Post on 07-Jun-2020
Protocolli d’Impiego e Risultati Clinici
Maria Luisa De Rimini UOD Cardiologia Nucleare
AORN Ospedali dei Colli - Monaldi
Napoli
Utilizzo in SPECT e PET Pesaro
13 Settembre 2014
Rapiscan agonista selettivo A2A
Receptor
Subtype Response to an Agonist
A1 Slows AV / SA Nodal Conduction
A2A
Coronary Vasodlation
Sympathetic excitation
A2B Mast Cell Degranulation
A3 Bronchoconstriction ? Preconditioning?
Methylxanthines (caffeine, aminophyline) block adenosine receptors
Adenosine
Cell Membrane
Adenosine Regadenoson
A2A
Increase myocardial blood flow by 2 to 4-fold
Regadenoson was approved for clinical use in Europe in 2011
FDA Issues Warning on Regadenoson and Adenosine : pts with Unstable Angina
J Nucl Med. 2014;55:12N
Coronary Blood Flow J Nucl Cardiol 2007;14:514-520
Pilot Myocardial
Perfusion Imaging J Am Coll Cardiol.2005 6;46:2069-75
Caffeine Interaction J Am Coll Cardiol 2008;51:328-329
Asthma Safety J Nucl Cardiol 2008;15(3):329-36
COPD Safety J Nucl Cardiol 2008;15(3):319-28
Sub-maximal Exercise Safety J Nuclear Cardiol 2009; 65(16):63–72
ADVANCE MPI Trials*
Two randomised, double blind
studies in patients undergoing stress
myocardial perfusion imaging
J Nucl Cardiol 2007;14:645-658 J Am Coll Cardiol 2008;1:307-316
J Am Coll Cardiol Img 2009;2:959–68
Healthy Volunteer
Safety Study Gordi T Clin Pharmacokinet
2006;45:1201-1212
Renal Impairment J Clin Pharmacol 2007;47:825-833
Phase 1 Phase 2 Phase 3
* ADenosine Versus RegAdeNoson Comparative Evaluation for Myocardial Perfusion Imaging
Asthma / COPD J Nucl Cardiol 2012 Aug;19(4):681-92
Renal Impairment J Nucl Cardiol 2012 Apr;19(2):319-29
Caffeine J Nucl Cardiol 2011;18:759
Post - approval
Regadenoson-induced coronary hyperemia
Intr
aco
ron
ary
AP
V R
atio
Time (min)
Lieu HD et al. J Nucl Cardiol 2007;14:514-520
rapid onset of action
Rapiscan effect on CBF
ADVANCE MPI 2 (Adenosine vs. Regadenoson Comparative Evaluation for Myocardial Perfusion Imaging
Double-blind, randomized trial comparing image results in patients undergoing standard gated adenosine SPECT MPI who were then randomized in a 2:1 ratio to either regadenoson (N = 495) or a second adenosine SPECT (N = 260)
JJ Mahmarian et al JACC CI.2009
Total Perfusion Defect Size Relationship between the adenosine and regadenoson induced perfusion defect size (PDS)
ADVANCE MPI 2 (Adenosine vs. Regadenoson Comparative Evaluation for Myocardial Perfusion Imaging
Double-blind, randomized trial comparing image results in patients undergoing standard gated adenosine SPECT MPI who were then randomized in a 2:1 ratio to either regadenoson (N = 495) or a second adenosine SPECT (N = 260)
JJ Mahmarian et al JACC CI.2009
Ischaemic Defect Size Relationship between the adenosine and regadenoson induced perfusion defect size (PDS)
PD
S R
ega
de
no
son
PDS Adenosine
Side Effect Profile
AR with an incidence ≥ 5%
Iskandrian JNC 2007; 14:645
Cerqueira JACC Img 2008; 1: 307
N=1764 patients
Regadenoson in Europe: First- year experience of regadenoson stress
combined with submaximal exercise inpatients undergoing myocardial
perfusion scintigraphy Brinkert M, Reyes E, Underwood SR et al. Royal Brompton Hospital, London, UK 2013 under review
Cabrera R, et al. JNC February 2013 HR change SBP change DBP change
Bp
m/m
mH
g
Reg alone
Reg walk
P=0.001
Regadenoson + low-level exercise
n =887
n =485
Protocol
Cabrera R, et al. JNC February 2013
Variable (%) Reg alone Reg Walk P value
Chest pain 20 16 0.05
Flushing 14 10 0.02
Dizziness 5 10 0.001
Abdominal symptoms 21 12 0.001
Dyspnoea 54 56 0.4
Aminophylline use 11 6 0.001
P=0.47
P=0.006
Reg alone
Reg walk
%
Conclusion Among patients undergoing standard treadmill stress testing for MPI who do not reach THR, the administration of Reg at peak exercise is safe and without major adverse events. Future large prospective studies are warranted to further evaluate the off-label use of Reg in this setting.
Wael A, et al. Eur J Nucl Med Mol Imaging 2013;40:341
Exercise + Regadenoson
Reg. +++ Dyp - Ade -
Wael A, et al. Eur J Nucl Med Mol Imaging 2013;40:341
Exercise + Regadenoson
combining Reg with standard symptom-limited treadmill stress test is an efficient alternative and provides not only exercise functional capacity but also a diagnostic MPI by
inducing maximal hyperemia at the time of tracer injection
J Nucl Cardiol 2008
Circulation. 2014;130:350-379
Women capable of maximal exercise should have an exercise MPI, whereas those who are functionally incapable should undergo a pharmacological stress test with 1 of several vasodilator agents (ie, dipyridamole, adenosine, or regadenoson). When using Rb-82 or [13N]ammonia (N-13 ammonia) PET, absolute blood flow at rest and stress may be ascertained to provide
measurements of myocardial flow reserve.
Diagnostic evaluation algorithm for women presenting with suspected ischemic heart
disease (IHD) symptoms and intermediate IHD risk and intermediate-high IHD risk.
Mieres J H et al. Circulation. 2014;130:350-379
Copyright © American Heart Association, Inc. All rights reserved.
Pharmacological Stress Agent in MPI SPECT Studies with Radionuclides
Selective adenosine A2A receptor agonist
0 1 2 // 30 min
Radiotracer
Regadenoson (0.4 mg/5ml)
Saline injection (10-20 ml)
Monitor HR, BP and ECG
Single-dose, non-weight-adjusted (400mcg) Bolus
Radiopharmaceutical myocardial extraction directly proportional to CBF
Onset of action within 30 sec
Similar side effect profile to adenosine but better tolerability
99mTc – Tetrofosmin Vasodilator/Basal
Pre-Stent
Stent
82Rb PET Vasodilator/Basal
• Risoluzione spaziale e temporale
• Quantizzazione assoluta MBF – CFR
•Correzione Attenuazione
• Imaging Ibrido Di Carli MF, Hachamovitch R. Circulation 2007; 115:1464–80
PET/CT 82Rb
PET-CT
Bateman TM, et al. J Nucl Card 2006
PET vs SPECT: Higher Accuracy, Lower Radiation exposure
13 N-ammonia 82Rb 99mTcMibi/Tetr
Effetcive Dose (mSv) 0.74 – 2.48 2.5 – 4 10.7 - 16
Hardware: CdZnTe: Lower Dose
RF N13-
Ammonio O-15 Rb-82
T½ 9.96’ 2’ 76’’
Att.
(MBq) 370 700-1500 1100-1500
Uso Perfus. Perfus. Perfus.
Vantaggi MBF MBF
•MBF
•Prodotto da
generatore
PET Cardiaca
EJNMMI Vol.32, No 7; 2005
Flusso (ml/m) / Perfusione
PET Differente cinetica di ciascun tracciante
0
1
2
3
4
5
6
0 1 2 3 4 5 6
Absolute flow (ml/g/min)
Me
as
ure
d/m
od
elle
d f
low
82Rb
99mTc-MIBI MRI/CT contrast 18F-FBnTP
13N-ammonia 18F-Flurpiridaz
15O-water
PET o SPET con Quantizzazione? Differente cinetica di ciascun tracciante
EJNMMI Vol.32, No 7; 2005
Quantitative PET: MBF N-13 Ammonia
0 5 10 sec
20min – 60min
CT
Regadenoson 0.4 mg bolus
Flush N-13 Ammonia
Dynamic Stress PET
CT Scout
PET N-13 Ammonia
10 sec
N-13 Ammonia
Dynamic Basal PET
0 5 10 15 20 25 30
CT-AC
CT Angio
mdc 82 Rb
Rest PET
CT-AC Stressor
82 Rb
Stress PET
CT Scout
82Rb Fast Protocol 35’ Rest / Dypiridamole
10 sec 10 sec
0 5 10 15 20 25 30
CT-AC
82 Rb
Dynamic Basal PET
82 Rb
Dynamic Stress
PET
CT Scout
82Rb Fast Protocol 35’ Rest / Regadenoson
Regadenoson 0.4 mg bolus
10 sec 10 sec
Flush
Stent: Culprit Lesion
MVD
Phase Analisys
Vasodilator LVEF= 45% Basal LVEF = 48%
Stent: CDx e CX
US: FE del VS = 45%
MSCT: St. multiple non occlusive
Diabete da 7 a., no insulina
Dispnea da moderato sforzo
Prognostic Value
• Summed Scores SSS; SRS; SDS
N Mild-Moder Severe
SDS < 3 3 - 8 > 8
SSS < 4 4 -13 > 13
• LVEF; RWM; RWT; Volume
Berman DS et al. Am J Cardiol 2000;86:1171-1175
• % Extension
Path TID value: ≥1.18 men / ≥1.22 women
cCTA and SPECT MPI • Stress Test: 85% max HR • Pharmacologic Stress Test: Regadenoson 0.4 mg iv bolus Saline flush Radiotracer stress dose
20 sec
PET Summed Score di Perfusione e LVEF
Lertsburupa et al. JNC 2008
Inclusion criteria were prospective studies, observational studies, retrospective studies, and case series published in peer-reviewed journals, involving humans; using either Rb-82 PET, or technetium (Tc)-99m SPECT 2006 – marzo 2012
99mTc-Sestamibi stress G-SPECT: scan a 30’-45’: 82Rb PET:
Stress G-PET
•LVEF durante test iperemico
•LVEF post-stress (tardivo)
82Rb PET: migliore stima di patologia ischemica multivascolare o del Tr. Comune.
(Equilibrio Ischemico)
Joanne D Schuijf and Jeroen J Bax; Heart 2008;94;255-257
S. Dorbala et al. J Nucl Med 2007; 48:349–358
AHA Scientific Statement. Circulation 2002
GSPECT: Valore Prognostico Incrementale LVEF (<45%) e ESV (>70ml) Post-Stress
Predittori Indipendenti di Morte Cardiaca
Sharir T. et al. Circulation 1999
SSS < 4 (Equilibrio Ischemico)
TID vn 0.98-1.13
AHA Scientific Statement. Circulation 2002
7% pz con MVD: Perfusione omogenea
Perfusione + LV EF: Definizione di equilibrio ischemico nel 100% pz
Stress 82Rb GPET
LVEF durante test iperemico
Lertsburapa et al. JNC 2008; 15:745-753
Prognosi
J Nucl Cardiol February 2014, Volume 21 pp 4-16
Circulation. 2014;129:2518-2527
CMD = CFR <2.0
• CFR: powerful incremental predictor of MACE (hazard ratio, 0.80 [95% confidence interval, 0.75–086] per 10% increase in CFR; P<0.0001)
• CFR: favorable net reclassification improvement (0.280 [95% confidence interval, 0.049–0.512]), after adjustment for clinical risk and ventricular function
Conclusions The high prevalence of CMD in both sexes suggests that it may be a useful target for future therapeutic interventions
Gender Tot pts CMD
Men 405 51%
Women 813 54% Regardless of sex:
Circulation. 2014;129:2518-2527
…. there is now increasing evidence using both
SPECT and PET techniques, to suggest that a
‘‘warranty period’’ of 2 years (e.g., \2% risk of
death ? MI) following normal MPI may be extended
to [3 years or shortened to \1 year according to the
corresponding MFR results
deKemp et al Journal of Nuclear Cardiology July/August 2011
STRESS TIME
O2
DEMAND
Chest pain Global dysfunction
Wall motion abnormality
Perfusion
heterogeneity
Ischemic Cascade
"The strenghts of MPI”
Imaging and Ischemic Cascade
Majmudar MD, Nahrendorf M, J Nucl Med Vol. 53 • No. 5 • May 2012
Oltre la Punta dell’Iceberg
PET: Quantizzazione assoluta MBF (ml/m)
Macro 2,5mm Micro <300mm
N Engl J Med. Feb. 2007; 356
•Funz. Endoteliale
• Microcircolo
• Ris. coronarica
• Circoli collaterali
Tio RA et al., J Nucl Med 2009
CAD Patients
CAD Patients with Ischemia
Herzog BA et al., JACC 2009
Valore prognostico della Riserva di Flusso Coronarico PET
A total of 7,061 patients from 4 centers underwent a clinically indicated rest/stress rubidium-82 PET MPI, with a median follow-up of 2.2 years. The primary outcome of this study was cardiac death (n 169), and the secondary outcome was all-cause death (n 570)
Dorbala S et al. JACC Vol. 61, No. 2, 2013;
Regadenoson PET
%
N=134 patients
Ali et at. J Nuc Med 2013
The short duration of maximal hyperemia with regadenoson (2.3 min), combined with the short half-life of 82Rb (76s), are potential challenges to optimal regadenoson 82Rb imaging
….studies confirm that the hyperemic response of Regadenoson is comparable to that of dipyridamole during 82Rb MPI…..the clinical efficacy of Regadenoson as a vasodilator stress agent, when used with relative 82Rb MPI in a much larger cohort of patients, applying obstructive CAD on angiography as the gold standard.
J Nucl Med 2013;54:1748-1754
LVEF reserve is high in patients without significant ischemia or significant angiographic jeopardized myocardium
** *
Coronary Blood Flow Regadenoson vs Adenosine in Awake Dogs
40
80
120
160
Baseline 0.1 500 10 1 100
Dose of agonist (µg/kg)
CBF
(ml/min)
***
***
***
***
***
***
Regadenoson
ED50 =0.34 ± 0.08 mg/kg
*** *** ***
***
Adenosine
ED50=51 ± 15 mg/kg
Δ = 150 fold
Trochu JN et al. J Cardiovasc Pharmacol 41:132-39, 2003
R-R (ms) QT (ms) QTcF (ms)
Baseline 3 min Baseline 3 min Baseline 3 min
Regadenoson
(µg/kg)
2.5 699 ± 42 549 ± 50* 237 ± 6 223 ± 3* 268 ± 5 273 ± 5
5.0 701 ± 46 489 ± 23* 241 ± 5 217 ± 6* 272 ± 3 277 ± 6
10.0 675 ± 46 424 ± 17* 239 ± 9 212 ± 3* 273 ± 7 282 ± 7
Values are mean ± SEM, *) p<0.05, QTcF = QT/(R-R) 1/3
Modified from Gong Z. et al. JCP, 2008
Effects of Regadenoson on Heart Rate (R-R) and QT Interval
82Rb PET Rest / Regadenoson
Scan Protocol
TID
J Nucl Med 2013;54:1748-1754
Regadenoson LVEF reserve as function of Duke Jeopardy Score. LLK = low likelihood
J Nucl Med 2013;54:1748-1754
Fusi
on
F
DG
-PET
T
rue
FISP
MR
I
courtesy Markus Schwaiger
Population 10 pts: Reversible ischemia at SPECT MPI
N-13 ammonia/ MR Gd - Regadenoson
Sens. 100% Spec 80% NPV 100%
This allows us to predict or rule out CAD with more certainty, and in some instances, it allows us to detect disease processes such as areas of hibernating heart muscle that would not have been detected using conventional stress testing methods like SPECT
Jeffrey M.C. Lau
SNMMI 2014: PET/MR for detecting Coronary Artery Disease