John D. Friedman

Optimal Medical Therapy With or Without Percutaneous Coronary Intervention to Reduce Ischemic Burden Results From the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Nuclear Substudy

Background— Extent and severity of myocardial ischemia are determinants of risk for patients with coronary artery disease, and ischemia reduction is an important therapeutic goal. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) nuclear substudy compared the effectiveness of percutaneous coronary intervention (PCI) for ischemia reduction added to optimal medical therapy (OMT) with the use of myocardial perfusion single photon emission computed tomography (MPS). Methods and Results— Of the 2287 COURAGE patients, 314 were enrolled in this substudy of serial rest/stress MPS performed before treatment and 6 to 18 months (mean=374±50 days) after randomization using paired exercise (n=84) or vasodilator stress (n=230). A blinded core laboratory analyzed quantitative MPS measures of percent ischemic myocardium. Moderate to severe ischemia encumbered ≥10% myocardium. The primary end point was ≥5% reduction in ischemic myocardium at follow-up. Treatment groups had similar baseline characteristics. At follow-up, the reduction in ischemic myocardium was greater with PCI+OMT (−2.7%; 95% confidence interval, −1.7%, −3.8%) than with OMT (−0.5%; 95% confidence interval, −1.6%, 0.6%; P<0.0001). More PCI+OMT patients exhibited significant ischemia reduction (33% versus 19%; P=0.0004), especially patients with moderate to severe pretreatment ischemia (78% versus 52%; P=0.007). Patients with ischemia reduction had lower unadjusted risk for death or myocardial infarction (P=0.037 [risk-adjusted P=0.26]), particularly if baseline ischemia was moderate to severe (P=0.001 [risk-adjusted P=0.08]). Death or myocardial infarction rates ranged from 0% to 39% for patients with no residual ischemia to ≥10% residual ischemia on follow-up MPS (P=0.002 [risk-adjusted P=0.09]). Conclusions— In COURAGE patients who underwent serial MPS, adding PCI to OMT resulted in greater reduction in ischemia compared with OMT alone. Our findings suggest a treatment target of ≥5% ischemia reduction with OMT with or without coronary revascularization.

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

BACKGROUND The incremental prognostic value of stress single photon emission computed tomography (SPECT) for the prediction of cardiac death as an individual end point and the implications for risk stratification are undefined. METHODS AND RESULTS We identified 5183 consecutive patients who underwent stress/rest SPECT and were followed up for the occurrence of cardiac death or myocardial infarction. Over a mean follow up of 642+/-226 days, 119 cardiac deaths and 158 myocardial infarctions occurred (3.0% cardiac death rate, 2.3% myocardial infarction rate). Patients with normal scans were at low risk (< or =0.5%/y), and rates of both outcomes increased significantly with worsening scan abnormalities. Patients who underwent exercise stress and had mildly abnormal scans had low rates of cardiac death but higher rates of myocardial infarction (0.7%/y versus 2.6%/y; P<.05). After adjustment for prescan information, scan results provided incremental prognostic value toward the prediction of cardiac death. The identification of patients at intermediate risk of nonfatal myocardial infarction and low risk for cardiac death by SPECT may result in significant cost savings when applied to a clinical testing strategy. CONCLUSIONS Myocardial perfusion SPECT yields incremental prognostic information toward the identification of cardiac death. Patients with mildly abnormal scans after exercise stress are at low risk for cardiac death but intermediate risk for nonfatal myocardial infarction and thus may benefit from a noninvasive strategy and may not require invasive management.

Exercise Myocardial Perfusion SPECT in Patients Without Known Coronary Artery Disease Incremental Prognostic Value and Use in Risk Stratification

BACKGROUND We evaluated the incremental prognostic value, the role in risk stratification, and the impact on patient management of myocardial perfusion single-photon emission computed tomography (SPECT) in a population of patients without prior myocardial infarction, catheterization, or revascularization. METHODS AND RESULTS We examined 2200 consecutive patients who at the time of their dual-isotope SPECT had not undergone catheterization, coronary artery bypass surgery, or percutaneous transluminal coronary angioplasty and had no known history of previous myocardial infarction. Follow-up was performed at a mean of 566 +/- 142 days (97% complete) for hard events (cardiac death and myocardial infarction) and for referral to cardiac catheterization or revascularization within 60 days after nuclear testing. Examination of clinical, exercise, and nuclear models by use of pre-exercise tolerance test (ETT), post-ETT, and nuclear information using a stepwise Cox proportional hazards model and receiver-operating characteristic curve analysis revealed that nuclear testing added incremental prognostic value after inclusion of the most predictive clinical and exercise variables (global chi2 = 12 for clinical variables; 31 for clinical + exercise variables; 169 for nuclear variables; gain in chi2, P < .0001 for all; receiver-operating characteristic areas: 0.66 +/- 0.04 for clinical, 0.73 +/- 0.04 for clinical + exercise variables, 0.87 +/- 0.03 for nuclear variables, P = .03 for gain in area with exercise variables; P < .001 for increase with nuclear variables). Multiple logistic regression analysis revealed that scan information contributed 95% of the information regarding referral to catheterization with further additional information provided by presenting symptoms and exercise-induced ischemia. Referral rates to early catheterization and revascularization paralleled the hard event rates in all scan categories - very low referral rates in patients with normal scans and significant increases in referral rates as a function of worsening scan results. Even after stratification by clinical and exercise variables such as the Duke treadmill score, pre- and post-ETT likelihood of coronary artery disease, presenting symptoms, sex, and age, the nuclear scan results further risk-stratified the patient subgroups, thus demonstrating clinical incremental value. CONCLUSIONS In a patient population with no evidence of previous coronary artery disease at overall low risk (1.8% hard event rate), myocardial perfusion SPECT adds incremental prognostic information and risk-stratifies patients even after clinical and exercise information is known. It appears that referring physicians use this test in an appropriate manner in selecting patients to be referred to catheterization or revascularization.

Incremental Prognostic Value of Post-Stress Left Ventricular Ejection Fraction and Volume by Gated Myocardial Perfusion Single Photon Emission Computed Tomography

BACKGROUND The incremental prognostic value of post-stress left ventricular ejection fraction (EF) and volume over perfusion has not been investigated. METHODS AND RESULTS We identified 1680 consecutive patients who underwent rest Tl-201/stress Tc-99m sestamibi gated single photon emission computed tomography (SPECT) and who were followed-up for 569+/-106 days. Receiver-operator characteristics analysis defined an EF<45%, an end-systolic volume (ESV) >70 mL, and an end-diastolic volume >120 mL as optimal thresholds, yielding moderate sensitivity and high specificity in the prediction of cardiac death. Patients with an EF> or = 45% had mortality rates <1%/year, despite severe perfusion abnormalities, whereas patients with an EF<45% had high mortality rates, even with only mild/moderate perfusion abnormalities (9.2%/year; P<0.00001). Similarly, an ESV< or = 70 mL was related to a low cardiac death rate (<1.2%/year), even for patients with severe perfusion abnormalities, whereas patients with an ESV>70 mL and only mild/moderate perfusion abnormalities had high death rates (8.2%/year; P<0.00001). Patients with an EF<45% and an ESV< or = 70 mL had low cardiac death rates (1.7%/year); those with an EF<45% but an ESV>70 mL had high death rates (7.9%/year; P<0.02). Multivariate Cox proportional hazards regression showed that perfusion variables and ESV were independent predictors of overall coronary events, whereas EF and ESV demonstrated incremental prognostic values over prescan and perfusion information in predicting cardiac death and cardiac death or myocardial infarction. CONCLUSIONS Post-stress EF and ESV by gated-SPECT have incremental prognostic values over prescan and perfusion information in predicting cardiac death, and they provide clinically useful risk stratification.

Separate acquisition rest thallium-201/stress technetium-99m sestamibi dual-isotope myocardial perfusion single-photon emission computed tomography: A clinical validation study

OBJECTIVES This study assessed the validity of a novel approach to myocardial perfusion scintigraphy that provides the opportunity to avoid the drawbacks of standard same-day rest/stress technetium-99m sestamibi myocardial perfusion studies by using separate-acquisition dual-isotope rest thallium-201 and exercise technetium-99m sestamibi single-photon emission computed tomography (SPECT). BACKGROUND Standard same-day rest/stress technetium-99m sestamibi myocardial perfusion studies are cumbersome, associated with a potential decrease in perceived stress defect severity compared with thallium-201 due to the presence of rest technetium-99m sestamibi and may be unable to differentiate hibernating from infarcted myocardium. METHODS The dual-isotope procedure was performed in 63 patients without previous myocardial infarction undergoing coronary angiography to evaluate sensitivity and specificity for coronary artery disease and in 107 patients with a low (< 5%) likelihood of coronary artery disease to evaluate normalcy rate. To validate defect reversibility, the dual-isotope SPECT study was compared with stress/rest technetium-99m sestamibi SPECT studies in a separate group of 31 patients with previous documented myocardial infarction who underwent a rest technetium-99m sestamibi study in addition to the dual-isotope SPECT study. RESULTS In angiographic correlations, dual-isotope SPECT demonstrated high sensitivity for detecting patients with > or = 50% stenosis (91%, 55 patients) and > or = 70% stenosis (96%, 52 patients). In a small group of patients, high specificity was also observed (75% for < 50% stenosis [8 patients] and 82% for < 70% stenosis [11 patients]). A very high normalcy rate of 95% was also found. In the patient group assessed for defect reversibility, in zones with no previous myocardial infarction, segmental agreement for defect type between rest thallium-201 and rest technetium-99m sestamibi studies was 97% (kappa = 0.79, p < 0.001). In myocardial infarct zones, segmental agreement for defect type was 98% (kappa = 0.93, p < 0.001). Image quality was generally good to excellent. CONCLUSIONS Our findings demonstrate that separate-acquisition dual-isotope myocardial perfusion SPECT is accurate for coronary artery disease detection, correlates well with rest-stress sestamibi studies for assessment of defect reversibility and results in good to excellent image quality. This approach provides an excellent method for the combined assessment of stress myocardial perfusion and myocardial viability.

Late reversibility of tomographic myocardial thallium-201 defects: an accurate marker of myocardial viability

Twenty-one patients were studied who underwent thallium-201 stress-redistribution single photon emission computed tomography (SPECT) both before and after coronary artery bypass grafting (n = 15) or transluminal coronary angioplasty (n = 6). All patients underwent thallium imaging 15 min, 4 h and late (18 to 72 h) after stress as part of the preintervention thallium-201 scintigram. In a total of 201 tomographic myocardial segments with definite post-stress thallium-201 perfusion defects in which the relevant coronary arteries were subsequently successfully reperfused, the 4 h redistribution images did not predict the postintervention scintigraphic improvement: 67 (85%) of the 79 4 h reversible as well as 88 (72%) of the 122 4 h nonreversible segments improved (p = NS). The 18 to 72 h late redistribution images effectively subcategorized the 4 h nonreversible segments with respect to postintervention scintigraphic improvement: 70 (95%) of the 74 late reversible segments improved after intervention, whereas only 18 (37%) of the 48 late nonreversible segments improved (p less than 0.0001). The frequency of late reversible defects and the frequency of postrevascularization improvement of late nonreversible defects are probably overestimated by this study because of referral biases. The cardiac counts and target to background ratios from late redistribution studies resulted in satisfactory cardiac images for visual interpretation. For optimal assessment of the extent of viable myocardium by thallium-201 scintigraphic studies, late redistribution imaging should be performed when nonreversible defects are observed on 4 h redistribution images.

Comparison of technetium 99m methoxy isobutyl isonitrile and thallium 201 for evaluation of coronary artery disease by planar and tomographic methods

To compare stress/rest technetium 99m methoxy isobutyl isonitrile (Tc-MIBI) with stress redistribution thallium 201(T1-201) myocardial perfusion imaging, 36 patients were studied by single photon emission computerized tomography (SPECT) and planar methods. For SPECT, overall sensitivities for identification of patients with coronary artery disease were 93% (14/15) by Tc-MIBI and 80% (12/15) by TI-201 (p = NS). For planar methods, overall sensitivities were 73% (11/15) by both TI-201 and Tc-MIBI. Overall specificity was 75% (3/4 patients with normal coronary arteries) for both tracers with SPECT and Tc-MIBI by planar imaging and was 50% for planar TI-201 (p = NS). The normalcy rates for overall identification of coronary artery disease were determined in 17 patients with a low likelihood of disease. For SPECT, normalcy rates were 100% by Tc-MIBI and 77% by TI-201 (p = NS). For planar, they were 94% by Tc-MIBI and 88% by TI-201 (p = NS). Vessel sensitivities in the 35 stenosed coronary arteries (greater than or equal to 50% stenosis) for SPECT were 87% by Tc-MIBI and 77% by TI-201 (p = NS). For planar, the vessel sensitivities were 60% by Tc-MIBI and 54% by TI-201 (p = NS). For both tracers, the SPECT vessel sensitivities were significantly higher (p less than 0.005) than planar vessel sensitivities. The vessel specificities in 22 coronary vessels with less than 50% stenosis were 86% by SPECT Tc-MIBI and TI-201, 80% by planar Tc-MIBI and 73% by planar TI-201 (p = NS, SPECT vs planar, Tc-MIBI vs TI-201). Regarding myocardial segmental agreement, for the presence of stress defects the agreement was 91% for the 720 SPECT segments and 95% for the 540 planar segments. For severity of stress defects based on semiquantitative visual scoring, the exact agreement was 87% for SPECT and 80% for planar. For the pattern of reversibility in myocardial segments with stress defects, the agreement was 97% for SPECT and 91% for planar. This study demonstrated that Tc-MIBI and TI-201 correlate well on both planar and SPECT images with respect to the identification of patients with coronary artery disease, identification of disease in individual coronary arteries, the presence and severity of perfusion defects, and the assessment of defect reversibility. Furthermore, SPECT Tc-MIBI was shown to be superior to planar Tc-MIBI for the identification of individual diseased vessels.

Adenosine myocardial perfusion single-photon emission computed tomography in women compared with men: Impact of diabetes mellitus on incremental prognostic value and effect on patient management

OBJECTIVES This study was designed to assess the incremental prognostic value of adenosine stress myocardial perfusion single-photon emission computed tomography (MPS) in women versus men, and to explore the prognostic impact of diabetes mellitus. BACKGROUND Limited data are available regarding the incremental value of adenosine stress MPS for the prediction of cardiac death in women versus men and the impact of diabetes mellitus on post-adenosine MPS outcomes. Of 6,173 consecutive patients who underwent rest thallium-201/adenosine technetium-99m sestamibi MPS, 254 (4.1%) were lost to follow-up, and 586 with early revascularization < or = 60 days after MPS were censored, leaving 2,656 women and 2,677 men. RESULTS Women had significantly smaller adenosine stress, rest, and reversible defects than men. During 27.0 +/- 8.8 month follow-up, cardiac death rates were lower in women than men (2.0%/year vs. 2.7%/year, respectively, p < 0.05). Before and after risk adjustment, cardiac death risk increased significantly in both men and women as a function of MPS results. Multivariable models revealed that MPS results provided incremental prognostic value over pre-scan data for the prediction of cardiac death in both genders. Also, while comparative unadjusted rates of early (< or =60 days post-test) coronary angiography (17% vs. 23%) and revascularization (8% vs. 12%) were significantly lower in women (p < 0.05), after adjusting for MPS, these rates were similar in men and women. Importantly, diabetic women had a significantly greater risk of cardiac death compared with other patients. Also, after risk adjustment, patients with insulin-dependent diabetes mellitus (IDDM) had higher risk of cardiac death for any MPS result than patients with non-insulin-dependent diabetes mellitus. CONCLUSION The findings suggest that adenosine MPS has comparable incremental value for prediction of cardiac death in women and men and that MPS is appropriately influencing subsequent invasive management decisions in both genders. Diabetic women and patients with IDDM appear to have greater risk of cardiac death than other patients for any MPS result.

Gated Technetium-99m Sestamibi for Simultaneous Assessment of Stress Myocardial Perfusion, Postexercise Regional Ventricular Function and Myocardial Viability: Correlation with Echocardiography and Rest Thallium-201 Scintigraphy

OBJECTIVES This study compares technetium-99m sestamibi (sestamibi) electrocardiographic (ECG) gated single-photon emission computed tomography (gated SPECT) and echocardiography for the evaluation of myocardial function and assesses the feasibility of single-injection, single-acquisition stress perfusion/rest function technetium-99m sestamibi-gated SPECT as an alternative to conventional stress/rest imaging for assessment of myocardial perfusion and viability. BACKGROUND Simultaneous assessment of stress perfusion and rest function is possible with gated SPECT acquisition of stress-injected technetium-99m sestamibi. METHODS Rest thallium-201 SPECT followed by stress sestamibi-gated SPECT (acquired 0.5 to 1 h after sestamibi injection) was performed in 58 patients. Echocardiography was performed immediately after or before gated SPECT in 43 of the patients. All studies were analyzed by semiquantitative visual scoring. Sestamibi-gated SPECT studies were read for stress perfusion and rest wall motion and thickening. Reversibility on sestamibi-gated SPECT was defined as the presence of a definite stress defect with normal or mildly impaired wall motion or thickening on gated SPECT: RESULTS There was high segmental score agreement between gated SPECT and echocardiography for wall motion (91%, kappa = 0.68, p < 0.001) and thickening (90%, kappa = 0.62, p < 0.001). Correlation for global wall motion (r = 0.98, p < 0.001) and thickening (r = 0.96, p < 0.001) scores between the two modalities was excellent. In 32 patients without previous myocardial infarction, there was excellent agreement for reversibility between stress sestamibi-gated SPECT and rest thallium-201/stress sestamibi (98%, kappa = 0.93, p < 0.01). However, in 26 patients with previous infarction, discordance between the two approaches was frequent, with 26% (20 of 78) of nonreversible defects by stress sestamibi-gated SPECT being reversible by rest thallium-201/stress sestamibi and 21% (23 of 112) of reversible defects by stress sestamibi-gated SPECT being nonreversible by rest thallium-201/stress sestamibi. CONCLUSIONS Gated SPECT of stress-injected sestamibi correlates well with echocardiographic assessment of regional function and thus adds information to perfusion SPECT: In patients without previous myocardial infarction, a single-injection stress perfusion/rest function approach using sestamibi-gated SPECT can substitute for conventional stress/rest myocardial perfusion imaging, adding a rest perfusion study only if there are nonreversible defects or consideration of attenuation artifacts. In patients with previous myocardial infarction, the gated SPECT approach does not replace the need for a rest perfusion study.

Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy

AIMS Although pre-revascularization ischaemia testing is recommended, the interaction between the extent of ischaemia and myocardial scar with performance of revascularization on patient survival is unclear. METHODS AND RESULTS We identified 13 969 patients who underwent adenosine or exercise stress SPECT myocardial perfusion scintigraphy (MPS). The percent myocardium ischaemic (%I) and fixed (%F) were calculated using 5 point/20-segment MPS scoring. Patients lost to follow-up (2.8%) were excluded leaving 13 555 patients [35% with history (Hx) of known coronary artery disease (CAD), 65% exercise stress, 61% male, age 66 ± 12]. Follow-up was performed at 12-18 months for early revascularization and at >7 years for all-cause death (ACD) (mean follow-up 8.7 ± 3.3 years). All-cause death was modelled using Cox proportional hazards modelling adjusting for logistic-based propensity scores, MPS, revascularization, and baseline characteristics. During FU, 3893 ACD (29%, 3.3%/year) and 1226 early revascularizations (9.0%) occurred. After risk-adjustment, a three-way interaction was present between %I, early revascularization, and HxCAD, such that %I identified a survival benefit with early revascularization in patients without prior myocardial infarction (MI), whereas no such benefit was present in patients with prior MI (overall model χ(2)= 3932, P < 0.001; interaction P < 0.021). Further modelling revealed that after excluding patients with scar >10% total myocardium, %I identified a survival benefit in all patients. CONCLUSION In this large observational series with long-term follow-up, patients with significant ischaemia and without extensive scar were likely to realize a survival benefit from early revascularization. In contrast, the survival of patients with minimal ischaemia was superior with medical therapy without early revascularization.