Article

lock Open Access lock Peer-Reviewed

0

Views

ORIGINAL ARTICLE

Postoperative Bleeding Following Preoperative Clopidogrel Administration in Patients with Haemoglobin Level Above 110 g/L Undergoing Urgent CABG

Sasa Milan KacarI; Aleksandar MikicI; Mirjana Božidar KacarI

DOI: 10.21470/1678-9741-2017-0083

ABBREVIATIONS AND ACRONYMS

ACS = Acute coronary syndrome

ACT = Activated clotting time

ANOVA = Analysis of variance

CABG = Coronary artery bypass grafting

CPB = Cardiopulmonary bypass

CURE = Clopidogrel in Unstable angina to prevent Recurrent Events

DAPT = Dual antiplatelet therapy

FFP = Fresh frozen plasma

MACCE = Major adverse cardiac and cerebrovascular events

PCI = Percutaneous coronary intervention

RBC = Red blood cells

INTRODUCTION

Ischemic heart disease is the most prevalent cause of death in Serbia; representing 57% of total mortality. Acute coronary syndrome (ACS) is one of the most dramatic subtypes of ischemic heart disease and represents an important challenge. Dual antiplatelet therapy (DAPT), mostly with acetylsalicylic acid and clopidogrel (P2Y12 receptor inhibitor), has become the basis of ACS therapy. Indeed, it is well established that DAPT in ACS significantly decreases the incidence of new thrombotic and ischemic events[1-4].

ACS patients rarely demand coronary artery bypass grafting (CABG). However, up to 10% of these patients may present with clinical findings requiring urgent or emergent coronary surgery[5]. Noteworthy these patients constitute a surgical challenge due to the fact that majority of them received DAPT prior to coronary angiography, as well as taking into account their inherent hemodynamic instability and potential unknown or unrecognized comorbidity[6-8]. Furthermore, there is an elevated surgical risk due to the deleterious effects of DAPT on hemostasis during and after CABG[5].

Before CABG one must take into account the deterioration of platelet function by the preoperative DAPT usage, as well as the impairment of platelet function due to cardiopulmonary bypass (CPB) per se. Up to date, the management of preoperative antiplatelet therapy in CABG differs considerably among surgeons. In this respect, there is conflict between guidelines and prejudices regarding the preoperative aspirin usage. Indeed, in one hand, published data suggest that aspirin treatment should be held for 7-10 days preoperatively in patients undergoing elective CABG[9], whereas more recent reports indicate that patients with coronary artery disease referred to CABG should continue aspirin treatment until the surgical procedure[10]. Likewise, clopidogrel usage was established to improve outcome after ACS by reducing early stent failure and diminishing allcause mortality and cardiovascular mortality[11].

However, numerous studies have shown that CABG performed within 5 days of clopidogrel administration is associated with increased postoperative bleeding, reoperation for bleeding and prolonged hospital stay. Indeed, current guidelines recommend to postpone CABG if possible for 5 or more days after clopidogrel withdrawal[12]. On the other hand, withdrawing all DAPT for more than 5 days before surgery can increase the risk of fatal and non-fatal ischemic events, as well as increasing the mortality of patients with ACS[11]. Indeed, although mediastinal bleeding after CABG is not uncommon, it has an important influence on mortality and morbidity[9].

Sabatine et al.[13] showed that preoperative anemia, if present, is an independent predictor of major adverse cardiovascular events in patients with ACS. In patients with ACS without ST elevation, the risk for cardiovascular death, myocardial infarction, or recurrent ischemia increases if hemoglobin levels are below 110 g/L. It is the same in patients with ST elevation myocardial infarction, but when hemoglobin levels fall below 140 g/L[13].

Low hemoglobin level is a strong predictor for postoperative need for transfusion, especially in CABG patients operated using extracorporeal circulation[14].

The aim of this study was to examine if DAPT affects postoperative bleeding in patients with haemoglobin levels above 110 g/L, who underwent urgent or emergent CABG, less than five days after stopping DAPT therapy.

METHODS

From March 2008 to June 2012, 122 patients with ACS underwent CABG using CPB, in the first 10 days after the coronary catheterization, by the same surgical team at the Institute for Cardiovascular diseases in Sremska Kamenica (Novi Sad). All patients received DAPT before coronary catheterization. All surgeries were described as urgent or emergent. Exclusion criteria were elective patients, combined procedures, reoperations, offpump revascularizations and preoperative anemia (hemoglobin levels less than 110 g/L). The following data were recorded: standard demographics, comorbidity and routine intraoperative and postoperative parameters, including blood loss and transfusion requirements in the first 48 hours postoperatively. The primary outcome was blood loss in the first 48 hours along with transfusion requirements, and the need for reoperation for bleeding. The secondary outcome was in-hospital mortality and hospital length of stay.

The patients were classified into two groups: 65 patients operated within 4 days (group 1), and specifically (day 0, 26 patients; day 1, 18 patients; day 2, 10 patients; day 3, 10 patients; day 4, 1 patient), whereas 57 patients operated from 5th to 10th day after clopidogrel discontinuation (group 2).

All operations were performed in normothermia, using CPB. The standard circuit was primed with a crystalloid solution. We were using roller pump in all patients. Standard heparinization protocol was applied (300 U/kg). Tranexamic acid was given to all patients in dosage of 30 mg/kg. Cold crystalloid cardioplegia (10-15 mL/kg) was used for myocardial protection. After weaning from CPB, heparin was neutralized with protamine sulfate (1 mg/100 U heparin).

The clinical criterion for platelet and fresh frozen plasma (FFP) transfusion was excessive bleeding despite the fact that the activated clotting time (ACT) value was normal and that there was no recognized surgical bleeding. The criteria for erythrocyte transfusion were a fall in hemoglobin below 90 g/L. The indication for re-exploration was bleeding over 400 mL during the first hour, 300 mL for 2-3 hours, or more than 200 mL/h during the next four hours despite the normal value of ACT. The late re-exploration was indicated when there was an echocardiographically proven pericardial effusion greater than 1.5 cm, or cardiac tamponade.

Statistical Analysis

Statistical analysis was performed using SPSS 17.0 statistical software. Continuous variables were evaluated using analysis of variance (ANOVA); categorical variables were evaluated using χ2 analysis or Fisher's exact test. Multivariable models were created using logistic regression techniques for dichotomous outcomes and linear regression techniques for continuous outcomes.

RESULTS

Baseline characteristics of all patients are presented in Table 1. There were no statistically significant differences in age, gender, presence of diabetes, renal failure, peripheral vascular disease, chronic obstructive pulmonary disease, neurologic disorders or gastrointestinal disease between the two groups.

Table 1 - Baseline characteristics of patients.
    Group 1 Group 2 P-value
Gender Men 39 (68.4%) 44 (66.7%) Non-significant
Women 18 (31.6%) 22 (33.3%)
Age Mean age ± SD 61.8±8.1 60.8±9.6 Non-significant
Over 65 years old 21 (36.8%) 25 (37.9%)
Diabetes 9 (15.8%) 12 (18.2%) Non-significant
Renal failure 3 (5.3%) 1 (1.5%) Non-significant
Peripheral vascular disease 11 (19.3%) 13 (19.7%) Non-significant
Chronic obstructive pulmonary disease 18 (31.6%) 22 (33.3%) Non-significant
Neurologic disorder 4 (7%) 7 (10.6%) Non-significant
Gastrointestinal disease 1 (1.8%) 5 (7.6%) Non-significant
Table 1 - Baseline characteristics of patients.

Intraoperative data are presented in Table 2. There were no statistically significant differences in the respective variables such as number of grafts, CPB time or aortic cross-clamping time.

Table 2 - Intraoperative characteristics of patients.
Intraoperative characteristics Group 1 Group 2 P-value
Patients with more than 3 grafts 51 (77.3%) 40 (70.2%) 0.371
CPB time (min) (mean ± SD) 63.7±20.7 59.5±18.8 0.251
Aortic cross-clamping time (min) 37.8±12.6 35.7±11.9 0.353

CPB=cardiopulmonary bypass; SD=standard deviation

Table 2 - Intraoperative characteristics of patients.

Intraoperative characteristics of patients are presented in Table 3. Interestingly, there was a surprisingly significant increase in the number of patients whose postoperative chest drainage was more than 500 mL in the control group (group 2) as compared to the group 1 - 62.1% of patients in group 2, and 40.4% in group 1 (P=0.019). Mean chest tube losses for 48 hours after surgical revascularization were 0.65 L in group 1 and 0.68 L in group 2 (Table 3). We show that patients in group 1 received a greater statistically significant quantity of red blood cells (RBC), platelets and cryoprecipitate compared to group 2 patients. The mean quantities of transfused RBC were 0.64 L and 0.47 L, respectively. There was no significant difference in the quantity of received FFP. Thus, the mean quantity of FFP given to the group 1 was 0.27 L, and to group 2 was 0.2 L. Platelets have been given to 12 patients in group 1, and to 1 patient in group 2.

Table 3 - Postoperative chest drainage.
Postoperative chest drainage Group 1 Group 2 P-value
Mean chest drainage 0.65 L 0.68 L Non-significant
Chest drainage more than 500 mL 40.4 62.% 0.019
Table 3 - Postoperative chest drainage.

There was no in-hospital and 30-day mortality observed in any group. Two patients underwent reexploration for excessive bleeding, one in each group. The median length of stay was 13 days for group 1 and 19 days for group 2 patients.

DISCUSSION

Impaired platelet function affects hemostasis, which may result in excessive postoperative blood loss and increased surgical complications and mortality. The etiology of excessive postoperative blood loss is multifactorial, including small body size, female gender and concomitant procedures[6,7]. In many patients with ACS, DAPT is not the only therapy that can influence surgical bleeding. Preoperative anticoagulants can affect hemostasis to a greater extent, and can be an important factor in the etiology of excessive blood loss. Moreover, about 3% of all CABG patients require reoperation for bleeding, which is followed by significant morbidity and mortality[7,8]. Under these circumstances, disseminated intravascular coagulopathy, hemodynamic instability and death are not uncommon. Furthermore, excessive blood loss is associated with increased blood and platelet transfusions, as well as administration of coagulation factors.

Anemia, if present, increases the need for postoperative transfusions. Anemia is also associated with increased mortality and postoperative morbidity in CABG patients[15,16]. That is the reason why we excluded patients with preoperative hemoglobin levels below 110 g/L in our study.

The results of the present study show that the use of clopidogrel within 5 days of CABG (in non-anemic patients) was not associated with increased postoperative blood losses, as well as with an increased number of re-explorations for postoperative bleeding. The preoperative use of clopidogrel, however, was associated with an increased number of RBC and platelet transfusions.

Over the last years, different clinical studies on DAPT in ACS have shown conflicting results. Differences in these findings and conclusions can be explained by variations in surgical indications, presence of comorbidity, differences in cardiological, anesthesiologic and surgical skills, as well as differences in preoperative therapy. Indeed, many studies have shown that clopidogrel administration prior to surgical revascularization is followed by increased incidence of postoperative bleeding, transfusion requirements and re-explorations with prolonged hospital stay[17-20].

Berger et al.[19] compared two groups of patients in relatively large retrospective study. In the group of patients who received clopidogrel in less than 5 days prior to CABG, there was an increased incidence of bleeding, re-explorations and increased hospital stay. On the other hand, this group of patients had significantly increased incidence of preoperative myocardial infarction and cerebrovascular accidents, previous percutaneous coronary intervention (PCI) procedures and more urgent surgical revascularizations. There were no differences in mortality and major adverse cardiac and cerebrovascular events (MACCE)[19]. Furthermore, Yende et al.[18] reported increased re-exploration rate in patients with DAPT within 5 days of surgical revascularization. The study by Hongo et al.[17] demonstrated increased 24-hour chest tube drainage, transfusion requirements, and reoperation rate for bleeding of patients on clopidogrel within 7 days of operation. In summary, the authors of both studies were against routine DAPT administration before PCI because of the increased morbidity risk if emergent CABG was mandatory. In a small series of 55 patients receiving clopidogrel preoperatively, significantly increased blood losses and transfusion requirements were reported[21]. A subgroup analysis of the Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) trial identified 912 patients who had discontinued clopidogrel within 5 days of CABG In this group of patients, there was an increased risk of minor bleeding complications and a trend towards an increased risk of major bleeding complications, defined as substantially disabling bleeding or requiring more than 2 units of packed RBC transfusion, was shown[5,22]. On the other hand, in a recent study by Chen et al.[23], preoperative clopidogrel exposure was not associated with increased RBC transfusion. Furthermore, there are some studies that underline the influence of both surgical and institutional experience on the results[24].

In our study, only one surgical team (same surgeon and anesthesiologist) operated all patients enrolled in a specialized institution. There were no elective patients, and the decision of a surgical timing was made according to the clinical status of the patient. When considering mortality and morbidity of patients enrolled, we can see that there was no mortality in both groups of patients, but that patients in group 2 had a longer postoperative hospital stay compared to patients in group 1. However, these observations were restricted to in-hospital mortality and 30-day mortality.

According to current guidelines, it is suggested to optimally refrain from using clopidogrel within at least 5 days prior to elective surgery to minimize the risks of postoperative coagulopathy; that the emergent patients should proceed immediately to surgery, while semi-urgent patients should be treated on a case-by-case basis[25-27].

The cardiologist, anesthesiologist and the surgeon must balance the risk of further ischemic events against the risk of postoperative bleeding and, according to our institutional policy, we operate all unstable patients and wait for 5 or more days in patients who can be medically stabilized.

CONCLUSION

Urgent and emergent surgical revascularization using CPB in patients with ACS who were on DAPT preoperatively (withdrawal period 1-4 days), whose hemoglobin level is not less than 110 g/L, is a safe and effective procedure. The results of the present study showed that preoperative use of clopidogrel did not increase the risk of postoperative bleeding and did not affect the in-hospital and 30-day mortality. Further prospective randomized studies in a larger number of patients with a longer follow-up are needed to draw a conclusion that would benefit this important and special subgroup of patients.

It should be noted that the particularity of the targeted patient group, in addition to the ongoing recommendations, requires an integrated patient-to-patient approach to determine pro et contra of early or emergent surgery despite an alleviated risk of bleeding and complications.

REFERENCES

1. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK;Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators.Effects of clopidogrel in addition to aspirin in patients with acute coronarysyndromes without ST-segment elevation. N Engl J Med.2001;345(7):494-502. [MedLine]

2. Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G,Theroux P, et al. Effect of clopidogrel pretreatment before percutaneouscoronary intervention in patients with ST-elevation myocardial infarctiontreated with fibrinolytics: the PCI-CLARITY study. JAMA.2005;294(10):1224-32.

3. Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, et al; COMMIT(ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group.Addition of clopidogrel to aspirin in 45,852 patients with acute myocardialinfarction: randomised placebo-controlled trial. Lancet.2005;366(9497):1607-21.

4. Mehta SR, Yusuf S, Peters RJ, Bertrand ME, Lewis BS, Natarajan MK,et al; Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE)Investigators. Effects of pretreatment with clopidogrel and aspirin followed bylong-term therapy in patients undergoing percutaneous coronary intervention: thePCI-CURE study. Lancet. 2001;358(9281):527-33.

5. Chu MW, Wilson SR, Novick RJ, Stitt LW, Quantz MA. Does clopidogrelincrease blood loss following coronary artery bypass surgery? Ann Thorac Surg.2004;78(5):1536-41.

6. Despotis GJ, Filos KS, Zoys TN, Hogue CW Jr, Spitznagel E, LappasDG. Factors associated with excessive postoperative blood loss and hemostatictransfusion requirements: a multivariate analysis in cardiac surgical patients.Anesth Analg. 1996;82(1):13-21. [MedLine]

7. Dacey LJ, Munoz JJ, Baribeau YR, Johnson ER, Lahey SJ, Leavitt BJ,et al. Reexploration for hemorrhage following coronary artery bypass grafting:incidence and risk factors. Northern New England Cardiovascular Disease StudyGroup. Arch Surg. 1998;133(4):442-7.

8. Woodman RC, Harker LA. Bleeding complications associated withcardiopulmonary bypass. Blood. 1990;76(9):1680-97.

9. Kulik A, Chan V, Ruel M. Antiplatelet therapy and coronary arterybypass graft surgery: perioperative safety and efficacy. Expert Opin Drug Saf.2009;8(2):169-82.

10. Nenna A, Spadaccio C, Prestipino F, Lusini M, Sutherland FW, BeattieGW, et al. Effect of preoperative aspirin replacement with enoxaparin inpatients undergoing primary isolated on-pump coronary artery bypass grafting. AmJ Cardiol. 2016;117(4):563-70. [MedLine]

11. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DEJr, et al; American College of Cardiology; American Heart Association Task Forceon Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for theManagement of Patients With Unstable Angina/Non-ST-Elevation MyocardialInfarction); American College of Emergency Physicians; Society forCardiovascular Angiography and Interventions; Society of Thoracic Surgeons;American Association of Cardiovascular and Pulmonary Rehabilitation; Society forAcademic Emergency Medicine. ACC/AHA 2007 guidelines for the management ofpatients with unstable angina/non-ST-Elevation myocardial infarction: a reportof the American College of Cardiology/American Heart Association Task Force onPractice Guidelines (Writing Committee to Revise the 2002 Guidelines for theManagement of Patients With Unstable Angina/Non-ST-Elevation MyocardialInfarction) developed in collaboration with the American College of EmergencyPhysicians, the Society for Cardiovascular Angiography and Interventions, andthe Society of Thoracic Surgeons endorsed by the American Association ofCardiovascular and Pulmonary Rehabilitation and the Society for AcademicEmergency Medicine. J Am Coll Cardiol. 2007;50(7):e1-e157. [MedLine]

12. Cruden NL, Morch K, Wong DR, Klinke WP, Ofiesh J, Hilton JD.Clopidogrel loading dose and bleeding outcomes in patients undergoing urgentcoronary artery bypass grafting. Am Heart J.2011;161(2):404-10.

13. Sabatine MS, Morrow DA, Giugliano RP, Burton PB, Murphy SA, McCabeCH, et al. Association of hemoglobin levels with clinical outcomes in acutecoronary syndromes. Circulation. 2005;111(16):2042-9.

14. Sandoughdaran S, Sarzaeem MR, Bagheri J, Jebelli M, Mandegar MH.Predictors of blood transfusion in patients undergoing coronary artery bypassgrafting surgery. Int Cardivasc Res J. 2013;7(1):25-8.

15. Joshi SS, George A, Manasa D, Savita HM, Krishna PT, Jagadeesh AM.Propensity-matched analysis of association between preoperative anemia andin-hospital mortality in cardiac surgical patients undergoing valvular heartsurgeries. Ann Card Anaesth. 2015;18(3):373-9.

16. Ranucci M, Di Dedda U, Castelvecchio S, La Rovere MT, Menicanti L;Surgical and Clinical Outcome Research (SCORE) Group. In search of the idealrisk-scoring system for very high-risk cardiac surgical patients: a two-stageapproach. J Cardiothorac Surg. 2016;11:13.

17. Hongo RH, Ley J, Dick SE, Yee RR. The effect of clopidogrel incombination with aspirin when given before coronary artery bypass grafting. J AmColl Cardiol. 2002;40(2):231-7.

18. Yende S, Wunderink RG. Effect of clopidogrel on bleeding aftercoronary artery bypass surgery. Crit Care Med.2001;29(12):2271-5.

19. Berger JS, Frye CB, Harshaw Q, Edwards FH, Steinhubl SR, Becker RC.Impact of clopidogrel in patients with acute coronary syndromes requiringcoronary artery bypass surgery: a multicenter analysis. J Am Coll Cardiol.2008;52(21):1693-701.

20. Mehta RH, Roe MT, Mulgund J, Ohman EM, Cannon CP, Gibler WB, et al.Acute clopidogrel use and outcomes in patients with non-ST-segment elevationacute coronary syndromes undergoing coronary artery bypass surgery. J Am CollCardiol. 2006;48(2):281-6.

21. Chen L, Bracey A, Radovancevic R, Charles CD, Cooper JR, NussmeierNA. Influence of clopidogrel (Plavix) on perioperative blood loss andtransfusion requirements in patients undergoing aortocoronary bypass graftsurgery with cardiopulmonary bypass. Anesth Analg.2002;93:SCA34.

22. CURE Study Investigators. Effects of clopidogrel in addition toaspirin in patients with acute coronary syndromes without ST-segment elevation.N Engl J Med. 2001;345:494-502. [MedLine]

23. Chen K, Garg J, Malekan R, Spielvogel D, Ahmad H. Assessingintraoperative bleeding risk in patients undergoing coronary artery bypassgrafting with prior exposure to clopidogrel: single center retrospectiveanalysis. Am J Ther. 2017;24(6):e648-52. [MedLine]

24. Kim JH, Newby LK, Clare RM, Shaw LK, Lodge AJ, Smith PK, et al.Clopidogrel use and bleeding after coronary artery bypass graft surgery. AmHeart J. 2008;156(5):886-92.

25. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al;ESC Committee for Practice Guidelines. ESC Guidelines for the management ofacute coronary syndromes in patients presenting without persistent ST-segmentelevation: The Task Force for the management of acute coronary syndromes (ACS)in patients presenting without persistent ST-segment elevation of the EuropeanSociety of Cardiology (ESC). Eur Heart J.2011;32(23):2999-3054. [MedLine]

26. Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, FalkV, et al; ESC Committee for Practice Guidelines (CPG). Management of acutemyocardial infarction in patients presenting with persistent ST-segmentelevation: the Task Force on the Management of ST-Segment Elevation AcuteMyocardial Infarction of the European Society of Cardiology. Eur Heart J.2008;29(23):2909-45.

27. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, et al.;Task Force on Myocardial Revascularization of the European Society of Cardiology(ESC) and the European Association for Cardio-Thoracic Surgery (EACTS); EuropeanAssociation for Percutaneous Cardiovascular Interventions (EAPCI). Guidelines onmyocardial revascularization. Eur Heart J. 2010;31(20):2501-55.

No financial support.
No conflict of interest

Authors' roles & responsibilities

SMK Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; final approval of the version to be published

AM Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; final approval of the version to be published

MBK Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; final approval of the version to be published

Article receive on Monday, April 17, 2017

CCBY All scientific articles published at rbccv.org are licensed under a Creative Commons license

Indexes

All rights reserved 2017 / © 2024 Brazilian Society of Cardiovascular Surgery DEVELOPMENT BY