Published online before print September 8, 2009, doi: 10.1161/CIRCIMAGING.108.831164
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Original Articles |
Incremental Prognostic Value of Myocardial Perfusion Imaging in Patients Referred to Stress Single-Photon Emission Computed Tomography With Renal Dysfunction
From the Division of Nuclear Medicine and Molecular Imaging (S.D., M.D.C.), Department of Radiology, the Noninvasive Cardiovascular Imaging Program (M.A.M., S.D., M.D.C.), Departments of Medicine and Radiology, Brigham & Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Marcelo F. Di Carli, MD, Brigham & Women’s Hospital, ASB-L1 037-C, 75 Francis St, Boston, MA 02115. E-mail mdicarli{at}partners.org
Received October 27, 2008; accepted August 19, 2009.
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Abstract |
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Background— Coronary artery disease is the main cause of mortality and morbidity in patients with impaired renal function. The aim of this study was to evaluate the prognostic implications of single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) in patients with impaired renal function.
Methods and Results— We included 7348 consecutive patients (mean age, 64±13 years; 51% men) referred for SPECT-MPI between March 2002 and October 2006. Renal function was estimated using the estimated glomerular filtration rate formula. Patients were followed up for the incidence of all-cause mortality. Patients with decreased glomerular filtration rate were more often older, with higher prevalence of conventional risk factors (P<0.001). After a median follow-up of 2.6 years (25th to 75th percentiles, 1.5 to 3.7), 693 (9.4%) patients died. The risk of death increased with worsening kidney function. At each stage of impaired renal function, patients with abnormal SPECT-MPI had increased hazard of adverse events (P<0.0001). Using Cox proportional hazards analysis, the magnitude of total perfusion deficit and ischemia on MPI were associated with worse outcome after adjusting for confounding variables including glomerular filtration rate and ejection fraction.
Conclusions— SPECT-MPI adds modest incremental prognostic information to identify patients at higher relative risk of death across a wide spectrum of renal function.
Key Words: single-photon emission computed tomography • myocardial perfusion imaging • renal insufficiency • end-stage renal disease • coronary artery disease • mortality
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Introduction |
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Cardiovascular disease is the main cause of mortality and morbidity among patients with impaired renal function. Approximately 50% of individuals with end-stage renal disease die of a cardiovascular cause,1,2 and their cardiovascular mortality rate is 15 to 30 times higher than the age-adjusted cardiovascular mortality rate in the general population.3,4 Single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) is a powerful tool to diagnose coronary artery disease, identify patients at high and low clinical risk, and aid in their treatment.5–7 SPECT-MPI has been previously reported in small retrospective series to add incremental prognostic information in patients with end-stage renal disease and patients referred for kidney transplantation.8–11 However, the prognostic value of SPECT-MPI across the different stages of impaired renal function has not been previously evaluated.
Clinical Perspective on p 429
The objective of this study was to determine the incremental prognostic implications of myocardial perfusion SPECT in predicting mortality in a large, prospective cohort of patients with known or suspected coronary artery disease (CAD) across the entire spectrum of renal function.
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Methods |
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Patient Population
Consecutive patients referred for a SPECT-MPI for investigation of known or suspected CAD at the Brigham and Women’s Hospital between March 2002 and October 2006 were included in this analysis. Patients with prior heart transplantation, cardiomyopathy, advanced valvular heart disease, and recent myocardial infarction (MI) with elevated biomarkers within 30 days of the SPECT-MPI were excluded from this analysis. Patient demographics, clinical history, and medications used were collected at the time of the imaging study using a standardized questionnaire, and all data were entered into a database. The human research committee at Brigham and Women’s Hospital (Boston, Mass) approved this study.
Stress and Imaging Protocols
All patients underwent rest/stress 99mTc sestamibi SPECT-MPI as described previously.12 Patients performed a symptom-limited exercise treadmill test or pharmacological stress testing (adenosine or dobutamine) by use of standard protocols. Patients were instructed not to consume coffee or other products containing caffeine for 24 hours before the test. During both types of stress testing, heart rate, blood pressure, and a 12-lead ECG were recorded at baseline and every minute thereafter. Patients with any abnormality on their resting ECG other than sinus bradycardia were considered to have an abnormal resting ECG. The 12-lead ECG was monitored continuously for development of arrhythmia or ischemic ST-segment response. The Duke treadmill score was calculated for patients who underwent exercise testing.13 In accordance with laboratory protocol,12 patients unable to exercise underwent adenosine stress and, when adenosine was contraindicated, dobutamine stress testing was performed (5.6% of patients). Subjects who weighed more than 250 lb underwent a 2-day rest-stress study with approximately 30 mCi of 99mTc sestamibi on each day. Imaging was performed 45 minutes after injection of radiotracer with a 2-headed 
camera (e.cam model; Siemens Medical Systems, Malvern, Pa) with step-and-shoot rotation, 32 projections over a 90° arc for each head (64 projections over a 180° arc), 30 seconds per projection, and 64x64 matrices. Gated images were acquired by use of 8 frames per cardiac cycle. Transverse images were reconstructed with a Butterworth filter (order of 5 and cutoff frequency of 0.792 cycles per pixel) for the rest and stress studies.
Image Analysis
Experienced observers assessed all studies using semiquantitative visual analysis on a standard 17-segment model and a 5-point scoring system.14 Global summed scores were computed for the stress images (summed stress score [SSS], reflecting the combined extent and severity of ischemia plus scar) and rest images (summed rest score [SRS], reflecting the extent and severity of myocardial scar), as well as their difference (summed difference score [SDS], reflecting the combined extent and magnitude of myocardial ischemia). An MPI result was considered to be normal if the SSS was 
3 and abnormal when the SSS was 
4. Equivocal studies (n=25) were excluded from this analysis. Among these 25 patients, 21 patients had a glomerular filtration rate (GFR) >60, whereas 3 patients had a GFR between 30 and 60. Only 1 patient had GFR <30. At the end of the follow-up duration, 1 patient with an equivocal scan died. Ischemia on scans was categorized as mild when the SDS was 1 to 3, moderate when the SDS was 4 to 7, or severe when the SDS was >7. High-risk scans were defined as myocardium at risk >20%. Myocardium at risk was estimated by dividing SSS by 68. Left ventricular ejection fraction (LVEF) was analyzed on the stress images using commercially available software.
Quantification of Renal Function
Creatinine measured within 180 days (median, 5.5 days; 25th to 75th percentiles; 0.3 to 27.7) was used to estimate the renal function on all patients. When patients had multiple creatinine values, we used the test temporally closest to the SPECT imaging test.
Patients with estimated GFRs were calculated using the Levey modification of diet in renal disease formula, GFR=175xstandardized Scr–1.154xage–0.203x1.212 (if black)x0.742 (if female).15 The calculated GFR values were categorized as <30 mL/min per 1.73 m2, 30 to 59 mL/min per 1.73 m2, 60 to 89 mL/min per 1.73 m2, and 90 mL/min per 1.73 m2, based on the Kidney Disease Outcomes Quality Initiative classification of kidney function.16 Patients on dialysis were included in group 4 (GFR <30 mL/min) irrespective of their creatinine.
Follow-Up and Confirmation of End Point
The primary end point of our analysis was all-cause mortality, which was verified by the Social Security Death Index (accessed June 2007). The annualized mortality rate for each group was calculated by dividing the observed mortality rate during the follow-up duration by the mean follow-up time for the group.
Statistical Analysis
Statistical analyses were performed using SPSS (version 13.0; SPSS Inc, Chicago, Ill). S-PLUS 2000 software (Insightful Corporation, Seattle, Wash) was used for all multivariable modeling; supplemental libraries were incorporated. Categorical data are presented as percent frequencies and compared between groups by 
2 or Fisher exact test. Continuous variables are presented as mean±1 standard deviation and compared using Student t test. Nonnormally distributed variables are presented as median and 25th to 75th interquartile range and were compared using nonparametric testing (Mann–Whitney test). Kaplan–Meier analysis for event-free survival was applied and compared using log-rank testing. Multivariable survival analysis was performed using a Cox proportional hazards model.17 The primary analysis was to assess the association between calculated GFR and survival time free of all-cause death after adjusting for baseline clinical, historic, and imaging covariates. For all multivariate modeling, the threshold for variable entry into models was P<0.05 and the threshold for variable removal was P>0.10. Selection of variables for entry consideration was based on clinical judgment, results of previous publications, and the expertise of the investigators. Care was given to examination of assumptions, including proportional hazards, linearity, and additively, as well as avoidance of model overfitting by maintaining an events-to-covariate ratio of at least 20:1. Incremental prognostic value was defined as significant increase in the Wald statistic and likelihood ratio tests or an increase in the area under the curve of receiver-operator characteristics analysis, after the addition of imaging data to an optimized model of preimaging data alone.
The following candidate variables were considered in the models: age, black race, Hispanic race, smoking, hypertension, diabetes, hyperlipidemia, atrial fibrillation, resting heart rate, hematocrit, angina, sex, heart failure, prior CAD, GFR, SSS, SRS, SDS, ejection fraction, and angina. Baseline medications and angiographic extent of CAD were not included in the model. Angiographic extent of CAD was not included because only a subgroup of patients underwent coronary angiography. We also examined these covariates for collinearity as well as interactions. All continuous variables were included as continuous and were not dichotomized.
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Results |
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Patient Characteristics
A total of 7348 patients fulfilled the inclusion criteria. Table 1 summarizes the baseline characteristics of the study cohort. As expected, patients with impaired renal function were older and had a higher prevalence of hypertension, diabetes, dyslipidemia, and prior CAD. In addition, there was an increased use of cardioprotective medications including aspirin, angiotensin-converting enzyme inhibitors, β-blockers, and lipid-lowering medications with declining renal function (Table 2).
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In this cohort, 59.3% of patients underwent exercise stress testing, 35.1% underwent adenosine stress, and 5.6% underwent dobutamine stress (Table 3). With declining renal function, fewer patients underwent exercise stress testing (67% versus 20% in patients with GFR >90 versus <30 mL/min/1.73 m2, respectively), and fewer patients achieved >85% of their age predicated maximal heart rate (56.2% versus 32.1% in patients with GFR >90 versus <30 mL/min/1.73 m2, respectively, P<0.001). In contrast, the frequency of ischemic ECG changes (6.4% and 12.5% in patients with GFR >90 versus <30 mL/min/1.73 m2, respectively, P<0.001) and intermediate-high Duke treadmill scores (33.6% and 62.5% in patients with GFR >90 versus <30 mL/min/1.73 m2, respectively, P<0.001) increased with worsening kidney function.
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Overall, 2265 patients (30.9%) had abnormal MPI, with 438 patients (19.4%) showing fixed perfusion defects and 1827 patients (80.6%) showing reversible defects. The frequency of myocardial perfusion abnormalities increased with worsening kidney function (25.1% and 45.8% in patients with GFR >90 versus <30 mL/min/1.73 m2, respectively, P<0.001). In addition, the frequency of high-risk scans defined as myocardium at risk >20% increased as the renal function worsened (Table 3).
Outcomes
Over the follow-up period (median, 2.6 years; 25th to 75th percentiles; 1.5 to 3.7), 693 patients (9.4%) died of all causes. As expected, the annualized rate of death increased with worsening renal function (Figure 1). Importantly, the annualized death rate was significantly higher in patients with abnormal renal function compared with those with normal renal function at any abnormal scan (Figure 2). In comparison, observed mortality rates in the United States in age-matched patients without renal dysfunction are 0.4% and 0.3% in men and women, respectively.18 Indeed, the risk of death in patients with GFR <60 mL/min/1.73 m2 was almost double in the setting of abnormal compared with normal nuclear scans. Figure 3 shows the Kaplan–Meier survival curves of the study patients stratified by the renal function group.
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Multivariate Survival Analysis
Using Cox proportional hazard analysis, we constructed multiple models to assess the independent predictors of all-cause mortality. A clinical model including sex, age, race, history of hypertension, diabetes, hyperlipidemia, heart failure, prior CAD (MI, percutaneous coronary intervention, and coronary artery bypass surgery), hematocrit, angina, and ability to exercise was first constructed. As seen in Figure 4, adding GFR to the clinical model resulted in a significant increase in the global
2. Total defect size as estimated by the SSS (Model 4) added modest but significant predictive power to the model after adjusting for clinical variables and LVEF (Model 2) (model global 2 increased from 763 to 785, P<0.001, Table 4). In addition, we noted an interaction between exercise stress testing and age (Table 4).
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A separate model was constructed to assess the impact of ischemia (SDS) on the final outcome. The magnitude of ischemia as assessed by the SDS (Model 3) added modest but significant predictive value to the model after adjusting for clinical variables and LVEF (Model 2) (model global
2 increased from 763 to 784, P<0.001, Table 4 and Figure 4). In addition, we noted a significant interaction between ischemia and renal function (interaction 2=9.8, P=0.0018). Indeed, at any level of ischemic burden, there was increase in the risk of death with worsening renal function (Figure 5). This interaction results in a greater difference in inter-renal function class risk with increasing ischemia (additive effect of ischemia with renal function on risk). A subgroup analysis was performed examining the models presented in a subgroup of 5677 patients in whom renal function was measured within 1 month of the MPI study. This subanalysis revealed that no material differences were present; the covariates were all still significant, and no meaningful changes in the hazard ratio estimates occurred.
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Discussion |
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Renal impairment is prevalent in the community, a fact that may not only reflect the aging of the population but importantly the epidemic of obesity and diabetes and its associated risk factors.19 The presence of renal dysfunction and the cluster of risk factors associated with it predispose people to accelerated atherogenesis and increased cardiovascular event risk. Our study demonstrates that an interaction exists between renal function and the magnitude of perfusion deficit as assessed by stress MPI such that mortality rates almost double among patients with moderate or severe renal impairment (GFR <60 mL/min/1.73 m2) in the presence of abnormal stress nuclear scans, a finding that is incremental to other demographic and clinical data. However, we did not find an interaction between renal function and ischemic burden in patients with mild renal impairment. We observed that the same level of ischemia was associated with an increase in the adjusted relative risk of death with worsening renal function. These findings could expand the prognostic role of stress imaging to this important patient cohort.
In addition, we observed that mortality rates almost double among patients with moderate or severe renal impairment in the presence of an abnormal stress nuclear scan. Figure 2 demonstrates that the annual mortality rate in patients with severe renal impairment and a normal scan exceeds 10% per year. However, the mortality rate among patients with severe renal impairment and abnormal scan is nearly 25%. Although SPECT-MPI does not appear to identify patients with low absolute risk, it could be used for identification of patients with a lower relative risk in conjunction with other risk markers.
Our analysis is in agreement with smaller retrospective series that included only patients with advanced renal failure on dialysis. Dahan et al11 investigated the diagnostic and prognostic accuracies of combined dipyridamole-exercise thallium imaging in 60 asymptomatic hemodialysis patients. Sensitivity, specificity, positive and negative predictive values, and overall accuracy of thallium-201 to detect CAD were 92%, 89%, 71%, 98%, and 90%, respectively. After a median follow-up of 2.8 years, the positive predictive value of thallium imaging for major coronary events was 47% and its negative predictive value was 91%. The probability of survival free of coronary events was significantly higher in patients with normal thallium uptake than in those with abnormal thallium (adjusted risk ratio, 9.2; P<0.005).11 Patel et al8 investigated 174 patients who underwent SPECT-MPI before renal transplantation. In multivariable analysis, an abnormal perfusion SPECT study was the only predictor of cardiac events (P=0.006). The 42-month cardiac event-free survival rate was 97% in patients with normal SPECT images and 85% in patients with abnormal SPECT images.8 Dussol et al10 evaluated 97 patients older than 50 years referred for kidney transplantation who underwent SPECT-MPI before the transplant. Inducible myocardial ischemia was seen in 10% of the patients and was associated with increased future events.10 These series are limited to patients with advanced renal impairment and are limited by small numbers and small number of events.
Our study is also in agreement with a recently published analysis that evaluated the prognostic value of dobutamine stress echo among the entire strata of renal function in 2292 patients. This analysis showed that new wall motion abnormalities during dobutamine stress echo and GFR were powerful independent predictors for all-cause mortality, cardiac death, and nonfatal MI.20 A recent publication by Hakeem et al21 followed up 1652 consecutive patients who underwent stress SPECT-MPI for cardiac death (mean, 2.2±0.8 years), finding the presence of ischemia to be independently predictive of cardiac death, all-cause mortality, and nonfatal MI. Both perfusion defects (hazard ratio, 1.90; 95% CI, 1.47 to 2.46) and severe renal impairment (hazard ratio, 1.96; 95% CI, 1.29 to 2.95) were independent predictors of cardiac death after accounting for risk factors, left ventricular dysfunction, pharmacological stress, and symptom status. Our study extends these findings in a larger cohort with higher frequency of exercise testing (60% versus 35%). We also noted that there is a significant interaction between ischemia and renal function. This interaction results in a greater difference in inter-renal function class risk with increasing ischemia (additive effect of ischemia plus renal function on risk).
Multiple mechanisms have been suggested to explain the increased mortality rates in patients with renal failure. These mechanisms include anemia, increased oxidative stress, derangements in calcium-phosphate homeostasis, inflammation, and conditions promoting coagulation.22 In addition, prior studies have shown that renal impairment is associated with smaller ventricular size and larger atrial size. These changes were associated with worse long-term outcomes.23,24 Our data suggest that atherosclerosis resulting in ischemia is another important potential mechanism. Indeed, we observed a significant increase in the frequency of abnormal stress nuclear scans suggestive of obstructive CAD with worsening renal function. In addition, our multivariable analyses indicate that there is an interaction between the decline in renal function, the magnitude of inducible ischemia, and decreased survival. Although patients with advanced renal failure are known to have high all-cause mortality,25 our findings suggest that it is possible to identify patients who have a higher-than-expected risk of death.
We observed that the relative risk of death increased with worsening renal function even in patients with normal stress nuclear scans. This phenomenon is consistent with similar post-test risk patterns in other high-risk cohorts (eg, prior CAD, diabetics).5,26 This is probably related to the fact that post-test risk is contextual and thus, post-test risk would be expected to be higher in a population with higher clinical risk even in the absence of overt evidence of obstructive CAD.27 Another possible explanation for these findings may be related to the fact that SPECT imaging may underestimate the extent of underlying CAD due to balance reduction in myocardial blood flow.28 Perhaps the development of methods for absolute quantification of myocardial perfusion may help us improve risk assessments in the future.
Strengths and Limitations
Our study has several strengths. This is the largest series of consecutive patients referred for SPECT-MPI with various degrees of renal insufficiency. We used the estimated GFR to assess for the renal function rather than serum creatinine. In addition, we evaluated the incremental prognostic value of SPECT-MPI throughout a wide spectrum of renal function. On the other hand, our analysis has some limitations. Although most of the baseline data were prospectively recorded, the renal function was retrospectively added to the database. In addition, the measurement of renal function was not concomitant with the SPECT-MPI; however, the median duration between the SPECT-MPI and the measured creatinine was short (5.5 days). We also did not have data on microalbuminuria to assess for subclinical renal insufficiency among patients with GFR >90 mL/min per 1.73 m2. We used all-cause death rather than cardiac death as our primary end point because we did not have access to the cause of death in all patients. We did not perform a reclassification analysis. Although our study showed a statistically significant association between stress MPI information (SSS and SDS) and all-cause mortality that was additive to a prediction model including clinical variables and LVEF (Table 4), our study cannot define the cost and clinical impact of our statistical models for reclassifying patients into low- or high-risk categories.
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Conclusions |
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Stress MPI adds modest incremental prognostic information to identify patients at higher relative risk of death across a wide spectrum of renal function. Future research is warranted to investigate the clinical impact of this information in risk reclassification and to assess whether invasive and pharmacological tools to reduce the degree of ischemia in these patients would alter their outcomes.
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Acknowledgments |
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Disclosures
None.
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References |
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Footnotes |
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Guest Editor for this article was Salvador Borges-Neto, MD.
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