1	"David S" David S. Enterline, M.D. Mark D. Marchand, M.D. Charles E. Spritzer, M.D. Department of Radiology Duke University Medical Center, Durham, NC
2	CME Disclosures David S. Enterline, MD Bracco Diagnostics, Inc. Radiology Advisory Board Speakers Bureau Mark D. Marchand, M.D. None Charles E. Spritzer, M.D. None
3	Learning Objectives To describe our institutional strategy for gadolinium chelate use To help others develop a rationale for patient screening prior to gadolinium use Policy formulated by review of: Regulatory Guidelines Current literature on NSF Society Recommendations
4	Regulatory Agency NSF Summary United States FDA Alerts of June 2006, December 2006, and May 2007 ACR Guidelines of June 2007 United Kingdom and Europe EMEA Influences agents centrally authorized for European countries (i.e., only Vasovist) MHRA Notices of February 2007 and June 2007 UK agency responsible for ensuring safety of medicines/medical devices ESUR Notice of July 2007
5	Approval Status of GBCA
6	Chronic Kidney Disease Definitions
7	FDA Initial PHA GBCA for MRI (6/06) Notification that NSF occurs in patients with renal failure Possible link between NSF and GBCA at high doses for MRA Described 25 cases of NSF in renal failure patients who received Omniscan for MRA Made recommendations GBCA, especially at high doses, should be used only if clearly necessary in patients with advanced renal failure (GFR <15 mL/min/1.73 m²) Prompt dialysis in patients with advanced renal dysfunction who receive GBCA-enhanced MRA may be prudent Despite lack of evidence that dialysis can prevent or treat NSF, recommendation based on average excretory rates of Gd in first to third hemodialysis sessions (78%, 96%, and 99%, respectively) (Okada, et al) Stated that it is not yet determined whether exposure by patients with renal failure to GBCA during MRA test causes NSF
8	FDA Updated PHA: (12/06) Additional information on NSF May occur in patients with moderate to end-stage kidney disease after MRI or MRA with GBCA Described reports of 90 patients with moderate to end-stage kidney disease who developed NSF 2 days to 18 months after MRI or MRA with GBCA Many, but not all, received high doses of GBCA Provided notification to HCP and patients Patients with moderate to end-stage kidney disease who receive an MRI or MRA with a GBCA may get NSF Patients who believe they may have NSF should contact their doctor (described signs and symptoms in detail) In patients with moderate- to end-stage kidney disease requiring an imaging study, avoid GBCA-enhanced MRI or MRA whenever possible If these patients must receive a GBCA, prompt dialysis following the MRI or MRA should be considered
9	FDA Updated Alert: (5/07) Most recent FDA alert requests addition of a boxed warning and new warnings to full prescribing information for all GBCA GBCA increases the risk for NSF in patients with: acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73 m²), or acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of GBCA unless the diagnostic information is essential and not available with non-contrast MRI. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any readministration.
10	FDA Updated Alert: (5/07) Additional new warnings Repeated or higher than recommended doses of a GBCA are among the factors that may increase the risk for NSF For patients receiving HD, consider prompt HD following GBCA administration to enhance the contrast agent's elimination Unknown if HD prevents NSF Determine renal function of patients via medical history or laboratory tests prior to using a GBCA Risk, if any, for developing NSF among patients with mild to moderate renal insufficiency or normal renal function not known
11	FDA Updated Alert: GBCA for MRI (5/07) Development of NSF has occurred following single and multiple administrations of GBCAs Specific agent not always identified Where identified, most commonly reported agent was Omniscan, followed by Magnevist and OptiMARK NSF also developed following sequential administration of Omniscan and MultiHance, and Omniscan and ProHance Distribution for individual GBCAs may relate to multiple factors, including More limited use of some GBCAs Under-reporting of NSF Characteristics of agent and lack of patients’ complete GBCA exposure history
12	ACR Guidance Document for Safe MR Practices (6/07) For patients with stage 1 or 2 CKD No special treatment or handling Exception: patients with any level of renal disease should not receive Omniscan for contrast-enhanced MR For patients with stage 3–5 kidney disease or acute kidney injury (AKI) Recommend refraining from administering any GBCA unless benefit clearly outweighs potential risk(s) When risk outweighs benefit, consider administering lowest dose that would still provide diagnostic benefit
13	ACR Guidance Document for Safe MR Practices (6/07) For patients on HD given GBCA, immediately transport patient to HD upon termination of MRI examination Initiate HD ≤2 hours following administration of the GBMCA Consider an additional HD session within 24 hours of first Strong reason to hesitate to administer GBCA to peritoneal dialysis (PD) patients PD seems relatively ineffective at clearing Gd from the body
14	ACR Guidance Document for Safe MR Practices (6/07) For patients not already on HD, decision to initiate HD following Gd administration “should not be taken lightly” Insufficient data to recommend initiating HD in patients with stage 3 with same considerations stages 4/5 Vast majority of cases occurred in patients with severe- to end-stage renal disease, many on dialysis Few, if any, cases of NSF have occurred in patients with moderate renal disease Risks of initiating HD must be weighed against risk of developing NSF for each case
15	ACR Guidance Document for Safe MR Practices (6/07) Other practice-related recommendations All requests for MR should prescreened Add question about presence of a history of “kidney disease or dialysis” Prospectively checking for renal function, SCr, or GFR prior to MRI or MRA not required Patients with stages 3–5 renal disease must have a written order from a radiologist specifying contrast-enhanced MRI with a specific contrast agent Prospective documentation of a risk–benefit assessment for each such patient is considered advisable All patients with stages 3–5 kidney disease in whom a GBCA is to be administered should provide informed consent when practical
16	UK MHRA* Initial Recommendations (2/07) Omniscan contraindicated in Patients with severe renal impairment (GFR <30 mL/min) Patients who have had, or who are awaiting, liver transplantation Should be used only after careful consideration in neonates and infants up to 1 year of age All other GBCA Should be used only after careful consideration in patients with severe renal impairment (GFR <30 mL/min/1.73 m²) Not enough evidence to advise initiation of dialysis for GBCA Based on results where dialysis of 10 patients within 2 days of Omniscan did not prevent development of NSF (Broome, et al)
17	UK MHRA Updated Regulatory Position (6/07) Omniscan contraindicated in Patients with severe renal impairment (GFR <30 mL/min) Patients who have had, or are awaiting, liver transplantation Should be used only after careful consideration in Neonates and infants up to 1 year of age Patients with moderate renal impairment (GFR 30–59 mL/min) Magnevist Contraindicated with severe renal impairment (GFR <30 mL/min) Should be used only after careful consideration in Patients with moderate renal impairment (GFR 30–59 mL/min) Neonates and infants up to 1 year of age All other GBCA Should be used only after careful consideration in patients with severe renal impairment (i.e., GFR <30 mL/min)
18	UK MHRA Updated Regulatory Position (6/07) All patients, particularly those >65 years of age, should be screened for renal dysfunction by obtaining a history and/or laboratory tests before these GBCA are used HD shortly after administration of a GBCA in patients currently receiving hemodialysis may be useful for removal of contrast agent from the body However, there is no evidence to suggest that hemodialysis can prevent or treat development of NSF
19	ESUR: 07/07 The risk of inducing NSF must always be weighed against the risk of denying patients Gd-enhanced scans For patients at higher risk, the benefits and risks of Gd enhancement should be considered particularly carefully Patients with CKD 4 and 5 (GFR < 30 mL/min/1.73 m²) Always use smallest possible amount of contrast agent to achieve an adequate diagnostic examination Never use more than 0.3 mmol/kg of any GBCA Patients on dialysis Patients with reduced renal function who have had or are awaiting liver transplantation Patients at lower risk include Patients with CKD 3 (GFR 30–59 mL/min/1.73 m²) Children under 1 year, because of immature renal function
20	ESUR Guidelines
21	ESUR Guidelines
22	ESUR: 07/07 Immediate HD after administration of GBCA >9 hours of HD (3 sessions) is required to remove a GBCA Efficacy of HD can be variable, depends on many factors No evidence that immediate HD protects against NSF In patients already being dialyzed May be helpful to schedule dialysis session after Gd contrast examination Should not cause delays in obtaining important diagnostic information Initiating HD for the sole purpose of removing a GBCA is not recommended in patients not already receiving HD Procedure itself associated with significant potential morbidity
23	Summary of Similarities & Differences Among NSF Guidelines (as of March, 2008)
24	Duke University Radiology GBCA Policy Highlights Screen patients for renal and liver disease Radiologist involved when eGFR <60 Consider alternative studies Consider non-contrast MRI and MRA only Consider gadolinium dose reductions Choose agent – MultiHance at half dose (? GRF 45) At eGFR <30, contrast use relatively contraindicated. Need informed consent and order. If gadolinium administered, consider dialysis At eGFR <15, avoid use, use extreme caution
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26	Duke University Radiology GBCA Policy Policy Flowsheet is followed All patients fill out screening form I-Stat point of care test performed if GBCA used and SCr and eGFR not recently available. If elevated, SCr obtained All GBCA doses and agents recorded Patients with acute renal failure and severe liver failure or transplant are particularly scrutinized
27	Conclusion Patient safety for GBCA administration for enhanced MRI has become a primary concern with the advent of NSF A dedicated departmental policy is important to ensure uniform safe use of these agents.
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29	References Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. Am J Roentgenol. 2007;188:586-592. ESUR Guideline*: Gadolinium Based Contrast Media and Nephrogenic Systemic Fibrosis. European Society Urogenital Radiology Web site. Available at: http://www.esur.org/fileadmin/NSF/NSF-ESUR_Guideline_Final.pdf. Accessed March 19, 2008. Gadolinium-containing Contrast Agents for Magnetic Resonance Imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance Public Health Advisory. Food and Drug Administration Web site. Available at: http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm. Accessed March 19, 2008. Information on Gadolinium-Containing Contrast Agents. Food and Drug Administration Web site. Available at: http://www.fda.gov/CDER/DRUG/infopage/gcca/default.htm. Accessed March 19, 2008. Kanal E, Barkovich AJ, Bell C et al. ACR Blue Ribbon Panel on MR Safety. ACR guidance document for safe MR practices: 2007. Am J Roentgenol. 2007;188:1447-1474.
30	References Kanal E, Broome DR, Martin DR, Thomsen HS. Response to the FDA's May 23, 2007, nephrogenic systemic fibrosis update. Radiology. 2008;246:11-14. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. National Kidney Foundation Web site. Available at: http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm. Accessed March 19, 2008. Okada S, Katagiri K, Kumazaki T, Yokoyama H. Safety of gadolinium contrast agent in hemodialysis patients. Acta Radiol. 2001;42:339-341. Nephrogenic Systemic Fibrosis (NSF) and gadolinium-containing MRI contrast agents: Public Assessment Report, Questions and Answers, and Dear Healthcare Professional Communication. MHRA=Medicines and Healthcare products Regulatory Agency Web site. Available at: http://www.mhra.gov.uk/SearchHelp/Search/Searchresults/index.htm?within=Yes&keywords=nsf. Accessed March 19, 2008.
31	References Nephrogenic Systemic Fibrosis (NSF) with gadolinium-containing magnetic resonance imaging (MRI) contrast agents – Update. MHRA=Medicines and Healthcare products Regulatory Agency Web site. Available at: http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON2031543. Accessed March 19, 2008. Update on Magnetic Resonance Imaging (MRI) Contrast Agents Containing Gadolinium and Nephrogenic Fibrosing Dermopathy Public Health Advisory. Food and Drug Administration Web site. Available at: http://www.fda.gov/CDER/DRUG/advisory/gadolinium_agents_20061222.htm. Accessed March 19, 2008.