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Antiplatelet therapy preceding coronary artery surgery: implications for bleeding, transfusion requirements and outcome

Picker, S. M.*; Kaleta, T.*; Hekmat, K.; Kampe, S.; Gathof, B. S.*

European Journal of Anaesthesiology: April 2007 - Volume 24 - Issue 4 - p 332–339
doi: 10.1017/S0265021506002262
Review
Free
SDC

Background and objective: Bleeding after cardiac surgery correlates with morbidity and mortality. The aim of this study was to determine the influence of antiplatelet therapy on bleeding and transfusion rates in coronary artery bypass grafting.

Methods: Forty patients receiving aspirin and/or clopidogrel/ticlopidine within 7 days prior to surgery were retrospectively compared to 40 control patients lacking antiplatelet therapy for at least 8 preoperative days. Blood loss was assessed as chest-tube drainage during the first 12 h after surgery. Units transfused were recorded intraoperatively and during stay in the intensive care unit.

Results: Both groups were comparable for pre- and intraoperative data. Irrespective of single or combined antiplatelet therapy, treated patients demonstrated lower fractions of the creatine-kinase isoenzyme MB (5.8 ± 3.1 vs. 8.2 ± 4.1%; P = 0.004) and infarction rates (0 vs. 3; P = 0.240) than control patients, but had significantly more haemorrhages (940 ± 861 mL vs. 412 ± 590 mL; P = 0.002) and transfusion requirements (red cells: 4.5 ± 4.9 vs. 1.5 ± 2.3, plasma: 4.9 ± 6.4 vs. 1.3 ± 2.5, platelets: 1.5 ± 1.3 vs. 0.1 ± 0.2; all P ≤ 0.001). The differences to control patients were more pronounced for only short antiplatelet therapy free intervals or ongoing antiplatelet therapy (P≤2 days ≤ 0.019). For antiplatelet therapy free intervals longer than 2 days, bleeding and transfusion rates (except for platelets) were nonsignificantly higher as compared to control patients (P ≥ 0.058).

Conclusions: To overcome increased blood loss and transfusion rates, antiplatelet therapy should be discontinued for at least 2 days before elective coronary surgery. Whether patients at high risk for myocardial infarction might benefit from ongoing antiplatelet therapy remains to be investigated.

*University of Cologne, Department of Transfusion Medicine, Cologne, Germany

University of Cologne, Department of Thoracic and Cardiovascular Surgery, Cologne, Germany

University of Cologne, Department of Anesthesiology, Cologne, Germany

Correspondence to: Susanne M. Picker, Department of Transfusion Medicine, University of Cologne, Kerpener St. 62, 50924 Cologne, Germany. E-mail: susanne.picker@uk-koeln.de; Tel: +49 221 478 4868/3877; Fax: +49 221 478 3155

Accepted for publication 18 September 2006

First published online 23 January 2006

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Introduction

Bleeding after cardiac surgery still remains a common complication and correlates with morbidity and mortality [1]. Irreversible inhibition of platelet function (antiplatelet therapy (APT)) using the cyclooxygenase inhibitor acetylsalicylic acid (Aspirin®; Bayer Vital, Leverkusen, Germany) and/or antagonists of adenosine diphosphate (ADP), ticlopidine (Tiklyd®; Sanofi Aventis, Frankfurt, Germany), clopidogrel (Iscover®; Sanofi Synthelabo Limited, Fawdon, UK) has been proven to reduce the risk of myocardial infarction and other cardiac events, to be beneficial for the treatment of instable angina and to reduce stent thrombosis [2-4]. Consequently, nearly all patients presenting for coronary artery bypass grafting (CABG) are under APT. The impact of APT on perioperative blood loss, however, still remains under discussion as studies published in this field yielded contradictory results reporting either an increased [1,5-14] or an ambivalent influence of APT [15-19] on bleeding and transfusion requirements. As a consequence, even though definitive guidelines hardly exist [14], APT is frequently withdrawn prior to surgical or diagnostic procedures. This may expose patients to an increased risk for cardiovascular syndromes or even cardiovascular death, reported to occur in up to 4-10% shortly after aspirin withdrawal [14,20-22], mainly within the first 48 h after revascularization [23]. As the pharmacological efficacy of currently used APT agents is well established, and common surgical as well as anaesthetic experience give rise to supposedly increased bleeding rates under APT during cardiopulmonary bypass (CPB, per se associated with systemic inflammatory and haemostatic disorders), the purpose of this study was to determine the influence of APT on blood loss, transfusion requirement, reintervention (identified as risk factor for an adverse outcome after cardiac surgery [19]) and outcome such as acute myocardial infarction (AMI) or hospital stay. Additionally, it was evaluated whether different lengths of preoperative ATP free intervals or the combined regimens of APT influence the parameters mentioned above.

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Materials and methods

Records of 80 consecutive patients who underwent first time elective CABG on CPB from January to September 2004 in the Department of Thoracic and Cardiovascular Surgery of the University Hospital of Cologne were retrospectively reviewed. Forty patients received APT (100 mg aspirin and/or 250 mg ticlopidine day−1, or 100 mg aspirin and/or 75 mg clopidogrel day−1) within 1-7 days prior to surgery. This cohort was opposed to 40 control patients (CON) not receiving any APT the last 8 days prior to surgery and undergoing CABG at the same day by the same staff. Exclusion criteria were concomitant non-coronary procedures such as valvular or aortic surgery, emergency procedures and APT other than aspirin, ticlopidine or clopidogrel.

Non-pulsatile blood flow was established using roller pump speed of 2.4 L min−1× m2 and a hollow fibre membrane oxygenator (Quadrox; Jostra, Hirrlingen, Germany), with 1500 mL of crystalloid priming solution. Body temperature, measured within the urinary bladder was kept between 32 and 36°C. Cardioplegia was achieved either by 20 mL kg−1 of cold Bretschneider's solution (Dr Franz Köhler Chemie, Alsbach-Hähnlein, Solingen, Germany) or by the method based on Calafiore and colleagues [24] (KCl 14.9% 30 mL, B. Braun Melsungen AG, Melsungen, Germany plus MgSO4 50% 10 mL, Intresa Arzneimittel GmbH, Freiburg, Germany plus acetylcysteine 9 mL, Hexal AG, Holzkirchen, Germany). After cessation of CPB, blood of the oxygenator was returned along with blood salvaged from the operative field, using a cell saver (Brat 2; Cobe Cardiovascular, Arvada, CO, USA).

All patients received standard total intravenous anaesthesia (body weight-adjusted doses of sufentanil, propofol and pancuronium) as well as antifibrinolytic therapy with either high-dose aprotinin (Trasylol®; Bayer Vital, Leverkusen, Germany, bolus of 2×106 KIU plus 2×106 KIU in CPB-prime plus continuous infusion of 5×105 KIU h−1 during CBP) or 2 g of tranexamic acid (Cyklokapron®; Pfizer Manufacturing Belgium NV, Puurs, Belgium, bolus of 0.5 g plus 0.5 g in CPB-prime plus 1 g post-CPB). Antifibrinolytic drugs were administered intraoperatively in all cases, and postoperatively only with bleeding complications. After median sternotomy and before cannulation for CPB, a bolus of unfractionated heparin of 300 U kg−1 was administered and fully reversed with protamine sulphate (ratio 1 : 1) at the end of CPB. After surgery, all patients were transferred to the intensive care unit (ICU) and mechanically ventilated until achievement of stable haemodynamics. Fluid therapy consisted of crystalloids at a basic of 40-60 mL h−1, including additional fluids, when considered necessary by the attending clinician.

The intraoperative transfusion trigger for homologous red blood cells (RBCs) was set to haemoglobin (Hb) ≤6 g dL−1 and the postoperative trigger to Hb ≤8 g dL−1. Transfusion of fresh frozen plasma (FFP) was conducted at international normalized ratio (INR) >1.5 with excessive bleeding of >200 mL h−1 for two consecutive hours. Transfusion trigger for platelets was set at platelet count <50×109 L−1 with excessive bleeding of >200 mL h−1 for two consecutive hours. Surgical reintervention was performed if bleeding exceeded 200 mL h−1 for six consecutive hours or 400 mL during the first hour. All blood products given intraoperatively and during ICU stay were recorded. The thoracic drainage volume was measured for up to 12 h after surgery, whereby the drained blood was not re-infused.

Apart from ventilation time, length of ICU and hospital stay, all adverse clinical events such as AMI, renal failure, thromboembolic complications and multiple organ failure were recorded. AMI was diagnosed by the appearance of new Q-waves in the electrocardiogram (ECG) and verified by creatine-kinase isoenzyme MB (CK-MBmax) >30 U L−1.

Results are presented as mean ± standard deviation (SD) if not otherwise stated. Statistical comparisons were made with the two-tailed t-test for independent samples (continuous data) and the χ2-test and the two-tailed Fisher's exact test (non-continuous scale data), respectively, depending on the frequency of variables observed. According to a previous power analysis obtained by data of our institution [25] indicating an SD for the 24 h blood loss of approximately 350 mL, we estimated a cohort of about 40 patients per group as sufficient to allow a significant difference of 200 mL in the 12 h chest tube drainage between the two study groups, with 90% power at 0.05 significance level. All statistical tests were performed using commercially available software (SPSS 11.0 for Windows; SPSS Software GmbH, Munich, Germany). A P value of <0.05 was considered significant.

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Results

As demonstrated in Table 1, APT and CON patients were well matched for preoperative patient characteristics, clinical and laboratory features, except for CK-MB, which was significantly higher in CON patients but remained within the normal range. Preoperative risk factors, assessed using the EuroSCORE [26], were comparable for both study groups. However, the ejection fraction was slightly higher in APT patients, though not at a statistically significant level. Intraoperative data, such as aortic-cross-clamp time, CPB time, number of distal anastomoses and use of internal thoracic artery, were similar between the two study groups, except for antifibrinolytic drug use (Table 2): intraoperatively (where all patients received antifibrinolytics), aprotinin was administered more often to CON than to APT patients, who received more tranexamic acid. The frequency of antifibrinolytic drugs, used postoperatively, was significantly higher in APT (21 vs. 4, P = 0.027). Tranexamic acid was the favoured drug of this period (18 vs. 4 aprotinin, P = 0.001). The postoperative parameters evaluated, such as ICU stay as well as 30-day mortality, were similar for both groups, except for CK-MBmax. Expressed as percent of total CK, it was elevated postoperatively in both groups, whereby CON patients demonstrated significantly higher values than APT patients (P = 0.004). The differences remained significant until discharge from hospital (APT 10.4 ± 3.5% vs. CON 13.5 ± 7.6%, P = 0.021), whereby normal values were reached again in both groups. Of note, three CON but no APT patient experienced perioperative myocardial infarction. Because of the small study size, this difference did not reach statistical significance. Renal replacement therapy was performed in one APT patient who simultaneously suffered from postoperative pneumonia and died at the eighth postoperative day from multiorgan failure due to sepsis. The mean serum creatinine levels from baseline (APT 1.0 ± 0.4 mg dL−1 vs. CON 1.0 ± 0.2 mg dL−1) to discharge (APT 1.2 ± 0.6 mg dL−1 vs. CON 1.1 ± 0.6 mg dL−1) were comparable for both groups. Re-exploration for bleeding was required in eight APT patients, which was not significantly different from CON patients (3, P = 0.190). The same was true for hospital stay, which was 1 day longer for APT patients (P = 0.080). Intra-aortic balloon pump or ventricular assist devices were not necessary in either study group.

Table 1

Table 1

Table 2

Table 2

Chest tube drainage (12 h) was more than twofold higher in APT than in CON patients (940 ± 861 mL vs. 412 ± 590 mL, P = 0.002, Fig. 1). The mean decrease in haemoglobin levels from baseline (APT 14.0 ± 1.7 g dL−1 vs. CON 13.5 ± 1.5 g dL−1) to discharge (APT 11.9 ± 1.6 g dL−1 vs. CON 12.2 ± 1.5 g dL−1) was similar in both groups. As a result of the significantly higher blood loss, APT patients demonstrated higher transfusion requirements for all blood derivates (units): RBCs (4.5 ± 4.9 vs. CON 1.5 ± 2.9, P = 0.001), FFP (4.9 ± 6.4 vs. CON 1.3 ± 2.5, P = 0.001), platelets (1.5 ± 1.3 vs. CON 0.1 ± 0.2, P < 0.001, Fig. 2).

Figure 1.

Figure 1.

Figure 2.

Figure 2.

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Subgroup analysis

Of the total of 40 APT patients, 11 (27.5%) were on aspirin alone, 28 (70%) on a combination of aspirin and clopidogrel or ticlopidine and one patient (2.5%) was on clopidogrel alone. Of the total, 18 (45.0%), 13 (32.5%) and 9 APT patients (22.5%) stopped APT for at least 2 days, 3-5 days and 6-7 days prior to surgery, respectively.

No differences between patients on aspirin alone and patients on a combination of aspirin and an ADP antagonist were noted in respect of blood loss and transfusion requirements (Table 3). Bleeding and transfusion requirements increased as the length of the preoperative APT free interval decreased. All APT subgroups demonstrated higher blood loss (Fig. 3) and transfusion requirements (Fig. 4) than CON patients. The differences to CON patients, however, reached statistical significance only for Subgroup 1 (APT free <3 days), whereas the other two subgroups (APT free for 3-5 days, APT free >5 days) were not significantly different from CON patients (P ≥ 0.058), except for higher platelet requirements in Subgroup 2 (P = 0.007, Fig. 4). Additionally, the mean of CK-MBmax, measured postoperatively, was lower in all APT subgroups as compared to CON patients, proving clearly statistical significance to CON patients only for Subgroup 1 (P<3 days = 0.012), whereas the other two subgroups were weekly (P3-5 days = 0.045) or non-significantly (P>5 days = 0.090) lower than CON patients (Fig. 5).

Table 3

Table 3

Figure 3.

Figure 3.

Figure 4.

Figure 4.

Figure 5.

Figure 5.

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Discussion

The purpose of this study was to evaluate the influence of APT on postoperative bleeding and transfusion rates in patients undergoing CABG on CPB. Furthermore, it was determined if different application regimens (single or combined) or different lengths of APT free intervals, prior to surgery (<3, 3-5 and 6-7 days), affect the parameters mentioned above. We observed more chest tube drainage, and higher amounts of blood products transfused (particularly platelets) in all patients who received APT than in CON patients (without APT for at least 8 preoperative days). Differences to CON patients were significantly more pronounced for APT patients with only short APT free intervals (<3 days). The intake of an ADP antagonist, in addition to aspirin, had no further influence on bleeding and transfusion rates.

Though our results are in accordance with recent reports on the perioperative influence of APT [1,6,26] including a meta-analysis on 49 590 patients [14], some investigations denied any relation between preoperative APT and transfusion requirements. Provided that the preoperative bleeding time was normal, Rawitscher and colleagues [15] reported no association between preoperative aspirin ingestion and blood loss, which agreed with Vuylsteke and colleagues [16] also reporting no increased blood loss or transfusion requirements after recent APT with aspirin. However, only a few patients of the cohorts, examined in these studies, had received aspirin within 2 days of surgery, making a comparison to our data problematic.

When analysing blood loss and transfusion demands in CABG, the intraoperative antifibrinolytic regimen should also be taken into account. In our study, significantly more CON patients than APT patients received aprotinin, reported to be superior over tranexamic acid in decreasing intraoperative blood loss [28]. However, as shown recently in a prospective randomized trial performed in our centre [25], higher transfusion demands due to elevated blood loss were not prevented by the use of aprotinin instead of tranexamic acid. Moreover, a recent investigation of Mangano and colleagues [29], involving 4374 patients undergoing operative revascularization reported similar efficacies of aprotinin vs. tranexamic acid and aminocaproic acid in reducing blood loss. Therefore, we do not believe that the significant differences in bleeding rates and transfusion requirements observed in our study could have resulted from differences in the intraoperative antifibrinolytic regimen.

The study performed by Reich and colleagues [17] was in accordance with our data with respect to increased blood loss after preoperative APT, but could not confirm increased transfusion requirements. This may be the result of re-infusion of drained blood, which was not performed in our study.

Weightman and colleagues [30] compared the effect of different lengths of aspirin withdrawal, prior to CABG, using similar APT free intervals as performed in our study. Only patients who stopped taking aspirin <3 days had increased transfusion demands. We could confirm this finding as differences with respect to blood loss and transfusion requirements between APT and CON patients reached statistical significance only for the shortest APT free interval of less than 3 days, whereas the other APT subgroups were non-significantly higher than CON patients.

The combined intake of aspirin, along with an ADP antagonist emerged, as the standard for prevention of stent thrombosis [31-33], and is observed in an increasing number of patients presenting for CABG. Unlike others [33-36] reporting increased haemorrhages, transfusion and re-interventions upon combined APT, there were no significant differences between patients on aspirin alone, and patients taking an additional ADP antagonist in our study. This finding may be explained by the small number of patients on combined APT (n = 28) in our study, which therefore complied favourably with Hekmat and colleagues [1], also investigating a relatively small cohort of patients on combined APT (n = 29). Comparing the results of a previous study, performed in our institution in 1998 (ADP antagonists not yet available) [37], with the results of the present study, increased transfusion demands emerged until nowadays (RBCs 4.4 vs. 4.5; FFP 1.5 vs. 4.9; platelets 0.7 vs. 1.5 units), suggesting that a more aggressive APT as performed today, indeed, may increase transfusion demands, especially for platelets and FFP.

In accordance with previous investigations [8,10,12,27] but contrary to Hekmat and colleagues [1], we found higher re-exploration rates for bleeding in APT patients (8 vs. 3). The difference to CON patients, though clinically relevant, was not significant, and could change in higher study sizes. Whether transfusion of blood derivates, even when leukoreduced, provoke increased postoperative infection rates, via an immunomodulation of the recipient, is an ongoing discussion in transfusion medicine. There is evidence that the extent of transfusion-induced immunomodulation depends on the number of units transfused [38]. Due to our small study size, we are not able to draw any conclusion on transfusion-related postoperative infection rates. The only patient, however, dying from sepsis-induced multiorgan failure was a highly transfused, also very old (aged 93 yr) APT patient. The question is, whether such patients benefit from delaying surgery for at least 2-3 days to avoid increased transfusion rates, which probably intensify a latent but pre-existing immune deficient state. As reported by Vamvakas and Carven [39], the hospital stay was dependent on transfusion rate, as APT patients, receiving at least threefold more transfusions than CON patients, stayed longer in hospital for 1 day. Although not significant, this difference could become relevant when analysing cost effectiveness. In an environment with increasingly shrinking economic resources, delaying CABG for at least 2-3 days could be beneficial, if clinically possible, and outweigh the drawback of increased transfusion demands. On the other hand, our data underline the pharmacological efficacy of APT on pre- and postoperative CK-MB values, remaining significantly lower in APT patients, even in those who stopped APT until the last 5 preoperative days, but particularly in those who continued APT until surgery (≤2 days). Thus, we believe that differences in myocardial infarction rates (APT 0 vs. CON 3, P = 0.390) could become significant in larger size studies, particularly as lower perioperative infarction rates were also reported elsewhere for patients pre-treated with aspirin as compared to patients without aspirin [40]. Therefore, unlike others [41], we would not recommend that aspirin be generally discontinued 7 days preoperatively in patients undergoing elective surgery on CBP, as is fairly routine at present. It is our finding that patients who continued or shortly discontinued their APT prior to surgery had a lower incidence of postoperative myocardial infarction and lower CK-MB values. This highlights the dilemma of the clinician who has to choose the lesser of two evils: increased blood loss or increased cardiovascular events, both associated with increased morbidity and mortality. The increased use of procoagulatory drugs such as antifibrinolytics, clotting factors or platelets to further diminish blood loss, raises concern about its safety, as all of these factors (namely aprotinin, see below) are reported to significantly increase ischaemic events after operative revascularization [23]. Thus, the question, whether a brief (2-day) period of APT withdrawal, prior to CABG (possibly bridged by short-acting antiplatelet drugs such as flurbiprofen), might be safe even for patients at high risk for AMI, should be evaluated in controlled, prospective clinical trials, comparing short APT free intervals with continuous use. Because at present, only estimates can be done to further quantify the incidence of cardiovascular events after APT withdrawal, such studies are urgently needed [14]. Interestingly, among all potentially reversible factors occurring with operative revascularization, only early postoperative onset of APT (recommended within the first 6-12 h [42], as performed also in our institution, to 48 h [23]) was associated with reduced rates of death (1.3 vs. 4.0%) and ischaemic complications (AMI 2.5 vs. 5.4%, stroke 1.3 vs. 2.6% and renal failure 0.9 vs. 3.4%). In contrast to current belief, risks of haemorrhage, gastritis, infection or impaired wound healing remained unchanged [23].

Regarding potential study limitations, one should note the inhomogeneity of our study groups with respect to the antifibrinolytic regimen used. More by chance (due to the preference of the respective surgeon) than by any kind of selection, aprotinin was administered more often to CON than to APT patients (36 vs. 27, P = 0.027, Table 2). This could probably have biased blood loss, but also has accounted for the higher frequency of cardiovascular events observed with CON patients. A recent investigation, involving 3013 patients undergoing primary cardiac surgery, gave evidence that aprotinin, and not tranexamic acid, was associated with a dose-dependent multiorgan damage affecting the kidneys (doubling to tripling in the risk of renal failure), the heart (55% increase in the risk of AMI and heart failure) and the brain (181% increase in the risk of stroke or encephalopathy) [29]. Unlike tranexamic acid, aprotinin shows high affinity for the kidneys and impairs the endothelium-derived relaxation by inhibition of nitric oxide synthesis and release. Together with the inhibition of plasmin and activated protein C, this may promote formation of disseminated platelet-fibrin thrombin as shown recently upon the examination of patients who had received aprotinin [43].

In conclusion, this study has demonstrated higher bleeding and transfusion demands in APT compared to CON patients. In turn, the beneficial effect of APT on perioperative CK-MB values and infarction rates was underlined, particularly in patients with continuous treatment or only short APT free intervals (<3 days).

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                    Keywords:

                    PLATELET AGGREGATION INHIBITORS; ASPIRIN; CLOPIDOGREL; TICLOPIDINE; BLOOD TRANSFUSION; CORONARY ARTERY BYPASS; CARDIOPULMONARY BYPASS; CARDIAC SURGERY

                    © 2007 European Society of Anaesthesiology