Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity

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1 European Heart Journal (2004) 25, Clinical research Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity Carlo Briguori a,b *, Antonio Colombo b, Anna Violante a, Pasquale Balestrieri a, Fiore Manganelli a, Pietro Paolo Elia a, Bruno Golia a, Stefano Lepore a, Guido Riviezzo a, Pierfranco Scarpato a, Amelia Focaccio a, Mariateresa Librera a, Erminio Bonizzoni c, Bruno Ricciardelli a a Laboratory of Interventional Cardiology and Department of Cardiology, Clinica Mediterranea, Naples, Italy b Laboratory of Interventional Cardiology, Vita e Salute University School of Medicine, University of Milan, Milan, Italy c Institute of Medical Statistics and Biometry, University of Milan, Milan, Italy Received 3 July 2003; received in revised form 20 October 2003; accepted 27 November 2003 KEYWORDS Contrast media; Kidney; Complications; Prevention Aims Prophylactic administration of N-acetylcysteine (NAC) (600 mg orally twice daily), along with hydration, prevents contrast agent-associated nephrotoxicity (CAN) induced by a low dose of non-ionic, low-osmolality contrast dye. We tested whether a double dose of NAC is more effective to prevent CAN. Methods and results Two-hundred-twenty-four consecutive patients with chronic renal insufficiency (creatinine level 1.5 mg/dl and/or creatinine clearance <60 ml/ min), referred to our institution for coronary and/or peripheral procedures, were randomly assigned to receive 0.45% saline intravenously and NAC at the standard dose (600 mg orally twice daily; SD Group; n=110) or at a double dose (1200 mg orally twice daily; DD Group; n=114) before and after a non-ionic, low-osmolality contrast dye administration. Increase of at least 0.5 mg/dl of the creatinine concentration 48 h after the procedure occurred in 12/109 patients (11%) in the SD Group and 4/114 patients (3.5%) in the DD Group (P=0.038; OR=0.29; 95% CI= ). In the subgroup with low (<140 ml, or contrast ratio 1) contrast dose, no significant difference in renal function deterioration occurred between the 2 groups. In the subgroup with high ( 140 ml, or contrast ratio >1) contrast dose, the event was significantly more frequent in the SD Group. Conclusions Double dose of NAC seems to be more effective than the standard dose in preventing CAN, especially with high volumes of non-ionic, low-osmolality contrast agent The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. Introduction Radiocontrast media can lead to a reversible form of acute renal failure that begins soon after the contrast dye administration and is generally benign. 1 However, especially in high-risk patients, transient dialysis may * Corresponding Author: Carlo Briguori M.D., Ph.D, Interventional Cardiology, Clinica Mediterranea, Via Orazio, 2,I-80121, Naples, Italy. Tel.: ; Fax: address: briguori.carlo@hsr.it (C. Briguori). be required: this renal failure requiring dialysis after coronary interventions is associated with poor outcomes, including 40% in-hospital mortality and 19% 2-year survival. 2 4 Periprocedural hydration 5 and the use of a small amount of low osmolality contrast agent 6 9 are generally recommended in patients at risk of contrast-agent associated nephrotoxicity (CAN). Tepel et al. 10 firstly reported that oral N-acetylcysteine (NAC) (600 mg twice daily) along with hydration is more effective than hydration X/04/$ - see front matter 2003 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. doi: /j.ehj

2 Contrast media and acute renal failure 207 alone in preventing CAN in patients with chronic renal insufficiency receiving small amount (75 ml) of low osmolality contrast dye. Other studies confirmed or refuted this preliminary observation. When the amount of contrast dye is high ( 140 ml), NAC (600 mg twice daily for 2 days) along with hydration does not seem to be as effective as with small amount of contrast agent. 14 A potential mechanism of NAC in preventing contrast-dye nephrotoxicity is the prevention of direct oxidative tissue damage by scavenging reactive oxygen species; 10,17,18 this antioxidant effect seems to be dosedependent. 19 We therefore hypothesized that with a higher amount of contrast dye a higher dose of NAC might be necessary. Methods Patient population This is a prospective, randomized study conducted in our institution from January to September The local Ethics Committee approved the study protocol. All patients gave written informed consent. Patients scheduled for elective coronary and/or peripheral angiography and/or angioplasty were eligible for the study if they had chronic impairment of renal function (serum creatinine concentration 1.5 mg/dl and/or creatinine clearance <60 ml/min) and stable serum creatinine concentrations. Patients were randomly assigned to receive intravenous saline and the NAC at the standard dosage (SD Group) or at a double dosage (DD Group) before and after administration of the contrast agent. Saline (0.45%) was given intravenously at a rate of 1 ml/kg of body weight per hour for 12 h before and 12 h after administration of the contrast agent. 5 NAC (Fluimucil, Zambon Group SpA, Milan, Italy) was given orally at a dose of 600 mg twice daily in the SD Group, 10 and at a dose of 1200 mg twice daily in the DD Group on the day before and on the day of administration of the contrast agent, for a total of 2 days. None of the patients received theophylline, dopamine, mannitol, or furosemide during the study. Serum creatinine, blood urea nitrogen, sodium and potassium were measured immediately before and 48 h after administration of the contrast agent; additional measurements were performed in all cases of significant impairment of renal function. Creatinine clearance (CrCl) was calculated by applying the Cockcroft-Gault formula. 20 Contrast agent Iobitriolo (Xenetin-350, 350 mg iodine/ml, Guerbet, France) a non-ionic, low-osmolality contrast agent was used. Two different cut offs were used to define a high amount of contrast dye administered in each enrolled patient: 1) 140 ml 14 and 2) (5 kg body weight) divided by serum creatinine (mg/dl): a weight-and creatinine-adjusted maximum contrast dose (MCD). 6 This contrast limit was converted to a dichotomous variable by dividing the actual amount of contrast received by the calculated MCD to determine the contrast ratio. If the ratio was >1 then the MCD was defined as exceeded Study end-point An acute contrast-agent associated nephrotoxicity in renal function was defined as an increase in the serum creatinine concentration 0.5 mg/dl of the baseline value 48 h or need for dialysis after administration of the contrast media. 5 Acute renal failure requiring dialysis was defined as a decrease in renal function necessitating acute haemodialysis, ultrafiltration or peritoneal dialysis in the first 5 days post-intervention. Side effects during NAC administration were recorded in the 2 groups. The reported side effects are: 22 gastrointestinal (vomiting, nausea), central nervous system (chills, fever, drowsiness, dizziness), and respiratory (bronchospasm, rhinorrea, hemoptysis). Statistical analysis A total sample size of 210 subjects randomised with a 1:1 allocation ratio was calculated to achieve a power (1-β) of 90% to detect a difference of 15% between the null hypothesis that both group proportions are 20% and the alternative hypothesis that the proportion in the DD group is 5%, using a two-sided Chi-square test with a significance level of Continuous variables are given as mean±1 standard deviation. Unpaired Student s t test was performed to determine differences between mean values for continuous variables when appropriate. Categorical variables were analysed by Chi-square test. Creatinine concentration was not normally distributed; therefore, median and interquartile ranges (IQR) are reported and the nonparametric Wilcoxon and Mann Whitney tests were used to assess differences. To test our hypothesis (that is, with a higher amount of contrast media a higher dose of NAC might be necessary) we used an ANCOVA model after transforming creatinine levels into natural logarithm (to overcome the problem of the non normal distribution), putting the log-creatinine concentration at 48 h as dependent variable, treatment strategy (as defined in SD and DD groups) as fixed factor, and baseline log-creatinine level and the amount of contrast dye as covariates. We also estimated the fixed effects by splitting the effect of amount of contrast media in the 2 groups of treatment. Correlation coefficient between changes in serum creatinine concentration and length of in-hospital stay was estimated using the Pearson s correlation test. Probability values <0.05 were considered significant. Data were analysed with SPSS 10.0 (Chicago, Illinois) for Windows. Results Clinical characteristics Two-hundred-twenty-four patients were enrolled. One patient in the SD Group experienced acute pulmonary oedema overnight before coronary angiography and was, therefore, excluded from the analysis. The clinical and biochemical characteristics of the 223 patients in the 2 groups are shown in Tables 1 and 2. The total amount of intravenous hydration was comparable: SD Group= 1824±384 ml vs DD Group=1834±350 ml (P=0.94). One patient in the DD Group experienced minor side effect (nausea and vomiting) on the second day of NAC administration. Contrast agent-associated nephrotoxicity The median serum creatinine concentration for all patients was 1.60 (IQR= ) mg/dl. In the SD Group, the creatinine concentration decreased from a median value of 1.56 (IQR= ) to 1.50 (IQR= ) mg/dl 48 h after contrast agent administration (P=0.046). In the DD Group, the creatinine concentration

3 208 C. Brogouri et al. Table 1 Clinical characteristics of the patients treated with the standard dose (SD Group) and with the double dose (DD Group) of acetylcysteine SD Group (n=109) DD Group (n=114) P Age (years) 67±8 66± Male 86 (79%) 96 (84%) 0.30 Weight (kg) 74±12 74± Height (m) 1.66± ± Body-mass Index (kg/m 2 ) 27±4 27± Blood Pressure (mmhg) Systolic 135±18 137± Diastolic 77±9 78± Mean 96±10 98± Left Ventricular Ejection Fraction (%) 52±12 53± Systemic Hypertension 80 (77%) 85 (75%) 0.75 Diabetes Mellitus 47 (43%) 47 (41%) 0.68 Peripheral Chronic Artery Disease 24 (22%) 30 (26%) 0.17 Drugs ACE inhibitor 65 (60%) 71 (62%) 0.78 Calcium channel blocker 45 (41%) 52 (45%) 0.71 Angiotensin II receptor inhibitor 16 (15%) 14 (12%) 0.69 Diuretic 49 (45%) 48 (42%) 0.68 Performed procedure Coronary angiography 57 (52%) 61 (53.5%) 0.80 PCI 14 (13%) 8 (7%) 0.20 Coronary angiography and ad hoc PCI 28 (26%) 32 (28%) 0.76 Peripheral angiography 10 (9%) 13 (11%) 0.81 Volume of Contrast media (ml) 184± ± ml 53 (49%) 56 (49%) 1.00 Contrast ratio >1 26 (24%) 28 (24.6%) 0.88 Table 2 Biochemical characteristics of the patients treated with the standard dose (SD Group) and with the double dose (DD Group) of acetylcysteine SD Group (n=109) DD Group (n=114) P Serum Creatinine, median (IQR a ), mg/dl Baseline 1.56 ( ) 1.61 ( ) 0.14 After 48 h 1.50 ( ) 1.46 ( ) 0.77 Serum Creatinine 2.0 mg/dl) 15 (14%) 22 (19%) 0.37 Creatinine Clearance (ml/min) 45±13 44± Serum Urea Nitrogen (mg/dl) Baseline 65±23 69± After 48 h 58±28 58± Serum Sodium (meq/l) Baseline 142±3 143± After 48 h 142±4 143± Serum Potassium (meq/l) Baseline 4.8± ± After 48 h 4.4± ± a IQR=interquartile range. decreased from a median value of 1.61 (IQR= ) to 1.46 (IQR= ) mg/dl 48 h after contrast agent administration (P<0.001). There was a significant difference in the serum log-creatinine concentration 48 h after contrast media administration between the two treatment strategies even when including the baseline serum log-creatinine level and the amount of contrast media as covariate (F=6.52, P=0.001 by ANCOVA model). The

4 Contrast media and acute renal failure 209 Fig. 1 Panel A: schematic representation of the distribution of the occurrence of contrast agent-associated nephrotoxicity in patients treated with the standard dose (Standard Dose Group) and with the double dose (Double Dose Group) of acetylcysteine. Panel B: schematic representation of the distribution of the contrast agent-associated nephrotoxicity in patients who received a small (<140 ml) or a large ( 140 ml) amount of contrast dye and treated with the standard dose (Standard Dose Group) or with the double dose (Double Dose Group) of acetylcysteine. estimated fixed effects of ANCOVA-in which we split the effect of the amount of contrast media in the 2 groups of treatment-showed that the relationship between the amount of contrast agent and the creatinine levels at 48 h after the procedure was statically significant only in the Group SD (P<0.001) but only borderline in the Group DD (P=0.07). CAN (that is, increase 0.5 mg/dl of creatinine concentration) occurred in 12/109 patients in the SD Group (11%) and 4/114 patients in the DD Group (3.5%) (P=0.038; OR=0.29; 95% CI= ; (Fig. 1, Panel A). In no case renal failure requiring temporary dialysis occurred. In the 94 diabetic patients, renal function deterioration occurred in 4/47 (8.5%) in SD Group and in 1/47 (2.1%) in the DD Group (P=0.36). In the 38 patients with left ventricular ejection fraction <40%, renal function deterioration occurred in 4/22 (18.2%) in SD Group and 1/16 (6.3%) in the DD Group (P=0.37). Length of in-hospital stay (from admission to discharge) was longer in the SD Group than DD Group (2.6±0.9 vs 2.2±0.6 days; P=0.018). Furthermore we found a direct correlation between the absolute change of creatinine concentration and the length of hospital stay (r=0.25; P=0.004). Amount of contrast dye and nephrotoxicity The amount of contrast agent was similar in the 2 groups (Table 2). The amount of contrast dye administered was higher in the 16 patients who experienced an acute contrast-associated nephrotoxicity than in the remaining 207 patients (287±130 ml vs 171±110 ml, P<0.001). According to the selected cut off, a large amount of contrast dye occurred as follows: (1) 140 ml: 53/109 (49%) cases in the SD Dose Group, and 56/114 (49%) cases in the DD Group (P=1.0); (2) contrast ratio >1: 26/109 (24%) cases in the SD Group and 28/114 (25%) cases in the DD Group (P=0.88). In patients (n=114) who received a contrast dose <140 ml (mean value=101±23 ml; range= ml; median=100 ml) a significant renal function deterioration occurred in 2/56 (3.6%) in the SD Group and 1/58 (1.7%) in the DD Group (P=0.61) (Fig. 1, Panel B). In patients (n=168) with a contrast ratio 1(mean value= 132±61 ml; range= ml; median=120 ml) a significant renal function deterioration occurred in 3/82 (3.7%) in the SD Group and in 1/86 (1.2%) of the DD Group (P=0.36). In patients who received a large amount of contrast dye a significant renal function deterioration occurred significantly less often in the DD Group. In particular, in the subgroup (n=109) with contrast dose 140 ml (mean value=254±102 ml; range= ml; median=245 ml) the event occurred in 10/53 (18.9%) cases in the SD Group, and in 3/56 (5.4%) of the DD Group (P=0.039; OR=0.24; 95% CI= ) (Fig. 1, Panel B). In the subgroup (n=55) with the contrast ratio >1 (mean value=308±111 ml; range= ml; median=300 ml), a significant renal function deterioration occurred in 9/27 (31.3%) in the SD Group and in 3/28 (10.7%) of the DD Group (P=0.055; OR=0.24; 95% CI= ). Discussion The main result of the present study is that a double dose of NAC seems to be more effective in preventing CAN especially when a large amount of a non-ionic low osmolality contrast dye is utilized. Radiographic contrast media accounts for 10% of all causes of hospital-acquired acute renal failure and represents the third cause of in-hospital renal function deterioration after decreased renal perfusion and post-operative renal insufficiency. 23 Increase of 0.5 mg/dl of creatinine level after contrast media administration represents a clinically important

5 210 C. Brogouri et al. adverse event at least because it can increase the duration of hospitalization Furthermore, the in-hospital mortality rate in patients developing renal insufficiency is directly related to the magnitude of the increase in serum creatinine concentration. 2 4,24 The mechanism by which contrast-induced renal failure occurs is not well understood. The two major theories are renal vasoconstriction, 25 and direct toxic effects of the contrast agents Optimal strategy to prevent CAN remains uncertain. At present, recommendations are (1) periprocedural hydration, 5 (2) use of a lowosmolality contrast, 7 9 and (3) limiting the amount of contrast agent. 6,21 Recently, the preliminary data on the effectivess of prophylactic administration of NAC aroused considerable interest. 10 NAC and contrast agent-associated nephrotoxicity NAC, a potent antioxidant that scavenges a wide variety of oxygen-derived free-radicals, may prevent a CAN both by improving renal haemodynamics and by avoiding direct oxidative tissue damage. 17,18,29 Tepel et al. 10 firstly reported that NAC (600 mg orally twice daily) plus hydration before and after administration of contrast agent is more effective than hydration alone in preventing CAN in patients with chronic renal insufficiency who were undergoing computed tomography with a constant dose (75 ml) of a nonionic, low-osmolality contrast agent. Other studies confirmed or refuted this preliminary observation. In our previous report 14 we did not find any significant effect of the NAC treatment (according to the dosage suggested by Tepel) on the occurrence of contrast-associated nephrotoxicity in 183 patients with renal insufficiency (who had coronary and/or peripheral angiography and/or angioplasty). In this study the mean contrast dose was 194±127 (range ) ml. We postulated that the higher amount of contrast dye administered may account for the discordance between our study 14 and the previous ones The findings of the present study support our hypothesis of the need for higher dose of NAC with larger amount of contrast media. The antioxidant effect of NAC seems to be dosedependent. 19 In vitro, NAC dose-dependently increases the synthesis of cellular glutathione in umbilical endothelial cells depleted of their glutathione by incubation in a sulphur-amino acid-free medium. 19 Our findings, combined with our previous observation of a protection by the standard dose of NAC limited to patients exposed to low amount of contrast-agent, 14 supports a dosedependent protective effect of NAC. Role of the amount of contrast dye The administration of a small amount of contrast dye and the avoidance of repetitive studies closely spaced represent ones of the well-established recommendations to prevent CAN.[6 21,30,31] Low dose has been variably defined as <70 ml, <125 ml, <140 ml, or <5 ml/kg (to a maximum of 300 ml) divided by the plasma creatinine concentration. 4,6,8,14,21 The mean dose for coronary angiography is 130 ml, and for PCI is 191 ml. 32 In the study by Tepel et al. 10 a constant low (75 ml) dose of contrast was administered. Shyu et al. 12 and Kay et al. 13 used a quite low (median value= ml) dose of contrast agent. Our study suggests a significant benefit of the double dose (1200 mg orally twice daily) of NAC when a large ( 140 ml or contrast ratio >1) amount of contrast dye is necessary. Study limitations Iodixanol (an iso-osmolality non-ionic contrast media) seems to be less nephrotoxic than the low-osmolality nonionic contrast agents. 33 Association of iodixanol and NAC should be investigated. In conclusion, prophylactic administration of double dose of NAC seems to be more effective than the standard dose in preventing CAN, especially when high volumes of a non-ionic, low-osmolality contrast agent are used. Our findings also support once more the necessity for limiting the amount of contrast media when dealing with patients with impaired renal function. References 1. Parfrey PS, Griffiths SM, Barrett BJ et al. Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. N Engl J Med 1989;320: Chertow GM, Christiansen CL, Cleary DP. Prognostic stratification in critically ill patients with acute renal failure requiring dialysis. Arch Intern Med 1995;155: Gruberg L, Mehran R, Dangas G et al. 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