introduction to nuclear cardiology iii: clinical value of nuclear stress testing matthew m....

Introduction to Nuclear Cardiology III:Clinical Value of Nuclear Stress Testing

Matthew M. Schumaecker, MD, FACCCarilion 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 disease Patients without disease

Test is positive True Positive False Positive

Test is negative False Negative True Negative

FNTP

TPySensitivit

Basic Epidemiologic Concepts

Patients with disease Patients without disease

Test is positive True Positive False Positive

Test is negative False Negative True Negative

FPTN

TNySpecificit

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 ScansN=500

450 Negative50 Positive

Abnormal ScansN=500

450 Positive50 Negative

All patients catheterized

Observed sensitivity: 450/(450+50) = 90%Observed specificity: 450/(450+50) = 90%

Assuming 90% true sensitivity and 90% true specificityIdeal model: all patients are referred to catheterization

Modified from Berman and Germano, Clinical Gated Cardiac SPECT. Blackwell Futura 2006. p.190

SPECT Results

Cath Results

Understanding Referral Bias

1000 patients referred to

SPECT

Normal ScansN=500

N=25 (5%)

22 Negative3 Positive

Abnormal ScansN=500

N=350 (70%)

315 Positive35Negative

Observed sensitivity: 315(315+3) = 99%Observed specificity: 22/(22+35) = 39%

Assuming 90% true sensitivity and 90% true specificityReal model: only some patients are referred to catheterization

Modified from Berman and Germano, Clinical Gated Cardiac SPECT. Blackwell Futura 2006. 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


Diagnostic Accuracy of Adenosine SPECT for the Detection of CAD


Diagnostic Accuracy of Dobutamine SPECT for the Detection of CAD


Diagnostic Accuracy - Metanalysis

Schuijf et al. 2005, Heart (91);1110-1117

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. 1995 Aug;20(8):674-77.

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; 2006. p.195

0 = Normal1 = Slight reduction of uptake2 = Moderate reduction of uptake3 = Severe reduction of uptake4 = Absent uptake

Segmental Scoring: 17-Segment Model (Newer)

0 = Normal1 = Slight reduction of uptake2 = Moderate reduction of uptake3 = Severe reduction of uptake4 = Absent uptake

Segmental Scoring: 20-Segment Model (Older)

Hachamovitch R, Berman DS, Shaw LJ, et al. Circulation. 1998 Feb 17;97(6):535-43.

Cardiac Death and MIby SPECT Degree of Normalcy

Summed Stress Score(older 20 segment model)

Ascribed Degree of Normalcy

<4 Normal

4-8 Mildly Abnormal

9-13 Moderately Abnormal

>13 Severely Abnormal


Cardiac Death and MIby SPECT Degree of Normalcy


Black boxes– Cardiac deathWhite boxes – Myocardial infarction

n=5534

Cumulative Survivalby SPECT Degree of Normalcy


n=5534

Cumulative Event-Free Survivalby SPECT Degree of Normalcy


n=5534

Cardiac Death Rate Stratified by Revascularization vs. Medical Therapy and by SPECT Degree of Normalcy


Black boxes – Medical TherapyWhite boxes – Revascularization

Myocardial Infarction Rate Stratified by Revascularization vs. Medical Therapy and by SPECT Degree of Normalcy


Black boxes – Medical TherapyWhite boxes – Revascularization

Cardiac Death and MINormal and Abnormal SPECT Studies

Navare SM, Mather JF, Shaw LJ, Fowler MS, Heller GV. J Nucl Cardiol. 2004 Sep-Oct;11(5):551-61.White boxes – Exercise MPIBlack boxes – Pharmacologic MPI

Selection Bias

Cardiac Death and MI Normal and Abnormal SPECT Studies


Cardiac Death and MIfor Normal and Abnormal SPECT Studies


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; 2006. p. 198

Prognosis of a Negative SPECT Study

Shaw LJ, Hendel R, Borges-Neto S, et al. J Nucl Med. 2003 Feb;44(2):134-9

Card

iac

Surv

ival

Rat

es

Prognosis of a Negative SPECT StudyHigh 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; 2006. p. 198-9

Prognosis of a Negative SPECT StudyHigh Risk Subgroups

Hachamovitch R, Hayes S, Friedman JD, et al. J Am Coll Cardiol. 2003 Apr 16;41(8):1329-40.

Prognostic Value of an Equivocal Study

Berman DS, Hachamovitch R, Kiat H, et al. J Am Coll Cardiol. 1995 Sep;26(3):639-47.

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. 1995 Sep;26(3):639-47.

Germano G, Berman D. Clincial Gated Caridac SPECT: Blackwell Publishing; 2006. 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. 2005 May 3;45(9):1494-504.

Prognostic Validation of SPECTin the Community Setting

Thomas GS, Miyamoto MI, Morello AP, 3rd, et al. NUC Study J Am Coll Cardiol. 2004 Jan 21;43(2):213-23.

Economic ImplicationsEND 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. 1999 Mar;33(3):661-9.


Shaw LJ, Hachamovitch R, Berman DS, et al. 1999 Mar;33(3):661-9.


Shaw LJ, Hachamovitch R, Berman DS, et al. 1999 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


• 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. 2006 May-Jun;13(3):338-44.


Mazzanti M, Germano G, Kiat H, et al. SPECT. J Am Coll Cardiol. 1996 Jun;27(7):1612-20.

Transient Ischemic DiliationIn Patients with Otherwise Normal SPECT

White boxes – Cardiac death, MI or RevascularizationBlack boxes – Cardiac death or MI

Abidov A, Bax JJ, Hayes SW, et al. J Am Coll Cardiol. 2003 Nov 19;42(10):1818-25.

Cardiac SPECT in Acute Chest PainThe ERASE Trial

• Injection of 99m-Tc during chest pain should reveal flow disparities if chest pain is anginal.

• 2475 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 PainThe ERASE Trial

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References21. Sabharwal NK, Lahiri A. Role of myocardial perfusion imaging for risk stratification in suspected or known coronary artery disease. Heart. 2003 Nov;89(11):1291-7.22. 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. 2003 May;14(3):239-45.23. Hashimoto J, Suzuki T, Nakahara T, Kosuda S, Kubo A. Preoperative risk stratification using stress myocardial perfusion scintigraphy with electrocardiographic gating. J Nucl Med. 2003 Mar;44(3):385-90.24. 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. 2003 Nov 19;42(10):1818-25.25. Elhendy A, Bax JJ, Poldermans D. Dobutamine stress myocardial perfusion imaging in coronary artery disease. J Nucl Med. 2002 Dec;43(12):1634-46.26. 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. 2001 Apr;37(5):1310-5.27. 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. 1999 Mar;33(3):661-9.28. 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. 1998 Feb 1;128(3):216-23.29. 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. 1998 Feb 17;97(6):535-43.30. 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. 1997 Mar 1;79(5):600-5.31. 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. 1996 Jun;27(7):1612-20.32. 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. 1996 Jul;28(1):34-44.33. 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. 1996 Mar 15;27(4):803-9.

introduction to nuclear cardiology iii: clinical value of nuclear stress testing matthew m....

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