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Effectiveness of Acetylcysteine in Prevention of Contrast Nephropathy
February 2005
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.
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 therapeutic procedure; Group IV: Scr 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 4.5 mg/dl.
A subgroup of 219 patients had calculated pre-procedure creatinine clearance = 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) = 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 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 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 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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