International Journal of Cardiology 172 (2014) 375–380 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard Nephropathy after administration of iso-osmolar and low-osmolar contrast media: Evidence from a network meta-analysis Giuseppe Biondi-Zoccai a,⁎,MarziaLotrionteb,HenrikS.Thomsenc,EnricoRomagnolid, Fabrizio D'Ascenzo e, Arturo Giordano f,g, Giacomo Frati a a Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy b Heart Failure and Cardiac Rehabilitation Unit, Columbus Integrated Complex, Rome, Italy c Copenhagen University Hospital, Herlev, Denmark d Division of Cardiology, Policlinico Casilino, Rome, Italy e Division of Cardiology, University of Turin, Turin, Italy f Unità Operativa di Interventistica Cardiovascolare, Presidio Ospedaliero Pineta Grande, Castel Volturno, Italy g Unità Operativa di Emodinamica, Casa di Salute Santa Lucia, San Giuseppe Vesuviano, Italy article info abstract Article history: Background/objectives: Contrast-induced nephropathy (CIN) may be a severe complication to the administration Received 20 December 2013 of iodine-based contrast media for diagnostic or interventional procedure using radiation exposure. Whether Accepted 18 January 2014 there is a difference in nephrotoxic potential between the various agents is uncertain. We aimed to perform a Available online 24 January 2014 systematic review and network meta-analysis of randomized trials on iodine-based contrast agents. Methods: Randomized trials of low-osmolar or iso-osmolar contrast media were searched in CENTRAL, Google Keywords: Scholar, MEDLINE/PubMed, and Scopus. Risk of CIN was appraised within a hierarchical Bayesian model Angiography computing absolute rates (AR) and odds ratios (OR) with 95% credibility intervals, and probability of being Contrast-induced nephropathy Mixed treatment comparison best (Pbest) for each agent. Network meta-analysis Results: A total of 42 trials (10048 patients) were included focusing on 7 different iodine-based contrast media. Systematic review Risk of CIN was similarly low with iodixanol (AR = 5.7% [2.2%–13.9%], Pbest = 18.8%), iomeprol (AR = 6.0% [2.2%–15.4%], Pbest = 24.8%), iopamidol (AR = 6.1% [2.2%–15.5%], Pbest = 21.5%), and ioversol (AR = 6.0% [2.1%–16.4%], Pbest = 31.3%). Conversely, CIN was twice as common with iohexol (AR = 11.2% [4.1%–29.5%], Pbest = 0.1%) and ioxaglate (AR = 11.0% [4.0%–26.9%], Pbest b 0.1%), with both proving less safe than iodixanol (respectively OR = 2.18 [1.22–3.92] and 2.05 [1.26–3.29]), iomeprol (OR = 2.08 [1.04–4.17] and 1.96 [1.06–3.48]) and iopamidol (OR = 2.04 [1.15–3.85] and 1.92 [1.06–3.45]). Data on iopromide were less conclusive (AR = 6.9% [2.6%–17.1%], Pbest = 3.6%). Conclusions: Iodixanol, iomeprol, iopamidol and ioversol are iodine-based contrast media with a similar renal safety profile. Iohexol and ioxaglate have a poorer renal safety profile, whereas further data may be required on iopromide. © 2014 Elsevier Ireland Ltd. All rights reserved. 1. Introduction the risk of adverse reactions [1,2]. One of the more common untoward effects associated with contrast media administration is contrast- Administration of iodine-based contrast media is one of the corner- induced nephropathy (CIN). Accordingly, momentous efforts have stones of modern diagnostic imaging, enabling accurate visualization of been applied to develop contrast agents with as little as possible risk minute anatomic structures and pathologic conditions during interven- of renal damage [3]. tional procedures, conventional radiography and computed tomogra- This has translated into a shift from old agents with high osmolarity phy (CT) scanning in radiology. Moreover, contrast media are crucial to new ones with lower osmolarity, as indeed this chemical property for several therapeutic procedures. Contrast agents have however has been identified as a potentially important factor in renal safety been considered, at least in the past, as potentially hazardous, given [4,5]. Several studies have focused on the comparison between contrast agents, many exploiting as comparator iodixanol, which is a iso-osmolar non-ionic dimer [6,7]. However, uncertainty persists on whether there is any meaningful difference in renal safety between iodixanol and the ⁎ Corresponding author at: Department of Medico-Surgical Sciences and other non-ionic agents. Systematic reviews incorporating network Biotechnologies, Sapienza University of Rome, Latina, Corso della Repubblica 79, 04100 Latina Italy. meta-analysis (i.e. mixed treatment comparison) can maximize the E-mail address: [email protected] (G. Biondi-Zoccai). information yield stemming from complex evidence networks, 0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2014.01.075 376 G. Biondi-Zoccai et al. / International Journal of Cardiology 172 (2014) 375–380 2. Methods This review was conducted in keeping with ongoing guidelines and is registered on- line at metcardio.org (Protocol #6-2012). All reviewing activities were conducted inde- pendently by two skilled systematic reviewers, with divergences resolved after consensus. 2.1. Search MEDLINE/PubMed was searched according to Biondi-Zoccai et al. [9], combining a dedicated string for randomized trials as follows: (iodixanol OR iomeprol OR ioxaglate OR iopamidol OR iopromide OR iohexol OR iopamidol OR iopental OR iopentol OR iopramide OR ioversol) AND (nephropathy OR ((kidney OR renal) AND (insufficiency OR damage OR injury OR failure))). CENTRAL, Google Scholar and Scopus were also searched for additional citations. No language restriction was enforced. Queries were last updated on June 30, 2013. 2.2. Selection Citations were initially screened at the title and abstract level, and discarded if clearly not pertinent. Potentially suitable citations were retrieved as full reports. They were then Fig. 1. Review profile. included if reporting a randomized trial, on low-osmolar or iso-osmolar radiographic con- trast agents, and reporting data on renal safety. Studies including high-osmolar contrast agents as comparators were conversely excluded a priori to minimize their confounding providing results which are more statistically precise and externally effect on the evidence network. valid than single randomized trials, or pairwise meta-analyses [8]. Accordingly, we aimed to perform a network meta-analysis of random- 2.3. Abstraction and appraisal ized trials comparing low-osmolar or iso-osmolar contrast agents Major design, patient, and procedural features were abstracted from the shortlisted focusing on renal safety. studies. Outcomes of interest were the short-term (≤30 days) rate of CIN, defined as an Table 1 Study features. First author Year Acronym Study type 1st Rx 2nd Rx Sample Primary endpoint Follow-up Andersen 1993 NA Open RCT Iodixanol Ioxaglate 74 Creatinine clearance decrease N25% 2 days Aspelin 2005 NEPHRIC Double-blind RCT Iodixanol Iohexol 129 Peak increase in creatinine 3 days Barrett 2006 IMPACT Double-blind RCT Iodixanol Iopamidol 153 Creatinine increase ≥25% or ≥0.5 mg/dL 3 days Bertrand 2000 VIP Double-blind RCT Iodixanol Ioxaglate 1314 Major adverse cardiac events 2 days Bolognese 2012 CONTRAST-AMI Single-blind RCT Iodixanol Iopromide 465 Creatinine increase ≥25% 1 month Carraro 1998 NA Double-blind RCT Iodixanol Iopromide 64 Creatinine increase ≥50% Hospital discharge Chalmers 1999 NA Open RCT Iodixanol Iohexol 102 Creatinine increase ≥10% 1 week Chen 2012 DIRECT Double-blind RCT Iodixanol Iopromide 562 Creatinine increase ≥50% 4 days Chuang 2009 NA Double-blind RCT Iodixanol Iohexol 50 Peak increase in creatinine 1 week Conroy 1994 NIOPAM Double-blind RCT Iodixanol Iopamidol 180 Imaging yield Hospital discharge Davidson 2000 COURT Double-blind RCT Iodixanol Ioxaglate 815 Major adverse cardiac events 1 month Dillman 2012 NA Double-blind RCT Iohexol Iopamidol 389 Peak increase in creatinine 3 days Feldkamp 2006 NA Double-blind RCT Iodixanol Iopromide 83 Creatinine increase ≥25% 2 days Grossman 1996 NA Double-blind RCT Iodixanol Iohexol 148 Imaging yield Hospital discharge Hardiek 2008 NA Double-blind RCT Iodixanol Iopamidol 102 Creatinine increase ≥25% 1 week Jakobsen 1996 NA Double-blind RCT Iodixanol Iohexol 16 Peak increase in creatinine 4 days Jo 2006 RECOVER Double-blind RCT Iodixanol Ioxaglate 275 Creatinine increase ≥25% or ≥0.5 mg/dL 1 week Juergens 2009 NA Double-blind RCT Iodixanol Iopromide 191 Creatinine increase ≥25% or ≥0.5 mg/dL 1 week Kuhn 2008 NA Double-blind RCT Iodixanol Iopamidol 248 Adverse events 2 days Laskey 2009 NA Double-blind RCT Iodixanol Iopamidol 417 Peak increase in creatinine 1 week Lee 1996 NA Double-blind RCT Iodixanol Iohexol 126 Adverse events 3 days Manke 2003 NA Double-blind RCT Iodixanol Iomeprol 328 Pain Hospital discharge Mehran 2009 ICON Double-blind RCT Iodixanol Ioxaglate 146 Peak increase in creatinine 1 month Nguyen 2008 NA Double-blind RCT Iodixanol Iopromide 117 Peak increase in creatinine 3 months Nie 2008 NA Double-blind RCT Iodixanol Iopromide 208 Creatinine increase ≥25% or ≥0.5 mg/dL 1 month Nossen 1995 NA Open RCT Iodixanol Iohexol 16 Pharmacokinetics Hospital discharge Poirier 1996 NA Double-blind RCT Iodixanol Iohexol 49 Imaging yield Hospital discharge Rosenblum 1996 NA Double-blind RCT Iodixanol Ioxaglate 46 Adverse events Hospital discharge Rudnick 2008 VALOR Double-blind RCT Iodixanol Ioversol 334 Creatinine increase ≥0.5 mg/dL 1