There was significant heterogeneity in all these analyses. In an attempt to explain the heterogeneity, 2 separate post hoc analyses were conducted. Heterogeneity was not explained on the basis of the stressor (dobutamine, dipyridamole, or atropine) or the year the study was conducted. We used the more conservative random effects model in all calculations of summary LR.
There were 20 studies (9 SE and 13 TI with 2 common studies) where a ROC curve could be constructed. The cumulative ROC for SE was 0.80 (95% CI, 0.76–0.84) and 0.75 (95% CI, 0.70–0.80; not significant) for TI (Fig. 2). In a further analysis of quantitative SE the LR of a negative SE was a better predictor of an uneventful operation than TI (LR, 0.23; 95% CI, 0.17-0.32 versus 0.44; 95% CI, 0.36–0.54; P < 0.02). The finding of a moderate-to-large abnormality occurred in 16.2% of SE tests and 14.6% of TI tests. These findings were associated with a LR 8.35 (95% CI, 5.6–12.45) with no difference between the two techniques. This evaluation of cumulative ROC again revealed mild heterogeneity. The heterogeneity was no longer significant when we eliminated the 2 studies with ROC more than 0.96 (I2 = 0%).
The results of stress testing were used, in 37 studies, to refer patients for coronary angiography. The rate of referral to angiography was more than 2 times more frequent in patients screened with TI. The percentage of patients who were revascularized was the same whether they were screened with TI or SE.
This meta-analysis shows SE has better predictive powers compared to TI. The LR of a positive SE was twice that of positive TI. A negative SE reduces the probability of MI or death. Sensitivity analysis confirmed these findings. There were fewer false negative SE results after analysis of vascular patients, including only higher quality studies, and after eliminating all studies conducted before 1996. We also found fewer false negative SEs in the quantitative studies where ROC was calculated. The second major finding of this study revealed, in quantitative screening tests, that a moderate-to-large defect, detected by either SE or TI, is highly predictive of postoperative events.
A negative TI does not reliably reduce the probability of a postoperative cardiac event. This meta-analysis has found that more than one third of the cardiac events occurred in patients with a negative test. This finding has important clinical implications because careful patient selection is required to make safe interventions. Medical therapy is not without significant side effects. Beta-adrenergic antagonists started de novo after cardiac surgery increase length of hospital stay (88). In noncardiac surgery, β-adrenergic blockade increases the need to treat hypotension and bradycardia and may increase the incidence of heart failure (10). In lower risk patients β-adrenergic antagonists may cause harm (11). A finding of a moderate-to-larger defect also has important implications.
The recently completed CARP trial has been used by some to advocate for no preoperative testing. We disagree with this assessment of the results (89). First, many of the patients in the trial did not conform to the current America Heart Association/American College of Cardiology guidelines for testing. Second, the trial did not have the power to assess in-hospital cardiac events. There was a trend toward a 20%–25% reduction in MI. Third, in subgroup analysis, the patients who would most benefit from testing (moderate-to-high risk Eagle criteria and Revised Cardiac Risk Index patients) seemed to benefit from revascularization if a moderate or large defect was demonstrated. Regrettably, this landmark trial was underpowered to demonstrate an effect in this subgroup of patients. The present meta-analysis shows that patients with moderate-to-large defects, by either test, have an almost ninefold increase in the risk of MI or death after noncardiac surgery. In a surgical population with a perioperative MI incidence of 5%, the finding of a moderate perfusion defect carries a 40%–50% chance of a perioperative MI. Based on the CARP trial and this meta-analysis, any patient in our institution with moderate-to-large perfusion defect continues to be referred for coronary angiography. The false negative rate we describe suggests that fewer patients will be missed if SE is used. The results of this meta-analysis extend the findings of Etchells et al. (8) by showing that moderate or multiple defects on SE are at least as accurate as the demonstration of a large perfusion defect on TI. A negative test does not reliably confirm less risk of perioperative cardiac event, although a positive SE is 2 times more predictive than a positive TI. We continue to support the contention that an accurate and quantitative ischemic assessment is required in all moderate-to-high risk patients.
There are important differences in the way these studies were conducted. Postoperative MI is often clinically silent, and many postoperative MIs go undetected. Our finding that routine screening protocols exist more frequently in SE studies would have been expected to inflate the sensitivity measurement of SE. We have attempted to control for this effect by using a sensitivity analysis entering only those trials in either group that used routine screening and blinding. The sensitivity analysis showed that the comparative LRs were not changed and the statistical significance of the differences between the groups was maintained. The sensitivity and specificity of SE and TI may have been artificially changed by postoperative care. It is natural for physicians to alter the care of patients with positive preoperative screening tests to try to diminish postoperative morbidity. Knowledge of increased risk may increase monitoring. A variety of measures are thought to decrease perioperative MI, including β-blockade (90,91), administration of α-adrenergic agonists (92), calcium channel blockers (93), and thoracic epidural analgesia (94). We contend that therapeutic interventions do not explain the results of this meta-analysis. First, in studies that supply these data, we could not detect a difference in perioperative treatment regimens. Second, the rates of preoperative revascularization are similar. Finally, the crude MI and death rates are not different when the 2 study groups are compared.
We have chosen the LR and ROC as our primary outcome measurements. These measures have been used in the last 2 meta-analyses on this subject (8,9). Odds ratios and relative risk have been criticized and can be inaccurate for classifying or predicting risk (13). The LR incorporates elements of both the sensitivity and specificity and expresses the odds that a given level of test result (a perfusion defect or regional wall motion abnormality) would be expected in the target disorder, in this case the odds of a postoperative MI or death.
The shortcomings of meta-analysis are well recognized and we have documented them (92–94). These shortcomings are even more pronounced when evaluating diagnostic testing because a variety of definitions may be used as end-points. We have tried to control for this in our analysis by using a standardized end-point from which to calculate sensitivity and specificity. Several other deficiencies must be addressed.
First, studies in this meta-analysis were conducted over more than 2 decades. In a post hoc sensitivity analysis we could not demonstrate a difference based on the date of study or a change in accuracy over the span of these studies (see online appendix at www.anesthesia-analgesia.org). Second, as was noted by others (8), the general quality of the publications is poor. The sensitivity analyses show that the differential between SE and TI is largest in the studies where blinding was incorporated. The analysis is also limited in that there has been no control of the planned interventions after a positive test. Third, it is possible that the underlying patient characteristics are different. We tried to control for this by evaluating the baseline characteristic where possible, but little information was actually given. The overall morbidities among studies were not different nor was there a difference in the percentage of patients who were revascularized as a result of these investigations. Fourth, we noted a large amount of heterogeneity. Accordingly we used the conservative random effects model. Our attempt to explain the heterogeneity was not successful. We note that there was little heterogeneity in the analysis of quantitative studies. The results of the quantitative studies mirror the finding of the whole study. Finally, the method used to combine the ROC curves uses the inverse of the variance to weight studies. In this case, more weighting is given to studies with an ROC approaching 1. The analysis found 2 TI studies with an ROC of 0.5 and 2 studies with values at 0.6, whereas the lowest SE ROC was 0.73. These low values are underweighted, and this meta-analysis may have minimized the difference between SE and TI studies. A strength of this analysis is the number of studies and the number of subjects evaluated. Funnel plots do not suggest a publication bias. Furthermore, it is unlikely that any missed studies, should they exist, would influence the major findings of this study. Systematic reviews and meta-analysis are best for hypothesis generation but not for testing. To demonstrate a superior negative predictive test, in a randomized controlled trial based on an event rate of 6% and a 25% reduction, more than 10,000 patients would be required. This would necessitate incorporation of a standardized management algorithm for positive study results and a routine screening protocol for perioperative events.
In conclusion, in this meta-analysis we adjusted for the known problems in combining diagnostic tests and used the identical diagnostic criteria for each study. The preoperative risks of both SE and TI appear to be similar. We used several sensitivity analyses; the results show that SE has superior negative predictive ability. Second, moderately large defects, detected by either method, are highly predictive of subsequent postoperative cardiac events. In considering the clinical utility of our analysis, we would suggest that a negative TI should result in little change in perioperative management. All patients with a positive test should be considered at increased risk for an event and managed with maximal medical therapy. Patients with moderately large defects should be referred for angiography. SE, as a screening tool in patients with suspected cardiac disease before noncardiac surgery, has many positive features, including better negative predictive power, and we conclude that it is superior to TI in predicting postoperative cardiac events.
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