IAEA International Conference on Integrated Medical Imaging in CV Disease 2013

IAEA International Conference on Integrated Medical Imaging in CV Disease 2013 How to Stress My Patient Choosing the Proper Stress Test Consultant and Advisory Board for Astellas 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

Stress Myocardial Perfusion Imaging Possible Stressor Modalities Exercise Treadmill/Bicycle Stress Pharmacologic Stressors Dipyridamole Adenosine Regadenoson Pharmacologic Vasodilators Dobutamine beta agonist

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 Pharmacologic Stress Images: Raw Data Stress 1 Stress 2

New Tracers: Flurpiridaz F-18 PET Imaging Rationale F-18 PET : Low energy - better spatial resolution Can be performed with exercise stress Extraction linear to myocardial blood flow N N O Stress/Rest study : 2mSv C l O Rb-82: 1.7-7.5mSv (10-60mCi) N-13 Ammonia: 1.5mSv (20mCi) O 1 8 F 2-tert-Butyl-4-chloro-5-[4-(2- (18F)fluoro-ethoxymethyl)-benzyloxy]-2H-pyridazin-3-one Yu et al. J Nucl Cardiol 2007;14:789-98

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 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 Blair, SN JAMA 1989; 262:2395-2401

Exercise Capacity and Mortality In Asymptomatic (n=8715) And Symptomatic (n=8214) Women Mieres, J. H. et al. Circulation 2005;111:682-696

Cole, CR et al N ENGL J MED 1999; 341:1351 1357. Heart Rate Recovery Immediately After Exercise Predicts Mortality 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 (25 th - 75 th 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

Duke Treadmill Score Predicting Mortality in Symptomatic Patients Value primarily limited to men Survival Estimates for Men (n=2249) 1 Survival Estimates for Women (n=976) 1 0.9 0.9 Probability of Survival 0.8 0.7 0.6 0.5 High (12%) Moderate (54%) Low (34%) 72% CAD>75% 2yr. Mortality: 4.9% Probability of Survival 0.8 0.7 0.6 0.5 High (4%) Moderate (63%) Low (33%) 32% CAD>75% 2 year Mortality 1.9% 0 1 2 0 1 2 Years Years Duke Treadmill Score = Exercise time (min) - (5 x ST depression) - (4 x angina index) Alexander KP et al. J Am Coll Cardiol 1998;32:1657

Exercise Myocardial Perfusion Imaging Prognosis in Patients Achieving 10 METS 509 consecutive patients with ETT SPECT >10METS and >85% PHR 86% symptomatic, 22% known CAD; 10% with Ischemic ST changes Convert to pharmacologic stress if THR not achieved for non-cardiac reason. 1 Survival Free of Cardiac Death/Nonfatal MI 0.8 0.6 0.4 0.2 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 0 0 0.5 1 1.5 2 2.5 Years Bourque JM et al. J Nucl Cardiol 2011;18:230

Integration of Duke Treadmill Score and Exercise SPECT Results Annual Cardiac Death/MI Event Rate (%/year) 9 6 3 Normal Mildly Abnormal Mod-sev Abnormal 0 Low (37%) Intermediate (60%) High (3%) Duke Treadmill Score 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 limitations 1 Submaximal exercise can reduce sensitivity for detecting the presence and extent of ischemia in patients with known or suspected significant CAD. 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.

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 Some patient groups are more likely than others to require pharmacologic stress agents Elderly 2 Obese 3 Women 4 1.Henzlova et al. J Nucl Cardiol. 2006;13:e80. 3.Duvall et al. J Nucl Cardiol. 2006;12:202 2. Hashimoto et al. J Nucl Cardiol. 1999;6:612. 4. Wenger. Cardiovasc Res. 2002;53:558.

Assessing Medical Therapy with Serial Exercise SPECT Benefit with Combination Anti-Ischemic Rx A PDS = 26% LV B C PDS = 2% LV 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 60 50 46% p <0.001 p <0.01 False Positive Rate for Septal Defects (%) 40 30 Peak HR 141+/-22 p = ns 20 10 0 11% Peak HR 88+/-17 Peak HR 115+/-23 8% Exercise Adenosine Dobutamine (26/57) (4/35) (1/13) Vaduganathan et al J Am Coll Cardiol 1996;28:543

Alternatives to Exercise Stress Testing Pharmacologic Stressors With MPI Pharmacologic Stressors Dipyridamole Adenosine Regadenoson Pharmacologic Vasodilators Dobutamine beta agonist

Physiologic Effects of Stressor Agents Adenosine and dipyridamole stimulate a variety of adenosine receptors with different physiologic effects A 2A Agonists A 2A Coronary vasodilatation Peripheral vasodilation (partial) Anti-inflammatory adenosine A 1 A-V conduction Negative chronotropy Chest pain (?) Preconditioning enhances dipyridamole A 2B Peripheral vasodilation Mast cell degranulation (human) Bronchiolar constriction Modified from R. Barrett A 3 Preconditioning (?) Bronchoconstriction Selective stimulation of adenosine A 2A receptor to induce prominent coronary hyperemia and reduce untoward effects. Regadenoson

Dobutamine Pharmacologic Considerations

Comparison of Various Properties of Pharmacologic Stress Agents 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 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, 54 th ed. 2000.

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 3.5 3.0 400 μg reg (n=8) 400 μg reg + amino (n=4) Regadenoson: Similar hyperemic response as with exercise stress APV ratio 2.5 2.0 1.5 Time to 2.0-fold above baseline: 30 sec Duration at 2.5-fold above baseline: 2.3 min 1.0 0 2 4 6 8 10 Time (min) Lieu HD et al. J Nucl Cardiol. 2007;14:514-520.

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

Stress MPI Adenosine/ Dipyridamole: Contraindications 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)

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 Total Perfusion Defect Size Mean serum caffeine levels 3.1+/-1.6mg/l (range 1-7mg/l, 60% 1-3mg/l) Zoghbi et al JACC 2006; 47: 2296

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 Total Perfusion Defect Size Mean serum caffeine levels 3.1+/-1.6mg/l (range 1-7mg/l, 60% 1-3mg/l) Zoghbi et al JACC 2006; 47: 2296

Stress MPI Dobutamine: Contraindications 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

Pharmacologic Stress Testing Dobutamine SPECT Reserved for Patient s with >1 degree AV block without a pacemaker DOB SPECT R.I.P. 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%* * improves to >90% with AC and gating AHA/ACC/ASNC Guidelines, 2003

Regadenoson: Selective A2A Adenosine Receptor Agonist ADVANCE MPI: Primary Endpoint Regadenoson similar to Adenoscan in assessing the extent of reversible perfusion defects* Visual Analysis by 3 experts *48% patients with ischemia on baseline adenosine study

Exercise SPECT Gender and Risk Stratification Hard Event Rate (%) 20 10 F/U 20±5 months Revascularization Rate 60 days 7.5% men / 4.5% women, p <.04 *p <0.001 vs Men Men Women * 0 Normal Probably Normal Equivocal Scan Result Probably Abnormal Abnormal Hachamovitch et al J Am Coll Cardiol 1996;28:34

Adenosine SPECT MPI Perfusion Defect Severity Predicts CD and MI 8 7 Myocardial infarction Cardiac death 7.4 Event Rate, %/year 6 5 4 3 2 1 0.9 1.0 0.8 2.5 3.4 4.0 3.8 0 Normal 0 3 Mildly Abnormal 4 8 Moderately Abnormal 9 13 Severely Abnormal >13 Summed stress score (SSS) Hachamovitch R, et al. Circulation. 1998;97:535-543.

Regadenoson Comparable to Adenosine ADVANCE MPI 2 Trial: Quantitative SPECT Total PDS/ Ischemia 100 Total Perfusion Defect Size Similar Total/Ischemic PDS: Regadenoson should provide comparable diagnostic and prognostic information as Adenosine Ischemic Perfusion Defect Size PDS Regadenoson PDS Regadenoson 80 60 40 20 100 80 60 40 20 0 y = 0.9602x + 0.4813 r = 0.97, p<0.001 0 20 40 60 80 100 PDS Adenosine 1 y = 0.9227x + 0.5031 r = 0.95, p<0.001 Mahmarian et al. JACC Imaging 2009; 2: 959 0 0 20 40 60 80 100 PDS Adenosine 1

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