Int Urol Nephrol DOI 10.1007/s11255-012-0363-1 NEPHROLOGY - ORIGINAL PAPER The effectiveness of N-acetylcysteine in preventing contrast-induced nephropathy in patients undergoing contrast-enhanced computed tomography: a meta-analysis of randomized controlled trials Mei-Yi Wu • Hui-Fen Hsiang • Chung-Shun Wong • Min-Szu Yao • Yun-Wen Li • Chao-Ying Hsiang • Chyi-Huey Bai • Yung-Ho Hsu • Yuh-Feng Lin • Ka-Wai Tam Received: 12 July 2012 / Accepted: 12 December 2012 Ó Springer Science+Business Media Dordrecht 2012 Abstract undergoing CT. The primary outcome was the inci- Background N-Acetylcysteine (NAC) is reported to dence of contrast-induced nephropathy, and the have potential for preventing of contrast-induced requirement for dialysis. The secondary outcome was nephropathy (CIN) in patients undergoing coronary the change of serum creatinine. angiography. However, the effectiveness of NAC in Results Six randomized controlled trials were preventing CIN in patients undergoing contrast- identified with a total of 496 patients meeting the enhanced computed tomography (CT) is still contro- criteria for this study. Prophylactic administration versial. We conducted a meta-analysis of relevant of NAC in patients with serum creatinine above randomized controlled trials (RCTs) to further exam- 1.2 mg/dL undergoing contrast-enhanced CT, along ine this issue. with hydration, reduced the risk of CIN (relative Methods RCTs were identified by computerized risk 0.20; 95 % confidence interval: 0.07–0.57). searching in PubMed, EMBASE, SCOPUS, and Requirement for dialysis was not significantly Cochrane databases. Two reviewers independently different between the NAC group and the control assessed the methodological quality of each study. A group. meta-analysis was performed to evaluate the effec- Conclusions This review provides evidence of the tiveness of NAC in preventing CIN in patients efficacy of NAC in preventing the incidence of CIN M.-Y. Wu Á Y.-H. Hsu Á Y.-F. Lin C.-H. Bai Division of Nephrology, Department of Internal School of Public Health, Taipei Medical University, Medicine, Taipei Medical University, Taipei, Taiwan Shuang Ho Hospital, Taipei, Taiwan K.-W. Tam (&) H.-F. Hsiang Á Y.-W. Li Á C.-Y. Hsiang Division of General Surgery, Department of Surgery, Department of Nursing, Taipei Medical University Taipei Medical University Hospital, No. 252 Wu-Hsing Hospital, Taipei, Taiwan Street, Taipei 11031, Taiwan e-mail: [email protected] C.-S. Wong Department of Emergency Medicine, Taipei Medical K.-W. Tam University, Shuang Ho Hospital, Taipei, Taiwan Center for Evidence-Based Medicine, Taipei Medical University, Taipei, Taiwan M.-S. Yao Department of Radiology, Taipei Medical University, Wan Fang Hospital, Taipei, Taiwan 123 Int Urol Nephrol and recommends that NAC be more widely used in previous studies have elevated the use of theophylline, high-risk patients undergoing contrast-enhanced CT. calcium antagonists, dopamine, atrial natriuretic pep- On the basis of the evidence reviewed, further research tide, and other agents as preventive strategies in CIN; involving large RCTs may be warranted. the results have been heterogeneous and are difficult to compare across different treatment strategies [6]. Keywords N-Acetylcysteine Á Contrast-induced Accumulating evidence indicates that reactive oxygen nephropathy Á Computed tomography Á Meta-analysis species have a role in the renal damage caused by contrast agents [7]. Several randomized controlled trials (RCTs) and meta-analyses evaluating the anti- Introduction oxidative agent N-acetylcysteine (NAC) in preventing CIN in patients undergoing coronary angiography Contrast-induced nephropathy (CIN) is a major com- have yielded promising results [8]. However, the plication of intravenous administration of an iodine effectiveness of NAC in preventing CIN in patients contrast medium and is usually defined as an increase undergoing contrast-enhanced computed tomography in serum creatinine greater than 25 % or 44.2 lmol/L (CT) is still controversial. In this report, we system- ([0.5 mg/dL) within 3 days of intravascular contrast atically review the data from randomized trials to administration in the absence of an alternative cause evaluate the effect of NAC in the preventing CIN in [1]. Contrast-induced nephropathy (CIN) is uncom- the study population. mon in patients with normal renal function, ranging from 0 to 10 % [2]. However, the incidence is perhaps as high as 50 % in patients with preexisting renal Methods impairment or certain risk factors [3]. The most critical risk factors for CIN include preexisting renal Review protocol insufficiency, old age, diabetes mellitus, reduced left ventricular systolic function, advanced congestive We utilized the Preferred Reporting Items for Sys- heart failure, kidney transplantation, reduced effective tematic Reviews and Meta-analyses (PRISMA) state- arterial volume, and concurrent administration of ment, explanation and elaboration document, and nephrotoxic drugs or drugs that interfere with the checklist to guide our methodology and reporting [9]. regulation of renal perfusion, such as angiotensin- The systematic review described herein was accepted converting-enzyme inhibitors [1]. Administering a by the online PROSPERO international prospective large dose of intravenous contrast and using high- register of systematic reviews of the National Institute osmolar contrast agents in patients with renal impair- for Health Research (CRD42012002094). ment also increase the risk for CIN [4]. Despite a high rate of renal function recovery following CIN, the Search methods consequences of this complication include prolonged hospitalization, increased risk for renal failure and The studies were identified by computerized searching association with dialysis, increased health care cost, in the PubMed, EMBASE, SCOPUS, and Cochrane potentially irreversible reduction in renal function, and databases. The following MeSH search headings were higher mortality [3]. Therefore, preventive measures used: acetylcysteine, radio induced or contrast for CIN are crucial. induced, renal insufficiency or renal failure or kidney The effects of various interventions in preventing injury or nephropathy, and computed tomography. CIN have been evaluated in clinical trials. The results These terms and their combinations were also of several studies have demonstrated a considerable searched as text words. All included studies were also reduction in the incidence of CIN using adequate entered into the PubMed ‘related articles’ function and intravenous fluid hydration, low-osmolality contrast the science citation index. In addition, we attempted to media instead of high-osmolar agents and iso-osmolar identify other studies by hand-searching the reference agents instead of low-osmolar agents [5]. The sections of these papers and by contacting known 123 Int Urol Nephrol experts in the field. Finally, unpublished trials were Data synthesis and analysis sought in the ClinicalTrials.gov registry (http:// clinicaltrials.gov/). No language restrictions were We used the following outcomes to evaluate the applied. The final search was performed in October efficacy of NAC in preventing CIN for patients 2012. The full search strategies are available in the undergoing contrast-enhanced CT: the incidence of ‘‘Appendix’’. CIN, the requirement for dialysis, changes of serum creatinine, and cystatin C level. We conducted the analysis using the statistical Study selection package Review Manager, Version 5.1 (Cochrane Collaboration, Oxford, England). We statistically To be included in our analysis, studies were analyzed the dichotomous outcomes using risk ratios required to meet the following criteria: RCTs (RRs) as the summary statistic. Continuous outcomes that have evaluated the efficacy of acetylcyste- were analyzed using the weighted mean difference ine, administered orally or intravenously, versus a (WMD). Both types of summary statistics were control group with hydration alone to prevent CIN reported with 95 % confidence intervals (CIs). A in patients undergoing contrast-enhanced CT, have pooled estimate of the RR was computed using the documented clearly the inclusion and exclusion DerSimonian and Laird random-effect model [10], criteria used for patient selection, have adequately which provides a more appropriate estimate of the documented the administration of acetylcysteine, average treatment effect when trials are statistically and have precisely documented the definition and heterogeneous, and usually yields wider CIs, thereby evaluation of CIN. The studies were excluded resulting in a more conservative statistical claim. v2 from the analysis if any one or more of the statistics tests (Q statistics) and I2 test were used to test following conditions applied: patients enrolled in for heterogeneity between controlled trials. the trials had undergone other contrast-enhanced diagnostic and therapeutic procedures concomi- tantly; trials compared NAC with another active Results treatment. When duplication papers using overlap- ping data sets were published, the study with the Characteristics of the trials larger population was included. Figure 1 shows a flowchart for selecting trials. Our Data extraction and quality assessment initial search strategy yielded 386 citations, 254 of which were ineligible based on our screening of Two reviewers (M.Y. Wu and K.W. Tam) inde- titles and abstracts; thus, we retrieved the full text pendently extracted the following information of 132 studies. Of these, 37 were excluded