The Relative Renal Safety of Iodixanol Compared with Low-Osmolar Contrast Media

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provided by Elsevier - Publisher Connector JACC: CARDIOVASCULAR INTERVENTIONS VOL. 2, NO. 7, 2009 © 2009 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 1936-8798/09/$36.00 PUBLISHED BY ELSEVIER INC. DOI: 10.1016/j.jcin.2009.05.002

The Relative Renal Safety of Iodixanol Compared With Low-Osmolar Contrast Media

A Meta-Analysis of Randomized Controlled Trials

Michael Reed, MD,* Pascal Meier, MD,* Umesh U. Tamhane, MD,* Kathy B. Welch, MS, MPH,† Mauro Moscucci, MD,‡ Hitinder S. Gurm, MD* Ann Arbor, Michigan; and Miami, Florida

Objectives We sought to compare the nephrotoxicity of the iso-osmolar contrast medium, iodixanol, to low-osmolar contrast media (LOCM).

Background Contrast-induced acute kidney injury (CI-AKI) is a common cause of in-hospital renal failure. A prior meta-analysis suggested that iodixanol (Visipaque, GE Healthcare, Princeton, New Jersey) was associated with less CI-AKI than LOCM, but this study was limited by ascertainment bias and did not include the most recent randomized controlled trials.

Methods We searched Medline, Embase, ISI Web of Knowledge, Google Scholar, Current Contents, and International Pharmaceutical Abstracts databases, and the Cochrane Central Register of Con- trolled Trials from 1980 to November 30, 2008, for randomized controlled trials that compared the incidence of CI-AKI with either iodixanol or LOCM. Random-effects models were used to calculate summary risk ratios (RR) for CI-AKI, need for hemodialysis, and death.

Results A total of 16 trials including 2,763 subjects were pooled. There was no significant difference in the incidence of CI-AKI in the iodixanol group than in the LOCM group overall (summary RR: 0.79, 95% confidence interval [CI]: 0.56 to 1.12, p ϭ 0.19). There was no significant difference in the rates of post-procedure hemodialysis or death. There was a reduction in CI-AKI when iodixanol was compared with ioxaglate (RR: 0.58, 95% CI: 0.37 to 0.92; p ϭ 0.022) and iohexol (RR: 0.19, 95% CI: 0.07 to 0.56; p ϭ 0.002), but no difference when compared with iopamidol (RR: 1.20, 95% CI: 0.66 to 2.18; p ϭ 0.55), iopromide (RR: 0.93, 95% CI: 0.47 to 1.85; p ϭ 0.84), or ioversol (RR: 0.92, 95% CI: 0.60 to 1.39; p ϭ 0.68).

Conclusions This meta-analysis including 2,763 subjects suggests that iodixanol, when compared with LOCM overall, is not associated with less CI-AKI. The relative renal safety of LOCM compared with iodixanol may vary based on the speciﬁc type of LOCM. (J Am Coll Cardiol Intv 2009;2: 645–54) © 2009 by the American College of Cardiology Foundation

From the *University of Michigan School of Medicine, VA Ann Arbor Healthcare System, and †Center for Statistical Consultation and Research, University of Michigan, Ann Arbor, Michigan; and the ‡University of Miami, Miami, Florida. Dr. Moscucci participated in a continuing medical education program sponsored by Bayer, a manufacturer of contrast media. Manuscript received April 24, 2009; accepted May 3, 2009. 646 Reed et al. JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 7, 2009 Iodixanol Versus LOCM JULY 2009:645–54

Contrast-induced acute kidney injury (CI-AKI) is a common Methods complication of intra-arterial and intravenous contrast administration. As the population ages, the incidence of CI-AKI likely will We performed a computerized search to identify relevant rise with the increased referrals for cardiac catheterization and articles from 1980 through November 30, 2008, using radiology studies with intravenous contrast and with the increased MEDLINE (National Library of Medicine, Bethesda, prevalence of risk factors for CI-AKI, such as chronic kidney Maryland), Embase, ISI Web of Knowledge, Google Scholar, disease, diabetes, and anemia (1–3). CI-AKI typically occurs Current Contents, and International Pharmaceutical Abstracts within the first 48 to 72 h after exposure to intravascular iodinated databases, as well as the Cochrane Central Register of Con- contrast medium. CI-AKI rarely directly results in immediate trolled Trials. We used the following keywords: “iso-osmolar,” death or the need for immediate hemodialysis, but it is associated “iodixanol” (Visipaque, GE Healthcare, Princeton, New Jer- with increased cost, increased hospital stay, and increased in- sey), “low-osmolar,” “iohexol” (Omnipaque, GE Healthcare, hospital and long-term morbidity and mortality (2,4,5). Princeton, New Jersey), “iopamidol” (Isovue, Bracco Diagnos- Sodium bicarbonate and acetylcysteine have been shown tics, Princeton, New Jersey), “iopromide” (Ultravist, Bayer in multiple studies to prevent CI-AKI, although there is HealthCare Pharmaceuticals, Montville, New Jersey), “iover- significant heterogeneity among the existing trials (6–9). sol” (Optiray, Tyco, Tyco Healthcare, Mallinckrodt Inc., Prevention of CI-AKI with prophylactic hydration and Hazelwood, Missouri), “iomeprol” (Iomeron, Bracco Diagnos- minimization of total contrast volume are well-established tics, Princeton, New Jersey), “nephrotoxicity,” “contrast ne- means of preventing CI-AKI (10,11). phropathy,” “radiocontrast,” “renal failure,” and “randomized.” The choice of the contrast media used may also influence Abstract lists from the 2006 to 2008 scientific meetings of the the risk of CI-AKI. The use of high-osmolar contrast media American Heart Association, the American College of Cardi- results in more CI-AKI than the more contemporary low- ology, the European Society of Cardiology, and the Transcath- osmolar contrast media (LOCM) or the iso-osmolar contrast eter Cardiovascular Therapeutics were viewed. Other Internet- medium, iodixanol (Visipaque, based sources of information were also used to identify any Abbreviations GE Healthcare, Princeton, New other studies of interest. When needed, further information on and Acronyms Jersey) (12,13). Early studies sug- the trials was obtained from the study investigators. confidence interval gested that iodixanol is even less Study selection, data extraction, and quality assessment. A ؍ CI contrast-induced harmful to renal function than study was included if it randomized patients undergoing ؍ CI-AKI acute kidney injury some types of LOCM are (14,15). contrast media application to either LOCM or iodixanol, and low-osmolar A previous meta-analysis (16) if data on renal function were routinely ascertained in all ؍ LOCM contrast medium/media suggested a dramatic reduction in patients. Data were independently abstracted by 3 reviewers risk ratio CI-AKI with iodixanol when (M.R., P.M., U.T.) and disagreements were resolved by ؍ RR compared with LOCM. How- consensus. Reviewers were not blinded to study authors or ever, this analysis included trials that were not specifically outcomes. Attempts were made to retrieve the data from the designed to study the incidence of CI-AKI and in which renal original source in unpublished studies. Baseline demographic, function was not systematically determined in all patients. clinical, and procedural characteristics of each trial were re- Thus, this study was limited by ascertainment bias (17). corded, including mean age, average contrast volume, prophy- These data provided the rationale for the American College of lactic hydration volume, information about sex, diabetes, chronic Cardiology/American Heart Association’s revised 2007 guidelines kidney disease, type of procedure, type of LOCM used, the use of for the management of patients with unstable angina/non–ST- prophylactic therapies such as acetylcysteine, and the definition of elevation myocardial infarction, which now give a class IA recom- CI-AKI used. We assessed trial quality by evaluating specific mendation for the use of iso-osmolar contrast media for coronary elements of study design (i.e., concealment of allocation during angiography in patients with chronic kidney disease (18). More randomization, intention-to-treat analysis, and blinded assess- recently, several larger randomized controlled trials have been ment of outcome measures), but did not use a quality score given published and have shown no difference in CI-AKI when iodixa- the limitations inherent to such an approach (24). nol was compared with different types of LOCM (19–22). Also, End points, data synthesis, and data analysis. The primary end a recent meta-analysis comparing iodixanol to a pool of nonionic point was the incidence of CI-AKI as defined by each LOCM showed no significant reduction in the rates of CI-AKI individual study protocol. Secondary end points were the need (23). There are significant pharmacological differences between for renal replacement therapy and mortality. Data from all the various LOCM agents, and the disparate results of these trials selected studies were combined to estimate the pooled risk may be in part related to the specific LOCM agent used. The ratios (RR) for iodixanol versus LOCM using a random-effects objective of this systematic review and meta-analysis was to model. Significant between-study heterogeneity was expected integrate the latest randomized clinical trials to provide a compre- regarding study populations and because different LOCM hensive comparison of the nephrotoxicity of the iso-osmolar agent were used as comparators; therefore, a random-effects model iodixanol and the currently available LOCM. was used to produce across-study summary RR with 95% JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 7, 2009 Reed et al. 647 JULY 2009:645–54 Iodixanol Versus LOCM

confidence intervals (CI). All analyses were performed on an fied the pre-determined inclusion criteria and were considered intention-to-treat basis. Continuity correction was used when in the analysis (Fig. 1)(15,19–22,32–42). One study has not an event did not occur in 1 group (25). We quantitatively been published as a peer-reviewed report yet but was presented evaluated the presence of heterogeneity across trials with the Q at the Transcatheter Therapeutics 2006 meeting (40). 2 2 and I statistics, with an I value of 25% indicating low, 50% at Table 1 summarizes the characteristics of the 16 trials least moderate, and 75% high between-study heterogeneity. included in our analysis. Of the 2,763 subjects, a total of 1,383 To assess the effect of individual studies on the summary were randomly assigned to iodixanol (Visipaque) and 1,380 to estimate of effect, we performed an influence analysis, in which LOCM. Each of the 16 trials was designed as a superiority trial the pooled estimates were recalculated by omitting 1 study at a and used creatinine change or CI-AKI as a primary or time. Publication bias was tested by plotting a funnel plot, by secondary outcome. Nine of the trials involved coronary formal testing using rank order correlation and Egger test of angiography alone, 1 trial involved coronary or peripheral intercept, and by the Orwin fail-safe N (26–29). Duval- angiography, 1 trial involved peripheral angiography, and 5 Tweedie trim and fill method was used to assess for presence of involved intravenous injection of contrast for computed to- and impact of missing studies (30). An exploratory meta- mography scans. Twelve of the trials (2,266 of 2,763 patients in regression using a mixed-effect model was performed to assess the pooled analysis) only included patients with moderate or the impact of select variables (age, diabetes, baseline renal severe renal insufficiency, which was variably defined as serum function, contrast volume) on the incidence of CI-AKI. creatinine Ն1.5 mg/dl and/or creatinine clearance Ͻ60 ml/min Finally, an omnibus test was used to test the validity of each (14,20,33,37,39,40), estimated glomerular filtration rate Ͻ60 subgroup analysis (31). All analyses were performed using Ͻ Comprehensive Meta-Analysis software, version 2.0 (Biostat, ml/min (19,22), creatinine clearance 60 ml/min (15), serum creatinine Ն1.7 mg/dl in men and Ն1.5 mg/dl in women (21), Englewood, New Jersey) and Statistical Analysis System soft- Ͼ ware, release 9.2 for Windows 2002 to 2008 (SAS Institute, and serum creatinine 1.7 mg/dl (35). Thirteen trials included Cary, North Carolina). patients with diabetes mellitus. Ten trials used prophylactic hydration and 6 trials used prophylactic acetylcysteine. There Results were no relevant differences noted between the baseline characteristics of the iodixanol and LOCM groups of patients in A total of 120 articles were reviewed. Ninety articles were each of the individual trials. The type of LOCM agent used in initially rejected because they did not directly compare iodixa- each study was ioxaglate (Hexabrix, Guerbet Group, Villepinte, nol and LOCM, or because they did not document renal France) (n ϭ 4), iopromide (Ultravist, Bayer HealthCare Phar- function as an outcome or safety end point. Of the 30 maceuticals, Montville, New Jersey) (n ϭ 4), iohexol (Om- remaining studies, 14 were rejected because they were not nipaque, GE Healthcare) (n ϭ 3), iopamidol (Isovue, Bracco randomized controlled trials. The remaining 16 studies satis- Diagnostics) (n ϭ 3), ioversol (Optiray, Tyco Healthcare Group,

Figure 1. Flow Diagram of Selection Strategy

Flow diagram depicting the selection strategy for trials used in this meta-analysis. CI-AKI ϭ contrast-induced acute kidney injury; LOCM ϭ low-osmolar contrast media. 648

Table 1. Key Features of Trials Included in the Meta-Analysis

Juergens et al., 2008 (38) Nguyen et al., 2008 (41) PREDICT, 2008 (19) VALOR, 2008 (21) ACTIVE, 2008 (20) CARE, 2007 (22) IMPACT, 2006 (34) oiao essLOCM Versus Iodixanol Reed

Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM al. et

Subjects, n 91 100 65 61 123 125 156 143 72 76 210 204 76 77 Male, % 79 73 69 62 50 43 45 38 64 76 60 68 67 70 Age, yrs, mean Ϯ SD 70.2 Ϯ 9.2 69.4 Ϯ 10.2 63.0 Ϯ 11.7 65.8 Ϯ 13.4 68.3 Ϯ 1.99 69.5 Ϯ 10.05 71.1 Ϯ 9.9 72.6 Ϯ 10.2 65.4 Ϯ 12.1 67.1 Ϯ 14.1 70.5 Ϯ 9.9 72.9 Ϯ 9.0 67.0 Ϯ 11.5 67.3 Ϯ 13.0 Diabetes, % 35 46 35 16 100 100 52 52 13 28 44 38 28 19 Baseline SCr, mg/dl 1.61 1.63 1.77 1.75 1.41 1.46 2.0 1.92 1.7 1.7 1.44 1.46 1.5 1.6 eGFR, ml/min/1.73 m2, 47.6 Ϯ 16.5 45.6 Ϯ 15 51.8 Ϯ 16.6 53.0 Ϯ 26.0 49.9 Ϯ 11.6 47.6 Ϯ 13.5 36.5 Ϯ 11.3 38.8 Ϯ 11.1 NA NA NA NA NA NA mean Ϯ SD Mean contrast 101 116 115 100 101.6 106.5 118.4 129.9 125 100 136.4 133.7 125 109 volume, ml Mean hydration 1,175 1,119 NA NA 928.4 832.5 1,311 1,420 1,369 1,125 11.5 11.2 644 552 volume, ml (ml/kg) (ml/kg) NAC use, % 100 100 12.3 13.1 1.6 2.4 71.1 76.2 0 0 42.3 38.7 0 0 Reason for contrast Coronary angiography CT (IV) CT (IV) Coronary angiography CT (IV) Coronary angiography CT (IV) Type of LOCM Iopromide Iopromide Iopamidol Ioversol Iomeprol Iopamidol Iopamidol CI-AKI deﬁnition SCr 1 Ͼ0.5 mg/dl SCr 1 Ͼ0.5 mg/dl SCr 1 Ͼ25% SCr 1 Ͼ0.5 mg/dl SCr 1 Ͼ0.5 mg/dl SCr 1 Ͼ0.5 mg/dl SCr 1 Ͼ25% or Ͼ25% CI-AKI time frame, 2 1–3 2–3 3 2–3 3 2–3 days Creatinine assessment, 2, 7 1, 2, 3 2–3 1, 2, 3 2–3, 7 45–120 (h), 7 2–3 days Total patients, N 191 126 248 199 148 414 153

Primary outcome CI-AKI Creatinine change CI-AKI CI-AKI CI-AKI CI-AKI CI-AKI 2009 7, NO. 2, VOL. INTERVENTIONS, CARDIOVASCULAR JACC:

Chalmers and Jackson, Feldkamp et al., 2006 (37) ICON, 2006 (40) RECOVER, 2006 (15) NEPHRIC, 2003 (14) 1999 (36) Carraro et al., 1998 (35) Tveit et al., 1994 (42)

Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM

Subjects, n 105 116 71 74 140 135 64 105 116 71 74 140 135 64 Male, % 75 76 87 88 56 56 64 75 76 87 88 56 56 64 Age, yrs, mean Ϯ SD 60.6 Ϯ 10.0 62.1 Ϯ 9.2 71.5 Ϯ 9.9 71.3 Ϯ 12.3 66.1 Ϯ 8.6 68.7 Ϯ 7.5 71.1 Ϯ 6.0 60.6 Ϯ 10.0 62.1 Ϯ 9.2 71.5 Ϯ 9.9 71.3 Ϯ 12.3 66.1 Ϯ 8.6 68.7 Ϯ 7.5 71.1 Ϯ 6.0 Diabetes, % 40 35 42 49 34 36 100 40 35 42 49 34 36 100 Baseline SCr, mg/dl 1/04 1.03 1.86 1.8 1.38 1.3 1.49 1/04 1.03 1.86 1.8 1.38 1.3 1.49 eGFR, ml/min/1.73 m2, NA NA NA NA NA NA NA NA NA NA NA NA NA NA mean Ϯ SD Mean contrast Ͻ1,000 Ͻ1,000 217 204 204.6 194.8 163 Ͻ1,000 Ͻ1,000 217 204 204.6 194.8 163 volume, ml 2009:645–54 JULY Mean hydration 1,000 1,000 1,700 1,700 8 (ml/kg) 8 (ml/kg) 977 1,000 1,000 1,700 1,700 8 (ml/kg) 8 (ml/kg) 977 volume, ml NAC use, % 0 0 NA NA 0 0 NA 0 0 NA NA 0 0 NA

Continued on next page AC ADOACLRITRETOS O.2 O ,2009 7, 2009:645–54 NO. JULY 2, VOL. INTERVENTIONS, CARDIOVASCULAR JACC:

Table 1. Continued

Chalmers and Jackson, Feldkamp et al., 2006 (37) ICON, 2006 (40) RECOVER, 2006 (15) NEPHRIC, 2003 (14) 1999 (36) Carraro et al., 1998 (35) Tveit et al., 1994 (42)

Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM Iodixanol LOCM

Reason for contrast Coronary angiography Coronary angiography Coronary angiography Coronary or peripheral Peripheral angiography CT (IV) Coronary angiography angiography Type of LOCM Iopromide Ioxaglate Ioxaglate Iohexol Iohexol Iopromide Ioxaglate CI-AKI deﬁnition SCr 1 Ͼ25% SCr 1 Ͼ0.5 mg/dl SCr 1 Ͼ0.5 mg/dl SCr 1 Ͼ0.5 mg/dl SCr 1 Ͼ25% SCr 1 Ͼ50% Not deﬁned or Ͼ25% CI-AKI time frame, 2 3 2 3712 days Creatinine assessment, 2 1, 2 1, 2 2, 3, 7 1, 2–7 1, 2 ? days Total patients, N 221 145 275 129 102 64 102 Primary outcome CI-AKI Creatinine change CI-AKI Creatinine change CI-AKI CI-AKI Creatinine change

Klow et al., 1993 (39) Andersen et al., 1993 (32)

Iodixanol LOCM Iodixanol LOCM

Subjects, n 35 37 36 38 Male, % NA NA 75 66 Age, yrs, mean Ϯ SD 54 Ϯ 955Ϯ 954 56 Diabetes, % NA NA NA NA Baseline SCr, mg/dl NA NA 1.05 0.98 eGFR, ml/min/1.73 m2, mean Ϯ SD NA NA 93 Ϯ 985Ϯ 29 Mean contrast volume, ml 175 174 107 106 Mean hydration volume, ml NA NA NA NA NAC use, % NA NA NA NA Reason for contrast Coronary angiography Coronary angiography Type of LOCM Iohexol Ioxaglate CI-AKI deﬁnition SCr 1 Ͼ50% GFR 2 Ͼ25% oiao essLOCM Versus Iodixanol CI-AKI time frame, days 2 2 Creatinine assessment, days 1, 2 1, 2 Total patients, N 72 74 Reed Primary outcome Adverse events Adverse events

CI-AKI ϭ contrast-induced acute kidney injury; CT (IV) ϭ computed tomography (intravenous); eGFR ϭ estimated glomerular ﬁltration rate; LOCM ϭ low-osmolar contrast media; NA ϭ not applicable; NAC ϭ N-acetylcysteine; SCr ϭ serum creatinine; SD ϭ standard al. et deviation. 649 650 Reed et al. JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 7, 2009 Iodixanol Versus LOCM JULY 2009:645–54

Mallinckrodt Inc.) (n ϭ 1), and iomeprol (Iomeron, Bracco In a subset analysis of the 8 studies involving 1,793 Diagnostics) (n ϭ 1). Ioxaglate is the only ionic dimer included; patients in the setting of coronary angiography and inter- the other agents are nonionic monomers. The definition of ventions, there was no difference in CI-AKI between CI-AKI varied among the trials. Most studies (n ϭ 6) defined patients randomized to iodixanol and LOCM (RR: 0.82, CI-AKI as an absolute increase of creatinine by at least 0.5 mg/dl 95% CI: 0.55 to 1.21; p ϭ 0.31) (Fig. 3). A subgroup (20–22,33,35,41) or as a relative increase by at least 25% (n ϭ 4) analysis limited to data specific for diabetic patients (n ϭ (19,36,37). A few studies used a composite of the 2 definitions 914, 7 studies) demonstrated similar findings (RR: 0.64, (n ϭ 3) (15,34,38,40). One trial used the definition of a relative 95% CI: 0.29 to 1.44; p ϭ 0.285). Meta-regressions did not increase of at least 50% (39), and 2 trials based their definition suggest an association between the relative effect of iodixa- on a decrease of glomerular filtration rate of at least 25% nol and the average baseline creatinine level of each study (32,42). For each study, we used the corresponding pre- (slope ϭ –0.029, standard error [SE]: 0.028; p ϭ 0.31) or defined primary end point. any of the other variables studied (data not shown). Clinical end points. CONTRAST-INDUCED ACUTE KIDNEY A stratified analysis by the specific LOCM explained part of INJURY. The primary clinical end point of our meta-analysis the observed heterogeneity and demonstrated a relatively lower was CI-AKI. There was an overall trend in favor of iodixanol, risk of CI-AKI with iodixanol than with iohexol (RR: 0.19, but no significant difference in the overall risk of CI-AKI 95% CI: 0.07 to 0.56; p ϭ 0.002) or ioxaglate (RR: 0.58, 95% between the iodixanol and the pooled LOCM groups. CI: 0.37 to 0.92; p ϭ 0.022) (Fig. 4). No relative difference in CI-AKI occurred in 128 of 1,379 patients receiving iodixa- the risk of CI-AKI was observed between iodixanol and nol and in 158 of the 1,375 patients assigned to LOCM iopamidol (RR: 1.20, 95% CI: 0.66 to 2.18; p ϭ 0.55), treatment (RR: 0.79, 95% CI: 0.56 to 1.12; p ϭ 0.189) (Fig. iopromide (RR: 0.93, 95% CI: 0.47 to 1.85; p ϭ 0.84), or 2). There was moderate heterogeneity across studies regard- ioversol (RR: 0.92, 95% CI: 0.60 to 1.39; p ϭ 0.68). Only 1 ing clinical or patient characteristics and protocols, and also study used iomeprol and thus a pooled analysis was not according to formal tests (I2 ϭ 44.7; Q ϭ 23.5, p ϭ 0.036). performed, but this is the 1 study that actually shows a higher An influence analysis omitting 1 individual study at a time incidence of CI-AKI with iodixanol (20). An omnibus test was to determine if a single study dominated the results of the used to investigate the validity of the subgroup analysis and pooled analysis did not change the lack of difference confirmed a significant difference in CI-AKI when comparing between iodixanol and the pool of LOCM agents, suggest- the type of LOCM (p ϭ 0.004), but not when comparing the ing that no single individual study overwhelmingly influ- route (intravenous vs. intra-arterial, p ϭ 0.07) of contrast enced the overall results of the pooled analysis. administration.

Figure 2. Forest Plot of RR of CI-AKI

Forest plot of risk ratios (RR) of contrast-induced acute kidney injury (CI-AKI) of pooled trials. Total number of patients in iodixanol group ϭ 1,291. Total number of patients in the low-osmolar contrast media (LOCM) group ϭ 1,289. ACTIVE ϭ Abdominal Computed Tomography: IOMERON 400 versus VISIPAQUE 320 Enhancement Study; CARE ϭ Cardiac Angiography in Renally Impaired Patients Study; CI ϭ confidence interval; ICON ϭ Ionic Versus Nonionic Contrast to Obviate Worsening Nephropathy After Angioplasty in Chronic Renal Failure Patients; IMPACT ϭ renally IMpaired PAtients undergoing Computed Tomography; IX ϭ iodixanol; NEPHRIC ϭ Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low-Osmolar Non-Ionic Contrast Media Study; PREDICT ϭ Patients with Renal Impairment and Diabetes undergoing Computed Tomography; RECOVER ϭ Renal Toxicity Evaluation and Comparison Between Visipaque and Hexabrix in Patients With Renal Insufficiency Under- going Coronary Angiography; VALOR ϭ Visipaque Angiography/Interventions With Laboratory Outcomes in Renal Insufficiency Study. JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 7, 2009 Reed et al. 651 JULY 2009:645–54 Iodixanol Versus LOCM

Figure 3. Forest Plot of RR of CI-AKI of Patients Undergoing Coronary Angiography

Forest plot of risk ratios (RR) of contrast-induced acute kidney injury (CI-AKI) in studies of patients undergoing coronary angiography. Total number of patients in iodixanol group ϭ 873. Total number of patients in the low-osmolar contrast media (LOCM) group ϭ 875. Abbreviations as in Figures 1 and2.

There was no suspicion of publication bias based on NEED FOR HEMODIALYSIS. Need for hemodialysis was re- funnel plot symmetry and according to formal testing (rank corded in 12 trials. In 9 of these, no event was observed in Ϫ order correlation or Kendall taub: 0.022, 1-tailed p value: either of the study arms. A total of 2 patients in the 0.48, Egger test intercept: Ϫ0.24, 95% CI: Ϫ1.83 to 1.35, iodixanol arms (n ϭ 1,031) required hemodialysis (range: 1-tailed p value: 0.37) (Fig. 5). The classic fail-safe N was 0% to 1.5%), and 9 patients in the LOCM arms (n ϭ 1,036; not valid for our analysis because there was no significant range: 0% to 9.2%). This difference was not statistically difference between the 2 groups; thus, an Orwin fail-safe N significant (RR: 0.37, 95% CI: 0.08 to 1.68; p ϭ 0.20). was derived. Using an imputed RR of 0.3 favoring iodixanol MORTALITY. Data for mortality were available from 9 over LOCM, 15 studies would be required to achieve a studies (n ϭ 1,491 patients). No death was recorded in significant pooled RR of CI-AKI under 0.5. Using a less either study arm in 6 of these trials. The overall mortality stringent RR of 0.39 as described in the prior meta-analysis rate was not significantly different between the 2 treatment (16), 30 such studies would be needed. groups: 7 deaths in the 743 patients assigned to iodixanol

Figure 4. Forest Plot of RR of CI-AKI by Contrast Media

Forest plot of risk ratios of contrast-induced acute kidney injury. Analyses stratiﬁed by the different low-osmolar contrast media compared with iodixanol. Abbre- viations as in Figures 2 and3. 652 Reed et al. JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 7, 2009 Iodixanol Versus LOCM JULY 2009:645–54

Figure 5. Funnel Plot of SE by Log RR

Funnel plot of standard error (SE) by log risk ratio (RR), demonstrating absence of publication bias.

(range: 0% to 4.9%) and 5 deaths in the 748 patients more likely to cause CI-AKI compared with iodixanol than randomized to LOCM (range: 0% to 3.6%), with a sum- others. In our stratified analysis, iodixanol is associated with a mary RR of 1.38 (95% CI: 0.33 to 5.79, p ϭ 0.663). relatively lower rate of CI-AKI when compared with ioxaglate or iohexol, but there is no relative difference in CI-AKI when Discussion comparing iodixanol with iopromide, iopamidol, iomeprol, or ioversol. This suggests that the risk of CI-AKI cannot be The main finding of this systematic review of the published studies and meta-analysis is that there is no significant explained by osmolarity alone (Table 2). Ionicity is a feature difference in the incidence of CI-AKI when using iodixanol unique to ioxaglate among the LOCM, and our stratified than when using a pool of ionic and nonionic LOCM. The analysis suggests this agent is relatively more likely to result in vast majority of these trials (12 of 16) included subjects with CI-AKI. Whether viscosity is a significant factor in the risk of elevated mean creatinine. Although the inclusion of both developing CI-AKI is not known. In fact, the exact mecha- ionic and nonionic forms of LOCM as well as of intrave- nism of CI-AKI is imperfectly established, but it is thought to nous and intra-arterial contrast injection helps make the involve renal medullary hypoxia due to renal artery vasocon- results of this analysis more generalizable, it should also be striction and hyperviscosity or direct renal cytotoxicity from noted that our subgroup analysis of only those trials involv- contrast agents (43,44). ing coronary angiography also does not show a benefit of The lack of significant difference in mortality and need iodixanol over other LOCM. for hemodialysis between those treated with iodixanol and A stratified analysis that indirectly compared the various those treated with LOCM is not surprising, given the sheer types of LOCM demonstrated that some LOCM are relatively infrequency of this outcome and given that the follow-up in

Table 2. Key Characteristics of Different Contrast Media

Iodine Osmolarity Viscosity

Generation Class Type of Molecule Examples (mg I/ml) (mOsm/kg-H2O) at 37°C

First High-osmolar Ionic monomer Diatrizoate (Hypaque) 370 2,076 8.4 Second Low-osmolar Ionic dimer Ioxaglate (Hexabrix) 320 600 7.5 Low-osmolar Nonionic monomer Iopamidol (Isovue) 370 796 9.4 Iohexol (Omnipaque) 350 844 10.4 Iopromide (Ultravist) 300 607 4.9 Ioxilan (Oxilan) 350 695 8.1 Ioversol (Optiray) 320 792 9.0 Third Iso-osmolar Nonionic dimer Iodixanol (Visipaque) 320 290 11.8 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 2, NO. 7, 2009 Reed et al. 653 JULY 2009:645–54 Iodixanol Versus LOCM

many of these trials was very short. With that said, even Study limitations. Our meta-analysis is subject to the limi- modest elevations in serum creatinine after contrast expo- tations inherent to all meta-analysis. There is a risk of sure are associated with increased long-term morbidity and publication bias, although this tested nonsignificant in our mortality. In a retrospective analysis of 9,067 post-PCI study. There is possibility of limited power and a type II patients, the 1-year survival of patients with renal failure was statistical error, but this is unlikely as demonstrated by the 70.3% and without renal failure was 93.6% (4). high Orwin fail-safe number. Also, not all trials reported Although the pooled analysis trended in favor of iodixanol, standardizations on hydration or prophylactic medications this was not statistically significant—a finding that differs from used. Finally, although CI-AKI is associated with worse the results of a previous meta-analysis published by McCul- long-term prognosis, the included trials focused primarily lough et al. (16) that indicated that the use of iodixanol is on short-term elevations in creatinine rather than long-term associated with lower rates of CI-AKI than LOCM, particu- outcomes of harder end points. larly in patients with chronic kidney disease and diabetes (16). Conclusions The subjects used in the analysis by McCullough et al. (16) were taken from a pool of trials that did not explicitly use This systematic review and meta-analysis demonstrates that the CI-AKI as an end point, which may have resulted in ascer- use of iodixanol, when compared with a pool of LOCM, does not tainment bias and lack of control of confounding variables. In result in less nephrotoxicity. There appears to be no difference in fact, although creatinine typically peaks at 48 to 72 h after the risk of nephrotoxicity when iodixanol is compared with intravascular contrast exposure, only 40% of the subjects had iopamidol, iopromide, and ioversol, whereas iodixanol appears to creatinine checks at 48 h and less than 20% had creatinine cause less nephrotoxicity than ioxaglate and iohexol do. Further checks at 72 h. In addition, 83% of the subjects in the LOCM trials comparing various iso-osmolar and low-osmolar media are arm received ioxaglate or iohexol, both of which were associ- needed in order to determine the optimal contrast agent for use in ated with relatively more CI-AKI in our stratified analysis. patients with chronic renal insufficiency and the impact of indi- Finally, the study by McCullough et al. (16) only included vidual contrast media on long-term outcomes. trials through 2003, and there are several randomized controlled trials published since 2003 that we included in this Acknowledgment current study. The data presented here provide an updated and The authors are especially grateful to Gupreet K. Rana, Clinical more comprehensive look at the nephrotoxicity of iodixanol Education Librarian, Taubman Medical Library, University of versus various LOCM. We only included trials designed to Michigan, for her help during the search for published reports. look at CI-AKI as an end point, thus ensuring adequate control of confounding variables in the 2 study arms and Reprint requests and correspondence: Dr. Hitinder S. Gurm, minimizing the likelihood of ascertainment bias. Our results Department of Medicine, Division of Cardiovascular Medicine, corroborate those of a recent meta-analysis that showed no University of Michigan Cardiovascular Center, 2A394, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109-5853. significant difference in the rates of CI-AKI when iodixanol was E-mail: [email protected]. compared with a pool of nonionic LOCM (23). However, our study includes both ionic and nonionic forms of LOCM and provides a direct comparison of coronary angiography trials. REFERENCES The 2007 ACC/AHA guidelines update gives a class IA 1. Rich MW, Crecelius CA. Incidence, risk factors, and clinical course of recommendation for the use of iso-osmolar contrast media acute renal insufficiency after cardiac catheterization in patients 70 years for coronary angiography in the setting of unstable angina or of age or older. A prospective study. Arch Intern Med 1990;150:1237–42. non–ST-segment elevation myocardial infarction and renal 2. 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