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CARDIOVASCULAR ANESTHESIA

Epidural Analgesia Reduces Postoperative Myocardial Infarction: A Meta-Analysis

W. Scott Beattie, MD PhD, FRCPC^*, Neal H. Badner, MD FRCPC, and Peter Choi, MD FRCPC^*

*Departments of Anesthesia, McMaster University, Hamilton, Ontario, Canada; and Department of Anesthesia, University of Western Ontario, London, Ontario, Canada

Address correspondence and reprint requests to W. Scott Beattie, MD, University of Toronto, Department of Anesthesia, Room 3EN357, 100 Elizabeth St., Toronto, Ontario, Canada M5G 1P5. Address e-mail to scott.beattie{at}uhn.on.ca

	Abstract

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Postoperative cardiac morbidity and mortality continue to pose considerable risks to surgical patients. Postoperative epidural analgesia is considered to have beneficial effects on cardiac outcomes. The use in high-risk cardiac patients remains controversial. No study has shown that postoperative epidural analgesia decreases postoperative myocardial infarction (PMI) or death. All studies are underpowered to show such a result, and the cost of conducting a large trial is prohibitive. We performed a metaanalysis to determine whether postoperative epidural analgesia continued for more than 24 h after surgery reduces PMI or in-hospital death. The available databases were searched for randomized controlled trials of epidural analgesia that was extended at least 24 h into the postoperative period. The search yielded 17 studies, of which 11 were randomized controlled trials comprising 1173 patients. Metaanalysis was conducted by using the fixed-effects model, calculating both an odds ratio and a rate difference. Postoperative epidural analgesia resulted in better analgesia for the first 24 h after surgery. The rate of PMI was 6.3%, with lower rates in the Epidural group (rate difference, -3.8%; 95% confidence interval [CI] -7.4%, -0.2%; P = 0.049). The frequency of in-hospital death was 3.3%, with no significant difference between Epidural and Nonepidural groups (rate difference, -1.3%; 95% CI, -3.8%, 1.2%, P = 0.091). Subgroup analysis of postoperative thoracic epidural analgesia showed a significant reduction in PMI in the Epidural group (rate difference, -5.3%; 95% CI, -9.9%, -0.7%; P = 0.04).

IMPLICATIONS: Postoperative epidural analgesia, especially thoracic epidural analgesia, continued for more than 24 h reduces postoperative myocardial infarctions.

	Introduction

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Myocardial infarction is a leading cause of postoperative morbidity (1,2). The role of postoperative epidural analgesia in reducing perioperative risk is controversial. A recent systematic review (3) demonstrated reduced mortality in patients receiving neuraxial blockade. Most deaths were related to cardiovascular causes. The metaanalysis could not demonstrate a reduction in cardiac deaths. Postoperative myocardial infarction (PMI) is predominately non-Q wave and clinically silent, with the peak incidence within the first 24 h (4–10). PMI is usually preceded by prolonged ST depression, which is an accurate predictor of myocardial infarction (8–12).

Postoperative epidural analgesia has many features that would tend to reduce ischemia. Unfortunately, most studies have not extended the use of epidural analgesia into the critical first 24 h. All individual studies have lacked the statistical power to demonstrate a difference in PMI or death. Many epidural studies and all spinal anesthetic studies do not extend analgesia past the first 12 h. The cost of conducting such a study is prohibitive. Metaanalysis allows insight into this controversial subject (13).

This metaanalysis was designed to determine the effect of postoperative epidural analgesia on postoperative cardiac morbidity. Studies that used epidural analgesia for more than 24 h after surgery and reported either PMI or death as an outcome were included.

	Methods

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Randomized controlled trials (RCTs) examining the role of postoperative epidural analgesia administered for 24 h or more after surgery and whose outcomes included PMI or death were retrieved. We searched MEDLINE (1966 to December 1998) without language restriction by using the Medical Subject Heading terms "pain, postoperative," "anesthesia, epidural," "postoperative complications," "myocardial infarction," "congestive heart failure," and "death." A prior search (14) of postoperative pain management had concluded that pertinent literature is found in this database only. In addition, all English-language anesthesia journals (Acta Anaesthesiologica Scandinavica, Anaesthesia, Anesthesiology, Anesthesia & Analgesia, British Journal of Anaesthesia, Canadian Journal of Anaesthesia,andRegional Anesthesia & Pain Medicine) since 1987 were hand-searched for articles and abstracts that prospectively examined postoperative epidural analgesia. Finally, the Science Citation Index was searched under the reference "Yeager et al., Anesthesiology 1987" (15).

All citations were reviewed by two of the authors. Disagreements were resolved by consensus. We included articles that used a randomized design, examined the role of postoperative epidural analgesia in humans, and reported PMI or death as outcomes. Because the peak incidence of PMI is in the first 24 h, we excluded studies that used epidural analgesia for <24 h after surgery.

All included papers were graded by using the scale of Jadad et al. (16), which is a five-point validated scale that assesses randomization, blinding, and withdrawals. Data were abstracted by one investigator. We abstracted the patient characteristics, details of the surgical and analgesic interventions, cardiac outcomes, and other effects of epidural analgesia (pain relief and coagulation).

All trials had a 2 x 2 outcome table that permitted the use of the Peto odds ratio (17) and the event rate difference with their 95% confidence interval (CI). A fixed effects model was chosen. Calculations were performed by using Review Manager 4.1 (Wintertree Software, Inc., Nepean, Ontario, Canada). We chose the rate difference as our primary statistic because it allows for an accurate representation when one group within a study has an event rate of zero. We used the Breslow-Day method (18) to assess heterogeneity. Subgroup analysis of the level of epidural placement (thoracic or lumbar) was also performed. Because the choice of studies to include and the choice of statistical model could affect the estimates of treatment effect, we performed two sensitivity analyses: one analysis used the fixed effects model, excluding the controversial study of Yeager et al. (15), and another analysis used the random effects model (19).

	Results

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Our search found 204 studies. Of these studies, 17 were comparisons of postoperative epidural analgesia to a parenteral form of analgesia (15,20–35) and fulfilled the criteria of evaluating epidural analgesia with the specific cardiovascular outcomes. Reasons for exclusion included lack of randomization (20–24) and duplicate publication (25). Eleven RCTs (26–35) with a total of 1173 patients, comparing postoperative epidural analgesia to systemic analgesia, remained for analysis. Three studies (26–28) did not report PMI; all 11 studies reported death rate, although there were no deaths in 2 studies (29,30).

Table 1 summarizes the type of epidural, the surgical population, and the metaanalysis of the effect of postoperative epidural analgesia on PMI and death. Six studies used high lumbar or thoracic epidurals, and five used lumbar epidurals. Of the eight studies reporting PMI, two studies (15,29) observed no PMI in patients receiving epidural analgesia. The overall frequency of PMI was 6.3% in 685 patients.

View larger version (22K): [in this window] [in a new window]   Figure 1. The effect of postoperative epidural anesthesia on in-hospital death. OR = odds ratio, CI = confidence interval.

View larger version (20K): [in this window] [in a new window]   Figure 2. The effect of postoperative epidural anesthesia on postoperative myocardial infarction. OR = odds ratio, CI = confidence interval.

The sensitivity analysis is presented in Table 2. The odds ratios are within 7%. The use of the random effects model yields wider CIs, making the result not significant. Exclusion of the study of Yeager et al. (15) again yielded wide CIs.

Three of the 11 RCTs reported postoperative ST changes as measured by continuous Holter monitoring. One study did not report the results of ST Holter monitoring, even though it was recorded. Together, the three studies reported a 25% incidence of postoperative ischemia with a decreased incidence of postoperative ischemia in the first 24 h in the Epidural group, although this was not statistically significant (rate difference, -7.5%; P = 0.19). One study reported duration of ischemia. The data showed a shorter mean duration of each ischemic event for patients receiving epidural analgesia. This difference was not found to be significant.

Two studies (28,29) reported postoperative coagulation data. Both studies found a statistically significant reduction in their respective variables favoring postoperative epidural analgesia.

	Discussion

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This systematic review shows that postoperative epidural analgesia continued for 24 hours after surgery decreases PMI. Subgroup analysis suggests that thoracic epidural analgesia is superior to lumbar epidural analgesia in reducing PMI. The statistical significance of this metaanalysis is dependent on the model used (fixed effects versus random effects) and the studies included. We chose to use the rate difference as our primary statistic because it permits an accurate representation when one group has no events. The calculated odds ratio for studies is changed by an artificial value in studies where the event rate is zero for a group. Sensitivity analysis shows a consistent trend toward a reduction in PMI. The variation between the fixed and random effects models is <5%. The decrease in PMI noted in this study is similar to that suggested in a recent systematic review of centroneuraxial blockade (3). Our study differs from that report in several respects. First, our analysis is for 24 hours of postoperative epidural analgesia and specifically excludes studies of spinal anesthesia. Second, this analysis was designed specifically for cardiac morbidity, and third, it includes studies up to the year 1999.

The utility of postoperative epidural analgesia in reducing postoperative cardiac morbidity has created much controversy since Yeager et al. (15) concluded that postoperative epidural analgesia reduced the overall complication rate in high-risk patients. Their article generated much controversy with respect to its design (unblinded, poor analgesia in the control group), the decision to terminate the study early (a large difference between the two treatment groups), and the high rate of morbidity. We assessed the effect of excluding this article. The trend toward reduction in PMI is preserved, but this difference did not achieve significance. The remaining trials do not have the power to demonstrate a statistical difference at this level of morbidity.

The conduct of a metaanalysis must follow preset criteria. These include the formulation of a question a priori, a well described search technique, selection of studies, and accepted analysis of data. The methodology used in this study has been applied to other studies analyzing interventions to improve cardiac outcomes (3,36,37). We have taken care to avoid the bias that can occur from the inclusion of multiple publications involving identical patients. We believe that this study fulfills the criteria for a valid metaanalysis. We performed tests for data homogeneity by using the Breslow-Day method. We chose the fixed effects model as our primary analytic tool. This methodology has been used in other similar metaanalyses (3,14). We performed sensitivity analysis to assess the effect of different modeling. The random effects model is more conservative, but the results are similar and the net result within 5%.

The proportion of patients taking ß-blockers was identical in the Epidural and Control groups. The Epidural group had a more frequent incidence of angina (26.8% vs 15.4%), but this difference was not statistically significant (P = 0.051). These findings make it difficult to ascribe the difference with postoperative epidural analgesia to ß-adrenergic blocker usage. Further studies should add risk stratification, according to a predetermined risk index, to the randomization process to avoid any skewing of the patient populations.

Our results should be considered with caution. First, we have noted the difficulty in determining cardiac risk within the study populations on the basis of available data and the potential for bias. Second, none of these trials was double-blinded, and the evaluation of myocardial infarction could be influenced by treatment choice. We have analyzed the data by using both the fixed effects model and the random effects model with inclusion and exclusion of specific trials. There is a consistent reduction in the infarction rate no matter which method is used. As the model becomes more conservative, the studies lack the power to show statistical significance. We would further argue for inclusion of the study of Yeager et al. (15); contrary to belief, the infarction rate in this study (5.5%) was not higher than that in the other studies quoted. Exclusion does not alter the trend toward lower infarction rate but reduces the power to show significance.

In conclusion, postoperative epidural analgesia reduces PMI. Use of the more conservative random effects model continues to show a trend toward a reduction of PMI, but the trials assessed with this analytic tool do not possess the power to show a statistically significant difference. The purpose of this analysis was not to highlight the controversies in metaanalysis technique, but to evaluate whether further trials of postoperative epidural analgesia are warranted. The reduction of PMI by 40% in patients with thoracic epidural analgesia is consistent with the degree of benefit in the recent systematic review (3). These results are similar to other metaanalyses of epidural analgesia in different populations analyzing different outcomes (14,38).

The demonstration of reduced cardiac events with postoperative epidural analgesia is important because many high-risk patients cannot tolerate ß-adrenergic blockers, which also reduce PMI. Our findings suggest that in high-risk cardiac patients, epidural postoperative analgesia is warranted and should be used more widely. Further trials are warranted.

	Footnotes

 
Presented in part at the Canadian Anesthesiologists’ Society 54th Annual Meeting, Vancouver, Canada, June, 1997.

	References

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