SPECT myocardial perfusion imaging as an endpoint

Melody Sherwood Fadi G. Hage FACC Jack Heo FACC Leslee J. Shaw FACC FASNC Manuel D. Cerqueira FACC FASNC Ami E. Iskandrian MACC FASNC The wide acceptance of SPECT myocardial perfusion imaging (MPI) in patient care has led increasingly to its use as an endpoint in single- or multi-center studies.1-6 These studies differ in scope and complexity and may involve issues beyond reproducibility and repeatability, not to say that these are not important. We shall look at two examples to bring up salient features.3,4 Two NIH-NHLBI sponsored studies ''the international study of comparative health effectiveness with medical and invasive approaches (ISCHEMIA)'' trial will be conducted in 8,000 patients from *400 worldwide centers and ''The effect of transendocardial delivery of autologous bone marrow mononuclear cells in chronic heart failure (The FOCUS-CCTRN Trial)'' in 92 patients was completed in five centers are examples worth considering because of marked variability in design and requirements.3,4 The ISCHEMIA trial will compare a strategy of catheterization-guided care to no catheterization-guided care. Importantly, only patients with moderate-severe ischemia will be enrolled, defined with stress MPI as C10% ischemic myocardium. All patients will undergo a blinded coronary computed tomographic angiography to exclude significant left main stenosis and to rule out non-obstructive CAD.3 The FOCUS Trial examined whether administration of bone marrow mononuclear cells, through transendocardial injections, would improve myocardial perfusion, reduce left ventricular (LV) end-systolic volume, and enhance maximal oxygen consumption in patients with IMAGE INTERPRETATION - coronary artery disease (CAD) or LV dysfunction, and limiting heart failure or angina.4 In the ISCHEMIA trial, the inclusion criteria required the presence of ischemia involving at least 10% of LV myocardium as this trial follows prior stable ischemic heart disease trials by focusing on higher risk CAD patients with a substantial ischemic burden, but importantly is based on the current equipoise as to whether the degree of ischemia remains vital to therapeutic effectiveness; notably a strategy that includes revascularization, while in the FOCUS trial, one of the three primary endpoints required at least 10% absolute reduction in ischemic burden. Unfortunately, requiring 10% ischemic burden excluded too many patients and the final third of enrolled patients included those with both fixed and reversible defects. Although an echocardiographic core lab was used to standardize the echo measured variables, SPECT studies were interpreted only at the site of enrollment. On-site reading tends to overcall ischemia when compared to core lab reading. Of note the ISCHEMIA trial required one study at entry while the FOCUS trial required two studies, one before and the second 6 months after treatment. How is 10% of the myocardium measured? Is the use of 10% appropriate in both the studies? While these questions might sound simple; in point of fact they are anything but simple and they will be the subject of this editorial viewpoint (Table 1). Just to repeat, in the ISCHEMIA trial, the 10% threshold for ischemia was one of the entry criteria while in the FOCUS trial it was one of the endpoints. Interpretation of MPI is easier and more reproducible when the images are of high quality or if they are clearly normal regardless of whether visual or automated methods are used.7-16 Quality is difficult to define but it is affected by many steps during acquisition and processing including patient motion, filtering, collimation, alignment, and scaling, issues that are not corrected by attenuation correction algorithms whether done by CT or external transmission source. It is for this reason that in multi-center trials, a core laboratory is recommended to assure uniform processing. Even when everything is performed consistent with current guideline statements, there remain unpredictable factors of attenuation artifacts and tracer activity in the liver and more importantly in an adjacent loop of the bowel. These factors could vary in the rest or stress studies and that is one of the reasons of why studies that include serial testing are inherently more difficult than studies based on a single study.7,8 In patient care studies, serial images should be reviewed side-by-side so that the reader can adjudicate the contributions of the extraneous factors on image interpretation (whether done by visual or automated analysis, see below). This crucial step of side-by-side reading is often not used or allowed in research studies, which in our opinion is unfortunate as this direct simultaneous comparison with treatment blinding provides the best opportunity to assess the factors listed above and how they may impact on serial study measurements. How should the images be interpreted? There are several ways but the common approaches include the use of a segmental scoring system or quantitative polar maps. It should be clear that even the automated methods require some reader supervision and blinded acceptance of computer generated scores is ill-advised. Automated or more precisely supervised automated methods have better performance in terms of reproducibility (same image processed twice) and repeatability (two sequential acquisitions after tracer injection) than visual analysis, which in research studies translate to a smaller sample size.7,11 SCORES AND MAPS The scoring system could be generated by visual or automated methods. The summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) are global scores that reflect total, fixed, and reversible abnormality, respectively, and could readily be converted to % LV myocardial abnormality [if a normal SSS is 68 for example (17-segment model where a score of 4 in a segment indicates a normal tracer activity; 17 9 4 = 68), then SSS of 34 means that the perfusion abnormality involves 50% of LV myocardium].7,8 The SSS or % abnormality is a global number and thus does not specify the vascular territory or whether the abnormality is in 1, 2, or 3 vascular territories (although such could be done). Though the SSS (or SDS or SRS) could be converted to % LV abnormality, this may or may not be similar to the % abnormality obtained by polar maps because a given SSS may represent a mild abnormality involving a number of segments or a severe abnormality involving much smaller number of segments in which case the polar maps will show a larger abnormality in the first than the second patient. The polar maps (or bulls eye images), which was used in the COURAGE (optimal medical therapy with or without percutaneous coronary intervention to reduce ischemic burden: results from the COURAGE trial) and BARI2D (a randomized trial of therapies for type 2 diabetes and coronary artery disease) nuclear sub-studies have provided information on % total abnormality (fixed ? reversible), % reversible (...truncated)