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Ann Thorac Surg 2005;79:1210-1216
© 2005 The Society of Thoracic Surgeons
Bristol Heart Institute, Bristol Royal Infirmary, Bristol, United Kingdom
Accepted for publication September 24, 2004.
* Address reprint requests to Dr Ascione, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom (E-mail: r.ascione{at}bristol.ac.uk).
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Abstract |
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 Top Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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METHODS: Outcomes for in-hospital referrals for CABG between January 2001 and January 2002 were prospectively recorded. Exposure to aspirin, heparin, and clopidogrel during the 5 days before surgery was recorded, and their effect on outcome was explored using multiple regression methods. The effect of clopidogrel given within 48 hours before surgery versus stopped at least 48 hours before the operation was also investigated.
RESULTS: In-hospital referral patients represented 40% (473 of 1,185) of the total surgical population; 304 (64.7%) were prescribed aspirin, 116 (24.7%) heparin, 91 (19.4%) clopidogrel, and 133 (28.3%) had all anticoagulants stopped 5 days before surgery. In-hospital mortality was 2.3% (95% confidence interval [CI]: 1.1 to 4.1) and was highest among those exposed to clopidogrel (odds ratio 16.9, 95% CI: 2.10 to 136, p = 0.008). Seven of the 11 deaths occurred in patients given clopidogrel. Postoperative intraaortic balloon pump, arrhythmia, reintubation, and stroke were all significantly more common when clopidogrel was prescribed (relative risk estimates all greater than 1.5, p values all 
0.021). Blood loss was 37% higher in the patients given clopidogrel (95% CI: +3% to +82%, p = 0.033). Clopidogrel patients were more likely to need a reoperation for bleeding (p < 0.001) and require transfusions (p 0.015). Intubation time and hospital stay were also longer (p = 0.021 and p = 0.019, respectively). Heparin was also associated with longer hospital stay (p < 0.001) and aspirin use with reduced stay (p = 0.041), but for all other outcomes, no association with aspirin or heparin use was found. Comparison of subgroups of clopidogrel patients suggested mortality was highest when clopidogrel was given in the 48 hours before surgery.
CONCLUSIONS: Our study suggests that among in-hospital referral patients, preoperative exposure to clopidogrel within 5 days before CABG may increase early mortality and morbidity, and that the mortality risk is greatest when the drug is given within 48 hours of surgery.
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Introduction |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The aim of this study was to investigate the effect of preoperative exposure to aspirin, heparin, and clopidogrel on early in-hospital outcomes among in-hospital referral patients requiring CABG during the same hospital admission.
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Material and Methods |
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Anesthetic and Surgical Techniques
Anesthetic technique, heparin, and protamine management were standardized for all patients and has been previously reported [8]. For patients undergoing on-pump CABG, nonpulsatile flow was used (2.4 L · m–2 · min–1). Systemic temperature was kept between 34°C and 36°C. Myocardial protection was achieved by using intermittent anterograde hyperkalemic warm blood cardioplegia [8]. For patients undergoing off-pump CABG, the target vessel was exposed, opened, an intracoronary shunt was used, and the anastomosis performed using a pressure stabilizer [9].
Postoperative Management
Patients were transferred to the intensive care unit (ICU) and managed according to unit protocols [6–8]. Patients were extubated as soon as they met the following criteria: hemodynamic stability, no excessive bleeding (<80 mL/h), normothermia, and consciousness with pain control. Fluid management postoperatively consisted of 5% dextrose infused at 1 mL · kg–1 · h–1, with additional Gelofusine or blood to maintain normovolemia and hematocrit greater than 24%. Aspirin 300 mg daily was started on the first postoperative day.
Management of Postoperative Bleeding and Related Treatment
On arrival in the ICU, all patients underwent a routine coagulation screening. In the case of excessive bleeding (more than 150 mL/h for longer than 2 consecutive hours), derangements of the coagulation profile were treated with a diagnosis-directed therapy. Elevation of activated clotting time (ACT) of longer than 30 seconds when compared with baseline was treated with an additional 25 mg dose of protamine. Values of prothrombin time, activated partial thromboplastin time, and International Normalized Ratio (INR) of more than 1.5 times control, suggesting factor deficiency, were corrected by infusion of fresh frozen plasma. A platelet count of less than 80,000/µL was an indication for platelet transfusion. A hematocrit of less than 24% was corrected by transfusion of red blood cells. The total blood loss was measured starting immediately after closure of the chest in the operating theater until the chest drains were removed, providing the drainage was less than 20 mL/h for 3 consecutive hours. Indications for reopening were a blood loss greater than 500 mL over the first hour, more than 300 mL for 2 consecutive hours, more than 200 mL for 3 consecutive hours, or more than 1 L over the first 8 hours.
Data Collection, Monitoring, and Definitions
All perioperative clinical and outcome data were collected prospectively and entered into the Patient Activity Tracking System (PATS) database (Dendrite Systems, London, UK). Antiplatelet/anticoagulant therapy data for the first 3 months of the study were extracted retrospectively from the clinical notes, whereas thereafter the data were collected prospectively. Ascertainment was checked against the unit database, and data for a small number of cases missed were obtained retrospectively.
Clinical diagnostic criteria for preoperative and postoperative myocardial infarction were new Q waves of greater than 0.04 ms or a reduction in R waves greater than 25%, or both, in at least two leads. Pacing, arrhythmias, and inotrope requirement were recorded and defined as previously reported [10]. Pulmonary complications included chest infection, ventilation failure, reintubation, and tracheostomy. Postoperative blood loss was defined as total chest tube drainage [11]. Patients with focal neurologic deficits (motor weakness, dysphasia, aphasia, cognitive deficits, seizures, or coma) were evaluated by staff intensivists. The clinical diagnosis of stroke was made by the intensivist and confirmed by a neurologist on the basis of the clinical findings. A computed tomography scan was routinely performed in these patients as soon as the clinical condition allowed the patient to be moved. Renal complications included acute renal failure as defined by the requirement of hemodialysis. Finally, infective complications were defined by positive culture and requirement for antibiotic therapy [10]. In calculating the Thrombolysis In Myocardial Infarction (TIMI) risk score [12], we were unable to include family history as a risk factor for coronary artery disease, as this is not recorded in the database.
Statistical Analysis
The data are presented for the study population as a whole and for three subgroups: patients whose anticoagulant therapy was stopped 5 days before surgery; patients who received only aspirin or heparin, or both; and patients who were given clopidogrel (with or without aspirin or heparin, or both).
The effect of different anticoagulant therapies on in-hospital outcomes was assessed using standard regression methods: multiple linear regression for continuous variables, logistic regression for binary variables, and Cox proportional hazards regression for time to event variables. Model assumptions were checked and, where untenable, alternative models were explored. Analyses were carried out using Stata version 8.2 (Stata Corporation, College Station, TX).
All analyses were adjusted for differences in preoperative risk factors (demographic and cardiac factors, and comorbidity), and differences in operative procedure among patients. These potential confounding variables were specified in advance of the analysis, and no attempt was made to assess their statistical significance, either individually or together. Potential confounders were excluded only when the analysis became unstable and the regression coefficients could not be estimated. That occurred when a variable was completely confounded with the outcome. (Details of the variables included in the adjustment are given in the footnote to Table 3).
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Robust confidence intervals were calculated, taking account of clustering of patients within surgeons. Outcomes with fewer than 10 events were not subjected to statistical analysis. No correction was made for number of outcomes assessed, but our interpretation of the findings takes into account both the consistency and magnitude of the associations, as well as their statistical significance.
A posthoc analysis, subdividing the clopidogrel use into (a) clopidogrel stopped at least 48 hours before surgery and (b) clopidogrel taken within 48 hours of the operation, was carried out for those outcomes where an association with clopidogrel use was found in the main analysis. Differences in risk for the two subgroups were compared using the 
2 test (binary and time-to-event variables) or the F-test (continuous variables).
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Results |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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The in-hospital outcome is reported in Tables 2, 3, and 4. There were 11 in-hospital deaths (2.3%). After adjustment differences in preoperative and operative risk factors between patients, clopidogrel was found to be associated with an estimated 17-fold increase in risk of death (odds ratio 16.9, 95% CI: 2.10 to 136, p = 0.008). There was no relation between in-hospital death and use of either aspirin or heparin (p = 0.16 and p = 0.10, respectively). Causes of in-hospital death included 2 strokes, 2 myocardial infarctions, 5 low cardiac output, and 2 septicemia events. Postoperative intraaortic balloon pump, arrhythmia, reintubation, and neurologic complications, including stroke, were found to be independently associated with clopidogrel, but not with aspirin or heparin (Table 3). Clopidogrel increased the risk of all these complications by more than 50% (relative risk estimates all greater than 1.5, p values all 0.021). For stroke, the estimated risk was more than 8 times higher when clopidogrel was given in the 5 days before surgery (p = 0.016). There were 10 (6 permanent and 4 transient) in-hospital strokes (2.2%); 6 patients had been prescribed clopidogrel (4 permanent and 2 transient). All 6 permanent stroke patients were investigated with computed tomography scan, which showed 2 hemorrhagic (both in the clopidogrel group) and 4 ischemic etiologies.
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0.58 for all comparisons). Platelet and fresh frozen plasma transfusion rates increased >4-fold (p 0.015 for both outcomes) when clopidogrel was used but no association with aspirin or heparin use was found (p 0.26 for all comparisons). The pattern for red cells usage was somewhat different; the data suggest that the combination of clopidogrel and aspirin was associated with an increased risk of a red cell transfusion, but when either drug was given alone (or with heparin) the risk was not significantly different to when the drug was not prescribed (table 4). Preoperative anticoagulant therapy did not appear to influence postoperative ITU stay (p 0.12 for all comparisons). In contrast, patients prescribed clopidogrel or heparin stayed in hospital significantly longer than other patients (p = 0.019 clopidogrel and p < 0.001 heparin), while aspirin was associated with a shorter stay (p = 0.041). The estimated "risk" of discharge for the clopidogrel group was 0.73, which indicates that at any given time, patients who were not prescribed clopidogrel were 1.37 times (0.73-1) more likely to be discharged than clopidogrel patients. Clopidogrel patients were also intubated for longer than other patients (p = 0.021), where the intubation times were similar. For all other outcomes considered there were no significant differences between the anticoagulant therapies.
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Comment |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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After adjustment for preoperative and operative differences between patients, clopidogrel was found to be independently associated with an estimated 17-fold increase in risk of death and significantly worse peri-operative outcomes. Clopidogrel patients were more likely to experience arrhythmia and to require IABP support, they had longer intubation times and a higher reintubation rate, experienced 37% more blood loss, a higher rate of reopening for bleeding, an increased transfusion requirement, and an eight times higher risk of stroke compared with patients who were not prescribed clopidogrel. For most outcomes, the risk was similar for those prescribed clopidogrel in the two days before surgery and those who stopped taking the drug between 2 and 5 days before the operation. However, the death rate was significantly higher when the drug was given in the immediate preoperative period.
The high early mortality in the clopidogrel group is, at least in part, a consequence of the marked increase in hospital morbidity; in addition to the two strokes and peri-operative myocardial infarctions, three patients were reoperated for bleeding, four had an IABP fitted, two were dialysed, and five of the seven lost 1000mls or more of blood.
The marked increase in blood loss and transfusion requirements seen in our series is in keeping with the results of others [13–14]. Hongo et al [13] in a consecutive series of 224 patients, of whom 59 had preoperative clopidogrel exposure within 7 days before surgery, found that clopidogrel in combination with aspirin was associated with significantly higher bleeding, transfusion requirements, and a 10-fold increase reoperation for bleeding. Similar results were reported by Ray et al [14]. The potent inhibition of platelet function achieved by the combination of aspirin and clopidogrel has been reported to prolong bleeding time [15] with an increased risk of major hemorrhage [16]. Moreover, the combined antiplatelet effect of clopidogrel and aspirin might be amplified by CPB-related platelet dysfunction [17–18].
The higher incidence of stroke in patients with preoperative clopidogrel exposure was somewhat unexpected, considering that for nonsurgical patients there is evidence to suggest that clopidogrel, either alone or combined with aspirin, may prevent the occurrence of ischemic stroke [5]. Grau et al [19] found that the combination of clopidogrel and aspirin as compared with each drug alone led to a strong prolongation of collagen/ADP closure times, which may indicate a lower risk of thrombosis but also a higher risk of hemorrhage. Hemorrhagia was the etiology in 2 out of 4 permanent stroke seen in our clopidogrel group. Another possible explanation could be the higher incidence of transfusion rate observed in the clopidogrel group, which has been reported as an independent predictor of stroke after CABG [20].
There are several limitations to the present study, which deserve mention. It might be argued that without blinding the patients and their carers, some of the outcomes could be biased by knowledge of the type of preoperative anticoagulant therapy. Although this is possible, we believe that the use of local guidelines on postoperative bleeding management would have minimized the opportunity for bias. Also, retrospective identification of the anticoagulant therapy for some patients could have been biased by the knowledge of the patients' outcome. However, we don't believe this to be the case here as the anticoagulant therapy data were extracted from the patient's clinical record by a research registrar who had no involvement in the analysis of the data or access to the study database. The only outcome that would have been immediately apparent was an in-hospital death and higher in-hospital mortality was not anticipated a priori. It might also be argued that our findings could be due to different risk profiles. However, there is little in our data to suggest that the patients given clopidogrel were "sicker" than those given other anticoagulants/antiplatelet; more patients treated with clopidogrel had a poor ejection fraction, but not significantly so, TIMI scores and use of intravenous nitrates were similar for those treated with clopidogrel and those given aspirin and/or heparin without clopidogrel, and history of previous myocardial infarction was similar across the stable and treated groups. Although the adjusted effects may still be influenced by residual confounding, the magnitude of the increased risk of adverse outcomes shown with clopidogrel are such that it is unlikely that residual confounding could reverse the direction of these effects.
While our study has allowed us to isolate the independent effect of each anticoagulant/antiplatelet therapy, the power to detect interactions (ie, nonadditive effects) was low and a larger study would provide additional insight in this regard. Similarly the subgroups examined in the posthoc analysis were small. The risk estimates for the group given clopidogrel in 48 hours before surgery were close to the overall estimates by virtue of this being the larger subgroup. The confidence intervals for the smaller group of 22 patients were necessarily wide and the lack of statistical significance for this subgroup should not be taken as confirmation of no effect; for the majority of outcomes there was insufficient evidence to indicate a differential effect between the two groups. Again a larger study is warranted.
It might be argued that the findings of our study might not be applicable to a health-care system, where in-hospital referral patients are offered an operation within 12 to 24 hours. A short waiting time, however, might be an argument against the use of preoperative clopidogrel in these patients.
In conclusion, our data suggest that in in-hospital referral patients undergoing CABG, exposure to clopidogrel within 5 days before surgery may be associated with a significant increase in early in-hospital mortality and morbidity and that the mortality risk is greatest if the patient is exposed to clopidogrel in the 48 hours before surgery. However, our data are too few to allow us to make firm recommendations about when clopidogrel should be stopped. Since the advantages of clopidogrel in the management of patients with severe coronary disease are established [6, 7], it would be of great value to be able to clearly identify the best time to stop clopidogrel before surgery so as to allow maximum benefit from its antiplatelet properties while preventing its deleterious effects. To this end, a randomized trial is warranted.
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Acknowledgments |
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