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Beyond NSF: Acute GBCA adverse reactions

Martin R. Prince, MD, PhD, FACR

DimplingPapular morphology

Nephrogenic Systemic Fibrosis (NSF)

DisclosuresPatent Agreements: GE, Siemens, Philips, Hitachi,

Toshiba, Bayer, Bracco, Mallinckrodt, Medrad, Nemoto, Topspins, Epix, Lantheus

•

NSF Associations• Renal Failure: 80% on dialysis • Pro-inflammatory Conditions• Acidosis• Hyperphosphatemia• Epoetin• Gadolinium Contrast Agents

– High dose– Nonionic

JMRI 2009;30:1298-1308

RSNA 2010: Ayako Taketomi-Takahashi et. al.

13,252 GBCA enhanced examsAgent: Incidence of Reaction typeGadodiamide 0.14% nonionic linearGd:DTPA 0.55% ionic linearGd:DOTA 0.34% macrocyclic ionGadoteridol 2.32% macrocyclic non

History of Gd rxn 21% pooled

Adverse Reactions - 105 MRI centersMurphy et al. Academic Radiology 1999;6:656-664

Contrast agent n AE rateGadoteridol 64005 0.27% nonallergic(Macrocyclic) 0.14% allergic

0.02% severe

Gd:DTPA 687555 0.067% total(linear ionic) 0.001% severe

Gadodiamide 74275 0.031% total(linear nonionic) 0.00% severe

00.050.1

0.150.2

0.250.3

0.350.4

0.45

Macro-cyclic

Linearionic

Linearnonionic

total AEsevere AE

(These AE rates are specific to the experience at the institutions studied in this publication.)

Contrast agents

# of Exams

Mild AE

Moder-ate AE

Severe AE

All events Events per 1000 injections

Arrest, death

Gadobenate(Multihance)

33,114 31 7 3 41 1.2* 3

Gd: DTPA(Magnevist)

66,157 26 6 0 32 0.5 0

Gadodiamide(Omniscan)

55,703 8 1 0 9 0.2 0

Gadoteriodol(Prohance)

3371 8 2 1 11 3.3 0

Total 158,796 73 16 4 93* 0.6 3

Adverse events in 158,796 GBCA administrations

*statistically significantly higher than Gd:DTPA and gadodiamide with p < 0.001

AJR 2011:196:w138-143AJR 2011;196:138-143

Comparison of adverse event patients with age/exam matched controlsAE Patients (n = 94) Controls (n = 94) p-value

Gender (f/m) 72/22 = 3.3 49/45 = 1.1 < 0.001 (w/Yates)

Weight (lbs) 157 37 163 42 0.6

Creatinine (mg/dL) 0.89 0.31 0.97 0.05 0.4

Mean Gd Dose(mL) 17.0 7.8 18.4 9.3 0.24

Asthma 8 2 0.1

Prior Gd exposure 51 48 0.8

Prior Gd reaction 8 0 0.007 (Fisher’s exact)

Prior allergic event 38 16 < 0.001

Inpatient 6 8 0.8

Steroid pre-treatment

4 0 0.1

Rate of GBCA adverse events by type* of MRI examinationType of GBCA-enhanced exam

# of Exams # of Reactions Reactions/10,000 Exams

Brain 72,756 33 4.5

Orbit/Face/Neck 3940 3 7.6

Spine 23,656 8 3.4

Cardiac 7328 4 5.5

Breast 4304 4 9.3

Abdomen 20,992 28 13**

Pelvis 7328 4 5.5

Extremity 4492 4 8.9

MR Angiography 14,000 6 4.3

Total 158,796 94 5.9

* When > one type of study was performed with a single injection, the study was only counted once based upon the primary reason. * *statistically significantly higher rate compared to brain (p < 0.001)

US FDA Medwatch Database

2004 to 2009www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformationInformatio

n/Surveilance/AdverseDrugEffects/ucm082193.htm

• All spontaneous reports of adverse events to the FDA are entered into an Adverse Event Reporting System (AERS) • AE occurred outside US and NSF excluded

Market Share Data• available from IMS Health Incorporated (www.imshealth.com), provided directly by companies in the form of liters of GBCA sold each year.• Converted into doses administered by dividing the total volume sold for each agent by 17 mL• Each manufacturer contacted for doses administered each year to verify IMS data

Adverse events in USA reported to Food and Drug Administration from 2004-2008 (excluding NSF)

Gadobenate dimeglumine

Gadoteridol Gd:DTPA Gadodiamide Optimark

Death 8 4 23 3 1Doses (millions)

2.2 2.4 22 12.2 4.5

Deaths per million doses

3.6 1.7 1 .2 .2

AJR 2011:196:w138-143

Comparison between local reports and FDA Local: adverse events/1000 injectionsFDA: deaths/million

00.5

11.5

22.5

33.5

4

Gadobenate Gd: DTPA Gadodiamide

Gadobenate dimeglumine (Multihance)

more severe AEs (1 death)

FDA data more deaths with Gadobenate dimeglumine

Gadobenate contraindicated if prior Gd rxn

Incidence of death (Gd) < 1/million

(comparable to the risk of death from a car accident if driving 78 miles)

Gadolinium based contrast agents are extraordinarily safe

One in 1 million chance of death

• Driving 78 miles (~100 kilometers)• One chest X-ray• Smoking 1.4 cigarettes• Drinking 1.5 bottles of wine

National Tranportation Safety Board 2008

ACR manual on Radiation Safety

http://tobaccodocuments.org/lor/03732381-2387.html

http://www-nrd.nhtsa.dot.gov/Pubs/811291.PDF

18

Pooled Data from 7 Studies

Murphy, et al. Acad Radiol. 1999;6:656-664.

Li, et al. Br J Radiol. 2006;79:368-371.

Dillman. et al. AJR. 2007;189:1533–1538.

Bleicher, et al. AJR. 2008;191:W307-311.

Abujudeh, et al. AJR. 2010;194:430-434.

Forsting, et al. Eur J Radiol. 2010. 74:e186-192.

Morgan, et al. Radiology. 2011; 259:109-116.

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Pooled Data from 7 Studies(numbers in green are our data)

GBCA Injections Non-severe%

Severe%

Total 999,808 0.08 (0.06) 0.004 (0.003)

Gadopentetate 715,211 0.02 (0.05) 0.0007 (0)

Gadodiamide 74,275 0.02 (0.02) 0 (0)

Gadoteridol 94,185 0.36 (0.3) 0.02 (0.03)

Gadobenate 28,256 0.6 (0.1) 0.04 (0.009)

Gadobutrol 14299 0.5 0.01

Unspecified 87,881 0.1 0.006

Courtesy of HL Zhang, MD

Leiner & Kucharczyk JMRI special issue on NSF

2009:30:1233-5

“Risk is relative, not absolute.

Not only is the risk of NSF small

compared with the risk of CIN

but also with risk of severe

allergic reactions…”

ionic vs. nonionicin 337,647 patients

Katayama et al Radiology 1990;175:616-8

Total 12.66% 3.13% 0.22Severe 0.22% 0.04% 0.19Very severe 0.04% 0.004% 0.10Death* n = 1 n = 1

* Death rate ~ 6/1 million

(These AE rates are specific to the experience at the institutions studied in this publication.)

Ionic Nonionic odds ratio

“…nonionic contrast media significantly reduce the frequency of severe and

potentially life-threatening ADRs to contrast media at all levels of risk and…use of these media represents the most effective means of increasing the safety of contrast media

examinations”

Katayama et al Radiology 1990;175:616-8(These AE rates are specific to the experience at the institutions studied in this publication.)

Adverse reactions: Iodinated contrast vs. GBCA

Hunt, AJR 2009; 193:1124–1127

Nonionic Iodine

GBCA

Total dose 298,491 158,439# Reactions 458 (0.15%) 64 (0.04%)- Need treatment 79 (0.03%) 15 (0.01%)- Severe 15 (0.005%) 4 (0.0025%)Death 1 (0.00034%)

Risk factors• Previous reaction to GBCA• H/O asthma and other allergies• Previous allergic reactions to iodinated

contrast agents

Suggestions on how to prevent adverse events

• Outpatient center: NSF is rare, code = 911– ACLS trained radiologists– Crash cart– Run Mock codes– Consider nonionic Gadolinium– prefer hand injection; avoid remote power injection

• Hospital based MRI: code team readily available– Consider ionic and macrocyclic agents

• Only one GBCA consider nonionic Macrocyclic

Summary• Gadolinium is extraordinarily safe

– but• Allergic Reactions can be lethal:

– Most acute reactions are mild– Severe reactions can be life threatening– Crash Cart, ACLS training, mock codes– Consider nonionic Gd when GFR >30

especially in outpatient imaging centers where code team is 911

– Consider nonionic macrocyclic if GFR< 30