Background. Acetylcysteine may provide prophylaxis against contrast nephropathy (CN) in some patients. Its benefit may vary according to the characteristics of patients and contrast used. The objective is to evaluate the effectiveness of oral acetylcysteine in preventing CN after coronary procedures in our practice. Methods. We prospectively studied 397 patients with a creatinine level equal to or above 1.3 mg/dl, diabetes mellitus, or 70 + years of age who underwent a coronary procedure. Patients were randomly assigned to receive either acetylcysteine or placebo and 0.9% saline before and after the contrast agent. High- or low-osmolality contrast was used according to the discretion of the interventional cardiologist. Serum creatinine was measured before and 24 to 48 hours after the procedure. Results. An increase of >= 25% in the baseline creatinine level 24 to 48 hours after the procedure occurred in 14 (7.1%) of 196 acetylcysteine patients and in 17 (8.4%) of 201 placebo patients (p = 0.62). In the acetylcysteine group, the mean baseline serum creatinine concentration was 1.30 ± 0.56 mg/dl and increased 0.076 ± 0.21 mg/dl 24 to 48 hours after administration of contrast, whereas in the placebo group, it was 1.27 ± 0.51 mg/dl and increased 0.101 ± 0.28 mg/dl (p = 0.33). In the subgroup with estimated baseline creatinine clearance < 60 ml/minute, no difference was found in the incidence of CN (9.1% in the acetylcysteine group; 11.7% in the placebo; p = 0.66). By multivariate analysis, left ventricular ejection fraction <= 40%, volume of contrast > 200 ml, and estimated creatinine clearance (but not acetylcysteine) were related to CN. Conclusions. Oral acetylcysteine was not effective as a prophylactic treatment against CN for patients with a potential risk and submitted to coronary angiographic procedures with predominantly high-osmolality contrast.

       Contrast nephropathy (CN) is a recognized complication following cardiac catheterization. Ongoing advances in catheter-based technologies have resulted in an increased number of procedures performed which, in turn, could be related to an increase in in-hospital morbidity and mortality.^1,2 Important risk factors for acute renal failure related to contrast agents are pre-existing renal dysfunction — particularly diabetic nephropathy, reduced intravascular volume, administration of a high volume of contrast, and the use of high-osmolality agents.^3,4
       The known antioxidant properties of acetylcysteine have raised the possibility that this agent could protect patients from oxidative-mediated contrast nephropathy.⁵ Several randomized trials have demonstrated the efficacy of the drug in reducing the incidence of CN.^5,6,8,10-12 However, other studies have found no benefit.^7,9,13–20 Three published meta-analyses suggest that the drug prevents CN,^21–23 but results of two of the three analyses were inconclusive.^24–25 This discrepancy appears to be due to the inclusion of different trials in each analysis. Other studies with negative results were not included in these analyses.^14,19,20 Nonionic contrast was used in almost every patient.

Figure 1

Flow of patients through the trial.

Figure 2

Stratified randomization.

       In our practice, we use ionic and high-osmolality contrast agents, mainly due to its cost. Additionally, some patients have borderline renal dysfunction and the creatinine level is an insensitive criterion to determine it — especially in older patients and patients with reduced muscle mass.²⁶ We studied the effectiveness of acetylcysteine, an inexpensive and non-toxic drug, in preventing CN in a group of patients commonly submitted to cardiac procedures and with a higher risk of renal dysfunction. We carried out a prospective, placebo-controlled, double-blind, randomized study of prophylactic oral administration of acetylcysteine to patients with creatinine levels >= 1.3 mg/dl, diabetes mellitus, or >= 70 years of age.

Methods
       Study population. This randomized, double-blind, placebo-controlled trial was conducted at the Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia and at Santa Casa de Porto Alegre from March 2001 to July 2002. The Research and Ethics Committees of both hospitals approved the study protocol. All patients signed a written consent form.
       Patients scheduled for elective cardiac procedures (diagnostic and therapeutic) were eligible if they had recruitment serum creatinine (Scr) equal to or above 1.3 mg/dl, suffered from diabetes mellitus, or were >= 70 years of age. Dialyzed patients and those with acute renal failure were excluded. Patients were classified as “diabetic” if they required insulin or oral hypoglycemic agents.
       Study protocol. Stratified randomization was carried out by performing a separate randomization procedure within each of four groups based on laboratory recruitment (previous data) and plan of procedures. Group I: Scr >= 1.3 mg/dl and diagnostic procedure; Group II: Scr < 1.3 mg/dl and diagnostic procedure; Group III: Scr >= 1.3 mg/dl and therapeutic procedure; Group IV: Scr < 1.3 mg/dl and therapeutic procedure. Some patients did not have recent laboratory results but were eligible to participate in the study due to their age or diabetes mellitus criteria. The patients were randomly allocated to either the acetylcysteine or the placebo group based on a table of random numbers. The administration of the drug was double-blind.
       Patients received either oral acetylcysteine (Zambon Group, Brazil; 600 mg twice daily) or matching placebo. Two doses were administered on the day before the procedure, two more doses on the day of the procedure, and one dose the day following the procedure. Physiological saline (0.9%) was given intravenously: 1,000 ml before and 1,000 ml after the procedure — unless the patient’s physician opposed it for clinical reasons. Intake of oral fluid was encouraged. Serum creatinine and urea levels were measured immediately before the procedure (baseline) and 24 to 48 hours after it was completed.
       The analysis was performed in the hospital laboratory at each study center. Standard coronary angiography or percutaneous coronary intervention was performed. The type of contrast to be used was left to the discretion of the interventional cardiologist. Creatinine clearance (CrCl) was calculated by applying the Cockcroft-Gault formula to the baseline serum creatinine level: CrCl = ([140 - age] x weight / serum creatinine x 72), with female gender adjustment: CrCl female = CrCl x 0.85.²⁷
       Outcome. The primary outcome was the occurrence of contrast nephropathy and the change in serum creatinine concentration pre- and post-procedure. Secondary end points were hospital mortality, need for dialysis and severity of adverse drug effects. Finally, we determined the independent risk factor for contrast nephropathy.
       Definition. Contrast nephropathy was defined as an increase of 25% or more in serum creatinine, or an absolute change of 0.5 mg/dl for post-procedure creatinine of at least 1.3 mg/dl 24 to 48 hours after completion of the procedure.
       Statistical analysis. Analysis was carried out on all randomized patients who received at least four doses of the study medication. Continuous variables are given as the mean ± SD. The Student t-test was performed to determine differences between mean values for continuous variables. Categorical variables were analyzed by the chi-square test or by the Fischer exact test. Multiple logistic regression analysis was used to examine the effect of acetylcysteine, with adjustment for the inclusion or not in a hydration protocol, and to identify independent risk factors in the incidence of contrast nephropathy.
       The sample size was determined on the assumption that acetylcysteine would lower the incidence of contrast nephropathy by 65%. The expected event rate for placebo was 12% (a error of 0.05; b error of 0.20). To account for the possibility of patients lost in the follow-up, the planned sample size was around 200 patients for each group. Data were analyzed with SPSS for Windows, release 10.0.

Results
       From March 2001, to July 2002, 414 patients scheduled for elective coronary angiography or percutaneous coronary intervention were enrolled in the study (Figure 1). They were stratified according to a screening serum creatinine level higher or lower than 1.3 mg/dl and by diagnostic or therapeutic procedures (Figure 2). Of these, 17 patients had to be excluded from the analysis of the primary end point because the scheduled procedure was not performed, the laboratory exams were not collected, or the patient did not receive the drug. The baseline features of these 17 patients without follow-up did not differ significantly from those in the remaining population.
       The clinical and biochemical data, as well as other information concerning the procedure, are shown in Table 1. The mean (SD) baseline serum creatinine level was 1.30 ± 0.56 and 1.27 ± 0.51 in the acetylcysteine and placebo groups, respectively. Estimated creatinine clearance < 60 ml/minute was found in 50.5% of the patients in the acetylcysteine group, and in 59.7% of the patients in the placebo group (p = 0.07). It was observed that 40% of patients from groups II and IV (stratified groups based on recruitment Scr < 1.3) had estimated creatinine clearance < 60 ml/minute (calculated by the Cockcroft-Gault formula and baseline serum creatinine level). The number of patients not hydrated was small and differed between the acetylcysteine and placebo groups (8.7% x 3.5%, p = 0.03). The other baseline features were very similar. Nonionic, low-osmolality contrast (ioversol, iohexol, iopamidol) was used in 6.1% of the patients in the NAC group and in 2.5% of the patients in the placebo group (p = 0.09). All other patients received high-osmolality contrast (diatrizoate, iothalamate).
       There were no significant differences between the groups regarding the absolute changes in serum creatinine and urea concentrations (Table 2). The serum creatinine concentration increased in the acetylcysteine group from 1.30 mg/dl (range 0.5 to 5.8) to 1.38 mg/dl (range 0.7 to 6.3). In the control group, the change in the mean serum creatinine level went from 1.27 mg/dl (range 0.5 to 4.6) to 1.37 mg/dl (range 0.6 to 5.1). The incidence of contrast nephropathy was similar between the groups, with an odds ratio of 0.83 (95% CI, 0.4–1.74; Table 2). Whether the patient was hydrated did not change the result. The odds ratio, adjusted for hydration, was 0.80 (95% CI, 0.38–1.68).
       In the acetylcysteine group, the mean serum urea concentrations decreased from 52 ± 34 to 48 ± 31 mg/dl 24 to 48 hours after administration of the contrast agent. In the placebo group, the mean serum urea decreased from 50 ± 29 to 46 ± 28mg/dl 24 to 48 hours after administration of contrast. The change in mean serum urea was similar between the groups (-3.91 ± 13.92 in the acetylcysteine group and -4.13 ± 13.23 in the placebo group; p = 0.87).
       The clinical outcomes are shown in Table 3. The occurrence of in-hospital mortality and adverse effects attributed to the drug were similar in both groups. None of the patients needed to interrupt administration of the drug due to adverse effects. The need for dialysis occurred in one patient from each group. Both patients had baseline serum creatinine levels > 4.5 mg/dl.
       A subgroup of 219 patients had calculated pre-procedure creatinine clearance < 60ml/minute (Figure 3). There was no significant difference between the rate of renal failure in acetylcysteine (9 out of 99; 9.1%) compared to placebo (14 out of 120; 11.7%) in these study subgroups (OR 0.76, CI95% 0.31–1.83). In the subgroup of diabetic patients with Scr >= 1.3 mg/dl (n = 62), the incidence of contrast nephropathy was 11.4% in the NAC group and 14.8% and in the placebo group (p = 0.72).
       By logistic regression, we found that estimated left ventricular ejection fraction (LVEF) <= 40% by angiography, volume of contrast >= 200 ml, and estimated creatinine clearance (but not acetylcysteine) were independent risk factors for acute renal function deterioration (Table 4).

Discussion
       Trials of prophylactic measures to prevent contrast nephropathy in humans have evaluated hydration strategies, furosemide, mannitol, dopamine, calcium-channel blockers, theophylline, endothelin receptor antagonist, atrial natriuretic peptide, prostaglandin, captopril, fenoldapam, hemodialysis, and acetylcysteine.^{5–20,28–38} Currently, only peri-procedure hydration, the use of low-osmolar or iso-osmolar contrast agents, and perhaps acetylcysteine, are considered for patients at high risk of contrast nephropathy.^39–41 Given that the results of the published studies involving acetylcysteine are conflicting, we need to evaluate its efficacy in patients with some potential risks in our practice.
       This study was designed to evaluate the effectiveness of acetylcysteine in preventing CN in our practice. The patients were selected if they had Scr >= 1.3 mg/dl, or other risk factors such as diabetes mellitus or age of >= 70 years. We found a large number of diabetic and older patients who had normal recruitment serum creatinine, but some renal dysfunction (CCl < 60ml/min). These patients also deserve to receive preventive treatment against contrast nephropathy.²⁶
       We found that the prophylactic oral administration of acetylcysteine to a wide range of patients with potential risk did not reduce the incidence of contrast nephropathy in patients who underwent coronary procedures. Low-osmolality contrast was used in a minority of our patients due to its cost. We would expect a greater incidence of contrast nephropathy and a more pronounced effect of the drug in preventing it. The need for dialysis was low in both groups, occurring in patients with severe renal dysfunction. The small difference in the acetylcysteine group which had a slightly larger number of patients who were not hydrated, did not change the results significantly. The only variables related to contrast nephropathy were: estimated creatinine clearance, contrast volume >= 200 ml, and left ventricular ejection fraction <= 40%.
       The use of acetylcysteine to prevent renal damage after contrast administration was evaluated in seventeen trials,^5–20 six of which showed benefits from the drug (Table 5).^{5,6,8,10–12} There are some differences among studies regarding the type of contrast used and its dosage, the dose of acetylcysteine, the number of patients included, the baseline creatinine value, and the definition of contrast nephropathy. The use of isotonic (0.9% saline) or half-isotonic (0.45%) hydration may have contributed to the different results, since 0.9% saline proved to be superior in preventing contrast nephropathy.⁴² Unlike our study, all of these trials used low-osmolality contrast only. The benefit of acetylcysteine could be attenuated by using high-osmolality contrast for this kind of patient. In those trials, we can observe that serum creatinine decreased after exposure to contrast and acetylcysteine, whereas it increased in ours. This is the first study on a large number of patients to test high-osmolality contrast with N-acetylcysteine.
       The lower-risk profile of our study population compared with those previous trials may be responsible for the lack of benefit shown with the use of acetylcysteine. Nevertheless, the incidence of CN in subgroups at great risk (Scr < 60 ml/min) showed no advantages with the use of the drug.
       Study limitations. Serum creatinine was only measured between 24 to 48 hours after completion of the procedure. Therefore, we may have missed a later increase in serum creatinine in some patients.
       Since our aim was to test acetylcysteine in a wide range of patients at potential risk, such as elderly or diabetic patients, we included some who had an estimated creatinine clearance at normal values. We were unable to pinpoint clear, small differences in those with more severe renal dysfunction.
       Oral acetylcysteine was not effective as a prophylactic treatment against acute renal dysfunction in patients with potential risk factors who underwent coronary procedures where predominantly high-osmolality contrast was used.

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