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CLINICAL SCIENCE |
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*Division of Nephrology and Hypertension, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Biostatistics, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and Division of Cardiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Correspondence to Dr. Abhijit V. Kshirsagar, CB 7155, 348 MacNider Hall, Chapel Hill, NC 27599-7155. Phone: 919-966-2561, ext. 259; Fax: 919-966-4251; E-mail: sagar{at}med.unc.edu
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Abstract |
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Introduction |
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We therefore performed a systematic review and meta-analysis of available prospective controlled trials to quantify and compare reported associations of oral N-acetylcysteine with the incidence of nephropathy after exposure to radiocontrast media. For this review, we examined several key questions. Is there evidence of publication bias? Are there differences among the study results compatible with chance variation? Are there characteristics of studies or participating patients associated with meaningful changes in the association of administration of N-acetylcysteine and the incidence of radiocontrast-induced nephropathy? And most importantly, does the existing literature currently support a conclusion regarding the effectiveness of administration of oral N-acetylcysteine to reduce the occurrence of radiocontrast-induced nephropathy?
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Materials and Methods |
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Identification of Relevant Trials
Identification of relevant trials was performed by three study authors (AVK, AM, NF). We performed a MEDLINE search of the literature from 1966 to March 2003 using the terms N-acetylcysteine and radiocontrast. Searches of EMBASE and the Cochrane Collaboration’s register, CENTRAL, were also performed between 1974 and March 2003 using the terms N-acetylcysteine, contrast, and clinical trial. In addition, we reviewed abstracts from the annual meetings of the American Society of Nephrology, National Kidney Foundation, American Heart Association, and Radiologic Society of North America from 1999 to 2002, and from the American College of Cardiology from 1999 to 2003, to identify studies not yet published at the time of our literature search. We also reviewed the bibliographies of original and review articles that investigated N-acetylcysteine. We were also aware of an ongoing trial at the University of North Carolina examining the effect of N-acetylcysteine on the prevention of radiocontrast nephropathy directed by three of the contributing authors (MA, CDC, EMO). The study was initially designed to enroll 100 patients but was terminated after recruitment of 25 patients for reasons of study personnel. The study authors (MA, CDC, EMO) offered to share results of their unpublished study after learning of our intention to perform this systematic review.
Data Analyses
Specific data to be incorporated into the analysis were abstracted independently from the articles by three researchers (AVK, AM, NF) without masking. The three researchers extracted the information and recorded it on preprinted forms. The three researchers then met to confirm findings and to resolve any differences. We did not test formally for agreement among the three researchers with a kappa statistic. The extracted information included the following: definition of radiocontrast-induced nephropathy, number of patients at initiation of study, average patient age, prevalence of diabetes and congestive heart failure, average baseline SCr concentration, hydration protocol, total hydration volume, weight before and after administration to assess hydration status, type of radiocontrast medium, average volume of radiocontrast medium, dose of N-acetylcysteine, timing of N-acetylcysteine administration, change in SCr concentration after 48 h, incidence of radiocontrast-induced nephropathy (as defined below), and the proportion of individuals needing dialysis. Information that was not clearly presented within the body of the article or abstract was clarified by contacting the primary investigators (5,6,10,11).
The clinical end point investigated was the risk of radiocontrast-induced nephropathy measure at or after 48 h. Radiocontrast induced nephropathy was defined as (1) a 0.5 mg/dl or more increase in SCr from baseline after 48 h, or (2) a 25% or more increase in SCr from baseline after 48 h. Our definition was based on the current literature and was used by all studies incorporated in the meta-analysis. Physiologically, the peak elevation of the SCr concentration after administration of radiocontrast media is known to occur after 48 h and generally begins to drop after 96 h. Furthermore, studies have shown that a creatinine change of 25% or more has the same mortality as larger changes and is a sensitive predictor of the future need for dialysis (12,13).
Statistical Analyses
Evidence of publication bias was investigated by means of funnel plot, Begg and Mazumdar’s test (14), and the test of Egger et al. (15) If there is no publication bias, the expected shape of this plot is a symmetrical, funnel-shaped distribution of effect estimates above and below the summary estimate, with the more precise estimates more tightly clustered and the less precise estimates more widely dispersed around the summary value. Begg and Mazumdar’s test is a rank correlation test of the null hypothesis that the studies’ estimates are not associated with their estimated standard errors. The test of Egger et al. regresses the z-score on the standard error. The expected intercept of this regression equation is zero when the estimates and their standard errors are unassociated. Thus, both tests are tests of funnel plot symmetry.
Heterogeneity of the trials was assessed by means of Cochran’s Q statistic, which has a 
2 distribution with degrees of freedom equal to one minus the number of estimates. When all trials produce unbiased estimates of the same true population value and their results therefore differ only by chance, the expected value of this statistic equals the degrees of freedom (16). The test of homogeneity was conducted for all studies and also for various subsets of studies, including the trials that used a randomization scheme and trials that used both randomization and placebo. We also conducted tests of homogeneity for all studies using relative risk or odds ratio as a means of sensitivity analysis.
We performed meta-regression analyses to assess the association between risk difference estimates from the trials and characteristics of those trials and their participating patients. All study characteristics were selected a priori as potentially influential. The small number of trials precluded the use of multivariable meta-regression. Selected characteristics were: (1) randomized trial (versus nonrandomized); (2) N-acetylcysteine given the day before (versus day of); (3) placebo used (versus no placebo); (4) abstract (versus peer-reviewed journal article); (5) iso-osmotic contrast used (versus low-osmolality contrast used); (6) average baseline SCr of all study subjects within each trial; (7) difference in average baseline SCr between treatment and control groups within each trial; (8) average contrast volume within each trial; (9) difference in average volume between treatment and control groups within each trial; (10) average age of subjects within each trial; (11) difference in average age between treatment and control groups; (12) average prevalence of diabetes within each trial; (13) difference in diabetes prevalence between treatment and control groups within each trial; and (14) the type of saline used, 0.9% or 0.45%. The meta-regression was conducted both for all studies and, as a sensitivity analysis, for the studies in which randomization to treatment group was a feature of the study design. We estimated the association between treatment and outcome by using the risk difference with 95% confidence intervals calculated for each study, and a summary or aggregate risk difference by using the Metan program in Stata.
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Results |
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list important study and subject characteristics of the 16 prospective controlled trials with a total of 1538 subjects. Twelve of the 16 studies assigned intervention by a randomization process. Participants in ten studies received a placebo, whereas participants in six did not receive a placebo. Nine studies were published in peer-reviewed journals, six were published as an abstract at the time of our search, and one study was unpublished. All of the cited were published within the last 3 yr, with the majority published in the year 2002. Except for the study by Tepel et al. (2), the indication for radiocontrast media exposure was for a coronary artery angiography/intervention.
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All 1538 individuals, whether in the N-acetylcysteine group or in the placebo group, were provided intravenous saline hydration before the administration of radiocontrast media; 0.45% saline, rather than 0.9% saline, was predominantly used. Seven hundred twenty-one subjects were assigned to receive oral N-acetylcysteine, and 817 individuals were assigned to receive a control therapy. Individuals in the N-acetylcysteine group were given the drug orally at a dose of 600 mg twice a day 1 d before and on the day of exposure to radiocontrast media in the majority of studies. In the study by Shyu et al. (19), the dose of N-acetylcysteine was 33% less than the other studies, whereas in the study by Agrawal (unpublished), the initial dose of N-acetylcysteine was 33% higher than the other studies. Finally, in the studies by Durham et al. (3) and Diaz-Sandoval et al. (20), individuals were dosed at different times than in the other studies.
Figure 2 displays the results of the funnel plots for all 16 trials. There was little evidence of publication bias in these studies by visual inspection, and by the tests of Begg and Mazumdar (14) and of Egger et al. (15). Figure 3 is a forest plot displaying estimated risk difference from each of the 16 controlled trials. In parentheses after the year of publication is the relative weight, which is one over the within-study variance expressed as a percentage of the maximum of these values. In other words, the shortest line is 100 and the longest line is 3. The point estimates and 95% confidence intervals vary widely among these studies, as confirmed by the homogeneity test (P < 0.001). Roughly one-third of the point estimates suggest a beneficial effect of N-acetylcysteine, one-third suggest no effect, and one-third suggest a beneficial effect of the control intervention. Notably, the forest plot graphically demonstrates the high degree of heterogeneity of study results in a great degree of nonoverlap among the confidence intervals. We did not present the aggregate risk difference estimate because of the high degree of heterogeneity observed among the studies. Of note, heterogeneity was also present and was highly significant when using relative risk or odds ratio as the primary outcome measure.
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There was no clinically significant change in the identified patient and study characteristics when meta-regression was limited to only the 11 randomized clinical trials. There was no difference in the incident need for hemodialysis between the two groups.
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Discussion |
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We regarded the presence of such pronounced heterogeneity to contraindicate reliance on any single summary estimate of treatment effect. An aggregated summary estimate in such a circumstance would be an oversimplification, as the presence of heterogeneity clearly suggests the existence of study characteristics, patient characteristics, or both, that appreciably influence the magnitude, and perhaps also the direction, of the effect estimates that different trials produce. We did not subscribe to the view that incorporation of the among-study variance (random-effects model) into the computation of a summary estimate accommodates or accounts for inconsistent results among the studies. Rather, we concurred with the observation of DerSimonian and Laird that "in drawing inferences from heterogeneous but logically related studies...the use of regression analysis to characterize differences in study outcomes may be more appropriate" (21) and have followed that advice.
As such, univariate meta-regression analysis has suggested that patient characteristics and study design may account for discrepant results of the effect of N-acetylcysteine. On closer examination, these characteristics are plausible explanations of the observed heterogeneity and may serve to direct future investigations of the use of N-acetylcysteine. Speculatively, the identified characteristics may also guide clinicians to carefully choose certain groups of patients for the intervention.
Take for example, the characteristic, the time of dosing of N-acetylcysteine. Studies whose participants were dosed with N-acetylcysteine on the day before the procedure were more likely do demonstrate a reduction of radiocontrast-induced nephropathy than those studies dosing participants on the day of the procedure. Individuals receiving their first dose of N-acetylcysteine on the day before, rather than on the day of, the radiocontrast media may have greater systemic levels of the antioxidant agent. However, peak serum levels of N-acetylcysteine occur 1 h after oral administration, and the half-life of reduced N-acetylcysteine is approximately 2 h (22). Reduction in renal function, furthermore, should not alter the elimination pathway for the agent.
Other important characteristics identified by the univariate meta-regression include the age of subjects, prevalence of diabetes mellitus, and the type and volume of radiocontrast media used by the individual studies. Studies with a higher proportion of elderly individuals or diabetic patients, or studies that used a high volume of radiocontrast media or that used a relatively high osmolality agent, were associated with a change in the estimated risk difference in a direction favoring N-acetylcysteine. Most of these identified characteristics are known to be risk factors for the development of radiocontrast-induced nephropathy (23). Thus, it is conceivable that the effectiveness of N-acetylcysteine may be greatest among a population of individuals with a high baseline risk of developing radiocontrast-induced nephropathy.
Yet there were some inconsistent findings with respect to the risk factors for contrast nephropathy. Notably, the level of renal function at baseline was not associated with a change in the estimated effect of N-acetylcysteine. It may be that SCr concentration is too imprecise and insensitive as an estimate of GFR (24). Furthermore, the estimated effect N-acetylcysteine was greater among the group of individuals with intravenous hydration greater than 12 h compared to the group receiving less than 12 h of saline hydration. We have no pathophysiologic explanation for the finding, and speculatively, this may reflect an intrinsic anomaly of the data set.
The findings of our systematic review should be interpreted in the context of both intrinsic limitations of meta-analysis, and in the context of our own study-specific (subject matter) limitations. In systematic reviews, the traditional unit of analysis is each study, rather than patients. Thus, the power to detect a difference in aggregate or to identify explanatory variables by meta-regression is greatly diminished compared with large primary trials with individual-level data (or to meta-analyses with individual-level data). Furthermore, interpretation of any results for study or patient characteristics that must be represented by study population average values or percentages are prone to the ecologic fallacy (25).
Second, although we have strongly demonstrated heterogeneity, we were not able to identify any single characteristic of studies or patients within levels or categories of which the results are consistent. Nor, among the randomized trials, did the results of the placebo-controlled trials differ materially from those that did not use placebo controls. The small number of studies made it difficult to determine whether multiple study and patient characteristics in combination might render the results more consistent.
Third, we predominately identified and used published studies. Our search strategy identified only one unpublished trial, and thus our results are heavily weighted on the findings of these published trials. We identified an unpublished study of quality at our local institution. It is quite likely that other unpublished studies exist at other institutions, and we hope that the publication of this study will allow for the eventual analysis of these other studies. The exclusion of unpublished data are generally associated with an overestimate of the true effect in meta-analysis (26). By far the single most common reason for the inability to publish a trial is the lack of statistical significance, although some have suggested that the quality of unpublished trials may not be comparable to those accepted in peer-reviewed journals (27). The unpublished study included in this analysis was of high quality, randomized, placebo controlled, and masked. In addition, we did not use a masked assessment of study quality, nor did we formally test agreement among the independent observers.
Acute renal failure remains a common clinical occurrence among hospitalized patients (28–30). The development of acute renal failure increases morbidity (31,32), cost (33), and mortality (34–37). Exposure to radiocontrast media is a common iatrogenic cause of acute renal failure among hospitalized patients with chronic kidney disease (38). The use of nonionic, low-osmolality radiocontrast media (39,40) and the administration of intravenous fluids (41,42) have attenuated the risk of developing acute renal failure. Initial studies suggested a highly beneficial effect of N-acetylcysteine, and clinicians rapidly adopted the agent into their armamentarium.
This systematic review suggests that the role of oral N-acetylcysteine in the prevention of radiocontrast-induced nephropathy has yet to be defined. The literature as it currently exists is profoundly heterogeneous, making any single summary estimate invalid. Thus, the analysis could not demonstrate an added benefit of oral N-acetylcysteine among all individuals with preexistent renal insufficiency. Meta-regression analysis identified some important study and patient characteristics that may partially explain the heterogeneity: the time of N-acetylcysteine administration, advanced age, presence of diabetes mellitus, and the volume and type of radiocontrast media. It is biologically plausible that these characteristics would affect the relationship of N-acetylcysteine and therefore may serve to guide future research in this field.
Our results may have some important immediate and long-term implications. First, rather than the indiscriminate use of N-acetylcysteine, clinicians may better direct their efforts at proven interventions (intravenous saline, low-osmolality/iso-osmolality contrast media). Second, clinicians should be judicious in their decision to order radiographic tests. Third, given the low side-effect profile and cost of N-acetylcysteine, a large, randomized, placebo-controlled trial should be conducted. Large randomized-controlled trials have been known to differ with findings of meta-analyses (43,44). Alternatively, a pooled analysis of individual patient data may be a more economical way of answering the question and likely should be done as a prelude to a mega-trial. In conclusion, the findings of this systematic review do not support the routine use of N-acetylcysteine for the prevention of radiocontrast-induced nephropathy.
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Acknowledgments |
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