The review examined differences between studies evaluating the efficacy of N-acteylcysteine for the prevention of contrast-induced nephrotoxicity (CIN). The authors concluded that there was no support for using N-acetylcysteine to prevent CIN. The review was generally well-conducted and the conclusions are likely to be reliable.

To examine heterogeneity among studies evaluating N-acetylcysteine (NAC) for the prevention of contrast-induced nephrotoxicity (CIN).

MEDLINE, EMBASE, International Pharmaceutical Abstracts, Derwent Drug File, Adis R&D Insight, Adis Clinical Trials Insight, Biological Abstracts, CINAHL, Web of Science and the Cochrane Library (including the Cochrane CENTRAL Register) were searched from inception to September 2004; the search terms were reported. No language or publication restrictions were applied. In addition, conference proceedings from seven specified societies over the last 5 years were screened.

Randomised controlled trials (RCTs) that evaluated the efficacy of NAC for the prevention of CIN and provided sufficient outcome data for analysis were eligible for inclusion. The primary review outcomes were CIN, as defined in the individual studies, and the change in creatinine. The review also assessed the occurrence of kidney injury requiring dialysis.

The majority of patients in the included studies were undergoing left heart catheterisation with or without percutaneous coronary intervention; the volume of contrast ranged from 75 to 347 mL. Most of the studies included a preponderance of males, the mean age ranged from 62 to 76 years, and 12 to 67% of the patients were diabetic. NAC was given orally in almost all of the studies.

Two reviewers screened identified citations and abstracts.

Two reviewers independently assessed validity using the Jadad criteria.

Data on the incidence of CIN and change from baseline in creatinine levels were extracted onto a standardised form. Authors were contacted for additional data, if required.

Two reviewers independently extracted data and any discrepancies were resolved through discussion.

Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical heterogeneity was assessed using the Cochrane Q statistic and the I² statistic. Publication bias was assessed using the tests of Begg and Mazumdar, Egger, and Higgins and Thompson. Meta-regression was used to examine the effect on log RR of study characteristics and patient characteristics and total NAC dose. A separate meta-regression analysis was used to examine the effect of the population CIN rate. All meta-regression analyses were weighted by the inverse variance. Several sensitivity analyses were performed including jackknife-k, modified L'Abbe plots and a best-fit Gaussian model.

Twenty-two RCTs (n=2,746) were included.

The Jadad scores ranged from 1 to 5 out of 5. Eleven RCTs scored 3 or more points.

Statistically significant heterogeneity was found when all studies were pooled (I²=37%; p=0.04); no pooled estimate was provided. Visual inspection of the funnel plot suggested publication bias may be present, but none of the statistical tests were statistically significant. None of the patient or study characteristics were significantly associated with the efficacy of NAC. The sensitivity analysis identified 4 small studies that contributed most to the heterogeneity. The same 4 studies were identified by the L’Abbe plot as being outliers. These studies had relatively large increases in creatinine in control groups and relatively large decreases in creatinine in NAC groups.

The cluster analysis identified 2 clusters which showed statistically significantly different treatment effects (p<0.0001); the individual clusters were statistically homogeneous (I²=0% and p>0.5 for both). Cluster 1 comprised 18 studies (89% of patients) and showed no significant difference in CIN between treatment groups (RR 0.87, 95% CI: 0.68, 1.12, p=0.28). Cluster 2 comprised 4 studies (representing 11% of patients) and showed a large reduction in CIN with NAC compared with control (RR 0.15, 95% CI: 0.07, 0.33, p<0.0001). Studies in cluster 2 used low or moderate doses of NAC, were published earlier, were smaller and of lower quality, and control groups reported more CIN compared with cluster 1 groups. In addition, the 4 studies showing a benefit in cluster 2 used half-normal saline infusions.

There was no significant difference between NAC groups and control in the occurrence of dialysis in either of the clusters.

The review findings do not support the use of NAC for the prevention of CIN.

The review question was stated clearly. Several relevant sources were searched and attempts were made to minimise publication and language bias. Appropriate methods were used to minimise reviewer error and bias during the review process. Study validity was assessed but only aggregate scores were reported. Appropriate methods were used for the meta-analyses, assessment of heterogeneity and exploration of potential sources of heterogeneity. The review was generally well-conducted and the conclusions are likely to be reliable.

Practice: The authors stated that the review findings do not support the use of NAC for the prevention of CIN.

Research: The authors stated that future studies of treatment to prevent CIN should assess primary end points other than change in creatinine.

Intramural Program of the NIH Clinical Centre; NIDDK.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.