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 ?

Thank you

joaovitola@quantamn.com.br

www.quantamn.com.br