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Impact of Continued Hospitalization in Patients Pre-treated with Clopidogrel Prior to Coronary Angiography and Undergoing Corona
January 2005
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 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.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.
1. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. J Am Med Assoc 2002;288:2411–2420.
2. Bertrand ME, Rupprecht H-J, Urban P, et al. Double blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared wth ticlopidine in combination iwth aspirin after coronary stenting: the Clopdigrel Aspirin Stent International Cooperative Study (CLASSICS). Circulation 2000;102:624–629.
3. Pache J, Kastrati A, Mehilli J, et al. Clopidogrel therapy in patients undergoing coronary stenting: Value of a high-loading-dose regimen. Cathet Cardiovasc Intervent 2002;55:436–441.
4. Kastrati A, Mehilli J, Schulen H, et al., A clinical trial of abciximab in elective percutaneous coronary intervention after pre treatment with clopidogrel. N Engl J Med 2004;350:232–238.
5. Neumann FJ, Kastrati A, Pogatsa-Murray G, et al. Evaluation of prolonged antithrombotic pretreatment (“cooling-off” strategy) before intervention in patients with unstable coronary syndromes: A randomized controlled trial. J Am Med Assoc 2003;290:1593–1599.
6. Peters RJ, Mehta SR, Fox KA, et al. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: Observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation 2003;108:1682–1687.
7. Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527–533.
8. Hongo RH, Ley J, Dick SE, et al. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002;40:231–237.
9. Gansera B, Schmidtler F, Spiliopoulos K, et al. Urgent or emergent coronary re-vascularization using bilateral internal thoracic artery after previous clopidogrel antiplatelet therapy. Thorac Cardiovasc Surg 2003;51:185–189.
10. Yende S, Wunderink R. Effect of clopidogrel after coronary artery bypass surgery. Crit Care Med 2001;29:2271–2275.
11. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction –2002: Summary article. Circulation 2002;106:1893–1900.
12. Bernstein AD, Parsonnet VA. Bedside estimation of risk as an aid for decision-making in cardiac surgery. Ann Thorac Surg 2000;69:823–828.
13. Holloway DS, Summaria L, Sandesara J, et al. Decreased platelet number and function and increased fibrinolysis contribute to post-operative bleeding in cardiopulmonary bypass patients. Thromb Haemost 1988;59:62–67.
14. Harker LA. Bleeding After Cardiopulmonary Bypass. N Engl J Med 1986;62:1659–1668.
15. Mammen EF, Koets MH, Washington BC, et al. Hemostasis changes during cardiopulmonary bypass surgery. Semin Thromb Hemost 1985;11:281–292.
16. Rinder CS, Bohnert J, Rinder HM, et al. Platelet activation and aggregation during cardiopulmonary bypass. Anesthesiology 1991;75:388–393.
17. Brasil LA, Gomes WJ, Salomao R, Buffolo E. Inflammatory response after myocardial revascularization with or without cardiopulmonary bypass. Ann Thorac Surg 1998;66:56–59.
18. Spiess BD. The contribution of fibrinolysis to post-bypass bleeding. J Cardiothorac Vasc Anesth 1991;5:13–17.
19. Ascione R, Williams S, Lloyd CT, et al. Reduced post-operative blood loss and transfusion requirement after beating-heart coronary operations: A prospective randomized study. J Thorac Cardiovasc Surg 2001;121:689–696.
20. Nuttall GA, Erchul DT, Haight TJ. A comparison of bleeding and transfusion in patients who undergo coronary artery bypass grafting via sternotomy with and without cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2003;17:447–451.
