Effect of aspirin in coronary artery bypass grafting

Effect of Aspirin in Coronary Artery Bypass Grafting Alain Vuylsteke, MD, Amo Oduro, FRCA, MRCP, Emil Cardan, MD, and Ray D. Latimer, FRCA Objectives: To evaluate the effect of aspirin (ASA) therapy on postoperative blood loss, transfusion requirements, reoperation for bleeding, duration of stay in the intensive care unit and in the hospital in a selected population undergoing a first coronary artery bypass grafting (CABG) surgery. Design: Prospective observational study in consecutive patients during a 3-month period. Setting: A teaching cardiothoracic center. Participants:Two hundred forty consecutive patients undergoing elective coronary artery bypass grafting surgery for the first time. Interventions: Two hundred forty consecutive patients admitted for a first CABG the day before surgery were visited. Patients with an abnormal routine coagulation screen or taking drugs that might have affected their coagulation mechanisms were prospectively excluded (n = 96). The date of the last dose of ASA was recorded in the

144 remaining patients, and data were acquired prospectively. Measurements and Main Results: Total mediastinal blood drainage, blood products usage, reopening, and duration of intensive care unit and hospital stay were recorded. Patients were grouped by days free of ASA. There were no significant differences detected between groups. Conclusions: In patients undergoing a first CABG and with no known factors affecting their coagulation, ASA therapy did not appear to increase blood loss, reopening for bleeding, or blood products usage requirements during the hospital stay, ASA therapy did not influence the duration of stay in intensive care or in the hospital. Copyright © 1997 by W.B. Saunders Company

SPIRIN (ASA) irreversibly acetylates cyclooxygenase and blocks the conversion of arachidonic acid to cyclic endoperoxides and their derivatives, inhibiting the production of thromboxane (TXA2) in platelets and of prostacyclin (PGI2) in the vascular endothelium. L2After maturation from megakaryocytes, platelets lose their ability to synthesize any new enzymes, including cyclooxygenase. This loss persists during their lifespan, 1,2 which is approximately 7 d a y s ) When ASA is stopped, the platelets whose cyclooxygenase has been inhibited are progressively replaced by new ones and, after 1 week, the patient has recovered a population of platelets with normal cyclooxygenase activity. Meanwhile, endothelial cells have already regained their ability to synthesize new cyclooxygenase and so to produce prostacyclin. This situation leads to an imbalance between the endothelial prostacyclin and the thromboxane produced by the platelets. Prostacyeli n acts as a vasodilator and antiaggregant, counterbalancing the effect of thromboxane, which is a vasoconstrictor and proaggregant. Therefore, it can be hypothesized that isolated production of prostacyclin might be more deleterious than the inhibition of both together. The maximum negative effect of ASA on platelet aggregation might occur a few hours or days after the last dose of ASA because of the maximum imbalance at that time. However, ASA is not the only drug currently given to patients with cardiovascular diseases that might alter the aggregation or coagulation cascades, and the use of dipyridamole, nonsteroidal anti-inflammatory agents and other platelet inhibitors is widespread. Previous studies looking at the effect of ASA on postoperative bleeding in cardiac surgery have shown either an increase in postoperative bleeding 44 or no detectable effect. 9-12 In one study, there was increased mediastinal tube drainage, but without increase in the allogeneic transfusion requirements because autotransfusion was used.13 A prospective observational study was conducted to assess the effect of ASA on the postoperative bleeding and transfusion requirements in a highly selected population undergoing coronary artery bypass graft surgery (CABG) under routine clinical practice. Other objectives were to ascertain if preoperative ASA

does affect the frequency of reopening for bleeding and the length of stay in the intensive care unit (ICU) and in the hospital.

A

KEY WORDS: cardiac surgery, aspirin, postoperative bleeding, transfusion

METHODS

After approval by the local ethical committee, all 240 patients undergoing a CABG for the first time between July and Octob m 1995 were visited on the day before surgery. All notes were reviewed, and, if no abnormality was detected in the routine clotting screen (activated partial thromboplastin time, prothrombin time, fibrinogen level and platelet count), a standard preoperative assessment was conducted. The patient was asked about all medications, including over-the-counter or nonprescribed drugs taken during the previous month. If none of the drugs listed in Table 1 had been taken during the previous month and if no coagulation problem was known, the patient was included in the study. The dose and the precise date of the last ingestion of ASA were recorded. The next day, all patients underwent CABG surgery, including the use of the left internal mammary artery graft. Standard transfusion policy was followed. All patients had their cardiopulmonary bypass (CPB) circuit primed with a crystalloid solution and membrane oxygenators were used. Standard normovolemic hemodilution was performed by the venesection of 1 U of blood at the start of surgery, which was returned after reversal of heparin. The dose of heparin was in all cases 300 IU/kg with an upper limit of 5,000 iU in the prime at the beginning of CPB. The protamine dose was 3 mg/kg in all cases, supplemented after transfusion of the blood drained from the CPB reservoir if the activated coagulation time (ACT) was raised above its preoperative value. No patient received aprotinin, desmopressin acetate, tranexamic acid, or aminocaproic acid. The day after surgery, all operative and intensive care records were reviewed. Because of hospital policy asking patients to discontinue ASA 1 week before surgery, patients were separated in two groups. One group included all patients who had ASA less than a week before surgery, and the second included all other patients. Total mediastinal blood drainage

From the Department of Anaesthesia, Papworth Hospital, Cambridge, UK. Address reprint requests to Alain Vuylsteke, MD, Department of Anaesthesia, Papworth Hospital, Cambridge, CB3 8RE, United Kingdom. Copyright © 1997 by W.B. Saunders Company 1053-0770/97/ll 07-000453.00/0

Journal of Cardiothoracic and Vascular Anesthesia, Vol 11, No 7 (December), 1997: pp 831-834

831

VUYLSTEKE ET AL

832

Table 1. Drugs Causing Patient Exclusion From Study

was 11.0 _+ 1.8 g/dL (minimum and maximum of 6.9 and 16.8 mg/dL, respective!y): A subsequent power analysis showed that the chance of detecting a'300-mL difference in total blood drainage or of 1 U of blood transfused is as high as 99.9%. However, the chance of detecting a 100-mL difference is only 50%.

Aspirin at a higher close than 325 mg Steroids NSAIDs O'~er-the-counter medications, nor prescribed drugs Unknown or unidentified drug Abbreviation: NSAID. nonsteroidal anti-inflammatory agent.

DISCUSSION

was compared between these two groups. Secondary aims were to detect a difference in the usage of blood products, or a prolonged stay in the ICU or hospital, related to the time elapsed since the last dose of ASA. Furthermore. all patients who had taken aspirin within 8 days before surgery were separated using the number of days free of aspirin as group identifier, and a Jonckheere-Terpstra test ~4 was used to detect a monotonic decrease in bleeding between these groups. Resultsare expressed as mean and standprd deviation, or percentage where appropriate. Comparisons were~conducted using either a Fisher exact test or a Wilcoxon rank sum test. The Jonckheere-Terpstra tes04 was used to test the hypothesis that there was a decrease in total blood drainage between patients grouped by number of days free of ASA. Power analyses were conducted.

In this study, preoperative ingestion of ASA did not increase the postoperative mediastinal blood drainage and the transfusion rates of blood products during the hospital stay. In addition, ASA did not affect the time of discharge from the ICU or the length of stay in the hospita !. Similarly, ASA had no effect on tlae rate of reopening of the chest for bleeding. Although a study with a much larger sample size may find a statistically significant difference in the total blood drainage related to the time elapsed since the last dose of ASA, the clinical relevance of such a finding in this reasonably homogenous group of patients is questionable. In other words, this study might not have detected a small difference between groups (type 2 error), but the difference would probably not be of clinical relevance. This study is different fi'om previous ones in several ways. First, because of the prospective inclusion of patients, it avoided the inclusion of patients under the influence of known or unknown substances that might affect the coagulation cascade or the endothelial function related to the aggregation mechanisms, or might act in synergy with ASA. Second, all patients underwent the same type of surgery under the same routine practice. Third, as the study was observational, neither the standard care nor the transfusion policy was modified for the purpose of the study. Fourth, all patients may have benefited from an autotransfusion of blood venesected before heparinization. F!nally, the first hour's mediastinal drainage was also assessed. The autologous transfusion of fresh whole blood and careful surgical hemostasis (as shown by a mean hemoglobin concentration higher than 10 g/dL on arrival in the ICU) might be reasons for these negative findings. The collection of blood intraoperatively before CPB was first reported in 1957 by Dodrill et a115 and adopted by others. ~6It has been claimed that the hemostatic effect Of 1 U of fresh whole blood is at least equal to that of I U of platelets. ~7As the activation of platclets occurs during CPB,~8 the blood venesected at the start of surgery was preserved. ASA not only inhibits the TXA2 production, but also Causes more deterioration in platelet dysfunction after CPB. 19 However,

RESULTS

Two hundred forty consecutive patients underwent first-time CABG surgery in this institution during the study period. One hundred forty-four patients fulfilied the entry criteria and were prospectively studied. No significant differences between groups wer~ observed. Table 2 gives the main characteristics of this population. Age, sex. body mass index, duration of bypass. ischemic ume. number of venous grafts, surgeon involved, and preoperative treatment were equally distributed throughout all groups. For the patients who did receive aspirin within a week of surgery, no significant correlation ~inasmuch as no monotonic trend) was found between the total blood drainage and the time elapsed since the last dose of ASA. as shown in Table 3 (p = 0.178 using the Jonckheere-Terpstra test~. Two patients had to be reopened for bleeding. One had never been treated with ASA. and the other had stopped it 4 days before. The effect of the time elapsed since the last dose of ASA on /1) units of blood transfused. (2 units of fresh frozen plasma transfused. (3) units of platelets transfused, (4) hemoglobin levels at the arrival and at discharge from ICU, as well as their differential, (5) length of stay in the ICU, and (6) length of stay in the hospital were analyzed and are reported in Table 3. There was no statistical significant difference in the studied population (p > 0.2 in all cases). Mean hemoglobin on arrival in the ICU

Table 2. Characteristics of Study Population Days Free of Aspirin

Patients (n) Age (years) Female (%) Body mass index (kg/m2) Bypass time (min) Ischemic time (rain) Numbetofvenousgrafts

~7

:>7

1

2

86 61 (8.5) 19

58 62(9.2) 19

8 62(9.9) 13

6 64(8.5) 17

27(4.8) 75.5 (21.3) 45.2 (15.1) 2.5 (1.0)

28.4(3.7) 74.4 (21.8) 44.7 (16.1) 2.3 (1.0)

27.4(2.9) 26.0(2.5) 65.6 (19.4) 75.0 (22.5) 40.0 (14.3) 42.7 (8.5) 2.3 (0.7) 1.8 (1.2)

3

4

5

6

7

8

All Patients

8 66(9.6) 25

12 60(8.1) 8

6 63(i0.2) 33

13 58(7.0) 31

33 60(8.1) 9

21 62(10.7) 14

144 61 (8.8) 19

26,6(2.7) 83.0 (15.4) 53.6 (9,8) 3.0 (1.2)

26.5(4.3) 84.9 (20.5) 50.3 (18.6) 2.9 (0,7)

31.9(5.1) 71.8 (30.3) 43.7 (20.9) 2.2 (1,0)

27.9(2.4) 76.4 (19.5) 43.9 (10.8) 2.9 (0.8)

26.1(6.3) 72.9 (22,0) 43.7 (16.1) 2.2 (1.1)

28.3(3,3) 27.6(4.5) 70.8 (17.6) 75.1 (21.4) 43.1 (13.7) 45.0 (15.4) 2.0 (0.7) 2:4 (1.0)

ASPIRIN'S EFFECT IN CABG

833

Table 3, Effect of Days Free of Aspirin on Experimental Data Days Freeof Aspirin

-<7

>7

1

2

3

4

5

6

7

8

Patients (n) 86 58 8 6 8 12 6 13 33 21 Mediastinal blood drainage (mL) 685 (327) 654 (289) 691 (181) 550 (192) 925 (489) 808 (546) 567 (168) 681 (279) 629 (231) 658 (217) Blood (U) 1.1 (1.8) 1.5 (3.2) ~1.1 (2.2) 0.3 (0.5) 2.8 (2.8) 1.3 (2.3) 0.5 (0.8) 1.0 (1,7) 0.8 (1.3) 2.4 (4.9) Fresh frozen plasma (U) 0.1 (0.6) 0.2 (0.2) 0.1 (0.4) 0 0.8 (1.8) 0.1 (0.3) 0 0 0 0 (0.2) Platelets (U) 0.2 (0.5) 0 (0.8) 0.4 (0.7) 0 0.6 (1.2) 0.3 (0.9) 0 0 0 0.4 (1.2) Hemoglobin on arrival in ICU (g/dL) 11.1 (1.8) 10.7 (1.6) 10.9 (1.9) 11.2 (0.8) 10.0 (1.2) 11.5 (2.1) 11.6 (1.4) 1i.4 (1.8) 11.1 (2.1) 10.3 (1.4) Hemoglobin on discharge from ICU (g/dL) 11.6 (1.7) 11.5 (1.9) 12.2 (1.4) 11.4 (1.0) 12.1 (2.7) 11.6 (1.3) 1"~.3(2.2) 11.5 (1.4) 11.5 (1.8) 11.1 (1.7) Patients discharged in the first 24 hours of critical care stay (%) 89 91 88 67 100 83 100 85 100 81 Length of stay in hospital/days) 9 (2.9) 9 (4.4) 10 (4.3) 8 (2.6) 10 (2.3) 9 (2.3) 9 (1.7) 8 (3.8) 8 (2.7) 9 (4.2) Abbreviation: ICU, intensive care unit.

platelet dysfunction is mostly transient and reverses within a few hours after CPB. 2°,2~ Evidence that platelet activity unrelated to T X A 2 is important in determining blood loss and allogeneic transfusion has been shown. Intraoperative plasmapheresis with reinfusion of autoiogous platelet-rich plasma postoperatively has been shown to reduce postoperative blood loss and h o m o l o g o u s transfusions, and this beneficial effect was not altered by the presence or absence of ASA. 22 Because A S A has been shown to decrease the rate o f thrombosis in the venous grafts and has been given systemati-

cally at the start o f surgery, 12,23,a4 and A S A did not significantly increase the total mediastinal blood drainage and the use o f blood products in the population studied, the rationale to stop A S A a few days before surgery 7,s should be questioned, as previously proposed. 9

ACKNOWLEDGMENT

The authors thank Per Nystr6m, MSc, for his help in statistical analysis.

REFERENCES

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platelet aggregation and increases postoperative blood loss Aprospectire. randomised, placebo-controlled, double-blind clinical trial in 100 patients with chronic stable angina. Eur J Cardiothorac Surg 8:404-409, 1994 11. Williams S, Borgstein NG, Gallandat Huet RCG: CABG, aspirin, transfusion. J Cardiovasc Anesth 3:812-813, 1989 (suppl 6) 12. Lorenz RL. Schaeky CV, Weber M, et al: Improved aortocoronary bypass patency by low-dose aspirin (100 mg daily). Effects on platelet aggregation and thromboxane formation. Lancet 1:1261-1264, 1984 13. Reich DL. Patel GC, Vela-Cantos E et al: Aspirin does not increase homologous blood requirements in elective coronary bypass surgery. Anesth Analg 79:4-8. 1994 14. Lehmann EL: Testing equality against ordered alternatives, in Lehmann EL: Nonparametrics: Statistical Methods Based on Ranks Test. San Francisco. CA, Holden-Day, 1975, pp 232-238 [5. Dodrill FD. Marshall N. Nyboer J, et al: The use of the heart-lung apparatus in human cardiac surgery. J Thorac Surg 33:60-73, 1957 16. Hallowell R Bland JHL, Buckley MJ, Lowenstein E: Transfusion of fresh autologous blood in open-heart surgery. A method for reducing bank blood requirements. J Thorac Cardiovasc Surg 64:941-948 , 1972 17. Lavee J. Martinowitz U, Mohr R, et al: The effect of transfusion of fresh whole blood versus platelet concentrates after cardiac operations. A scanning electron microscope study of platelet aggregation on extracellular matrix. J Tborac Cardiovasc Surg 97:204-212, 1989 18. de Haan J. Schonberger J, Haan J, et al: Tissue-type plasminogen activator and fibrin monomers synergistically cause platelet dysfunction

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