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