Prognostic Value of Myocardial Perfusion Studies in Patients with End-Stage Renal Disease Assessed for Kidney or Kidney-Pancreas Transplantation: A Meta-Analysis

Materials and Methods

We searched for references included in the National Library of Medicine’s MEDLINE database using OVID between 1977 and October 2000. Primary studies were identified using combinations of MeSH headings and textwords for coronary artery disease, transplantation, prognosis, end-stage renal disease (ESRD), stress nuclear scintigraphy, and dobutamine stress echocardiography. Independently, two researchers (CGR and DJT) reviewed the citation list and identified possibly relevant articles. We obtained all articles judged potentially relevant by either reviewer for further evaluation. A manual search of the reference lists of all review and primary articles identified other possibly relevant studies, which we retrieved for further evaluation. We hand-searched published abstracts, for the years 1995 to 2000, from the proceedings of the American Society of Nephrology, the American College of Cardiology, and the American Heart Association and identified other potentially relevant studies.

We used the following criteria to select articles. First, the study population had to include adult patients with chronic renal insufficiency or ESRD assessed for kidney or kidney-pancreas transplantation. Second, myocardial perfusion testing (exposure) had to include either nuclear scintigraphy (thallium or sestamibi) or DSE. The study had to report the outcomes of cardiac death (CD) and/or MI in the cohort of patients according to the MPS result. The minimum sample size was five patients. Disagreements were resolved by discussion and consensus.

The methodologic quality of individual articles is an important consideration for assessing whether the results of a study are biased. In duplicate and independently, two of us (CGR and DJT) used the following criteria (13) to judge the quality of the original articles.

Results

One hundred sixty-six studies were identified using our search strategy, 11 of which were published in English and met all inclusion criteria (11,12,16,18–25). One additional study was identified from references of the primary studies and review articles (26). Of the 12 studies included for analysis, four used DSE, and the other eight studies used myocardial scintigraphy. Of the myocardial scintigraphy studies, four used dipyridamole as a pharmacologic stress agent, and four used exercise.

Six other studies were identified as potentially relevant, but they were excluded for a variety of methodologic reasons. Two studies did not meet the criterion of independent reporting of MI and cardiac death and were excluded (27,28). One abstract was potentially relevant, but it contained insufficient data to classify MI and cardiac death by MPS result (29). The three remaining studies evaluated diabetic transplant candidates using stress-induced ECG abnormalities and/or failure to attain target heart rate in their definition of a positive test (30–32) and were excluded.

Table 1 summarizes the characteristics and methodology of the 12 individual studies. The interobserver agreement for consecutive cohort assembly, definition of positive test result, blinding of interpreter of test to clinical status of the patient, and completeness of follow-up were reflected in the following κ values of 0.68, 0.93, 0.77, 0.96, respectively. Follow-up of patients was over 98% complete in each study.

Risk of Myocardial Infarction

Nine of 388 patients with negative MPS had an MI, whereas 21 of 282 with a positive MPS had an MI, representing an annualized event rate of 1.6% and 4.3% for negative and positive MPS, respectively (Tables 2 and 3). Figure 1A shows the individual study and pooled relative risk (RR) for MI. The RR of MI following a positive test was 2.73 (95% CI, 1.25 to 5.97; P = 0.01) when compared with patients with a negative test. No significant heterogeneity existed among individual study results (P = 0.71).

View this table:

• View inline
• View popup

Table 2. Cardiac events classified by population type and characteristics of myocardial perfusion abnormality

View this table:

• View inline
• View popup

Table 3. Cardiac events and patient follow-up^a

• Download figure
• Open in new tab
• Download powerpoint

Figure 1. Myocardial infarction. (A) Positive versus negative tests; (B) Reversible defects versus negative tests; (C) Fixed defects versus negative tests; (D) Reversible versus fixed defects.

When considering the nature of the positive test result (fixed or reversible), the RR of MI was increased in individuals with reversible perfusion defects. In the comparison of reversible defects to normal perfusion images, the RR of MI was 6.19 (95% CI, 1.69 to 22.7; P < 0.01; Figure 1B). Similarly, the RR of MI was 7.07 (95% CI, 0.93 to 53.5; P = 0.058) when comparing reversible defects to fixed defects (Figure 1D). The RR of MI was not increased in individuals with fixed defects compared with normal perfusion images (RR 1.12 [95% CI, 0.1 to 12.2]; Figure 1C).

Risk of Cardiac Death

Sixteen of 505 patients with negative MPS had a CD versus 63 of 408 patients with a positive test, representing an annualized event rate of 1.8% and 6.9% for negative and positive MPS, respectively (Tables 2 and 3). Figure 2A shows the individual study and pooled RR of cardiac death. The RR of a CD among patients with a positive test was 2.92 (95% CI, 1.66 to 5.12; P < 0.001) compared with patients with a negative test. No significant heterogeneity existed among individual study results (P = 0.79)

• Download figure
• Open in new tab
• Download powerpoint

Figure 2. Cardiac death. (A) Positive versus negative tests; (B) Reversible defects versus negative tests; (C) Fixed defects versus negative tests; (D) Reversible versus fixed defects.

The presence of both reversible and fixed perfusion abnormalities was associated with an increased risk of CD when compared with normal test results. Patients with reversible defects also had a RR of CD 3.82 (95% CI, 1.83 to 7.94; P < 0.001; Figure 2B) compared with patients with normal images. Similarly, the RR of CD was 4.74 (95% CI, 2.26 to 9.92; P < 0.001) when patients with fixed defects were compared with those with normal test results (Figure 2C). The RR of CD was not increased in patients with reversible defects compared with those with fixed perfusion defects (RR 0.78 [95% CI, 0.48 to 1.25]; P = 0.29; Figure 2D).

If future MI or CD is considered the gold standard against which MPS results are to be applied, the sensitivity of MPS is 0.80 for CD and 0.70 for MI. The specificity is 0.59 for both MI and CD. The overall incidence of MI was 4.5% and of CD was 8.7%, representing average annualized event rates of 2.8% for MI and 4.3% for CD. The positive predictive value for MI is 7.4% and for CD is 15.4%. The negative predictive value of normal MPS in the combined analysis was 97.7% for MI and 96.9% for CD.

Discussion

The results of this meta-analysis confirm that individuals with abnormal MPS before kidney or kidney-pancreas transplantation are at higher future risk for cardiac events than those individuals with normal tests. Compared with patients with normal tests, those with evidence of inducible ischemia (reversible defects, new wall motion abnormality) have a sixfold increase in the risk of MI and an almost fourfold risk of cardiac death. In addition, patients with noninducible ischemia (fixed defects, resting wall motion abnormality) also have a significantly higher risk of cardiac death (RR, 4.7) but not MI (RR, 1.1). Diabetic patients have a similar pattern of risk, with reversible defects alone strongly associated with MI (RR, 9.3) and both fixed and reversible defects associated with cardiac death (RR, 4.0 to 4.7).

The results of our meta-analysis may be limited by several potential biases. In many studies we included, positive test results led to coronary angiography and may have introduced a verification bias. Verification bias occurs when the screening test result leads to a confirmatory or gold standard test such as a coronary angiogram (33). If the results of coronary angiography led to coronary revascularization, the rate of MI and cardiac death may change and could alter the predictive accuracy of the noninvasive cardiac tests. For example, the results of a randomized controlled trial of surgical revascularization versus medical therapy by Manske et al. (34) suggest diabetic patients with asymptomatic CAD benefit from pretransplant coronary revascularization. In this study, 26 patients with type I diabetes mellitus, left ventricular ejection fraction >35%, and asymptomatic coronary artery lesions judged to be hemodynamically significant were randomized to medical therapy, consisting of ASA and a calcium channel blocker or revascularization. Nine of thirteen patients in the medical group versus 2 of 13 in the revascularization group experienced fatal or nonfatal myocardial infarctions. This study suggests that coronary revascularization in patients with type I diabetes reduces the risk of subsequent cardiac events, and this could result in an underestimate of the risk associated with a positive MPS. The effect of this potential bias on our results cannot be estimated because the numbers of patients treated with revascularization have not been reported in the studies we reviewed.

In nondiabetic patients with ESRD, the effect of verification bias on the predictive accuracy of noninvasive cardiac testing is more difficult to assess. No randomized controlled trial comparing medical therapy versus revascularization exists, so optimal treatment strategies are unknown. If verification bias in nondiabetic patients led to angioplasty or bypass procedures, the noninvasive cardiac tests would overestimate the risk of MI and cardiac death if revascularization increased perioperative risk and/or did not improve the long-term prognosis. There is evidence to support this pattern of morbidity and mortality in ESRD patients who are treated with coronary revascularization. In a large observational study of 14,306 diabetic and nondiabetic ESRD patients who had coronary revascularization, in-hospital mortality rate ranged from 5.4 to 12.5%; by 2 yr, 30 to 40% of patients had either died of heart disease or had nonfatal MI (35). These findings suggest that a verification bias could overestimate the accuracy of positive MPS.

Four of the twelve studies included in this meta-analysis used exercise instead of pharmacologic stress, which may introduce bias in two ways. First, patients unable to exercise to achieve a target heart rate may have falsely negative MPS. If these patients had a future risk of cardiac events similar to the risk of patients with positive MPS, their inclusion in the normal test group would tend to decrease the relative risk of future cardiac events associated with a positive test, thereby underestimating the true risk associated with a positive MPS. Second, it is unclear whether patients with ESRD selected for pharmacologic stress have exercise capacity that is more limited than patients selected for exercise testing. In the general population, exercise capacity is a powerful independent prognostic factor in men referred for exercise testing (36). Therefore, it is possible that underlying comorbidity, as reflected in ability to exercise, may influence the choice of either pharmacologic or exercise testing, which could result in misleading risk estimates when the results of the two strategies are combined. However, the lack of heterogeneity in the pooled analysis suggests that the results are probably generalizable to both groups’ patients.

Several methodologic features of the studies we reviewed limit our understanding of the prognostic accuracy of MPS. First, because we were unable to determine from the primary studies when patients had cardiac events, the usual statistical analysis applied to survival data could not be performed. As a consequence, the findings in Table 3 are limited to a description of the proportions of patients with and without cardiac events according to their MPS test result, and the average event rate per 100 patient-years of follow up. Second, the results of our meta-analysis are based on univariate analyses and are not adjusted for other important prognostic factors such as age, diabetes, and known coronary artery disease. It is therefore important to ask whether the noninvasive test results are still valid when these other prognostic variables are considered. Older age, diabetes, and left ventricular dysfunction and hypertrophy are strongly associated with MI and cardiac death in ESRD patients (5,37,38). However, only 1 of the 12 studies included in this meta-analysis used multivariate analysis to confirm the independent prognostic value of noninvasive tests in predicting cardiac outcomes. Bates and colleagues reported that in 53 patients that a new wall motion abnormality was associated with future cardiac events (odds ratio 12.7) (21). Brown et al. (27) found that both reversible defects on thallium scintigraphy and left ventricular dysfunction were independently associated with the combined outcome of future MI or CD. Recently, we have confirmed the findings of these investigators. In a study of 441 consecutive patients being assessed for kidney transplantation, we used a Cox regression analysis to confirm that abnormal thallium/sestamibi test results were still predictive of MI and CD (RR, 2.5) when adjusted for both age and diabetes (39). Similar results were found in a meta-analysis of 15 published reports on preoperative pharmacologic stress risk stratification of patients without kidney disease undergoing vascular surgery (40). Taken together, these findings provide preliminary support that MPS accurately stratify risk in ESRD patients who have multiple risk factors for heart disease.

What are the implications of our findings for the clinician assessing patients for kidney and kidney-pancreas transplantation? First, the combined analysis of any MPS abnormality has adequate sensitivity for future MI or CD (0.70 and 0.80, respectively). Thus, when the average annualized incidence is between 3 to 5%, the negative predictive value exceeds 96%. These values are comparable to MPS test properties in detecting angiographically significant CAD (24). Second, our results also show that evidence of inducible ischemia on MPS is strongly associated with MI and cardiac death in both diabetic and nondiabetic patients, supporting the recommendation that such patients be evaluated with coronary angiography (5–8). Third, we found that patients with non-inducible ischemia were at significantly higher risk for future cardiac death but not MI. However, we could not establish if the higher risk of cardiac death in these patients was related to ongoing ischemia, left ventricular dysfunction, arrhythmias, or a combination of these processes, becuase the studies in our meta-analysis did not control for key prognostic factors. Parfrey et al. (41) reported that left ventricular hypertrophy and systolic dysfunction are independent risk factors for de novo ischemic heart disease, especially in older patients and those with diabetes. At present, however, it is unknown which demographic and clinical factors are associated with and mediate the higher risk of death from heart disease in patients with non-inducible ischemia. In the absence of other data, and given the higher mortality risk for patients with non-inducible ischemia on MPS, our practice has been to offer cardiac catheterization to these individuals.

Can the clinician be reassured by the finding of a normal MPS in asymptomatic patients who are at higher risk because of older age or diabetes? The patients included in this meta-analysis, including those with normal tests, all had risk factors for cardiac disease (as the original indication for the MPS). For example, Table 3 shows that among 102 diabetic patients with normal MPS, the incidence of MI was 2.4% per year. Similarly, among 141 diabetic patients with normal MPS, the incidence of CD was 0.9% per year. Although the specificity of MPS for future cardiac events is low, the negative predictive value is high for both MI and CD. These findings indicate a relatively low event rate among high-risk patients with normal tests; however, when compared with young patients without diabetes or other risk factors for CAD, patients with normal MPS still appear to be at higher risk. In two studies that followed low-risk patients, cardiac death occurred in 1 of 94 patients followed for a mean of 48 mo (12) and in none of 72 patients followed for a mean of 12.2 mo (11). These findings suggest that over time, patients who have risk factors and normal MPS still have a higher cardiac risk than previously recognized.

In summary, we performed a meta-analysis of 12 observational studies involving 913 patients assessed with MPS as part of their cardiac evaluation before kidney or kidney-pancreas transplantation. We conclude that in patients with ESRD assessed for transplantation and evaluated using nuclear scintigraphy or DSE, a negative test result is associated with a low event rate for each of MI and cardiac death. Conversely, patients with abnormal myocardial perfusion studies are at higher long-term risk for MI or cardiac death. This was observed for both fixed and reversible perfusion defects. The data from these studies should be useful to clinicians when counseling patients about cardiac risk and making decisions about subsequent cardiac investigations before kidney or kidney-pancreas transplantation.