J Cardiovasc Med 2017, 18: a Service of Nuclear Cardiology, Madonna della Fiducia Clinic, b Ostia

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1 Original article Impact of coronary revascularization on the clinical and scintigraphic outlook of patients with myocardial ischemia Francesco Nudi a,b,c, Enrica Procaccini a,b, Francesco Versaci d, Alessandro Giordano e, Annamaria Pinto a,b, Giandomenico Neri a,b, Giacomo Frati f,g, Orazio Schillaci h, Alessandro Nudi c, Fabrizio Tomai i and Giuseppe Biondi-Zoccai g,h Aims The impact of coronary revascularization on outcomes and ischemic burden among patients with objective proof of ischemia is not yet established. We appraised the impact of revascularization on outcomes and residual ischemia in patients with objective evidence of ischemia at myocardial perfusion scintigraphy (MPS). Methods We queried our database for stable patients with myocardial ischemia at MPS, excluding those with prior myocardial infarction, systolic dysfunction, or cardiomyopathy. The impact of revascularization (defined as revascularization as first follow-up event) on outcomes and changes in myocardial was appraised with propensity-matched analyses. Results From 6195 patients, propensity matching yielded 1262 pairs of patients undergoing revascularization versus not undergoing revascularization. After 35.2 W 23.9 months, revascularization was associated with lower risks of cardiac death [2 (0.2%) versus 10 (0.8%) in those not revascularized, P U 0.038] and of the composite of cardiac death or myocardial infarction [17 (1.3%) versus 37 (2.9%), P U 0.007]. In addition, revascularization was associated with a higher rate of improvement in ischemia degree after 28.1 W 20.7 months of follow-up (P < 0.001), with 257 (69.3%) patients with moderate or severe ischemia at baseline MPS improving after revascularization versus 136 (42.0%) in the nonrevascularization group. Conversely, revascularization did not prove impactful on follow-up MPS in patients with only minimal or mild ischemia at baseline MPS (P < 0.001). Conclusion In a large series of patients with objective evidence of myocardial ischemia at MPS, especially when moderate or severe, revascularization was associated with a better clinical prognosis and a lower ischemic burden at repeat MPS. J Cardiovasc Med 2017, 18: Keywords: coronary artery bypass grafting, coronary artery disease, maximal ischemia score, myocardial ischemia, myocardial perfusion imaging, myocardial perfusion scintigraphy a Service of Nuclear Cardiology, Madonna della Fiducia Clinic, b Ostia Radiologica, c Etisan, Rome, d Division of Cardiology, S. Maria Goretti Hospital, Latina, Italy, e Institute of Nuclear Medicine, Catholic University, Rome, f Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, g Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, h Department of Nuclear Medicine, Tor Vergata University of Rome and i Division of Cardiology, European Hospital, Rome, Italy Correspondence to Francesco Nudi, MD, Service of Hybrid Cardio Imaging, Madonna della Fiducia Clinic, Via Giuseppe Mantellini 3, Rome, Italy Tel: ; fax: ; francesco.nudi@gmail.com Received 14 October 2016 Revised 6 December 2016 Accepted 30 December 2016 Introduction The impact of coronary artery disease (CAD) demands accuracy in selecting its most appropriate management strategy. In the last decade, myocardial perfusion scintigraphy (MPS) has become a cornerstone in the choice of treatment, with a favorable risk benefit and cost benefit impact based on three main reasons. 1 First, available studies on MPS have demonstrated the accuracy of this test in defining myocardial ischemia and provide prognostic data. 1 3 Second, recent comparative data on medical therapy versus coronary revascularization in stable CAD have questioned whether routine revascularization is always necessary in this setting. 4 7 Third, on a pathophysiologic basis, there is limited correlation between anatomic detail (i.e. coronary stenosis) as shown by coronary angiography and functional data (i.e. myocardial ischemia in the region fed by the stenotic coronary segment) as appraised invasively with fractional flow reserve or noninvasively with MPS or other imaging modalities. 6 9 The latter two aspects are intertwined, as recent studies have limited the enthusiasm for a treatment strategy based only on the anatomic detail in comparison with functional data, isolated or combined with the corresponding anatomic data. 6,7 The benefits stemming from revascularization in comparison with medical therapy seem stronger when myocardial ischemia is detectable, but the impact of revascularization on both clinical outcomes and ischemic burden remains unclear. 2,10 12 Indeed, any favorable impact of a given therapy for CAD should be accurately ß 2017 Italian Federation of Cardiology. All rights reserved. DOI: /JCM

2 Outlook of myocardial ischemia Nudi et al. 405 measured in terms of its capacity of reducing event rates as well as ischemia. As the evidence base informing the choice of management in patients with objective evidence of myocardial ischemia is still limited, 4 7,10 12 the goal of our work was to appraise the clinical outlook of a large series of patients with stable CAD and objective evidence of myocardial ischemia at MPS, distinguishing between those undergoing revascularization during follow-up versus those not receiving revascularization as first follow-up event. Methods Design The current study is a retrospective observational one stemming from a comprehensive observational research project of prospectively collected data entered into a dedicated administrative database (OPCCardioPro, Etisan; Rome, Italy), which has been approved by the local ethics committee. All patients provided written informed consent for imaging test, data collection, and followup assessment. Patients Patients undergoing MPS for the diagnostic or prognostic workup of CAD after 2004 were identified by querying our institutional database. Patients were excluded from retrieval if ineligible for at least 12-month follow-up, aged less than 18 years, reporting recent (<6 months) unstable angina or prior myocardial infarction (MI), left ventricular systolic dysfunction (ejection fraction <45%), or dilated cardiomyopathy (end-diastolic volume index >130 ml/ m 2 ), and, per definition, lack of ischemia at index MPS. In addition, to appraise changes in myocardial ischemia over time, we queried our database to link the first subsequent MPS performed for control purposes of ischemic heart disease [i.e. in the absence of recent (<6 month) instability]. This control MPS included MPS performed for obvious stable clinical symptoms (e.g. recurrence of stable angina), as well as those prescribed for routine monitoring of patients at the referring physician s discretion. Stress and imaging protocol Patients were exercised in a fasting state having discontinued long-acting nitrates, beta-blockers, and calciumchannel antagonists for at least 24 h. Symptom-limited dynamic or pharmacologic stress (with dipyridamole) testing were performed according to standard protocol. 3,13 15 Poststress and rest gated single-photon emission computed tomography was performed 3 min and 6 24 h after 201Tl injection with the patient in the supine position. A dual-head gamma camera (Millennium MG, GE Healthcare, Milan, Italy), equipped with a low-energy, generalpurpose collimator, was used according to a standard protocol for data acquisition and elaboration. The gated data were processed with completely automated software (QGS 3.0, Cedars-Sinai Medical Center; Los Angeles, California, USA). From the established 20-unit segmentation method, seven regions were graphically obtained to quantify the degree of myocardial perfusion. This segmentation approach was in keeping with the anatomic distribution of the main coronary vessels: 1 apical; 2 anteromedio-distal; 3 antero-proximal; 4 septal; 5 posterolateral; 6 lateral (which corresponds to the anatomic variability in coronary dominance); and 7 inferior. 3,14,15 Semiquantitative interpretation of stress/rest images was performed based on the seven-region model by consensus of two experienced observers using both visual assessment of the color-coded tomographic images for the three axes and the SD polar map of detectable tracer uptake, finally obtaining a five-point scoring system (0, normal uptake; 1 minimally reduced uptake; 2 mildly reduced uptake; 3 moderately reduced uptake; and 4 severely reduced or absent uptake). 3,14,15 This score directly yielded five classes of maximal ischemia score (MIS): 0 no ischemia; 1 minimal ischemia; 2 mild ischemia; 3 moderate ischemia; and 4 severe ischemia. 3,14,15 Outcomes of interest were the long-term rates of allcause death, cardiac death, MI, revascularization, or their composite, with cardiac death defined as any death with a specific cardiac cause or without any established noncardiac cause but occurring suddenly. Revascularization was performed according to the referring physician s discretion, including timing and type (percutaneous versus surgical). Accordingly, most likely a conservative management was chosen for patients at higher risk of complications and at lower likelihood of benefit from revascularization. Details on coronary angiography and revascularization occurring before MPS were also systematically sought, distinguishing CAD burden according to the number of vessels with one or more diameter stenosis at least 70%. Statistical analysis Continuous variables are reported as mean SD, and categorical variables are reported as N (%). To minimize confounding, propensity scores were computed with a nonparsimonious binary logistic regression analysis and used to create 1 : 1 matched pairs with a propensity score caliper with the Stata psmatch2 command, including several variables (Online supplement; com/jcm/a102). Afterward, propensity-matched pairs were used to compute P values for effects with linear regression for panel data for continuous variables, logistic regression for panel data for categorical variables, and Cox proportional hazard analysis stratified by propensity score deciles for time to event data. In addition, standardized differences (%) were computed, with differences considered minor if 10% or less. 16 Several sensitivity analyses were performed, including unadjusted bivariate analyses in the overall sample and in patients not matched, using

3 406 Journal of Cardiovascular Medicine 2017, Vol 18 No 6 unpaired Student t test for continuous variables and Fisher exact test for categorical variables. Notably, prior disease or procedures were not considered as a treatment for the study purpose because their clinical impact was already encompassed by the baseline MPS and also taken into account as confounders by the propensity score analysis. Statistical significance was set at the two-tailed 0.05 level. Computations were performed with Stata 13 (StataCorp, College Station, Texas, USA). Results Out of a total of 6195 patients, 1780 (28.7%) undergoing revascularization and 4415 (71.2%) not undergoing revascularization as first follow-up event (Online supplement; propensity matching yielded 1262 pairs of patients (totaling 2524). Propensity matching reduced substantially the imbalances in baseline features and characteristics of the first MPS (Tables 1 and 2), in comparison with the overall population. Specifically, P values and standardized differences were non-significant for all baseline and procedural features, with the notable exclusion of the antiplatelet therapy during follow-up, which was more common in the revascularization group (P ¼ 0.279, standardized difference ¼ 12.8%); statin therapy during follow-up, which was also more common in the revascularization group (P ¼ 0.591, standardized difference ¼ 10.3%); and baseline MIS, was with minimal ischemia more common in the nonrevascularization group (P ¼ 0.007, standardized difference ¼ 9.8%). Clinical outcomes after months of follow-up showed that patients undergoing revascularization were significantly less likely to suffer from cardiac death [2 (0.2%) versus 10 (0.8%), P ¼ 0.038] and the composite of cardiac death or MI [17 (1.3%) versus 37 (2.9%), P ¼ 0.007; Table 3], with an evident interaction between severity of myocardial ischemia at baseline MPS and the outlook after revascularization. Specifically, the benefits of revascularization appeared greater, at least in absolute terms, in patients with moderate or severe ischemia at baseline MPS [cardiac death in 8 (1.4%) undergoing revascularization versus 22 (4.0%) in the others] than in patients with minimal or mild ischemia at baseline MPS [9 (1.3%) versus 15 (2.1%)] (Fig. 1). Similar results were found at survival analysis, with revascularization being associated with a significantly lower hazard of cardiac death or MI [hazard ratio ¼ 0.46 (95% confidence interval ), P ¼ 0.009]. Notably, coronary angiography, without ensuing revascularization, was also performed during follow-up in 229 (18.2%) patients in the conservative group. Repeat MPS was performed after months of follow-up in 1723 patients. Revascularization was associated with significant improvements at follow-up MPS in Table 1 Patient features after propensity matching according to the occurrence of coronary revascularization as first event during follow-up Feature No PCI/CABG (N ¼ 1262) PCI/CABG (N ¼ 1262) P Standardized difference Age (years) % BSA (m 2 ) % BMI (kg/m 2 ) Female sex 187 (14.8%) 184 (14.6%) % Family history of coronary artery disease 609 (48.3%) 605 (47.9%) % Diabetes mellitus No 843 (66.8%) 806 (63.9%) 6.1% Impaired glucose tolerance 85 (6.7%) 95 (7.5%) 3.1% Noninsulin-dependent diabetes 285 (22.6%) 301 (23.9%) 3.1% Insulin-dependent diabetes 49 (3.9%) 60 (4.8%) 3.9% Hypertension 961 (76.2%) 958 (75.9%) % Hypercholesterolemia 767 (60.8%) 775 (61.4%) % Hypertriglyceridemia 246 (19.5%) 239 (18.9%) % Smoking history 862 (68.3%) 877 (69.5%) % Prior coronary revascularization 548 (43.4%) 563 (44.6%) % Prior coronary angiography findings No significant stenosis 78 (11.7%) 55 (9.4%) 7.5% Single-vessel disease 243 (36.5%) 231 (39.6%) 6.4% Two-vessel disease 199 (29.9%) 188 (32.2%) 5.0% Three-vessel disease 146 (21.9%) 110 (18.8%) 7.7% Anginal symptoms 833 (66.0%) 820 (65.0%) % Atrial fibrillation 6 (0.5%) 6 (0.5%) 1 0 Chronic renal failure 37 (2.9%) 27 (2.1%) % Medical therapy Angiotensin-converting enzyme inhibitor 596 (68.3%) 585 (68.8%) % or angiotensin-receptor blocker Antiplatelet agent 782 (89.6%) 792 (93.2%) % Beta-blocker 522 (59.8%) 520 (61.2%) % Calcium-channel antagonist 276 (31.6%) 275 (32.4%) % Nitrate 253 (29.0%) 231 (27.2%) % Statin 671 (76.9%) 689 (81.1%) % BMI, body mass index; BSA, body surface area; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention.

4 Outlook of myocardial ischemia Nudi et al. 407 Table 2 Features of baseline myocardial perfusion scintigraphy and coronary angiography after propensity matching according to the occurrence of coronary revascularization as first event during follow-up Feature No PCI/CABG (N ¼ 1262) PCI/CABG (N ¼ 1262) P Standardized difference Type of stress Exercise 1158 (91.8%) 1136 (90.0%) 6.3% Pharmacologic stress 104 (8.2%) 126 (10.0%) 6.3% Chest pain during stress 373 (29.6%) 363 (28.8%) % Maximum ST segment deviation (mm) % Workload (W) % Metabolic equivalent of task (MET) % Stress left ventricular ejection fraction (%) % Stress left ventricular end-diastolic volume index (mm/m 2 ) % Maximal ischemia score Minimal ischemia 241 (19.1%) 194 (15.4%) 9.8% Mild ischemia 468 (37.1%) 494 (39.1%) 4.1% Moderate ischemia 423 (33.5%) 466 (36.9%) 7.1% Severe ischemia 130 (10.3%) 108 (8.6%) 5.8% CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention. terms of chest pain (P ¼ 0.050), ischemia severity (P < 0.001), and ejection fraction (P ¼ 0.001). There was also a clear interaction between ischemia severity at baseline and the benefits of revascularization, as 257 (69.3%) patients with moderate or severe ischemia at baseline MPS improved after revascularization in comparison with 136 (42.0%) in the nonrevascularization group. Conversely, revascularization did not prove impactful on follow-up MPS in patients with only minimal or mild ischemia at baseline MPS [with no, minimal, or mild ischemia at follow-up in 441 (92.1%) of those undergoing revascularization versus 516 (94.0%) of those not undergoing revascularization, P < for the interaction between baseline severity of ischemia at MPS and revascularization] (Fig. 2). Even at survival analysis, revascularization was associated with a higher likelihood of improvement in ischemia [hazard ratio ¼ 1.47 ( ), P ¼ 0.019]. Several sensitivity analyses, including analyses encompassing all patients from the initial set of 6195 patients, as well as analyses confined to those with moderate or severe baseline ischemia but excluded from propensity matching, confirmed in direction and magnitude of statistical significance the main analyses. Finally, explorative comparative analysis of percutaneous versus surgical revascularization did not show significant differences between the two types of revascularization. Discussion The high prevalence of CAD and the high costs associated with its management have led to a comprehensive reappraisal of the available therapeutic strategies, that is, medical therapy or coronary revascularization, mainly concerning two key issues: the ability to reduce myocardial ischemia and its impact on patient prognosis. MPS is a cornerstone in the workup of patients with suspected or established CAD, given its noninvasiveness, wide availability, and precise diagnostic and prognostic details. 1,10,13 In several observational studies, revascularization appeared beneficial, especially in patients with higher grade ischemia. 10 Nonetheless, recent pivotal randomized trials appraising the prognostic benefit of revascularization versus optimal medical therapy have not systematically exploited results of MPS or similar imaging modalities as an entry criterion. 4,5 Specifically, although all patients enrolled in the Clinical Outcomes Utilizing Revascularization And Aggressive Drug Evaluation (COURAGE) trial and in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) study had a detailed Table 3 Clinical outcomes after propensity matching according to the occurrence of coronary revascularization as first event during follow-up Outcome No PCI/CABG (N ¼ 1262) PCI/CABG (N ¼ 1262) P One-year follow-up Cardiac death 4 (0.3%) 2 (0.2%) Myocardial infarction 15 (1.2%) 7 (0.6%) Cardiac death or myocardial infarction 19 (1.5%) 9 (0.7%) Long-term follow-up Time to last contact (months) Death 17 (1.4%) 2 (0.2%) Cardiac death 10 (0.8%) 2 (0.2%) Myocardial infarction 27 (2.1%) 15 (1.2%) Cardiac death or myocardial infarction 37 (2.9%) 17 (1.3%) CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention.

5 408 Journal of Cardiovascular Medicine 2017, Vol 18 No 6 Fig % 5.0% 4.0% 3.0% 2.0% 1.0% 0.0% 0.3% 0.3% Cardiac death 2.1% No PCI/CABG 1.3% Minimal or mild ischemia at baseline MPS PCI/CABG Moderate or severe ischemia at baseline MPS coronary anatomy assessment at study entry, objective proof of myocardial ischemia was not a mandatory selection criterion. 4,5 Conversely, the FAME trials demonstrate the lack of correlation between anatomic and functional data, and also the importance of the presence of myocardial ischemia, as mainly patients with objective proof of ischemia benefited from coronary revascularization. 6,7 Subgroup analyses exploiting MPS from COURAGE and BARI 2D (serially and only at follow-up, respectively) have shed important insights on the role of revascularization versus medical therapy in stable CAD. Specifically, Shaw et al. 11 analyzed repeat MPS in 314 patients randomized to revascularization versus medical therapy, finding that at least 5% decrease in myocardial ischemia was achieved in 33% of those undergoing PCI versus 19% 1.5% 0.0% 4.0% 1.4% Cardiac death or MI Cardiac death Cardiac death or MI Incidence of clinical outcomes at long-term follow-up after propensity matching according to the occurrence of coronary revascularization as first event during follow-up, stratifying patients according to ischemia severity at baseline myocardial perfusion scintigraphy (MPS). CABG, coronary artery bypass grafting; MI, myocardial infarction, PCI, percutaneous coronary intervention. Fig % 94% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 92% 0.3% 0.3% 6% 8% No, minimal or mild No PCI/CABG Moderate or severe Minimal or mild ischemia at baseline MPS 42% 1.5% PCI/CABG 69% 0.0% No, minimal or mild 58% 31% Moderate or severe Moderate or severe ischemia at baseline MPS Prevalence of maximal ischemia score (MIS) at repeat myocardial perfusion scintigraphy (MPS) according to MIS at baseline MPS and after propensity matching according to the occurrence of coronary revascularization as first event during follow-up. CABG, Coronary artery bypass grafting; PCI, percutaneous coronary intervention. treated medically. Notably, if the analysis was limited to only those with moderate or severe baseline ischemia, PCI reduced myocardial ischemia (using an absolute 5% cutoff) in 78% of patients treated with revascularization versus 52% for medical therapy. 11 The BARI 2D trial has not reported similar data on paired MPS, but did report on 1505 patients undergoing follow-up MPS. 12 In this patient sample, 59% of patients undergoing revascularization had no evidence of myocardial ischemia in comparison with 49% of those undergoing medical therapy only. Of note, in these trials as well as in a similar observational studies, persistent ischemia at follow-up MPS was an independent prognostic factor. Building upon these data and the prior evidence base on the accurate prognostic role of MPS, we aimed to appraise the clinical and ischemic outlook of patients with objective proof of myocardial ischemia at MPS at our institution. Our results suggest that revascularization is associated, among those with moderate or severe ischemia at baseline MPS, with important clinical benefits, including a lower risk of cardiac death or MI, as well as a lower prevalence of residual moderate or severe ischemia at repeat MPS. Conversely, there was no remarkable benefit of revascularization on follow-up ischemia among patients without moderate or severe ischemia at baseline. Accordingly, our findings clearly reinforce the unique role of MPS to guide decision-making: absence of moderate or severe ischemia at baseline accurately predicted a favorable clinical and ischemic outlook. It should though be borne in mind that the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches randomized trial is ongoing, comparing in 5000 selected patients with at least moderate ischemia on stress imaging a routine invasive strategy with cardiac catheterization followed by revascularization and optimal medical therapy versus a conservative strategy of optimal medical therapy, with catheterization and revascularization reserved for those who fail optimal medical therapy. 17 The current work has several limitations, including the observational, administrative, and retrospective design. The nonrandomized design may give indirect advantages to the revascularization or the nonrevascularization groups, without any easy logical approach to identify the impact of confounders (especially unknown or unreported). Indeed, the fact that patients dying before any chance of being revascularized were assigned to the nonrevascularization group may lead to tautology issues. In addition, the decision to perform repeat MPS for control purposes was based on clinical criteria, and thus there was an inherent selection bias in performing a repeat MPS. Nonetheless, to minimize the impact of this confounding feature, repeat MPS was included as a covariate in the propensity model. However, control MPS was performed in about 50% of the patients, thus softening our conclusions on the effects of revascularization on scintigraphic outcomes. Finally, detailed analysis of angiographic

6 Outlook of myocardial ischemia Nudi et al. 409 disease was beyond the scope of our work (for baseline angiographies) or not possible (for post-mps angiographies in the nonrevascularization group), and thus we cannot exclude residual confounding or effect modification by other, and more refined, angiographic features, such as SYNTAX score. Conclusion In a large series of patients with objective evidence of myocardial ischemia at MPS, especially when moderate or severe, revascularization was associated with a better clinical prognosis and a lower ischemic burden at repeat MPS. Acknowledgements The work was supported by Etisan, Rome, Italy. There are no conflicts of interest. References 1 Beller GA. First annual Mario S. Verani, MD, Memorial lecture: clinical value of myocardial perfusion imaging in coronary artery disease. J Nucl Cardiol 2003; 10: Iskander S, Iskandrian AE. Risk assessment using single-photon emission computed tomographic technetium-99m sestamibi imaging. J Am Coll Cardiol 1998; 32: Nudi F, Pinto A, Procaccini E, et al. A novel clinically relevant segmentation method and corresponding maximal ischemia score to risk-stratify patients undergoing myocardial perfusion scintigraphy. J Nucl Cardiol 2014; 21: Boden WE, O Rourke RA, Teo KK, et al., COURAGE Trial Research Group. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007; 356: Frye RL, August P, Brooks MM, et al., BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009; 360: Tonino PA, De Bruyne B, Pijls NH, et al., FAME Study Investigators. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009; 360: De Bruyne B, Pijls NH, Kalesan B, et al., FAME 2 Trial Investigators. Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012; 367: Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 1995; 92: Gaur S, Achenbach S, Leipsic J, et al. Rationale and design of the HeartFlowNXT (HeartFlow analysis of coronary blood flow using CT angiography: NeXt steps) study. J Cardiovasc Comput Tomogr 2013; 7: Hachamovitch R, Hayes SW, Friedman JD, et al. Comparison of the shortterm survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003; 107: Shaw LJ, Berman DS, Maron DJ, et al., COURAGE Investigators. 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. Circulation 2008; 117: Shaw LJ, Cerqueira MD, Brooks MM, et al. Impact of left ventricular function and the extent of ischemia and scar by stress myocardial perfusion imaging on prognosis and therapeutic risk reduction in diabetic patients with coronary artery disease: results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. J Nucl Cardiol 2012; 19: Berman DS, Kiat H, Friedman JD, et al. Separate acquisition rest thallium- 201/stress technetium-99m sestamibi dual-isotope myocardial perfusion single-photon emission computed tomography: a clinical validation study. J Am Coll Cardiol 1993; 22: Nudi F, Neri G, Schillaci O, et al. Time to and risk of cardiac events after myocardial perfusion scintigraphy. J Cardiol 2015; 66: Nudi F, Schillaci O, Neri G, et al. Prognostic impact of location and extent of vessel-related ischemia at myocardial perfusion scintigraphy in patients with or at risk for coronary artery disease. J Nucl Cardiol 2016; 23: Biondi-Zoccai G, Romagnoli E, Agostoni P, et al. Are propensity scores really superior to standard multivariable analysis? Contemp Clin Trials 2011; 32: Wasilewski J, Poloński L, Lekston A, et al. Who is eligible for randomized trials? A comparison between the exclusion criteria defined by the ISCHEMIA trial and 3102 real-world patients with stable coronary artery disease undergoing stent implantation in a single cardiology center. Trials 2015; 16:411.