IAEA International Conference on Integrated Medical Imaging in CV Disease 2013

How to Stress My Patient

Choosing the Proper Stress Test

John J. Mahmarian, MD, FACC, FASNC, FSCCT

Professor of Medicine, Department of Cardiology Weill Cornell Medical College

Director, Nuclear Cardiology and CT Services Methodist DeBakey Heart and Vascular Center

The Methodist Hospital Houston, Texas

Consultant and Advisory Board for Astellas

Stress Myocardial Perfusion Imaging Possible Stressor Modalities

• Exercise Treadmill/Bicycle Stress

• Pharmacologic Stressors • Dipyridamole • Adenosine • Regadenoson • Dobutamine – beta agonist

Pharmacologic Vasodilators

Exercise Stress: Contraindications

• Acute myocardial infarction (<4 days) • Acute coronary syndrome • Decompensated CHF • Uncontrolled Hypertension (BP>200/110mmhg) • Uncontrolled symptomatic cardiac arrhythmias or associated hemodynamic compromise • Severe aortic stenosis • Acute pulmonary embolism • Acute myocarditis/pericarditis • Acute aortic dissection/ aortic aneurysm • Severe pulmonary hypertension

Exercise Is the Preferred Stressor When Performing Myocardial Perfusion Imaging

• Exercise is the preferred method to induce hyperemia in patients who are able to adequately exercise who do not have contraindications

Achieve at least 85% of the maximal predicted heart rate for age Five metabolic equivalents (METS)

• Exercise provides additional diagnostic and prognostic information

Heart rate, blood pressure, ECG changes, exercise-induced symptoms, functional capacity, ventricular ectopy, heart rate recovery

• Better SPECT image quality (heart-to-background ratio)

• CAVEATS:

1) In patients without a prior cardiac history, anti-ischemic medications should not be taken the morning of the test! – potential false (-) results

2) PET can only currently be performed with pharmacologic agents

Henzlova et al. J Nucl Cardiol. 2006;13:e80. Anagnostopoulos et al. Heart. 2004;90(suppl 1):i1. Verna et al. J Nucl Cardiol. 2007;14:818.

Advantages of exercise stress

Less Sub-diaphragmatic Count Activity

Stress 1 Stress 2 Pharmacologic Stress Images: Raw Data

Yu et al. J Nucl Cardiol 2007;14:789-98

2-tert-Butyl-4-chloro-5-[4-(2- (18F)fluoro-ethoxymethyl)-benzyloxy]-2H-pyridazin-3-one

N

N

O

C l

O

O 1 8

F

New Tracers: Flurpiridaz F-18 PET Imaging

Stress/Rest study : 2mSv Rb-82: 1.7-7.5mSv (10-60mCi)

N-13 Ammonia: 1.5mSv (20mCi)

Rationale F-18 PET : Low energy - better spatial resolution Can be performed with exercise stress Extraction linear to myocardial blood flow

Exercise Treadmill Testing Limitations Symptomatic Patients

• Meta-analysis of 147 studies involving 24,047 patients

Sensitivity: 68% (50-72) Specificity: 77% (69-90) (Gibbons et all ACC/AHA 2002 Guidelines for exercise

testing Circulation 2002;106:1883)

• Diagnostic accuracy particularly poor in women: 53% false positive findings

(Weiner et al CASS study NEJM 1979;301:230)

Advantage of Exercise Stress: Improving Risk Stratification ETT In Asymptomatic Subjects The Aerobics Center Longitudinal Study

Blair, SN JAMA 1989; 262:2395-2401

10,224 men and 3,120 women with no prior history of CAD; mean follow-up 8 years Deaths: 240 men, 43 women

MEN Women

Take-home message: More METS = Better Survival

Mieres, J. H. et al. Circulation 2005;111:682-696

Exercise Capacity and Mortality In Asymptomatic (n=8715) And Symptomatic (n=8214) Women

Heart Rate Recovery Immediately After Exercise Predicts Mortality

Cole, CR et al N ENGL J MED 1999; 341:1351–1357.

2428 patients 57+/-12 years, 63% men; No history of CHF, coronary revascularization or pacemaker; 9.2% with known CAD Heart rate recovery at 1 minute: median 17bpm (25th - 75th percentile 12 to 23bpm)

Normal Heart Rate Recovery at l minute: >12bpm

Defining Risk from ETT Duke Treadmill Score Calculation

Duke Treadmill Score = Exercise time (min) - (5 x ST depression) - (4 x angina index)

-5 10 High Moderate Low Risk

Alexander KP et al. J Am Coll Cardiol 1998;32:1657

Duke Treadmill Score Predicting Mortality in Symptomatic Patients

Survival Estimates for Men (n=2249) Survival Estimates for Women (n=976)

0.5

0.6

0.7

0.8

0.9

1

0 1 2

High (12%)Moderate (54%)Low (34%)

Prob

abili

ty o

f Sur

viva

l

Years

Prob

abili

ty o

f Sur

viva

l

Years

0.5

0.6

0.7

0.8

0.9

1

0 1 2

High (4%)Moderate (63%)Low (33%)

72% CAD>75% 2yr. Mortality: 4.9%

32% CAD>75% 2 year Mortality 1.9%

Duke Treadmill Score = Exercise time (min) - (5 x ST depression) - (4 x angina index)

Value primarily limited to men

Exercise Myocardial Perfusion Imaging Prognosis in Patients Achieving ≥10 METS

Bourque JM et al. J Nucl Cardiol 2011;18:230

0

0.2

0.4

0.6

0.8

1

0 0.5 1 1.5 2 2.5

Years

Surv

ival

Fre

e of

Car

diac

D

eath

/Non

fata

l MI

509 consecutive patients with ETT SPECT >10METS and >85% PHR 86% symptomatic, 22% known CAD; 10% with Ischemic ST changes

90% Normal SPECT

Reversible Defect: 6% >10% Ischemic PDS: 0.6%

CAVEAT: 35% >10 METS OR THR>85% 17% >10METS AND THR>85% Only 31% Women

Convert to pharmacologic stress if THR not achieved for non-cardiac reason.

Integration of Duke Treadmill Score and Exercise SPECT Results

0

3

6

9

Low (37%) Intermediate(60%)

High (3%)

Normal Mildly AbnormalMod-sev Abnormal

Duke Treadmill Score

Annu

al C

ardi

ac D

eath

/MI

Even

t Rat

e (%

/yea

r)

Hachamovitch R et al. Circulation 2002;105:823-829

The Clinical Need for Pharmacologic Stressors Exercise Limitations

• 50% of patients are unable to perform adequate exercise stress due to non-cardiac limitations1

1. Botvinick. J Nucl Med Technol. 2009;37:14. 2. Hashimoto et al. J Nucl Cardiol. 1999;6:612. 3. Duvall et al. J Nucl Cardiol. 2006;13:202. 4. Wenger. Cardiovasc Res. 2002;53:558.

• Submaximal exercise can reduce sensitivity for detecting the presence and extent of ischemia in patients with known or suspected significant CAD.

When to Consider Pharmacologic Stress Agents

• Patients who may not be able to achieve an adequate

heart rate and blood pressure response due to:1

• Cardiopulmonary limitations • Orthopedic limitations • Limited exercise capacity • Lack of motivation • Paced rhythm

1.Henzlova et al. J Nucl Cardiol. 2006;13:e80. 3.Duvall et al. J Nucl Cardiol. 2006;12:202

• Some patient groups are more likely than others to require pharmacologic stress agents

• Elderly2

• Obese3

• Women4

2. Hashimoto et al. J Nucl Cardiol. 1999;6:612. 4. Wenger. Cardiovasc Res. 2002;53:558.

B

A

PDS = 26% LV

PDS = 2% LV

C

Assessing Medical Therapy with Serial Exercise SPECT Benefit with Combination Anti-Ischemic Rx

Mahmarian JJ in Atlas of Nuclear Cardiology, in press, 2005

When to Consider Use of Pharmacologic Stress Agents (cont’d)

• Exercise is a suboptimal stressor in • Left bundle branch block (LBBB) • Paced rhythm due to septal wall perfusion artifacts on MPI

Henzlova et al. J Nucl Cardiol. 2006;13:e80.

Stress Myocardial Perfusion SPECT False Positive Results with LBBB

Vaduganathan et al J Am Coll Cardiol 1996;28:543

46%

11%8%

0

10

20

30

40

50

60

Exercise Adenosine Dobutamine

False Positive Rate for Septal

Defects (%)

(26/57) (4/35) (1/13)

p <0.001

p = ns

p <0.01

Peak HR 141+/-22

Peak HR 88+/-17 Peak HR

115+/-23

Alternatives to Exercise Stress Testing Pharmacologic Stressors With MPI

• Pharmacologic Stressors • Dipyridamole • Adenosine • Regadenoson • Dobutamine – beta agonist

Pharmacologic Vasodilators

• Adenosine and dipyridamole stimulate a variety of adenosine receptors with different physiologic effects

• Selective stimulation of adenosine A2A receptor to induce prominent coronary hyperemia and reduce untoward effects.

Physiologic Effects of Stressor Agents

adenosine

dipyridamole

Coronary vasodilatation Peripheral vasodilation (partial)

Anti-inflammatory

A1

↓ A-V conduction Negative chronotropy

Chest pain (?) Preconditioning

A2B Peripheral vasodilation Mast cell degranulation (human)

Bronchiolar constriction A3

Preconditioning (?) Bronchoconstriction

enhances

A2A Agonists

A2A

Modified from R. Barrett

Regadenoson

Dobutamine Pharmacologic Considerations

Comparison of Various Properties of Pharmacologic Stress Agents

Johnston DL et al. Mayo Clinic Proc. 1995;70:331-336. Rossen JD et al. J Am Coll Cardiol. 1991; 18:485-491. Hilleman DE et al. Ann Pharmacother. 1997;31:974-979. Taillefer R et al. J Nucl Cardiol. 1996;3:204-211. Physicians’ Desk Reference, 54th ed. 2000.

Adenosine Dipyridamole Dobutamine

Half-life <10 sec 33-62 min 2 min

Mean time to peak coronary flow velocity 55 sec 6.5 min ≤10 min

Onset of action Seconds 2 min 1-2 min

Mechanism of action Direct Indirect Indirect

Patients with side effects requiring medical intervention 0.6% 16% NA

Exercise, Adenosine and Dipyridamole Effects on Peak Coronary Blood Flow

Peak Coronary Blood Flow

Chan SY et al. J Am Coll Cardiol. 1992;20:979-985. Krivokapich J et al. Am J Cardiol. 1993;71:1351-1356.

Regadenoson Hyperemia Induction and Blocking with Aminophylline in Man

Lieu HD et al. J Nucl Cardiol. 2007;14:514-520.

Time to 2.0-fold above baseline: 30 sec Duration 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 μg reg (n=8) 400 μg reg + amino (n=4)

Regadenoson: Similar hyperemic response as with exercise stress

Pharmacologic Vasodilators Administration Protocols

Dipyridamole and Adenosine • Weight-based • Intravenous pump infusion

Adenosine injection [package insert]. Deerfield, IL: Astellas Pharma US, Inc. Dipyridamole injection USP [package insert]. Bedford, OH: Bedford Laboratories.

Stress Protocols Dobutamine SPECT

• Absolute • Ongoing wheezing • >1° AV block without a pacemaker/ sick sinus

syndrome • Hypotension (SBP <90 mmHg) • Recent (<24 hr) use of dipyridamole (adenosine) (caffeine- coffee/tea 12 hours?)

• Relative • Remote history of reactive airway disease • Severe sinus bradycardia (HR <40 BPM)

Stress MPI Adenosine/ Dipyridamole: Contraindications

Where Do You Buy Your Coffee Caffeine Content of Popular Coffee

• Starbucks Coffee • Short (8 oz.): 180mg; Decaf – 15mg • Tall (12 oz): 260mg; Decaf – 20mg • Grande (16 oz.): 330mg; Decaf – 25mg •Venti (20-24oz.): 415mg; Decaf – 30mg

• McDonald’s Coffee Small coffee (12 oz): 109mg Large coffee (16 oz): 145mg

Effects of Caffeine on Adenosine SPECT •30 patients with reversible defects in >=1 vascular territory on initial SPECT •Second SPECT performed 1 hour after drinking an 8 oz cup of coffee. • No caffeine 24 hours prior to second SPECT •Caffeine blood levels 1hour after coffee

Mean serum caffeine levels 3.1+/-1.6mg/l (range 1-7mg/l, 60% 1-3mg/l)

Zoghbi et al JACC 2006; 47: 2296

Total Perfusion Defect Size

Effects of Caffeine on Adenosine SPECT •30 patients with reversible defects in >=1 vascular territory on initial SPECT •Second SPECT performed 1 hour after drinking an 8 oz cup of coffee. • No caffeine 24 hours prior to second SPECT •Caffeine blood levels 1hour after coffee

Mean serum caffeine levels 3.1+/-1.6mg/l (range 1-7mg/l, 60% 1-3mg/l)

Zoghbi et al JACC 2006; 47: 2296

Total Perfusion Defect Size

• Recent (<1 week) AMI • Unstable angina • LVOT obstruction • Critical aortic stenosis • Poorly controlled atrial tachyarrhythmias • Prior history of ventricular tachycardia • Uncontrolled hypertension • Aortic dissection and/or aneurysm

Stress MPI Dobutamine: Contraindications

DOB SPECT

R.I.P.

Pharmacologic Stress Testing Dobutamine SPECT

Reserved for Patient’s with >1 degree AV block without a pacemaker

COPD/Asthma: Regadenoson

Meta-Analysis of SPECT Results CAD Detection

Exercise 33 studies in 4480 patients Sensitivity: 89% Specificity: 73%*

Vasodilator Stress: Adenosine/Dipyridamole 24 Studies in 2492 patients Sensitivity: 89% Specificity: 75%*

Dobutamine Stress 24 studies in 1208 patients Sensitivity: 85% Specificity: 72%*

AHA/ACC/ASNC Guidelines, 2003 * improves to >90% with AC and gating

Regadenoson: Selective A2A Adenosine Receptor Agonist ADVANCE MPI: Primary Endpoint

Regadenoson similar to Adenoscan in assessing the extent of reversible perfusion defects*

*48% patients with ischemia on baseline adenosine study

Visual Analysis by 3 experts

Exercise SPECT Gender and Risk Stratification

0

10

20

Normal ProbablyNormal

Equivocal ProbablyAbnormal

Abnormal

MenWomen

Hachamovitch et al J Am Coll Cardiol 1996;28:34

Scan Result

Har

d Ev

ent R

ate

(%)

F/U 20±5 months

Revascularization Rate 60 days 7.5% men / 4.5% women, p <.04

*p <0.001 vs Men

*

Adenosine SPECT MPI Perfusion Defect Severity Predicts CD and MI

Hachamovitch R, et al. Circulation. 1998;97:535-543.

0.9 1.0

3.4

7.4

0.8

2.5

4.0 3.8

0

1

2

3

4

5

6

7

8

Normal 0–3 Mildly Abnormal4–8

ModeratelyAbnormal 9–13

SeverelyAbnormal >13

Summed stress score (SSS)

Even

t Rat

e, %

/yea

r

Myocardial infarctionCardiac death

y = 0.9602x + 0.4813r = 0.97, p<0.001

0

20

40

60

80

100

0 20 40 60 80 100

PDS Adenosine 1PD

S R

egad

enos

on

Regadenoson Comparable to Adenosine ADVANCE MPI 2 Trial: Quantitative SPECT Total PDS/ Ischemia

y = 0.9227x + 0.5031r = 0.95, p<0.001

0

20

40

60

80

100

0 20 40 60 80 100

PDS Adenosine 1

PDS

Reg

aden

oson

Total Perfusion Defect Size

Ischemic Perfusion Defect Size

Mahmarian et al. JACC Imaging 2009; 2: 959

Similar Total/Ischemic PDS: Regadenoson should provide comparable diagnostic and prognostic information as Adenosine

Dobutamine Tc-99m SPECT Long Term Prognostic Results

532 consecutive patients, age 61yrs, 58% men, 15% diabetic, 44% prior MI, 35% REV Mean FU 8.0+/-1.5yrs. 67 CD, 34 NFMI, 49 late REV(1.5% event rate/year)

Cardiac Death All Events

Schinkel et al. Radiology 2002; 225:701-706

Choosing the Proper Stress Agent • Exercise stress Preferred stressor modality in patients

who can perform adequate exercise and who do not have LBBB or a paced rhythm

• Pharmacologic vasodilator stress Recommended in all others if no

specific contraindications and currently in patients referred for PET

• Dobutamine stress Reserved for patients with advanced AV block (without a pacemaker) or in patients with reactive airway disease (if regadenoson is not available) • The choice of any pharmacologic

agent will depend on local availability, economic constraints and physician preference