title: A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity.
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.
  
  
  CONCLUSIONS
  This meta-analysis does not support the efficacy of NAC to prevent CIN.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA. dgonzales@cc.nih.gov
authors.forename: Denise A
authors.initials: DA
authors.lastname: Gonzales
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Norsworthy
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kern
authors.forename: Steve
authors.initials: S
authors.lastname: Banks
authors.forename: Pamela C
authors.initials: PC
authors.lastname: Sieving
authors.forename: Robert A
authors.initials: RA
authors.lastname: Star
authors.forename: Charles
authors.initials: C
authors.lastname: Natanson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Danner
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000368:Aged; D016000:Cluster Analysis; D003287:Contrast Media / Q000009:adverse effects*; D003404:Creatinine / Q000378:metabolism; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017594:Publication Bias; D016032:Randomized Controlled Trials as Topic; D012044:Regression Analysis; D006435:Renal Dialysis; D012307:Risk Factors; D012680:Sensitivity and Specificity
chemical_list: D003287:Contrast Media; D003404:Creatinine; D000111:Acetylcysteine