Calendars

Combined clopidogrel and aspirin treatment up to surgery increases the risk of postoperative myocardial infarction, blood loss and reoperation for bleeding in patients undergoing coronary artery bypass grafting

Description
Combined clopidogrel and aspirin treatment up to surgery increases the risk of postoperative myocardial infarction, blood loss and reoperation for bleeding in patients undergoing coronary artery bypass grafting
Categories
Published
of 7
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Share
Transcript
  Combined clopidogrel and aspirin treatment up to surgery increasesthe risk of postoperative myocardial infarction, blood loss andreoperation for bleeding in patients undergoing coronary artery bypass grafting † Antonio Miceli, Simon M.J. Duggan, Giuseppe Aresu, Paolo M. de Siena, Francesco Romeo,Mattia Glauber, Massimo Caputo and Gianni D. Angelini* Bristol Heart Institute, University of Bristol, Bristol, UK* Corresponding author. Bristol Heart Institute, University of Bristol, Bristol BS2 8HW, UK. Tel: +44-117-9283145; e-mail: g.d.angelini@bristol.ac.uk (G.D. Angelini).Received 2 February 2012; received in revised form 26 April 2012; accepted 17 May 2012 Abstract  OBJECTIVES : Recent guidelines suggest that patients undergoing coronary artery bypass grafting (CABG) should discontinue clopidogreland aspirin (ASA) 5 and 2 – 10 days, respectively, before surgery to reduce postoperative bleeding and its complications. The aim of ourstudy was to evaluate the relationship between the timing of discontinuing clopidogrel+ASA and early clinical outcomes in patientsundergoing CABG. METHODS : Four thousand three hundred and thirty consecutive patients underwent isolated CABG from April 2004 to February 2009.Of these, 926 patients received double antiplatelet therapy in the 14 days prior to surgery. Patients were strati fi ed into three groups:clopidogrel+ASA within 5 and 2 days, respectively, before surgery (Group A,  n =287); clopidogrel within 5 days+ASA stopped 2 – 10days before surgery or clopidogrel stopped 5 days+ASA within 2 days of surgery (Group B,  n =308) and clopidogrel+ASA discontinued>5 and 10 days, respectively, before surgery (control group,  n =331). RESULTS : Overall mortality was 0.8%. The incidence of postoperative myocardial infarction (MI) was 5.2, 1 and 1.8% in Groups A, B andcontrol, respectively ( P  =0.004). Reoperation for bleeding occurred in 4.5, 2.9 and 1.2% ( P  =0.04) and total chest drainage was 761±473, 720±421 and 687±302 ml in Groups A, B and control, respectively ( P  =0.06). Multivariable analysis revealed that Group A was anindependent predictor of postoperative MI ( P  =0.02), reoperation for bleeding ( P  =0.02), blood transfusions ( P  =0.003) and bloodlosses ( P  =0.015). CONCLUSIONS : Clopidogrel in combination with ASA up to the time of surgery is associated with an increased risk of postoperativeMI, blood loss and reoperation for bleeding in patients undergoing CABG. Keywords:  Antiplatelet therapy  •  Coronary artery bypass grafting INTRODUCTION Combined clopidogrel and aspirin (ASA) treatment has beenshown to reduce mortality and morbidity in the setting of acutecoronary syndrome (ACS) and percutaneous coronary interven-tion, making double antiplatelet therapy a class I recommenda-tion and Grade A evidence in the American College of Cardiology and America Heart Association guideline [1].Consequently, most patients with ACS receive these drugs. Thereare still signi fi cant controversies regarding the preoperative useof double antiplatet treatment in patients undergoing coronaryartery bypass grafting (CABG). Several retrospective studies haveshown that clopidogrel in association with ASA given <5 daysbefore surgery is associated with more blood products,re-explorations for bleeding and an increase in chest drain bloodloss [2 – 6]. Nevertheless, randomized trials have suggested thatpatients undergoing CABG after clopidogrel and ASA bene fi tfrom adverse anti-ischaemic effects without an increase in life-threatening bleeding. The authors of the Clopidogrel in Unstableangina to prevent Recurrent ischaemic Events (CURE) and AcuteCatheterization and Urgent Intervention Triage strategy (ACUITY)found, respectively, 1.7 and 4.6% risk reduction in cardiovascularevents associated with 2.1 and 0.6% increased risk in majorbleeding among CABG patients [7, 8]. However, subanalyses of  these studies revealed that patients undergoing CABG within 5days of receiving clopidogrel had, respectively, 5.2 and 5.5%increased risk for major bleeding and, interestingly, 3.1 and 5.7%increased risk for composite ischaemic events compared withpatients who received clopidogrel >5 days before surgery. † Presented as oral presentation at the 59th Annual Scienti fi c Session of theAmerican College of Cardiology, Atlanta, Georgia, 14 – 16 March 2010.© The Author 2012. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. European Journal of Cardio-Thoracic Surgery 43 (2013) 722 – 728  ORIGINAL ARTICLE doi:10.1093/ejcts/ezs369 Advance Access publication 24 June 2012  Recent guidelines suggest that patients undergoing CABG shoulddiscontinue clopidogrel and ASA 5 and 2 – 10 days, respectively,before surgery to reduce postoperative bleeding and its compli-cations [9]. Despite these recommendations, 10 – 30% of patientswho require urgent CABG are still operated on under the effectof these drugs [3, 10]. Therefore, the aim of our study was to evaluate the relationship between the timing of discontinuingclopidogrel in combination with ASA and early clinical outcomesin patients undergoing CABG. MATERIALS AND METHODS Patient selection, data collection andde fi nitions The study was approved by the clinical audit committee of theUniversity Hospitals Bristol National Health Service FoundationTrust to meet ethical and legal requirements, and individualconsent was waived. This was a retrospective, observational,cohort study of prospectively collected data from consecutivepatients who underwent isolated CABG at the Bristol HeartInstitute between April 2004 and February 2009. The data collec-tion form is entered in a database (Patient Analysis and TrackingSystem; Dendrite Clinical Systems, London, UK) and includes  fi vesections that are  fi lled in consecutively by anaesthetists, sur-geons, intensive care unit, high-dependency unit and wardnurses. The base sample contained detailed clinical informationon  ≏ 4330 patients. Of these, 3061 patients were excluded fromthe study because they were not on double antiplatelet treat-ment. The remaining patients (1269, 29%) underwent CABGsurgery under the effect of double antiplatelet treatment.Further exclusion criteria were patients who had unknownpreoperative use or timing of ASA and clopidogrel ( N =24),unknown bleeding data ( N =208) and those with preoperativecritical state ( N =57), de fi ned as any one or more of the follow-ing: ventricular tachycardia or  fi brillation or aborted suddendeath, preoperative cardiac massage, preoperative ventilationbefore arrival in the anaesthetic room, preoperative inotropicsupport, intraaortic balloon counterpulsation or preoperativeacute renal failure (anuria or oliguria <10 ml/h) or emergencyoperation ( N =54), de fi ned as an operation carried out on refer-ral before the beginning of the next working day). The  fi nalsample size was 926 patients who received double antiplatelettherapy in the last 14 days prior to surgery. Patients were strati- fi ed into three groups: clopidogrel+ASA within 5 and 2 days, re-spectively, before surgery (Group A,  n =287); clopidogrel within5 days before surgery+ASA stopped 2 – 10 days before surgeryor clopidogrel stopped 5 days prior to surgery+ASA within 2days of surgery (Group B,  n =308) and clopidogrel+ASA discon-tinued >5 and 10 days, respectively, before surgery (controlgroup,  n =331, Fig. 1). In-hospital mortality was de fi ned as anydeath occurring within 30 days of operations. A diagnosis of postoperative myocardial infarction (MI) was based on the pres-ence of Q-waves >0.04 ms and/or a reduction in R-waves >25%in at least two contiguous leads on electrocardiogram (ECG).Postoperative renal dysfunction was de fi ned as a serum creatin-ine level >200  μ mol/l. A diagnosis of stroke was made if therewas evidence of new neurological de fi cit with morphologicalsubstrate con fi rmed by computer tomography or nuclear mag-netic resonance imaging. Postoperative blood loss was de fi nedas total chest tube drainage and indications for chest re-exploration were blood loss >500 ml over the  fi rst hour, >300 mlfor two consecutive hours or >200 ml for three consecutivehours. Unstable angina was de fi ned as rest angina requiring ivnitrates until arrival in the anaesthetic room. Finally, priority of surgery was de fi ned as urgent (medical factors require thepatient to stay in hospital waiting for an operation) and elective(the clinical status of the patient allows discharge from the hos-pital with readmission for surgery at a later date). The decisionto perform off-pump or on-pump CABG technique was basedon individual surgeon preference. Anaesthetic, surgical technique and postoperativemanagement  Anaesthetic and surgical techniques were standardized for allpatients and have been reported previously. Brie fl y, for patientsundergoing on-pump CABG, cardiopulmonary bypass was insti-tuted with the use of ascending aortic cannulation and two-stagevenous cannulation of the right atrium. The membrane oxygen-ator was primed with 1000 ml of Hartmanns crystalloid, 500 mlgelofusine, 0.5 g/kg mannitol, 7 ml of 10% calcium gluconateand 6000 IU heparin. Alpha-stat pH management was used, andthe systemic temperature was kept between 34 and 36°C, re-spectively. Myocardial protection was achieved with intermittenthyperkalaemic warm blood cardioplegia. For off-pump CABG, Figure 1:  Study pro fi le.       A      D      U      L      T      C      A      R      D      I      A      C A. Miceli  et al.  / European Journal of Cardio-Thoracic Surgery  723  the Bristol technique was used to expose the coronaries andprovides stabilization to undertake the anastomosis [11]. At theend of surgery, patients were transferred to the intensive careunit and managed according to the unit protocol. In the case of bleeding >150 ml for longer than consecutive 2 h, derangementsof the coagulation pro fi le were treated with a diagnosis-directedtherapy. Elevation of activate clotting time >130 s was treatedwith additional 25 mg dose of protamine. Values of prothrombintime, activated partial thromboplastin time and internationalnormalized ratio of >1.5 times control were corrected with freshfrozen plasma. A platelet count <80000/µl was an indicator forplatelet transfusion. A haematocrit <23% was the threshold fortransfusion of red blood cell. The blood was all leuco fi ltrated.According to unit policy, patients received ASA 300 mg supposi-tory  per rectum  within 6 h after surgery and then from the dayafter both 75 mg ASA and 75 mg clopidogrel per day for 1 year.In case of bleedings, antiplatelet treatment was delayed to theday after. Statistical analysis Continuous data were expressed as mean±standard deviation(SD), and categorical data as percentages. The Kolmogorov – Smirnov test was used to check for normality of data beforefurther analysis. Differences among groups were compared withthe  χ  2 test or Fisher ’ s exact test for categorical variables andanalysis of variance test with a  post hoc   Bonferroni test orKruskal – Wallis test and Mann – Whitney  U -tests with Bonferronicorrection as appropriate for continuous variables. Multivariablelogistic and linear regression analyses were performed to assessthe effect of combined clopidogrel and ASA therapy on post-operative MI, re-exploration, blood transfusions and bleedingafter adjusting for potentially confounding variables listed inTable 1. Clinically relevant variables with a  P  -value <0.2 on uni-variate analysis were incorporated in the multivariable models.Results are reported as percentages and odds ratios (ORs) with95% con fi dence interval (CI). All reported  P- values are two-sided, and  P- values of <0.05 were considered to indicate statis-tical signi fi cance. All statistical analysis was performed with SPSS15.0 (SPSS Inc., Chicago, IL, USA). RESULTS Preoperative baseline characteristics are outlined in Table 1.There was no difference in age, sex, cardiac risk factors, chronicpulmonary disease, extracardiac arteriopathy as well as left ven-tricular function. However, patients in Groups A and B had ahigher incidence of left main disease, unstable angina and Table 1:  Preoperative baseline characteristics Variable Group A ( n =287) Group B ( n =308) Control group ( n =331)  P  -valueAge (years±SD) 65.5 ±9 66±9.9 65.5 ±10.9 0.77Female,  n  (%) 56 (19.5) 52 (16.9) 63 (19) 0.67Diabetes,  n  (%) 49 (17.1) 54 (17.5) 72 (21.8) 0.25Hypertension,  n  (%) 207 (72.1) 220 (71.4) 250 (75.5) 0.46Chronic pulmonary disease,  n  (%) 27 (9.4) 31 (10.1) 37 (11.2) 0.76Extracardiac arteriopathy,  n  (%) 20 (7) 30 (9.7) 35 (10.6) 0.28Previous cardiac operations,  n  (%) 4 (1.4) 10 (3.2) 12 (3.6) 0.21Preoperative EF (%),  n  (%)Good 202 (70.4) 224 (72.7) 238 (71.9) 0.81Fair 74 (25.8) 68 (22.1) 78 (23.6)Poor 11 (3.8) 16 (5.2) 15 (4.5)NYHA class III – IV,  n  (%) 73 (25.4) 70 (22.7) 92 (27.8) 0.34CCS class 3 – 4 155 (54)* 162 (52.6)* 130 (39.3) <0.0001Recent ACS 186 (64.8)* § 167 (54.2)* 108 (32.6) <0.0001Unstable angina,  n  (%) 62 (21.6)* 67 (21.7)* 30 (9.1) <0.0001MI within 30 days,  n  (%) 152 (53)* § 116 (37.7)* 60 (18.1) <0.0001MI between 31 – 90 days,  n  (%) 25 (8.7) 45 (14.6) 46 (13.9) 0.06MI >90 days,  n  (%) 30 (10.5)* 54 (17.5)* 128 (37.7) <0.0001Preoperative haemoglobin (mg/dl, SD) 13.3 ±1.55* 13.5±1.5 13.8 ±1.4 <0.0001Stop ASA (days±SD) 0.9±0.2* § 2.1±1.5* 6.8±2.4 <0.0001Stop clopidogrel (days±SD) 2.5±1.6* § 6.6±3.6* 8.4±2.1 <0.0001Heparin IV until operation 29 (10.1) 29 (9.4) 27 (8.2) 0.69Aprotinin,  n  (%) 35 (12.2)* § 19 (6.2) 15 (4.5) 0.001Tranexanic acid,  n  (%) 219 (76.3) 247 (80.2) 249 (75.2) 0.3CAD, mean (SD) 2.6±0.66 2.66±0.58 2.63 ±0.58 0.2LMS >50%,  n  (%) 85 (29.6)* 93 (30.1)* 68 (20.5) 0.008Urgent surgery,  n  (%) 243 (84.7)* § 233 (75.6)* 126 (38.1) <0.0001No. of grafts (mean, SD) 2.74 ±0.77 2.72±0.76 2.7±0.78 0.72Off-pump surgery,  n  (%) 177 (65.6) 210 (68.2) 217 (65.6) 0.25EF: ejection fraction; CCS: Canadian cardiovascular society; ACS: acute coronary syndrome; MI: myocardial infarction; CAD: coronary artery disease; LMS:left main stenosis.* P  <0.01 vs control. § P  <0.01 vs Group B. A. Miceli  et al.  / European Journal of Cardio-Thoracic Surgery 724  preoperative MI within 30 days, advanced Canadian cardiovas-cular society (CCS) class and urgent surgery as well as the higherintraoperative use of aprotinin than the control group. No differ-ence was found among groups in the use of off-pump proced-ure. Postoperative clinical outcomes are shown in Table 2.Overall mortality was 0.8% with no difference among the threegroups. The incidence of postoperative MI was 5.2, 1 and 1.8%in Groups A, B and control, respectively ( P  =0.003). No differ-ence was found in the incidence of postoperative renal dysfunc-tion, atrial  fi brillation and stroke. Reoperation for bleedingoccurred in 4.5, 2.9 and 1.2% ( P  =0.04) and total chest drainagewas 761±473, 720±421 and 687±302 ml in Groups A, B andcontrol, respectively ( P  =0.066). The mean number of red bloodcells and platelets transfusion as well as the incidence of bloodproducts transfused was higher in Group A (Table 2). Postoperative myocardial infarction Predictors of postoperative MI on univariate analysis were: clopi-dogrel+ASA within 5 and 2 days, respectively, before surgery(Group A, OR 3.26, 95% CI 1.43 – 7.4,  P  =0.005), clopidogrelwithin 5 days before surgery+ASA stopped 2 – 10 days beforesurgery or clopidogrel stopped 5 days prior to surgery+ASAwithin 2 days of surgery (Group B, OR 0.4, 95% CI 0.14 – 1.2,  P  =0.09), ejection fraction (EF)<50% (OR 2, 95% CI 0.8 – 4.5,  P  =0.12), hypertension (OR 0.5, 95% CI 0.2 – 1.2,  P  =0.1), MI within30 days before surgery (OR 1.9, 95% CI 0.8 – 4.2,  P  =0.136) andnumber of diseased coronary arteries (OR 0.67, 95% CI 0.37 – 1.2, P  =0.175). However, on multivariable analysis, clopidogrel+ASAwithin 5 and 2 days, respectively, before surgery was the onlyindependent risk factor for postoperative MI (OR 2.8, 95%CI 1.2 – 6.7,  P  =0.02). Figure 2 shows that the risk of MI increasedwith decreasing the time from the last dose of clopidogrel andASA. Re-exploration for bleeding and blood loss Predictors of re-exploration for bleeding on univariate analysiswere EF<30% (OR 2.9, 95% CI 0.8 – 10,  P  =0.1), clopidogrel+ASAwithin 5 and 2 days, respectively, before surgery (Group A, OR2.3, 95% CI 1.05 – 5,  P  =0.036), NYHA class III – IV (OR 0.4, 95% CI0.1 – 1.3,  P  =0.011) and preoperative haemoglobin (OR 1.22, 95%CI 0.9 – 1.6,  P  =0.15). Multivariable analysis showed that poor EF(OR 4.4, 95% CI 1.12 – 16.4,  P  =0.026) and clopidogrel+ASAwithin 5 and 2 days, respectively, before surgery (OR 2.6, 95% CI1.14 – 5.5,  P  =0.023) were independent risk factors forre-exploration.On univariate analysis, predictors of blood loss were clopido-grel+ASA within 5 and 2 days, respectively, before surgery ( P  =0.04), age ( P  =0.039), male gender ( P  <0.0001), extracardiacarteriopathy ( P  =0.008), redo operation ( P  =0.12), unstableangina ( P  =0.1), advanced NYHA class ( P  =0.003), diabetes ( P  =0.01), hypertension ( P  =0.04), preoperative haemoglobin ( P  =0.007), aprotinin ( P  =0.04), tranexanic acid ( P  =0.2), left mainstenosis ( P  =0.15) and off-pump surgery ( P  =0.2). Multivariablelinear regression identi fi ed that the use of clopidogrel and ASAwithin 5 and 2 days, respectively, before surgery (  β  =0.08,  P  =0.015) was an independent risk factor for bleeding. In addition,sex male (  β  =0.09,  P  =0.01), unstable angina ( β =0.1,  P  =0.003),NYHA class III – IV (  β  =0.72,  P  =0.03), aprotinin (  β  = − 0.16,  P  <0.0001) and tranexanic acid (  β  = − 0.13,  P  <0.0001) were inde-pendent predictors for blood loss. Figures 2 and 3 show that the risk of re-exploration for bleeding and blood loss increased withdecreasing the time from the last dose of clopidogrel and ASA. Blood transfusions Predictors of univariate analysis were gender (OR 0.35, 95% CI0.24 – 0.5,  P  <0.0001), unstable angina (OR 2.7, 95% CI 1.8 – 2.9,  P  <0.0001), chronic pulmonary disease (OR 2.4, 95% CI 1.5 – 2.8),EF<50% (OR 2, 95% CI 1.4 – 2.7,  P  <0.0001), preoperative haemo-globin (OR 0.55, 95% CI 0.5 – 0.6,  P  <0.0001), clopidogrel+ASAwithin 5 and 2 days, respectively, before surgery (Group A, OR1.8, 95% CI 1.3 – 2.5,  P  =0.001), heparin IV (OR 1.8, 95%CI 1.3 – 2.6), off-pump procedures (OR 0.6, 95% CI 0.4 – 0.8,  P  =0.003),advanced NYHA class (OR 1.6, 95% CI 1.1 – 2.3,  P  =0.007),advanced CCS class (OR 1.5, 95% CI 1.1 – 2.1,  P  =0.01), age (OR1.05, 95% CI 1.02 – 1.07,  P  =0.001), number of diseased coronaryarteries (OR 1.5, 95% CI 1.02 – 2,  P  =0.01) and urgent surgery (OR1.4, 95% CI 1 – 2,  P  =0.056).On multivariable analysis, clopidogrel+ASA within 5 and 2days, respectively, before surgery were an independent risk factor for blood transfusions (OR 1.9, 95% CI 1.2 – 2.9,  P  =0.003).Other predictors were heparin IV (OR 2.7, 95% CI 1.5 – 4.7,  P  =0.001), off-pump procedures (OR 0.45, 95% CI 0.3 – 0.8,  P  =0.001), gender (OR 0.5, 95% CI 0.3 – 0.8,  P  =0.003), pulmonarydisease (OR 1.9, 95% CI 1.1 – 3.1,  P  =0.03), EF<50% (OR 1.8, 95%CI 1.2 – 2.8,  P  =0.006), preoperative haemoglobin (OR 0.7, 95% CI0.6 – 0.8,  P  <0.0001) and advanced age (OR 1.04, 95% CI 1.02 – 1.06,  P  =0.001). Table 2:  Early clinical outcomes Group A( N =287)Group B( N =308)Controlgroup( N =331) P  -valueMortality, % ( n ) 1 (0.3) 0.6 (2) 1.2 (4) 0.45Postoperative MI,% ( n )5.2 (15)* § 1 (3) 1.8 (6) 0.004Stroke, % ( n ) 0.3 (1) 0.3 (1) 0.3 (1) 1Re-exploration, %( n )4.9 (14)* 2.9 (9) 1.2 (4) 0.04PRD, % ( n ) 8.5 (24) 8.9 (27) 7.3 (24) 0.74POAF, % ( n ) 24 (69) 23.4 (72) 28.1 (93) 0.33Bleeding (ml±SD) 761±473 720±421 687±302 0.06Transfusions (Unit)Red blood cells 0.8±1.6* § 0.5±2.2 0.3±0.9 0.001Fresh frozenplasma0.12±0.670.9±0.5 0.05 ±0.020.33Platelets 0.2±0.6* § 0.1±0.4 0.03 ±0.2 <0.0001Blood product exposureRed blood cells 25.4 (73)* 17.5 (54) 15.1 (50) 0.003Fresh frozenplasma3.5 (10) 3.6 (11) 1.8 (6) 0.33Platelets 15 (43)* § 7.1 (22)* 2.7 (9) <0.0001MI: myocardial infarction; PRD: postoperative renal dysfunction;POAF: postoperative atrial fibrillation.* P  <0.01 vs control. § P  <0.01 vs group B.       A      D      U      L      T      C      A      R      D      I      A      C A. Miceli  et al.  / European Journal of Cardio-Thoracic Surgery  725  DISCUSSION Our study demonstrates that the use of clopidogrel in combin-ation with ASA up to the time of surgery is associated with anincreased risk of postoperative MI and reoperation for bleedingin patients undergoing CABG. Moreover, patients who were stillunder the effect of dual antiplatelet therapy had a higher bloodloss as well as higher number and rate of blood transfusions. Figure 2:  Probability of postoperative myocardial infarction and re-exploration for bleeding according to the time from last clopidogrel+ASA dose administrationto the time of surgery. Figure 3:  Predicted chest tube output according to the time from last clopidogrel+ASA dose administration to the time of surgery. A. Miceli  et al.  / European Journal of Cardio-Thoracic Surgery 726
Search
Similar documents
View more...
Related Search
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks
SAVE OUR EARTH

We need your sign to support Project to invent "SMART AND CONTROLLABLE REFLECTIVE BALLOONS" to cover the Sun and Save Our Earth.

More details...

Sign Now!

We are very appreciated for your Prompt Action!

x