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J Thorac Cardiovasc Surg 2003;125:1481-1492
© 2003 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology |
From the Ischemia Research and Education Foundation, San Francisco, Calif (P.H H., L.S., D.T.M.),b the McSPI Research Group, San Francisco, Calif (E.O., N.N., P.D., R.F., P.A., L.S., D.T.M.),a the Departments of Anesthesiology at Ludwig-Maximilians University, Munich, Germany (E.O.),c the Texas Heart Institute, Houston, Texas (N.A.N.),d University of Manitoba Health Sciences Center, Winnipeg, Canada (P.C.D.),e Saint Thomas' Hospital, London, United Kingdom (R.O.F.),f the Royal Infirmary of Edinburgh, Edinburgh, Scotland, United Kongdom (R.P.A.),g Stanford University Medical Center (L.S.),i Stanford, Calif, and Pharmacia Corporation, Skokie, Ill (M.C.S. and R.H.).h
Received for publication June 26, 2002. Revisions requested Aug 26, 2002; revisions received Oct 8, 2002. Accepted for publication Oct 18, 2002. Address for reprints: Dennis T. Mangano, PhD, MD, c/o Editorial Office, Ischemia Research and Education Foundation, 250 Executive Park Blvd, Suite 3400, San Francisco, CA 94134 (E-mail: dnmngn{at}aol.com).
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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1 Opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) are administered parenterally as analgesics in the early postoperative period to alleviate such pain. 2 However, the efficacy of these analgesic drugs is limited by side effects that impede patient rehabilitation after surgical intervention. Opioids, such as morphine sulfate, can be associated, particularly in older patients, with respiratory depression, excessive sedation, and confusion, and parenteral NSAIDs, such as ketorolac, can be associated with gastrointestinal ulceration, renal dysfunction, and bleeding caused by platelet inhibition. 3 Therefore development of new analgesics that are not only efficacious but also have an improved side-effect profile would enhance patient comfort and well-being and even reduce resource use costs.
In ambulatory patients and general surgical patients, among the newest approaches to acute pain control is selective inhibition of the cyclooxygenase 2 (COX-2) enzyme, which mediates inflammatory prostaglandin synthesis. 4-6 Inhibiting the inducible COX-2 isoform results in desirable anti-inflammatory and analgesic effects, whereas nonselective inhibition of the constitutive COX-1 and COX-2 enzymes is associated with gastrointestinal, platelet-related, renal, and other adverse side effects. 7 Conventional NSAIDs nonspecifically inhibit both COX isoforms. 8-11
Higher-risk populations have not been specifically studied in prior selective COX-2 inhibitor analgesia clinical trials, resulting in limited experience with efficacy and safety in these populations. Therefore we prospectively studied patients undergoing CABG surgery by using a new parenteral combined with oral COX-2 selective inhibitor.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Preoperative inclusion criteria were age of less than 77 years, body mass index (BMI) of less than or equal to 40 kg/m2, weight of greater than 55 kg, left ventricular ejection fraction of greater than or equal to 35%, and New York Heart Association class of I to III. In addition, in each patient the presence of adequately treated blood pressure and absence of psychologic illness were confirmed. Exclusion criteria were patients undergoing emergency surgery and those with a recent (<48 hours) myocardial infarction, insulin-dependent or uncontrolled diabetes (fasting blood sugar >350 mg/dL or 19.4 mmol/L), increased concentrations of liver enzymes (aspartate aminotransferase or alanine aminotransferase >1.5 of the upper limit of normal), creatinine level of greater than 1.5 mg/dL (or 133 µmol/L), or any coagulopathy. Also excluded were patients with stroke or transient ischemic attack within 6 months and those with substance abuse (opioids, any other analgesics, or alcohol), allergy to nonsteroidal anti-inflammatory agents, or a history of gastric or duodenal ulcer.
Intraoperative exclusion criteria included a complicated intraoperative course, cardiopulmonary bypass time exceeding 3 hours, or insertion of an intra-aortic balloon pump. In the postoperative period and before randomization, patients were excluded from the study if they were receiving 3 or more inotropic infusions, had a symptomatic dysrhythmia, had new Q-wave myocardial infarction, had a cardiac index of less than 1.5 L/min, had a chest tube output of greater than 500 mL in a 2-hour period, had a temperature of less than 36°C or greater than 38°C, had a urine output of less than 50 mL/h, had a hemoglobin level of less than 8 g/dL (or 1.24 mmol/L), or had a serum creatinine level exceeding 1.2 mg/dL (or 106 µmol/L) or 30% greater than the baseline value.
Study procedures before drug administration
Preoperative cardiac medications were continued until the time of surgical intervention. Anesthesia was induced by using fentanyl and/or midazolam, isoflurane, and a muscle relaxant for tracheal intubation. Anesthesia was maintained with isoflurane and/or propofol, fentanyl, midazolam and pancuronium in all institutions. Although the conduct of the anesthesia and surgical intervention was similar for each institution, no attempts were made to further standardize techniques. Cardiopulmonary bypass was used in 89% (411/462) of patients with hemodilution, mild-to-moderate hypothermia, and membrane oxygenators, with no difference between groups. In 11% (51/462) of patients, off-pump CABG was performed. For initial management in the intensive care unit, propofol, morphine, or midazolam for sedation and analgesia were administered at the discretion of the treating clinician. All patients in both study groups received aspirin (80-325 mg/d), starting by the time of the first dose of study medication. In each patient the trachea was extubated within 15 hours of surgical intervention. Subsequently, those meeting the inclusion and exclusion criteria were randomized.
Administration of parecoxib/valdecoxib
Intravenous administration of the study drug (40 mg of parecoxib or placebo) began within 30 minutes of extubation of the trachea immediately after a baseline pain assessment but before initiation of patient-controlled analgesia (PCA). The study drug was then administered intravenously every 12 hours and was continued for a minimum of 72 hours to allow uniform assessment of efficacy and safety over the first 3 days among all participating centers. All patients had access to intravenous morphine sulfate by means of PCA for supplemental pain medication starting immediately after tracheal extubation and continuing for at least 24 hours and thereafter at the discretion of the treating clinician. In addition to study-mandated treatments, all other medications required to manage a patient's individual care were permitted, with the exception of NSAIDs.
After 72 hours, if the patient were able to tolerate oral medication, the intravenous dosing scheme was changed to an enteral (oral) scheme, at which time either 40 mg of valdecoxib or placebo was administered every 12 hours. Supplemental pain medication consisting of combinations of codeine (30 mg) and acetaminophen (300 mg or 500 mg) in doses of 1 to 2 tablets every 4 to 6 hours was available to all patients and administered at their discretion. At the time of discharge from the hospital, each patient received the oral study medication and supplementary pain medication, with instructions to continue study-mandated treatment after hospitalization. The oral dosing period was scheduled to last from the end of intravenous dosing to day 14.
Evaluation of analgesic efficacy
The primary measure for comparing efficacy of parecoxib/valdecoxib versus control was the amount of morphine sulfate (or morphine equivalents consumed). 12-14 Additional assessments included a daily pain intensity score recorded as peak intensity on a 4-point categoric scale. A clinical investigator evaluated pain intensity daily for each day of treatment. Also, the peak pain intensity difference between maximum daily sternotomy pain and pretreatment sternotomy pain was calculated for each day of treatment.
At the time of transition from intravenous to oral drug administration, before hospital discharge, and on day 14 (study termination or sooner if premature termination occurred), physician and patient global assessments of the effects of the study medications were obtained. On discharge from the hospital, each patient received a patient diary to continue daily pain assessments. The diary included the modified Brief Pain Inventory, a validated instrument designed to evaluate the effect of pain on the patient's ability to perform daily living activities.
Safety assessment
Safety was assessed on the basis of the occurrence of clinical adverse events (AEs) and serious adverse events (SAEs), as reported by the principal investigator at each site. AEs were judged to be serious if they resulted in a fatality or hospitalization or if the principal investigator believed that the event was life threatening or otherwise medically significant. The principal investigator at each study site also made a judgment as to whether there was a probable, uncertain, or lack of relationship of each AE to study treatment. When multiple episodes of the same AE were reported, the greatest known attribution was presented. All events occurring from the time of the first dose through the 30-day postdosing period were included. The World Health Organization Adverse Reaction Terminology dictionary 15 was used to code the investigator's description of AEs, and the resulting primary terms were used in the calculation of incidence for comparative analysis. In addition to AE assessment, safety was evaluated on the basis of physical examination, measurement of vital signs, recording of electrocardiographs, and collection of blood samples for clinical laboratory measurements at the time of changing from intravenous to oral drug administration, before hospital discharge, and on day 14 (study termination or sooner if premature termination occurred).
Statistical analysis
Efficacy
The proportion of patients who received opioids, including morphine PCA, during fixed time intervals was compared between treatment groups by using the Cochran-Mantel-Haenszel test stratified by country. Mean morphine consumption by means of PCA and total opioid (morphine equivalents) consumption were compared on the basis of time intervals by using an analysis of variance (ANOVA) with treatment and country as factors and with the time to first morphine dose as an additional factor when appropriate. Oral opioid use per day was recorded and compared between treatment groups by using a Wilcoxon test. No assumption was made for missing values in the primary efficacy variable (morphine consumption). Peak pain intensity difference was analyzed by using an ANOVA with treatment and country as factors and baseline pain intensity as a covariate. Except for the primary efficacy variable (morphine consumption), the approach of last observation carried forward was adopted to account for missing values. When multiple time periods were combined for presentation, the largest P value among the combined periods was reported. The patient's and the physician's global evaluations of study medication at the time of transition from intravenous to oral administration, discharge from the hospital, and final visit were compared between treatment groups by using the Cochran-Mantel-Haenszel test stratified by country.
Safety
The incidences of both AEs and SAEs were compared between treatment groups by using the Fisher exact test, which provides a P value for each comparison. Multiple logistic regression was used to evaluate potential risk factors for SAEs. The changes from baseline values in laboratory tests and vital signs were compared between treatment groups with a 1-way ANOVA. The intent-to-treat cohort was used in all safety and efficacy analyses of morphine consumption. The intent-to-treat cohort consisted of all patients who received a dose of study medication, a total of 462 patients (311 patients in the parecoxib/valdecoxib group and 151 patients in the control group).
Treatment group assignment and power
Patients were randomized to one of the 2 treatment groups in a ratio of 2:1 for parecoxib/valdecoxib versus control treatment. The sample sizes of 300 patients in the group receiving intravenous 40 mg of parecoxib/oral 40 mg of valdecoxib and 150 patients receiving placebo were sufficient to detect a minimum difference of 12 mg in the average consumption of morphine between the 2 groups by using a 2-sided test at a 5% level of significance with 85% power. These sample sizes were sufficient to detect at least one occurrence of AEs of 1% incidence in the treatment group and 2% in the control group with 95% confidence and to compare individual AE rates of 1% versus 7% by using a 2-sided test at a 5% level of significance with 80% power.
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Results |
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). Except for a BMI of greater than 30 kg/m2 (P = .037) and a trend toward increased prevalence of peripheral vascular disease (P = .097) in the P/V group (Tables 1 and 2), the proportion of patients with cardiac disease-related risk factors was similar between the P/V and control groups (Table 2).
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Efficacy
Primary efficacy measure: Morphine consumption
Morphine consumption by means of PCA after the initial administration of study medication was assessed during each 24-hour interval. The amount of morphine PCA used by patients in the P/V group was significantly less than that in the control group for the periods from 0 to 24 hours (P = .015), 24 to 48 hours (P = .020), and 72 to 96 hours (P = .023). Total morphine and total opioid (morphine equivalent) consumption at 24 hours was approximately 23% less in the P/V group relative to the control group for morphine PCA (P = .009, Table 3). In addition, significant cumulative reductions (approximately 20% relative to control, P = 0.039) were seen at 72 hours. By the 96- to 120-hour interval, only 3 patients were receiving morphine PCA.
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16) was 2.6% in both groups (P/V group, 8 patients; control group, 4 patients). Similar proportions (P = .512) of patients in the P/V group (29.6%) versus the control group (26.5%) received blood products, with mean transfusion requirements not differing (P = .398) between groups (2.30 units per patient vs 2.55 units per patient, respectively).
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Sternal wound infections occurred in 10 (3.2%) P/V group patients versus zero patients in the control group (P = .035). These were characterized by the investigators as 5 sternal wound infections, 2 deep sternal wound infections, 2 superficial sternal wound infections, and 1 sternal wound dehiscence caused by infection. Other than parecoxib/valdecoxib use, no other risk factor (eg, body mass) was associated with sternal wound infection.
Myocardial infarction was reported as an SAE in 1.6% (5/311) of P/V group patients versus 0.7% (1/151) of control patients (P = .669). Four of the 5 myocardial infarctions in the P/V group patients were given a diagnosis in the immediate perioperative period (within 24 hours of surgical intervention), whereas the other fifth occurred 14 days after the last dose of study medication.
Cerebrovascular complications occurred in 9 (2.9%) P/V group patients versus 1 (0.7%) patient in the control group (P = .177). Risk factors significantly associated with occurrence of a cerebrovascular complication by means of stepwise logistic regression analysis included age of greater than 65 years (odds ratio = 8.15), BMI of greater than 30 kg/m2 (odds ratio = 7.18), and history of cerebrovascular disease (odds ratio = 16.62).
Renal events occurred in 6 (1.9%) P/V group patients versus zero patients in the standard care group (P = .184). None of these events required treatment with dialysis. Among P/V group patients, a history of diabetes was significantly associated with development of a renal event (P = .017).
Relationship to study medication
Of the 116 events in the P/V group, 97 events were classified as not related to the study drug by the investigator, 19 were classified as having an uncertain relationship to the study drug, and 1 (renal function abnormality) was classified as probably related to the study drug. Regarding the control group, of the 26 events, 24 were classified as not related to the study drug, 2 as having an uncertain relationship to the study drug, and none as having a probable relationship to the study drug.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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16-18 Over the past several decades, significant gains in the management of patients undergoing coronary artery surgery have been achieved through improved intraoperative monitoring, myocardial preservation, and surgical technique. Advances have also been made in the area of pain control drugs. These include a variety of techniques (spinal opioids and local anesthetics) and drugs (natural and synthetic opioids, sedative-hypnotics, 
2-adrenergic agonists, and NSAIDs). Ideally, these therapies provide not only patient comfort but also mitigation of untoward cardiovascular responses (hypertension, tachycardia, and myocardial ischemia), pulmonary responses (shunting and splinting), and other inflammatory and secondary sympathetic responses. 2
However, as the age of patients undergoing CABG surgery increases, the prevalence of comorbid conditions will increase, and therefore therapies demonstrating reductions in untoward side effects will be desirable. Such therapies should facilitate early discharge or at least limit prolonged hospitalization for this population. Early ambulation is critical and will require more complete pain relief while preserving cognition. 19 Use of opioids or sedatives-hypnotics will necessarily have to be limited. The use of NSAIDs, which profoundly affect the pain response yet have little effect on the sensorium (sedation, confusion, and disorientation), has been a major advance in the postoperative care of these patients. However, although effective, the initially developed nonselective NSAIDs (eg, ketorolac tromethamine [INN: ketorolac]) are associated with gastrointestinal ulceration and bleeding, antiplatelet effects, renal dysfunction, 3,8-11 and, more recently, congestive heart failure, the latter of which was found to be more prevalent and severe in older patients. 20-23 Nonetheless, despite these drawbacks, nonsteroidal anti-inflammatory agents have been recently studied for brief periods (<48 hours) in managing postoperative pain after cardiac surgery. 24-26
However, other novel approaches have been sought, with the most recent being the selective inhibition of the COX-2 enzyme, thereby blocking inflammatory prostaglandin synthesis. The inducible form of this enzyme provides both analgesic and anti-inflammatory effects when inhibited. 7,23,27 In contrast, inhibition of the constitutive COX-1 enzyme is associated with gastrointestinal, renal, and bleeding side effects. Because the efficacy of the COX-2 inhibitors celecoxib and rofecoxib, as well as parecoxib/valdecoxib, has been demonstrated in patients undergoing general surgery, we assessed the latter in higher-risk patients (ie, those with coronary artery disease undergoing revascularization). If effective and safe, then NSAID-associated gastrointestinal and platelet-associated complications might be circumvented, and other benefits might be gained by means of mitigation of the reperfusion-associated inflammatory response.
Because untoward pain responses after CABG surgery might last for several days, a COX-2 agent that could be administered both intravenously and orally was appealing.
Efficacy findings
Our study was designed to compare a novel COX-2 inhibitor regimen (ie, intravenous parecoxib, followed by oral valdecoxib) to a control regimen that included PCA. Although a number of centers typically use a less-aggressive approach to pain control, we believed that such a stringent standard for the control group was appropriate because any new therapy should have efficacy exceeding that of the most aggressive pain control regimens. 2 We found a statistically significant reduction in morphine PCA use in the P/V group for periods from 0 to 24 hours, 24 to 48 hours, and 72 to 96 hours. These findings were supported by the consistent reductions in the amount of total opioids consumed for each 24-hour period up to 168 hours, patient's perception of pain, physician's global assessment, and improvement in pain-related quality of life.
Safety findings
Regarding safety, however, we found several results that raised concern. First, although the overall incidence of AEs was comparable in the 2 groups, significantly more patients in the P/V group had SAEs than in the control group (P = .015). Of specific concern is that the incidence of sternal wound infections was significantly greater in the P/V group patients compared with that in control subjects (10/311 vs 0/151, P = .035). The effects of NSAIDS on sternal wound complications in the CABG surgical setting have not been previously reported. The COX-2 enzyme enables prostaglandin release and inflammatory response, and inhibition of this enzyme by nonspecific COX inhibitors (eg, NSAIDs), as well as specific COX-2 inhibitors (eg, parecoxib and valdecoxib), might impede reparative inflammatory responses and increase susceptibility to sternum infections. An alternative hypothesis is that the reduced rates for fever and tachycardia among P/V group patients might have delayed detection of an infection, resulting in further progression and greater consequence. Moreover, it should be considered that full-dose study drug administration was continued for a 2-week period in all P/V group patients, regardless of their need for analgesics, which might have contributed to increased susceptibility to or delayed recognition of infection. Regardless of mechanism, these safety issues merit careful consideration because of the importance of sternal complications in this setting, not only for NSAIDS and COX-2 inhibitors but also for any new medication that can impair normal inflammatory reparative processes.
Second, the incidence of both cardiovascular and cerebrovascular SAEs was proportionally, but not significantly, greater in P/V group patients than in control patients, potentially implicating a thrombosis-mediated association with COX-2 inhibitor use. 28 Nearly all of our patients underwent cardiac surgery with cardiopulmonary bypass and hypothermia. In such patients the delicate balance between platelets, endothelial cells, and serum clotting factors is disturbed, with a consequent thrombosis and clot lysis occurring disparately and unpredictably throughout the vascular system. Given that COX-2 inhibitors are platelet sparing, they might tip the balance toward thrombosis during periods of platelet activation. In addition, it has been argued that because COX-1 is unaffected, consequent release of thromboxane A2 further promotes platelet activation and thrombosis. Of note are 3 recently published analyses addressing this issue in chronically treated patients with arthritis. 28,29 The first 28 contrasted the results of the CLASS (celecoxib) and VIGOR (rofecoxib) clinical trials, with historical controls derived from the aspirin trials. Using a summary statistic, the authors emphasized the potential association between COX-2 inhibition and thrombogenic events (myocardial infarction, stroke, and vascular death). The second, 29 in contrast, addressed a meta-analysis involving patients with both osteoarthritis and rheumatoid arthritis with respect to the use of rofecoxib versus placebo versus ibuprofen or diclofenac, finding no significant association among these groups for vascular events. In addition, a separate analysis of the CLASS study data found no increased risk of serious cardiovascular thrombotic events associated with celecoxib compared with naproxen and ibuprofen. 30 Given that 4 of the 5 infarctions in this trial occurred perioperatively (ie, in close proximity to the administration of the first intravenous parecoxib/valdecoxib dose), if an association is inferred, then the acute intravenous administration of a COX-2 inhibitor must precipitate coronary artery thrombosis acutely (a hypothesis similar to that proposed by the recent work of Mukherjee et al 28).
On the other hand, any extrapolation of the above chronic treatment regimens to treatment of acute pain in the perioperative setting must be made cautiously. Furthermore, it must be understood that arterial thrombosis after surgical revascularization might be precipitated by a number of other phenomena, including 28,31-36 mechanically induced endovascular injury; acute reversal of heparin, precipitously increasing serum thrombin levels; concomitant use of antifibrinolytic agents (eg, aprotinin or episolon aminocaproic acid) to mitigate hemorrhage; instigation of a generalized inflammatory response, leading to platelet activation; and centralization of activated platelets. All are operative here, making it difficult if not impossible to discern an independent association between the study drug and thrombosis in our trial of a limited sample size. However, perhaps because patients likely received such aspirin not immediately on reperfusion but rather hours later, substantial platelet activation might have already occurred and precipitated a cascade leading to myocardial infarction and stroke. 39 The observation that 4 of the 5 myocardial infarction events occurred within the immediate perioperative period is consistent with this hypothesis. Clearly, resolution of this important issue is necessary, particularly for higher-risk patients, such as ours.
Third, regarding the interaction between antifibrinolytic therapy use and COX-2 inhibitors, we found the following. Of the 311 patients receiving COX-2 inhibitors, 193 (62%) also received antifibrinolytic therapy, and of these, 4 had either pulmonary embolism, myocardial infarction, thrombophlebitis, or arterial dissection versus 1, 4, 2, and 0 patients, respectively, who received COX-2 inhibitors but did not receive antifibrinolytics. For the control group, one patient who received antifibrinolytics had one of these 4 complications versus no patients among those not receiving antifibrinolytics. Although there is no evidence of interaction, the numbers are small, and their significance must be assessed in a larger trial.
Fourth, the incidence of renal insufficiency in P/V group patients was proportionally greater than that for control patients, although the incidence of increased renal function test parameters was equal. Both COX-2 and COX-1 inhibition can be associated with impaired renal function. 9 Given that even renal dysfunction without failure is associated with reduced survival and increased cost in these patients 16 and given the possibility of a type I error, then the significance of this safety observation remains unresolved.
Finally, as with any new therapy, the cost-effectiveness must be assessed if the therapy has been proved effective and safe, and we will address such separately in the next trial.
Limitations of the current study
There are several limitations to the present study. First, our trial was marginally powered (68%) to detect a 2-fold difference (20% vs 10%) in SAEs between study groups and was not powered (6%) to detect differences for specific SAEs. Moreover, the incidence of the SAEs in the control group patients was considerably lower than expected when compared with that reported in large-scale studies and clinical trials among similar patients (6% for Q-wave infarction, 3% for stroke, and 7% for renal dysfunction). 16,17,37 Consequently, a larger trial with equal numbers of patients in each treatment group is necessary to resolve these safety findings.
Second, several potentially important outcomes were not measured, such as chest tube output in the first 24 to 48 postoperative hours. Use of agents that are platelet sparing, such as COX-2 inhibitors, might mitigate blood loss in these patients, an effect not assessed in our trial.
Third, the control group actually received a nearly ideal standard of care (ie, analgesia in this clinical trial), given that they had ready access to morphine PCA and were closely observed for management of pain. Such a standard might be difficult to achieve in practice, especially given current efforts to limit postoperative resources. Consequently, one might speculate that even greater benefit can be realized with parecoxib/valdecoxib, given their ease of use.
Fourth, only a single dosage regimen and duration of parecoxib/valdecoxib was assessed. Considering that lower doses of parecoxib and valdecoxib also have been shown effective, 4-6,38 then the potential to achieve the desired analgesic benefits with possibly lower risk of AEs with lower doses, shorter periods of administration, or both needs to be explored with future studies.
Fifth, we did not include a group receiving nonspecific NSAID agents, and therefore comparisons with such drugs in these patients cannot be surmised.
Sixth, regarding generalization, as for any clinical trial, inclusion and exclusion criteria can impose rather strict limits. Here, we estimate that our findings would be strictly applicable to approximately 220,000 patients or 30% of patients undergoing CABG with cardiopulmonary bypass annually throughout the world. Therefore caution should be exercised in the application of these findings to the entire CABG surgery population.
Finally, because of issues raised here, a follow-up trial should be designed to provide greater insight into the safety concerns and efficacy benefits in this population. In view of the limited power of this study, a larger trial will be needed to address relative frequency of uncommon events that might be associated with parecoxib/valdecoxib therapy.
Conclusion
The intravenous-oral parecoxib/valdecoxib regimen demonstrated superiority for pain relief over an aggressive therapeutic regimen supplemented with PCA. However, the higher incidence of SAEs observed with the parecoxib/valdecoxib regimen, as well as the higher incidence of sternal infections, raise important concerns and mandate comprehensive evaluation in a large-scale trial before use in patients undergoing CABG surgery.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Quality Assurance
Carolyn Dudek, RN
Analysis Coordination
Dan Canafax, PharmD
William Spickler, MD, PhD
Laurie Carlson, RN
Juliet Li, MD
Camelia Dumitrescu, MD
Susan Owen, RN
Kathleen Luden
Analysis Group
Ping Hsu, PhD
David Kardatzke, PhD
Nick Paszty
Electrocardiographic Analysis
Polina Voloshko, MD
Adam Zhang, MD
Ricardo Dea, MD
Lucy Zhu, MD
Margarita Savina, MD
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Appendix 2 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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Keith Allen, MD, St Vincent Hospital, Indianapolis, Ind
Peter Alston, MD, Royal Infirmary, Edinburgh, Scotland
Prasad Atluri, MD, VA Medical Center, Houston, Tex
Elliott Bennett-Guerrero, MD, Columbia Presbyterian Medical Center, New York, NY
Steven Boyce, MD, Washington Hospital Center, Silver Spring, Md
David Bronheim, MD, The Mt Sinai Medical Center, New York, NY
Edward Busse, MD, Regina General Hospital, Regina, Canada
Jean Bussieres, MD, Laval Hospital, Sainte-Foye, Canada
Marguerita Camacho, MD, Montefiore Medical Center, Bronx, NY
Maria Chakerian, MD, Bay Area Center for Pain & Palliative Care, Los Gatos, Calif
Davy Cheng, MD, Toronto General Hospital, Toronto, Canada
Colm Cole, MD, St Paul's Hospital, Vancouver, Canada
Paul Dlabal, MD, Cycle Solutions, Inc, Austin, Tex
Roger Dreiling, MD, Corvalis Clinic, Corvalis, Ore
Peter Duke, MD, University of Manitoba, Winnipeg, Canada
Jean-Yves Dupuis, MD, University of Ottawa Heart Institute, Ottawa, Canada
Michael Eaton, MD, University of Rochester Medical Center, Rochester, NY
Jeffrey Everett, MD, University of Iowa, Iowa City, Iowa
Rob Feneck, MD, St Thomas Hospital, London, United Kingdom
Andreas Fiehn, MD, Klinikum Kassel, Kassel, Germany
Barry Finnegan, MD, University of Alberta, Edmonton, Canada
Michael Fiocco, MD, Union Memorial Hospital, Silver Spring, Md
Jane Fitch, MD, Baylor College of Medicine, Houston, Tex
Manuel Fontes, MD, New York Presbyterian (Cornell), New York, NY
Mark Fox, MD, Cardiothoracic Centre, Liverpool, United Kingdom
Susan Garwood, MD, Yale University, New Haven, Conn
George Gordon, MD, New England Medical Center, Boston, Mass
Michael Grave, MD, Long Island Jewish Hospital, New Hyde Park, NY
Richard Hall, MD, QE II Health Sciences Center, Halifax, Canada
Kenneth Hanger, MD, Roper Care Alliance Hospital, Mt Pleasant, SC
Charles Hantler, MD, University of Texas Health Sciences Center, San Antonio, Tex
Gunter Hempelmann, MD, Justus-Liebig University, Giessen, Germany
William Higgs, MD, Gulf Coast Clinical Services, Inc, Mobile, Ala
Andreas Hoeft, MD, University of Bonn, Bonn, Germany
Charles Hogue, MD, Washington University, St Louis, Mo
Mitchell Jacobs, MD, North Shore University Hospital, Manhasset, NY
Shubjeet Kaur, MD, University of Massachusetts Memorial Health Center, Worcester, Mass
Hurley Knott, MD, SORRA Research, Birmingham, Ala
Dan Kopacz, MD, Virginia Mason Medical Center, Seattle, Wash
Michael Koren, MD, Jacksonville Center for Clinical Research, Jacksonville, Fla
John Laschinger, MD, Sinai Hospital of Baltimore, Silver Spring, Md
John Leslie, MD, Mayo Clinic Hospital, Phoenix, Ariz
Stephen Lincoln, MD, St Joseph's Medical Center, Silver Spring, Md
Phil Malan, MD, University of Arizona, Tucson, Ariz
Eike Martin, MD, University of Heidelberg, Heidelberg, Germany
Raymond Martineau, MD, Montreal Heart Institute, Montreal, Canada
Joseph Mathew, MD, Duke University Medical Center, Durham, NC
David Mazer, MD, St Michael's Hospital, Toronto, Canada
Richard McLean, MD, Hamilton Health Sciences Corp, Hamilton, Canada
Stan Mogelnicki, MD, St Joseph's Hospital, Atlanta, Ga
Chris Mora Mangano, MD, Stanford University Medical Center, Stanford, Calif
Lars Newsome, MD, Scripps Memorial Hospital, La Jolla, Calif
Nancy Nussmeier, MD, Texas Heart Institute, Houston, Tex
Elisabeth Ott, MD, University of Munich, Munich, Germany
James Park, MBChB, South Cleveland Hospital, Middlesbrough, United Kingdom
Eric Pierce, MD, Boston University Medical Center, Boston, Mass
Evan Pivalizza, MD, Hermann Hospital, University of Houston, Houston, Tex
Joseph Quinlan, MD, University of Pittsburgh, Pittsburgh, Pa
Fiona Ralley, MD, University of Western Ontario, London, Canada
James Ramsay, MD, Emory University Hospital, Atlanta, Ga
Lowell Reynolds, MD, Center for Pain Management, Loma Linda Medical Center, Loma Linda, Calif
Gary Roach, MD, Kaiser Foundation Hospital, San Francisco, Calif
Louis Samuels, MD, Hahnemann University Hospital, Philadelphia, Pa
Jens Scholz, MD, University Hospital Eppendorf, Hamburg, Germany
Ketan Shevde, MD, Maimonides Medical Center, Brooklyn, NY
David Smith, MD, Southhampton General Hospital, Southhampton, United Kingdom
Hans Sonntag, MD, University of Goettingen, Goettingen, Germany
Bruce Spiess, MD, Medical College of Virginia, Richmond, Va
Ethan Stein, MD, Mary Washington Hospital, Silver Spring, Md
Louis Suarez, MD, Appleton Medical Center, Appleton, Wis
Steven Timmis, MD, William Beaumont Hospital, Royal Oak, Mich
James Todd, MD, Peninsula Regional Medical Center, Silver Spring, Md
Bruce Toporoff, MD, Southwest Clinical Research, Inc, Phoenix, Ariz
Mark Trankina, MD, Shands Hospital University of Florida, Gainesville, Fla
Hamed Umedaly, MD, University of British Columbia, Vancouver, Canada
Hugo Van Aken, MD, University of Muenster, Muenster, Germany
Joseph Van DeWater, MD, Medical Center of Central Georgia, Macon, Ga
Eugene Viscusi, MD, Thomas Jefferson University Hospital, Philadelphia, Pa
Timothy Votapka, MD, Evanston Northwestern Healthcare, Evanston, Ill
Alain Vuylsteke, MD. Papworth Hospital NHS Trust, Cambridge, United Kingdom
Mark Wallace, MD, University of California, San Diego, La Jolla, Calif
Herb Ward, MD, VA Medical Center Surgical Services, Minneapolis, Minn
David Whitaker, MD, Manchester Royal Infirmary, Manchester, United Kingdom
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Acknowledgments |
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and 2 for a complete list of the Investigators and Centers. 
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1Appendix 2References |
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