Stress/Rest Myocardial Perfusion Abnormalities by Gated SPECT: Still the Best Predictor of Cardiac Events in Stable Ischemic Heart Disease

Patients

Starting in 2000, we adopted a fully computerized clinical report that allowed handling and recording of the clinical and administrative data of all patients admitted. From this database, we retrospectively selected a group of consecutive patients admitted for known or suspected IHD who had undergone a complete diagnostic work-up that included stress/rest myocardial perfusion imaging and coronary arteriography. Patients with acute or recent ST segment elevation myocardial infarction (MI), previous coronary artery bypass graft surgery, chronic renal failure under dialysis treatment, or primary overt hyperthyroidism (free triiodothyronine level > 420 pg/dL or free thyroxine level > 1.85 ng/dL, with an undetectable thyrotropin level) were excluded from the study. Thus, a study cohort of 676 patients was selected; patient characteristics are shown in Tables 1 and 2.

At hospital discharge, 492 of these patients (73%) were affected by IHD. In 479 patients, the diagnosis was based on the angiographic evidence of coronary stenoses in at least 1 of the major coronary arteries or secondary branches. In 13 patients with normal coronary arteries, the diagnosis was based on the evidence of a previous MI (documented by clinical records, 8 patients) or on the recording of electrocardiographic patterns of Prinzmetal angina (collected during hospitalization, 5 patients). The 184 patients with normal coronary arteries in whom the suspicion of IHD was not confirmed were affected by dilated cardiomyopathy or myocarditis (60 patients), syndrome X (77 patients), or valvular heart disease (8 patients). The remaining 39 subjects were unaffected by disease.

Diagnostic Work-up

The diagnostic work-up included clinical evaluation, laboratory tests, 12-lead electrocardiography (ECG), 2-dimensional echocardiography, stress/rest gated SPECT, and coronary arteriography. Gated SPECT was performed before coronary arteriography in 623 patients (92%) and after arteriography in the remaining 53 patients (8%). The time interval between gated SPECT and coronary angiography was 11 ± 4 d (range, 1–19 d). Patients experiencing cardiac events during this time were excluded from the study.

Follow-up

Patients were followed up by periodic examinations in the outpatient setting. In patients who did not attend this program, follow-up data were obtained using written telephone interview (administered to the patient or the patient's family by dedicated personnel) or mail questionnaires. In case of negative answers, the local demographic registry was queried. Cardiac death was defined as death caused by acute MI, death caused by heart failure, or a sudden and unexpected death not related to any possible cause; nonfatal MI was documented by clinical records. The study protocol was approved by the local committee on human research. In addition, patients gave written informed consent to have their clinical data prospectively collected for research purposes.

Statistical Analysis

Continuous variables were expressed as mean ± SD, and categoric variables were expressed as percentages. The primary endpoint was the occurrence of cardiac events, defined as cardiac death or nonfatal acute MI. Predictors of survival were initially identified by univariate analysis performed using the Cox proportional hazards regression model. Categoric variables were included in the model as dummy variables. The independent predictors of survival at each of the different stages of diagnostic work-up were identified using multivariate Cox regression analysis and included all the variables collected at that stage. A backward elimination procedure was used to select the independent variables, that is, those variables resulting in a significant outcome. Once the independent predictors of survival at the different steps of the diagnostic work-up were identified, these predictors were entered into a Cox proportional hazards regression analysis to obtain the final independent predictors of cardiac event–free survival. The incremental prognostic information obtained at each step of the diagnostic process was evaluated by the χ² improvement.

To assess the prognostic value of the Cox proportional hazards regression models, we used the time-dependent receiver-operating-characteristic (ROC) curve estimation from censored survival data using the nearest-neighbor estimation method (26). The linear prognostic scores obtained from the final Cox models were considered in the analysis. The area under the time-dependent ROC curves (AUC) was used to express the prognostic accuracy of the final Cox models. All statistical tests were 2-tailed; a P value of less than 0.05 was considered significant. Statistical analysis was performed with free and commercially available software (JMP 4.0 [SAS Institute Inc.]; SPSS 10.0 [SPSS Inc.]; R: A Programming Environment for Data Analysis and Graphics, version 2.7.1 [R Foundation for Statistical Computing]; and STATA [StataCorp LP]).

Predictors of Cardiac Event–Free Survival

As shown in Table 3, several variables were significant predictors of cardiac event–free survival at univariate analysis. Multivariate Cox regression analysis determined that the following variables were independent predictors at the different stages of diagnostic work-up: among clinical data, a previous MI; among laboratory tests, serum creatinine and the ratio between LDL and HDL cholesterol levels; among electrocardiographic and echocardiographic variables, LVEF; among the variables extracted from gated SPECT, SRS and SDS; and among angiographic variables, the score of the extent of coronary stenoses (Table 4). When all the above predictors were evaluated together (Table 5), only SRS and SDS, serum creatinine, and LDL/HDL cholesterol levels were (in descending order of significance) the final independent predictors of cardiac event–free survival (global χ² = 38.84, P < 0.0001). An SRS value greater than or equal to 4 identified patients at risk of cardiac events, with a sensitivity of 48% and a specificity of 70%. An SDS value greater than or equal to 6 identified patients at risk, with a sensitivity of 48% and a specificity of 75%.

In the 492 patients in whom the diagnosis of IHD was ascertained, SRS (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.12–1.28; χ² = 26.67; P < 0.0001) and SDS (HR, 1.15; 95% CI, 1.04–1.28; χ² = 7.30; P = 0.0069) were the only final independent predictors of survival (global χ² = 27.72, P < 0.0001). The AUC showed a good prognostic value for the 2 final Cox models (AUC = 0.75 for total patients [95% CI, 0.68–0.82] and AUC = 0.73 for patient with ascertained IHD [95% CI, 0.65–0.82]).

Incremental Prognostic Value

Figure 2 demonstrates that the prognostic information significantly increased, adding to the clinical variables those extracted from laboratory tests, 12-lead ECG, echocardiography, and gated SPECT in hierarchical order. The selected variables were those that were independent predictors of event-free survival at the different stages of diagnostic work-up. Once the above variables were considered, coronary arteriography did not add any significant prognostic information. Conversely, if the information provided by coronary arteriography was made available after ECG and echocardiography, gated SPECT still significantly improved the prognostic information (Fig. 3).

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 2. 

Incremental prognostic value during diagnostic work-up. Information provided by stress/rest gated SPECT is available after clinical examination, laboratory tests, and ECG and echocardiography but before coronary arteriography.

• Download figure
• Open in new tab
• Download powerpoint

FIGURE 3. 

Prognostic value during diagnostic work-up when information provided by gated SPECT is available after coronary arteriography.

Effect of Treatment

Of the 492 patients with ascertained IHD, 187 were treated medically and 305 were revascularized (180 by percutaneous coronary interventions, 110 by coronary artery bypass graft surgery, and 15 by both). Medically treated patients had less extensive IHD than those who were revascularized. Specifically, medically managed patients had lower values of SDS (4.9 ± 3.5 vs. 5.7 ± 2.9, P = 0.0001), a lower number of coronary stenotic vessels (0.7 ± 1.0 vs. 1.9 ± 0.9, P = 0.0005), and a lower score of coronary stenoses (6.0 ± 4.8 vs. 8.7 ± 4.2, P < 0.0001) than did revascularized patients. Cardiac events occurred in 12 medically managed and in 25 revascularized patients. At multivariate Cox regression analysis, the type of treatment (P = 0.485) did not affect the ability of gated SPECT (SRS: HR, 1.20; 95% CI, 1.12–1.28; P = 0.000; and SDS: HR, 1.15; 95% CI, 1.04–1.27; P = 0.008) to predict event-free patient survival.

A total of 256 patients were revascularized within 60 d of nuclear testing (165 by percutaneous coronary interventions, 84 by coronary artery bypass graft surgery, and 7 by both) and 49 subsequently. Censoring of the patients at the time of revascularization cardiac events occurred in 12 patients, and SRS was the only final independent predictor of cardiac event–free survival (HR, 1.24; 95% CI, 1.12–1.37; P = 0.0006).

Gated SPECT and LVEF

Since the initial study performed using gated blood-pool scintigraphy (30) in post-MI patients, LVEF has been acknowledged to be a powerful predictor of mortality in patients with IHD. The prognostic impact of LVEF has been widely confirmed in large multicenter studies (11,31). Furthermore, the prognostic impact of LVEF has been extended to a wide variety of patients, including those with heart failure, cardiomyopathies, and valvular heart disease (32). Thus, the value of LVEF has become one of the main determinants of therapeutic decision making, as in the case of implantable cardioverter defibrillators or cardiac resynchronization therapy (33). In the present study, when the prognostic power of LVEF at rest was compared with that of scar-tissue extent, the power of LVEF disappeared.

This observation is not surprising, because LVEF represents a global normalized ratio and is susceptible to changes in preload and afterload and contractility. On the other side, SRS is an index of normalized uptake, coupled to viable or scarred segments and normalized to control subjects, and is independent of hemodynamic changes, myocardial contractility, and medical treatment. The superiority of perfusion imaging in prognostic stratification might suggest a superiority in guiding decision making; however, this hypothesis should be addressed in specific prospective studies.

In a previous study, poststress EF and end-systolic LV volumes were shown to have incremental prognostic values over prescan and perfusion information (34). Subsequently, poststress EF was the strongest predictor of mortality, whereas the SDS was the strongest predictor of MI (35). The divergence with these studies could be explained by the way we performed the prognostic analysis. Indeed, Sharir et al. (34,35) censored patients revascularized within 60 d of nuclear testing. However, when we censored revascularized patients the number of events was small, and SRS was the only final independent predictor of cardiac events. Furthermore, we combined the 2 endpoints cardiac death and nonfatal MI. Finally, enrolling patients who had undergone coronary arteriography might have selected a patient population at higher risk than in previous studies, in which patients were enrolled mainly on the basis of symptoms and the pretest probability of IHD.

Gated SPECT and Coronary Anatomy

The greater diagnostic accuracy of stress-induced myocardial perfusion abnormalities over electrocardiographic signs of ischemia and greater contribution of nuclear imaging to risk stratification are widely acknowledged. It is also well known that myocardial perfusion imaging is superior to coronary arteriography in risk stratification of patients with IHD. In 1992, Pollock et al. demonstrated that myocardial perfusion is superior to coronary arteriography in risk stratification of IHD patients (4); at variance with our study, these authors used ²⁰¹Tl and static planar imaging, and all the patients had suspected IHD. In a series of 316 patients, Iskandrian et al. (5) showed the independent and incremental prognostic information of exercise SPECT thallium imaging even when catheterization data are available; unlike us, these authors studied patients with definite coronary artery disease who were medically treated. In addition, in none of the above studies were laboratory variables and echocardiography considered. This study largely confirms the advantages of perfusion imaging over clinical, electrocardiographic, laboratory, and resting echocardiographic data and shows the incremental prognostic value of gated SPECT information over angiographic data. Thus, the severity and extent of stress-induced myocardial perfusion abnormalities provide a better prognostic stratification than does the severity of coronary artery disease, using both a 50% and a 70% stenosis threshold and taking into account the proximality of the lesions along the coronary tree. This observation should suggest a wider use of myocardial perfusion imaging in risk stratification of patients with known or suspected IHD.

Gated SPECT and Laboratory Examinations

In previous myocardial perfusion imaging studies, the prognostic value of several laboratory tests has received little attention. Chronic kidney disease is known to be an important risk factor for atherosclerosis. In the setting of chronic kidney disease, myocardial perfusion abnormalities are common (13). However, most radionuclide imaging studies have examined populations with end-stage renal failure. Whether mild forms of renal dysfunction are associated with IHD among patients with positive myocardial perfusion imaging has not been investigated previously. This study shows the prognostic impact of even mild increments in creatinine levels.

In cardiac patients, a low triiodothyronine syndrome has been related to a poor outcome (14), and a mildly altered thyroid status has been associated with an increased risk of mortality (14). More recently, thyrotropin levels within the reference range were positively and linearly associated with IHD mortality (36). In our study, thyroid status was not able to predict event-free survival, probably because of the relatively small sample size and because of the inclusion of several patients without heart failure.

In previous studies, HDL cholesterol level was a significant inverse predictor of subsequent major cardiovascular events (15,16). When the LDL cholesterol level achieved in patients receiving therapy was considered, the role of HDL cholesterol was less marked, though still of borderline significance. The relationship remained significant even in patients whose LDL cholesterol level was less than 70 mg/dL (16). Our study shows a negative incremental prognostic value for a reduction in the ratio between LDL and HDL cholesterol levels. Finally, we did not find any prognostic impact of C-reactive protein, likely because of the selection of patients in the chronic phase of IHD.

Study Limitations

A limitation of this study is the selection of patients who have an intermediate pretest probability of coronary artery disease and thus do not reflect the general population of subjects undergoing gated SPECT for known or suspected IHD. More likely enrolled patients—though stable—reflect a higher-risk population, as indirectly shown by the high prevalence of previous MI (43%) and the main cardiovascular risk factors and by the fact that all enrolled patients underwent coronary arteriography. Another limitation is related to the small patient cohort, which does not allow an in-depth evaluation of the potential benefits of treatment.

A mandatory clarification concerns the difference between prognostic and diagnostic impact. Specifically, our considerations on myocardial perfusion imaging are limited to the prognostic stratification; we were aware that several variables that did not enter into our prediction model (such as coronary arteriography) carry clinically significant information in terms of diagnosis and therapeutic decision making.

In clinical practice, stress echocardiography is widely used for risk stratification of patients with IHD. Stress echocardiography was not performed in this study because patients were selected on the basis of having undergone gated SPECT. Finally, the values of cardiac peptides were not available for the entire patient population and were not considered among the tested predictors.