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

Gonzales DA, Norsworthy KJ, Kern SJ, Banks S, Sieving PC, Star RA, Natanson C, Danner RL - BMC Med (2007)

Bottom Line: Benefit in cluster 2 was unexpectedly associated with NAC-induced decreases in creatinine from baseline (p = 0.07).Dialysis use across all studies (five control, eight treatment; p = 0.42) did not suggest that NAC is beneficial.This meta-analysis does not support the efficacy of NAC to prevent CIN.

View Article: PubMed Central - HTML - PubMed

Affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA. dgonzales@cc.nih.gov

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.

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Related in: MedlinePlus

Cluster analysis based on changes in creatinine. A: Modified L'Abbé plot showing the results of model-based, unsupervised cluster analysis. Unlike Figure 5A, studies are unweighted for easier visualization. Cluster analysis (see the Methods section) applied to the 22 studies found two distinct populations of trials. Crosshairs and circles denote the mean ± SD of each cluster. B: Aggregate NAC treatment effect and heterogeneity analysis of each cluster. The entire group of 22 studies had unacceptable heterogeneity (I2 = 37%; p = 0.04) making the summary point estimate unreliable (not shown). Cluster 1 (n = 18; 2445 patients) is homogeneous and shows no benefit (RR = 0.87; 95% CI 0.68–1.12, p = 0.28). Cluster 2 (N = 4; 301 patients) is also homogeneous and indicates that NAC is very beneficial (RR = 0.15; 95% CI 0.07–0.33, p < 0.0001).
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Figure 6: Cluster analysis based on changes in creatinine. A: Modified L'Abbé plot showing the results of model-based, unsupervised cluster analysis. Unlike Figure 5A, studies are unweighted for easier visualization. Cluster analysis (see the Methods section) applied to the 22 studies found two distinct populations of trials. Crosshairs and circles denote the mean ± SD of each cluster. B: Aggregate NAC treatment effect and heterogeneity analysis of each cluster. The entire group of 22 studies had unacceptable heterogeneity (I2 = 37%; p = 0.04) making the summary point estimate unreliable (not shown). Cluster 1 (n = 18; 2445 patients) is homogeneous and shows no benefit (RR = 0.87; 95% CI 0.68–1.12, p = 0.28). Cluster 2 (N = 4; 301 patients) is also homogeneous and indicates that NAC is very beneficial (RR = 0.15; 95% CI 0.07–0.33, p < 0.0001).

Mentions: Using a model-based, unsupervised clustering approach [87], our modified L'Abbé plot defined two different subpopulations of trials within the overall meta-analysis (Figure 6A). Dividing the 22 PRCTs based on their assignment to cluster 1 (18 studies, 89% of patients) [12,13,15-24,26-31] or cluster 2 (four studies, 11% of patients) [10,11,14,25], these two sets of trials were found to have significantly different treatment effects (p < 0.0001) and both were internally homogeneous (Figure 6B). Group membership likelihoods were greater than 90% for the 18 studies assigned to cluster 1 and greater than 99% for the four studies assigned to cluster 2. Cluster 1 studies (2445 patients) showed no benefit from NAC administration to prevent CIN (RR = 0.87; 95% CI 0.68–1.12, p = 0.28). Cluster 2 studies (301 patients) indicated a large benefit from NAC treatment (RR = 0.15; CI 0.07–0.33, p < 0.0001). The four highly beneficial trials in cluster 2 all employed oral NAC at low or moderate doses and in this regard were not different in design from some larger trials that grouped with cluster 1. Likewise, cluster 2 patients received iopromide, ioxilan or iopamidol, contrast agents which did not appear to explain the large apparent benefit of NAC in these studies. However, cluster 2 studies were published earlier, are smaller in size and of lower quality as measured by Jadad scores (Table 3; p = 0.01, three study characteristics combined). Notably, control subjects experienced more CIN in cluster 2 compared with cluster 1 trials (31% ± 10% versus 12% ± 6%; p = 0.03). These increased episodes of CIN in cluster 2 were not associated with any consistent pattern of patient-related characteristics that increase risk for CIN (Table3).


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

Gonzales DA, Norsworthy KJ, Kern SJ, Banks S, Sieving PC, Star RA, Natanson C, Danner RL - BMC Med (2007)

Cluster analysis based on changes in creatinine. A: Modified L'Abbé plot showing the results of model-based, unsupervised cluster analysis. Unlike Figure 5A, studies are unweighted for easier visualization. Cluster analysis (see the Methods section) applied to the 22 studies found two distinct populations of trials. Crosshairs and circles denote the mean ± SD of each cluster. B: Aggregate NAC treatment effect and heterogeneity analysis of each cluster. The entire group of 22 studies had unacceptable heterogeneity (I2 = 37%; p = 0.04) making the summary point estimate unreliable (not shown). Cluster 1 (n = 18; 2445 patients) is homogeneous and shows no benefit (RR = 0.87; 95% CI 0.68–1.12, p = 0.28). Cluster 2 (N = 4; 301 patients) is also homogeneous and indicates that NAC is very beneficial (RR = 0.15; 95% CI 0.07–0.33, p < 0.0001).
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Related In: Results  -  Collection

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Figure 6: Cluster analysis based on changes in creatinine. A: Modified L'Abbé plot showing the results of model-based, unsupervised cluster analysis. Unlike Figure 5A, studies are unweighted for easier visualization. Cluster analysis (see the Methods section) applied to the 22 studies found two distinct populations of trials. Crosshairs and circles denote the mean ± SD of each cluster. B: Aggregate NAC treatment effect and heterogeneity analysis of each cluster. The entire group of 22 studies had unacceptable heterogeneity (I2 = 37%; p = 0.04) making the summary point estimate unreliable (not shown). Cluster 1 (n = 18; 2445 patients) is homogeneous and shows no benefit (RR = 0.87; 95% CI 0.68–1.12, p = 0.28). Cluster 2 (N = 4; 301 patients) is also homogeneous and indicates that NAC is very beneficial (RR = 0.15; 95% CI 0.07–0.33, p < 0.0001).
Mentions: Using a model-based, unsupervised clustering approach [87], our modified L'Abbé plot defined two different subpopulations of trials within the overall meta-analysis (Figure 6A). Dividing the 22 PRCTs based on their assignment to cluster 1 (18 studies, 89% of patients) [12,13,15-24,26-31] or cluster 2 (four studies, 11% of patients) [10,11,14,25], these two sets of trials were found to have significantly different treatment effects (p < 0.0001) and both were internally homogeneous (Figure 6B). Group membership likelihoods were greater than 90% for the 18 studies assigned to cluster 1 and greater than 99% for the four studies assigned to cluster 2. Cluster 1 studies (2445 patients) showed no benefit from NAC administration to prevent CIN (RR = 0.87; 95% CI 0.68–1.12, p = 0.28). Cluster 2 studies (301 patients) indicated a large benefit from NAC treatment (RR = 0.15; CI 0.07–0.33, p < 0.0001). The four highly beneficial trials in cluster 2 all employed oral NAC at low or moderate doses and in this regard were not different in design from some larger trials that grouped with cluster 1. Likewise, cluster 2 patients received iopromide, ioxilan or iopamidol, contrast agents which did not appear to explain the large apparent benefit of NAC in these studies. However, cluster 2 studies were published earlier, are smaller in size and of lower quality as measured by Jadad scores (Table 3; p = 0.01, three study characteristics combined). Notably, control subjects experienced more CIN in cluster 2 compared with cluster 1 trials (31% ± 10% versus 12% ± 6%; p = 0.03). These increased episodes of CIN in cluster 2 were not associated with any consistent pattern of patient-related characteristics that increase risk for CIN (Table3).

Bottom Line: Benefit in cluster 2 was unexpectedly associated with NAC-induced decreases in creatinine from baseline (p = 0.07).Dialysis use across all studies (five control, eight treatment; p = 0.42) did not suggest that NAC is beneficial.This meta-analysis does not support the efficacy of NAC to prevent CIN.

View Article: PubMed Central - HTML - PubMed

Affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA. dgonzales@cc.nih.gov

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.

Show MeSH
Related in: MedlinePlus