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