João V. Vitola, MD, PhD

Cardiologist and Nuclear Medicine Physician Quanta Diagnostico Nuclear

Curitiba - Brazil

Pharmacological stress agents and protocols

DISCLOSURES

Honorarium – Research and Conferences in Nuclear Cardiology

BMS, CVT, Astellas, Pgx Health/Forest laboratories, Lantheus Medical ImagingInternational Atomic Energy Agency

Royalties – Publications in Nuclear Cardiology

Springer-Verlag-Nuclear Cardiology and Correlative Imaging: a teaching file, NY, 2004

Lippincott Williams & Wilkins, - Nuclear Medicine teaching File, 2009

1- Collect data – medical historyTalk to the patient – define the ideal stress protocol for that patientEstimation of pre test probability based on age, symptoms, risk factorsWhy pharm stress ? Any contraindication ? COPD/ AVB/ LV arr?

2- Rest ECG and Stress data

LBBB ? PM ? Previous infarct ?Any ECG changes induced by stress ?

3- Imaging analysis

4 –Final report (1+2+ 3)

Consider info from history , ECG and stress data for image interpretation

Stress Protocols

Exercise (“ max” )Bruce, Ellestad, Modified Bruce, Kattus, NaughtonBike

Pharm stress

Regadenoson and padenoson

Combined or hybrid : exercise + vasodilator - DipEx, AdenoEx, RegExDipyridamole / AdenosineDobutamine

Mieres J et al. in Vitola and Delbeke: Nuclear Cardiology and Correlative Imaging, Springer 2004Chapter 12, page 333

Selecting Patients for Pharm Stress – before and after nucs

http://www-pub.iaea.org/MTCD/Publications/PDF/Pub1566_web.pdf

Selecting Patients for Pharm Stress

Goal: To Test Coronary Reserve

Reserve coronary flow

Baseline flow

hyperemia

% Stenosis

20 40 60 80 100

Cor

onar

y flo

w (m

l.min

.g-1

)5

4

3

2

1

0

Gould, L 1974

• Exercíse– Increase Oxygen Demand

• Adenosine– A2 , AMPc, decrease intracelular calcium, relax SMC – decrease R2 resistance

• Dipyridamole– inhibits adenosine deaminase and adenosine reuptake– increase endogenous adenosine

• Dobutamine– B1, contractility, HR– Increase Oxygen Demand

MECHANISMS OF ACTIONThe goal is hyperemia

http://www-pub.iaea.org/MTCD/Publications/PDF/Pub1566_web.pdf

ml/m

in/g

AdenDipExerc Dobut0

1

2

3

4

5

6

BaseIskandrian AS et al. J.Nucl.Cardiol.;27(4):803-9,1994.

Modalities and Hyperemic Flow

Does Higher Flow (MORE HYPEREMIA) Means higher sensitivity ? effects of myocardial extraction plateau

0,10

0,08

0,06

0,00

0,02

0,04

0 3 4Coronary flow (ml.min.g-1)

99mTc-Mibi201Tl

% D

ose.

gram

tiss

ue

1 2

Protocols – inject tracer at peak hyperemia

BERGMANN et al.JACC 1989;14:639-52

Normal VolunteersMBF - H2

15O - PET

Dip 0.56 mg/kg

All patients respond the same ? Why a wide SD ?

Exercise Favored as a Stress Modality

Vitola JV et al (QUANTA Database, n = 41671)

Vitola JV et al (QUANTA Database, n = 41671)

Frequency of Abnormality on SPECT Men vs Women - Exercise vs Pharm Stress

Exercise Below Average

Pharm Above Average

Elderly patients undergoing Pharm Stress have a worse prognosisMortality in a higher risk subset (>75 yo) according to stress

modality : Exercise vs Pharmacologic stress (n=1358)

Vitola J et al. - ASNC presentation 2012; Baltimore/USA

Combined protocol : Vasodilator + low level exercise

Vitola J et al, J Nucl Cardiol 2001, 8 (6):652-9

DipEx since 1998

JNC 2009

Vasodilator ExerciseIMAGE QUALITY

Exercise vs VasodilatorBLOOD FLOW distribution

heart/ liver

Dip Exercise(46%)

1.3 0.3 1.9 0.5*

Taillefer et al

Dip Exer + Dip(23%)

1.3 0.5 1.6 0.6*

Vitola et al

*p<0.05

Vitola J et al, J Nucl Cardiol 2001, 8 (6):652-9

200 1 2 3 4 5 6 min

…Holly 2003Crossover trialn=35Exercise=variable

Adenosine

Exercise, Bruce Protocol (treadmill)

Tc-99m

Samady 2002Crossover trialn=41

Exercise, Modified Bruce Protocol (treadmill)

Adenosine

Tc-99m

Thomas 2000Parallel trialn=507

Exercise to tolerance (treadmill)

Adenosine

Tc-99m

Hashimoto 1999Parallel trial designn=462

Exercise, 0.5-1.7 mph @ 0% grade (treadmill)

Adenosine

Tc-99m

Elliot 2000Crossover trialn=19Exercise=6 min

Courtesy: R Thompson, MD

Adenosine + exercise

Dip DipEx

Isch Patients 30 39*Isch Segts/pt (multivessel) 1.3 1.5 2.5 2.2*Extent (% polar map) 16.8 12.9 26.4 18.5*Lung Uptake 5 16*TID 4 10*

Stein et al., Am J Cardiol, 75:568-72, 1995 *p<0.001

Increased Sensitivity of MPIDipEx(n=54)

AdAd

AdAd

Short AxisShort Axis

Vertical Long AxisVertical Long Axis

Ad-ExAd-Ex

Rest Rest

RestRest

Ad-EXAd-EX

Horizontal Long AxisHorizontal Long Axis

CF

Tc-99m-sestamibi

Samady H et al, J Nucl Cardiol 2002;9:188-196

0 1 2 3 54 6 7 8

Tc-99m

Thomas, Thompson et al. 2008RCT trialn=60

Exercise 1.7 mph at 0% grade

Regadenoson + exercise

Reg

Thomas,Thompson, et al. J Nucl Cardiol 2009;16:63–72

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

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 Performed with Exercise (US)

G Thomas

Indication– Incapacity to exercise (consider adding low workload

exercise)– LBBB, PM (vasodilator alone)– On Medications

Limitations compared to exercise– Side effects– Sensitivity of the ECG ( < 6 %)– Information from exercise not available– Liver uptake – inferior artifacts– Non-responders

VASODILATORS

LBBB or RV pacing

• O’Keefe AHJ 1992;124:614-21

O’Keefe AHJ 1992;124:614-21

Indication– Incapacity to exercise – COPD

Protocol– 10 / 20 / 30 / 40 microgramas/kg/min (push to max

HR)

DOBUTAMINE

ATROPINE up to 2 mg in 4 boluses (0.5 + 0.5 + 0.5 + 0.5)* *careful Glaucoma and BPH

• HR response variable• BP response variable• Hyperemia variable• Arrythmias/other side effects• Fragile patient (Elderly COPD)• VT (4%)

DOBUTAMINELimitations

Side effect Adenosine Dipyridamole Dobutamine

Any 81% 47% 75%

Flushing 37% 43% 14%Dyspnea 35% 3% 14%Chest Pain 35% 20% 31%STdepression 6% 8% 30%GI disconfort 15% 6% -Headache 14% 12% 14%AV Block 8% 0% 0%Arrythmia 3% 5% 50%

Adenosine/Dipyridamole Dobutamine

Hypotension HipertensionCOPD (steroids/hospit) Frequent Ventr EctopyAV Block > 1 Uncontrolled AF/Flutter

Obstruction LV outflow Aortic Aneurysm

General ContraindicationsAMI within 24 horasACSUncontrolled CHF

Specific Contraindications

Stress testingConclusions

• Understand the population you are studying ~ choose wisely the right stress for the right patient

• Try to understand and answer the clinical question being asked

• Build a strong cooperation with clinicians by providing good quality comprehensive NC work ~ go beyond reading images !

• Prefer exercise. If exercise is not possible, good pharmacologic stress alternatives are available

• www.iaea.org – recommendations for a successful NC practice

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Thank you

joaovitola@quantamn.com.br

CURITIBA - BRASIL