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Comparative Effect of Contrast Media Type on the Incidence of Contrast-Induced Nephropathy: A Systematic Review and Meta-analysisComparative Effect of Contrast Media Type FREE

John Eng, MD; Renee F. Wilson, MS; Rathan M. Subramaniam, MD, PhD, MPH; Allen Zhang, BS; Catalina Suarez-Cuervo, MD; Sharon Turban, MD, MHS; Michael J. Choi, MD; Cheryl Sherrod, MD, MPH; Susan Hutfless, PhD; Emmanuel E. Iyoha, MBChB, MPH; and Eric B. Bass, MD, MPH
[+] Article, Author, and Disclosure Information

This article was published at www.annals.org on 2 February 2016.


From Johns Hopkins University School of Medicine and Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.

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

Grant Support: By the Agency for Healthcare Research and Quality (contract 290-2012-00007I).

Disclosures: Dr. Eng reports a contract from the Agency for Healthcare Research and Quality during the conduct of the study. Ms. Wilson reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Dr. Subramaniam reports grants from the Agency for Healthcare Research and Quality during the conduct of the study and a grant from Bayer Health Care and consulting fees from Philips Healthcare outside the submitted work. Dr. Choi reports that he is President Elect of the National Kidney Foundation. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-1402.

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 Dr. Eng (e-mail, jeng@jhmi.edu).

Requests for Single Reprints: John Eng, MD, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287; e-mail, jeng@jhmi.edu.

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

Ms. Wilson, Mr. Zhang, Mr. Iyoha, and Dr. Bass: Johns Hopkins University, Evidence-based Practice Center, 624 North Broadway, Suite 648, Baltimore, MD 21205.

Dr. Subramaniam: Johns Hopkins Outpatient Center, 601 North Caroline Street, Room 3235, Baltimore, MD 21287.

Dr. Suarez-Cuervo: 112 Affirmed Court, Elizabethtown, KY 42701.

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

Dr. Sherrod: PO Box 1582, Cordova, TN 38088.

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

Author Contributions: Conception and design: J. Eng, R.F. Wilson, R.M. Subramaniam, S. Turban, E.B. Bass.

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

Drafting of the article: J. Eng, R.F. Wilson, R.M. Subramaniam, M.J. Choi.

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

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

Statistical expertise: J. Eng, E.B. Bass.

Obtaining of funding: E.B. Bass.

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

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


Ann Intern Med. 2016;164(6):417-424. doi:10.7326/M15-1402
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Background: Iodine contrast media are essential components of many imaging procedures. An important potential side effect is contrast-induced nephropathy (CIN).

Purpose: To compare CIN risk for contrast media within and between osmolality classes in patients receiving diagnostic or therapeutic imaging procedures.

Data Sources: PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and Scopus through June 2015.

Study Selection: Randomized, controlled trials that reported CIN-related outcomes in patients receiving low-osmolar contrast media (LOCM) or iso-osmolar contrast media for imaging.

Data Extraction: Independent study selection and quality assessment by 2 reviewers and dual extraction of study characteristics and results.

Data Synthesis: None of the 5 studies that compared types of LOCM reported a statistically significant or clinically important difference among study groups, but the strength of evidence was low. Twenty-five randomized, controlled trials found a slight reduction in CIN risk with the iso-osmolar contrast media agent iodixanol compared with a diverse group of LOCM that just reached statistical significance in a meta-analysis (pooled relative risk, 0.80 [95% CI, 0.65 to 0.99]; P = 0.045). This comparison's strength of evidence was moderate. In a meta regression of randomized, controlled trials of iodixanol, no relationship was found between route of administration and comparative CIN risk.

Limitations: Few studies compared LOCM. Procedural details about contrast administration were not uniformly reported. Few studies specified clinical indications or severity of baseline renal impairment.

Conclusion: No differences were found in CIN risk among types of LOCM. Iodixanol had a slightly lower risk for CIN than LOCM, but the lower risk did not exceed a criterion for clinical importance.

Primary Funding Source: Agency for Healthcare Research and Quality.

2 22016.


Iodine contrast media are essential to many diagnostic and therapeutic procedures that involve imaging. An important potential side effect is contrast-induced nephropathy (CIN), most commonly defined in past studies 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 contrast administration in the absence of an alternative cause (1).

The precise mechanism of CIN is not entirely understood. The leading theories are that it results from hypoxic injury to the renal tubules induced by renal vasoconstriction or by direct cytotoxic effects of contrast media (2, 3); alternatively, some experts have argued—and recent evidence suggests—that acute kidney injury occurring after intravascular contrast administration is caused by coexisting risk factors and is only coincidentally related to the contrast media, especially when administered intravenously (4, 5). Regardless of the cause, acute kidney injury after intravascular contrast administration remains a major concern for referring clinicians.

Osmolality of contrast media is a key factor determining its tolerability (6). Since the 1990s, low-osmolar contrast media (LOCM) (2 to 3 times plasma osmolality) have been the standard of care for intravascular injection. A newer class of intravascular contrast, iso-osmolar contrast media (IOCM), is isotonic to plasma. Iodixanol is the only IOCM available for intravascular injection. The literature contains conflicting reports about whether iodixanol is associated with less risk for CIN than LOCM (7, 8). International guidelines from the Kidney Disease: Improving Global Outcomes Acute Kidney Injury Work Group mention IOCM and LOCM, but they do not make recommendations about selection between them (9).

We did a systematic review of randomized, controlled trials (RCTs) to determine the comparative effects of different types of intravascular contrast media on CIN risk in patients having diagnostic imaging studies or image-guided procedures. We hypothesized that updating past reviews with more recent RCTs may help us understand conflicting reports about CIN risk. Some reports suggest that intra-arterial administration may be associated with greater risk than intravenous administration (4, 10, 11), so we also investigated whether the comparative effects vary according to the route of administration.

We developed and followed a review protocol, which is included in the full technical report on which this article is based (12).

Data Sources and Searches

We searched (without date or language restrictions) PubMed, EMBASE, and the Cochrane Library for RCTs published through 30 June 2015, as well as the Scopus database for conference proceedings and other reports (Appendix Table 1). We also reviewed the reference lists of relevant articles and related systematic reviews, searched ClinicalTrials.gov to identify ongoing studies, and asked an external expert panel to identify trials missing from our final list of eligible articles.

Table Jump PlaceholderAppendix Table 1. Search Strategy 
Study Selection

We selected all RCTs that compared 1 or more contrast media types (LOCM or IOCM) with CIN incidence as the main outcome in patients having diagnostic imaging or image-based therapeutic procedures. Studies had to report the incidence of CIN based on serum creatinine levels or glomerular filtration rates at baseline and within 72 hours of contrast injection. Studies could involve patients of any age and preprocedure risk for CIN. There were no restrictions on how the contrast classes were compared, so studies comparing different types of LOCM and those comparing LOCM with IOCM were included.

Two reviewers independently screened titles and abstracts to identify articles for inclusion. If necessary, the full text of articles was reviewed. Articles in a language other than English were excluded at the full-text level. Discrepancies between the 2 reviewers that remained after full-text review were resolved by consensus. At random intervals during screening, quality checks were done to ensure that eligibility criteria were applied consistently.

Data Extraction and Quality Assessment

For each eligible study, 1 investigator extracted pertinent data about study characteristics, patient population, imaging procedure type, comparisons, results, and statistical analysis. A second investigator reviewed the extracted data for accuracy. Discrepancies between the 2 investigators were resolved by consensus. Article and data management were done within the DistillerSR Web service (Evidence Partners).

Two reviewers independently assessed each study's risk of bias using the following 5 items from the Cochrane Risk of Bias Tool for randomized studies: allocation sequence generation, allocation concealment, investigator blinding, incomplete outcomes, and selective outcome reporting (13). Discrepancies were resolved by consensus.

Data Synthesis and Analysis

When evaluating changes in CIN risk, we followed published guidelines for selecting a minimally important clinical difference based on the overall observed event rate in the studies (14). Taking into consideration the potential effect of CIN on a patient's overall health and well-being, the clinical experts on our team decided that a 25% reduction in the relative risk for CIN would be clinically important, which is consistent with the published guidance suggesting a range of reduction in relative risk of 20% to 30% in determining optimal information size (14).

For each comparison in our review, the study team assigned a grade (high, moderate, low, or insufficient) for the strength of evidence (SOE) associated with the entire group of studies that represented the particular comparison. Grades for SOE were assigned by consensus of the senior study team members (J.E., R.W., R.S., and E.B.). This grading scheme considered all of the following domains in the Agency for Healthcare Research and Quality guidelines for comparative effectiveness reviews: study limitations, precision, directness, consistency, reporting bias, and magnitude of effect (15).

The study limitations domain was assessed by examining the risk-of-bias items for each study involved in the comparison. Study limitations were considered high if more than half of the studies in a group scored negatively in at least 1 of the risk-of-bias items, low if more than half of the studies in the group scored positively in all 5 risk-of-bias items, or medium if neither the high nor the low criteria were met.

The precision domain was assessed by following guidance from the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group (14). We rated a group of studies as precise if the total number of patients exceeded the optimum information size (14) and the 95% CI excluded a pooled relative risk of 1.0. If the total number of patients exceeded the optimum information size but the CI did not exclude a relative risk of 1.0, we only rated the evidence as precise if the CI excluded the possibility of a 25% minimally important clinical difference as defined previously (relative risk <0.75 or >1.25). For the main outcome of interest, CIN, we calculated an optimum information size of 2000 patients based on an expected 0.1 probability of CIN and a minimally important relative risk of less than 0.75 or greater than 1.25.

The SOE of a group of studies was graded high if the study limitations domain was considered low and all other SOE domains were scored positively. The SOE was downgraded for each domain that was scored negatively. If the magnitude of effect was very large, the SOE was upgraded.

We did de novo meta-analyses of all studies on a given comparison if study heterogeneity was not important by clinical, qualitative, and statistical criteria (16). We calculated pooled risks by using a random-effects model and the DerSimonian–Laird method (17). We used a funnel plot and the Harbord modified test for small study effects (18) to look for asymmetry in the reporting of results, which can be seen when publication bias exists. Analyses were done in Stata, version 13 (StataCorp).

Role of the Funding Source

The Agency for Healthcare Research and Quality selected the review topic and funded this research under a contract. A representative from the Agency provided technical assistance during creation of the full evidence report on which this article is based and provided comments on draft versions of that report (12). The Agency did not directly participate in the literature search; determination of study eligibility criteria; data collection, analysis, or interpretation; or preparation, review, or approval of the manuscript for publication.

The literature search revealed 29 RCTs for summary and analysis (Figure 1). Five RCTs compared 2 or more types of LOCM in 826 patients (Appendix Table 2) (1923). Twenty-five RCTs compared the IOCM iodixanol with 1 or more types of LOCM in 5053 patients (Appendix Table 2) (19, 2447). One RCT reported data on both types of comparisons (19). In the 5 RCTs that compared LOCM, 4 studies scored negatively in 1 or more of the 5 risk-of-bias items (Appendix Table 3). In the 25 RCTs comparing iodixanol and LOCM, all studies scored negatively in 1 or more of the 5 risk-of-bias items (Appendix Table 4). Of the 29 RCTs included in our review, 14 (48%) studies (19, 20, 29, 3338, 4043, 45) received funding support from industry sources, all of which were contrast media manufacturers.

Grahic Jump Location
Figure 1.

Summary of evidence search and selection.

* Sum of reasons for exclusion exceeds 443 because reviewers were not required to agree on the reason.

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Table Jump PlaceholderAppendix Table 2. Study Characteristics 
Table Jump PlaceholderAppendix Table 3. Risk of Bias for RCTs Comparing LOCMs* 
Table Jump PlaceholderAppendix Table 4. Risk of Bias for RCTs Comparing Iodixanol and LOCMs* 

No study comparing 2 LOCM reported a statistically significant or clinically important difference between study groups in the incidence of CIN or a related measure of renal function change (Table 1). The overall analysis did not suggest that any 1 LOCM was superior to another, although the number of studies and total sample sizes were small. The SOE of this comparison was graded as low (Table 2). Randomized, controlled trials comparing LOCM did not report CIN outcomes similarly enough to be combined numerically in a meta-analysis.

Table Jump PlaceholderTable 1. Results of Studies Comparing LOCM 
Table Jump PlaceholderTable 2. Grading Strength of Evidence 

In the meta-analysis, we found a slight reduction in CIN risk with iodixanol compared with a diverse group of LOCM that just reached statistical significance (pooled relative risk, 0.80 [95% CI, 0.65 to 0.99]; P = 0.045) (Figure 2 and Appendix Table 5). Two studies (19, 24) were omitted from the meta-analysis because they did not explicitly classify renal outcomes as CIN. The SOE associated with this comparison was graded as moderate (Table 2). The point estimate of the reduced risk did not exceed the minimally important relative risk of 0.75. When the analysis was stratified by route of administration, the pooled relative risk for the intra-arterial route was 0.80 (CI, 0.64 to 1.01; P = 0.059) and for the intravenous route it was 0.84 (CI, 0.42 to 1.71; P = 0.64), suggesting no difference in comparative CIN risk by route of administration. No statistically significant or clinically important differences were reported between iodixanol and types of LOCM with regard to the need for renal replacement therapy (24, 26, 33, 35, 37, 44), cardiovascular outcomes (26, 28, 32, 34, 35, 39, 41), death (26, 27, 3335, 3739), adverse events (24, 26, 2830, 3236, 39, 41, 44), or image and diagnostic quality (29, 39). We did not see any definitive evidence of a difference in CIN incidence between iodixanol and LOCM that varied according to patient characteristics or contrast dose.

Grahic Jump Location
Figure 2.

Graphical summary of meta-analysis of randomized, controlled trials comparing iodixanol and LOCM with contrast-induced nephropathy as the primary outcome.

The solid vertical line represents the null hypothesis (relative risk equal to 1), and the dashed vertical line represents the pooled estimate from the meta-analysis. Studies are shown in reverse chronologic order, grouped by route of administration. LOCM = low-osmolar contrast media, RR = relative risk.

Grahic Jump Location
Table Jump PlaceholderAppendix Table 5. Results of Studies Comparing Iodixanol With LOCM 

We did meta regression analyses between CIN incidence and each of the following covariates: age, baseline creatinine, diabetes, sex, route of administration, and funding support from industry sources. No significant associations were found, although the statistical power was limited by the relatively small number of studies that involved each covariate. We found no suggestion of publication bias by funnel plot or the Harbord modified test for small study effects (P = 0.47).

In this systematic review, the small number of trials comparing 2 LOCM reported no statistically significant or clinically important differences in the risk for CIN. For the trials comparing iodixanol with LOCM, we found a slight reduction in CIN risk for iodixanol that just reached statistical significance. However, the point estimate of this reduction did not exceed a minimally important relative risk difference of 0.25. Most trials in our review involved patients receiving intra-arterial contrast media. In the few trials involving intravenous contrast, we saw no evidence that the relationship between contrast type and CIN risk differed from that seen in the intra-arterial trials.

We found no difference among types of contrast media in the potential sequelae of CIN, such as cardiovascular events, death, need for renal replacement therapy, or other adverse events. Because we excluded studies that did not report data on CIN, studies that reported only nonrenal outcomes were excluded from our analysis. A recent meta-analysis of RCTs comparing iodixanol and LOCM that included studies of nonrenal outcomes found no conclusive evidence that iodixanol is superior to LOCM with respect to cardiovascular events (48). This is congruent with the findings from our data set, which focused on renal outcomes.

Considering systematic reviews that have been published during the period of our literature search, our estimate of relative risk was very similar to that of 3 meta-analyses comparing iodixanol with LOCM (7, 49, 50), even though our review included 6 RCTs that have been published since those studies, which reported no significant reduction of CIN with iodixanol compared with LOCM. Five other systematic reviews reported a lower incidence of CIN with iodixanol than with LOCM, but all had important limitations and included different sets of studies than our review (8, 5154). In one of these meta-analyses (51), the 2 studies that most favored iodixanol (55, 56) were excluded from our analysis because CIN-related outcomes were inadequately defined. Two other systematic reviews made indirect comparisons of contrast agents (52, 53) and reported differences between iodixanol and the LOCM iohexol but not with other types of LOCM. One of the indirect comparison studies was a network analysis that pooled all outcomes (not just CIN) (52), and the other indirect comparison study included observational data (not just RCTs) (53). The fourth review included only trials of iodixanol that were sponsored by its manufacturer (54), and the fifth meta-analysis (8) included a large unpublished positive trial comparing iodixanol with iopromide. Data for this trial are only available in a 2010 meeting abstract; to date, the study has not been published.

Our review addressed a clinical comparison involving contrast media and did not seek to review evidence about the pathophysiology, causal pathway, or epidemiology of CIN. The precise mechanism of CIN is not entirely understood. Some evidence exists from propensity score–matched, retrospective studies that questions the strength of the relationship between contrast administration and CIN (5). This relationship is important for designing future research (11, 57), but it does not affect the conclusions of this review about the comparative effect of contrast media type on observed CIN.

This review's definition of CIN is the one most commonly found in past studies examining the risk, prevention, and treatment of CIN. More recent consensus definitions of acute kidney injury have been developed (58, 59), but these classification systems have not yet been used extensively in the CIN literature. Although some guidelines have used the term “contrast-induced acute kidney injury” instead of CIN (9), we chose the older term, CIN, because of its dominance in published studies.

Our review has limitations. We generally considered LOCM together as a group even though 7 different LOCM chemical compounds were used in the studies we reviewed. Although direct comparisons of types of LOCM are sparse, indirect evidence suggests that iohexol may differ from other types of LOCM. The greatest CIN reduction with iodixanol was reported in a study comparing it with iohexol (45). Two indirect comparisons also suggested that differences exist between iohexol and other types of LOCM (52, 53), but these comparisons are not compelling. As mentioned previously, 1 study was a network meta-analysis that pooled all outcomes without focusing on a homogeneous body of studies using a similar definition of the main outcome of interest. The other study was designed to assess other comparisons, such as N-acetylcysteine versus intravenous saline, and the iodixanol versus LOCM comparison was a secondary, nonrandomized analysis.

We found that studies examining the risk for CIN with different types of contrast media generally provided little detail about clinical indications for the diagnostic or therapeutic procedures or other clinical details, such as the severity of renal impairment. As a result, we could not assess whether the comparisons among types of contrast media depended on the indications for use of contrast media or baseline renal function. The studies frequently omitted details about total contrast volume, length of procedure, and contrast injection rates. These clinical and technical factors are potential sources of heterogeneity among the studies. Our inclusion criteria did not select studies based on these characteristics, so the results probably apply to a diverse population of patients and procedures. Future research should focus on identifying clinical factors that may be associated with a benefit of iodixanol compared with LOCM.

In conclusion, CIN risk did not differ among types of LOCM, but the body of evidence was small and associated with low SOE. We found moderate SOE that iodixanol had a slightly lower risk for CIN than a diverse group of LOCM that just reached statistical significance, but the lower risk did not exceed a minimally important clinical difference. No relationship was found between route of administration and comparative CIN risk. For clinicians, these findings suggest that the choice between the IOCM iodixanol and types of LOCM will not have a clinically important effect on CIN risk.

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PubMed
CrossRef
 
Chuang FR, Chen TC, Wang IK, Chuang CH, Chang HW, Ting-YuChiou T, et al. Comparison of iodixanol and iohexol in patients undergoing intravenous pyelography: a prospective controlled study. Ren Fail. 2009; 31:181-8.
PubMed
CrossRef
 
Hernández F, Mora L, García-Tejada J, Velázquez M, Gómez-Blázquez I, Bastante T, et al. Comparison of iodixanol and ioversol for the prevention of contrast-induced nephropathy in diabetic patients after coronary angiography or angioplasty. Rev Esp Cardiol.. 2009; 62:1373-80.
PubMed
CrossRef
 
Juergens CP, Winter JP, Nguyen-Do P, Lo S, French JK, Hallani H, et al. Nephrotoxic effects of iodixanol and iopromide in patients with abnormal renal function receiving N-acetylcysteine and hydration before coronary angiography and intervention: a randomized trial. Intern Med J. 2009; 39:25-31.
PubMed
CrossRef
 
Laskey W, Aspelin P, Davidson C, Rudnick M, Aubry P, Kumar S, et al, DXV405 Study Group. Nephrotoxicity of iodixanol versus iopamidol in patients with chronic kidney disease and diabetes mellitus undergoing coronary angiographic procedures. Am Heart J. 2009; 158:822-828.
PubMed
CrossRef
 
Mehran R, Nikolsky E, Kirtane AJ, Caixeta A, Wong SC, Teirstein PS, et al. Ionic low-osmolar versus nonionic iso-osmolar contrast media to obviate worsening nephropathy after angioplasty in chronic renal failure patients: the ICON (Ionic versus non-ionic Contrast to Obviate worsening Nephropathy after angioplasty in chronic renal failure patients) study. JACC Cardiovasc Interv. 2009; 2:415-21.
PubMed
CrossRef
 
Wessely R, Koppara T, Bradaric C, Vorpahl M, Braun S, Schulz S, et al, Contrast Media and Nephrotoxicity Following Coronary Revascularization by Angioplasty Trial Investigators. Choice of contrast medium in patients with impaired renal function undergoing percutaneous coronary intervention. Circ Cardiovasc Interv. 2009; 2:430-7.
PubMed
CrossRef
 
Hardiek KJ, Katholi RE, Robbs RS, Katholi CE. Renal effects of contrast media in diabetic patients undergoing diagnostic or interventional coronary angiography. J Diabetes Complications. 2008; 22:171-7.
PubMed
CrossRef
 
Kuhn MJ, Chen N, Sahani DV, Reimer D, van Beek EJ, Heiken JP, et al. The PREDICT study: a randomized double-blind comparison of contrast-induced nephropathy after low- or isoosmolar contrast agent exposure. AJR Am J Roentgenol. 2008; 191:151-7.
PubMed
CrossRef
 
Nguyen SA, Suranyi P, Ravenel JG, Randall PK, Romano PB, Strom KA, et al. Iso-osmolality versus low-osmolality iodinated contrast medium at intravenous contrast-enhanced CT: effect on kidney function. Radiology. 2008; 248:97-105.
PubMed
CrossRef
 
Nie B, Cheng WJ, Li YF, Cao Z, Yang Q, Zhao YX, et al. A prospective, double-blind, randomized, controlled trial on the efficacy and cardiorenal safety of iodixanol vs. iopromide in patients with chronic kidney disease undergoing coronary angiography with or without percutaneous coronary intervention. Catheter Cardiovasc Interv. 2008; 72:958-65.
PubMed
CrossRef
 
Rudnick MR, Davidson C, Laskey W, Stafford JL, Sherwin PF, VALOR Trial Investigators. Nephrotoxicity of iodixanol versus ioversol in patients with chronic kidney disease: the Visipaque Angiography/Interventions with Laboratory Outcomes in Renal Insufficiency (VALOR) Trial. Am Heart J. 2008; 156:776-82.
PubMed
CrossRef
 
Solomon RJ, Natarajan MK, Doucet S, Sharma SK, Staniloae CS, Katholi RE, et al, Investigators of the CARE Study. Cardiac Angiography in Renally Impaired Patients (CARE) study: a randomized double-blind trial of contrast-induced nephropathy in patients with chronic kidney disease. Circulation. 2007; 115:3189-96.
PubMed
CrossRef
 
Barrett BJ, Katzberg RW, Thomsen HS, Chen N, Sahani D, Soulez G, et al. Contrast-induced nephropathy in patients with chronic kidney disease undergoing computed tomography: a double-blind comparison of iodixanol and iopamidol. Invest Radiol. 2006; 41:815-21.
PubMed
CrossRef
 
Feldkamp T, Baumgart D, Elsner M, Herget-Rosenthal S, Pietruck F, Erbel R, et al. Nephrotoxicity of iso-osmolar versus low-osmolar contrast media is equal in low risk patients. Clin Nephrol. 2006; 66:322-30.
PubMed
CrossRef
 
Jo SH, Youn TJ, Koo BK, Park JS, Kang HJ, Cho YS, et al. Renal toxicity evaluation and comparison between visipaque (iodixanol) and hexabrix (ioxaglate) in patients with renal insufficiency undergoing coronary angiography: the RECOVER study: a randomized controlled trial. J Am Coll Cardiol. 2006; 48:924-30.
PubMed
CrossRef
 
Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ, Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media Study Investigators. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003; 348:491-9.
PubMed
CrossRef
 
Carraro M, Malalan F, Antonione R, Stacul F, Cova M, Petz S, et al. Effects of a dimeric vs a monomeric nonionic contrast medium on renal function in patients with mild to moderate renal insufficiency: a double-blind, randomized clinical trial. Eur Radiol. 1998; 8:144-7.
PubMed
CrossRef
 
Jakobsen JA, Berg KJ, Kjaersgaard P, Kolmannskog F, Nordal KP, Nossen JO, et al. Angiography with nonionic X-ray contrast media in severe chronic renal failure: renal function and contrast retention. Nephron. 1996; 73:549-56.
PubMed
CrossRef
 
Zhang BC, Wu Q, Wang C, Li DY, Wang ZR. A meta-analysis of the risk of total cardiovascular events of isosmolar iodixanol compared with low-osmolar contrast media. J Cardiol. 2014; 63:260-8.
PubMed
CrossRef
 
From AM, AlBadarin FJ, McDonald FS, Bartholmai BJ, Cha SS, Rihal CS. Iodixanol versus low-osmolar contrast media for prevention of contrast induced nephropathy: meta-analysis of randomized, controlled trials. Circ Cardiovasc Interv. 2010; 3:351-8.
PubMed
CrossRef
 
Reed M, Meier P, Tamhane UU, Welch KB, Moscucci M, Gurm HS. The relative renal safety of iodixanol compared with low-osmolar contrast media: a meta-analysis of randomized controlled trials. JACC Cardiovasc Interv. 2009; 2:645-54.
PubMed
CrossRef
 
Dong M, Jiao Z, Liu T, Guo F, Li G. Effect of administration route on the renal safety of contrast agents: a meta-analysis of randomized controlled trials. J Nephrol. 2012; 25:290-301.
PubMed
CrossRef
 
Biondi-Zoccai G, Lotrionte M, Thomsen HS, Romagnoli E, D'Ascenzo F, Giordano A, et al. Nephropathy after administration of iso-osmolar and low-osmolar contrast media: evidence from a network meta-analysis. Int J Cardiol. 2014; 172:375-80.
PubMed
CrossRef
 
Sharma SK, Kini A. Effect of nonionic radiocontrast agents on the occurrence of contrast-induced nephropathy in patients with mild-moderate chronic renal insufficiency: pooled analysis of the randomized trials. Catheter Cardiovasc Interv. 2005; 65:386-93.
PubMed
CrossRef
 
McCullough PA, Bertrand ME, Brinker JA, Stacul F. A meta-analysis of the renal safety of isosmolar iodixanol compared with low-osmolar contrast media. J Am Coll Cardiol. 2006; 48:692-9.
PubMed
CrossRef
 
Hill JA, Winniford M, Cohen MB, Van Fossen DB, Murphy MJ, Halpern EF, et al. Multicenter trial of ionic versus nonionic contrast media for cardiac angiography. The Iohexol Cooperative Study. Am J Cardiol. 1993; 72:770-5.
PubMed
CrossRef
 
Chalmers N, Jackson RW. Comparison of iodixanol and iohexol in renal impairment. Br J Radiol. 1999; 72:701-3.
PubMed
CrossRef
 
Newhouse JH, RoyChoudhury A. Quantitating contrast medium-induced nephropathy: controlling the controls [Editorial]. Radiology. 2013; 267:4-8.
PubMed
CrossRef
 
Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative workgroup. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004; 8:R204-12.
PubMed
CrossRef
 
Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al, Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007; 11:R31.
PubMed
CrossRef
 

Figures

Grahic Jump Location
Figure 1.

Summary of evidence search and selection.

* Sum of reasons for exclusion exceeds 443 because reviewers were not required to agree on the reason.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Graphical summary of meta-analysis of randomized, controlled trials comparing iodixanol and LOCM with contrast-induced nephropathy as the primary outcome.

The solid vertical line represents the null hypothesis (relative risk equal to 1), and the dashed vertical line represents the pooled estimate from the meta-analysis. Studies are shown in reverse chronologic order, grouped by route of administration. LOCM = low-osmolar contrast media, RR = relative risk.

Grahic Jump Location

Tables

Table Jump PlaceholderAppendix Table 1. Search Strategy 
Table Jump PlaceholderAppendix Table 2. Study Characteristics 
Table Jump PlaceholderAppendix Table 3. Risk of Bias for RCTs Comparing LOCMs* 
Table Jump PlaceholderAppendix Table 4. Risk of Bias for RCTs Comparing Iodixanol and LOCMs* 
Table Jump PlaceholderTable 1. Results of Studies Comparing LOCM 
Table Jump PlaceholderTable 2. Grading Strength of Evidence 
Table Jump PlaceholderAppendix Table 5. Results of Studies Comparing Iodixanol With LOCM 

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Jevnikar AM, Finnie KJ, Dennis B, Plummer DT, Avila A, Linton AL. Nephrotoxicity of high- and low-osmolality contrast media. Nephron. 1988; 48:300-5.
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Semerci T, Cuhadar S, Akçay FA, Aydin TK, Atay A, Köseoglu M, et al. Comparing the renal safety of isoosmolar versus low-osmolar contrast medium by renal biomarkers N-acetyl-β-D-glucosaminidase and endothelin. Angiology. 2014; 65:108-12.
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Limbruno U, Picchi A, Micheli A, Calabria P, Cortese B, Brizi G, et al. Refining the assessment of contrast-induced acute kidney injury: the load-to-damage relationship. J Cardiovasc Med (Hagerstown). 2014; 15:587-94.
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Bolognese L, Falsini G, Schwenke C, Grotti S, Limbruno U, Liistro F, et al. Impact of iso-osmolar versus low-osmolar contrast agents on contrast-induced nephropathy and tissue reperfusion in unselected patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (from the Contrast Media and Nephrotoxicity Following Primary Angioplasty for Acute Myocardial Infarction [CONTRAST-AMI] Trial). Am J Cardiol. 2012; 109:67-74.
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Serafin Z, Karolkiewicz M, Gruszka M, Strózecki P, Lasek W, Odrowaz-Sypniewska G, et al. High incidence of nephropathy in neurosurgical patients after intra-arterial administration of low-osmolar and iso-osmolar contrast media. Acta Radiol. 2011; 52:422-9.
PubMed
CrossRef
 
Shin DH, Choi DJ, Youn TJ, Yoon CH, Suh JW, Kim KI, et al. Comparison of contrast-induced nephrotoxicity of iodixanol and iopromide in patients with renal insufficiency undergoing coronary angiography. Am J Cardiol. 2011; 108:189-94.
PubMed
CrossRef
 
Zo'o M, Hoermann M, Balassy C, Brunelle F, Azoulay R, Pariente D, et al. Renal safety in pediatric imaging: randomized, double-blind phase IV clinical trial of iobitridol 300 versus iodixanol 270 in multidetector CT. Pediatr Radiol. 2011; 41:1393-400.
PubMed
CrossRef
 
Chuang FR, Chen TC, Wang IK, Chuang CH, Chang HW, Ting-YuChiou T, et al. Comparison of iodixanol and iohexol in patients undergoing intravenous pyelography: a prospective controlled study. Ren Fail. 2009; 31:181-8.
PubMed
CrossRef
 
Hernández F, Mora L, García-Tejada J, Velázquez M, Gómez-Blázquez I, Bastante T, et al. Comparison of iodixanol and ioversol for the prevention of contrast-induced nephropathy in diabetic patients after coronary angiography or angioplasty. Rev Esp Cardiol.. 2009; 62:1373-80.
PubMed
CrossRef
 
Juergens CP, Winter JP, Nguyen-Do P, Lo S, French JK, Hallani H, et al. Nephrotoxic effects of iodixanol and iopromide in patients with abnormal renal function receiving N-acetylcysteine and hydration before coronary angiography and intervention: a randomized trial. Intern Med J. 2009; 39:25-31.
PubMed
CrossRef
 
Laskey W, Aspelin P, Davidson C, Rudnick M, Aubry P, Kumar S, et al, DXV405 Study Group. Nephrotoxicity of iodixanol versus iopamidol in patients with chronic kidney disease and diabetes mellitus undergoing coronary angiographic procedures. Am Heart J. 2009; 158:822-828.
PubMed
CrossRef
 
Mehran R, Nikolsky E, Kirtane AJ, Caixeta A, Wong SC, Teirstein PS, et al. Ionic low-osmolar versus nonionic iso-osmolar contrast media to obviate worsening nephropathy after angioplasty in chronic renal failure patients: the ICON (Ionic versus non-ionic Contrast to Obviate worsening Nephropathy after angioplasty in chronic renal failure patients) study. JACC Cardiovasc Interv. 2009; 2:415-21.
PubMed
CrossRef
 
Wessely R, Koppara T, Bradaric C, Vorpahl M, Braun S, Schulz S, et al, Contrast Media and Nephrotoxicity Following Coronary Revascularization by Angioplasty Trial Investigators. Choice of contrast medium in patients with impaired renal function undergoing percutaneous coronary intervention. Circ Cardiovasc Interv. 2009; 2:430-7.
PubMed
CrossRef
 
Hardiek KJ, Katholi RE, Robbs RS, Katholi CE. Renal effects of contrast media in diabetic patients undergoing diagnostic or interventional coronary angiography. J Diabetes Complications. 2008; 22:171-7.
PubMed
CrossRef
 
Kuhn MJ, Chen N, Sahani DV, Reimer D, van Beek EJ, Heiken JP, et al. The PREDICT study: a randomized double-blind comparison of contrast-induced nephropathy after low- or isoosmolar contrast agent exposure. AJR Am J Roentgenol. 2008; 191:151-7.
PubMed
CrossRef
 
Nguyen SA, Suranyi P, Ravenel JG, Randall PK, Romano PB, Strom KA, et al. Iso-osmolality versus low-osmolality iodinated contrast medium at intravenous contrast-enhanced CT: effect on kidney function. Radiology. 2008; 248:97-105.
PubMed
CrossRef
 
Nie B, Cheng WJ, Li YF, Cao Z, Yang Q, Zhao YX, et al. A prospective, double-blind, randomized, controlled trial on the efficacy and cardiorenal safety of iodixanol vs. iopromide in patients with chronic kidney disease undergoing coronary angiography with or without percutaneous coronary intervention. Catheter Cardiovasc Interv. 2008; 72:958-65.
PubMed
CrossRef
 
Rudnick MR, Davidson C, Laskey W, Stafford JL, Sherwin PF, VALOR Trial Investigators. Nephrotoxicity of iodixanol versus ioversol in patients with chronic kidney disease: the Visipaque Angiography/Interventions with Laboratory Outcomes in Renal Insufficiency (VALOR) Trial. Am Heart J. 2008; 156:776-82.
PubMed
CrossRef
 
Solomon RJ, Natarajan MK, Doucet S, Sharma SK, Staniloae CS, Katholi RE, et al, Investigators of the CARE Study. Cardiac Angiography in Renally Impaired Patients (CARE) study: a randomized double-blind trial of contrast-induced nephropathy in patients with chronic kidney disease. Circulation. 2007; 115:3189-96.
PubMed
CrossRef
 
Barrett BJ, Katzberg RW, Thomsen HS, Chen N, Sahani D, Soulez G, et al. Contrast-induced nephropathy in patients with chronic kidney disease undergoing computed tomography: a double-blind comparison of iodixanol and iopamidol. Invest Radiol. 2006; 41:815-21.
PubMed
CrossRef
 
Feldkamp T, Baumgart D, Elsner M, Herget-Rosenthal S, Pietruck F, Erbel R, et al. Nephrotoxicity of iso-osmolar versus low-osmolar contrast media is equal in low risk patients. Clin Nephrol. 2006; 66:322-30.
PubMed
CrossRef
 
Jo SH, Youn TJ, Koo BK, Park JS, Kang HJ, Cho YS, et al. Renal toxicity evaluation and comparison between visipaque (iodixanol) and hexabrix (ioxaglate) in patients with renal insufficiency undergoing coronary angiography: the RECOVER study: a randomized controlled trial. J Am Coll Cardiol. 2006; 48:924-30.
PubMed
CrossRef
 
Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ, Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media Study Investigators. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003; 348:491-9.
PubMed
CrossRef
 
Carraro M, Malalan F, Antonione R, Stacul F, Cova M, Petz S, et al. Effects of a dimeric vs a monomeric nonionic contrast medium on renal function in patients with mild to moderate renal insufficiency: a double-blind, randomized clinical trial. Eur Radiol. 1998; 8:144-7.
PubMed
CrossRef
 
Jakobsen JA, Berg KJ, Kjaersgaard P, Kolmannskog F, Nordal KP, Nossen JO, et al. Angiography with nonionic X-ray contrast media in severe chronic renal failure: renal function and contrast retention. Nephron. 1996; 73:549-56.
PubMed
CrossRef
 
Zhang BC, Wu Q, Wang C, Li DY, Wang ZR. A meta-analysis of the risk of total cardiovascular events of isosmolar iodixanol compared with low-osmolar contrast media. J Cardiol. 2014; 63:260-8.
PubMed
CrossRef
 
From AM, AlBadarin FJ, McDonald FS, Bartholmai BJ, Cha SS, Rihal CS. Iodixanol versus low-osmolar contrast media for prevention of contrast induced nephropathy: meta-analysis of randomized, controlled trials. Circ Cardiovasc Interv. 2010; 3:351-8.
PubMed
CrossRef
 
Reed M, Meier P, Tamhane UU, Welch KB, Moscucci M, Gurm HS. The relative renal safety of iodixanol compared with low-osmolar contrast media: a meta-analysis of randomized controlled trials. JACC Cardiovasc Interv. 2009; 2:645-54.
PubMed
CrossRef
 
Dong M, Jiao Z, Liu T, Guo F, Li G. Effect of administration route on the renal safety of contrast agents: a meta-analysis of randomized controlled trials. J Nephrol. 2012; 25:290-301.
PubMed
CrossRef
 
Biondi-Zoccai G, Lotrionte M, Thomsen HS, Romagnoli E, D'Ascenzo F, Giordano A, et al. Nephropathy after administration of iso-osmolar and low-osmolar contrast media: evidence from a network meta-analysis. Int J Cardiol. 2014; 172:375-80.
PubMed
CrossRef
 
Sharma SK, Kini A. Effect of nonionic radiocontrast agents on the occurrence of contrast-induced nephropathy in patients with mild-moderate chronic renal insufficiency: pooled analysis of the randomized trials. Catheter Cardiovasc Interv. 2005; 65:386-93.
PubMed
CrossRef
 
McCullough PA, Bertrand ME, Brinker JA, Stacul F. A meta-analysis of the renal safety of isosmolar iodixanol compared with low-osmolar contrast media. J Am Coll Cardiol. 2006; 48:692-9.
PubMed
CrossRef
 
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