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Pharmacologic Stress using A2a Agonist
DISCLOSURESDISCLOSURESHonorarium Honorarium –– Research and Conferences in Nuclear CardiologyResearch and Conferences in Nuclear Cardiology
BMS, CVT, BMS, CVT, AstellasAstellasInternational Atomic Energy AgencyInternational Atomic Energy Agency
Royalties Royalties –– Publications in Nuclear CardiologyPublications in Nuclear CardiologySpringerSpringer--VerlagVerlag--Nuclear Cardiology and Correlative Imaging: a teaching file,Nuclear Cardiology and Correlative Imaging: a teaching file, NY, 2004NY, 2004LippincottLippincott Williams & Wilkins, Williams & Wilkins, -- Nuclear Medicine teaching FileNuclear Medicine teaching File, 2009, 2009
JoãoJoão V. Vitola, MD, PhDV. Vitola, MD, PhD
Cardiologist and Nuclear Medicine Physician Cardiologist and Nuclear Medicine Physician Quanta Quanta DiagnosticoDiagnostico NuclearNuclear
CuritibaCuritiba -- BrazilBrazil
J Nucl Cardiol 2007; 14:645-58
Regadenoson FDA approved in April 2008N = 784
Phase 3 Studies: ADVANCE MPI 1 and 2Phase 3 Studies: ADVANCE MPI 1 and 2
•• ADADenoscan enoscan VVersus ersus RRegegAAdenosodenosoN N CComparative omparative EEvaluation for valuation for MMyocardial yocardial PPerfusion erfusion IImagingmaging
•• Two phase 3, randomized, doubleTwo phase 3, randomized, double--blind blind studies in patients undergoing stress MPIstudies in patients undergoing stress MPI
•• N=2015N=2015 with known or suspected CAD with known or suspected CAD indicated for pharmacologic stress MPIindicated for pharmacologic stress MPICerqueira M et al, for the ADVANCE MPI Investigators. JACC: Cardiovasc Imaging. 2008.
WHAT DO WE KNOW IN 2009 ?WHAT DO WE KNOW IN 2009 ?
REGADENOSON = ADENOSINEREGADENOSON = ADENOSINE
•• IDENTIFY INDIVIDUALS WITH ISCHEMIAIDENTIFY INDIVIDUALS WITH ISCHEMIA•• QUALITY OF IMAGESQUALITY OF IMAGES•• SOME POTENTIAL ADVANTAGES TO BE DISCUSSEDSOME POTENTIAL ADVANTAGES TO BE DISCUSSED
New PerspectivesNew Perspectives•• BolusBolus administrationadministration
RegadenosonRegadenoson--induced Blood Flowinduced Blood FlowTime to 2.4-fold above baseline: 33 secDuration at ≥2.5-fold above baseline: 2.3 min
0 2 4 6 8 10
APV
ratio
1.0
1.5
2.0
2.5
3.0
3.5
Time (min)
400 mcg regadenoson
Lieu HD, et al. J Nucl Cardiol. 2007;14(4):514-520.
Window for Tracer Uptake
***
***
Time to 2.4-fold above baseline: 33 sec
Bolus Administration
Speeds Stress – Potential for a 2 - 3 min Stress TestEasier than adenosine pump
HowHow do do patientspatients feelfeel comparedcompared to to adenosineadenosine ??
84% equal or better
New PerspectivesNew Perspectives•• BolusBolus administrationadministration•• Standard doseStandard dose
Standard dose 400 Standard dose 400 ugug independentindependent ofof bodybody weightweight
RationalRational
Receptor Receptor bindingbinding = = FirstFirst passpass phenomenonphenomenonInitialInitial experienceexperience -- worksworks regardlessregardless ofof bodybody weightweight
furtherfurther evaluationevaluation desirabledesirable
New PerspectivesNew Perspectives
•• BolusBolus administrationadministration•• Standard doseStandard dose•• SelectivitySelectivity andand lowlow to to moderatemoderate receptor receptor bindingbinding affinityaffinity
Xu Circ 2000
SelectivitySelectivity
ADVANCE MPIADVANCE MPIChange in Systolic BP from BaselineChange in Systolic BP from Baseline
* Post-infusion for adenosine and post-bolus for regadenoson
-25-20-15-10-505
1015
0 5 10 15 20 25 30 35 40 45Time post Dosing* (min)
SBP
Chan
ge fro
m Ba
selin
e, mm
HgDecrease by 3 mmHg
Decrease by 7 mmHg
AdenosineRegadenoson
Courtesy Dr. Manuel Cerqueira, Cleveland
A1 A2BA3
Undesirable effects (eg, bronchospasm)
Undesirable effects (eg, AV block)
A2A
Increase coronary blood flow
SelectivitySelectivity
Gao Journal of Pharm Exp Ther 2001
SelectivitySelectivity
A1 A2BA3
Undesirable effects (eg, bronchospasm)
Undesirable effects (eg, AV block)
A2A
Increase coronary blood flow
SelectivitySelectivity
Perspective to Perspective to applyapply in COPDin COPD
•• VariousVarious typestypes ofof COPD COPD patientspatients•• LimitedLimited data data –– still still needsneeds cautioncaution•• FurtherFurther studiesstudies, , largerlarger experienceexperience is is
neededneeded•• WhatWhat is is thethe literatureliterature showingshowing ??
RegadenosonRegadenoson in Asthmain Asthma
•• Randomized, doubleRandomized, double--blind, crossover trial of blind, crossover trial of 24 mild asthmatics & 24 moderate asthmatics24 mild asthmatics & 24 moderate asthmatics
•• All with a positive response to All with a positive response to nebulizednebulizedadenosine adenosine monophosphatemonophosphate (AMP), a validated (AMP), a validated marker of airway inflammation.marker of airway inflammation.
•• RegadenosonRegadenoson was well toleratedwas well tolerated
Leaker B et al. JNC, 2008
Leaker B et al. JNC, 2008
RegadenosonRegadenoson in Asthmain Asthma
Pilot Study in COPD patients (n=49)
Thomas G et al. JNC 2008
Thomas G et al. JNC 2008
Thomas G et al. JNC 2008
Thomas G et al. JNC 2008
Experience in Patients With Bronchoconstrictive DiseaseExperience in Patients With Bronchoconstrictive Disease
•• Two randomized, doubleTwo randomized, double--blind, placeboblind, placebo--controlled, controlled, crossover studies in patients with COPD (N=49) or crossover studies in patients with COPD (N=49) or asthma (N=47)asthma (N=47)–– No change in measures of respiratory function up No change in measures of respiratory function up to 2 hours postto 2 hours post--dosingdosing
–– No SAEs or termination due to AEsNo SAEs or termination due to AEs–– Dyspnea was the most commonly reported AE but Dyspnea was the most commonly reported AE but was not associated with respiratory deteriorationwas not associated with respiratory deterioration
–– Very Very promissingpromissing but caution neededbut caution needed
New PerspectivesNew Perspectives•• BolusBolus administrationadministration•• Standard doseStandard dose•• SelectivitySelectivity andand lowlow to to moderatemoderate receptor receptor bindingbinding
•• SpecialSpecial issuesissues–– PotentialPotential to combine to combine withwith exerciseexercise
Regadenoson + low level exercise
Vitola J et al, J Nucl Cardiol 2001, 8 (6):652-9
DipEx since 1998
5%7%
17%
0%
5%
10%
15%
20%
2001 2002 2003 2004 2005
Adapted from imv Nuclear Medicine Census Market Summary Reports 11-02, 12-03, 7-06
% of Vasodilator Stress Studies % of Vasodilator Stress Studies Performed with Exercise (US)Performed with Exercise (US)
G Thomas
100,0%100,0%1059510595TotalTotal0,9%0,9%9999DobutaminaDobutamina11,2%11,2%11841184CombinadoCombinado17,8%17,8%18911891DipiridamolDipiridamol70,0%70,0%74217421ExercExercííciocio
PercentualPercentualFreqFreqüüênciaênciaStressStress
Tipo de exameExercício
70%
Dipiridamol18%
Combinado11%
Dobutamina1%
Vitola JV et al . Quanta database – Curitiba - Brazil
Exercise Favored as a Stress Modality
37.3% ofPharmacologicStressare combined
AdAd
AdAd
Short AxisShort AxisVertical Long AxisVertical Long Axis
Ad-ExAd-Ex
RestRest
RestRest
Ad-ExAd-Ex
Horizontal Long AxisHorizontal Long Axis
EK
Tc-99m-sestamibi
Samady H et al, JNC,;9:188-196
A Multi-center, Randomized, Double Blind, Placebo- and Active-controlled Trial of the Safety & Effect on Image Quality and Detection of Perfusion Defects in Patients
Undergoing Regadenoson Submaximal Exercise Testing vs. Adenosine Supine Exercise Testing
,
Gregory S. Thomas, Randall C. Thompson, Mahesh P. Shah Michael I. Miyamoto, Tze K. Ip, M Crager, Vandana S.
Mathur
The RegEx Trial
1. Thomas et al. . J Nucl Cardiol. May/June 2008 on line
2. Thomas GS, et al. J Nucl Cardiol 2007:14:S109
Study DesignStudy DesignDouble blind, randomized, placebo and active controlDouble blind, randomized, placebo and active control
AdenoSup
RegEx
PlcExAdenosine SPECT MPI
Supine position6 min protocol
Regadenoson SPECT MPILow level exercise
n = 39
PlaceboLow level exercise
n = 21
HemodynamicsHemodynamics:: Heart RateHeart Rate
AdoSup: mean ±±±± SE; RegEx, PlcEx: LS Mean ±±±± SE
60
70
80
90
100
110
120
0 10 20 30 40 50 60Minute
HR (b
pm)
AdenoSup HR RegEx HR PlcEx HR
HemodynamicsHemodynamics:: Systolic BPSystolic BP
AdoSup: mean ±±±± SE; RegEx, PlcEx: LS Mean ±±±± SE
120
130
140
150
160
0 10 20 30 40 50 60Minute
SBP (
mm H
g)
AdenoSup SBP RegEx SBP PlcEx SBP
49%
21% 21%
11%
0%0
5
10
15
20
25
30
35
40
45
50
Perce
ntage
of Pa
tients
(%)
muchbetter
somewhatbetter
about thesame
somewhatworse
muchworse
Patient QuestionnairePatient QuestionnaireQ: How does this compare to the test in which you were lying down?
~70% Pts felt better w/ RegEx
Conclusions of the Conclusions of the RegExRegEx TrialTrial•• This pilot trial suggest that it is feasible to add This pilot trial suggest that it is feasible to add
low level exercise to low level exercise to RegadenosonRegadenoson•• Compared to Compared to AdenoSupAdenoSup, , RegExRegEx appears to haveappears to have
–– Greater increase in heart rate Greater increase in heart rate –– Better patient tolerabilityBetter patient tolerability–– Fewer adverse effectsFewer adverse effects–– Improved target to background ratioImproved target to background ratio–– Improved image qualityImproved image quality–– Trend toward more pts with reversible defectsTrend toward more pts with reversible defects
Eixo Curto
Eixo Longo Vertical
Eixo Longo Horizontal
Cortes Tomográficos-Referência
Potential for “ on the fly ” protocol
• 30 secs from peak hyperemia•Pts on meds•Depressed chronotropic response•Effects of Max Hyperemia on MPI Sensitivity ?
ConclusionsConclusions• Regadenoson is similar to adenosine to detect ischemia
• Regadenoson has the advantage of bolus administration andless side effects than adenosine
• Potential for utilization in patients with bronchospasm
• Potential for combination with exercise
• FDA approved in 2008
• Will cost allow wide spread utilization ?