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The new england journal of medicine Parecoxib and Valdecoxib after Cardiac Surgery Nancy A. Nussmeier, M.D., Andrew A. Whelton, M.D., Mark T. Brown, M.D., Richard M. Langford, F.R.C.A., Andreas Hoeft, M.D., Joel L. Parlow, M.D., Steven W. Boyce, M.D., and Kenneth M. Verburg, Ph.D.
b a c k g r o u n d
Valdecoxib and its intravenous prodrug parecoxib are used to treat postoperative pain From the Texas Heart Institute at St. Luke’s Episcopal Hospital, Houston (N.A.N.); Uni- but may involve risk after coronary-artery bypass grafting (CABG). We conducted a ran- versal Clinical Research Center and Johns domized trial to assess the safety of these drugs after CABG.
Hopkins University School of Medicine, Bal-timore (A.A.W.); Pfizer, Global Research andDevelopment, Ann Arbor, Mich. (M.T.B., K.M.V.); St. Bartholomew’s Hospital, Lon- In this randomized, double-blind study involving 10 days of treatment and 30 days of don (R.M.L.); the Department of Anesthe-follow-up, 1671 patients were randomly assigned to receive intravenous parecoxib for siology and Intensive Care Medicine, Uni- at least 3 days, followed by oral valdecoxib through day 10; intravenous placebo fol- Queen’s University and Kingston General lowed by oral valdecoxib; or placebo for 10 days. All patients had access to standard Hospital, Kingston, Ont., Canada (J.L.P.);opioid medications. The primary end point was the frequency of predefined adverse and Washington Hospital Center, Wash- ington, D.C. (S.W.B.). Address reprint re- events, including cardiovascular events, renal failure or dysfunction, gastroduodenal quests to Dr. Nussmeier at the Texas Heart ulceration, and wound-healing complications.
Institute at St. Luke’s Episcopal Hospital,P.O. Box 20345, MC 1-226, Houston, TX77225-0345, or at [email protected].
As compared with the group given placebo alone, both the group given parecoxib andvaldecoxib and the group given placebo and valdecoxib had a higher proportion of pa- N Engl J Med 2005;352.
Copyright 2005 Massachusetts Medical Society. tients with at least one confirmed adverse event (7.4 percent in each of these two groupsvs. 4.0 percent in the placebo group; risk ratio for each comparison, 1.9; 95 percentconfidence interval, 1.1 to 3.2; P=0.02 for each comparison with the placebo group).
In particular, cardiovascular events (including myocardial infarction, cardiac arrest,stroke, and pulmonary embolism) were more frequent among the patients given pare-coxib and valdecoxib than among those given placebo (2.0 percent vs. 0.5 percent; riskratio, 3.7; 95 percent confidence interval, 1.0 to 13.5; P=0.03).
c o n c l u s i o n s
The use of parecoxib and valdecoxib after CABG was associated with an increased inci-dence of cardiovascular events, arousing serious concern about the use of these drugsin such circumstances.
Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine 12 hours through day 10. One group received pla- drugs (NSAIDs) are established phar- cebo throughout the 10-day period. Patients who nmacologic tools for treating postopera- were unable to tolerate oral medications continued tive pain. However, concern about the possibility to receive the intravenous study drug. After CABG,
of gastric ulceration, renal injury, and bleeding has all patients received aspirin in the allowed range of
limited the use of NSAIDs in some surgical and 75 to 325 mg daily through day 10. Other routinely
critical care settings.1 The selective cyclooxygen- administered postoperative medications, including
ase-2 (COX-2) inhibitor valdecoxib (Bextra, Pfizer) prophylaxis against deep-vein thrombosis, were
and its intravenous prodrug parecoxib (Dynastat, permitted, except for NSAIDs, sedating antihista-
Pfizer) were found to exert significant opioid-spar- mines, prophylactic antiemetic agents, intrathecal
ing effects after dental, gynecologic, orthopedic, and or epidural opioids, and local analgesics applied to
other noncardiac surgical procedures, apparently the surgical incision.
without causing serious adverse effects.2-5 Similar
efficacy was demonstrated in a study of parecoxib end points
and valdecoxib in patients recovering from coro- The primary end point was the combined inci-
nary-artery bypass grafting (CABG).6 In that study, dence of predefined adverse events in the following
however, these drugs were associated with a signif- four clinically relevant categories: cardiovascular
icantly higher overall incidence of serious adverse events, renal events, surgical-wound complications,
events, a significantly higher incidence of sternal- and gastrointestinal complications. Cardiovascu-
wound infections, and a higher incidence of post- lar events included cardiac, cerebrovascular, and pe-
operative cerebrovascular complications and myo- ripheral vascular events. Cardiac events included
cardial infarction. In nonsurgical settings, studies myocardial infarction, severe myocardial ischemia
of the long-term administration of COX-2 inhibi- (defined as typical ischemic chest discomfort last-
tors have aroused concern regarding their potential ing at least 10 minutes and associated with transient
to increase the risk of thromboembolic events.7-9 ST-segment changes of at least 1 mm on the elec-
To clarify the safety of parecoxib and valdecoxib ther- trocardiogram), sudden death from cardiac causes,
apy in patients after CABG, we undertook a large or unexpected death without an identifiable non-
randomized trial.
cardiac cause within 60 minutes after the onset ofsymptoms.
Myocardial infarction was diagnosed at autopsy or by the presence of two or more of the following: s t u d y d e s i g n a n d p r o c e d u r e s
prolonged chest pain (lasting more than 20 min- The CABG surgery study was conducted at 175 cen- utes) that was not relieved by antianginal agents;ters in 27 countries from January 2003 to January a creatine kinase MB level of more than 25 ng per2004 (see the Appendix). The study was a sponsor- milliliter within 72 hours after CABG (or in excessinitiated, randomized, double-blind, parallel-group, of 10 ng per milliliter more than 72 hours aftermultiple-dose, placebo-controlled study involving CABG) or a peak troponin I level of more than 3.7 µg10 days of study-drug administration and 30 days per liter; new wall-motion abnormalities that wereof follow-up. All patients had access to standard opi- consistent with the occurrence of a myocardialoid medications throughout the 10-day period. The infarction (a two-grade change) detected duringprotocol was approved by the institutional review catheterization, echocardiography, or radionuclideboard at each center. All patients gave written in- scanning; and new Q waves on serial electrocar-formed consent.
diography that were consistent with the occurrence The study included three randomized groups. of myocardial infarction.10 Cerebrovascular events One group received an initial intravenous dose included a new ischemic or hemorrhagic cerebro-of 40 mg of parecoxib on the morning after sur- vascular accident lasting 24 hours or longer or agery (day 1) and then 20 mg of parecoxib every 12 transient ischemic attack lasting less than 24 hours,hours for 3 days, followed by 20 mg of oral valde- diagnosed according to clinical criteria and con-coxib every 12 hours through day 10. One group re- firmed by a diagnostic study (e.g., computed tomog-ceived placebo intravenously every 12 hours for raphy or magnetic resonance imaging).11 Periph-3 days, followed by 20 mg of oral valdecoxib every eral vascular events included deep-vein thrombosis, Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. c o m p l i c a t i o n s o f p a r e c o x i b a n d v a l d e c o x i b i n c a b g defined as increased unilateral or bilateral leg swell- of a radiographic contrast agent within 24 hoursing, warmth, and edema, with a confirmatory diag- before entry, poorly controlled diabetes mellitus (de-nostic test, and pulmonary embolism, defined as fined by a blood glucose level of more than 350 mgchest pain, dyspnea, or hypoxemia, with a confirma- per deciliter [19.4 mmol per liter] or a glycosylatedtory imaging study.
hemoglobin value of more than 9.0 percent after Renal events included renal failure, defined as an overnight fast), and any preoperative coagulop- the need for hemodialysis or peritoneal dialysis af- athy. Patients who were undergoing CABG with-ter CABG, and severe renal dysfunction, defined by out cardiopulmonary bypass were excluded, as werea postoperative serum creatinine level of at least patients undergoing concomitant valvular or vas-2.0 mg per deciliter (176.8 µmol per liter), with an cular surgery and those in whom cardiopulmonaryincrease of at least 0.7 mg per deciliter (61.9 µmol bypass exceeded 3.5 hours. per liter) after randomization.12 Other prerandomization exclusion criteria were Gastroduodenal complications were defined as evidence of a new myocardial infarction (i.e., on a gastrointestinal ulcer resulting in bleeding (prov- the basis of creatine kinase MB or troponin levels,en on the basis of endoscopy), perforation, or ob- new Q waves, or a new elevation in the ST segmentstruction. Wound-healing complications included for more than 10 minutes), the use of an intraaor-infection of the superficial incisional site, deep in- tic balloon pump, a cardiac index of no more thancisional site, or organ or space and noninfectious 1.5 liters per minute per square meter of body-sur-separation or dehiscence of the wound.
face area, receipt of more than two pharmacologic The primary investigator at each site was respon- infusions to support blood pressure, symptomatic sible for reporting all adverse events to the spon- dysrhythmia, a new neurologic deficit, clinically sig-
sor, including directly observed events and those nificant bleeding (defined by a total chest-tube out-
spontaneously reported by the patients. Defini- put of more than 500 ml), a hemoglobin level of no
tions of the predefined end points of interest were more than 8 g per deciliter, urinary output of less
described in detail in the study protocol and reit- than 50 ml per hour, a creatinine level of at least
erated in a newsletter regularly distributed to all 1.8 mg per deciliter (159.1 µmol per liter), or an in-
investigational sites. An independent, external end- crease in the creatinine level of more than 30 per-
point committee (see the Appendix) whose mem- cent since the initial screening.
bers were unaware of the patients’ treatment as-
signments used these definitions to review the data statistical analysis
on adverse events. Adjudicated, predefined adverse We estimated that the enrollment of 500 patients
events in all four categories were combined for the per group would provide the study with a statisti-
primary safety analysis. A data and safety monitor- cal power of at least 80 percent to detect an approx-
ing board (see the Appendix) independently moni- imate doubling of the 4 percent estimated back-
tored safety outcomes throughout the study.
ground incidence of all predefined adverse eventscombined. All eligible patients were stratified first p a t i e n t p o p u l a t i o n
according to risk (high versus low) and then accord- Men and women who were undergoing elective, ing to geographic location (North America, Europe,primary CABG with cardiopulmonary bypass were or another location) before randomization. Patientseligible for the study. Inclusion criteria were an age were considered to be at high risk if they used aspi-of 18 to 80 years; New York Heart Association class rin daily for secondary cardiovascular prophylaxis,I, II, or III or an ejection fraction of at least 35 per- had a history of a cerebrovascular accident, or hadcent; a body-mass index (the weight in kilograms two or more of the following: an age of more thandivided by the square of the height in meters) of no 65 years, a body-mass index of more than 30, dia-more than 40; and a weight of more than 55 kg.
betes, hypertension, or a history of myocardial in- Exclusion criteria were a thromboembolic event farction, deep-vein thrombosis, or pulmonary em- (cerebrovascular accident, transient ischemic at- bolism. (Only 4 percent of the patients in all groupstack, deep-vein thrombosis, or pulmonary embo- combined did not meet the criteria for high risk.)lism) within 3 months before study entry, myocar- Each analysis included all patients who had tak- dial infarction within 7 days before entry, gastric or en at least one dose of study medication. For theduodenal ulcer within 60 days before entry, receipt primary safety analysis, Fisher’s exact test was used Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine to examine the proportion of patients in each group operative characteristics (Table 1) or operative char-
with at least one predefined adverse event. Similar acteristics (Table 2).
analyses were performed for individual events with-
in each of the four end-point categories. For pre- primary end point
defined cardiovascular events, analyses of the time As compared with the placebo group, both the group
to a first event were performed with the use of the given parecoxib and valdecoxib and the group given
log-rank test and presented by means of Kaplan– placebo and valdecoxib had significantly more pa-
Meier curves. All statistical comparisons included tients with at least one confirmed predefined ad-
treatment and country as factors, were two-tailed, verse event (7.4 percent in each of these two groups
and used an a value of 0.05; none of the compari- vs. 4.0 percent in the placebo group; risk ratio for
sons were adjusted for interim analyses.
each comparison with the placebo group, 1.9; 95 Pfizer held the data during the study. The au- percent confidence interval, 1.1 to 3.2; P=0.02 for thors had complete access to the data after unblind- each comparison with the placebo group) (Tableing. All final analyses were conducted by an inde- 3). Furthermore, the incidence of at least one pre-pendent statistician at the Texas Heart Institute in defined adverse event was also significantly higherHouston. The data reported here were those avail- in the pooled COX-2–inhibitor group than in theable to the authors as of February 14, 2005.
placebo group (7.4 percent vs. 4.0 percent; risk ra-tio, 1.9; 95 percent confidence interval, 1.1 to 3.1;P=0.01). Cardiovascular events were significantly more frequent in the group given parecoxib and c h a r a c t e r i s t i c s o f t h e p a t i e n t s
valdecoxib than in the placebo group (2.0 percent A total of 1671 patients underwent randomization: vs. 0.5 percent; risk ratio, 3.7; 95 percent confi-555 were assigned to the group given parecoxib and dence interval, 1.0 to 13.5; P=0.03) (Table 3). Thevaldecoxib, 556 to the group given placebo and val- incidence of cardiovascular events in the group giv-decoxib, and 560 to the placebo group. Enrollment en placebo and valdecoxib (1.1 percent) did not dif-and outcomes are outlined in Figure 1. There were fer significantly from that in either of the other twono significant differences among the groups in pre- groups (Table 3). In fact, three of the six events in Figure 1. Enrollment and Outcome.
Patients who discontinued the study were included in all analyses. All decisions about discontinuation were made by the primary investigator, except for those noted as the sponsor’s decision (made while study-group assignment was still blinded) in the case of four patients (e.g., because of failure to comply with the treatment regimen after discharge from the hospital).
Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. c o m p l i c a t i o n s o f p a r e c o x i b a n d v a l d e c o x i b i n c a b g the group given placebo and valdecoxib occurred ble 3). The incidence of all adverse wound-relatedin patients who had not yet begun treatment with events did not differ significantly between the pla-valdecoxib. The time-to-event analysis revealed that cebo group and the group given parecoxib and val-cardiovascular events occurred throughout and af- decoxib (P=0.48), but the difference between theter the 10-day period of drug administration in all placebo group and the group given placebo andgroups (Fig. 2). Analyses of cardiovascular events valdecoxib approached significance (P=0.08). Ain the pooled COX-2–inhibitor group and the con- comparison of surgical-wound events in the pooledtrol group did not reveal significant differences (1.6 COX-2–inhibitor group and the placebo group didpercent and 0.5 percent, respectively; risk ratio, 2.9; not reveal significant differences (4.3 percent and95 percent confidence interval, 0.8 to 9.9; P=0.08) 2.9 percent, respectively; risk ratio, 1.5; 95 percent(Table 3).
confidence interval, 0.8 to 2.7; P=0.15). A post hoc The incidence of noncardiovascular predefined analysis showed that sternal-wound infections or adverse events (wound-healing complications, renal other complications of sternal-wound healing, suchfailure or dysfunction, and gastroduodenal ulcers) as instability or dehiscence, occurred in 18 of thewas higher in the two COX-2–inhibitor groups than 544 patients in the group given parecoxib and val-in the placebo group, but not significantly so (Ta- decoxib (3.3 percent; 12 infections and 6 other com- Table 1. Preoperative Characteristics of All Randomized Patients.*
Placebo+Valdecoxib
Parecoxib+Valdecoxib
Characteristic
Placebo (N=560)
* Plus–minus values are means ±SD.
† Patients chose one of these four options.
Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Table 2. Characteristics of the Surgical Procedures.*
Placebo+Valdecoxib
Parecoxib+Valdecoxib
Characteristic
Placebo (N=560)
Duration of cardiopulmonary bypass — min Time from end of surgery to administration * Unless otherwise noted, the analysis includes all randomized patients. Plus–minus values are means ±SD.
plications of healing), 20 of the 544 patients in the who had undergone CABG,6 there were only 311group given placebo and valdecoxib (3.7 percent; patients in the group given parecoxib and valde-12 infections and 8 other complications of heal- coxib and 151 patients in the control group. Theseing), and 11 of the 548 patients in the placebo group numbers were sufficient only to detect a doubling(2.0 percent; 9 infections and 2 other complications in the total number of adverse events and an increaseof healing). There were no significant differences by a factor of seven in any single adverse event, suchamong the groups. Analysis of the incidence of ster- as myocardial infarction. In that study, the groupnal-wound events in the pooled COX-2–inhibitor given parecoxib and valdecoxib, as compared withgroup and the placebo group revealed no significant the placebo group, had more perioperative myo-differences (3.5 percent and 2.0 percent, respec- cardial infarctions (5 of 311 vs. 1 of 151) and cere-tively; P=0.10).
brovascular disorders (9 of 311 vs. 1 of 151) report- Eight deaths were reported during the study (Ta- ed by investigators as serious adverse events, but ble 3): seven during the study period and one after these differences were not significant. Our study,the 30-day follow-up period. Of these deaths, four which included more patients, showed a significant-occurred in patients given parecoxib and valdecox- ly higher incidence of combined thromboembolicib, one each caused by cardiac arrest, ventricular fi- events among patients receiving parecoxib and val-brillation, myocardial infarction, and pulmonary decoxib than among patients receiving placebo.
embolism. Three deaths occurred among patients The increased risk of thromboembolic events given placebo and valdecoxib, one each caused by among patients receiving parecoxib and valdecoxibcardiac arrest, cardiac failure, and pneumonia; all after CABG may be due to preexisting generalizedthese deaths occurred in patients who had not yet atherosclerotic disease, exposure to the additionalbegun treatment with valdecoxib. One patient in risks of cardiopulmonary bypass, or both. Certain-the placebo group died from intestinal perforation. ly, platelet activation resulting from shear stresses can occur in patients with atherosclerotic vessels.13When such patients undergo cardiopulmonary by- pass, contact between cellular and humoral blood We found that short-term COX-2 inhibition is asso- components and the synthetic surfaces of the ex-ciated with a significant risk of thromboembolic tracorporeal circuit results in the activation of plate-events in patients at high risk for such events. Al- lets, leukocytes, and endothelial cells, possibly pre-though a hint of this adverse effect was noted in an disposing patients to thrombotic events.14,15 Inearlier trial of parecoxib and valdecoxib in patients addition, aortic cross-clamping, which is necessary Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. c o m p l i c a t i o n s o f p a r e c o x i b a n d v a l d e c o x i b i n c a b g Table 3. Incidence of and Risk Ratios for Predefined Adverse Events and Death among Patients Who Received the Assigned Treatment.*
Both COX-2–
Placebo + Parecoxib +
Inhibitor
Placebo vs.
Placebo vs.
Placebo vs.
Placebo Valdecoxib Valdecoxib
Placebo +
Parecoxib +
Both COX-2–
Adverse Event
(N=548) (N=544)
(N=1088)
Valdecoxib
Valdecoxib
Inhibitor Groups
≥1 Confirmed events
Cardiovascular events
0.31 3.7 (1.0–13.5) 0.03 2.9 (0.8–9.9) Renal failure or dysfunction§
Upper gastrointestinal events 2 (0.4)
2.0 (0.4–11.1) 0.41 3.0 (0.6–15.2) 0.15 2.5 (0.6–11.6) 0.22 Surgical-wound events
3.0 (0.3–29.3) 0.31 4.1 (0.5–36.4) 0.18 3.6 (0.4–29.1) 0.20 * Some patients had more than one event. CI denotes confidence interval, and SSI surgical-site infection.
† P=0.02 for the comparison with the placebo group.
‡ P=0.03 for the comparison with the placebo group.
§ Renal failure or dysfunction was the only type of renal event that occurred.
¶ Gastric or duodenal ulcer was documented by means of endoscopy.
during many cardiac surgical procedures involving bility, inadequate myocardial protection duringcardiopulmonary bypass, results in ischemia–reper- bypass, coronary arterial embolization, or techni-fusion injury of the myocardium.16 Myocardial tis- cal complications, such as spasm or kinking of thesue may be particularly susceptible to ischemia dur- graft.
ing and after CABG because of underlying coronary FitzGerald17 has suggested that an exaggerated artery disease, perioperative hemodynamic insta- thrombotic response in patients receiving selec- Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Cardiovascular Event (%)
Days after Surgery
No. at Risk
Parecoxib+valdecoxib 544
Figure 2. Kaplan¡Meier Estimates of the Time to a Cardiovascular Event.
Cardiovascular events occurred throughout and after the 10-day period of drug administration in all groups. IV denotes intravenous.
tive COX-2 inhibitors may result from the ability of These aspirin doses, administered concurrently withthese drugs to inhibit the production of prostacy- a selective COX-2 inhibitor after CABG, may haveclin without affecting the production of throm- been insufficient to block the formation of throm-boxane A , which is mediated by cyclooxygenase-1 boxane by platelets in some patients.23 Also, 7 of the (COX-1). Prostacyclin, the predominant cyclooxy- 20 thromboembolic events (35.0 percent) occurredgenase product in endothelium, inhibits platelet ag- at least two days after all study medications had beengregation, prevents the proliferation of vascular discontinued. Another factor may be thrombocyto-smooth-muscle cells in vitro, and causes vasodil- sis, which is common within two weeks after sur-atation. Thromboxane A , on the other hand, is gery.24 In clinical conditions of enhanced platelet the chief COX-1–mediated product of platelets and regeneration, the prevalence of COX-2–dependentcauses platelet aggregation, vasoconstriction, and synthesis of thromboxane may be increased.25vascular proliferation.
In the previous CABG study, sternal-wound in- Cardiopulmonary bypass increases the levels fections and healing complications occurred more of both prostacyclin and thromboxane A .18,19 How- often among patients receiving parecoxib and val- ever, administration of aspirin, as in our study, the- decoxib than among those receiving placebo (3.2oretically inhibits the formation of thromboxane percent vs. 0 percent, P=0.04).6 Although sternal-by platelets. Low-dose aspirin prevents myocardial wound complications and all wound complicationsinfarction and stroke,20 and Mangano21 has shown were more frequent among patients receiving pare-that postoperative administration of aspirin is as- coxib alone or with valdecoxib in our study, the dif-sociated with a reduced risk of death and cardiovas- ference fell short of statistical significance. Becausecular and cerebrovascular ischemic complications the COX-2 enzyme mediates prostaglandin syn-after CABG requiring cardiopulmonary bypass. Al- thesis, inhibiting this enzyme might impede repar-though our study protocol required the adminis- ative inflammatory responses. Also, the analgesictration of 75 to 325 mg of aspirin daily, resistance of and antipyretic effects of parecoxib and valdecoxibplatelets to aspirin is known to occur after CABG.22 may have delayed the detection of an incipient ster- Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. c o m p l i c a t i o n s o f p a r e c o x i b a n d v a l d e c o x i b i n c a b g nal-wound infection. Furthermore, in patients un- cedures for atherosclerotic disease, although thisdergoing CABG with cardiopulmonary bypass, the population has not been studied.
increased incidence of serious adverse events, par- Supported in part by Pharmacia and Pfizer.
ticularly thromboembolic events, clearly outweighs Dr. Nussmeier reports having served as a consultant for Pfizer and an advisory-board member for Pfizer and Novartis and having any analgesic benefit of these agents.
received lecture fees from Pfizer on two occasions. Dr. Whelton re- Recent data have shown that patients receiving ports having received advisory fees from TAP Pharmaceuticals, Pfizer, other selective COX-2 inhibitors to prevent colo- GlaxoSmithKline, and Eyetech Pharmaceuticals; lecture fees from Pfizer; and consulting fees from Eyetech Pharmaceuticals. Drs. Brown rectal cancer have a higher incidence of serious ar- and Verburg are employees of Pfizer and report owning equity andterial thromboembolic events than do patients re- stock options in Pfizer. Dr. Langford reports having received grantceiving placebo.17,26 In view of all these findings, support and lecture fees from Pfizer and having served on advisory boards for Pfizer and Novartis. Drs. Hoeft, Parlow, and Boyce report this study, and other current data,27,28 selective having received funds from Pfizer to carry out research related toCOX-2 inhibitors should be avoided in patients this trial.
undergoing CABG. This caution should probably We are indebted to William K. Vaughn, Ph.D., for providing sta- tistical support and to Stephen N. Palmer, Ph.D., E.L.S., for editorial be extended to patients undergoing vascular pro- assistance.
a p p e n d i x
The following persons and institutions participated in the CABG surgery study: Investigators: Academisch Ziekenhuis-Vrije UniversiteitBrussel, Brussels — M. Diltoer; Akademiska Sjukhuset, Uppsala, Sweden — H. Tyden; Allegheny General Hospital, Pittsburgh — T.A.
Gasior; Allegheny Pain Management, Altoona Hospital, Altoona, Pa. — M. Drass; Amarillo Heart Clinical Research Institute, Amarillo, Tex.
— E. Rivera; Anaheim Memorial Medical Center, Anaheim, Calif. — H. Gogia; Arkansas Institute for Research and Education, Fayetteville— J. Weiss; Army’s Center for Cardiovascular Diseases, Bucharest — I. Tintoiu; Av Diaz Velez, Buenos Aires — M. Litvak; Baylor College ofMedicine, Houston — F. Masud; Baylor Medical Center at Irving, Irving, Tex. — J. Overbeck; Beth Israel Deaconess Medical Center, Boston— F. Sellke; Bikur Cholim Medical Center, Jerusalem — E. Deviri; Brevard Cardiothoracic Surgeons, Melbourne, Fla. — M. Malias; CardiacSurgical Associates, Clearwater, Fla. — J. Pruitt; Cardiosurgery, Nemocnice Ceske Budejovice, Czech Republic — D. Cocek; Cardiosurgery,Nemocnice na Homolce, Prague — P. Krivacek; Cardiothoracic Centre, Liverpool, United Kingdom — J. Murphy; Cardiovascular Associatesof Augusta, Augusta, Ga. — A. Chandler; Cardiovascular Surgery Clinic, Memphis, Tenn. — H. Garrett; Catharina Hospital, Eindhoven, theNetherlands — J. Schonberger; Centro Cardiologico Fondazione, Milan, Italy — A. Parolari; Centro Medico Nacional 20 de Noviembre,Mexico City — A. Castro; Christian-Albrechts-Universitaet, Kiel, Germany — J. Scholz; Centre Hospitalier Universitaire Liege, Liege, Bel-gium — M. Lamy; CHUS Hospital Fleurimont, Fleurimont, Que., Canada — M. Colas; Clinical Emergency Floreasca Hospital, Bucharest —S. Bradisteanu; Heart and Vascular Clinic of Northern Colorado, Fort Collins, Colo. — W. Miller; CMN SXXI IMSS-Hospital de Cardiología,Mexico City — G. Careaga; Col. Toriello Guerra C.P., Mexico City — E. Uruchurtu; Constituyentes, Buenos Aires — D. Nul; Crescent Clini-cal Research, Pensacola, Fla. — M. Mancao; CV Surgical Associates, Salisbury, Md. — J. Todd; Queens University and Kingston GeneralHospital, Kingston, Ont., Canada — J. Parlow; Bern University Hospital, Bern, Switzerland — F. Immer; Ospedale Cisanello-AOP-Pisana,Pisa, Italy — M. Mariani; Discovery Alliance, Charleston, S.C. — M. Edwards; Discovery Alliance, Hudson, Fla. — R. Sharma, R. Waters;Discovery Alliance, Mobile, Ala. — W. Higgs; Discovery Alliance, Pensacola, Fla. — S. Myers; Emory University Hospital, Atlanta — J. Ram-say; Feiringklinikken Feiring Heart Clinic, Feiring, Norway — T. Veel; FHS Research Center, Tacoma, Wash. — G. Johnston; FundacionCardio-Infantil, Bogota, Colombia — I. Franco; Fundacion Cardiovascular Del Oriente, Floridablanca, Colombia — O. Gomezese; Funda-cion Clinica Shaio, Bogota, Colombia — R. Buitrago; Fundacion Valle de Lili, Cali, Colombia — M. Villegas; Amphia Hospital, Breda, theNetherlands — P. Rosseel; General University Hospital, Prague — J. Linder; Georg-August-Universitaet, Goettingen, Germany — D. Ket-tler; Hadassah Ein Kerem Medical Center, Jerusalem — A. Elami; Health Science Centre, Winnipeg, Man., Canada — P. Duke; Henry FordHospital, Detroit — R. Brewer; Hopital Erasme, Brussels — D. Schmartz; Hospital Alemán, Buenos Aires — J. Lopez; Hospital Clinico Uni-versitario de Valencia, Valencia, Spain — J. Juste; Hospital de Bellvitge Ciudad Sanitaria L’Hospitalet de Llobregat, Barcelona, Spain — A.
Matarnala; Hospital Medica Sur, Mexico City — O. Gonzalez; Hospital Universitario La Paz, Madrid — A. Jimenez; ICCRS Policlinico, Pa-via, Italy — M. Vigano; IKEM, Prague — J. Pirk; Indiana/Ohio Heart, Fort Wayne — J. Ladowski; Istituto di Clinica Medica Generale e Tera-pia Medica I, Florence, Italy — G. Gensini; Instituto Integral Denton Cooley, Buenos Aires — G. Bortman; Institutul de Boli Carduivas-cykare Timisoara, Timisoara, Romania — S. Dragulescu; INTEGRIS Baptist Medical Center, Oklahoma City — J. Anderson; JacksonvilleCardiovascular Clinic, Jacksonville, Fla. — L. Lohrbauer; Jacksonville Center for Clinical Research, Jacksonville, Fla. — C. Cousar; Johan-nesburg, South Africa — A. Keene; John Radcliffe Hospital, Oxford, United Kingdom — R. Pillai; Juan Badiano No. 1 Col Seccion, MexicoCity — P. Luna; Kaiser Permanente Medical Center, San Francisco — G. Roach; Kaplan Medical Center, Rehowot, Israel — G. Bregman;Karolinska Hospital, Stockholm — H. Jonsson; Katedra Anestezjologii i Intensywnej Terapii, Warsaw — R. Szulc; Keck School of Medicineof the University of Southern California, Los Angeles — P. Lumb; Klinika Kardiochirurgii am w Warszawie, Warsaw — K. Suwalski; KlinikaKardiochirurgii, Szczecin, Poland — S. Wiechowski; Klinikum Kassel, Kassel, Germany — A. Fiehn; Kuopio University Hospital, Kuopio,Finland — P. Lahtinen; L’Hospital de la Santa Creu I Sant Pau, Barcelona, Spain — H. Litvan; Legacy Clinical Research and Technology Cen-ter, Portland, Oreg. — J. Lemmer; London Health Services Centre, London, Ont., Canada — F. Ralley; Mater Misericordiae Hospital, Dublin— B. Marsh; Medical University of South Carolina, Charleston — F. Spinale; Mercy General Health Partners, Muskegon, Mich. — T. Boeve;Michael E. DeBakey Veterans Affairs Medical Center, Houston — S. Saleh-Shenaq; Mid-Atlantic Cardiovascular Associates, Towson, Md. —J. Laschinger; Monash Medical Centre, Clayton, Australia — A. Tucker; Montreal Heart Institute, Montreal — R. Martineau; Mount AuburnHospital, Cambridge, Mass. — S. Tam; Mount Sinai Medical Center, New York — D. Bronheim; National Heart Centre, Singapore — Y.
Chua; Niculae Stancioiu Heart Institute, Cluj-Napoca, Romania — R. Capalneanu; North Ohio Heart Center, Sandusky — W. McGuinn;Northern California Medical Associates, Santa Rosa — P. Coleman; NuLife Clinical Research, Anaheim, Calif. — P. Wadhwa; Odense Uni-versitetshospital, Odense, Denmark — L. Andersen; Oklahoma Heart Institute, Tulsa — W. Leimbach, Jr.; Orange County Heart Instituteand Research Center, Orange, Calif. — D. Pan; Oulu University Hospital, Oulu, Finland — P. Laurila; Panorama Medi Clinic, Parow, West-ern Cape, South Africa — E. Vermaak; Pretoria Academic Hospital, Pretoria, Gauteng, South Africa — D. Du Plessis; Pretoria Heart Hospi- Downloaded from www.nejm.org on February 19, 2005 . For personal use only. No other uses without permission. Copyright 2005 Massachusetts Medical Society. All rights reserved. The new england journal of medicine tal, Pretoria, Gauteng, South Africa — J. Verster; Queen Elizabeth II Health Sciences Centre, Halifax, N.S., Canada — R. Hall; Queen’s Uni-versity, Kingston, Ont., Canada — B. Milne; Ramat Marpeh Medical Center, Petah Tikva, Israel — L.Priscu; Rambam Medical Center, Haifa,Israel — T. Adler; Regina General Hospital, Regina, Sask., Canada — S. Korkola; Research Institute of Transplantology and Artificial Or-gans of MoH, Moscow — I. Kozlov; Rigshospitalet, Copenhagen — P. Olsen; Royal University Hospital, Saskatoon, Sask., Canada — W.
McKay; Royal Victoria Hospital, Montreal — B. De Varennes; Ruprecht-Karls-Universitaet, Universitaetsklinik fuer Anaesthesiologie,Heidelberg, Germany — E. Martin; Russian Research Center of Surgery, Moscow — A. Eremenko; RWTH Aachen Klinik fur Anaesthesiol-ogie, Aachen, Germany — W. Buhre; Rx Trials, Silver Spring, Md. — J. Armitage, S. Boyce, P. Cho, E. Lefrak, A. Qazi; Sacramento Heart andVascular Medical Associates, Sacramento, Calif. — D. Roberts; Sarasota Memorial Health Care System Clinical Research Center, Sarasota,Fla. — C. Lewis; Sentara Norfolk General Hospital, Norfolk, Va. — G. Barnhart; Shaare Zedek Medical Center, Jerusalem — D. Bitran; She-ba Medical Center, Tel Hashomer, Israel — J. Lavee; Slovak Institute of Heart and Vascular Diseases, Bratislava, Slovakia — I. Olejarova; Ho-pitaux Universitaires de Geneve, Geneva — J. Romand; Soroka Medical Center, Beer Sheva, Israel — A. Appelbaum; Sourasky Tel-Aviv Med-ical Center, Tel Aviv — G. Uretzky; South Australian Cardiac Research, Ashford, Australia — J. Knight; St. Andrew’s Place, Spring Hill,Australia — T. Mau; St. Augustine’s Hospital, Berea, South Africa — S. Akoojee; St. Bartholomew’s Hospital, London — R. Langford; St.
James Hospital, Dublin — T. Ryan; St. Paul’s Hospital, Vancouver, B.C., Canada — C. Cole; St. Thomas Hospital, London — R. Feneck;Stanford Medical Center, Stanford, Calif. — C. Mangano; Sterling Research Group, Cincinnati — E. Roth; Sunnybrook and Women’s Col-lege Health Sciences Centre, Toronto — J. Kay; Szpital Kliniczny AM–Klinika Kardiochirurgii, Bialystok, Poland — R. Jackowski; TexasHeart Institute/St. Luke’s Episcopal Hospital, Houston — C. Collard; Dayton Heart Center, Dayton, Ohio — T. Markus; James Cook Univer-sity Hospital, Middlesbrough, United Kingdom — J. Park; Lady Davis Carmel Medical Center, Haifa, Israel — J. Gurevitch; Lindner ClinicalTrial Center, Cincinnati — S. Vester; Royal Infirmary of Edinburgh, Edinburgh — R. Alston; Toronto Hospital, Toronto — J. Karski; West-ern Pennsylvania Hospital, Pittsburgh — J. Grass; Thoraskliniken Universitetssjukhuset, Orebro, Sweden — M. Vidlund; Turku UniversityCentral Hospital, Turku, Finland — T. Savunen; UCLA Medical Center, Los Angeles — J. Jah; Jagiellonian University, Krakow, Poland —J. Sadowski; Unitas Hospital, Pretoria, South Africa — W. Mohr; Universitaet Bonn, Klinik und Poliklinik fuer Anaesthesiologie und spez-ielle Intensivmedizin, Bonn, Germany — A. Hoeft; Universitaetsklinik fuer Anaesthesiologie, Gefaesschirurgie, Graz, Austria — G. Rum-pold-Seitlinger; Universitaetsklinikum Giessen, Giessen, Germany — G. Hempelmann; Universitaetsklinikum Grosshadern, Munich,Germany — E. Ott; Universitaetsklinikum Hamburg-Eppendorf Klinik und Poliklinik fuer Anaesthesiologie, Hamburg, Germany —J. Esch; Universitaetsklinikum Muenster Anaesthesiologie, Muenster, Germany — H. Van Aken; Universitair Ziekenhuis Antwerpen, Ede-gem, Belgium — R. De Paep; University Community Hospital, Tampa, Fla. — M. Bloom; University Hospital Kralovaske Vinohrady, Prague— Z. Straka; University Hospital Motol, Prague — J. Vojacek; University of Alberta Hospital, Edmonton, Canada — B. Finegan; Universityof Arizona, Tucson — P. Lichtenthal; University of California San Francisco, San Francisco — I. Russell; University of Iowa Hospitals andClinics, Iowa City — J. Everett; University of Kansas Medical Center, Kansas City — P. Hild; University of North Texas Health Science Centerat Fort Worth, Fort Worth — A. Olivencia-Yurvati; University of Texas Medical School, Houston — E. Pivalizza; University of the Free State,Bloemfontein, South Africa — A. Kachellhoffer; University of Vermont, Burlington — J. Rathmell; University of Wisconsin Medical School,Madison — R. Love; Vancouver General Hospital, Vancouver, B.C., Canada — H. Umedaly; Viahealth Rochester General Hospital, Roches-ter, N.Y. — R. Kirshner; Vychodoslovensky Ustav Srdcovych Chorob, Kosice, Slovakia — M. Hulman; Weezenlanden Hospital, Zwolle, theNetherlands — A. Nierich; Wilgers Hospital, Pretoria, Gauteng, South Africa — M. Versace; William Beaumont Hospital, Royal Oak, Mich.
— C. Hatrick; Wisconsin Center for Clinical Research, Milwaukee — C. Lanzarotti; Wolfson Medical Center, Holon, Israel — B. Medalion;Yale New Haven Hospital, New Haven, Conn. — S. Garwood; Ziekenhuis Oost-Limburg-Campus, Sint Jan, Belgium — R. Heylen; End-Point Committee: P. Barash, J. Brinker, G. Gerstenblith, J. Goldstein P. Gorelick, M. Kelly, P. Waymack, A. Whelton (chair); Data and SafetyMonitoring Board: G. Faich (chair), P. Hsu, M. Newman, W. White, D. Berry.
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