This is the first double blind, multicentre, randomised study assessing the effect of N-acetylcysteine in preventing CIN in a population at low to moderate risk undergoing cardiac catheterisation with an ionic low osmolality contrast medium. Our findings indicate that oral N-acetylcysteine does not provide any benefit as compared with placebo to reduce the incidence of CIN in this patient population. In addition, the use of N-acetylcysteine was not beneficial in any of the predefined subgroups of patients with diabetes, creatinine > 132.6 μmol/l, and contrast volume < 1.5 ml/kg. The lack of a beneficial effect of N-acetylcysteine was confirmed by multivariate analysis with control for the difference in the creatinine concentration before the procedure.
The initial study by Tepel and colleagues,10
reporting that N
-acetylcysteine reduced the incidence of CIN in patients undergoing computed tomography, generated considerable enthusiasm regarding this low cost and easy to use drug. That study randomised treatment of 83 patients who had serum creatinine
106.08 μmol/l (or CrCl < 50 ml/min) undergoing computed tomography with a small fixed intravenous contrast medium volume of 75 ml and found an impressive 90% reduction in the relative risk of CIN. After that study, additional clinical trials carried out in patients undergoing coronary angiography, PCI, or both had, however, controversial results.11–19
Although in a meta-analysis N
-acetylcysteine has been shown to prevent CIN in patients with renal functional impairment undergoing cardiac catheterisation, the absence of small negative trials is a possible bias that may have influenced these findings as recognised by the authors.20
In addition, a recent systematic review by Kshirsagar and colleagues22
suggested that the role of N
-acetylcysteine in the prevention of CIN has yet to be defined.
The conflicting results between our study and previous studies may also be explained by the differences in the contrast media used. Our investigation was conducted with an ionic low osmolality contrast medium, which is used in almost half of PCIs performed outside the USA.23
All others studies used non-ionic contrast media. In experimental studies, ionic low osmolality contrast media and non-ionic contrast media have caused different degrees of renal hypoxia and structural damage in the tubule cells.24,25
It is conceivable that N
-acetylcysteine has distinctive effects on preventing nephrotoxicity caused by various contrast agents.
In the present study the serum baseline creatinine concentration in the placebo group was slightly lower, with a borderline significance, than in the N-acetylcysteine group, although the estimated CrCl was similar in both groups. We assume that baseline creatinine concentrations did not influence the effect of N-acetylcysteine as indicated by multivariate analysis.
The incidence of CIN in our investigation of patients with moderate renal failure (mean baseline creatinine 117.57 μmol/l) was 10.3%, similar to that found in other studies of patients at risk.11,14
These patient characteristics do not allow us to draw definite conclusion about the effect of N
-acetylcysteine on very high risk patients (creatinine
176.8 μmol/l), even with the subgroup and multivariate analysis performed. However, considering that only 4% of the population undergoing cardiac catheterisation has serum creatinine concentrations above 176.8 μmol/l,2
the present findings can be applied to the majority of patients undergoing cardiac catheterisation at risk for developing CIN.
The dose and route of administration of N
-acetylcysteine in our study were the same as those in the majority of previous studies: 600 mg orally every 12 hours for two days, beginning the day before the procedure. Recently, intravenous administration of N
-acetylcysteine has been shown to be effective in an initial study of only 80 patients.26
However, a larger clinical trial with 425 patients did not find a benefit.27
Secondary end points
Once the rise of creatinine is a surrogate end point, we also investigated the effect of oral N
-acetylcysteine on hard clinical end points (in hospital death, length of hospitalisation, and need for haemodialysis). The study of Kay and colleagues14
was the only one that investigated the length of hospital stay as a secondary end point. Our study did not shown any benefit of N
-acetylcysteine on in-hospital death, need for dialysis, and length of hospital stay. The high in-hospital mortality observed in this study may be explained by the high cardiovascular risk of the patients. More than half of the study patients had multivessel disease and some patients underwent surgical revascularisation during the study period.
-acetylcysteine was not effective in preventing CIN in any of the predefined subgroups. Diabetes mellitus is a well known independent risk factor for CIN.2,28
Post hoc analysis of a previous study indicated that N
-acetylcysteine may effectively prevent CIN in patients with diabetes.14
In our study the predefined subgroup analysis of 81 diabetic patients indicated that N
-acetylcysteine was not effective, independently of the presence or absence of diabetes mellitus. In another post hoc analysis,12N
-acetylcysteine provided protection for patients receiving < 140 ml of contrast medium during angiography. Our study did not confirm this finding.
This is the first multicentre study evaluating the role of oral N-acetylcysteine in preventing CIN in patients undergoing cardiac catheterisation with an ionic low osmolality contrast medium. Our major finding was that N-acetylcysteine did not prevent acute renal failure in patients at low to moderate risk of CIN.
On the basis of these findings, we believe that the use of N-acetylcysteine to prevent CIN in this patient population should not be encouraged. The recommended measures for preventing CIN continue to be appropriate hydration and the use of a small volume of contrast in patients at low to moderate risk of CIN undergoing cardiac catheterisation with an ionic low osmolality contrast medium remain.
Limitation of the study
A potential limitation of this study was that serum creatinine was only measured 48 hours after the procedure. Although most clinical trials on preventive measures for CIN have assessed creatinine during that period and creatinine usually increases 24 hours after exposure and peaks within 48–72 hours, a later increase in serum creatinine may have passed unnoticed in some patients. The CrCl was estimated by the Cockcroft-Gault formula, which is widely used in clinical practice and in clinical trials; however, it is not a formal measurement of CrCl.
The study sample size was calculated aiming at reaching statistical difference in primary outcomes. Therefore, although no trends were observed in the subgroups, our study has a limited statistical power for this analysis.
The use of N-acetylcysteine was not effective in preventing CIN in patients at low to moderate risk undergoing cardiac catheterisation with an ionic low osmolality contrast medium.