A randomized, double-blind, placebo-controlled trial of a COX-2 inhibitor (Rofecoxib) in patients undergoing coronary artery bypass surgery
http://www.100md.com
《血管的通路杂志》
a Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074 and the Heart Institute at National University Hospital, Singapore
b Biostatistics Unit, Faculty of Medicine, National University of Singapore
Abstract
The endothelium of patients with coronary artery disease shows increased expression of cyclooxygenase-2 (COX-2) during coronary artery bypass graft surgery (CABG) using cardiopulmonary bypass. This, together with serotonin, may lead to coronary microvessel spasm, which potentially, can contribute to myocardial ischemia and injury after surgery. We performed a randomized, double-blind, placebo-controlled trial in patients undergoing isolated CABG to determine whether short-term treatment with a selective COX-2 inhibitor, Rofecoxib (25 mg), given preoperatively and for 5 days after operation, can offer better myocardial protection in patients undergoing CABG by measuring serial cardiac troponin T (cTnT) levels. The study was powered to recruit 150 consecutive patients undergoing isolated CABG but the study was terminated prematurely by the worldwide withdrawal of rofecoxib. There were highly statistically significant (P<0.001) increases in cTnT in both groups at each time point (1, 6, 24 and 48 h after onset of cardiopulmonary bypass) compared to preoperative levels. cTnT levels were similar at all post-operative time points between the 2 groups. There is no evidence that short-term treatment with rofecoxib has a myocardial protective effect in patients undergoing CABG. There is also no evidence that its effect is deleterious to the myocardium in patients undergoing CABG.
Key Words: Cyclooxygenase-2; Myocardial protection
1. Introduction
Specific biochemical markers demonstrate that some degree of myocardial injury is an inevitable consequence of cardiac operations [1]. The pathophysiology of operative myocardial injury is complex and results from a combination of direct trauma from surgical manipulation and myocardial ischemia due to inadequacies in cardioprotection and coronary thrombosis, ischemia-reperfusion injury [2], the systemic inflammatory response syndrome [3] and altered vasomotor regulation [4] and coronary artery spasm [5]. Platelet activation occurs at the sites of coronary stenoses and endothelial injury and may be associated with serotonin release [6], which has been implicated in contributing to vasoconstriction in patients with coronary artery disease. Cyclooxygenase (COX)-2 is expressed in the endothelium of patients with coronary artery disease. This expression is enhanced in the reperfusion phase following blood cardioplegia during coronary artery bypass graft surgery (CABG). Consequently, prostaglandin release (likely thromboxane A2) is stimulated which then activates the contractile response of coronary arterioles to serotonin. This may lead to coronary microvessel spasm, which potentially, can contribute to myocardial ischemia and injury after surgery [7].
The aim of this study was to examine whether short-term treatment with a selective COX-2 inhibitor, Rofecoxib, has a protective effect on the myocardium during CABG by assessing serial measurements of cardiac troponin T (cTnT).
2. Patients and methods
The Hospital Ethics Committee approved this study, and written informed consent was obtained from all patients. This was a prospective, randomized, double blind, placebo-controlled trial performed at the Heart Institute at National University Hospital, Singapore between October 2002 and October 2004. Patients were randomized according to a list of random treatment codes generated by a biostatistician (Y.H.C.) using a block design. Patients were sequentially assigned to pre-packed treatments (Rofecoxib 25 mg or placebo) to be administered orally at least 4 h before CABG and daily thereafter for 5 days.
The inclusion criteria for the study included patients undergoing first-time isolated coronary artery bypass grafting. Exclusion criteria included allergy to COX-2 inhibitors, patients with renal impairment (serum creatinine >120 μmol/l) or a previous history of peptic ulcer disease. The study was discontinued for patients who developed renal impairment (post-operative serum creatinine level 177 μmol/l) [8] or clinical signs of gastrointestinal bleed after CABG. Recruited patients who underwent coronary endarterectomy were also excluded from further analysis.
Two surgeons (P.S.W. and C.N.L.) performed all the operations. Cardiopulmonary bypass was performed with nonpulsatile flow with a pump flow rate of 2.4 l·m2·min at moderate hypothermia with the temperature allowed to drift to 32 °C. Cold blood cardioplegia was used for myocardial protection. The left ventricle was vented through the right superior pulmonary vein. A membrane oxygenator and a roller pump were used with a 40-μm arterial line filter. Patients were managed using standardized intensive care protocols. All patients received aspirin 200 mg given through the nasogastric tube 4 h after surgery and clopidogrel 75 mg once a day was given thereafter. Patients were also given oral omeprazole 20 mg twice daily for the duration of the study. Blood samples were collected for analysis of cTnT.
Our aim was to assess serial measurements of cTnT preoperatively and at 1, 6, 24, and 48 h after the onset of cardiopulmonary bypass. Additionally, postoperative complications were also analyzed. In this study, cTnT levels higher than 3.4 μg/l 48 h was used to diagnose perioperative myocardial infarction (PMI) [9]. Electrocardiographic criteria for the diagnosis of PMI were based on new Q wave formation, loss of R wave progression or new permanent left bundle branch block.
All analyses were performed using SPSS version 12. For quantitative data, 2 sample t-test will be applied when normality (checked using Komologrov Smirnov 1 Sample test) and homogeneity assumptions were satisfied otherwise the equivalent non-parametric Mann–Whitney U-test will be applied. Associations of categorical outcomes with treatments will be assessed using Chi-square or Fisher's exact tests with odds ratios presented where applicable. Statistical significance was set at P<0.05 and Bonferroni adjustment for type I error was performed when multiple comparisons (for each post-operative time point) were carried out. Anticipating a mean (S.D.) clinical difference of 0.1 (0.2) μg/l for cTnT, 150 subjects (to be randomized equally to placebo or rofecoxib) will be required for a power of 80% and a 2-sided test 5% to achieve a significant result.
3. Result
Between October 2002 and October 2004, there were 264 isolated CABG performed. The trial recruitment process is outlined in Fig. 1. One hundred and fifty-seven patients were not enrolled because of refusal to participate (n=80 patients), renal impairment (n=39) and history of peptic ulcer disease (n=38 patients). One hundred and seven subjects were randomized (53 rofecoxib, 54 placebo). Twelve patients did not complete the study (Fig. 1). A further 19 patients who had undergone coronary endarterectomy and had elevated preoperative cTnT levels were also excluded from further analysis.
As shown in both Tables 1 and 2, the 2 groups were well matched with respect to the characteristics shown. There was 1 death within 7 days in the active group. The patient died of sudden hemorrhage from the proximal anastomotic site of the aorto-saphenous vein graft from sudden severe hypertension on the second postoperative day after an uneventful CABG. The mean number of grafts, internal mammary artery usage rate, cardiopulmonary bypass time, myocardial ischemia time, duration of postoperative ventilation and postoperative hospital stay were not significantly different in the 2 groups. There were also no significant differences in postoperative complications listed in Table 2.
There were highly statistically significant (P<0.001) elevations in cTnT levels in both groups at each time point compared to pre-operative levels. However, cTnT levels were similar at all post-operative time points between the 2 groups (Fig. 2). The peak increase in cTnT was at 6 h after onset of cardiopulmonary bypass.
4. Discussion
The use of COX-2 inhibitors in cardiovascular disease has been highly controversial and its safety has been questioned [10]. Rofecoxib, a selective COX-2 inhibitor, has recently been withdrawn after the trial APPROVe (Adenomatous Polyp Prevention on Vioxx) showed an adverse cardiovascular side-effect profile. Another study comparing several pain-relief regimes following CABG noted that adverse cardiovascular events were significantly more common among parecoxib/valdecoxib recipients than among double-placebo recipients [11].
COX-2 is expressed in atherosclerotic vessels but not in normal arteries [12]. Enhanced COX-2 expression by endothelial cells increases the production of prostaglandin I2 (PGI2) over thromboxane A2 (TXA2). Thus, inhibition of COX-2 blocks PGI-2 formation without inhibiting platelet-derived TXA2, thereby increasing platelet activation, adhesion, and aggregation with a resultant possibility for thrombosis and ischemic events [13].
Conversely, there is emerging evidence that selective COX-2 inhibition may have a beneficial effect on cardiovascular events in atherosclerosis. There is increased COX-2 expression in atherosclerotic vessels that is localized to macrophages, endothelial cells, and vascular smooth muscles within the atherosclerotic plaque, which play a key role in the development and progression of atherosclerosis. Thus, it has been speculated that selective COX-2 inhibition may reduce vascular inflammation and atherosclerotic progression [12].
During the conception of this study, there were no reports of the ability of Rofecoxib to reduce myocardial injury in CABG. Rofecoxib was chosen in view of its favorable pharmacokinetic profile and, at that time, the only major reported side effects were renal impairment and peptic ulcer disease. Although our trial comprised dataset from only 76 patients, both the groups of rofecoxib and placebo patients are well matched. This, we feel, carries more weight towards the validity of this study. Cardiac troponin T (cTnT) is superior compared to CK-MB for the prediction of myocardial infarction after cardiac surgical procedures [1]. The results of this study show that the profile and magnitude of the responses of cTnT is similar to those described previously in patients undergoing myocardial revascularization with cardioplegia [1]. The most surprising observation in the current study, in view of the recent safety concerns of COX-2 inhibitors, was that rofecoxib did not result in an elevation in biochemical markers of myocardial injury as judged at individual time points, compared to placebo. This is despite the fact that the group receiving rofecoxib comprised more patients who required urgent and emergency operations (Table 1), although this did not reach statistical significance.
Two patients in the rofecoxib group had ECG criteria of PMI whilst there was none in the placebo group. This, however, did not reach statistical significance. These patients had cTnT profiles that were within normal limits in the first 48 h. Both patients had small caliber coronary arteries with diffuse disease and there were intraoperative technical difficulties. This was identified as a possible contributing factor for the PMI. A further two patients (1 rofecoxib and 1 placebo) with elevated cTnT levels of >3. 4 μg/l at 48 h did not have ECG changes of PMI. One patient required revision of a proximal aorto-saphenous anastomosis 2 h after surgery, which may explain the rise in cTnT. There were no ECG changes of PMI possibly as a result of the subsequent improved coronary blood flow following the revision. The second patient underwent an emergency CABG for unstable angina with severe left main stem and triple vessel coronary artery disease. He required intra-aortic balloon pump support for 24 h after surgery and made an uneventful recovery.
A target of 150 patients would have made the data more robust and compelling. We were unable to achieve this because recruitment was low in the year 2003 because of the SARS crisis and the recent withdrawal of Rofecoxib from the market meant that the study had to be terminated. Furthermore, a significant number of patients were unable to complete the study. Due to relatively small patient numbers, any conclusions drawn from our study must be interpreted cautiously because of the possibility that the statistical power may be too small to detect clinically important differences between the groups.
In conclusion, our study found no evidence that short-term treatment with rofecoxib has a myocardial protective effect in patients undergoing CABG. There is also no evidence that its effect is deleterious to the myocardium in patients undergoing CABG.
Acknowledgements
This work was entirely funded by a research grant from the National Healthcare Group, Singapore, which is a public healthcare organization. The authors are indebted to the doctors, especially Dr K.A. Htun, nurses, perfusionists and administrative staff, in particular, N. Yeo, P.G. Chien, G. Vasantha and N.K. Siti of the Heart Institute at National University Hospital for all their help and, also, to all the patients who participated in the trial.
References
Januzzi JL, Lewandrowski K, MacGillivray TE, Newell JB, Kathiseran S, Servoss SJ. A comparison of cardiac troponin T and creatine kinase-MB for patient evaluation after cardiac surgery. J Am Coll Cardiol 2002; 39:1518–1523.
De La Ossa JC, Malago M, Gewertz BL. Neutrophil-endothelial cell binding in neutrophil-mediated tissue injury. J Surg Res 1992; 53:103–107.
Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983; 86:845–857.
Sellke FW, Boyle EM, Verrier ED. Endothelial cell injury in cardiovascular surgery: the pathophysiology of vasomotor dysfunction. Ann Thorac Surg 1996; 62:1222–1228.
Skarvan K, Graedel E, Hasse J, Stulz P, Pfisterer M. Coronary artery spasms after coronary artery bypass surgery. Anesthesiology 1984; 61:323–327.
Ashton JH, Benedict CR, Fitzgerald C, Raheja S, Taylor A, Campbell WB, Buja LM, Willerson JT. Serotonin as a mediator of cyclic flow variations in stenosed canine coronary arteries. Circulation 1986; 73:572–578.
Metais C, Bianchi C, Li J, Li J, Simons M, Selke F. Serotonin-induced human coronary microvascular during acute myocardial ischemia is blocked by COX-2 inhibition. Basic Res Cardiol 2001; 96:59–67.
Mangano M, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT. Renal dysfunction after myocardial revascularization: factors, adverse outcomes, and hospital resource utilization. Ann Intern Med 1998; 128:194–203.
Carrier M, Pellerin M, Perrault LP, Solymoss BC, Pelletier LC. Troponin levels in patients with myocardial infarction after coronary artery bypass grafting. Ann Thorac Surg 2000; 69:435–440.
FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004; 351:1709–1711.
Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM. Complications of COX-2 inhibitors parecoxib and valdecoxib after CABG. N Eng J Med 2005; 352:1081–1091.
Schonbeck U, Sukhova GK, Graber P, Coulter S, Libby P. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 1999; 155:1281–1291.
Caughey GE, Cleland LG, Penglis PS, Gamble JR, James MJ. Roles of cyclooxygenases (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2. J Immunol 2001; 167:2831–2838.(Poo-Sing Wong, Atasha Asm)
b Biostatistics Unit, Faculty of Medicine, National University of Singapore
Abstract
The endothelium of patients with coronary artery disease shows increased expression of cyclooxygenase-2 (COX-2) during coronary artery bypass graft surgery (CABG) using cardiopulmonary bypass. This, together with serotonin, may lead to coronary microvessel spasm, which potentially, can contribute to myocardial ischemia and injury after surgery. We performed a randomized, double-blind, placebo-controlled trial in patients undergoing isolated CABG to determine whether short-term treatment with a selective COX-2 inhibitor, Rofecoxib (25 mg), given preoperatively and for 5 days after operation, can offer better myocardial protection in patients undergoing CABG by measuring serial cardiac troponin T (cTnT) levels. The study was powered to recruit 150 consecutive patients undergoing isolated CABG but the study was terminated prematurely by the worldwide withdrawal of rofecoxib. There were highly statistically significant (P<0.001) increases in cTnT in both groups at each time point (1, 6, 24 and 48 h after onset of cardiopulmonary bypass) compared to preoperative levels. cTnT levels were similar at all post-operative time points between the 2 groups. There is no evidence that short-term treatment with rofecoxib has a myocardial protective effect in patients undergoing CABG. There is also no evidence that its effect is deleterious to the myocardium in patients undergoing CABG.
Key Words: Cyclooxygenase-2; Myocardial protection
1. Introduction
Specific biochemical markers demonstrate that some degree of myocardial injury is an inevitable consequence of cardiac operations [1]. The pathophysiology of operative myocardial injury is complex and results from a combination of direct trauma from surgical manipulation and myocardial ischemia due to inadequacies in cardioprotection and coronary thrombosis, ischemia-reperfusion injury [2], the systemic inflammatory response syndrome [3] and altered vasomotor regulation [4] and coronary artery spasm [5]. Platelet activation occurs at the sites of coronary stenoses and endothelial injury and may be associated with serotonin release [6], which has been implicated in contributing to vasoconstriction in patients with coronary artery disease. Cyclooxygenase (COX)-2 is expressed in the endothelium of patients with coronary artery disease. This expression is enhanced in the reperfusion phase following blood cardioplegia during coronary artery bypass graft surgery (CABG). Consequently, prostaglandin release (likely thromboxane A2) is stimulated which then activates the contractile response of coronary arterioles to serotonin. This may lead to coronary microvessel spasm, which potentially, can contribute to myocardial ischemia and injury after surgery [7].
The aim of this study was to examine whether short-term treatment with a selective COX-2 inhibitor, Rofecoxib, has a protective effect on the myocardium during CABG by assessing serial measurements of cardiac troponin T (cTnT).
2. Patients and methods
The Hospital Ethics Committee approved this study, and written informed consent was obtained from all patients. This was a prospective, randomized, double blind, placebo-controlled trial performed at the Heart Institute at National University Hospital, Singapore between October 2002 and October 2004. Patients were randomized according to a list of random treatment codes generated by a biostatistician (Y.H.C.) using a block design. Patients were sequentially assigned to pre-packed treatments (Rofecoxib 25 mg or placebo) to be administered orally at least 4 h before CABG and daily thereafter for 5 days.
The inclusion criteria for the study included patients undergoing first-time isolated coronary artery bypass grafting. Exclusion criteria included allergy to COX-2 inhibitors, patients with renal impairment (serum creatinine >120 μmol/l) or a previous history of peptic ulcer disease. The study was discontinued for patients who developed renal impairment (post-operative serum creatinine level 177 μmol/l) [8] or clinical signs of gastrointestinal bleed after CABG. Recruited patients who underwent coronary endarterectomy were also excluded from further analysis.
Two surgeons (P.S.W. and C.N.L.) performed all the operations. Cardiopulmonary bypass was performed with nonpulsatile flow with a pump flow rate of 2.4 l·m2·min at moderate hypothermia with the temperature allowed to drift to 32 °C. Cold blood cardioplegia was used for myocardial protection. The left ventricle was vented through the right superior pulmonary vein. A membrane oxygenator and a roller pump were used with a 40-μm arterial line filter. Patients were managed using standardized intensive care protocols. All patients received aspirin 200 mg given through the nasogastric tube 4 h after surgery and clopidogrel 75 mg once a day was given thereafter. Patients were also given oral omeprazole 20 mg twice daily for the duration of the study. Blood samples were collected for analysis of cTnT.
Our aim was to assess serial measurements of cTnT preoperatively and at 1, 6, 24, and 48 h after the onset of cardiopulmonary bypass. Additionally, postoperative complications were also analyzed. In this study, cTnT levels higher than 3.4 μg/l 48 h was used to diagnose perioperative myocardial infarction (PMI) [9]. Electrocardiographic criteria for the diagnosis of PMI were based on new Q wave formation, loss of R wave progression or new permanent left bundle branch block.
All analyses were performed using SPSS version 12. For quantitative data, 2 sample t-test will be applied when normality (checked using Komologrov Smirnov 1 Sample test) and homogeneity assumptions were satisfied otherwise the equivalent non-parametric Mann–Whitney U-test will be applied. Associations of categorical outcomes with treatments will be assessed using Chi-square or Fisher's exact tests with odds ratios presented where applicable. Statistical significance was set at P<0.05 and Bonferroni adjustment for type I error was performed when multiple comparisons (for each post-operative time point) were carried out. Anticipating a mean (S.D.) clinical difference of 0.1 (0.2) μg/l for cTnT, 150 subjects (to be randomized equally to placebo or rofecoxib) will be required for a power of 80% and a 2-sided test 5% to achieve a significant result.
3. Result
Between October 2002 and October 2004, there were 264 isolated CABG performed. The trial recruitment process is outlined in Fig. 1. One hundred and fifty-seven patients were not enrolled because of refusal to participate (n=80 patients), renal impairment (n=39) and history of peptic ulcer disease (n=38 patients). One hundred and seven subjects were randomized (53 rofecoxib, 54 placebo). Twelve patients did not complete the study (Fig. 1). A further 19 patients who had undergone coronary endarterectomy and had elevated preoperative cTnT levels were also excluded from further analysis.
As shown in both Tables 1 and 2, the 2 groups were well matched with respect to the characteristics shown. There was 1 death within 7 days in the active group. The patient died of sudden hemorrhage from the proximal anastomotic site of the aorto-saphenous vein graft from sudden severe hypertension on the second postoperative day after an uneventful CABG. The mean number of grafts, internal mammary artery usage rate, cardiopulmonary bypass time, myocardial ischemia time, duration of postoperative ventilation and postoperative hospital stay were not significantly different in the 2 groups. There were also no significant differences in postoperative complications listed in Table 2.
There were highly statistically significant (P<0.001) elevations in cTnT levels in both groups at each time point compared to pre-operative levels. However, cTnT levels were similar at all post-operative time points between the 2 groups (Fig. 2). The peak increase in cTnT was at 6 h after onset of cardiopulmonary bypass.
4. Discussion
The use of COX-2 inhibitors in cardiovascular disease has been highly controversial and its safety has been questioned [10]. Rofecoxib, a selective COX-2 inhibitor, has recently been withdrawn after the trial APPROVe (Adenomatous Polyp Prevention on Vioxx) showed an adverse cardiovascular side-effect profile. Another study comparing several pain-relief regimes following CABG noted that adverse cardiovascular events were significantly more common among parecoxib/valdecoxib recipients than among double-placebo recipients [11].
COX-2 is expressed in atherosclerotic vessels but not in normal arteries [12]. Enhanced COX-2 expression by endothelial cells increases the production of prostaglandin I2 (PGI2) over thromboxane A2 (TXA2). Thus, inhibition of COX-2 blocks PGI-2 formation without inhibiting platelet-derived TXA2, thereby increasing platelet activation, adhesion, and aggregation with a resultant possibility for thrombosis and ischemic events [13].
Conversely, there is emerging evidence that selective COX-2 inhibition may have a beneficial effect on cardiovascular events in atherosclerosis. There is increased COX-2 expression in atherosclerotic vessels that is localized to macrophages, endothelial cells, and vascular smooth muscles within the atherosclerotic plaque, which play a key role in the development and progression of atherosclerosis. Thus, it has been speculated that selective COX-2 inhibition may reduce vascular inflammation and atherosclerotic progression [12].
During the conception of this study, there were no reports of the ability of Rofecoxib to reduce myocardial injury in CABG. Rofecoxib was chosen in view of its favorable pharmacokinetic profile and, at that time, the only major reported side effects were renal impairment and peptic ulcer disease. Although our trial comprised dataset from only 76 patients, both the groups of rofecoxib and placebo patients are well matched. This, we feel, carries more weight towards the validity of this study. Cardiac troponin T (cTnT) is superior compared to CK-MB for the prediction of myocardial infarction after cardiac surgical procedures [1]. The results of this study show that the profile and magnitude of the responses of cTnT is similar to those described previously in patients undergoing myocardial revascularization with cardioplegia [1]. The most surprising observation in the current study, in view of the recent safety concerns of COX-2 inhibitors, was that rofecoxib did not result in an elevation in biochemical markers of myocardial injury as judged at individual time points, compared to placebo. This is despite the fact that the group receiving rofecoxib comprised more patients who required urgent and emergency operations (Table 1), although this did not reach statistical significance.
Two patients in the rofecoxib group had ECG criteria of PMI whilst there was none in the placebo group. This, however, did not reach statistical significance. These patients had cTnT profiles that were within normal limits in the first 48 h. Both patients had small caliber coronary arteries with diffuse disease and there were intraoperative technical difficulties. This was identified as a possible contributing factor for the PMI. A further two patients (1 rofecoxib and 1 placebo) with elevated cTnT levels of >3. 4 μg/l at 48 h did not have ECG changes of PMI. One patient required revision of a proximal aorto-saphenous anastomosis 2 h after surgery, which may explain the rise in cTnT. There were no ECG changes of PMI possibly as a result of the subsequent improved coronary blood flow following the revision. The second patient underwent an emergency CABG for unstable angina with severe left main stem and triple vessel coronary artery disease. He required intra-aortic balloon pump support for 24 h after surgery and made an uneventful recovery.
A target of 150 patients would have made the data more robust and compelling. We were unable to achieve this because recruitment was low in the year 2003 because of the SARS crisis and the recent withdrawal of Rofecoxib from the market meant that the study had to be terminated. Furthermore, a significant number of patients were unable to complete the study. Due to relatively small patient numbers, any conclusions drawn from our study must be interpreted cautiously because of the possibility that the statistical power may be too small to detect clinically important differences between the groups.
In conclusion, our study found no evidence that short-term treatment with rofecoxib has a myocardial protective effect in patients undergoing CABG. There is also no evidence that its effect is deleterious to the myocardium in patients undergoing CABG.
Acknowledgements
This work was entirely funded by a research grant from the National Healthcare Group, Singapore, which is a public healthcare organization. The authors are indebted to the doctors, especially Dr K.A. Htun, nurses, perfusionists and administrative staff, in particular, N. Yeo, P.G. Chien, G. Vasantha and N.K. Siti of the Heart Institute at National University Hospital for all their help and, also, to all the patients who participated in the trial.
References
Januzzi JL, Lewandrowski K, MacGillivray TE, Newell JB, Kathiseran S, Servoss SJ. A comparison of cardiac troponin T and creatine kinase-MB for patient evaluation after cardiac surgery. J Am Coll Cardiol 2002; 39:1518–1523.
De La Ossa JC, Malago M, Gewertz BL. Neutrophil-endothelial cell binding in neutrophil-mediated tissue injury. J Surg Res 1992; 53:103–107.
Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983; 86:845–857.
Sellke FW, Boyle EM, Verrier ED. Endothelial cell injury in cardiovascular surgery: the pathophysiology of vasomotor dysfunction. Ann Thorac Surg 1996; 62:1222–1228.
Skarvan K, Graedel E, Hasse J, Stulz P, Pfisterer M. Coronary artery spasms after coronary artery bypass surgery. Anesthesiology 1984; 61:323–327.
Ashton JH, Benedict CR, Fitzgerald C, Raheja S, Taylor A, Campbell WB, Buja LM, Willerson JT. Serotonin as a mediator of cyclic flow variations in stenosed canine coronary arteries. Circulation 1986; 73:572–578.
Metais C, Bianchi C, Li J, Li J, Simons M, Selke F. Serotonin-induced human coronary microvascular during acute myocardial ischemia is blocked by COX-2 inhibition. Basic Res Cardiol 2001; 96:59–67.
Mangano M, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT. Renal dysfunction after myocardial revascularization: factors, adverse outcomes, and hospital resource utilization. Ann Intern Med 1998; 128:194–203.
Carrier M, Pellerin M, Perrault LP, Solymoss BC, Pelletier LC. Troponin levels in patients with myocardial infarction after coronary artery bypass grafting. Ann Thorac Surg 2000; 69:435–440.
FitzGerald GA. Coxibs and cardiovascular disease. N Engl J Med 2004; 351:1709–1711.
Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM. Complications of COX-2 inhibitors parecoxib and valdecoxib after CABG. N Eng J Med 2005; 352:1081–1091.
Schonbeck U, Sukhova GK, Graber P, Coulter S, Libby P. Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions. Am J Pathol 1999; 155:1281–1291.
Caughey GE, Cleland LG, Penglis PS, Gamble JR, James MJ. Roles of cyclooxygenases (COX)-1 and COX-2 in prostanoid production by human endothelial cells: selective up-regulation of prostacyclin synthesis by COX-2. J Immunol 2001; 167:2831–2838.(Poo-Sing Wong, Atasha Asm)