New Developments / Technologies / Protocols in NC

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Marilynn Casey
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Honorarium Research / Advisor, Expert Services and Conferences in Nuclear Cardiology BMS, CVT, Astellas, Lantheus, PGx, IAEA

1 New Developments / Technologies / Protocols in NC João V. Vitola, MD, PhD Cardiologist and Nuclear Medicine Physician Quanta Diagnostico Nuclear Curitiba - Brazil DISCLOSURES Honorarium Research / Advisor, Expert Services and Conferences in Nuclear Cardiology BMS, CVT, Astellas, Lantheus, PGx, IAEA Royalties Publications in Nuclear Cardiology Springer-Verlag Verlag-Nuclear Cardiology and Correlative Imaging: a teaching file, NY, 2004 Lippincott Williams & Wilkins, - Nuclear Medicine teaching File,, 2009

2 To be discussed New Gamma Cameras: CZT technology New Hybrid systems: SPECT/CT and PET/CT 64 slices New Perfusion Tracer for PET - BMS New pharmacologic stressors the 2 min stress test: Regadenoson (FDA approved, n=784, USA, Brazil and Argentina) - bolus IV 400ug BMS Apadenoson - (PGx Health - Phase III, n = 753, USA and Brazil) bolus IV 100 or 150 ug

3 CZT Technology Ernest V. Garcia, PhD* Emory University School of Medicine Hi Joao, Please give my Cuban colleagues my best wishes for 2010! Ernie

4 Cadmium Zinc Telluride (CZT) - Direct Conversion Technology whose time has come Eliminates scintillation and photomultiplier tubes higher spatial resolution higher energy resolution smaller size Provides: improved image contrast improved multi-isotope imaging faster scanning / lower dose scans more flexibility in scanner design

5 Limitation of Conventional SPECT NaI(Tl) Crystal D e t e c t o r 1 Detector 2 Only a small portion of the NaI Crystal is used to view heart

6 Discovery NM 530c System Design Simultaneous Cardiac acquisition by all stationary detectors

7 Discovery NM 530c System Design m m 32 x 32 x 5 mm

8 Indirect vs. direct conversion Scintillator (e.g. NaI:Tl): kev Indirect X-ray or γ-ray e e Light generation Light transport Q.E. 20%-80% Charge generation Charge transport X-ray or γ-ray Noise Direct h hh h h ee e ee + anode - cathode electronics Direct Conversion (CZT): 30, kev CdZnTe Semiconductor Photosensor (PMT): 2000 photo-electrons Gain variation γ γ energy energy charge charge carriers carriers e e e e e e e e e e e e electronics Noise (APD/PD) Assuming no other sources of noise, Poisson statistics dictates energy resolution: γ γ energy energy light light photo-electrons photo-electrons

9 Energy Resolution CZT scintillator lightguide Energy Resolution for CZT is determined by: - crystal quality - incomplete charge collection PMT Energy resolution depends on - Light output of scintillator - Linearity & uniformity of scintillator - Uniformity of light collection - Quantum efficiency of PMT - Electronic noise Energy resolution can be improved by - Better scintillator - Better photosensor - Energy resolution can be improved by: - using perfect crystals - measuring and correction defects - compensating for incomplete charge collection: - using signal shape - using dual-sided readout: Anger 9.5% Alcyone 6.0% point sources in air 99m Tc: 140 kev 123 I: 159 kev kev 200

10 Spatial Resolution scintillator lightguide Not to scale PMT CZT Resolution for PMT based system is determined by: - Thickness of crystal (light spreading) - Size of PMT - Light output of scintillator - Optimization of light spread function - Position estimation algorithm Spatial resolution can be improved by - Segmenting scintillator - Smaller (or multi-anode) photomultipliers Resolution for CZT based system is determined by: - anode pitch - charge spreading Spatial resolution can be improved (somewhat) by: - using a smaller pitch - using proportional readout - more electronic channels

11 Discovery NM 530c System Design Multiple-Pinhole Collimator Design Front Tungsten 5mm pinhole inserts provide high energy collimation (I-123) and limits Pb x-rays (Tl-201) Back Thick Pb septa prevents crosstalk between detectors

12 Discovery NM vs. Ventri Energy Resolution FWHM/Peak Central (mm) Resolution Tangential (mm) Radial (mm) Point Kcts/min Sensitivity Phantom Kcts/min DNM 530c 5.7% Ventri 9.4% Ratio pinholes

13 Normal Example S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest

14 DNM 530c: Clinical Implications Fast min acquisitions Increase patient throughput Increase protocol flexibility Increase patient comfort and convenience Decrease patient radiopharmaceutical dose Decrease patient motion Simultaneous dual isotope imaging (= 10 X sensitivity) Potential to improve CFR calculations Significantly improve I-123 I (MIBG, BMIPP, rotenone ) imaging Improve bad beat rejection and diastolic function measurement (due to list mode acquisition)

15 Multicenter Comparison between DNM530c & Standard Dual Detector Cameras: Objectives (n=161) To determine diagnostic agreement between the new Discovery NM 530c (DNM530c) and standard dual detector cameras (S-SPECT) SPECT) in patients with known or suspected CAD. The secondary goals included the strength of agreement on a per-vessel analysis, the image quality, and the correlation of automated rest and stress left ventricular ejection fractions (LVEF).

Patient Example: Normal (male 5 6 5 176 lbs) S-SPECT

16 Patient Example: Normal (male lbs) S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest

17 Patient Example: Reversible LAD and RCA defects (male lbs) S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest

18 Abnormal Example S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest

19 Patient Example: Breast vs. Diaphragmatic Attenuation (female lbs) S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest

20 Patient Example: Fixed defects S-SPECT Discovery NM 530c 12 min stress/ 14 min rest 2 min stress/ 4 min rest

21 Image Quality Rest S-SPECTSPECT (n=330) Rest DNM530c (n=330) Stress S-SPECTSPECT (n=330) Stress DNM530c (n=330) Excellent 232 (70.3%) 275 (83.3%) 224 (67.9%) 282 (85.5%) Adequate 94 (28.5%) 47 (14.2%) 105 (31.8%) 41 (12.4%) Suboptimal 4 (1.2%) 8 (2.4%) 1 (0.3%) 7 (2.1%) Esteves et al. J Nucl Cardiol 2009, 16:

22 Conclusions about CZT A novel solid-state state-detector dedicated cardiac camera (DNM530c) has been developed by GE Healthcare and tested in a multicenter study. DNM530c provides rest/stress Tc-99m tetrofosmin myocardial perfusion images comparable to S-SPECT S SPECT at significantly shorter acquisition times.

23 Hybrid Technology PET/CT and SPECT/CT and New Perfusion Agent for PET ATEN. CORRECTION CALCIUM SCORE ANATOMY 64 SLICES PERFUSION (Absolute) VIABILITY LV FUNCT (True Str) Vitola JV, Cerci J, Delbeke D. PET/CT em Cardiologia, Ed. Revinter, Rio de Janeiro, 2010 (in Press)

24 CLINICAL CASES

25 Routine Attenuation Correction SPECT/CT Potential artifacts

26 Routine Attenuation Correction PET/CT Potential artifacts

27 55 yo, Family Hx, No Known CAD, Atypical Pain

29 AVAILABILITY OF PET TECHNOLOGY 2009 MOST FOR ONCOLOGY USE GE PH SI GE - 29 PH 19 SIEMENS 24

30 Future Direction for Cardiac PET Ideal PET MPI Imaging Agent High cardiac uptake with minimal redistribution Near linear myocardial uptake vs. flow up to 5 ml/min/g or more (high first pass extraction fraction) High target to non-target ratio (vs. lung, liver, bowel) Usable for both exercise and pharmacologic stress Usable for quantitation of absolute myocardial flow Available as unit dose ( 18 F-labeled compound) Adapted from: Glover, D and Gropler, R., J. Nucl. Card 14:6 p765-8 Ver. 18Aug 09

31 New PET perfusion tracer labeled with F-18F Chemical Structure of BMS Mitochondrial Complex 1 (MC-1) Inhibitor O N N C l O O 18 F 2-tert-Butyl-4-chloro-5-[4 [4-(2- (18F)fluoro-ethoxymethyl)-benzyloxy] benzyloxy]-2h-pyridazin-3-one Yu, et al., J Nucl Cardiol. 2007;14(6): Ver. 18Aug 09

32 First Pass Uptake in Isolated Rabbit Hearts 3 BMS (n=4) 201 Tl (n=3) Uptake m Tc-sestamibi (n=3) * * Coronary perfusion flow (ml/min/g) Yu, et al., J Nucl Cardiol. 2007;14(6): * Indicates p<0.05

33 Pre-Clinical Cardiac PET Imaging with BMS Normal Rat Coronary ligation in Rat Normal primate Yu, M et al. J Nucl Cardiol 2007, 14(6): Ver. 18Aug 09

34 Phase 1 Studies of BMS Study 101: Safety, dosimetry, and biodistribution. Single injection at rest. (n=13 healthy subjects) Study 102: Safety, dosimetry, and biodistribution. Separate day injection at rest and stress (12 subjects) Maddahi J, et al. JNM 2008 (abstract ) Ver. 18Aug 09

35 BMS Phase 1 Safety Independent Data Monitoring Committee and a renowned electrophysiologist reviewed the entire safety data-set None of the AEs were considered serious or related to study drug No clinically significant changes in Physical and neurological exams (incl. EEG) Vital signs Clinical labs (incl. Cardiac enzymes) no safety concerns and no warnings in ECG data Individual subjects had non-consistent single time-point QT/QTc prolongation Maddahi J, et al. JNM 2008 (abstract ) Ver. 18Aug 09

36 21 min. 35 min. 165 min. 202 min. 21 min. 35 min. 165 min. 202 min. Exercise BMS Adenosine Maddahi J, et al. JNM 2008; abstract

37 Summary and Conclusions Phase 1 BMS Highest dose organ: Stress (pharmacologic and exercise): heart Rest: kidneys Dosimetry is within the clinically acceptable range No adverse events related to the tracer were noted Stress imaging is feasible with both treadmill exercise and pharmacologic vasodilation Myocardium is clearly visualized for several hours after rest and stress injection with good myocardial to background ratio Five minute gated acquisition - starting 2 minutes after injection - yields high quality images Maddahi J, et al. JNM 2009

38 BMS Phase 2 Clinical Studies BMS (first in patient) Cohort 1: develop a one-day rest/stress imaging protocol; safety Patients with reversible defects on SPECT Cohort 2: assess diagnostic efficacy compared to SPECT in detecting CAD; safety Patients classified as low, intermediate or high pre-test likelihood (ACC/AHA Guidelines for exercise testing) Ver. 18Aug 09

Study 201 - Patient 006-003 003 Stress BMS747158 SA Rest Stress Rest

39 Study Patient Stress BMS SA Rest Stress Rest BMS HLA BMS VLA Stress Rest Stress Rest J. Maddahi, UCLA 39 Ver.18Aug 09

40 Phase III Ongoing discussion regarding protocol Compare MIBI SPECT vs 18 F BMS PET Latin American Patients first visit Brazil Feb / 2010 Goal to start second semester 2010

41 New Pharmacologic Stressors: A 2a N = 784 J Nucl Cardiol 2007; 14: Regadenoson (Lexiscan) FDA approved in April 2008

42 WHAT DO WE KNOW NOW? REGADENOSON = ADENOSINE IDENTIFY INDIVIDUALS WITH ISCHEMIA QUALITY OF IMAGES SOME POTENTIAL ADVANTAGES TO BE DISCUSSED

43 New Perspectives Bolus administration

44 Regadenoson-induced Blood Flow Time to 2.4-fold above baseline: 33 sec Duration at 2.5-fold above baseline: 2.3 min 3.5 Window for Tracer Uptake mcg regadenoson APV ratio Time (min) Lieu HD, et al. J Nucl Cardiol. 2007;14(4):

46 How do Patients Feel Compared to Adenosine?

47 84% equal or better

48 New Perspectives Bolus administration Standard dose

49 Standard dose 400 ug independent of body weight Rational Receptor binding = First pass phenomenon Initial experience - works regardless of body weight further evaluation desirable

50 New Perspectives Bolus administration Standard dose Selectivity and low to moderate receptor binding affinity

51 Selectivity Xu Circ 2000

52 Selectivity A 1 A 2B A 3 A 2A Undesirable effects (eg, AV block) Undesirable effects (eg, bronchospasm) Increase coronary blood flow

53 Selectivity Gao Journal of Pharm Exp Ther 2001

55 Selectivity A 1 A 2B A 3 A 2A Undesirable effects (eg, AV block) Undesirable effects (eg, bronchospasm) Increase coronary blood flow

56 Perspective to apply in COPD Various types of COPD patients Limited data still needs caution Further studies, larger experience is needed What is the literature showing?

57 New Perspectives Bolus administration Standard dose Selectivity and low to moderate receptor binding Special issues Potential to combine with exercise

58 Cortes Tomográficos-Referência Potential for on the fly protocol Eixo Curto Eixo Longo Vertical 30 secs from peak hyperemia Pts on meds Depressed chronotropic response Effects of Max Hyperemia on MPI Sensitivity? Eixo Longo Horizontal

59 Selective A 2A Adenosine Receptor Agonists NH 2 HO NH 2 N N N N O OH OH HO N O N NH HO N N H 2 N OH N N O N OH N N N N Binodenoson H 3 C O O H 3 C Apadenoson H N H N NH 2 N N N N O O OH OH Adenosine HO OH O Regadenoson CH 3 Zablocki J et al. Nucleosides Nucleotides Nucleic Acids. 2001;20: Gao Z et al. J Pharmacol Exp Ther. 2001;298:

60 Potential Apadenoson Protocol Fixed doses100 µg (< 100 kg) or 150 µg (> 100 kg) Bolus apadenoson Saline flush Inject tracer Minutes Adapted from Hendel RC et al. Abstract presented during the 2005 Annual Scientific Sessions of the American Heart Association. Dallas, Texas.

61 Phase III Apadenoson Goal of 753 patients Compare adenosine to apodenoson (1:2) 75 US and 20 Brazil centers Goal to start second semester 2010

62 Selective A 2A Adenosine Receptor Agonists Conclusions Regadenoson is similar to adenosine to detect ischemia. Apadenoson will be tested in Phase III. Regadenoson has the advantage of bolus administration and less side effects than adenosine. Apadenoson also bolus. Potential for utilization in COPD patients. Potential for combination with exercise new protocols Regadenoson FDA approved in Will cost allow wide spread utilization?

João V. Vitola, MD, PhD

Pharmacologic Stress using A2a Agonist João V. Vitola, MD, PhD Cardiologist and Nuclear Medicine Physician Quanta Diagnostico Nuclear Curitiba - Brazil DISCLOSURES Honorarium Research and Conferences in