Journals | Policy | Permission

Cardiology Research

Original Article

Volume 3, Number 5, October 2012, pages 209-213

Clopidogrel Within Few Hours of Coronary Artery Bypass Grafting Does Significantly Increase the Risk of Bleeding

For secondary prevention of coronary and cerebrovascular ischemic events, many patients are now receiving long-term clopidogrel (Plavix) with or without aspirin [1-3].

Clopidogrel is a potent inhibitor of platelet aggregation that works by irreversible blockage of adenosine diphosphate (ADP) mediated platelet activation. It has been demonstrated to reduce early stent failure [4], improve outcomes in acute coronary syndromes [5], and decrease all cause cardiovascular mortality [6].

For those who need emergency coronary artery bypass surgery (CABG), it may not always be possible to stop the antiplatelets before surgery. In those cases, there is an increased risk of postoperative bleeding [7].

Reoperation rate after CABG for bleeding is approximately 2% to 3%. Half of those reoperations have no identifiable surgical cause of bleeding [8, 9] and most likely caused by coagulopathy. An increase rate in postoperative bleeding results in a higher incidence of re-exploration and blood transfusion related complications [10] as well as prolonging the patients’ length of stay [8].

Advanced age and cardiopulmonary bypass time (CPB) are factors that enhance the postoperative bleeding after CABG [8, 9].

Controversy remains about the anti-aggregation agents that affecting thrombocyte function whether it does really increase the tendency of patients to have postoperative bleeding complications [11-13].

This is a prospective study between January, 2006 till December 2009, involved two groups of patients. Group A (65 patients) who received 300 mg of clopedogril at the time of coronary angiogram followed by emergency coronary artery bypass surgery (CABG) for critical coronary anatomy or ongoing chest pain. They were transferred to operating theatre within 2 hours of their angiography. And group B ( 206 Patients) who stopped clopedogril for a 7 days before elective coronary artery bypass surgery all patients in both groups were kept on 100 mg of aspirin till the day of surgery. All first time isolated CABGs that were done during the study period were included in the study. Those who were older than 70 years, Redo CABG, CABG plus other interventions and those who were on warfarin were excluded from the study. None of our cases in either group received low molecular weight heparin in the preoperative period. Clopidogrel was the only anti-platelet agent to be given to the patients in the emergency group. None of them received GPIIb/IIIA inhipitors, heparin or low molecular weight heparin while waiting for operation. The median time between receiving 300 mg of clopedogril and operation was 2 .15 hours (range 1.30 - 2.45 hours). All cases were done on pump, none received anti-fibrinolytic agents. Pre-operative patient characteristics and postoperative data were prospectively collected. Preoperative demographic characteristics and risk factors in both groups were prospectively collected (Table 1).

Click to view

Table 1. Preoperative and Intraoperrative Variable

To evaluate post operative bleeding, data about chest tube drainage during the first 12 hours the need for re-exploration and use of blood and blood product transfusion were collected (Table 2).

Click to view

Table 2. Results

The trigger to give blood is Haemoglubin level less than 10 g/dL.The trigger to give platelets is platelet count less than 150, we did not use sophisticated platelet function tests. The trigger to give Fresh Frozen Plasma is PT > 18. There was no clinical or laboratory evidence of preoperative bleeding disorders any patient in both groups. The study has been and approved by the ethical committee at Jordan University of Science and Technology in Jordan. The data were analyzed using the Statistical Package for Social Sciences (SPSS, version 19). Frequencies, percentages, mean, and median were used to describe the data wherever appropriate. Chi-square test was used to test the significance of the differences in the distribution of the studied variables between the two groups of patients and Mann-Whitney test to test for the significance of the differences between medians. A P-value of < 0.05 was considered statistically significant.

Postoperative data are presented in (Table 2). There was no significant difference between the haemoglubin levels between the two groups (11.9 g/dL for the clopedogril group versus 12.3 g/dL for control group), Operative data showed no statistically significant difference between the two groups regarding Bypass time and aortic cross clamp time. Regarding the number of grafts there was 2.7 grafts per case for Clopedogril group versus 3.1 grafts for the control group. The use of internal mammary artery was significantly less in the emergency group (53% (34/65) of Clopedogril group versus 86% (177/206) of the control group), and this is due to many causes as, patients hemodynamic instability during anesthesia (ECG changes, critical drop of blood pressure that require early inotrop support and to go on-pump as soon as possible), iatrogenic injury of internal mammary artery during harvesting technique, and critical left anterior descending artery (LAD) lesions with small caliber. All cases in the clopidogrel group received three or more units of packed red blood cells compared to 9.7 of the control group who needed three or more units of blood. This was statistically significant (P = 0.001). Regarding platelets' use 100% of clopedogril cases received six or more units of platelets' compared 17.5% in the control group (P = 0.001), 75% of clopedogril group received 8 or more units of fresh frozen plasma compared to 0% in the control group (P = 0.001).

Chest drainage in the first twelve hours in the clopidogrel group averaged at 1,230 ± 118.5 mL, compared to 791 ± 117.4 mL in the control group. This was also statistically significance (P = 0.001).

Eight patients (13.8%) of study group required reoperation for persistent postoperative bleeding in the study group compared to 6 patients (2.9%) in the control group (P = 0.001).

Two patients in group clopedogril group and four patients in control group had discrete surgical bleeding sites found at the time of reoperation (2 patients bleeding from a side branch of saphenous vein and 2 patients bleeding from a side branch of LIMA and 2 from veins in the chest wall, LIMA bed). Three patients in group A continued to bleed profusely after re-exploration and were given factor VII.

Antiplatelet therapy is critical in the management of coronary artery disease. For patients undergoing coronary artery bypass graft surgery (CABG), controversy remains regarding the safety of preoperative antiplatelet therapy and the optimal postoperative antiplatelet regimen to maintain graft patency and reduce ischemic events [14]. Englberger reported an increase in bleeding complications with a subsequent need for platelet and fresh frozen plasma transfusions in patients receiving clopidogrel within 3 days of surgery [15]. Yusuf et al [5] recommended that clopidogrel to be stopped 5 days before an elective CABG. Weber et al in their studies on the antiplatelet effect of clopidogrel in healthy volunteers have shown that platelet function requires seven days to recover after complete stoppage of the medication [16].

The American College of Cardiology and American Heart Association guidelines published in 2004 for CABG surgery states that “If clinical circumstances permit, clopidogrel should be withheld for five days before performance of CABG surgery [17].

Chu et al [18] in their prospective study that included 312 consecutive urgent or emergent CABG found that clopidogrel within 4 days of CABG is associated with increased blood losses and reoperation for bleeding. Furthermore, a recent study showed that as many as 5% of patients presenting for CABG may require their surgery to be done on urgent or emergency basis after exposure to clopidogrel [19]. For a patient whose CABG cannot be delayed safely, prophylactic platelet transfusion has been suggested [10]. Studies have shown that postoperative blood transfusion is an independent predictor of increased long-term mortality after cardiac surgery and, thus, have a direct impact on patient prognosis [20]. For these unwanted clopidogrel complications after coronary artery bypass surgery a reversible and direct-acting oral P2Y12-receptor antagonist (Ticagrelor),provide more consistent platelet inhibition than does clopidogrel, with more rapid onset and offset of action [21-23]. In the PLATelet inhibition and patient Outcomes (PLATO) trial, long-term reversible P2Y12 inhibition with ticagrelor was better than that with clopidogrel for the prevention of cardiovascular and total death, stent thrombosis, and myocardial infarction without an increase in the rates of major bleeding in a broad population of patients with acute coronary syndromes who were started on treatment as soon as possible after hospital admission [24]. Patients given ticagrelor had significant and clinically relevant reductions in cardiovascular and total deaths, myocardial infarction, and stent thrombosis, without an increase in risk of major bleeding [25].

Although the data were prospectively collected, the study is not a randomized trial and therefore subjected to the selection bias. The other limitation is the fact that all the study group cases were done on emergency basis which will undoubtedly lead to an increase in the incidence of almost all untoward events. Unfortunately we could not recruit elective cases into the study group because of the clear recommendations of stopping clopedogril for at least five days in elective cases.

The preoperative administration of 300 mg clopidogrel within few hours of coronary artery bypass graft surgery is associated with significant increase of post operative bleeding, surgical re-exploration and use of blood products.

1. Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288(19):2411-2420.
   doi pubmed
2. Alberts MJ, Easton JD. Clopidogrel plus aspirin for stroke prevention. Stroke. 2002;33(11):2546-2547, author reply 2546-2547.
   doi pubmed
3. Gerschutz GP, Bhatt DL. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study: to what extent should the results be generalizable?. Am Heart J. 2003;145(4):595-601.
   doi pubmed
4. Mishkel GJ, Aguirre FV, Ligon RW, Rocha-Singh KJ, Lucore CL. Clopidogrel as adjunctive antiplatelet therapy during coronary stenting. J Am Coll Cardiol. 1999;34(7):1884-1890.
   doi
5. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
   doi pubmed
6. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348(9038):1329-1339.
   doi
7. Kang W, Theman TE, Reed JF 3rd, Stoltzfus J, Weger N. The effect of preoperative clopidogrel on bleeding after coronary artery bypass surgery. J Surg Educ. 2007;64(2):88-92.
   doi pubmed
8. Dacey LJ, Munoz JJ, Baribeau YR, Johnson ER, Lahey SJ, Leavitt BJ, Quinn RD, et al. Reexploration for hemorrhage following coronary artery bypass grafting: incidence and risk factors. Northern New England Cardiovascular Disease Study Group. Arch Surg. 1998;133(4):442-447.
   doi pubmed
9. Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood. 1990;76(9):1680-1697.
   pubmed
10. Yende S, Wunderink RG. Effect of clopidogrel on bleeding after coronary artery bypass surgery. Crit Care Med. 2001;29(12):2271-2275.
    doi
11. Harker LA. Bleeding after cardiopulmonary bypass. N Engl J Med. 1986;314(22):1446-1448.
    doi pubmed
12. Tuman KJ, McCarthy RJ, O'Connor CJ, McCarthy WE, Ivankovich AD. Aspirin does not increase allogeneic blood transfusion in reoperative coronary artery surgery. Anesth Analg. 1996;83(6):1178-1184.
    pubmed
13. Sethi GK, Copeland JG, Goldman S, Moritz T, Zadina K, Henderson WG. Implications of preoperative administration of aspirin in patients undergoing coronary artery bypass grafting. Department of Veterans Affairs Cooperative Study on Antiplatelet Therapy. J Am Coll Cardiol. 1990;15(1):15-20.
    doi
14. Kulik A, Chan V, Ruel M. Antiplatelet therapy and coronary artery bypass graft surgery: perioperative safety and efficacy. Expert Opin Drug Saf. 2009;8(2):169-182.
    doi pubmed
15. Englberger L, Faeh B, Berdat PA, Eberli F, Meier B, Carrel T. Impact of clopidogrel in coronary artery bypass grafting. Eur J Cardiothorac Surg. 2004;26(1):96-101.
    doi pubmed
16. Weber AA, Braun M, Hohlfeld T, Schwippert B, Tschope D, Schror K. Recovery of platelet function after discontinuation of clopidogrel treatment in healthy volunteers. Br J Clin Pharmacol. 2001;52(3):333-336.
    doi pubmed
17. Eagle KA, Guyton RA, Davidoff R, Edwards FH, Ewy GA, Gardner TJ, Hart JC, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). Circulation. 2004;110(14):e340-437.
    doi
18. Chu MW, Wilson SR, Novick RJ, Stitt LW, Quantz MA. Does clopidogrel increase blood loss following coronary artery bypass surgery?. Ann Thorac Surg. 2004;78(5):1536-1541.
    doi pubmed
19. Genoni M, Tavakoli R, Hofer C, Bertel O, Turina M. Clopidogrel before urgent coronary artery bypass graft. J Thorac Cariovasc Surg. 2003;12:288-289.
    doi
20. Engoren MC, Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg. 2002;74(4):1180-1186.
    doi
21. Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, Wickens M, et al. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol. 2007;50(19):1852-1856.
    doi pubmed
22. Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27(9):1038-1047.
    doi pubmed
23. Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, Teng R, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120(25):2577-2585.
    doi pubmed
24. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.
    doi pubmed
25. Cannon CP, Harrington RA, James S, Ardissino D, Becker RC, Emanuelsson H, Husted S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet. 2010;375(9711):283-293.
    doi

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Cardiology Research is published by Elmer Press Inc.