Predictive Value of Myocardial Perfusion Single-Photon Emission Computed Tomography and the Impact of Renal Function on Cardiac DeathCLINICAL PERSPECTIVE
Background—Patients with chronic kidney disease (CKD) have worse cardiovascular outcomes than those without CKD. The prognostic utility of myocardial perfusion single-photon emission CT (MPS) in patients with varying degrees of renal dysfunction and the impact of CKD on cardiac death prediction in patients undergoing MPS have not been investigated.
Methods and Results—We followed up 1652 consecutive patients who underwent stress MPS (32% exercise, 95% gated) for cardiac death for a mean of 2.15±0.8 years. MPS defects were defined with a summed stress score (normal summed stress score <4, abnormal summed stress score≥4). Ischemia was defined as a summed stress score ≥4 plus a summed difference score ≥2, and scar was defined as a summed difference score <2 plus a summed stress score ≥4. Renal function was calculated with the Modified Diet in Renal Disease equation. CKD (estimated glomerular filtration rate <60 mL · min−1 · 1.73 m−2) was present in 36%. Cardiac death increased with worsening levels of perfusion defects across the entire spectrum of renal function. Presence of ischemia was independently predictive of cardiac death, all-cause mortality, and nonfatal myocardial infarction. Patients with normal MPS and CKD had higher unadjusted cardiac death event rates than those with no CKD and normal MPS (2.7% versus 0.8%, P=0.001). Multivariate Cox proportional hazards models revealed that both perfusion defects (hazard ratio 1.90, 95% CI 1.47 to 2.46) and CKD (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. Both MPS and CKD had incremental power for cardiac death prediction over baseline risk factors and left ventricular dysfunction (global χ2 207.5 versus 169.3, P<0.0001).
Conclusions—MPS provides effective risk stratification across the entire spectrum of renal function. Renal dysfunction is also an important independent predictor of cardiac death in patients undergoing MPS. Renal function and MPS have additive value in risk stratisfying patients with suspected coronary artery disease. Patients with CKD appear to have a relatively less benign prognosis than those without CKD, even in the presence of a normal scan.
Received September 24, 2007; accepted October 7, 2008.
The association between chronic kidney disease (CKD) and adverse cardiovascular outcomes has been well established in large community-based studies,1–4 in patients with a history of myocardial infarction (MI)5–7 or congestive heart failure,7–9 after CABG,10,11 and after percutaneous coronary interventions.1–14 Myocardial perfusion single-photon emission CT (MPS) has been validated as a powerful prognostic tool for predicting adverse cardiovascular outcomes in patients with known or suspected coronary artery disease (CAD).15–19 Although a large proportion of patients undergoing stress MPS have some degree of renal dysfunction, the prognostic value of MPS in the risk stratification of this cohort has not been investigated. Additionally, the impact of renal dysfunction in predicting adverse cardiac outcomes in patients undergoing MPS for evaluation of CAD has not been established. It is known that patients with CKD are more likely to die of cardiovascular disease than to develop end-stage renal disease.2–4 Studies evaluating the prognostic value of MPS have not included renal dysfunction in their analyses20 or have only included patients with end-stage renal disease who are renal transplant candidates.21–23 Hence, our objectives were severalfold: (1) to study the prognostic value of myocardial perfusion abnormalities on single-photon emission CT (SPECT) in the risk stratification of patients with varying degrees of renal dysfunction; (2) to study the impact of renal dysfunction on cardiovascular outcomes in patients undergoing MPS for evaluation of CAD; and (3) to determine whether renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL · min−1 · 1.73 m−2) combined with myocardial perfusion abnormalities on MPS (summed stress score [SSS]) provides additional prognostic information superior to either marker alone.
Clinical Perspective p 2549
This was an observational cohort of 1652 consecutive patients with known or suspected CAD undergoing stress MPS using a same-day protocol between June 2002 and July 2005 at the William S. Middleton Memorial Veterans Hospital, Madison, Wis. The study was approved by the hospital’s institutional review board.
Sources of Data
Using the Veterans Affairs Information System Technology and Architecture (VISTA) database, we reviewed inpatient and outpatient electronic records for patients. The Veterans Administration (VA), America’s largest integrated healthcare system, has a uniform, fully electronic national record system called the Computerized Patient Record System (CPRS). It provides networked, robust, and timely retrieval of remote-site patient data, including clinic visits, emergency department visits, outpatient phone contacts, and hospitalization records. Hospitalizations outside the VA are either recorded in physician notes or outside records are scanned and stored electronically in the VA system. Manual extraction of patient information and records from the VISTA/CPRS interface program was done by 3 investigators who were blinded to the renal and SPECT data.
The initial patient visit (closest to the time of MPS) was used to determine demographics, height, weight, cardiovascular symptoms, baseline ECG, and baseline cardiac risk factors. Patients were considered to have these risk factors if they had a documented diagnosis by a physician or supportive laboratory data or were taking medications that would support these diagnoses. History of CAD required either a previous coronary event or a documented CAD diagnosis via cardiac stress testing or coronary angiography. Further data, including medications taken at the time of MPS and laboratory findings, specifically hemoglobin and creatinine levels, were obtained from CPRS. Laboratory data were obtained a mean of 49±20 days from the time of MPS evaluation.
Imaging and Stress Protocol
Rest-stress myocardial SPECT imaging with technetium-99 sestamibi or tetrofosmin was performed. Thirty-two percent of patients underwent symptom-limited exercise testing with standard protocols with a 12-lead ECG recording each minute of exercise. At near-maximal exercise, a 20- to 30-mCi dose of 99Tc sestamibi or tetrofosmin was injected (actual patient dose varied with patient weight), and exercise continued for 1 minute after injection. Image acquisition was begun 15 minutes after isotope injection. Whenever possible, β-blockers, calcium channel blockers, and caffeine products were discontinued 24 hours before testing, and nitrate compounds were discontinued 6 hours before testing.
If the patient was predetermined to be unable to undergo a treadmill protocol or unable to achieve 85% of maximal predicted heart rate, the test was performed pharmacologically with use of a 4-minute adenosine infusion protocol (68% of the study group). Institutional protocol allows only the use of adenosine for pharmacological MPS studies. Patients who are unable to exercise and have contraindications to adenosine (eg, severe chronic obstructive pulmonary disease) generally undergo dobutamine stress echocardiography or cardiac catheterization. Technetium-99m was injected at the end of the third minute of infusion, and SPECT was initiated ≈60 minutes after the end of the adenosine infusion.24 During both types of stress tests, blood pressure was measured and recorded at rest, at the end of each stress stage, and at peak stress. The maximal degree of ST-segment change at 80 ms after the J point of the ECG was measured and assessed as horizontal, upsloping, or downsloping.
SPECT Acquisition Protocol
SPECT studies were performed with a dual-head Cardio Epic camera (ADAC Laboratories, Milpitas, Calif) with a circular 180° acquisition for 64 projections at 20 to 25 seconds per projection.24 During imaging, a 10% window centered on the 140-keV peak was used for 99mTc tracers. The low-pass Butterworth filter was used for all SPECT studies. Gated scans could not be performed in 5% of the patients because of arrhythmia, primarily atrial fibrillation.
Imaging Interpretation and Scintigraphic Indices
Semiquantitative visual interpretation was performed with short-axis and vertical long-axis myocardial tomograms divided into 20 segments for each study, as described previously.25 An SSS was obtained by adding the scores of the 20 segments of the stress sestamibi images with QP/QS software.16,26,27 Each segment was scored with a 5-point scoring system (0=normal, 1=mildly reduced, 2=moderately reduced, 3=severely reduced, and 4=absent uptake).26,28 The sum of segment scores at stress (SSS), scores at rest (summed rest score [SRS]), and differences between stress and rest score (summed difference score [SDS]) were calculated.16,17,25–27 Patients were divided into groups based on their SSS. SSS <4 was considered normal; 4 to 8, mildly abnormal; and >8, moderately to severely abnormal.17,26,27 The SSS was the primary focus of the present analysis. Patients were also divided into groups based on their SDS combined with their SSS. Patients with an SDS ≥2 and an SSS ≥4 were considered to have myocardial ischemia; patients with an SDS <2 and an SSS <4 were considered normal; and patients with an SDS <2 and an SSS ≥4were considered to have scar without ischemia. Poststress left ventricular (LV) ejection fraction by gated SPECT was also assessed with QP/QS software. The studies were interpreted by 3 board-certified nuclear cardiologists who were blinded to the demographic and laboratory data.
Classification of Renal Dysfunction
where GFR (mL · min−1 · 1.73 m−2) is glomerular filtration rate and SCr indicates serum creatinine. CKD was defined with the National Kidney Foundation31 definition of eGFR <60 mL · min−1 · 1.73 m−2 and was present in 601 patients (32%). eGFR was obtained at a mean of 49±20 days from the time of MPS. Patients in acute renal failure (defined by an increase in serum creatinine of ≥0.5 mg/dL in <2 weeks or an increase of >20% over baseline if baseline serum creatinine was ≥2.5 mg/dL) were excluded. Thirty-two such patients were excluded.
Patient Follow-Up and End Points
Patients were followed up for an average of 2.15±0.8 years. The minimum duration of follow-up was 6 months (for those who had no events; shorter for those who died), with only 44 patients having follow-up of less than 1 year. The primary end point was cardiac death (CD), defined as death due to any cardiac cause, including fatal MI, sudden arrhythmic death, and congestive heart failure; secondary end points were all-cause mortality (ACM) and nonfatal MI (NFMI; defined by the appropriate combination of elevated cardiac enzymes, ECG changes, and ischemic symptoms). Mortality data were gathered from the VA patient records and confirmed by the Social Security Death Index. Death status was determined as of month and year. Cause of death was adjudicated by 3 independent reviewers (blinded to the MPS and demographic data) through patient chart review, including death certificate and physician’s records, and conflicts were resolved by global consensus or by the senior investigator. Patients who underwent revascularization within 60 days after MPS were excluded from the end-point analysis. There were 94 such patients, 54 of whom had percutaneous coronary intervention and 40 of whom had CABG. For patients with multiple end points, the first event was counted, and subsequent events were censored for analysis. All data regarding end points were obtained from the CPRS system.
From the initial 1778-patient cohort, 32 patients were excluded because of acute renal failure. Ninety-four patients underwent revascularization within 60 days of the MPS evaluation and hence were excluded from end-point analysis. After the exclusion of these patients, 1652 patients formed the study population (Figure 1).
For analysis of baseline characteristics, all subjects were classified on the basis of the presence (defect; SSS ≥4) or absence (no defect; SSS <4) of perfusion defects, then further stratified by the presence or absence of CKD (eGFR above or below 60 mL · min−1 · 1.73 m−2). The Student t tests or Wilcoxon rank sum tests (for nonparametric data) were used to compare subject characteristics across renal function levels within each perfusion defect group. χ2 Tests were used for comparisons of dichotomous or categorical variables.
Unadjusted annual event rates for those with and without scan defects and CKD were calculated by first estimating overall event rates for these groups through calculation of Kaplan-Meier curves, then dividing the event rate by the mean follow-up time for each of the groups (with or without scan defect and with or without CKD). Event rates based on the presence of ischemia and scar in each of the groups (CKD present or absent) were calculated in a similar manner. Furthermore, median SSS, SDS, and eGFR were calculated for patients with and without each of these outcomes.
In the risk-adjusted analysis, multivariable Cox proportional hazards models were used to determine the independent impact of kidney function and scan defect on the same cardiac and mortality outcomes. The baseline models controlled for patient characteristics, including age, gender, smoking status, hypertension, hyperlipidemia, diabetes, and history of MI, as well as cardiovascular characteristics/symptoms, including angina, shortness of breath, and ejection fraction. The type of stress test the patient was able to undergo was also included in the model. Finally, indicator variables for presence/absence of CKD and scan defect were added. A statistically significant increase in the global χ2 index with the addition of kidney function, scan defect, or both variables to the baseline model was considered indicative of prognostic value of that variable for the outcomes of ACM, CD, and NFMI. Proportionality assumptions for the models were verified both by assessment of the significance of each of the covariates interacted with time in the proportional hazards models and by examination of plots of the Schoenfeld residuals versus time for all covariates. The models were validated by bootstrapping based on Efron’s technique.32
The level of statistical significance was a priori set at 0.05, and a 2-sided probability value was used for the analyses. All statistical calculations were performed with SAS version 9.1.2 (SAS Institute, Cary, NC).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Baseline characteristics of the 1652 patients included in the analyses are summarized in Table 1. Patients with CKD in both groups were older, more frequently diabetic, and less frequently smokers. Patients with no perfusion defects and CKD were less commonly male, more hypertensive, and tended to take calcium channel blockers more frequently. Patients with both perfusion defects and CKD were less often dyslipidemic and had a lower median ejection fraction. There was no difference in the 2 groups (CKD and no CKD) in terms of body mass index or history of CAD, MI, revascularization, or use of other drugs, including ACE inhibitors/angiotensin receptor blockers, β-blockers, statins, and nitrates. A total of 121 patients (7.3%) had ST-segment depression on stress ECG, of whom 91 (75%) had undergone exercise MPS and 30 (25%) had undergone adenosine MPS.
In the total population, 40% of perfusion scans were abnormal (SSS ≥4), with 20% mildly abnormal and 20% moderately to severely abnormal as described above. Overall, 604 patients (36.5%) had CKD (eGFR <60 mL · min−1 · 1.73 m−2). The mean eGFR was 67.63+21.05 mL · min−1 · 1.73 m−2 in patients with perfusion defects and 61.8±20 mL · min−1 · 1.73 m−2 in patients with no defect (P<0.01).
During the follow-up period of 2.15±0.8 years, there were 217 deaths of all causes, 114 CDs, and 73 NFMIs. The annualized rates of ACM, CD, and NFMI based on the level of eGFR and MPS defects are shown in Tables 2 and 3⇓, along with the total number of events for each group. The annualized rates of all 3 events were significantly higher in patients with perfusion defects than in those with no defects. Patients with CKD in both groups (with and without perfusion defects) had higher CD and ACM rates than those without CKD. Even in patients with no defects on MPS, the annual rate of CD and ACM was significantly higher for patients with CKD (Table 2).
Patients who experienced any of the outcomes (ACM, CD, or NFMI) during the course of the study had statistically significantly worse renal disease (demonstrated by median eGFR) and perfusion defects (demonstrated by SSS and SDS values), as shown in Table 4. Not surprisingly, the median SSS and SDS were higher in patients with CD than in those without the end point (SSS 9.0 versus 2.0, P<0.0001; SDS 3.0 versus 1.0, P<0.0001). Patients with CD also had a lower median eGFR than those without CD (51.6 versus 67.3 mL · min−1 · 1.73 m−2, P<0.0001).
Perfusion Defects and Outcomes
There was a significant increase in CD rate with increasing levels of perfusion defects across the entire continuum of renal function. The incidence of CD increased as a function of increasing severity of SSS. Patients in the mildly abnormal (SSS 4 to 8) and moderately to severely abnormal (SSS ≥8) MPS groups had statistically significant higher incidence of CD and ACM than those with normal MPS. This effect was further magnified among subgroups of eGFR from 59 to 30 and <30 mL · min−1 · 1.73 m−2. The same trend was worse for patients with abnormal MPS and declining level of kidney dysfunction (Figure 2).
Regarding CD in particular, a normal myocardial perfusion study in patients without CKD was associated with a low CD rate (0.8% per year). Comparatively, the CD rate was 3 times higher for patients with normal scans but with CKD (2.7% per year; Table 2).
When patients were stratified on the basis of the presence of myocardial ischemia and scar, the presence of either was strongly predictive of CD, NFMI, and ACM in both the CKD-positive and -negative groups. Additionally, within the ischemic and scar groups, eGFR <60 mL · min−1 · 1.73 m−2 conferred a higher CD and ACM rate than did eGFR >60 mL · min−1 · 1.73 m−2 (4.5% versus 11%, P<0.0001 for ischemia; 2.5% versus 5.3% for scar, P=0.019; Table 5). The presence of either ischemia or scar was strongly predictive of CD across the entire range of renal dysfunction and more powerfully predicted CD with declining levels of renal function (Figure 3).
A risk-adjusted Kaplan-Meier survival plot showing the independent and combined impact of MPS and kidney function on survival free from CD is shown in Figure 4. Survival probabilities for patients with CKD alone (normal MPS) and with abnormal MPS alone (normal CKD) were similarly reduced compared with those of patients without CKD and with normal MPS (95.1% with CKD and 92.8% with abnormal MPS versus 98.5% in patients with neither CKD nor abnormal MPS; Figure 4). Additionally, patients with both CKD and abnormal MPS had a decrement in survival that was greater than the combined individual effects of CKD and abnormal MPS.
Cox proportional hazards models were used to evaluate the impact of CKD and scan defect on the outcomes of CD, ACM, and NFMI while controlling for patient characteristics, symptom status (shortness of breath, angina), type of stress test the patient underwent, and LV dysfunction (ejection fraction <40%). Model results, displayed in Table 6, indicate that CKD was predictive of increased CD, with a hazard ratio (HR) of 1.96 (95% CI 1.29 to 2.95, P=0.0008), but it did not significantly predict ACM (HR 1.30, 95% CI 0.97 to 1.73, P=0.076). The HR of CKD for NFMI was also not significant, although there may have been too few events to be able to demonstrate a trend. The presence of a scan defect had a similar HR of 1.90 (95% CI 1.47 to 2.46, P<0.0001) for CD and was a significant predictor of increased risk for ACM (HR 1.33, 95% CI 1.12 to 1.59, P=0.0015) and NFMI (HR 1.51, 95% CI 1.11 to 2.06, P=0.0088). Other significant multivariate predictors of CD were diabetes mellitus (HR 1.49, 95% CI 1.01 to 2.20), shortness of breath (HR 1.81, 95% CI 1.11 to 2.94), pharmacological stress test (HR 1.78, 95% CI 1.01 to 3.15), and ejection fraction <40% (HR 3.52, 95% CI 2.31 to 5.37).
Bootstrapped parameter estimates were all within 0.11 or less of the model estimates, with the exception of gender. This was not surprising given that the majority of the participants were male, which makes it difficult to estimate this parameter. The closeness of the model estimates to the bootstrapped estimates confirms the robustness of the model.
Incremental Prognostic Value of MPS and CKD in Outcome Prediction
Table 7 shows that significant increases in global χ2 for the Cox proportional hazards models occurred after the addition of CKD and SSS to the baseline CD model (P<0.0001). Furthermore, the model χ2 increased significantly from the model that included SSS alone to the model that included both SSS and CKD, which suggests that knowledge of CKD adds additional predictive value to the model. A similar trend toward an increase in global χ2 value occurred for the ACM model. The NFMI model demonstrated a statistically significant increase in the global χ2 after the addition of SSS to the baseline variables (P=0.0082), but the addition of CKD alone was not significant (P=0.11).
To the best of our knowledge, this is the first study to evaluate the prognostic utility of myocardial perfusion abnormalities on SPECT in the risk stratification of patients with varying degrees of renal dysfunction. Additionally, it established the impact of renal function in predicting cardiac death in patients undergoing stress MPS. Most studies evaluating the prognostic utility of MPS and other variables have used either composite end points or ACM. In the present study, we separately analyzed the concrete end points of CD, ACM, and NFMI. In the present study population, CKD and the degree of defect on MPS were found to be independent predictors of CD and ACM. Together, they appear to have an additive value in risk prediction for CD and ACM. Abnormal MPS (SSS ≥4 and ischemia [SSS ≥4 plus SDS ≥2]), in addition, was strongly predictive of NFMI, as previously described.16,19 We found that the presence of ischemia, in particular, was independently associated with worse outcomes.
The present study was predominantly composed of individuals with stage III CKD (eGFR 30 to 60 mL · min−1 · 1.73 m−2), which reflects the bulk of the CKD patients in the United States.29,30 Other strengths of the present study include the use of glomerular filtration rate–estimating equations based on calibrated creatinine values rather than serum creatinine alone to estimate true level of kidney function. In addition, there was fair ascertainment of end points, because these patients were part of the VA health system, which allows robust documentation of clinical information (outcomes).
Patients with CKD had almost a 2-fold increase in CD during follow-up compared with those without CKD, and an increasing level of perfusion abnormalities on MPS was associated with a progressive decline in survival. The presence of both CKD and abnormal MPS conferred the highest risk of CD after adjustment for other cardiovascular risk factors as depicted in the multivariate regression model.
Incremental Prognostic Value of MPS Over Renal Function
The present study concurs with previous findings that indicate that increasing levels of perfusion abnormalities on MPS are associated with a progressive decline in survival. We demonstrated that across the entire continuum of renal function, perfusion abnormalities were powerful predictors of CD, MI, and NFMI. This trend became even stronger in patients with worsening renal function. This effect persisted after adjustment for other important known predictors of outcomes, including LV dysfunction (ejection fraction <40%), shortness of breath, diabetes, and inability to exercise (pharmacological stress). The present study also suggests that the presence of CKD is associated with an increased rate of CD and ACM relative to the absence of CKD, regardless of the presence or severity of MPS defects. Therefore, both CKD and abnormal MPS were independent predictors of CD and ACM in the present study population. The addition of both CKD and abnormal MPS to the model more accurately predicted death than the addition of either indicator alone.
Because NFMIs place patients at a higher risk of CD, it can be difficult to separate the contribution of each to predictive models; however, the present data offer the possibility of identifying distinct populations in which 1 event is significantly more likely to occur. The fact that the increase in global χ2 from the model that included SSS with baseline variables to the model that included CKD and SSS was not significant also suggests that CKD does not add to the predictive value of the NFMI model, whereas MPS defects alone did, as has been described previously.15–19 The presence of ischemia and scar were each independently predictive of all 3 end points, including NFMI.15–19
Most other studies have evaluated the prognostic utility in hemodialysis patient or renal transplant candidates. The meta-analysis by Rabbat et al21 evaluated the prognostic utility of stress MPS for predicting MI and CD in patients with end-stage renal disease assessed for kidney or kidney-pancreas transplantation. The authors included 12 studies, 8 of which evaluated thallium scintigraphy and 4 of which evaluated dobutamine stress echocardiography. They demonstrated that patients with evidence of inducible ischemia had a 6-fold increased risk of MI and a 4-fold increased risk of CD, whereas fixed defects were only predictive of CD (relative risk 4.7) and not MI. The present results are in agreement with this finding. However, the patients included in the studies meta-analysis were patients with end-stage renal disease (CKD stage V) awaiting transplantation, which represents a small fraction of the total CKD population. Furthermore, the major limitation of the meta-analysis was that only 1 of the 12 studies used multivariate analysis to confirm the independent prognostic value of perfusion abnormalities. This takes on added significance because these patients have a cluster of many risk factors that have individual prognostic significance.
Prognostic Value of Normal Perfusion Imaging Across Levels of Renal Function
The prognostic value of exercise and pharmacological MPS has been well established in several large studies that describe annualized hard event rates for a normal MPS in the range of 0.2% to 0.8%.15–20 Similarly, the present findings indicate that patients with normal MPS and no CKD (eGFR >60 mL · min−1 · 1.73 m−2) are at a very low risk of CD; the annualized CD rate was 0.8% for patients with eGFR >60 mL · min−1 · 1.73 m−2 and SSS <4 (<1% per year).15–20
Most MPS prognostic studies and large clinical trials have not included kidney function in their analyses.15–20 In the present study, patients with normal MPS but with CKD had a significantly higher CD rate (2.7% per year) than those with normal MPS and no CKD (0.8% per year). This trend has not been evaluated in previous studies. The survival probabilities for patients with CKD alone (normal MPS) and abnormal MPS alone (normal CKD) were similar (Figure 4). This brings an important point forward: Although the “warranty” period of a normal MPS scan is reported to be in the range of ≈2 years, this deduction has been based on studies that have not incorporated kidney function into their analysis. Hachamovitch et al33 followed up 7376 consecutive patients with normal exercise or adenosine myocardial perfusion for 665 days. The annual hard event rate was 0.6%, and the event rate increased over time. This finding was explained by the progressive nature of the underlying CAD and the presence of mildly obstructive CAD that could cause MI by plaque rupture. The investigators concluded that multiple clinical factors added incremental prognostic value in patients with normal findings on stress myocardial perfusion imaging, thus affecting their risk and its temporal pattern. Patients with CKD alone in the present study had a similar clustering of both traditional and nontraditional risk factors that add prognostic value to an otherwise normal scan. Because of the higher CD rate of patients this group, physicians may want to consider closer follow-up even in the presence of a normal MPS in patients with CKD. As this level of risk approaches the American College of Cardiology/American Heart Association definition of high risk (>3% annual cardiac death), it remains unclear whether cardiac catheterization would add any benefit in the management of these patients beyond that of aggressive risk factor modification.
The increased rate of CD relative to baseline in the group with CKD and normal MPS (2.7% versus 0.8%) may be due to mechanisms other than myocardial ischemia. There is growing evidence that patients with CKD have unrecognized LV dysfunction, both systolic and diastolic.34 The addition of ejection fraction to the present Cox proportional hazards model of CD greatly increased the global χ2 index, which indicates the importance of LV systolic dysfunction (LV ejection fraction <40%) as a predictor of CD in patients with CKD. Similarly, patients with balanced ischemia due to significant 3-vessel disease may appear normal or minimally abnormal on perfusion imaging.
Declining Renal Function and Adverse Events: CKD as CAD Risk Equivalent
Using eGFR as a marker of renal dysfunction, we were able to capture the continuum of the renal dysfunction spectrum. Estimation of eGFR with the MDRD equation is better than use of creatinine alone,35 because the creatinine concentration is affected by factors other than GFR and does not account for age and race.29,35 As demonstrated by the present results and several other studies, the risk of death and related morbidities rises slowly as the eGFR approaches 60 mL · min−1 · 1.73 m−2; events increase significantly at levels <60 mL · min−1 · 1.73 m−2 and are very prominent at eGFR values <45 mL · min−1 · 1.73 m−2.1–6 This may relate to the fact that as eGFR falls to <60 mL · min−1 · 1.73 m−2, many physiological and regulatory functions of the kidney start to wane, such as 1,25[OH] vitamin D and erythropoietin synthesis, which over time promotes increased vascular calcification, reduced oxygen-carrying capacity, and thus increased cardiovascular risk.36
The Framingham risk score does not take creatinine clearance into account. A recent study by Weiner et al37 concluded that the Framingham instrument demonstrates poor overall accuracy in predicting cardiac events in individuals with CKD. On multivariate analysis, hyperlipidemia was found to be protective for CD and ACM. Although it is not entirely clear, this may be due to the fact that these patients were more likely to be treated with statins than those without dyslipidemia (77% compared with 40%; P<0.0001). The enhanced risk for cardiovascular disease outcomes is likely multifactorial and related to both traditional and nontraditional cardiovascular disease risk factors. It is likely that the interplay between CKD and cardiovascular disease risk factors, including diabetes, hypertension, anemia, and inflammation, leads to enhanced cardiovascular risk.38,39 In the most recent hypertension guidelines, the National Kidney Foundation and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure have classified CKD as a cardiovascular disease risk equivalent.40 We concur that patients with CKD should be risk-stratified on initial contact and should receive aggressive medical management for cardiac risk factors.
The limitations of the present study relate primarily to the single-center experience and the nature of the study population. The subjects were predominantly male veterans with a high prevalence of CKD and CAD risk factors, including diabetes. This population is not at very low risk, as demonstrated by the high proportion of patients who required a pharmacological rather than an exercise stress test. Therefore, the applicability of these data to other populations is unclear. Additionally, significant differences existed between patients with and without CKD in 5 critical baseline characteristics. These differences indicate probable systematic differences in immeasurable factors for which we were unable to control. We did not have data on microalbuminuria, a component of kidney disease that independently predicts CAD.
Implications and Conclusions
The implications of the present study are severalfold. First, MPS has powerful prognostic value in predicting adverse cardiac outcomes in patients with varying degrees of renal function and can thus provide effective risk stratification. However, patients with CKD who have a normal perfusion study have worse prognosis and are at greater risk for CD and ACM. This subset of patients should be considered a high-risk group, and aggressive medical management, including optimal lipid goals, tight regulation of hemoglobin A1C, and blood pressure control, should be pursued. From these data, all patients undergoing MPS should have eGFR assessed as part of their evaluation. Moreover, eGFR should be integrated into clinical risk-prediction models for morbidity and mortality.
Whether medical management or invasive strategy is the better choice for patients with CKD and perfusion abnormalities remains unclear. Whether repeat stress testing should be performed in patients with CKD, especially those with normal MPS, remains to be seen. A “warranty period” for this cohort has yet to be determined.
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Although it is known that a substantial portion of death in patients with chronic kidney disease (CKD) is attributable to cardiac causes, risk-stratification methods in this group of patients have been less well described. In this study, we examine the impact of renal function on death rates and highlight the important role of single-photon emission CT (SPECT) imaging in the risk stratification of patients with varying degrees of renal dysfunction. In this study population of 1652 predominately male patients, patients with CKD had higher death rates than those without CKD, and the same trend was seen for patients with an abnormal myocardial perfusion SPECT. Cardiac death was low in patients with normal scans and no CKD (0.8% per year). It rose more than 3-fold to 2.7% per year in CKD patients with no perfusion defects on myocardial perfusion SPECT and was substantially higher (9.5% per year) in patients with CKD and perfusion defects on myocardial perfusion SPECT. An abnormal myocardial perfusion SPECT and CKD in synergy predicted death more accurately than either one alone. Additionally, across the entire spectrum of renal function, myocardial perfusion abnormalities on SPECT were powerful predictors of cardiac death and all-cause mortality. The presence of ischemia, in particular, was independently associated with cardiac death, nonfatal myocardial infarction, and all-cause mortality. A CKD patient with an abnormal myocardial perfusion SPECT is in the highest risk group. The best route of management (invasive versus medical therapy) in this group of patients remains to be defined. Even in the presence of a normal SPECT, CKD confers risk that requires special attention to risk factor modification.