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Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysisEffectiveness of Prevention Strategies for CIN FREE

Rathan M. Subramaniam, MD, PhD, MPH; Catalina Suarez-Cuervo, MD; Renee F. Wilson, MS; Sharon Turban, MD, MHS; Allen Zhang, BS; Cheryl Sherrod, MD, MPH; Jonathan Aboagye, MD, MPH; John Eng, MD; Michael J. Choi, MD; Susan Hutfless, PhD; and Eric B. Bass, MD, MPH
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This article was published at www.annals.org on 2 February 2016.


From Johns Hopkins University School of Medicine, Johns Hopkins University Bloomberg School of Public Health, and Johns Hopkins University Evidence-based Practice Center, Baltimore, Maryland.

Disclaimer: The authors of this article are responsible for its content. Statements in the article should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Acknowledgment: The authors thank Emmanuel Iyoha, Elisabeth Nannes, Oluwaseun Shogbesan, and Yohalakshmi Chelladurai for their contributions to this project.

Grant Support: By the Agency for Healthcare Research and Quality (contract 290-2012-00007-I), U.S. Department of Health and Human Services.

Disclosures: Dr. Subramaniam reports grants from the Agency for Healthcare Research and Quality during the conduct of the study and personal fees from Philips Healthcare outside the submitted work. Ms. Wilson reports other from the Johns Hopkins University Evidence-based Practice Center during the conduct of the study and personal fees from Prism Capital outside the submitted work. Dr. Turban Reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Dr. Eng reports support from a contract with the Agency for Healthcare Research and Quality. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/Conflict OfInterestForms.do?msNum=M15-1456.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.

Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Ms. Wilson (e-mail, rwilsob@jhmi.edu).

Requests for Single Reprints: Rathan M. Subramaniam, MD, PhD, MPH, Associate Professor of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, 601 North Caroline Street, Baltimore, MD 21287; e-mail, rsubram4@jhmi.edu.

Current Author Addresses: Dr. Subramaniam: Associate Professor of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, 601 North Caroline Street, Baltimore, MD 21287.

Drs. Suarez-Cuervo, Sherrod, Aboagye, and Bass; Ms. Wilson; and Mr. Zhang: Evidence-based Practice Center, Johns Hopkins University, 624 North Broadway, Suite 648, Baltimore, MD 21205.

Drs. Turban and Choi: Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 416, Baltimore, MD 21287.

Dr. Eng: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287.

Dr. Hutfless: Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Blalock Building, Room 449, 600 North Wolfe Street, Baltimore, MD 21287.

Author Contributions: Conception and design: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, A. Zhang, J. Eng, E.B. Bass.

Analysis and interpretation of the data: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, A. Zhang, C. Sherrod, J. Aboagye, M.J. Choi, S. Hutfless, E.B. Bass.

Drafting of the article: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, A. Zhang, C. Sherrod, J. Aboagye, J. Eng.

Critical revision of the article for important intellectual content: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, J. Aboagye, J. Eng, M.J. Choi, S. Hutfless, E.B. Bass.

Final approval of the article: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, A. Zhang, C. Sherrod, J. Aboagye, J. Eng, M.J. Choi, S. Hutfless, E.B. Bass.

Provision of study materials or patients: E.B. Bass.

Statistical expertise: A. Zhang, J. Eng, S. Hutfless.

Obtaining of funding: R.M. Subramaniam, E.B. Bass.

Administrative, technical, or logistic support: R.F. Wilson, A. Zhang, C. Sherrod, E.B. Bass.

Collection and assembly of data: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, A. Zhang, C. Sherrod, J. Aboagye, J. Eng, M.J. Choi.


Ann Intern Med. 2016;164(6):406-416. doi:10.7326/M15-1456
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Background: N-acetylcysteine, sodium bicarbonate, statins, and ascorbic acid have been studied for reducing contrast-induced nephropathy (CIN).

Purpose: To evaluate the comparative effectiveness of interventions to reduce CIN in adults receiving contrast media.

Data Sources: MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, and Scopus databases through June 2015. Risk of bias and overall strength of evidence (SOE) of studies were assessed.

Study Selection: Randomized, controlled trials of N-acetylcysteine, sodium bicarbonate, statins, or ascorbic acid that used intravenous (IV) or intra-arterial contrast media and defined CIN with enough data for meta-analysis.

Data Extraction: Two reviewers independently extracted data and assessed study quality.

Data Synthesis: Low-dose N-acetylcysteine plus IV saline compared with IV saline (risk ratio [RR], 0.75 [95% CI, 0.63 to 0.89]; low SOE), N-acetylcysteine plus IV saline compared with IV saline in patients receiving low-osmolar contrast media (RR, 0.69 [CI, 0.58 to 0.84]; moderate SOE), and statins plus N-acetylcysteine plus IV saline versus N-acetylcysteine plus IV saline (RR, 0.52 [CI, 0.29 to 0.93]; low SOE) had clinically important and statistically significant benefits. The following 3 comparisons suggested a clinically important difference that was not statistically significant: sodium bicarbonate versus IV saline in patients receiving low-osmolar contrast media (RR, 0.65 [CI, 0.33 to 1.25]; low SOE), statins plus IV saline versus IV saline (RR, 0.68 [CI, 0.39 to 1.20]; low SOE), and ascorbic acid versus IV saline (RR, 0.72 [CI, 0.48 to 1.01]; low SOE). Strength of evidence was generally insufficient for comparisons of the need for renal replacement, cardiac events, and mortality.

Limitation: Too few studies were done in patients receiving IV contrast media.

Conclusion: The greatest reduction in CIN was seen with N-acetylcysteine plus IV saline in patients receiving LOCM and with statins plus N-acetylcysteine plus IV saline.

Primary Funding Source: Agency for Healthcare Research and Quality.

2 22016.


Iodine contrast medium is an essential component of many diagnostic and therapeutic procedures that involve medical imaging. One important side effect of iodine contrast is contrast-induced nephropathy (CIN), defined as an increase in serum creatinine levels of more than 25% or 44.2 µmol/L (0.5 mg/dL) within 3 days of intravascular administration in the absence of an alternative cause (1). Because of increasing use of contrast media in radiologic and cardiologic procedures and the increasing prevalence of persons who are vulnerable to CIN (those with chronic kidney disease, diabetes mellitus, or hypertension, as well as elderly persons), kidney failure due to CIN is a substantial concern (2, 3). The reported incidence varies between 7% and 11% depending on the definition of CIN, study population, and setting (24). Some studies suggest that this incidence may be overestimated (4), especially when intravenous (IV) contrast media are used. An average additional cost of $10 345 is associated with a CIN-related hospital stay (5).

Many strategies have been used to prevent CIN. They include oral hydration; volume expansion with sodium chloride or bicarbonate or both; administration of N-acetylcysteine; withdrawal of metformin, angiotensin-converting enzyme inhibitors, angiotensin II–receptor blockers, or nonsteroidal anti-inflammatory drugs; hemofiltration or hemodialysis; statins; use of low-osmolar contrast media (LOCM), iso-osmolar contrast media (IOCM), or nonionic contrast media; and reducing the volume of contrast media administered. Despite these varied strategies, no clear consensus exists in clinical practice about the most effective intervention to prevent or reduce CIN.

Many meta-analyses have been published, but almost all of them have focused on specific therapies or included subspecialty–specific populations, which reduced the general applicability in clinical practice (611). The route of administration of contrast media may be a confounder because the baseline risk profile of patients having intra-arterial (IA) versus IV procedures may differ. Whether effectiveness of preventive interventions depends on the route of administration or the type of contrast media (IOCM or LOCM, the 2 types now in regular clinical use in the United States) is also unclear. We did a systematic review and meta-analysis to compare the preventive effect of strategies to reduce CIN, including subgroup analyses based on route of administration of contrast media or preventive strategies and the type of contrast media used.

We developed a protocol for this systematic review, which we posted online and registered in PROSPERO (CRD42013006217). The complete protocol is in the full report on which this article is based (12).

Data Sources and Searches

We searched MEDLINE, EMBASE, and the Cochrane Library through 30 June 2015 (Appendix Table). In addition, we searched the Scopus database for conference proceedings and other reports. We reviewed the reference lists of relevant articles and related systematic reviews to identify original articles that we might have missed. We also searched ClinicalTrials.gov and the U.S. Food and Drug Administration Web site.

Table Jump PlaceholderAppendix Table. Detailed Search Strategy 
Study Selection

We included studies of patients of all ages. We identified observational and randomized, controlled trials (RCTs) that included administration of N-acetylcysteine, sodium bicarbonate, sodium chloride, statins, or ascorbic acid to prevent CIN. The study groups received IOCM or LOCM via IV or IA injection, CIN outcome was explicitly defined, and sufficient data were reported to calculate the primary effect measure (relative risk reduction of CIN). Secondary outcomes included the need for renal replacement therapy, cardiac events, and mortality. We included only RCTs for the meta-analyses. All data from other studies and other strategies to reduce CIN incidence (such as adenosine antagonists, renal replacement therapy, diuretics, antioxidants, and vasoactive agents) were analyzed and included in the full report (12). We excluded studies of high-osmolar contrast medium because it is no longer used in clinical practice in the United States. We did not contact the authors for original data.

Data Extraction and Quality Assessment

Two reviewers independently screened the titles and abstracts for eligibility and independently assessed each study's risk of bias by using 5 items from the Cochrane Risk of Bias Tool for RCTs (3). We solved disagreements by consensus or a third reviewer when consensus was not possible. At random intervals during screening, we did quality checks to ensure that eligibility criteria were applied consistently. The second reviewer checked the accuracy of the data extracted by the first reviewer.

We graded the strength of evidence (SOE) on comparisons of interest for the key outcomes by using the grading scheme recommended in the Methods Guide of the Evidence-based Practice Center and considered the domains of study limitations, directness, consistency, precision, reporting bias, and magnitude of effect (13). Following the guidance of the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) Working Group (14), we rated evidence as precise if the total number of patients exceeded an optimum information size and the 95% CI excluded a risk ratio (RR) of 1.0. If the number of patients exceeded the optimum information size and the CI did not exclude the possibility of no difference (that is, RR of 1.0), we only rated the evidence as precise if the CI excluded the possibility of a clinically important benefit or harm (that is, RR <0.75 or >1.25). We classified the SOE pertaining to each comparison into 4 category grades (high, moderate, low, and insufficient) and assigned SOE grades by group consensus. The body of evidence was considered high-grade if study limitations were low and there were no problems in any other domain, and it was subsequently downgraded for each domain in which a problem was identified. If the magnitude of effect was very large, the SOE could be upgraded.

Data Synthesis and Analysis

The primary outcome was CIN, defined as an increase in serum creatinine levels of more than 25% or 44.2 µmol/L (0.5 mg/dL) within 3 days of intravascular administration of contrast media. We calculated individual study RRs and CIs and then obtained overall and subgroup summary RRs by using a random-effects model. For large comparisons with 18 or more studies, we used the DerSimonian–Laird random-effects estimator, with the estimate of heterogeneity taken from the inverse-variance, fixed-effect model (15). Although this method is often the standard estimator used by many meta-analysis software programs, it tends to underestimate CIs when fewer than 18 studies are compared (15). To compensate, we used the Knapp–Hartung small-sample estimator approach for comparisons with fewer than 18 studies. This method allows for small sample adjustments to the variance estimates and calculates CIs on the basis of the t distribution with k − 1 degrees of freedom (15). We used the Harbord modified test for small study effects to determine whether there was asymmetry in effect estimates.

To assess the clinical importance of differences in CIN incidence, a binary outcome, we followed guidance for selecting a minimally important difference on the basis of the overall event rate in the studies (14). Our clinical experts decided that a relative risk reduction of 25% would be clinically important, which is consistent with the guidance that suggests a reduction of 20% to 30% in determining optimal information size.

To account for factors that could be associated with a difference in CIN risk, we did a subgroup analysis on the basis of the route of administration (IA vs. IV) and type of contrast media (IOCM vs. LOCM), baseline serum creatinine level, sex, age, and prevalence of diabetes mellitus. A priori, we assumed that there would be considerable heterogeneity and therefore used a random-effects model. We also examined the I2, which measures the degree of heterogeneity across studies (I2 varies from 0% to 100%, with 0% indicating no heterogeneity). All statistical analyses were done in Stata, version 13 (StataCorp).

Role of the Funding Source

The Agency for Healthcare Research and Quality selected the topic and assigned it to the Johns Hopkins University Evidence-based Practice Center. The Agency assigned a task order officer who provided comments on the protocol and draft versions of the full evidence report. The Agency did not directly participate in the literature search, determination of study eligibility, data analysis or interpretation, or preparation of the manuscript for publication.

The literature search revealed 86 RCTs on interventions for preventing CIN (Appendix Figure). These study results were published between 1998 and 2015. Six studies were funded by industry sources (1621), 16 were funded by academia or government agencies, 33 had no funding statement, and the remainder reported no conflicts of interest. All findings from these studies were analyzed and described in the full report (12).

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Appendix Figure.

Summary of evidence search and selection.

CIN = contrast-induced nephropathy; RCT = randomized, controlled trial.

* 24 647 gray literature results were also found.

† Total does not sum to 371 because the 2 reviewers were not required to agree on reasons for exclusion.

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N-acetylcysteine Plus IV Saline Versus IV Saline

N-acetylcysteine is a direct scavenger of free radicals and improves blood flow through nitric oxide–mediated pathways, which results in vasodilatation. As a result, both the antioxidant and vasodilatory properties of N-acetylcysteine are believed to protect against CIN.

We included 54 RCTs on N-acetylcysteine plus IV saline versus IV saline with or without a placebo published since 2002 in the meta-analysis (1669).

The studies varied widely in patient and intervention characteristics. Study patients had renal dysfunction at baseline (defined as serum creatinine levels >106.08 µmol/L [>1.2 mg/dL]) in 35 studies. Table 1 summarizes the pooled RRs and CIs for subgroups by high- or low-dose N-acetylcysteine administration, route of administration (oral or IV), and type of contrast media (LOCM or ICOM). Pooled RRs for CIN and CIs were derived by using a random-effects model to pool studies comparing N-acetylcysteine with IV saline versus IV saline with or without a placebo.

Table Jump PlaceholderTable 1. Pooled RRs for CIN With NAC Compared With IV Saline 

High-dose N-acetylcysteine plus IV saline had a small effect on reducing CIN risk that was clinically unimportant and not statistically significant, and low-dose N-acetylcysteine plus IV saline had a borderline clinically important effect on preventing CIN. Both comparisons had low SOE. Sensitivity analyses revealed imprecise estimates of the pooled RR for CIN, when stratified by route of administration (Table 1). When given orally, N-acetylcysteine plus IV saline had a small effect on reducing CIN risk that was clinically unimportant but statistically significant, with low SOE. N-acetylcysteine plus IV saline had a clinically important benefit in reducing CIN risk when LOCM were used, with moderate SOE, but had a clinically unimportant effect when IOCM were used, with low SOE (Figure 1). We examined how the RRs varied according to baseline characteristics of the study population and did not see any significant difference by age, sex, baseline renal function, or the presence or absence of diabetes mellitus. We did not see a pattern indicative of a trend by study quality.

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Figure 1.

Pooled RRs for development of CIN in comparisons ofN-acetylcysteine plus IV saline versus IV saline in patients receiving contrast media.

CIN = contrast-induced nephropathy; IOCM = iso-osmolar contrast media; IV = intravenous; LOCM = low-osmolar contrast media; NAC = N-acetylcysteine; RR = risk ratio.

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The overall analysis did not suggest that any intervention was superior when we evaluated secondary outcomes, and the SOE was low or insufficient. The Harbord test for small study effects was done for all comparisons, and no asymmetry was detected (Table 2).

Table Jump PlaceholderTable 2. Summary of the Main Findings and SOE* 
IV Sodium Bicarbonate Versus IV Saline

A major hypothesis for using IV sodium bicarbonate to prevent CIN is that the alkalinization of tubular fluid diminishes the production of free oxygen radicals, which may cause CIN.

We included 19 RCTs on IV sodium bicarbonate versus IV saline (21, 35, 48, 59, 62, 6982). The studies varied widely in patient and intervention characteristics. Study patients had renal dysfunction at baseline in 10 studies. Contrast medium was administered via IV in 2 studies, IA in 14 studies, and IA or IV in 1 study, and 1 study did not report the route of administration. Six studies used IOCM, 12 used LOCM, and 1 did not report the type of contrast media (Supplement).

Intravenous sodium bicarbonate did not have a clinically important effect on CIN risk when compared with IV saline in all studies (pooled RR, 0.93 [95% CI, 0.68 to 1.27]). Intravenous sodium bicarbonate led to a clinically important reduction in CIN that was not statistically significant when compared with IV saline in patients receiving LOCM (RR, 0.65 [CI, 0.33 to 1.25]) and did not lead to reduction in CIN in patients receiving IOCM (RR, 1.02 [CI, 0.70 to 1.48]) (Figure 2). The SOE was low for all comparisons of IV sodium bicarbonate (Table 2).

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Figure 2.

Pooled RRs for development of CIN in studies of sodium bicarbonate, statins, and ascorbic acid in patients receiving contrast media.

CIN = contrast-induced nephropathy; IOCM = iso-osmolar contrast media; IV = intravenous; LOCM = low-osmolar contrast media; NAC = N-acetylcysteine; RR = risk ratio.

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The overall analysis did not suggest that IV sodium bicarbonate was superior to IV saline when we evaluated secondary outcomes, and the SOE was low or insufficient. The Harbord test for small study effects was done for all comparisons, and no asymmetry was detected (Table 2).

N-acetylcysteine Plus IV Saline Versus Sodium Bicarbonate

We included 7 RCTs (n = 1619) (21, 35, 48, 59, 62, 69, 83) that compared N-acetylcysteine with sodium bicarbonate (6 studies used IA administration, 1 did not report route of administration; 4 used LOCM, 3 used IOCM) (Supplement). This comparison showed no clinically important benefit in reducing CIN risk in 1 intervention over the other (RR, 1.11 [CI, 0.51 to 2.41]). The CI was so wide that we could not rule out the possibility of an important decrease or important increase in CIN risk (Figure 2). The SOE was graded as insufficient to draw conclusions about potential differences between the interventions in any outcome evaluated. The Harbord test for small study effects was done, and no asymmetry was detected (Table 2).

Statins

Statins have cholesterol-independent functionalities that play a role in various clinical contexts. The proposed mechanism related to CIN prevention is that they acted as stabilizers of the endothelium and free-radical scavengers in a model of ischemic nephropathy (84).

We did 2 separate meta-analyses on the studies of statins to reduce CIN incidence in patients receiving IA contrast. One analysis included 8 studies (n = 5024) on statin-naive patients that compared a statin plus IV saline with IV saline alone (8592). Two of the studies included only patients with chronic kidney disease, 3 included only those with cardiac issues, and 2 included patients with diabetes mellitus and chronic kidney disease. The analysis showed that statins had a clinically important but not statistically significant effect on reducing CIN risk (RR, 0.68 [CI, 0.39 to 1.20]) and low SOE (Table 2 and Figure 2). When we evaluated secondary outcomes, the SOE was insufficient to determine whether any intervention was superior.

Five studies (n = 1477) compared statins added to N-acetylcysteine and IV saline with N-acetylcysteine plus IV saline (9396) or sodium bicarbonate (97) (Supplement). Two of these studies included only patients with chronic kidney disease, 1 included those with cardiac disorders, 1 had a general population, and 1 had patients with diabetes mellitus and chronic kidney disease. Seven studies were not included in the meta-analyses because they included comparisons that were not similar enough to analyze (98104) or did not include a CIN outcome (105). The analysis showed a clinically important and statistically significant reduction in CIN (RR, 0.52 [CI, 0.29 to 0.93]) (Figure 2) and low SOE. When we evaluated secondary outcomes, the SOE was graded as insufficient. The Harbord test for small study effects was done for all comparisons, and no asymmetry was detected (Table 2).

Ascorbic Acid

As an antioxidant, ascorbic acid acts as a scavenger of reactive oxygen species, reducing oxidative stress and possibly preventing CIN.

We identified 8 RCTs (n = 2026) that compared ascorbic acid with IV saline or N-acetylcysteine and included 6 in the meta-analysis (32, 106110). We did not include 2 of the studies because they included N-acetylcysteine in both groups (111, 112). These studies included patients receiving cardiovascular interventions with IA administration of LOCM (3 studies), IOCM (1 study), or either LOCM or IOCM (2 studies) (Supplement).

Studies comparing ascorbic acid with IV saline showed a clinically important and statistically insignificant reduced risk for CIN (RR, 0.72 [CI, 0.48 to 1.01]). Three RCTs were included in a meta-analysis that compared ascorbic acid with N-acetylcysteine. The difference was clinically unimportant and statistically insignificant (RR, 0.89 [CI, 0.34 to 2.30]) (Figure 2). The SOE was low for both comparisons and insufficient for all secondary outcomes. The Harbord test for small study effects was done for all comparisons, and no asymmetry was detected (Table 2).

Many interventions to reduce CIN risk have been studied, but to date, the evidence has been inconclusive. In our analysis, evidence of a clinically important and statistically significant benefit was seen in studies of the following 3 comparisons: low-dose N-acetylcysteine plus IV saline versus IV saline (low SOE), N-acetylcysteine plus IV saline versus IV saline in patients receiving LOCM (moderate SOE), and statins plus N-acetylcysteine versus N-acetylcysteine (low SOE). A clinically important but statistically insignificant benefit was seen in studies of the following 3 comparisons: sodium bicarbonate versus IV saline in patients receiving LOCM (low SOE), statins plus IV saline versus IV saline alone (low SOE), and ascorbic acid plus IV saline versus IV saline (low SOE).

Our results are similar to the most recent meta-analysis on the effect of statins, published with a search end date of March 2014 (6), although that meta-analysis did not do a sensitivity analysis on the basis of IV saline or N-acetylcysteine administration along with statins. Despite previous reviews highlighting evidence on the effectiveness of statins to prevent CIN, they are not routinely used in clinical practice and we are not aware of any guidelines that recommend them for this indication. The findings reported in these studies could be partly explained by their direct effect on glomerular filtration rates that is independent of a protective effect on kidney function, as has been reported in 1 study (113). With increasing recognition of the cholesterol-independent vascular effects of statins, we need to reassess the role of statins in preventing CIN, especially because they are readily available, easy to administer, and relatively inexpensive.

Compared with IV saline alone, low-dose N-acetylcysteine plus IV saline had a clinically important decrease in CIN in patients receiving either IA or IV contrast media or when either low or high doses were used in patients receiving LOCM. The SOE was low for the first comparison (low-dose N-acetylcysteine) and moderate for the second comparison (in patients receiving LOCM), primarily because of limitations in the quality of studies and inconsistency in results. Our results are consistent with a recent meta-analysis that ended its search in September 2013 (7) and did not include sensitivity analysis by type of contrast media or high versus low doses. The low SOE may explain why low-dose N-acetylcysteine is not used more often and helps to explain differing recommendations on its use to prevent CIN. The joint American College of Cardiology/American Heart Association 2012 guideline recommends against the use of N-acetylcysteine for patients receiving IA contrast media in cardiac procedures (114), whereas the 2012 Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for Acute Kidney Injury suggests using oral N-acetylcysteine with IV fluids in patients with increased CIN risk, acknowledging low SOE (115). Although N-acetylcysteine is inexpensive and seems to be safe, the evidence may not be strong enough to support routine use, especially without more robust evidence of clinical outcomes other than CIN incidence.

Our analysis is less positive about the effectiveness of IV sodium bicarbonate compared with IV saline relative to recent meta-analyses by Jang (8) and Zhang (9) and their colleagues with search end dates of January 2012 and August 2014, respectively. Another meta-analysis reported that sodium bicarbonate was superior to IV saline (8) but included studies using a combination of IV sodium bicarbonate and N-acetylcysteine that we did not want to include in the comparison of sodium bicarbonate and IV saline. The meta-analysis by Zhang and colleagues (9) reported that sodium bicarbonate plus N-acetylcysteine was better than sodium bicarbonate alone, but that conclusion was based on a single study that used the combination of sodium bicarbonate plus N-acetylcysteine. All 3 meta-analyses suggested that sodium bicarbonate could benefit patients receiving LOCM, but we did not find a statistically significant benefit.

Although our meta-analysis suggested a possible clinical benefit for ascorbic acid plus IV saline compared with IV saline alone, the difference was not statistically significant. The SOE was low because the studies had important limitations, the comparators varied too much, and the effects were inconsistent and imprecise.

Future studies of the comparative effectiveness of interventions for preventing CIN should stratify patients according to baseline risk for CIN, especially because detecting a treatment effect in patients with low risk may be difficult. More research could strengthen the evidence about whether N-acetylcysteine or IV sodium bicarbonate is beneficial in a particular clinical context, such as patients with increased CIN risk who receive LOCM. The clinically important benefit of statins plus N-acetylcysteine demonstrated in this analysis provides a rationale for studies investigating whether the effect differs by dose, timing of administration, type of contrast media, or baseline risk of the patient population. Future studies could be done in persons without cardiovascular risk factors to determine whether the effectiveness of statin therapy for reducing CIN occurs in the absence of physiologic effects of statins on coexisting cardiovascular disease.

Applying existing evidence to patients receiving IV contrast media is difficult because most studies involved patients receiving IA contrast media for cardiovascular procedures. More research is needed to determine the effectiveness of interventions for preventing CIN in patients receiving IV contrast media because little evidence exists on the effectiveness of different regimens for hydration when administering contrast media.

Our search was broad but our meta-analysis may overestimate the effect of prevention strategies to reduce CIN if studies with negative results were not reported in our sources. The studies span over 2 decades, and there may have been changes in the practice of CIN prevention, such as increased screening, variation in definition of acute kidney injury, and variation in hydration, over time. Such changes could contribute to differences in outcomes.

This comprehensive review highlights the generally low SOE on interventions for preventing CIN while indicating that the greatest reduction in CIN risk has been achieved with low-dose N-acetylcysteine plus IV saline in patients receiving LOCM or with statins plus N-acetylcysteine plus IV saline.

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Figures

Grahic Jump Location
Appendix Figure.

Summary of evidence search and selection.

CIN = contrast-induced nephropathy; RCT = randomized, controlled trial.

* 24 647 gray literature results were also found.

† Total does not sum to 371 because the 2 reviewers were not required to agree on reasons for exclusion.

Grahic Jump Location
Grahic Jump Location
Figure 1.

Pooled RRs for development of CIN in comparisons ofN-acetylcysteine plus IV saline versus IV saline in patients receiving contrast media.

CIN = contrast-induced nephropathy; IOCM = iso-osmolar contrast media; IV = intravenous; LOCM = low-osmolar contrast media; NAC = N-acetylcysteine; RR = risk ratio.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Pooled RRs for development of CIN in studies of sodium bicarbonate, statins, and ascorbic acid in patients receiving contrast media.

CIN = contrast-induced nephropathy; IOCM = iso-osmolar contrast media; IV = intravenous; LOCM = low-osmolar contrast media; NAC = N-acetylcysteine; RR = risk ratio.

Grahic Jump Location

Tables

Table Jump PlaceholderAppendix Table. Detailed Search Strategy 
Table Jump PlaceholderTable 1. Pooled RRs for CIN With NAC Compared With IV Saline 
Table Jump PlaceholderTable 2. Summary of the Main Findings and SOE* 

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Letters

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Comments

Submit a Comment/Letter
N-acetylcysteine versus saline?
Posted on February 8, 2016
Steven D. Weisbord, MD, MSc Paul M. Palevsky, MD
VA Pittsburgh Healthcare System
Conflict of Interest: Drs. Weisbord and Palevsky are the Principal Investigators of the ongoing Department of Veterans Affairs sponsored PRESERVE trial (ClinicalTrials.gov ID#: NCT01467466) , a multi-center randomized clinical trial investigating intravenous sodium bicarbonate and oral N-acetylcysteine for the prevention of serious adverse outcomes following angiography.
To the Editor:
Subramaniam et al. report the results of a systematic review and meta-analysis funded by the Agency for Healthcare Research and Quality that evaluated specific interventions for the prevention of contrast-associated acute kidney injury (CA-AKI) (1). Of particular interest is their finding that ‘low dose N-acetylcysteine compared with IV saline had clinically important and statistically significant benefits.’ Careful inspection of the primary studies included in this meta-analysis clearly demonstrates that this is incorrect. Specifically, the authors report that they used ‘a random-effects model to pool studies comparing N-acetylcysteine with IV saline versus IV saline with or without a placebo.’ Thus, among clinical trials in which all patients received IV saline, they assessed the benefit of N-acetylcysteine compared to either no N-acetylcysteine or to placebo. A review of the studies incorporated into this analysis confirms this was in fact the comparison used in these trials. However, the authors inappropriately conclude that N-acetylcysteine is superior to IV saline for the prevention of CA-AKI. Rather, what their analysis suggests is that among patients who receive IV saline, the administration of N-acetylcysteine is associated with a lower incidence of CA-AKI than the administration of placebo or no N-acetytlcysteine.

The authors’ erroneous and misleading conclusion is potentially dangerous. Providers may interpret this finding as justifying the administration of N-acetylcysteine in lieu of IV crystalloid. It is, of course, much more feasible to administer oral N-acetycysteine than IV fluids to the large number of at-risk patients who undergo contrast-enhanced procedures in the outpatient setting and/or under more urgent circumstances. However, current evidence supports the administration of IV isotonic fluid prior to and following contrast-enhanced imaging procedures as the principal intervention to reduce the risk for CA-AKI in patients at elevated risk. In fact, this intervention is recommended in multiple published guidelines on the prevention of CA-AKI (2-4). Conversely, there has been remarkable inconsistency in the literature with regard to the benefit of N-acetylcysteine, leading some practice guidelines to recommend its use only in conjunction with IV isotonic fluid, while others recommend against its use at all (5). Until large scale randomized clinical trials that are adequately powered to determine the effectiveness of N-acetylcysteine for the prevention of not only CA-AKI, but serious patient-centered outcomes are conducted, suggestions that this agent is effective and can be administered in lieu of IV isotonic fluid are inappropriate.


1. Subramaniam RM, Suarez-Cuervo C, Wilson RF, Turban S, Zhang A, Sherrod C, et al. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Ann Intern Med. 2016.
2. Palevsky PM, Liu KD, Brophy PD, Chawla LS, Parikh CR, Thakar CV, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis. 2013;61(5):649-72.
3. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, Jr., et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(23):e663-828.
4. Rudnick M. Prevention of Contrast-Induced Nephropathy. In: UptoDate 2015.
5. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation;124(23):e574-651.

Unresolved heterogeneity underlies the apparent benefit of n-acetycysteine and statins in contrast nephropathy
Posted on March 3, 2016
Somjot Brar, Ayub Akbari, Swapnil Hiremath
Kaiser Permanente, Los Angeles (SB), Ottawa Hospital Research Institute (AA and SH)
Conflict of Interest: None Declared
We read the meta-analysis by Subramaniam (1) et. al. with interest. The investigators undertook a herculean effort by including multiple treatments for the prevention of contrast induced-acute kidney injury (CI-AKI), and should be congratulated for their efforts. However, it can be difficult to capture or identify important points of heterogeneity between studies for various treatments in the context of such an undertaking, which have not been adequately recognized in the present report and may have implications on the authors conclusions.

For many initial CI-AKI prevention trials, the sample sizes are small with large treatment effects (2). When these small studies have been followed by larger ones, these early promising results are not readily reproducible. Unfortunately, the larger trials are often smaller in number, and the meta-analytic framework does not give them adequate weight. Observing consistency between treatment effects in large and small studies would be reassuring which is lacking for many CI-AKI prevention strategies. Specifically, the result for the greater efficacy of low-dose N-acetylcysteine (NAC), which includes older, smaller trials of lower methodological quality (36 trials, 4874 participants), as compared to high-dose NAC (usually larger, higher quality trials, 18 trials, 4336 participants), makes little biological sense. The largest and possibly the best quality trial, which was done with high-dose NAC, included 2308 patients with a hazard ratio of 1.00 for the primary outcome (3). Even in subgroups at higher risk for CI-AKI, diabetics and estimated GFR <60, no significant benefit was observed. Similarly, the largest trial for statins, with almost 3000 patients, was about six times larger than the next largest trial (4). While this study did show a statistically significant benefit for statin treatment versus no statin treatment, the majority of patients were at very low risk for CI-AKI (CKD stage I or II). When the subset of approximately 500 patients with estimated GFR <60 were analyzed, no significant benefit for statin therapy was observed. These aspects of the literature can be readily lost when seen through the meta-analytical lens.

The aim of a meta-analysis is not solely to generate a summary estimate, but provide a structured framework to explore and understand sources of heterogeneity, both statistical and clinical. Identifying important heterogeneity between studies can at times provide more insight than the summary estimates (5). Unfortunately, this can be very time-consuming, in particular when multiple treatments are under review, and requires expertise in the treatments being evaluated.

1.Subramaniam RM, Suarez-Cuervo C, Wilson RF, Turban S, Zhang A, Sherrod C, et al. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Ann Intern Med. 2016.
2. Hiremath S, Brar SS. The evidence for sodium bicarbonate therapy for
contrast-associated acute kidney injury: far from settled science. Nephrol Dial
Transplant. 2010 Aug;25(8):2802-4
3. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patients
undergoing coronary and peripheral vascular angiography: main results from the
randomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT).
Circulation. 2011 Sep 13;124(11):1250-9.
4. Han Y, Zhu G, Han L, Hou F, Huang W, Liu H, Gan J, Jiang T, Li X, Wang W, Ding S, Jia S, Shen W, Wang D, Sun L, Qiu J, Wang X, Li Y, Deng J, Li J, Xu K, Xu B, Mehran R, Huo Y. Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease. J Am Coll Cardiol. 2014;63:62-70.
5. Gonzales DA, Norsworthy KJ, Kern SJ, Banks S, Sieving PC, Star RA, Natanson C,
Danner RL. A meta-analysis of N-acetylcysteine in contrast-induced
nephrotoxicity: unsupervised clustering to resolve heterogeneity. BMC Med. 2007
Nov 14;5:32

In Response
Posted on March 4, 2016
Eric Bass MD, MPH
Johns Hopkins University
Conflict of Interest: None Declared
Thank you for bringing to our attention the questions about our manuscript on the “Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy.” We summarize below our responses.

We agree the text should be clearer about how studies of N-acetylcysteine generally compared N-acetylcysteine plus IV saline to IV saline with or without placebo. This is also true for studies of statins and ascorbic acid, with use of IV saline in the intervention and comparator arms. To make this clearer, we prepared a more detailed version of the Appendix with information about use of IV saline in the intervention and comparisons groups. The new Appendix replaces the original version that was available in the on-line early article. For maximum clarity, we also made the following changes in the final print version of the article: 1) In multiple places, we changed the text from “N-acetylcysteine” to “N-acetylcysteine plus IV saline;” and 2) In the first paragraph of the discussion, we changed “ascorbic acid” to “ascorbic acid plus IV saline.” The fourth paragraph of the results section explains that analyses were based on “studies comparing N-acetylcysteine with IV saline versus IV saline with or without a placebo.” The second paragraph of the statins results indicates that studies “compared a statin plus IV saline with IV saline alone,” and the third paragraph of the statins results states that studies “compared statins added to N-acetylcysteine and IV saline with N-acetylcysteine plus IV saline.” Also, in the third paragraph of the discussion, we refer to the guideline which “suggests using oral N-acetylcysteine with IV fluids…”

We checked the meta-analysis and confirmed that the 95% confidence interval for high-dose N-acetylcysteine is correct, and changed the corresponding text to say that “high-dose N-acetylcysteine had a small effect on reducing CIN risk that was clinically unimportant and not statistically significant.”

To address concerns about the accuracy of information in Appendix Table 2, we had reviewers re-check all information presented in the appendix, and prepared a more detailed version of the appendix to replace the original on-line early version. The new appendix includes the following changes, none of which change the main findings and conclusions.
1. We added a footnote to clarify why the appendix only referred to use of IOCM and LOCM in the study by the ACT Investigators – “The study included patients who received HOCM, but reported results separately by type of contrast media received, so we were able to focus on the results from patients receiving IOCM or LOCM.”
2. We added information about the type of saline (or other fluid) that was used in the intervention and comparison groups of all studies, with footnotes to note when a study did not report the concentration of saline, and a footnote addressing one of the reader’s comments – “the study protocol recommended hydration with 0.9% saline with 93% or more of patients in both groups receiving 0.9% saline.”
3. We added wording and footnotes to clarify and provide more detail about characteristics of the studies, including: more information about patient characteristics in ACT 2011 (patients had at least one risk factor for contrast-induced acute kidney injury, and “about half of patients had a creatinine clearance less than 60 mg/min”); clarification of the type of cardiac condition included in Aslanger 2012; clarification of how the contrast media was left to the discretion of the cardiologists in Azmus 2005; clarification of how the study by Erturk 2014 had 3 arms; addition of a footnote to clarify that the study by Hsu 2012 included patients with renal dysfunction; addition of a footnote to clarify that the study by Kefer 2003 included patients with renal dysfunction; clarification that the study by Ochoa 2004 left the choice of contrast media to the discretion of the clinicians and did not report results separately by type of contrast media; clarification that the study by Seyon 2007 included patients with cardiac conditions; clarification that the studies by Beyazal 2014, Boucek 2013, Brar 2008, Kooiman 2014, and Lee 2011 included patients with chronic kidney disease; clarification that Masuda 2007 and Ueda 2011 did not report the concentration of saline used in the comparison group; clarification that the study by Yeganehkhah 2014 included patients at high risk for CIN; clarification that in Patti 2011 hydration was not reported, and only those with pre-existing renal failure were given normal saline; and clarification that in Yun 2014 IV saline was given at physician's discretion for both arms.
4. We corrected typographical errors, including: correction of the route of administration used for N-acetylcysteine in ACT with confirmation that it was correctly included in the analysis; correction of the type of contrast media listed for Jaffery 2012 with confirmation that it was correctly included in the analysis; correction of the type and route of administration for the contrast media listed for Boucek 2013 with confirmation that it was correctly included in the analysis; and clarification that the intervention infusion was for 7 hours in Boucek 2013.
5. We added two studies to the appendix (Gomes 2012 and Jo 2009) with confirmation that the studies were correctly included in the analyses and text.

After preparing the revised Appendix, we identified places in the body of the article where wording changes could help to clarify the information presented.
1. Results on IV Sodium Bicarbonate versus IV Saline, paragraph 2: changed from "Contrast media was administered via IV in 3 studies and IA in 14 studies, and 1 study did not report the route of administration," to "Contrast media was administered via IV in 2 studies, IA in 14 studies, IV or IA in 1 study, and 1 study did not report the route of administration."
2. Results on IV Sodium Bicarbonate versus IV Saline, paragraph 2: changed from "Seven studies used IOCM, 11 used LOCM, 1 used either IOCM or LOCM, and 1 did not report the type of contrast type," to "Six studies used IOCM, 12 used LOCM, and 1 study did not report the type of contrast media."
3. Results on N-acetylcysteine plus IV Saline Versus Sodium Bicarbonate, paragraph 1: changed from "1 used IV administration" to "1 did not report route of administration."
4. Results on Statins, paragraph 2: changed from "and 1 included only patients with diabetes mellitus" to "and 2 studies included patients with diabetes mellitus and chronic kidney disease."
5. Results on Statins, paragraph 3: changed from "high CIN risk" to "diabetes mellitus and chronic kidney disease."
6. Results on Ascorbic Acid, paragraph 2: changed from "All of these studies included patients receiving cardiovascular interventions via IA LOCM (Appendix Table 2)" to "These studies included patients receiving cardiovascular interventions with IA administration of LOCM (3 studies), IOCM (1 study), or either LOCM or IOCM (2 studies)."

We greatly appreciate the reader’s careful attention to the details presented in the article, and we hope the changes clarify the issues and concerns that were raised.


In Response
Posted on April 25, 2016
James Cain MD FACP, FASN, Jamie Goldstone MPH
Valley Nephrology Associates, Jefferson College of Health Sciences
Conflict of Interest: None Declared
The recent meta-analysis of contrast induced nephropathy by Subramanian(1) et. al. and any analysis of N-acetycysteine and creatinine may be in error due to inaccurate creatinine measurements
An “Urgent Medical Device Correction” dated March 17, 2016 issued by Siemens corporation regarding an interfering substance affecting creatinine measurements using the ”Trinder and Trinder like reaction assays” is brought to our attention. This reaction results in falsely low creatinine determinations in the presence of N-acetylcystein (NAC.) A similar warning was issued in May 2015 by Roche diagnostics.
This interference was described by Genzen et. al. in Clinical Biochemistry(2) in October of 2015.
The patients studied in this meta –analysis were given NAC in an effort to prevent nephrotoxicity. Falsely decreased results would create the impression of success. The conclusions reached here are valid only if the method used to measure the creatinine is not the Trinder method. No mention was made of the methods used to perform the creatinine assays in the publication.
Reply to Cain
Posted on May 11, 2016
Eric Bass, MD, MPH
Johns Hopkins Medical Institute
Conflict of Interest: None Declared
We appreciate the concern about the possibility of falsely low serum creatinine measurements in the presence of N-acetylcysteine (NAC) when the Trinder and Trinder-like reaction assays are used.(1) When we reviewed the study by Genzen et al (2015),(2) we found that NAC did not have any significant effect on the serum creatinine level at low doses of NAC. Thus, we see no reason to change our conclusion that low strength of evidence indicates that low-dose NAC plus intravenous saline compared with intravenous saline had a clinically important benefit.(3) The concern then mainly applies to studies using high doses of NAC. Many of the studies included in our review used high doses of NAC, which we defined as more than 1200 mg per day. It is possible that a few of the studies used doses of NAC that were high enough to cause a small effect on the creatinine level by the Trinder assay. Unfortunately, very few studies reported what assay was used to measure the serum creatinine. None of the studies reported using the Trinder assay. We cannot rule out the possibility that use of the Trinder assay contributed to a small overestimate of the effect of high-dose NAC, but that would not explain why we did not find a clinically important benefit for high-dose NAC with intravenous saline compared with intravenous saline alone. Although we stand by our conclusions regarding the effects of NAC on contrast induced nephropathy, we agree that studies of NAC to prevent nephrotoxicity should be more consistent in reporting the assay used to measure serum creatinine.



Sincerely,



Eric B. Bass, MD, MPH

Rathan Subramaniam, MD


1 Cain J and Goldstone J. Letters. Ann Intern Med. 2016 in press.




2 Genzen JR, Hunsaker JJ, Nelson LS, Faine BA, Krasowski MD. N-acetylcysteine interference of Trinder-based assays. Clin Biochem. 2016 Jan;49(1):100-4. doi: 10.1016/j.clinbiochem.2015.10.005. Epub 2015 Oct 21. PubMed PMID: 26500003.





3 Subramaniam RM, Suarez-Cuervo C, Wilson RF, Turban S, Zhang A, Sherrod C, Aboagye J, Eng J, Choi MJ, Hutfless S, Bass EB. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Ann Intern Med. 2016 Mar 15;164(6):406-16. doi: 10.7326/M15-1456. Epub 2016 Feb 2. PubMed PMID: 26830221.




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