doi: 10.1161/CIRCULATIONAHA.104.522805
(Circulation. 2005;112:I-286 – I-292.)
© 2005 American Heart Association, Inc.
Surgery for Coronary Artery Disease |
Preoperative Aspirin Therapy Is Associated With Improved Postoperative Outcomes in Patients Undergoing Coronary Artery Bypass Grafting
From the Department of Internal Medicine (K.A.B., B.D.P., U.V., S.L.K., R.S.W.), and the Divisions of Cardiovascular Diseases (K.A.B., B.D.P., U.V., S.L.K., R.S.W.), Biostatistics (A.G.R.), and Cardiothoracic Surgery (C.M.), Mayo Clinic College of Medicine, Rochester, Minn.
Correspondence to Dr R. Scott Wright, Mayo Clinic and Foundation, Associate Professor of Medicine and Cardiology, Gonda 5-477, 200 First St SW, Rochester, MN 55905. E-mail wright.scott{at}mayo.edu
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Abstract |
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Background— Aspirin is beneficial in the setting of atherosclerotic cardiovascular disease. There are limited data evaluating preoperative aspirin administration preceding coronary artery bypass grafting and associated postoperative outcomes.
Methods and Results— Using prospectively collected data from 1636 consecutive patients undergoing first-time isolated coronary artery bypass surgery at our institution from January 2000 through December 2002, we evaluated the association between aspirin usage within the 5 days preceding coronary bypass surgery and risk of adverse in-hospital postoperative events. A logistic regression model, which included propensity scores, was used to adjust for remaining differences between groups. Overall, there were 36 deaths (2.2%) and 48 adverse cerebrovascular events (2.9%) in the postoperative hospitalization period. Patients receiving preoperative aspirin (n=1316) had significantly lower postoperative in-hospital mortality compared with those not receiving preoperative aspirin [1.7% versus 4.4%; adjusted odds ratio (OR), 0.34; 95% CI, 0.15 to 0.75; P=0.007]. Rates of postoperative cerebrovascular events were similar between groups (2.7% versus 3.8%; adjusted OR, 0.67; 95% CI, 0.32 to 1.50; P=0.31). Preoperative aspirin therapy was not associated with an increased risk of reoperation for bleeding (3.5% versus 3.4%; P=0.96) or requirement for postoperative blood product transfusion (adjusted OR, 1.17; 95% CI, 0.88 to 1.54; P=0.28).
Conclusions— Aspirin usage within the 5 days preceding coronary artery bypass surgery is associated with a lower risk of postoperative in-hospital mortality and appears to be safe without an associated increased risk of reoperation for bleeding or need for blood product transfusion.
Key Words: aspirin • surgery • cardiopulmonary bypass • mortality
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Introduction |
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Management of aspirin therapy in the perioperative period in patients undergoing coronary artery bypass surgery is variable among surgeons and across medical centers. It is not uncommon for aspirin therapy to be withheld before coronary artery bypass surgery out of concern for increased bleeding risk, despite conflicting evidence regarding perioperative aspirin therapy and the associated risk of significant postoperative bleeding.1–8 Platelet inhibition is well appreciated to confer significant benefit in the setting of acute coronary syndromes,9–13 and, indeed, platelet inhibition with dipyridamole and aspirin has been shown to reduce the rates of acute and subacute bypass graft occlusion in patients undergoing coronary artery bypass surgery.14–17 There are little published data evaluating the effect of preoperative aspirin therapy on postoperative outcomes after coronary artery bypass surgery7 or on the safety of continuing aspirin therapy before surgery. Coronary artery bypass surgery is not always able to achieve complete revascularization because of technical and anatomic factors. Perioperative ischemia is often evident through the demonstration of postoperative cardiac biomarker release18–21 and is associated with an increased risk of short-term and intermediate-term mortality.18–23 To evaluate the potential effects of preoperative aspirin therapy in patients undergoing coronary artery bypass surgery, we performed a retrospective cohort analysis evaluating the association between aspirin therapy in the 5 days preceding coronary bypass surgery and early postoperative outcomes.
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Methods |
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Study Design
This study was a retrospective cohort study including 1636 consecutive patients who underwent first-time isolated coronary artery bypass grafting at our institution (Mayo Clinic) from January 1, 2000, through December 31, 2002. Patients were classified to 1 of 2 groups depending on whether or not they had received aspirin within the 5-day time period preceding coronary artery bypass grafting. We evaluated the association between preoperative aspirin therapy before coronary bypass surgery and prespecified a priori postoperative outcomes. This study was approved by the Mayo Foundation Institutional Review Board. All of the patients had previously granted permission for use of their medical records for research purposes.
Study Data
Data used in this analysis were retrieved from the Mayo Clinic-Rochester cardiovascular surgical database that includes data collected as part of the Society of Thoracic Surgeons Database project. This database prospectively collects a comprehensive list of prespecified data points in all of the consecutive patients undergoing coronary artery bypass surgery at our institution, including demographic, clinical, and outcome data.
Within the database, patients were coded as having a history of cerebrovascular disease if they had suffered a prior cerebrovascular accident, residual ischemic neurologic deficit, transient ischemic attack, or had a documented stenosis in the common and/or internal carotid circulation 
75%. Patients were coded as having renal insufficiency if the preoperative serum creatinine was 2 mg/dL. Hypercholesterolemia was defined as a serum total cholesterol 200 mg/dL, and/or low-density lipoprotein >130 mg/dL, and/or treatment with a cholesterol-lowering medication.
Outcome Measures
All of the outcome measures used in this analysis were prespecified. Given the subjective nature of many clinical outcomes, we only prespecified all-cause in-hospital mortality after coronary artery bypass surgery as the primary outcome measure. Prespecified secondary outcomes included rates of perioperative adverse cerebrovascular events, reoperation for bleeding, and receipt of postoperative blood product transfusion. Adverse cerebrovascular events were defined as a diagnosed cerebral vascular accident or transient ischemic attack during the postoperative hospitalization period. An independent review of the medical records of the patients who died after CABG was performed, and cardiovascular versus noncardiovascular cause of death was adjudicated.
Statistical Analysis
Continuous variables are reported as mean±SD or as medians and interquartile range. Categorical variables are reported as percentages. Wilcoxon rank sum-tests or 2-sample t tests were used, as appropriate, in univariate analysis of continuous data. The 
2 test was used in the univariate analysis of categorical data. Univariable and multivariable associations of demographic, clinical, and therapeutic variables with the end points were assessed via logistic regression.
Treatment decisions in nonrandomized, observational studies are commonly biased by extenuating factors and circumstances, which may be related to particular outcomes. Therefore, we used propensity scores as a continuous variable to help account for the nonrandomization of preoperative aspirin therapy. The variables selected for inclusion in the propensity score model included all of the preoperative variables that have been shown previously to influence in-hospital mortality after CABG,24 as well as other preselected variables, and are as follows: age, gender, date of surgery, body mass index, history of congestive heart failure, hypertension, tobacco smoking status, hypercholesterolemia, diabetes mellitus, creatinine concentration, renal failure, renal dialysis, left ventricular ejection fraction, prior myocardial infarction, angina, percutaneous coronary intervention on current admission, severity of mitral regurgitation, peripheral vascular disease, chronic obstructive pulmonary disease, history of ventricular arrhythmia, emergent/nonemergent surgical status, use of cardiopulmonary bypass, number of diseased vessels, number of distal anastamoses, left main disease (>50% stenosis), cardiogenic shock before surgery, intraaortic balloon pump use, inotropic medication therapy entering operating room, inotropic medication therapy on leaving operating room, antiarrhythmic medication therapy leaving the operating room, individual surgeon performing the CABG, and preoperative medications (ß-blockers, ACE inhibitors, digoxin, diuretics, calcium channel blockers, lipid-lowering therapy). The propensity score, defined as the probability that any given patient would receive preoperative aspirin therapy given all of the observed covariates, was used as a 2-step procedure in each end point with <60 events (in-hospital mortality, perioperative adverse cerebrovascular event, reoperation for bleeding, and non-red blood cell [RBC] blood product transfusion). First, the propensity scores were calculated using a logistic regression in which aspiring therapy was the dependent variable, and all of the other covariates were entered in the model as independent variables. The date of surgery was included in the propensity score as rates of preoperative aspirin usage varied between years (from 77.8% to 82.5%). The ability of the propensity model to discriminate between patients who did and did not receive aspirin therapy before CABG was assessed using the c-statistic. Second, the models for estimating the aspirin therapy effect in each of the end points were adjusted for the propensity score and other significant covariates. The different covariates were allowed to enter the model if they remained significant after the propensity score adjustment. However, we limited the number of covariates to 1 covariate per 10 events in all of the models. The goodness-of-fit of the model was assessed using the Hosmer-Lemeshow test. In cases were the number of events was >60, the multivariable models were calculated using stepwise logistic regression, with entry and retention in the model set at a significance level of 0.15 and 0.05, respectively. Odds ratios (ORs) and their associated 95% CIs were estimated. P<0.05 was considered statistically significant.
The coauthors A.G.R. and K.A.B. had full access to all of the study data and take responsibility for the integrity of the data and the accuracy of the data analysis. This study was approved by our Institutional Review Board. All of the subjects had given permission for the use of their medical record for research purposes.
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Results |
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Patient Characteristics
Of the 1636 patients included in the analysis, 1316 patients (80.4%) had received aspirin within the 5-day period preceding coronary artery bypass surgery, whereas the remaining 320 (19.6%) had not received aspirin within this time period. Demographic and clinical data of the patients who did and did not receive preoperative aspirin therapy are presented in Table 1.
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Age (69 years versus 69 years; P=0.57) and gender (male, 76.2% versus 72.5%; P=0.17) distributions were similar between groups as was left ventricular ejection fraction (mean, 57% versus 55%; P=0.79), smoking status, body mass index, percentage of patients with significant left main disease, angina, congestive heart failure, number of diseased coronary vessels, severity of mitral regurgitation, percentage of patients with hypertension, diabetes, renal insufficiency, known atherosclerotic cerebrovascular disease, and chronic obstructive pulmonary disease. Patients receiving preoperative aspirin therapy were more likely to have had a prior myocardial infarction and to have had a myocardial infarction with the 21 days preceding coronary bypass surgery. In addition, patients receiving preoperative aspirin therapy were more likely to have received preoperative ß-blockers, whereas there was a larger percentage of patients on dialysis in the no-aspirin group. Rates of preoperative angiotensin-converting enzyme inhibitor, digitalis, and intravenous inotrope administration were similar between groups. The mean length of postoperative hospitalization was similar in both groups (6 days versus 6 days; P=0.33).
Procedural Characteristics
Procedural characteristics, including the number of distal anastamoses, rates of internal mammary artery usage, time on cardiopulmonary bypass, and aortic cross-clamp time, were similar in both groups (Table 2). All of the patients in both groups received an internal mammary artery graft conduit with all of the bypass surgeries performed by 1 of 9 cardiovascular surgeons. The rates of patient aspirin usage preoperatively were similar between individual surgeons. Per clinical practice protocol, all of the patients received 81 mg of aspirin 6 hours postoperatively via nasogastric tube and subsequently 325 mg every 24 hours after coronary artery bypass grafting. The patients routinely received the antifibrinolytic tranexamic acid intraoperatively.
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Outcome Measures
Univariate Analysis
Thirty-six of the total 1636 patients (2.2%) died in-hospital after coronary bypass surgery. Of the 1316 patients receiving preoperative aspirin therapy, 22 died in-hospital after surgery whereas 14 of the 320 patients not receiving preoperative aspirin therapy died in-hospital after surgery. This resulted in an observed 61% relative reduction in all-cause in-hospital mortality in patients receiving preoperative aspirin therapy (1.7% versus 4.4%) with a univariate OR of 0.37 (95% CI, 0.19 to 0.74; P=0.004) for mortality (Table 3). Patients receiving preoperative aspirin were less likely to die of cardiovascular causes (0.5%) compared with those not receiving preoperative aspirin (2.2%). There was no increased risk of reoperation for bleeding in those receiving preoperative aspirin therapy (3.5% versus 3.4%; OR, 1.02; 95% CI, 0.52 to 1.99; P=0.96) (Table 3). There was a trend toward an increased need for postoperative blood product transfusion in the aspirin group, which did not reach statistical significance (OR, 1.25; 95% CI, 0.98 to 1.60; P=0.07). There was no significant difference in the rates of postoperative adverse cerebrovascular events in those receiving preoperative aspirin compared with those not receiving preoperative aspirin by univariate analysis (2.7% versus 3.8%; OR, 0.72; 95% CI, 0.37 to 1.40; P=0.34).
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Propensity and Multivariate Analysis
The final multivariate model assessing in-hospital mortality included the propensity score and age before surgery. The final multivariate model assessing perioperative adverse cerebrovascular events included the propensity score, age, and prior myocardial infarction. The multivariate models, including propensity scores for the in-hospital mortality and perioperative adverse cerebrovascular event outcomes, discriminated reasonably well between those who did and did not receive preoperative aspirin therapy (c-statistic, 0.72 and 0.73, respectively). The probability values associated with the Hosmer-Lemeshow tests were large (P=0.53 and P=0.93, respectively) indicating that there was not a lack of fit of these models. Results of the multivariate analysis are summarized in Table 3 and in Figure 1. The observed reduction in all-cause postoperative mortality in patients receiving preoperative aspirin persisted after statistical adjustment, including the propensity to have received preoperative aspirin therapy (adjusted OR, 0.34; 95% CI, 0.15 to 0.75; P=0.007). The adjusted rates of postoperative adverse cerebrovascular events were not statistically significant between the aspirin and no-aspirin groups, although the OR point estimate favored preoperative aspirin therapy (adjusted OR, 0.67; 95% CI, 0.32 to 1.50; P=0.31).
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Importantly, we observed no difference in the risk of reoperation for bleeding between groups after adjusting for differences between groups, including the propensity to have received preoperative aspirin therapy (adjusted OR, 0.80; 95% CI, 0.40 to 1.74; P=0.56). Patients receiving preoperative aspirin had similar requirements to those not receiving aspirin for postoperative RBC transfusion (adjusted OR, 1.19; 95% CI, 0.90 to 1.58; P=0.22). Rates of postoperative non-RBC blood product transfusion were also similar in both groups (adjusted OR, 0.84; 95% CI, 0.32 to 2.67; P=0.75). Combined, the rate of all of the postoperative blood product transfusions was not significantly different between groups (adjusted OR, 1.17; 95% CI, 0.88 to 1.54; P=0.28).
In a subgroup analysis of the 1289 patients without a myocardial infarction immediately preceding (within 21 days) coronary bypass grafting, preoperative aspirin therapy was significantly associated with reduced postoperative mortality (adjusted OR, 0.30; 95% CI, 0.12 to 0.57; P=0.008). This subgroup analysis suggests that the survival benefit observed with preoperative aspirin therapy is not confined to patients with a recent myocardial infarction but is also applicable to patients with stable coronary disease.
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Discussion |
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In this analysis of consecutive patients undergoing isolated coronary artery bypass surgery at our institution, we found that preoperative aspirin therapy is associated with a significantly lower risk of postoperative in-hospital mortality. We observed a 61% relative reduction and a 2.7% absolute reduction of in-hospital mortality rates in the patients that had received aspirin therapy within the 5-day time period preceding bypass surgery. This improvement in survival persisted after statistical adjustment, which included the propensity to have received preoperative aspirin therapy. Additionally, preoperative aspirin therapy appears to be safe without an increased risk of reoperation for bleeding or of postoperative blood product transfusion. We did not observe an associated statistically significant incremental benefit of preoperative aspirin on postoperative adverse cerebrovascular events, as has been reported in patients receiving aspirin in the postoperative period only.8 However, the OR for this outcome favored preoperative aspirin therapy, but our analysis likely lacked sufficient power to detect a statistically significant difference in this outcome measure. In this light, preoperative aspirin therapy appears to have a favorable impact on postoperative mortality in a clinical practice setting in which all of the patients routinely receive early postoperative aspirin therapy.
Aspirin therapy has been show to be beneficial in the setting of acute coronary syndromes where it significantly reduces mortality in patients with unstable coronary artery disease.9–13 It would be reasonable to postulate that preoperative aspirin therapy might also confer an early postoperative benefit given the well-proven benefit of platelet inhibition in the setting of acute coronary syndromes and myocardial ischemia, the reduction of early vein graft thrombosis when aspirin is started soon after coronary bypass surgery, and the associated reduction in postoperative ischemic cardiac, cerebrovascular, gastrointestinal, and renal complications with early initiation of postoperative aspirin therapy.8,14
There is limited published data evaluating the effects of perioperative aspirin therapy on postoperative outcomes after coronary bypass surgery. Dacey et al,7 using a case-control design of 368 in-hospital deaths after coronary artery bypass surgery, found that preoperative aspirin usage within 7 days before bypass surgery was associated with a 27% reduction of in-hospital mortality. In addition, there were no significant differences in chest tube drainage, blood product transfusion, or need for reexploration for hemorrhage in patients exposed to preoperative aspirin compared with those not receiving preoperative aspirin. In a nonrandomized prospective cohort study, Mangano8 has shown that initiation of aspirin therapy within the first 48 hours after coronary artery bypass surgery is associated with a significant reduction of in-hospital fatal and nonfatal adverse cardiac, cerebral, renal, and gastrointestinal ischemic complications. Additionally, initiation of early aspirin therapy did not result in an increased risk of reoperation for bleeding or blood product transfusion requirements. In the analysis by Mangano,8 discontinuation of aspirin therapy before coronary artery bypass surgery was a strong independent risk factor for postoperative mortality in the multivariate analysis. This finding additionally suggests that preoperative continuation of aspirin therapy is likely advantageous and that preoperative discontinuation of aspirin therapy may be detrimental.
Although there are reports of increased bleeding associated with preoperative platelet inhibition, the more current robust data suggest that there is not a significantly increased risk associated with administration of preoperative oral antiplatelet agents, with the exception of clopidogrel.1–8,25,26 Our data support this finding and support the published American College of Cardiology/American Heart Association guidelines on the management of patients undergoing coronary artery bypass surgery, which recommends the continuation of aspirin therapy up to the time of surgery in patients with a recent acute coronary syndrome, and that all other patients should receive aspirin within 24 hours of surgery.27 Our findings suggest that preoperative aspirin therapy may be beneficial regardless of the proximity of coronary bypass surgery to an acute ischemic myocardial event.
Limitations
Our analysis was retrospective in design, and preoperative aspirin therapy was not randomized; thus, our results may be influenced by treatment bias. However, we performed statistical adjustment including the use of propensity scores in an attempt to account for the nonrandomized nature of preoperative aspirin therapy. The available data did not enable us to precisely define the proximity of aspirin therapy to coronary bypass surgery within the 5-day period before surgery, and aspirin dosage information was not available. However, aspirin binds irreversibly to platelets and alters platelet function for the average 10-day to 14-day life span of the platelet and, therefore, had persistent biological platelet-inhibiting effects in the operative and immediate postoperative period in our aspirin group despite the timing of aspirin usage within the 5-day period preceding surgery. Our analysis was restricted to patients undergoing isolated coronary artery bypass surgery; therefore, our results may not be applicable to patients undergoing combined procedures, such as coronary artery bypass surgery, at the time of valve surgery. Our study encompasses the experience at a single tertiary care medical center; therefore, the generalizability of our findings may not extend to all of the clinical centers performing coronary artery bypass surgery.
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Conclusions |
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Our findings add to the currently available data evaluating perioperative aspirin therapy in patients undergoing coronary artery bypass surgery. The current study, along with the studies of Mangano8 and Dacey et al,7 show a consistent observation of improved postoperative outcomes associated with perioperative aspirin usage, without an associated increased risk of significant bleeding. The results of our study suggest that preoperative aspirin therapy may confer an incremental postoperative mortality benefit beyond that observed in patients receiving early postoperative aspirin only. An appropriately powered, randomized, controlled trial evaluating the optimal management of preoperative aspirin therapy before coronary artery bypass surgery would be useful to confirm our results.
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Acknowledgments |
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Divisional financial support for this study was provided through the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN. R.S.W. received research grant support from Bayer Pharmaceuticals.
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References |
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