A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity

Denise A Gonzales¹ , Kelly J Norsworthy¹ , Steven J Kern¹ , Steve Banks^{^}¹ , Pamela C Sieving² , Robert A Star³ , Charles Natanson¹ and Robert L Danner¹

¹Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA

²National Institutes of Health Library, National Institutes of Health, Bethesda, MD, USA

³Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

author email corresponding author email^Deceased

BMC Medicine 2007, 5:32doi:10.1186/1741-7015-5-32


Published:	14 November 2007

Abstract

Background

Meta-analyses of N-acetylcysteine (NAC) for preventing contrast-induced nephrotoxicity (CIN) have led to disparate conclusions. Here we examine and attempt to resolve the heterogeneity evident among these trials.

Methods

Two reviewers independently extracted and graded the data. Limiting studies to randomized, controlled trials with adequate outcome data yielded 22 reports with 2746 patients.

Results

Significant heterogeneity was detected among these trials (I²= 37%; p = 0.04). Meta-regression analysis failed to identify significant sources of heterogeneity. A modified L'Abbé plot that substituted groupwise changes in serum creatinine for nephrotoxicity rates, followed by model-based, unsupervised clustering resolved trials into two distinct, significantly different (p < 0.0001) and homogeneous populations (I²= 0 and p > 0.5, for both). Cluster 1 studies (n = 18; 2445 patients) showed no benefit (relative risk (RR) = 0.87; 95% confidence interval (CI) 0.68–1.12, p = 0.28), while cluster 2 studies (n = 4; 301 patients) indicated that NAC was highly beneficial (RR = 0.15; 95% CI 0.07–0.33, p < 0.0001). Benefit in cluster 2 was unexpectedly associated with NAC-induced decreases in creatinine from baseline (p = 0.07). Cluster 2 studies were relatively early, small and of lower quality compared with cluster 1 studies (p = 0.01 for the three factors combined). Dialysis use across all studies (five control, eight treatment; p = 0.42) did not suggest that NAC is beneficial.

Conclusion

This meta-analysis does not support the efficacy of NAC to prevent CIN.