NSF Coming and Going

Transcription

1 NSF Coming and Going Martin R. Prince, MD, PhD Cornell and Columbia Universities Patent agreements: GE, Philips, Siemens, Hitachi, Medrad, Epix, Lantheus, Bayer, Bracco, Nemoto, Mallinckrodt and Topspins Papular morphology Dimpling

2 NSF key points To prevent NSF Identify at risk patients: GFR< 30 ml/min, acute For these at risk patients verify Gd is necessary avoid high Gd doses (use 0.1mMol/kg or less) hand inject, experienced technologists For dialysis patients do MRI just before dialysis appt Virtually no new cases in 2008 or 2009! Nonionic linear Gd more reports of NSF Gadobenate Dimeglumine (ionic linear Gd) more reports of death (anaphylaxis)

3 Cases of NSF by Date of Onset* Gadodiamide Gd:DTPA < FDA & EMEA warnings

4

5 NSF: Association With Renal Disease GFR< 30 ml/min Stage I Stage II Stage III Stage IV Stage V GFR Dialysis CKD, chronic kidney disease; egfr, estimated glomerular filtration rate; PD, peritoneal dialysis Issa N et al. Cleve Clin J Med. 2008;75:

6 NSF: Clinical Images Areas of thick, hardened skin, commonly associated with brawny hyperpigmentation, and preferentially localized to the extremities Extensive thickening of the skin, peau de orange appearance and in some cases, distinct papules and subcutaneous nodules Mendoza FA et al. Sem Arthritis Rheum. 2006;35:

7 some patients with NSF (estimated at 5% or less) have an exceedingly rapid and fulminant disease course. Cowper et al

8 NSF major risk factors GFR < 30ml/min high dose pro-inflammatory thrombosis Biopsy site surgery trauma SLE inpatient >>. outpatients

9 Peau D orange Skin thickening

10 Skin features Papular morphology Dimpling

11 Joint Contractures Jeuvenile NSF Rheumatoid Arthritis

12 Cornell & Columbia All GBCA Total 15/83121 Standard dose 0/74124 High dose 15/ % egfr > 30 ml/min 0/ < egfr < 30 ml/min 2/ % egfr < 15 ml/min (no dialysis) 10/ % C = chronic hemodialysis* 1/ % chronic peritoneal dialysis 0/19 egfr< 30 ml/min w/o ARF 4/ % w/ ARF 11/ % ARF during rising creatinine and no dialysis for > 2 days 11/58 19% Radiology 2008;248

13 Cornell 1 case Exams with high dose Gd & GFR<30 = 284 Hospital MRI = 1 Outpatient MRI = 2 Time to exam = 3d Earlier use of dialysis Columbia 14 cases Exams with high dose Gd & GFR<30 = 507 Hospital MRI = 3 Outpatient MRI = 1 Time to exam = same day Higher threshold to initiate dialysis

14 Cornell & Columbia July 2006 to present July 2006 no Gd for GFR < 15 ml/min Dialysis after Gd in dialysis patients September 2007 careful for GFR < 30 ml/min Gadobenate Dimeglumine instead of Gadodiamide No cases of NSF since May, cardiac arrests and 1 death

15 NSF/NFD papers on Medline 200 n=424 Extrapolated from Jan Aug # of Papers Year

16 80 papers 292 NSF cases all biopsy confirmed 64 papers had data on the relationship of GBCA and NSF involving 243 patients. History of Gd exposure 220 Gd looked for but not found 23 Gd not discussed (16 papers) 49. Total = 292

17 Type of MRI scan (n=112) MRA 57 Brain 7 Pelvis 2 Liver 1 Abdomen 9 Lower extremity 4 MRCP 5 Spine 2 MRV 1 Multiple 23 DSA txp renal art. 1

18 Gadolinium dose Standard Dose (0.1mmol/kg): 23 High Dose (>0.15mmol/kg):164 Dose not specified: 56 Total 243 Multiple doses: 63 with at least 1 high dose: 55 only standard dose noted: 7 no dose noted 1

19 Gd Dose: Case Controlled studies Author # controls # with NSF GBCA dose controls GBCA dose NSF P Kallen ml 80 ml.01 Markmann mmol/kg Coolidge ml 0.23mmol/kg 0.44 mmol/kg 45 ml 0.39mmol/kg

20 Subsystolic Thigh Compression Thigh cuffs with extension tubing Inflation pressure = 60 mmhg Inflate just prior to mask acquisition Venous contamination is delayed calf station to 60 seconds

21 T = 0 Start Injection T = 18 s: 1 st station T = 41 s: 2 nd station 60 mm Hg A Curved Thigh Cuff for Suppressing Venous Enhancement on Peripheral MRA Honglei Zhang et al J. Cardoiovascular MR, 2007 T = 57 s: 3 rd station 57s 1:37min 2:17min 2:57min 3:37min

22 Subclavian Venography Inject both arms simultaneously with 20:1 Gd dilution with normal saline

23 Occluded Right Subclavian Vein

24 Gadolinium Chelate Type Gadodiamide: 163 Gadopentetate Dimeglumine: 10 Gadoversetamide : 5 Multiple: 7 Unknown type: 25 no gadolinium association 23 no mention of gadolinium: 49

25 Risk Factors: Chelate stability Chelates make Gd +++ chemically inert May allow Gd to enter cells (e.g. MultiHanc Allow rapid glomerular filtration half-life for excretion fecal elimination Normal renal function 1.5 hours negligible Moderate egfr hours 6% Severe egfr hours 9% egfr <15 but not on dialysis 34.3 hours Hemodialysis 2.6 hours Peritoneal dialysis 52.7 hours

26 Macrocyclic Complexes - OOC COO - - OOC N N Gd 3+ - OOC N N COO - - OOC N N Dotarem ProHance Gd-DOTA Gd-HP-DO3A COO - - OOC N N N Gd 3+ Gd 3+ N N - OOC OH COO - N Gadovist Gd-DO3A-butrol OH OH OH Linear Complexes COO - COO - - OOC Gd 3+ - OOC N N N COO - COO - CH 3 NHOC Gd 3+ - OOC N N N COO - CONHCH 3 Magnevist Omniscan Gd-DTPA Gd-DTPA-BMA Ionic nonionic

27 Transmetallation (Zn 2+, Cu 2+, Ca 2+, Fe 2+ Gd 2+ Zn 2+ Zn 2+ Gd 2+

28 Stabilty: Macrocyclic vs Linear chelates Kuo JACR 2008; 5:29-35

29 Why not switch to using Macrocyclic GBCA? * Recently cases reported with macrocyclics: ProHance and Gadovist FDA NSF mtg 12/8/09 ** Compounds with protein binding higher relaxivity and biliary excretion, have no cases of NSF reported: FDA NSF mtg 12/8/09 Gado trisodium (Ablavar) Gadoxetate trisodium (Eovist) Gadobenate Dimeglumine (MultiHance)

30 NSF: Change in incidence following a switch in gadolinium agents Altun et al Radiology 2009:253: Screen for at risk patients Gadobenate Dimeglumine maximum dose = 0.05 mmol/kg in at risk patients No cases of NSF in 549 at risk or on dialysis

31 Gadofosveset: 0.05 mmol/kg ~ 10ml 1x1.8x2.5 mm 3 1x1.8x2.5 mm 3 1x1x1 mm 3 Courtesy of Tim Leiner,

32 Risk Factors: Older Age is protective NSF Case Reports NSF Case Reports Columbia Gd MR GFR < < >90 Age (years) Age (years) < >90

33 Typical NSF Presentations (collected from 292 reported cases) Dialysis: 208/292 71% not specified 17 Hemodialysis 150 Peritoneal dialysis 37 CVVH 4 Renal transplant: 57/292 20% failing renal transplant: 34 12%

34 Radiology 2008;248: egfr < 15 ml/min (no dialysis) 10/ % Chronic hemodialysis 1/ %

35 Knopp et al Investigative Radiology 2006;41: Clinical Features of NSF Male: 136 Female: 116 Gender not specified: 30 SUM 45M 53 est 270M 318 Contractions: Limited range of motion: Death reported: 47 Death hastened by NSF: 2

36 US FDA Medwatch Database 2004 to /AdverseDrugEffects/ucm htm ~ 5 million reports outside US AE and NSF events excluded Gadobenate dimeglumine Gadoteridol Gd:DTPA Total AE hospitalized Death Gadodiami Market share Deaths per million doses

37 National Traffic Safety Administration in 1 million chance of death For every 78 miles driven in US

38 Adverse Reactions MRI centers Murphy et al. Academic Radiology 1999;6: Contrast agent: n AE rate Gadoteridol % nonallergi 0.35 total AE (Macrocyclic) 0.14% allergic 0.3 severe AE 0.02% severe Gd:DTPA 0.15 (linear ionic) % total 0.001% severe Gadodiamide % total (linear Gadoteridol nonionic) linear0.00% severe macrocyclic nonionic

39 Adverse Reactions > 1 million patients Murphy et al. Academic Radiology 1999;6: Katayama et al Radiology 1990; 175: total AE severe AE iodine ionic iodine nonionic Macrocyclic Linear ionic linear nonionic

40 Adverse Event Rates in 337,647 patients Ionic contrast agent: 12.66% Nonionic low osmolar agent: 3.13% Katayama et al Radiology 1990;175:616-8

41 Severe adverse events Ionic contrast agent: 0.22% Nonionic low osmolar agent: 0.04% Katayama et al Radiology 1990;175:616-8

42 nonionic contrast media significantly reduce the frequency of severe and potentially lifethreatening ADRs to contrast media at all levels of risk and that use of these media represents the most effective means of increasing the safety of contrast media examinations Katayama et al Radiology

43 Minimize Risk of NSF Ask about renal function Dialysis, Renal transplant If no known renal disease no change If egfr < 30ml/min or acute renal failure Monitor study to ensure Gd is necessary Use single dose Hand injection best technologist +/-Informed consent single dose risk < 1in10,000 If on dialysis schedule schedule MRI just before dialysis If patient has NSF do not give gadolinium

44 Summary NSF is disappearing Avoiding high dose reduces NSF risk Dialysis shortly after MRI reduces NSF risk NSF deaths < allergic reaction deaths Nonionic more reports of NSF but less adverse events & fewer deaths

45 NSF: proposed mechanism