Eur J Cardiothorac Surg 2004;25:419-423
© 2004 Elsevier Science NL
Clopidogrel does not increase bleeding and allogenic blood transfusion in coronary artery surgery
Hasan Karabuluta*,
Fevzi Toramana,
Serdar Evrenkayaa,
Onur Gokselb,
Sumer Tarcana,
Cem Alhana
a Department of Cardiovascular Surgery, Ac
badem Hospital, Tekin Sokak, No. 8, 34718 Acbadem, Istanbul, Turkey
b Siyami Ersek Thoracic and Cardiovascular Surgery Center, Istanbul, Turkey
Received 17 August 2003;
received in revised form 20 November 2003;
accepted 27 November 2003.
* Corresponding author. Tel.: +90-216-5444-214; fax: +90-216-3258-759
e-mail: hasankarabulut{at}turk.net
 |
Abstract
|
|---|
Objectives: Platelet dysfunction is one of the major reasons of postoperative bleeding following coronary artery surgery. The aim of this study was to evaluate the effects of clopidogrel; a specific and potent irreversible inhibitor of platelet aggregation; on bleeding and use of blood and blood products after coronary artery bypass surgery (CABG). Methods: Preoperative patient characteristics and perioperative and postoperative data were collected prospectively in 1628 consecutive patients undergoing isolated CABG performed by the same surgical and anesthesia team. Of these, 48 were receiving clopidogrel preoperatively. Of the 1628 patients, 1456 underwent elective and 172 (10.6%) underwent non-elective operation. Thirty-six (2.5%) of the elective patients and 12 (7%) of the non-elective patients were using clopidogrel, preoperatively. Baseline characteristics, chest tube output, and the need for reexploration or for blood and blood product transfusion of clopidogrel recipients and non-recipients were compared. The clopidogrel group had higher prothrombin time level (12.6±1.6; 11.5±1.7 s, P=0.013), however comparable aPTT level (32.6±4.5 vs. 31.4±4.5 s), and platelet count (275 000±98 000 vs. 280 000±72 000 dl-1). Results: The need for reexploration or for blood and blood product transfusion, chest tube output, ICU length of stay (20.1±2.9 vs. 21.9±13.5 h; P=NS), and hospital length of stay (5.5±1.7 vs. 5.4±2.1 days; P=NS) were similar in clopidogrel recipients and non-recipients, respectively. Further analysis demonstrated no significant difference in use of homologous blood or fresh frozen plasma, amount of postoperative bleeding and reoperation rates for bleeding as well as length of intensive care unit and hospital stay between the clopidogrel and the control groups both in elective and non-elective patients. Conclusions: The results of this study suggest that preoperative use of clopidogrel is not associated with increased bleeding and need for surgical exploration as well as risk of blood and blood product transfusion after CABG.
Key Words: Clopidogrel • Coronary artery bypass grafting • Transfusion
|
1. Introduction
|
|---|
As a specific and very potent irreversible inhibitor of thrombocyte aggregation, clopidogrel has been extensively used in cardiology practice for the last few years. It is not always possible for every patient to stop taking these and similar drugs appropriately before the operation. In these circumstances, surgeons are always anxious about the possibility of postoperative bleeding. In the field of coronary artery surgery, reoperation rates for bleeding for the first and the second operations are below 3 and 5%, respectively. Postoperative bleeding and reoperation due to bleeding result in more frequent use of blood and blood products, which in turn may cause a further range of complications [1]. Postoperative bleeding after coronary artery bypass grafting (CABG) is influenced by many factors such as advanced age, cardiopulmonary bypass time, the number of distal anastomosis, inadequate control of bleeding, and coagulation disorders as well as thrombocyte dysfunction [2,3]. It is still controversial whether antiaggregant agents affecting thrombocyte function really increase tendency to bleed after surgery [4–6]. There is an increased tendency to use thienopyridines, especially clopidogrel, ticlodipine and glycoprotein IIb/IIIa inhibitors for patients with coronary artery disease. These agents act differently on thrombocyte functions and their actions are different from aspirin [7–9]. In this study, we aimed to analyze whether clopidogrel increases postoperative bleeding and the use of blood and blood products.
|
2. Patients and methods
|
|---|
2.1. Selection of patients and management
One thousand six hundred and twenty-eight patients that have undergone isolated CABG operation between 1999 and 2002 were included in our study. Forty-eight of these patients had a history of taking at least 75 g/day clopidogrel for at least 2 days prior to their operation and 1580 patients did not. Cases with additional surgical procedures were excluded from the study. All of the operations were conducted by the same surgical and anesthesiology team. Patients were compared based on preoperative data (age, gender, body mass index, diabetes mellitus, renal compromise, ejection fraction, emergency basis for the operation, use of aspirin, heparin or clopidogrel, prothrombin time, activated prothrombin time, thrombocyte number), intraoperative data (bypass time, cross clamping time, number of distal anastomoses, use of left internal mammary artery (LIMA), right internal mammary artery (RIMA) and radial artery (RA)), postoperative data (amount of postoperative bleeding, rates for reoperation for bleeding, use of allogenic blood and blood products, length of stay in the intensive care unit and hospital), and risk score (EuroSCORE). The patients were further compared with respect to the priority of the operation (elective vs. non-elective). Indications for reoperation for postoperative bleeding were same for all patients [10]. Intraoperative or postoperative autotransfusion, transfusion of thrombocyte-rich autologous plasma, aprotinin or fibrinogen were not applied in either of the groups. Patients younger than 70 years had transfusion of homologous blood if their hematocrit levels were less than 21% and hemoglobin levels were less than 7 mg/dl, whereas patients older than 70 years were transfused if their hematocrit and hemoglobin levels were less than 24% and 8 mg/dl, respectively [11].
2.2. Statistical analysis
Baseline preoperative, intraoperative, postoperative data and functional results are expressed as the mean±SD.
Statistical analyses were performed using Mann–Whitney, 
2 and Fisher's exact test using SPSS statistical software (SPSS Inc, Chicago, IL). Variables were considered significant at P values less than 0.05.
|
3. Results
|
|---|
Preoperative data regarding the patient groups are shown in Table 1. There were no statistically significant differences between the two groups concerning preoperative findings except age, and prothrombin time (12.6±1.6 s in clopidogrel group vs. 11.5±1.7 s in control group; P<0.01). Fig. 1 depicts rates for use of aspirin and heparin for patients in the clopidogrel group. Twenty-one patients in this group used only clopidogrel; 24 patients used clopidogrel and aspirin and 3 patients used all three drugs. The patients in the control group using aspirin were 64.9% and those using heparin were 5.9%. Two groups showed no significant difference for the use of aspirin and heparin. Intraoperative data are shown in Table 2. We did not find any significant difference in bypass time, cross-clamping time, distal anastomosis time and use of LIMA, RIMA, RA between the two groups. Table 3 shows postoperative data. No significant difference was detected in the use of homologous blood or fresh frozen plasma, amount of postoperative bleeding and reoperation rates for bleeding between the clopidogrel and the control groups.
Of the 1628 patients, 1456 underwent elective and 172 (10.6%) underwent non-elective operation. Thirty-six (2.5%) of the elective patients and 12 (7%) of the non-elective patients were using clopidogrel, preoperatively. Further analysis of these subgroup of patients demonstrated no significant difference in use of homologous blood or fresh frozen plasma, amount of postoperative bleeding and reoperation rates for bleeding as well as length of intensive care unit and hospital stay between the clopidogrel and the control groups both in elective and non-elective patients (Tables 4 and 5).
|
4. Discussion
|
|---|
Clopidogrel, as a specific and very potent irreversible inhibitor of thrombocyte aggregation is an agent belonging to the thienopyridine group. It inhibits adenosine diphosphate from binding its receptor on the thrombocyte and thus inhibits selective ADP-stimulated glycoprotein IIb/IIIa complex with a resultant inhibition of the platelet aggregation [8]. Clopidogrel is quickly absorbed from the gastrointestinal tract and is quickly metabolized in the liver. Its inactive metabolite SR 26334 is a carboxylic acid derivative. Active metabolite, however, is not known yet [8]. Aspirin is an inhibitor of cyclooxygenase enzyme and thromboxane A2 with resultant inhibition of platelet aggregation. These two agents affect thrombocyte function in different ways and are seen to affect synergistically [1]. The clopidogrel vs. aspirin in patients at risk of ischemic events (CAPRIE) study on protective effects of clopidogrel and aspirin from deaths due to vascular events, stroke and myocardial infarction in atherosclerotic patients showed results in favor of clopidogrel with less incidence of hemorrhagic complications [12]. Despite the fact that the study reports that clopidogrel prolongs bleeding time [13], it is interesting to see less complications due to bleeding in the CAPRIE study. Bleeding time is an indicator of clopidogrel, but is not specific. A more specific indicator is PFA 100, but is not used in our study either [14]. We did not include bleeding time in the preoperative data, since we do not currently include bleeding time in our routine preoperative investigations, but activated partial thromboblastin time (aPTT), prothrombin time/international normalized ratio (INR), activated clotting time (ACT) are routinely done for all patients to investigate bleeding/coagulation disorders. The unavailability of PFA 100 is a limitation for this study. Using clopidogrel and aspirin together so as to prevent stent thrombosis has become a standard approach and in recent years there is an increased frequency of patients using clopidogrel prior to a CABG operation [15]. Some of these patients are operated on an emergency basis within 24 h of diagnosis and therefore, the suggested protocol of quitting clopidogrel 7 days prior to operation cannot be applied to this group of patients. Similarly in our study, 25% of 48 patients in the study group were operated in this manner; whereas this rate was 10% in the control group. At this stage, two questions worry the surgeon's mind: whether the patient will bleed and how much the patient will need blood/blood product. It was reported that clopidogrel increased postoperative bleeding, rate of reoperation due to bleeding, and the use of packed red blood cells and fresh frozen plasma [1,15]. Yende and Wunderink [1] reported eight reoperations due to bleeding in 51 patients. In the same study, as they also pointed out, different surgeons had conducted the operations and a bleeding focus could be found only in three patients during the reoperation. Transfusion criteria were left to the surgeon's choice. Seventy-five percent of the patients were operated on cardiopulmonary bypass and the rest on beating heart. Being the first report on the preoperative use of clopidogrel and bleeding after CABG operations, their study is to be criticized on the points mentioned. We aimed to overcome these issues by providing that the patients were operated by the same surgical team with all operations on cardiopulmonary bypass and the same established transfusion protocols applied to all patients. Advanced age is a known independent factor to increase tendency for postoperative bleeding [2]. We found age significantly higher in the clopidogrel group. It is noteworthy that rates of reoperation due to postoperative bleeding and the use of blood/blood products were not found to be different in both groups in spite of the fact that two important factors like advanced age and the use of clopidogrel existed in the study group. It would have been possible to argue that advanced age could change the results of this study if age was significantly higher in the control group or the clopidogrel group was found to have higher rates for reoperation and the use of blood/blood products.
In a recent study, Genoni and colleagues [16] raised the question of indications and appropriateness of clopidogrel administration during the immediate preoperative course due to an increased need for transfusion of blood and blood products. In their series of 13 patients undergoing urgent CABG, 6 were operated on while receiving clopidogrel and in the remaining 7 patients clopidogrel was stopped at least 7 days before the surgery. They demonstrated a higher intraoperative and postoperative transfusion rate in the former group of patients. However, the two groups seem not to be comparable with respect to use of preoperative intraaortic balloon pump (100 vs. 0%) and hemodynamic stability. On the other hand, operations were performed without extracorporeal circulation in 11 patients and it is not clear whether the heparin was reversed after the operation in those patients.
We could not show any increase in bleeding and use of blood and blood products as well as length of intensive care unit and hospital stay when we compared patients with or without clopidogrel undergoing non-elective operation.
In this study we also compared 1014 patients using aspirin preoperatively with 614 patients without using aspirin and we did not find any significant difference between two groups in postoperative bleeding and the use of blood/blood products. In the clopidogrel group of this study, patients that used only clopidogrel and 24 patients that used aspirin in addition to clopidogrel also showed no significant difference in postoperative bleeding and the use of blood/blood products.
In a multicenter study conducted in the USA and Canada, 16% of surgeons advocate routine preoperative use of antiplatelet drugs, and 18% of these surgeons prefer clopidogrel and 65% prefer aspirin [17]. We believe different results will be reported as the number of patients using clopidogrel prior to their operations and the number of studies on this issue increase.
In conclusion, we suggest that use of clopidogrel prior to CABG does not the increase the amount of postoperative bleeding, rates of reoperation due to postoperative bleeding and the use of blood/blood products regardless of the priority of the operation.
|
References
|
|---|
- Yende S., Wunderink R.G. Effect of clopidogrel on bleeding after coronary bypass surgery. Crit Care Med 2002;29:2271-2275.
- Dacey L.J., Munoz J.J., Baribeau Y.R., Johnson E.R., Lahey S.J., Leavitt B.J., Quinn R.D., Nugent W.C., Birkmeyer J.D., O'Connor G.T. Reexploration for hemorrhage following coronary artery bypass grafting. Arch Surg 1998;133:442-447.[Abstract/Free Full Text]
- Woodman R.C., Harker L.A. Bleeding complications associated with cardiopulmonary bypass. Blood 2000;76:1680-1697.
- Harker L.A. Bleeding after cardiopulmonary bypass. N Engl J Med 1986;314:1446-1447.[Medline]
- Tuman K.J., McCarthy R.J., O'Connor C.J., McCarthy W.E., Ivankovich A.D. Aspirin does not increase allogenic blood transfusion in reoperative coronary artery surgery. Anesth Analg 1996;83:1178-1184.[Abstract]
- Sethi G.K., Copeland J.G., Goldman S., Moritz T., Zadina K., Henderson W.G. 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;15:15-20.[Abstract]
- Quinn M.J., Fitzerald D.J. Ticlopidine and clopidogrel. Circulation 1999;100:1667-1672.[Abstract/Free Full Text]
- Coukell A.J., Markham A. Clopidogrel. Drugs 1997;54:745-750.[Medline]
- Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998;338:1488-1497.[Abstract/Free Full Text]
- Brown W.M., III, Jones E.L., Edmunds L.H., Jr Cardiac surgery in the adult. . New York: McGraw-Hill, 1997.
- Karabulut H., Toraman F., Alhan C., Tarcan S., Eren N., Ça
lar N. A single method decrease the use of homolog blood in coronary artery bypass surgery. J Turkish Thorac Cardiovasc Surg 1999;7:442-445.
- The CAPRIE Steering Committee. A randomized blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events. Lancet 1996;348:1329-1339.[CrossRef][Medline]
- Payne D.A., Hayes P.D., Jones C.I., Belham P., Naylor A.R., Goodall A.H. Combined therapy with clopidogrel and aspirin significantly increases the bleeding time through a synergistic antiplatelet action. J Vasc Surg 2002;35:1204-1209.[CrossRef][Medline]
- Vaughn C., Mychaskiw G., Sewell P. Massive hemorrhage during radiofrequency ablation of a pulmonary neoplasm. Anesth Analg 2002;94:1149-1151.[Abstract/Free Full Text]
- Hongo R.H., Ley J., Dick S.E., Yee R.R. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002;17:231-237.
- Genoni M., Tavakoli R., Hofer C., Bertel O., Turina M. Clopidogrel before urgent coronary artery bypass graft. J Thorac Cardiovasc Surg 2003;126:288-289.[Free Full Text]
- D'Ancona G., Donias H.W., Karamanoukian R.L., Bergsland J., Karamanoukian H.L. OPCAB therapy survey: off-pump clopidogrel, aspirin or both therapy survey. Heart Surg Forum 2001;4:354-358.[Medline]
Top
Abstract
1. Introduction
