Contrast-enhanced MRI: how do changing EU regulations impact daily practice?

Transcription

1 Safety considerations in contrast enhanced procedures Carlo Catalano Sapienza University of Rome Contrast-enhanced MRI: how do changing EU regulations impact daily practice?

2 CE MRI: EU regulations - Initial approval More than administrations worldwide - Very low rates of immediate adverse events (lower than most pharmaceuticals and iodinated C.A.) - Traces of Gd remain in the bone, brain and other tissues in Pts with normal renal function - The relationship between GBCA exposure, retention and symptoms is unclear

3 Sapienza Department of Radiology - 6 MR Systems: - Two 3 Tesla Systems (1 Neuro and 1 Body) - Four 1,5 Tesla Systems (1 Neuro and 3 Body) - Appr Exams annually - Appr. 70% of Exams with i.v. contrast - Contrast agents selected depending on the clinical indication

4 Sapienza Department of Radiology Magnetic Resonance Contrast Agents - Clinical perspective - Safety aspects adverse events - Financial economic aspects

5 Sapienza Department of Radiology Magnetic Resonance Contrast Agents Clinical indications Safety

6 Sapienza Department of Radiology Magnetic Resonance Contrast Agents Clinical indications Safety LOWEST POSSIBLE Gd DOSE

7 Sapienza Department of Radiology Magnetic Resonance Contrast Agents Clinical Indications - Neuro Imaging - Body Imaging - Vascular Imaging

8 MultiHance

9 Relaxivity comparisons at 1.5 T and 3T

10 MR Angiography with high relaxivity Gd-based c.a. 46 pts two identical MRA with different contrast protocol (13.8± ml/s Vs 27.6±5 2.8 ml/s) The image quality and diagnostic performance achieved with 0.1-mmol/kg gadobenate dimeglumine is at least equivalent to that achieved with 0.2-mmol/kg gadopentetate dimeglumine. LESS Gd DOSE (lower NSF risk, lower load) LOWER INJECTION VEL. (discomfort, poor IV access) AJNR Am J Neuroradiol 34: Apr 2013 LOWER Gd-BOPTA COSTS Vs. Gd-DTPA: lower dose with higher intravascular signal and SNR Radiol Med. 2003, 106(1-2): /09/2018 Pagina 10

11 Gerretsen, et al. Radiology June 2010 MultiHance on left Magnevist on right 0.1 mmol/kg

12 Achenbach, et al. JMRI 2010; 32: MultiHance 0.05 mmol/kg (half-dose) Gadavist 0.1 mmol/kg

13 8 ml MultiHance

14 Ultra low-dose for myocardial infarction imaging European Journal of Radiology 83 (2014) FEASIBLE - SNR and Myo CNR was higher in 0.1mmol/Kg BW - No significant differences in CNR IM/LVC for - Half Dose 5 min Vs. Stand Dose 10, 15 and 20 min - HD 10 min Vs. SD 15 and 20 min - Beneficial in patient with renal failure - Solution to identify subendocardial infarction Gd DOSE (0.05 mmol/kg BW) TIME (LGE 5-10 min after c.a.) COSTS 15/09/2018 Pagina 14

15 CMR for myocarditis diagnosis Lake Louise Criteria - MYOCARDIAL EDEMA: T2 RATIO >2.0 - EARLY Gd ENHANCEMENT: EGEr (Myo-to-MSK) LATE ENHANCEMENT: PATCHY, SUBEPI OR SEPTAL Friederich et al. White paper JACC 2009 Friederich et al., Circulation 1998 Laissy et al., Chest 2002 Abdel-Aty et al., J Am Coll Cardiol 2005 Gutberlet et al., Radiology 2008 Ro ttgen et al., Eur Radiol 2011 Chu et al. Int J Card Imag mmol/kg Gd-DTPA mmol/kg Gd-DOTA mmol/kg Gd-DTPA mmol/kg Gd-DTPA mmol/kg Gd-DTPA mmol/kg Gd-DTPA European Journal of Radiology 95 (2017) mmol/kg mmol/kg = 0.2 mmol/kg Gd-DTPA EARLY Localizer STIR T2w Cine-MR LGE before c.m. C.E. 0 3 min min 15/09/2018 Pagina 15

16 CMR for myocarditis diagnosis (EGEr > 4.0) Se: 0.61 Sp: 0.85 Ac: 0.70 European Journal of Radiology 95 (2017) /09/2018 FEASIBLE LOWER DOSE (0.1mmol/Kg Gd-BOPTA Vs. 0.2mmol/Kg Gd-DTPA) Despite the greater enhancement provided by gadobenate dimeglumine, the normalization of signal intensity measurements attenuates the effects of higher relaxivity.

17 Greater potential for dose reduction 0.1 mmol/kg Dotarem Anaplastic oligoastrocytoma Meningioma Metastases Relapsing brain metastasis 0.05 mmol/kg MultiHance

18 Breast MR 43-y.o. woman with 12-mm ILC Magnevist 0.1 mmol/kg MultiHance 0.1 mmol/kg Carbonaro L, et al. AJR. 2011;196:

19 Prostate MR mpmri: DCE capabilities -MORPHOLOGIC DESCRIPTORS: enhancement on fat supressed T1W/early substraction images -ANALYSIS OF TIME SIGNAL INTENSITY/[GD] CURVES -Qualitative curve shape analysis -Semi-quantitative -Full quantification with pharmacokinetic modelling Courtesy of A. Padhani

20 Prostate MR Case Example (Gd-DTPA) 63 y.o., PSA 10 ng(ml GS 7 (3+4)

21 Case Example (Gd-BOPTA) Explain cause of raised PSA 58 y.o. Pt, PSA 7ng/mL Definitive diagnosis GS 7 (3+4), pt2

22 - PRINCIPLES - HIFU is an Image-guided Intervention High Intensity Focused Ultrasound - Accurate Transcutaneous Ultrasound LocationCoagulative Necrosis - Real Totally Magnetic Time Thermal Feedback NON-INVASIVE Resonance - - Improved Safety and Efficacy Radioactive Decontamination - Low complication rates MR-Guided High-Intensity Focused Ultrasound: Current Status of an Emerging Technology. A. Napoli et al, CVIR 2013

23 DCE-MR in osteoid osteomas in a 22-yo male BASELINE 3y FOLLOW-UP MEAN VAS: 7 NIGHT VAS: 10 Napoli A et al: Radiology Oct: MEAN VAS: 0 NIGHT VAS: 0 since day 1 after Tx

24 DCE-MR in osteoid osteomas in a 22-yo male BASELINE 3y FOLLOW-UP Image courtesy: A Napoli, Rome MEAN VAS: 7 NIGHT VAS: 10 Napoli A et al: Radiology Oct: MEAN VAS: 0 NIGHT VAS: 0 since day 1 after Tx

25 Nephrogenic Systemic Fibrosis (NSF) ESUR classification of Gadolinium-based Contrast Agents: High-risk group (Simple Linear) Medium-risk group (Substitued Linear) Low-risk group (Macrocyclic) Omniscan MultiHance ProHance Magnevsit Primovist Dotarem (OptiMARK) ~580 unconfounded cases* (Vasovist) 0 unconfounded cases Gadovist ~4 unconfounded cases * Published, individual histologically-confirmed cases

26 CE MRA The initial approach: The more the better Journal of Cardiovascular Magnetic Resonance (2006) 8,

27 Published cases of NSF GBCA RISK SINGLE-AGENT NSF CASES (N) HIGH-RISK PATIENTS IN CLINICAL TRIALS (N) TOTAL EXPOSURE (N. of PATIENTS EXPOSED) OMNISCAN HIGH 438 N/A N/A MAGNEVIST HIGH 135 N/A >120 million OPTIMARK HIGH 8 N/A N/A MULTIHANCE MEDIUM 0 8,486 >29 million PRIMOVIST MEDIUM million GADOVIST LOW 3* million PROHANCE LOW 1 (disputed) 153 >21.6 million DOTAREM LOW million * Endrikat J et al. Invest Radiol. 2016; 51:537-43

28 NSF: not simply macrocyclic vs. linear Severe CKD (Stage 4 or 5; egfr <30 ml/min/1.72 m 2 ) Average volume of MultiHance administered: 23 ml Martin DR, et al. Radiology : Withdrawn because of lack of full accordance with the relevant institutional IRB protocol.

29 Restrictions on the use of linear gadolinium agents Feb 27th 2018 EMA July 7th 2017

30

31 Sapienza Department of Radiology Magnetic Resonance Contrast Agents Safety aspects: ESUR guidelines

32 ESUR guidelines on contrast agents Version 10.0 March 2018

33 ESUR guidelines on contrast agents Version 10.0 March 2018

34 How do changing EU regulations impact daily practice? We had to increase Gd-dose mmol/kg Macrocyclic instead of mmol/kg MultiHance in CE MRA Many patients feel uncertain and are afraid of any contrast agent Number of patients that refuse CM-Injection has increased dramatically Patients are not able to distinguish between linear and macrocyclic contrast agents now all contrast agents result in "Gadolinium Deposition Disease"

35 How do changing EU regulations impact daily practice? No more linear agents! Liver imaging Macrocyclic agents Dotarem Gadovist Prohance

36 Gd deposition - autopsy data

37

38 Gd-Deposition both in macrocyclic and linear Gd-Agents in patients with normal renal function

39 Radiology 06/2017

40 20 intravenous injections / 2.5 mmol gadolinium per kilogram (gadolinium-exposed group) or saline (control group) over a 26-day Six rats in each treatment group control gadodiamide-exposed gadobenate dimeglumine exposed gadobutrol-exposed gadoteridol-exposed) Unenhanced T1 signal intensities of the dentate nucleus were measured from MR images prior to GBCA injection and 3 days after final injection. Rat brain and renal, hepatic, and splenic tissues were harvested 7 days after final injection and subjected to inductively coupled plasma mass spectrometry and transmission electron microscopy for quantification and characterization of gadolinium deposits.

41

42 Dentate nucleus

43 Macrocyclic GBCAs: differences in Gd retention? Animals administered 20 GBCA injections over 5 weeks at 0.6 mmol/kg bodyweight per injection followed by 28 days recovery Bussi S, et al. JMRI 2018; 47:

44 Possible hypothesis Dotarem / Clariscan ProHance Gadovist Charge Negative Neutral Neutral Molecular weight Log P butanol:water More rapid clearance of ProHance due to: Lowest molecular size Highest lipophilicity Lowest viscosity Viscosity (mpa s) 2.0 [0.5 M] 1.3 [0.5 M] 4.96 [1.0 M]

45 AFTER the EMA decision Total: 16 ml ProHance

46 Subclavian steal syndrome 0.1 mmol/kg BW ProHance 3 ml ProHance Courtesy of Günther Schneider MD, PhD Saarland University Medical Center Homburg/Saar, Germany

47 Sapienza Department of Radiology Magnetic Resonance Contrast Agents Economic aspects: Costs - Increase in costs: We passed from a mean cost/exam of 16 to 25

48 Evaluating MR contrast agents Restrictions on the use of linear gadolinium agents A man who sees only one side of an argument is like a fish who sees the bait but not the hook

49 Priorities are to determine: - If Gd retention adversely affects the function of human tissues - If retention is casually associated with short or long-term clinical manifestations of disease - If vulnerable populations, such as children, are at greater risk for experiencing clinical disease

50 Thank you!