Introduction to Nuclear Cardiology III: Clinical Value of Nuclear Stress Testing Matthew M. Schumaecker, MD, FACC Carilion Clinic / VTSOM Assistant Professor of Medicine,

Objectives Review basic epidemiologic concepts Become familiar with ‘predictive value model’ of nuclear stress testing Become familiar with ‘prognosis-based model’ of nuclear stress testing Become familiar with cost-effectiveness of nuclear stress testing

What are we assessing? Exercise Cardiac SPECT is a physiologic test which gives us information pertaining to: Anatomic diagnosis – ability to predict underlying coronary artery disease Prognosis – ability to predict death, future cardiac events

Basic Epidemiologic Concepts Patients with diseasePatients without disease Test is positiveTrue PositiveFalse Positive Test is negativeFalse NegativeTrue Negative

Basic Epidemiologic Concepts Patients with diseasePatients without disease Test is positiveTrue PositiveFalse Positive Test is negativeFalse NegativeTrue Negative

Anatomic Diagnosis: Referral Bias In order to determine diagnostic accuracy of SPECT for underlying angiographically significant CAD in an unbiased manner, all subjects would have to undergo angiography. Actual referral rates to angiography are <5% in the setting of a normal scan. Referral rates to angiography are >60% in the setting of a markedly abnormal scan

Understanding Referral Bias 1000 patients referred to SPECT Normal Scans N= Negative 50 Positive Abnormal Scans N= Positive 50 Negative All patients catheterized Observed sensitivity: 450/(450+50) = 90% Observed specificity: 450/(450+50) = 90% Assuming 90% true sensitivity and 90% true specificity Ideal model: all patients are referred to catheterization Modified from Berman and Germano, Clinical Gated Cardiac SPECT. Blackwell Futura p.190 SPECT Results Cath Results

Understanding Referral Bias 1000 patients referred to SPECT Normal Scans N=500 N=25 (5%) 22 Negative 3 Positive Abnormal Scans N=500 N=350 (70%) 315 Positive 35Negative Observed sensitivity: 315(315+3) = 99% Observed specificity: 22/(22+35) = 39% Assuming 90% true sensitivity and 90% true specificity Real model: only some patients are referred to catheterization Modified from Berman and Germano, Clinical Gated Cardiac SPECT. Blackwell Futura p.190 SPECT Results Cath Results Only some patients are catheterized

Referral Bias - Conclusions False positives are referred to angiography more than true negatives This decreases the observed specificity and increases the observed sensitivity of SPECT for the detection of coronary artery disease.

Normalcy Rate The concept of normalcy rate was used in an attempt to correct for referral bias. Normalcy rate is the rate of normal studies in a population with a low likelihood of having CAD. Normalcy rate has been found to be 80-90% (higher with technetium-based agents).

Can SPECT detect CAD? – SPECT can only detect epicardial stenoses which produce significant reductions in coronary flow reserve. – Epicardial stenoses < 50-70% rarely have hemodynamic consequences, even during maximal vasodilation. – Stenoses < 50% can be clinically signficant, especially with respect to acute plaque rupture. – Therefore one can never rule out the presence of “coronary disease” based on a normal SPECT scan. – Only “signficant, obstructive coronary disease” can possibly be ruled out.

ROBUST Trial 2560 patients were randomized to thallium, sestamibi or tetrofosmin to determine qualitative differences between the three. 937 patients subsequently underwent cardiac catheterization Only 137 patients undergoing catheterization had not history of infarction, angiography or revascularization Overall sensitivity for the detection of coronary disease defined by subsequent angiography was 91% with a specificity of 87%.

SPECT Imaging in Women

Diagnostic Accuracy of Exercise SPECT for the Detection of CAD Underwood et. al., European Journal of Nuclear Medicine and Molecular Imaging Vol. 31, No. 2, February 2004

Diagnostic Accuracy of Dipyridamole SPECT for the Detection of CAD Underwood et. al., European Journal of Nuclear Medicine and Molecular Imaging Vol. 31, No. 2, February 2004

Diagnostic Accuracy of Adenosine SPECT for the Detection of CAD Underwood et. al., European Journal of Nuclear Medicine and Molecular Imaging Vol. 31, No. 2, February 2004

Diagnostic Accuracy of Dobutamine SPECT for the Detection of CAD Underwood et. al., European Journal of Nuclear Medicine and Molecular Imaging Vol. 31, No. 2, February 2004

Diagnostic Accuracy - Metanalysis Schuijf et al. 2005, Heart (91);

Specificity Improvement with Gated Imaging A fixed defect represents infarction or artifact, not ischemia (which would be reversible) Myocardial thickening (represented a brightening on a gated SPECT scan) will be abnormal in areas of significant infarction. Therefore, gated imaging assists the reader in discerning attenuation artifact from a true abnormality.

Specificity Improvement with Gated Imaging

Specificity Improvement with Prone Imaging Lisbona R, Dinh L, Derbekyan V, Novales-Diaz JA. Clin Nucl Med Aug;20(8):

Prognostic Value of Cardiac SPECT  Nuclear stress testing is a powerful risk- stratification tool that should be used in an adjunctive manner with other clinical indicators of cardiac risk (e.g., traditional risk factors, symptom-type, electrocardiogram, biomarkers, etc.) to create an integrative risk- assessment.

Advantages of an Outcomes-Based Modality Assessment The majority of cardiovascular events have been shown to occur independently of stenosis severity. However, CAD events have been found to correlate with abnormalities in coronary flow reserve. Identifying the at-risk patient will allow targeted use of aggressive, expensive testing. Germano G, Berman D. Clincial Gated Caridac SPECT: Blackwell Publishing; p.195

0 = Normal 1 = Slight reduction of uptake 2 = Moderate reduction of uptake 3 = Severe reduction of uptake 4 = Absent uptake Segmental Scoring: 17-Segment Model (Newer)

0 = Normal 1 = Slight reduction of uptake 2 = Moderate reduction of uptake 3 = Severe reduction of uptake 4 = Absent uptake Segmental Scoring: 20-Segment Model (Older) Hachamovitch R, Berman DS, Shaw LJ, et al. Circulation Feb 17;97(6):

Cardiac Death and MI by SPECT Degree of Normalcy Summed Stress Score (older 20 segment model) Ascribed Degree of Normalcy <4Normal 4-8Mildly Abnormal 9-13Moderately Abnormal >13Severely Abnormal Hachamovitch R, Berman DS, Shaw LJ, et al. Circulation Feb 17;97(6):

Cardiac Death and MI by SPECT Degree of Normalcy Hachamovitch R, Berman DS, Shaw LJ, et al. Circulation Feb 17;97(6): Black boxes– Cardiac death White boxes – Myocardial infarction n=5534

Cumulative Survival by SPECT Degree of Normalcy Hachamovitch R, Berman DS, Shaw LJ, et al. Circulation Feb 17;97(6): n=5534

Cumulative Event-Free Survival by SPECT Degree of Normalcy Hachamovitch R, Berman DS, Shaw LJ, et al. Circulation Feb 17;97(6): n=5534

Cardiac Death Rate Stratified by Revascularization vs. Medical Therapy and by SPECT Degree of Normalcy Hachamovitch R, Berman DS, Shaw LJ, et al. Circulation Feb 17;97(6): Black boxes – Medical Therapy White boxes – Revascularization

Myocardial Infarction Rate Stratified by Revascularization vs. Medical Therapy and by SPECT Degree of Normalcy Hachamovitch R, Berman DS, Shaw LJ, et al. Circulation Feb 17;97(6): Black boxes – Medical Therapy White boxes – Revascularization

Cardiac Death and MI Normal and Abnormal SPECT Studies Navare SM, Mather JF, Shaw LJ, Fowler MS, Heller GV. J Nucl Cardiol Sep-Oct;11(5): White boxes – Exercise MPI Black boxes – Pharmacologic MPI Selection Bias

Cardiac Death and MI Normal and Abnormal SPECT Studies Navare SM, Mather JF, Shaw LJ, Fowler MS, Heller GV. J Nucl Cardiol Sep-Oct;11(5): White boxes – Exercise MPI Black boxes – Pharmacologic MPI

Cardiac Death and MI for Normal and Abnormal SPECT Studies Navare SM, Mather JF, Shaw LJ, Fowler MS, Heller GV. J Nucl Cardiol Sep-Oct;11(5): White boxes – Exercise MPI Black boxes – Pharmacologic MPI

Cardiac Death and MI for Normal and Abnormal SPECT Studies Navare SM, Mather JF, Shaw LJ, Fowler MS, Heller GV. J Nucl Cardiol Sep-Oct;11(5): White boxes – Exercise MPI Black boxes – Pharmacologic MPI

Prognosis of a Negative SPECT Study Negative studies are associated with a very low hard event rate (i.e., death and non-fatal MI). Metaanalyis of > 27,000 patients with normal SPECT followed for mean of 26.8 months and found to have a hard event rate of 0.6%. This number is independent of radioisotope used or stress modality. Germano G, Berman D. Clincial Gated Caridac SPECT: Blackwell Publishing; p. 198

Prognosis of a Negative SPECT Study Shaw LJ, Hendel R, Borges-Neto S, et al. J Nucl Med Feb;44(2):134-9

Prognosis of a Negative SPECT Study High Risk Subgroups Not all patients subgroups enjoy the 0.6% hard event rate prognosis. Some subgroups with higher rates include: – Prior CAD (1.4%) – Diabetes Mellitus (1.0%, 1.8%) – Those chosen for pharmacological stress testing because they are unable to exercise (1.1%) Germano G, Berman D. Clincial Gated Caridac SPECT: Blackwell Publishing; p

Prognosis of a Negative SPECT Study High Risk Subgroups Hachamovitch R, Hayes S, Friedman JD, et al. J Am Coll Cardiol Apr 16;41(8):

Prognosis of a Negative SPECT Study High Risk Subgroups Hachamovitch R, Hayes S, Friedman JD, et al. J Am Coll Cardiol Apr 16;41(8):

Prognosis of a Negative SPECT Study High Risk Subgroups Hachamovitch R, Hayes S, Friedman JD, et al. J Am Coll Cardiol Apr 16;41(8):

Prognosis of a Negative SPECT Study High Risk Subgroups Hachamovitch R, Hayes S, Friedman JD, et al. J Am Coll Cardiol Apr 16;41(8):

Prognostic Value of an Equivocal Study Berman DS, Hachamovitch R, Kiat H, et al. J Am Coll Cardiol Sep;26(3):

Prognostic Value of a Mildly Abnormal Study 2.7%/year risk of MI <1%/year risk of death These patients are considered to have “flow limiting coronary disease” but are unlikely to die from this disease in the next 2- 3 years Contemporary meta-analyses suggest no advantage of PCI over medical therapy in the asymptomatic patient with mild coronary artery disease.

Prognostic Value of a Moderate or Severely Abnormal Study Much higher event rates Data still lacking confirming superiority of PCI over medical therapy in asymptomatic patients with moderate to severe coronary disease

Cost Effectiveness of Nuclear Stress Testing Berman DS, Hachamovitch R, Kiat H, et al. J Am Coll Cardiol Sep;26(3): Germano G, Berman D. Clincial Gated Caridac SPECT: Blackwell Publishing; p. 197 $253,307/Hard Event $93,310/Hard Event $59,096/Hard Event n=1282

Racial Differences Shaw LJ, Hendel RC, Cerquiera M, et al. J Am Coll Cardiol May 3;45(9):

Prognostic Validation of SPECT in the Community Setting Thomas GS, Miyamoto MI, Morello AP, 3rd, et al. NUC Study J Am Coll Cardiol Jan 21;43(2):

Economic Implications END Trial Economic Implications of Non-Invasive Diagnosis Two cohorts of outpatients with stable angina 5,423 randomized to cardiac cath 5,826 perfusion imaging with selective catheterization No recent hospitalizations Higher diagnostic and follow-up costs with aggressive strategy. Shaw LJ, Hachamovitch R, Berman DS, et al Mar;33(3):661-9.

Economic Implications END Trial Shaw LJ, Hachamovitch R, Berman DS, et al Mar;33(3):661-9.

Economic Implications END Trial Shaw LJ, Hachamovitch R, Berman DS, et al JACC Mar;33(3):661-9.

Transient Ischemic Diliation Two proposed mechanisms: 1.True cavity dilitation – i.e., post-stress stunning 2.Diffuse subendocardial ischemia

Transient Ischemic Diliation Upper limit of normal for men 1.18 Upper limit of normal for women 1.31 Rivero A, Santana C, Folks RD, et al. J Nucl Cardiol May-Jun;13(3):

Transient Ischemic Diliation Mazzanti M, Germano G, Kiat H, et al. SPECT. J Am Coll Cardiol Jun;27(7):

Transient Ischemic Diliation In Patients with Otherwise Normal SPECT White boxes – Cardiac death, MI or Revascularization Black boxes – Cardiac death or MI Abidov A, Bax JJ, Hayes SW, et al. J Am Coll Cardiol Nov 19;42(10):

Cardiac SPECT in Acute Chest Pain The ERASE Trial Injection of 99m- Tc during chest pain should reveal flow disparities if chest pain is anginal patients without ECG changes were randomized to usual care vs. rest injection sestamibi. Composite endpoint was 30 day or in-hospital death, MI. revascularization

Cardiac SPECT in Acute Chest Pain The ERASE Trial

References 1.Husmann L, Wiegand M, Valenta I, et al. Diagnostic accuracy of myocardial perfusion imaging with single photon emission computed tomography and positron emission tomography: a comparison with coronary angiography. Int J Cardiovasc Imaging Jun;24(5): Gaemperli O, Schepis T, Valenta I, et al. Functionally Relevant Coronary Artery Disease: Comparison of 64-Section CT Angiography with Myocardial Perfusion SPECT. Radiology Jun Schaeffer MW, Brennan TD, Hughes JA, Gibler WB, Gerson MC. Resting radionuclide myocardial perfusion imaging in a chest pain center including an overnight delayed image acquisition protocol. J Nucl Med Technol Dec;35(4): Hashimoto J, Nakahara T, Bai J, Kitamura N, Kasamatsu T, Kubo A. Preoperative risk stratification with myocardial perfusion imaging in intermediate and low-risk non-cardiac surgery. Circ J Sep;71(9): Gaemperli O, Schepis T, Koepfli P, et al. Accuracy of 64-slice CT angiography for the detection of functionally relevant coronary stenoses as assessed with myocardial perfusion SPECT. Eur J Nucl Med Mol Imaging Aug;34(8): Germano G, Berman D. Clincial Gated Caridac SPECT: Blackwell Publishing; Elhendy A, Schinkel AF, van Domberg RT, Bax JJ, Valkema R, Poldermans D. Non-invasive diagnosis of in stent stenosis by stress 99m technetium tetrofosmin myocardial perfusion imaging. Int J Cardiovasc Imaging Oct;22(5): Berman DS, Kang X, Nishina H, et al. Diagnostic accuracy of gated Tc-99m sestamibi stress myocardial perfusion SPECT with combined supine and prone acquisitions to detect coronary artery disease in obese and nonobese patients. J Nucl Cardiol Mar-Apr;13(2): Shaw LJ, Hendel RC, Cerquiera M, et al. Ethnic differences in the prognostic value of stress technetium-99m tetrofosmin gated single-photon emission computed tomography myocardial perfusion imaging. J Am Coll Cardiol May 3;45(9): Schuijf JD, Shaw LJ, Wijns W, et al. Cardiac imaging in coronary artery disease: differing modalities. Heart Aug;91(8): Majstorov V, Pop Gjorceva D, Vaskova O, Vavlukis M, Peovska I, Maksimovic J. Gender differences in detecting coronary artery disease with dipyridamole stress myocardial perfusion imaging using 99m-Tc sestamibi gated SPECT. Prilozi Aug;26(1): Wackers FJ, Young LH, Inzucchi SE, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care Aug;27(8): Thomas GS, Miyamoto MI, Morello AP, 3rd, et al. Technetium 99m sestamibi myocardial perfusion imaging predicts clinical outcome in the community outpatient setting. The Nuclear Utility in the Community (NUC) Study. J Am Coll Cardiol Jan 21;43(2): Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial perfusion SPECT. J Nucl Cardiol Mar-Apr;11(2): Navare SM, Mather JF, Shaw LJ, Fowler MS, Heller GV. Comparison of risk stratification with pharmacologic and exercise stress myocardial perfusion imaging: a meta-analysis. J Nucl Cardiol Sep-Oct;11(5): Kapetanopoulos A, Heller GV, Selker HP, et al. Acute resting myocardial perfusion imaging in patients with diabetes mellitus: results from the Emergency Room Assessment of Sestamibi for Evaluation of Chest Pain (ERASE Chest Pain) trial. J Nucl Cardiol Sep-Oct;11(5): Barrington SF, Chambers J, Hallett WA, O'Doherty MJ, Roxburgh JC, Nunan TO. Comparison of sestamibi, thallium, echocardiography and PET for the detection of hibernating myocardium. Eur J Nucl Med Mol Imaging Mar;31(3): Alexanderson E, Mannting F, Gomez-Martin D, Fermon S, Meave A. Technetium-99m-Sestamibi SPECT myocardial perfusion imaging in patients with complete left bundle branch block. Arch Med Res Mar-Apr;35(2): Shaw LJ, Hendel R, Borges-Neto S, et al. Prognostic value of normal exercise and adenosine (99m)Tc-tetrofosmin SPECT imaging: results from the multicenter registry of 4,728 patients. J Nucl Med Feb;44(2): Santana CA, Garcia EV, Vansant JP, et al. Gated stress-only 99mTc myocardial perfusion SPECT imaging accurately assesses coronary artery disease. Nucl Med Commun Mar;24(3):241-9.

References 21.Sabharwal NK, Lahiri A. Role of myocardial perfusion imaging for risk stratification in suspected or known coronary artery disease. Heart Nov;89(11): Rocchi G, Fallani F, Bracchetti G, et al. Non-invasive detection of coronary artery stenosis: a comparison among power-Doppler contrast echo, 99Tc-Sestamibi SPECT and echo wall-motion analysis. Coron Artery Dis May;14(3): Hashimoto J, Suzuki T, Nakahara T, Kosuda S, Kubo A. Preoperative risk stratification using stress myocardial perfusion scintigraphy with electrocardiographic gating. J Nucl Med Mar;44(3): Abidov A, Bax JJ, Hayes SW, et al. Transient ischemic dilation ratio of the left ventricle is a significant predictor of future cardiac events in patients with otherwise normal myocardial perfusion SPECT. J Am Coll Cardiol Nov 19;42(10): Elhendy A, Bax JJ, Poldermans D. Dobutamine stress myocardial perfusion imaging in coronary artery disease. J Nucl Med Dec;43(12): Daimon M, Watanabe H, Yamagishi H, et al. Physiologic assessment of coronary artery stenosis by coronary flow reserve measurements with transthoracic Doppler echocardiography: comparison with exercise thallium-201 single piston emission computed tomography. J Am Coll Cardiol Apr;37(5): Shaw LJ, Hachamovitch R, Berman DS, et al. The economic consequences of available diagnostic and prognostic strategies for the evaluation of stable angina patients: an observational assessment of the value of precatheterization ischemia. Economics of Noninvasive Diagnosis (END) Multicenter Study Group. J Am Coll Cardiol Mar;33(3): Solomon AJ, Gersh BJ. Management of chronic stable angina: medical therapy, percutaneous transluminal coronary angioplasty, and coronary artery bypass graft surgery. Lessons from the randomized trials. Ann Intern Med Feb 1;128(3): Hachamovitch R, Berman DS, Shaw LJ, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction. Circulation Feb 17;97(6): McClellan JR, Travin MI, Herman SD, et al. Prognostic importance of scintigraphic left ventricular cavity dilation during intravenous dipyridamole technetium-99m sestamibi myocardial tomographic imaging in predicting coronary events. Am J Cardiol Mar 1;79(5): Mazzanti M, Germano G, Kiat H, et al. Identification of severe and extensive coronary artery disease by automatic measurement of transient ischemic dilation of the left ventricle in dual-isotope myocardial perfusion SPECT. J Am Coll Cardiol Jun;27(7): Hachamovitch R, Berman DS, Kiat H, et al. Effective risk stratification using exercise myocardial perfusion SPECT in women: gender-related differences in prognostic nuclear testing. J Am Coll Cardiol Jul;28(1): Amanullah AM, Kiat H, Friedman JD, Berman DS. Adenosine technetium-99m sestamibi myocardial perfusion SPECT in women: diagnostic efficacy in detection of coronary artery disease. J Am Coll Cardiol Mar 15;27(4):803-9.