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Ann Thorac Surg 2005;80:149-152
© 2005 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Comparison of Two Strategies for the Management of Antiplatelet Therapy During Urgent Surgery

^a Department of Cardiothoracic Surgery, Northern General Hospital, Sheffield, United Kingdom
^b Cardiovascular Research Group, University of Sheffield, Sheffield, United Kingdom

Accepted for publication January 3, 2005.

^_* Address reprint requests to Dr Cooper, Northern General Hospital, Herries Rd, Sheffield, United Kingdom S57AU (Email: graham.cooper{at}sth.nhs.uk).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment References

 
BACKGROUND: The optimal management of aspirin and clopidogrel therapy before surgery in patients with acute coronary syndrome is uncertain. Aspirin and clopidogrel within 5 days of surgery increases postoperative bleeding and reexploration. However, in acute coronary syndrome patients the risk of bleeding must be balanced against the risks of discontinuing the treatment and delaying surgery.

METHODS: From June 2002 to July 2003, patients undergoing urgent coronary artery bypass graft surgery (CABG) for acute coronary syndrome were randomly assigned to one of two groups. The treatment group remained on aspirin and clopidogrel therapy till surgery, receiving intraoperative aprotinin. The placebo group received placebo for 5 days before surgery and received placebo infusions intraoperatively. Platelet reactivity in response to adenosine diphosphate was assessed by whole blood single-platelet counting. Of the 88 patients eligible, 50 entered the study.

RESULTS: Postoperative blood loss was significantly greater in the placebo group than in the treatment group (702 ± 120 mL versus 446 ± 62 mL, p = 0.004). This difference was observed as early as 8 hours postoperatively (385 ± 66 mL versus 266 ± 36 mL, p = 0.03). Patients in the placebo group also required more blood transfusions (1 ± 0.3 units versus 0.3 ± 0.2 units, p = 0.03). Three patients in each group underwent surgical reexploration for bleeding.

CONCLUSIONS: The strategy of continuing aspirin and clopidogrel therapy with intraoperative aprotinin reduces postoperative blood loss, transfusion requirements, prevents delay to surgical treatment, and may prevent major adverse cardiac events before surgery.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment References

 
In patients with acute coronary syndrome, addition of clopidogrel to conventional therapy, including aspirin within 24 hours of the onset of symptoms, decreases death from cardiovascular causes, nonfatal myocardial infarction, and stroke [1–3]. However, in patients with acute coronary syndrome who require in-house urgent surgery, whether to continue or discontinue aspirin and clopidogrel therapy before surgery is uncertain. Continuing preoperative antiplatelet therapy increases bleeding and reexploration after CABG surgery by as much as 10-fold [4–7]. This must be balanced against the risks of stopping antiplatelet therapy and delaying surgery.

Traditionally, the approach taken has been to stop aspirin and clopidogrel therapy for at least 5 days before surgery. This approach is supported by data from the CURE trial (Clopidogrel in Unstable Angina to Prevent Recurrent Ischaemic Events) [1]: in 910 patients in whom clopidogrel therapy was stopped more than five days before surgery, there was no evidence of major bleeding after surgery; in the 912 patients who stopped clopidogrel therapy within 5 days before CABG surgery, there was a trend toward an increase in major bleeding after CABG surgery (9.6% of patients in the clopidogrel group versus 6.3% in the placebo group, p = 0.06) [1].

An alternative approach might be to continue antiplatelet therapy preoperatively and treat the patient intraoperatively with aprotinin, which decreases bleeding after cardiac surgery [8]. In this study, a prospective, randomized, double-blind comparison of these two treatment strategies was performed. The primary aim was to assess the effect of either strategy on postoperative blood loss and blood transfusion requirements.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment References

 
The local Ethics Committee approved the study, and all patients gave written informed consent. Patients admitted with acute coronary syndrome requiring in-house urgent CABG with cardiopulmonary bypass surgery were considered for inclusion. Acute coronary syndrome was defined as patients with unstable angina or non–ST-segment elevation myocardial infarction (no ST-segment elevation but a serum troponin T level greater than 0.1 ng/mL) [2, 3]. Patients were recruited at the time of initial referral for surgery by two investigators (V.S., E.A.). The exclusion criteria were patients in whom CABG was performed less than 5 days of the decision to operate, impaired renal function, warfarin therapy, and other coagulopathies.

Simple randomization using sealed opaque envelopes to either group was performed by the pharmacy department, which also prepared and dispensed all medication. All clinicians, supporting staff, and investigators were masked to the groups to which each patient was allocated.

The treatment group continued clopidogrel and aspirin therapy till surgery; mean duration of treatment before surgery was 17 ± 4 days. The placebo group had both antiplatelet drugs discontinued 5 days before surgery (Fig 1). All patients continued to receive intravenous heparin, which was discontinued 30 minutes before surgery.

View larger version (33K): [in this window] [in a new window]   Fig 1. Treatment protocols for patients. (CPB = cardiopulmonary bypass; STEMI = ST-segment elevation myocardial infarction.)

The use of blood products and the decision to reexplore patients was not governed by any protocols. These products were not used prophylactically, but were only given after excessive postoperative bleeding.

In 10 consecutive patients, blood samples taken 60 minutes, and 4 hours and 24 hours postoperatively were analyzed immediately using whole blood single-platelet aggregometry in response to adenosine diphosphate (ADP [0.3, 1, 3, 10, and 30 µmol/L]) [9].

Dichotomous data was assessed with a Fisher exact test, normally distributed continuous data with an unpaired Student t test, and continuous data with a nonnormal distribution with a Mann-Whitney U test. Platelet aggregation was compared using two-way analysis of variance.

	Results

Top Abstract Introduction Patients and Methods Results Comment References

 
From June 2002 to July 2003, 935 isolated CABG procedures were performed, of which 88 (9.4%) were eligible for inclusion. In 11 patients, CABG was performed less than 5 days of the decision to operate, and these patients were excluded. Other exclusion criteria included impaired renal function (3), warfarin therapy (3) and other coagulopathies (2). Of the remaining 69 patients, 19 (28%) did not consent to partake in the study, leaving 50 patients who were randomized. The 19 patients who were not randomized were treated according to the preference of individual surgeons.

In the 5 days before surgery, 3 patients in the placebo group, compared with none in the treatment group, suffered a myocardial infarction (MI). One patient had an ST-segment elevation MI and 2 patients, a non–ST-segment elevation MI.

There were no differences between the two groups in preoperative or intraoperative details (Table 1). Postoperative blood loss at 8 hours and at the time of chest tube removal was significantly greater in the placebo group than the treatment group. The duration of chest tube drainage was greater in the placebo group. Patients in the placebo group received more blood transfusions compared with those in the treatment group. Three patients in each group underwent surgical reexploration for bleeding. There were 2 deaths in the treatment group, 3 and 6 days postoperatively, due to embolic intestinal ischemia (Table 2).

View larger version (14K): [in this window] [in a new window]   Fig 2. Percentage platelet aggregation assessed by whole-blood single-platelet counting in response to adenosine diphosphate (ADP) 0.3 to 30 µmol/L, comparing placebo group patients (n = 5; solid line) and aprotinin treatment group patients (n = 5; dashed line) at (A) 1 hour, (B) 4 hours, and (C) 24 hours postoperatively. Data are mean ± SEM. For all three time points, platelet aggregation was significantly impaired in the treatment group: p = 0.005, p < 0.001, and p < 0.001, respectively, for the three time points.

	Comment

Top Abstract Introduction Patients and Methods Results Comment References

The use of aprotinin is essential. Impaired platelet reactivity to ADP, specifically indicating a persisting effect of clopidogrel, was evident up to 24 hours postoperatively in the treatment group. Despite this, these patients bled less owing to the antifibrinolytic effect of aprotinin. In a recent study, clopidogrel therapy within 7 days of elective CABG resulted in increased blood loss, use of blood products, and a 10-fold increase in reexploration rates. These patients had received no intraoperative aprotinin [6]. Aprotinin may also prevent CPB induced platelet activation, an effect which has recently been demonstrated clinically in vivo and may reduce the inflammatory reaction to CPB [10–12]. Two patients in the treatment group that received aprotinin died from intestinal ischemia caused by emboli. The concern that aprotinin may increase postoperative thromoboembolism particularly in bypass grafts has previously been raised but is not supported by any available data [13].

Three patients per group were reexplored for bleeding. Most reexplorations occurred early in the study; 4 of the first 10 patients randomized were reexplored. Although the multiple clinicians involved agreed that this was a very important question to answer, there was a recognition that either strategy may lead to an increase in blood loss. We believe that this anxiety along with the fact that clinicians were blind to the treatment group of the patient led to an initial decrease in the threshold for reexploration. This would explain why 4 of the 6 reexplorations occurred early in the study, and is supported by the fact that in the 19 patients not included in the study, 15 received aspirin and clopidogrel therapy till surgery with intraoperative aprotinin. No patients were reexplored in this group.

Two further treatment strategies could have been included in our study. We did not include a group consisting of patients not on aspirin and clopidogrel but treated with aprotinin intraoperatively, on the basis that multiple studies have established the efficacy of aprotinin in reducing blood loss in this setting [8, 14]. Also some concern exists that in the absence of an increased risk of bleeding, aprotinin may affect graft patency [11, 15]. We did not include a group of patients taking clopidogrel and aspirin till surgery without intraoperative aprotinin, because increased blood loss and reexploration when this strategy is used is established [6].

In conclusion, for patients with acute coronary syndrome having urgent CABG, a strategy of continuation of aspirin and clopidogrel therapy before surgery, coupled with intraoperative use of aprotinin, may be adopted. In view of the deaths due to embolism, further investigation in a larger trial is warranted. Nevertheless, this strategy leads to a reduction in postoperative bleeding and blood transfusions, prevents delay to surgical treatment, and may prevent major adverse cardiac events before surgery.

	References

Top Abstract Introduction Patients and Methods Results Comment References

 

1. The Clopidogrel in Unstable Angina to prevent Recurrent Ischaemic Events Trial InvestigatorsEffects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.[Abstract/Free Full Text]
2. British Cardiac SocietyGuideline for the management of patients with acute coronary syndromes without persistent ECG ST segment elevation. Heart 2001;85:133-142.[Free Full Text]
3. ACC/AHA ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarctionexecutive summary and recommendations. Circulation 2000;102:1193-1209.[Free Full Text]
4. Ferraris VA, Ferraris SP, Joseph O, et al. Aspirin and postoperative bleeding after coronary artery bypass grafting Ann Surg 2002;235:820-827.[Medline]
5. Genoni M, Tavokoli R, Hofer C, et al. Clopidogrel before urgent coronary artery bypass graft J Thorac Cardiovasc Surg 2003;126:288-289.[Free Full Text]
6. Hongo RH, Ley J, Dick SE, et al. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting J Am Coll Cardiol 2002;40:231-237.[Abstract/Free Full Text]
7. Yende S, Wundering RG. Effect of clopidogrel on bleeding after coronary artery bypass surgery Crit Care Med 2001;29:2271-2275.[Medline]
8. Casati V, Guzzon D, Oppizzi M, et al. Tranexamic acid compared with high-dose aprotinin in primary elective heart operationseffects on perioperative bleeding and allogeneic transfusions. J Thorac Cardiovasc Surg 2000;120:520-527.[Abstract/Free Full Text]
9. Storey RF, Heptinstall S. Laboratory investigation of platelet function Clin Lab Haematol 1999;21:317-329.[Medline]
10. Poullis M, Manning R, Laffan M, et al. The antithrombotic effect of aprotininactions mediated via the proteaseactivated receptor 1. J Thorac Cardiovasc Surg 2000;120:370-378.[Abstract/Free Full Text]
11. Landis RC, Haskard DO, Taylor K. New antiinflammatory and platelet-preserving effects of aprotinin Ann Thorac Surg 2001;72(Suppl):S1808-S1813.[Abstract/Free Full Text]
12. Day JR, Punjabi PP, Randi AM, Haskard DO, Landis RC, Taylor KM. Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery Circulation 2004;110:2597-2600.[Abstract/Free Full Text]
13. Westaby S, Katsumata T. Aprotinin and vein graft occlusion––the controversy continues J Thorac Cardiovasc Surg 1998;116:731-733.[Free Full Text]
14. Laupacis A, Ferguson D. Drugs to minimize perioperative blood loss in cardiac surgerymeta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) investigators. Anesth Analg 1997;85:1258-1267.
15. Lass M, Simic O, Ostermeyer J. Re-graft patency and clinical efficacy of aprotinin in elective bypass surgery Cardiovasc Surg 1997;5:604-607.[Medline]

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Enoch Akowuah Vivek Shrivastava David Hopkinson Peter Braidley Graham Cooper Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Akowuah, E. Articles by Cooper, G. Search for Related Content PubMed PubMed Citation Articles by Akowuah, E. Articles by Cooper, G. Related Collections Extracorporeal circulation