial effect of the removal of the contrast medium. In the present study, all of the possible nephrotoxic factors were eliminated. Reprint requests and correspondence to: Dr. Hua-Chang Fang, The overwhelming positive effect of our study may be due Division of Nephrology, Kaohsiung Veterans General Hospital, 386 Ta-Chung First Rd, Kaohsiung, Taiwan 813. E-mail: to the high-risk population we chose; all of our patients had [email protected]. a residual CrCl of Ͻ25 ml/min/1.73 m2, which made the kidney very vulnerable to any further injury. Thus, the rapid REFERENCES removal of nephrotoxic contrast agents by hemodialysis was dramatically shown to be of great benefit. Considering that 1. Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. 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