Pre-treatment of patients with clopidogrel prior to coronary angiography (CAG) and possible percutaneous coronary intervention (PCI) is a standard practice. Candidates for coronary artery bypass surgery (CABG) are discharged or remain in the hospital until CABG after clopidogrel is discontinued. We investigated whether any differences exist in the rates of surgical complications and outcomes between these two groups of patients. We conclude that continued hospitalization of clopidogrel pre-treated patients does not confer any safety benefit with regard to post-operative complications and 30-day mortality. Discharging these patients after CAG may reduce hospitalization costs.

       Clopidogrel is an oral antiplatelet agent which selectively and irreversibly inhibits the platelet adenosine 5'-diphosphate (ADP) receptor. Antiplatelet effect is synergistic when administered with aspirin. Dual antiplatelet therapy with aspirin and clopidogrel is associated with a low incidence of ischemic events in patients undergoing percutaneous coronary intervention (PCI).¹ Earlier studies have used a loading dose of 300 mg before PCI,² but a subsequent registry of 864 patients demonstrated a high loading dose of 600 mg of clopidogrel given within 2–4 hours before PCI to be safe and produced a more favorable clinical outcome.³ High dose-loading with 600 mg of clopidogrel at least 2 hours before PCI was studied in the large Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR REACT) trial and also in the ISAR-COOL studies.^4,5
       Long-term clopidogrel therapy has been shown to significantly reduce the risk of adverse ischemic events.^1,6,7 Therefore, it has become standard practice to administer clopidogrel routinely before coronary angiography (CAG) and possible PCI, and to continue administration long-term. However, some patients pre-treated with clopidogrel are not suitable for PCI and instead require coronary artery bypass graft (CABG) surgery. Studies have reported increased post-operative bleeding and morbidity with dual antiplatelet therapy before CABG.^8-10 Hence, it is recommended to defer surgery for at least 5, and preferably 7 days after cessation of clopidogrel therapy to decrease bleeding complications.¹¹ In the instances where a patient is pre-loaded with clopidogrel before CAG and angiographic results favor CABG, the drug is discontinued and patients are discharged or remain hospitalized until surgery. It is not known whether any differences exist in the intra- and post-operative complications, or the 30-day mortality between these two groups.

Methods
       A retrospective analysis of medical records of patients pre-treated with clopidogrel prior to coronary angiography who had CABG within 5 days (n = 350) between January 2000 and December 2002 was conducted. All patients operated on between 0 to 2 days (n = 225) were excluded. Patients operated on 3–5 days after cessation of clopidogrel therapy who continued hospitalization (CH; n = 64) or discharged home (DH; n = 61) constituted the study population. The clopidogrel exposure prior to coronary angiography in these patients was a loading-dose of 300 mg, except for one patient who received 600 mg. The baseline characteristics, pre-operative risk factors, intra- and post-operative complications and 30-day mortality between the two groups were compared.
       Definitions. Post-operative cerebrovascular accident (CVA) was defined as a post-operatively occurring new focal neurologic deficit diagnosed by clinical findings and confirmed by a neurologist or by brain imaging (computed tomography or magnetic resonance imaging), persisting for more than 72 hours after onset, and which had been noted before discharge or death. Post-operative myocardial infarction (MI) was diagnosed by the presence of two of the following findings: 1) prolonged (> 20 minutes) chest pain not relieved by rest and/or nitrates; 2) serial electrocardiogram showing new ischemic changes, an enzyme level elevation (CK-MB > 5% of total CPK, CK > 2 times normal, or troponin I > 0.8 mcg/ml), or new wall motion abnormalities as documented by post-operative echocardiogram. Re-exploration due to hemorrhage occurred at the surgeon’s discretion, although it was usually indicated when chest tube drainage exceeded 500 ml in the first hour, 400 ml/hour in the first two hours, 300 ml/hour in the first 3 hours, 200 ml/hour in the first 4 hours, or in the case of cardiac tamponade. Operative mortality was defined as any death occurring within 30 days of surgery unless the cause of death was clearly unrelated to the procedure.
       Statistical Analysis. Continuous variables are presented as mean ± 1 standard deviation and were compared using the Student’s t-test. Categorical data are presented as frequencies and percentages and were compared using chi-square statistic, the Wilcoxon Test or Fisher’s exact test when appropriate. Mortality risk scores using Parsonnet's risk stratification model¹² were calculated to assess differences in pre-operative risk and to also infer variability between the study groups. Multiple logistic regression models were constructed to determine the association between pre-operative risk factors and post-operative bleeding, and 30-day mortality. The Hosmer and Lemeshow Goodness of Fit test was used to evaluate model fit. All statistical analyses were performed with SAS for Windows Version 8.0 (SAS Institute, Cary, North Carolina).

Results
       Clinical characteristics were comparable between the two groups except that the history of recent and remote MI was higher in the CH group compared to the DH group (p = 0.02 and < 0.01). Patients in the CH group had more left ventricular dysfunction (ejection fraction < 34%) compared to the DH group (p = 0.01). Surgical techniques (on-pump vs. off-pump surgery, number of grafts) were similar between the two groups. Intra- and post-operative characteristics were similar between the two groups except that intra-operative blood loss was higher in the DH group (p = 0.01). Multiple logistic regression model testing pre-operative risk factors for association with post-operative bleed and 30-day mortality did not yield any significant differences between the two groups.

Discussion
       The principal findings of our study indicate that CABG surgery can be undertaken 3–5 days after cessation of clopidogrel therapy with reasonable safety, and there is no impact of continued hospitalization on the intra- and post-operative complications or 30-day mortality.
       Hongo et al studied 59 patients who were given clopidogrel within 7 days prior to non-emergent CABG surgery and compared them to those who did not receive clopidogrel. They reported re-operation rates of 6.8%, a CVA incidence of 3.4% and a mortality rate of 1.7% in the clopidogrel-exposed patients compared to 0.6%, 4.8% and 3.6%, respectively, in the patients who did not receive clopidogrel.8 Contrarily, in our study re-operation for bleeding was required in only 3% of patients, CVA incidence was 1% and mortality was 2%. This could be due to a low dose of aspirin (81 mg) — a routine dose prescribed at our institution — in the majority of patients. This observation is supported by findings from the CURE study, which showed that bleeding risk increases with increasing aspirin dose, with or without clopidogrel administration.⁶ The second reason for the low incidence of complications could be due to the timing of surgery in these patients — 3 to 5 days after the last dose of clopidogrel. Hongo et al have shown that a delay of <= 3 days was associated with higher re-operations for bleeding as compared to a delay of > 3 days.⁸ Our study confirms this observation and indicates that CABG may be undertaken in patients pre-treated with clopidogrel between 3–5 days with lower complications.
       The primary reasons for patients to continue hospitalization are refractory angina, heart failure, and any catheterization-related complications. It may be assumed that stabilizing them prior to referring them to CABG will reduce the complication rates. In our study, the main reasons for continued hospitalization were history of recent MIs and lower left ventricular ejection fraction. Counterintuitively, the results of our study indicate no added advantage of CH with regard to the timing of CABG surgery.
       The institution of cardiopulmonary bypass is associated with dilutional thrombocytopenia,^13,14 coagulopathy,¹⁵ platelet function abnormalities secondary to shear-induced stress activation,¹⁶ and activation of a systemic inflammatory response and fibrinolysis.^17,18 Off-pump CABG has been demonstrated to be associated with reduced post-operative bleeding and surgical re-exploration rates.^19,20 In our study, more than half of the patients underwent off-pump CABG (Table 1), and on multivariate analysis, it was not associated with post-operative bleeding or 30-day mortality (Tables 3 and 4).
       Limitations. Limitations of our study ensue from its retrospective nature. We do not have complete details of the reasons for continued hospitalization in all of the patients. The results from the small number of patients in our study need to be validated in a larger cohort.

Conclusions
       We conclude from the present study that patients may be discharged after CAG and undergo CABG 3–5 days after the last dose of clopidogrel with reasonable safety. Continued hospitalization of the patients in the intervening period between CAG and CABG does not confer any benefit with regard to surgical complications and one-month mortality rates. This strategy will have economic implications in reducing the hospitalization costs.

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