Asian Cardiovasc Thorac Ann 2000;8:315-321
© 2000 Asia Publishing EXchange Pte Ltd
Preoperative Cholesterol and Thrombotic Complications After Coronary Bypass
Jan T Christenson, MD
Department of Cardiovascular Surgery and Cardiology
Hôpital de la Tour
Geneva, Switzerland
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For reprint information contact: Jan T Christenson, MD Tel: 41 22 372 7872 Fax: 41 22 372 7634 email: jtchristenson{at}hotmail.com Department of Surgery, Clinic for Cardiovascular and Thoracic Surgery, University Hospital, rue Micheli-du-Crest 24, Geneva 14 CH-1211, Switzerland.
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Abstract
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The relationship between preoperative lipid status and postoperative thrombocytosis was evaluated in 130 patients who were grouped according to their preoperative serum cholesterol level: group A, cholesterol 
6.2 mmol•L–1 (n = 40); group B, cholesterol < 6.2 but 5.2 mmol•L–1 (n = 22); group C, cholesterol < 5.2 but 4.7 (n = 18); and group D, cholesterol < 4.7 mmol•L–1 (n = 50). Patient demo-graphics, angiography findings, and operative data did not differ between the groups. The incidence of postoperative thrombocytosis (platelet count 400,000/µL) was 82.5%, 36.4%, 16.7%, and 2.0% for groups A to D, respectively. Patients who developed thrombocytosis had a significantly higher preoperative ratio of total cholesterol to high-density lipoprotein cholesterol than those with normal platelet counts. The incidence of thrombocytosis directly correlated with the preoperative total cholesterol level. A distinct separation point seems to be a total cholesterol level of 4.7 mmol•L–1. Preoperative lipid control with statins is emphasized to avoid postoperative thrombocytosis and thrombotic complications. The total cholesterol/high-density lipoprotein cholesterol ratio seems to be the best indicator of the risk of developing postoperative thrombocytosis.
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Introduction
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Major surgical procedures including cardiac surgery, are known to be followed by altered platelet behavior. A decrease in platelet count during cardiopulmonary bypass (CPB) has been well documented.1 This decrease is due to dilution, platelet destruction, and adhesion (heparinization and platelet sequestration), which can result in thrombocytopenia and platelet dysfunction and lead to postoperative hemorrhage. Following the initial decrease in platelet count, a pronounced increase in both platelet count and platelet adhesiveness has been noted. Marked post-CPB thrombocytosis (platelet count 400,000/µL) was found in 20% to 30% of patients undergoing coronary artery bypass grafting (CABG), and it was associated with a significant increase in late throm-botic complications such as vein graft occlusion and myocardial ischemia and infarction.2,3 The only common denominator found in patients who subsequently developed postoperative thrombocytosis was serum lipid disturbance, especially hypercholesterolemia.3 Patients with hyper-cholesterolemia have increased cholesterol in the platelet membrane, which may increase platelet sensitivity to aggregation agents.4,5 Low-density lipoprotein (LDL) mo-dification by CPB increases thrombogenicity by activating platelets and interfering with the fibrinolytic system.6
High serum cholesterol is regarded as the main cause of coronary arteriosclerosis. Dietary changes and the use of drugs if necessary, to reduce cholesterol concentrations (specifically, LDL-cholesterol) have been recommended. Statins, resins, and nicotinic acid are effective in lowering LDL-cholesterol.7 Lipid control with simvastatin for 4 weeks preoperatively in patients with serum cholesterol levels 6.2 mmol•L–1 significantly reduced postoperative thrombocytosis.8 The aim of this study was to establish the cholesterol level at which preoperative lipid-lowering therapy would be indicated to obtain optimal effects on post-CABG platelet dysfunction and thrombotic com-plications.
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Patients and Methods
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The study was undertaken between November 1997 and April 1998. All adult patients with coronary artery disease who underwent CABG were included in the study. Informed consent was obtained and the study was approved by the ethics committee on human research, "Commission d'Ethique", Geneva, Switzerland (ref. no. 97-19). The study was also approved and registered by the Office Intercantonal de Contrôle des Médicaments, Berne, Switzerland (ref. no. 1997S02368). Patients with a total serum cholesterol 6.2 mmol•L–1 were randomly assigned to undergo preoperative lipid-control treatment with simvastatin (Zocor; MSD, Glattbrugg, Switzerland) over a period of 4 weeks preoperatively, or remain untreated; these results have been reported earlier.8
In this study, all patients who did not receive preoperative lipid-control treatment with simvastatin were divided into 4 groups according to their preoperative total serum cholesterol level. A serum lipid profile including total serum cholesterol, high-density lipoprotein (HDL) cholesterol, LDL-cholesterol, triglyceride, apolipoprotein A-I, and lipoprotein(a), as well as platelet counts and platelet function were analyzed initially. Serum lipid analyses were repeated frequently during the postoperative period. All patients received postoperative anticoagulants for 6 weeks (heparin, warfarin) with a target partial thromboplastin time greater than 40 seconds.
In all cases, a platelet count was performed preoperatively and on a daily basis until hospital discharge. Mean platelet volume, platelet distribution width, plasminogen, fibrino-gen, and platelet adhesiveness were measured pre-operatively and on the 7th postoperative day. Serum hemo-globin, hematocrit, white blood cell count, urea, creatinine, creatine kinase (CK) and CK-MB fractions were monitored on a regular basis together with electrocardiograms, throughout the postoperative period. Angiography was not routinely performed during the early postoperative period. All preoperative clinical and catheterization data, operative data, and postoperative complications were entered into a computer database at the time of hos-pitalization. The left ventricular ejection fraction was calculated from the preoperative ventriculography. All other interventions and procedures were standardized and remained the same for all patients in each of the 4 groups.
Definitions
All definitions were made before the start of the study and were not altered during the study period. Postoperative myocardial infarction was defined as the appearance of new Q waves or significant loss of R wave, together with peak CK-MB levels greater than 10% of the total CK. Gastrointestinal complications comprised any gastrointes-tinal complications diagnosed. Transient renal failure was recorded when the serum urea was 9 mmol•L–1 and serum creatinine 125 µmol•L–1 in a patient with normal preoperative values. A neurologic event was any new neurologic event not present preoperatively. Postopera-tive thrombocytosis was defined as platelet counts 400,000/µL on consecutive daily measurements.
There were 130 patients who had not received lipid-lowering therapy preoperatively. They were grouped according to their preoperative total serum cholesterol level: group 1, cholesterol 6.2 mmol•L–1 (n = 40); group 2, cholesterol 5.2 mmol•L–1 (n = 62); group 3, cholesterol 4.7 (n = 80); and group 4, cholesterol < 4.7 mmol•L–1 (n = 50). By this type of grouping, a patient in groups 1 to 3 could contribute to more than one group. In a second set of analyses, the patients were separated into the following groups based on arbitrarily chosen intervals of preoperative cholesterol level: group A (total serum cholesterol 6.2 mmol•L–1, n = 40); group B (cholesterol < 6.2 but 5.2 mmol•L–1, n = 22); group C (cholesterol < 5.2 but 4.7 mmol•L–1, n = 18); and group D (cholesterol < 4.7 mmol•L–1, n = 50).
The mean age was 62.5 ± 11.0 years, with no statistically significant group differences. Sex distribution and pre-operative risk factors did not differ between the groups (Table 1
). Preoperative serum lipid profiles (Table 2) revealed a lower total cholesterol level and a lower ratio of total cholesterol to HDL-cholesterol (C/HDL-C) in group D compared to the other groups (A to C). All other preoperative laboratory data showed no significant group differences. Preoperative angiography gave a mean left ventricular ejection fraction of 0.51 ± 12 for group 1, 0.50 ± 0.12 for group 2, 0.49 ± 0.11 for group 3, and 0.53 ± 0.15 for group 4 (no statistically significant differences). In 83% of patients (108/130), there was triple-vessel coronary artery disease, and 22% (29/130) had left main coronary artery stenosis > 70%, with no group differences.
Anesthesia, CPB, surgical techniques, and postoperative treatment were standardized throughout the study period. Three independent surgeons who were unaware of the patient's group, performed all operations. Myocardial revascularization was carried out under normothermic CPB (35°C to 37°C). Myocardial protection was achieved by intermittent infusion of cold crystalloid cardioplegic solution (St. Thomas' Hospital no. 2) with addition of 100 mg allopurinol, and topical hypothermia using ice slush. All operations were performed through a median sternotomy and a cell-saving device was routinely used. The internal thoracic artery, harvested as a pediculated graft, was used in 86% of patients (112/130), and a sequential vein bypass was used in 78% (101/130). Coronary artery thromboendarterectomy was performed in 7 patients (5%). No other arterial grafts were used in this series. On average, patients received 3.7 ± 1.3 distal anastomoses. Ischemic time was 63.1 ± 27.5 minutes and CPB time was 78.4 ± 30.2 minutes. None of the operative parameters showed statistically significant differences between the groups.
All statistical analyses were performed using StatView version 4.5 (Abacus Concepts, Berkeley, CA, USA) computer software. Student's t test (one-sample paired test), the Mann-Whitney U test, and Fisher's exact test were employed where appropriate, to assess differences between groups for statistical significance. The Dubin-Watson statistic was used for analysis of correlation. A probability level of p less than 0.05 was regarded as significant. Data are presented as mean ± standard deviation for continuous variables.
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Results
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There was no hospital death nor any incidence of septicemia, mediastinitis, or wound infection during the study period. Postoperative low cardiac output including the need for intraaortic balloon pump support, early myocardial infarction (within 7 postoperative days), and pulmonary complications were equally distributed between the groups (Table 3). Hemorrhage, neurological events, and gastrointestinal complications occurred rarely and without group differences (Table 3). Late myocardial infarction (beyond 7 postoperative days) was more frequently diagnosed in groups 1 to 3 than in group 4 (Table 3) and it had a good correlation with the pre-operative total cholesterol level, r = 0.99. A similar trend was observed for the incidence of postoperative transient renal failure (Table 3) and there was a statistically significant difference between groups 1 and 4. Post-operative thrombocytosis occurred in 33 patients in group 1 (83%), 41 in group 2 (66%), 44 in group 3 (55%), and in only 1 patient in group 4 (2%), r = 0.96. There was no correlation between triglyceride and apolipoprotein A-I levels and the degree of postoperative thrombocytosis, or between CPB time and thrombocytosis.
Analysis of patients grouped according to the arbitrary preoperative cholesterol intervals revealed no differences between the groups with regard to preoperative demo-graphics, angiography findings, or operative data. The preoperative lipid profile revealed, as expected, generally lower lipid values (total cholesterol and LDL-cholesterol) for group D, with a gradual increase towards group A (Table 2
). Postoperative complications did not differ between the groups, except for possible thrombotic complications such as late myocardial infarction (diag-nosed beyond 7 postoperative days) and transient renal failure, and were comparable to the findings described in Table 3. The incidence of postoperative thrombocytosis in relation to C/HDL-C and late myocardial infarction can be seen in Table 4. Patients without postoperative thrombocytosis in groups A to C had markedly fewer thrombotic complications compared to those with throm-bocytosis. While there was a perfect correlation between the total serum cholesterol level and thrombocytosis (r = 0.95) and late postoperative myocardial infarction (r = 0.92), no such relationship could be detected between LDL-cholesterol levels and outcome parameters. It was only in group C that a significantly lower LDL-cholesterol level could be calculated, 3.49 ± 0.13 mmol•L–1 (in the 3 patients with postoperative thrombocytosis) compared to 2.86 ± 0.33 mmol•L–1 (in the other 15 patients without postoperative thrombocytosis), p < 0.0001. In groups A and B, there were no statistically significant differences: 4.32 ± 0.47 mmol•L–1 (n = 33) versus 4.51 ± 0.48 mmol•L–1 (n = 7), p = 0.762 for group A; and 3.74 ± 0.57 mmol•L–1 (n = 14) versus 3.89 ± 0.54 mmol•L–1 (n = 8), p = 0.772 for group B. In group D, the number of observations was too small to allow a meaningful comparison.
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Table 4. Postoperative Thrombocytosis and Preoperative Serum Cholesterol, Late Myocardial Infarction, and Transient Renal Failure (Groups A to D)
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When comparing postoperative outcome parameters for patients who initially had total cholesterol 6.2 mmol•L–1 but were successfully brought under control by simvastatin therapy for 4 weeks preoperatively (as reported previously) with group D from the present study (preoperative cholesterol, < 4.7 mmol•L–1), no statistically significant differences were detected.8 The incidence of postoperative thrombocytosis in group D (1/50 patients, 2.0%) was comparable to that of patients with preoperative lipid control (1/40 patients, 2.5%). There were no late myocardial infarctions in either group. Transient renal failure occurred in 3/40 patients (7.5%) with preoperative lipid control and in 1/50 (2.0%) of group D. Values of C/HDL-C were lower in group D (3.7 ± 0.9) compared to patients with preoperatively controlled hyperlipidemia (4.1 ± 0.9) but did not reach statistical significance. One patient in the simvastatin group and one in group D developed postoperative thrombocytosis; they both had relatively high C/HDL-C (5.5 and 5.6, respectively).
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Discussion
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Serum levels of total cholesterol and LDL-cholesterol have been recognized as important risk factors for coronary artery disease.9 Since platelets contribute actively to the thrombotic progress, they may also play an important role in the progress of arteriosclerotic vascular disease.10 Postoperative thrombocytosis is associated with a signifi-cantly increased risk of thrombotic complications such as early bypass graft occlusion and myocardial infarction.2,3,11 The common denominator in patients developing post-operative thrombocytosis is uncontrolled preoperative hyperlipidemia, especially hypercholesterolemia.2 There is a clear link between serum lipids and platelet function, particularly following surgery.4,5 Increasing evidence indicates that atherogenicity of lipids and lipoproteins is related to modifications such as oxidative, enzymatic, and physical alterations of these molecules.6,7,12 In clinical practice, lipid control in patients with symptomatic cardio-vascular disease is unacceptably poor, despite national and international recommendations on the benefits of such preventive measures.8,13 Large multicenter studies have demonstrated the positive impact of lipid control on both mortality and morbidity, and yet we experience large numbers of patients presenting for myocardial revascular-ization with inadequate or complete lack of control of a pathologic lipid profile.14–17 Statins are effective in lowering both total and LDL-cholesterol levels.7 Beside their lipid-lowering effect, the natural statins also have several non-lipid mechanisms such as modification of endothelial function, suppression of inflammatory responses, plaque stabilization, and inhibition of platelet aggregation.18–20
In a recent prospective randomized study, it was demon-strated that a 4-week simvastatin treatment achieved preoperative lipid control in patients undergoing elective CABG.8 It was also shown that the incidence of post-operative thrombocytosis and cardiac events was signifi-cantly reduced compared to controls, suggesting a direct platelet effect of simvastatin.8 A limitation of that study was that all patients had initial total serum cholesterol levels 6.2 mmol•L–1, which might be too high to start treatment in cases of established coronary artery disease, as suggested by others.7
This study was undertaken to establish the most suitable total cholesterol level for initiating lipid-lowering therapy in such patients. As time for treatment was limited, drug therapy with a statin was used. Except for differences in serum lipids, the study population was homogeneous in respect of demographic, angiographic, and operative data. There was a clear linear correlation between preoperative total cholesterol levels and postoperative thrombocytosis, as well as a correlation between preoperative cholesterol levels and the incidence of thrombotic complications. Other risk factors such as diabetes might affect the incidence of thrombotic complications, but this study failed to distinguish their importance as independent risk factors, in agreement with previous findings.8 Furthermore, the results suggest that the best preoperative indicator for postoperative thrombocytosis is C/HDL-C. All patients with postoperative thrombocytosis had C/HDL-C > 5, including the single patient with postoperative throm-bocytosis in group D. The outcome parameters for group D did not differ in any aspect from those reported earlier in patients who had preoperative lipid control with simvastatin.9 This suggests that preoperative therapy with simvastatin in patients with total cholesterol > 4.7 mmol•L–1 would be justified and should substantially reduce the risk of developing postoperative thrombo-cytosis, thus lowering the risks of early graft failure, myocardial infarction, and transient renal impairment. Long-term follow-up is pending.
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Acknowledgments
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This study was supported by a grant from Merck, Sharp & Dohme-Chibret SA, Glattbrugg, Switzerland.
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References
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Abstract
Introduction
