Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial
Robert S. Bresalier, M.D., Robert S. Sandler, M.D., Hui Quan, Ph.D., James A. Bolognese, M.Stat., Bettina Oxenius, M.D., Kevin Horgan, M.D., Christopher Lines, Ph.D., Robert Riddell, M.D., Dion Morton, M.D., Angel Lanas, M.D., Marvin A. Konstam, M.D., John A. Baron, M.D., for the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators
Background Selective inhibition of cyclooxygenase-2 (COX-2)may be associated with an increased risk of thrombotic events,but only limited long-term data have been available for analysis.We report on the cardiovascular outcomes associated with theuse of the selective COX-2 inhibitor rofecoxib in a long-term,multicenter, randomized, placebo-controlled, double-blind trialdesigned to determine the effect of three years of treatmentwith rofecoxib on the risk of recurrent neoplastic polyps ofthe large bowel in patients with a history of colorectal adenomas.
Methods A total of 2586 patients with a history of colorectaladenomas underwent randomization: 1287 were assigned to receive25 mg of rofecoxib daily, and 1299 to receive placebo. All investigator-reportedserious adverse events that represented potential thromboticcardiovascular events were adjudicated in a blinded fashionby an external committee.
Results A total of 46 patients in the rofecoxib group had aconfirmed thrombotic event during 3059 patient-years of follow-up(1.50 events per 100 patient-years), as compared with 26 patientsin the placebo group during 3327 patient-years of follow-up(0.78 event per 100 patient-years); the corresponding relativerisk was 1.92 (95 percent confidence interval, 1.19 to 3.11;P=0.008). The increased relative risk became apparent after18 months of treatment; during the first 18 months, the eventrates were similar in the two groups. The results primarilyreflect a greater number of myocardial infarctions and ischemiccerebrovascular events in the rofecoxib group. There was earlierseparation (at approximately five months) between groups inthe incidence of nonadjudicated investigator-reported congestiveheart failure, pulmonary edema, or cardiac failure (hazard ratiofor the comparison of the rofecoxib group with the placebo group,4.61; 95 percent confidence interval, 1.50 to 18.83). Overalland cardiovascular mortality was similar in the two groups.
Conclusions Among patients with a history of colorectal adenomas,the use of rofecoxib was associated with an increased cardiovascularrisk.
Nonsteroidal antiinflammatory drugs (NSAIDs) alleviate painand inflammation but may cause gastrointestinal ulceration andbleeding, presumably by inhibiting cyclooxygenase (COX)-mediatedproduction of prostaglandins. The discovery that there weretwo forms of cyclooxygenase, 1 (COX-1) and 2 (COX-2), providedthe impetus for the development of selective inhibitors of COX-2with a reduced risk of gastrointestinal complications whoseanalgesic and antiinflammatory efficacy was likely to be similarto that of nonselective COX inhibitors.
COX-2 is expressed at sites of inflammation, such as in atheromatousplaques, and in neoplasms, raising the possibility that COX-2inhibition might also be useful in the treatment or preventionof atherosclerosis and various cancers.1,2 However, predictingthe consequences of COX-2 inhibition on cardiovascular diseaseis not a straightforward proposition. COX-2 inhibition has severaleffects that could increase the risk of cardiovascular disease,including reducing prostacyclin levels, increasing blood pressure,decreasing angiogenesis,3,4,5,6,7,8,9,10,11 and destabilizingplaque.12
Rofecoxib is a selective COX-2 inhibitor that has been shownto be associated with significantly fewer gastrointestinal adverseevents than NSAIDs.13 In one trial,13 there were more cardiovascularevents among patients given a high dose of rofecoxib than amongthose given naproxen, an NSAID with platelet-inhibiting propertiesof unclear clinical relevance.4,5,14,15,16 Pooled data fromother randomized trials have not shown a significant differencein cardiovascular risk between rofecoxib and placebo or othernonselective NSAIDs.4,5,17 Observational studies have providedconflicting data on the association of rofecoxib with cardiovascularrisk: some studies suggested that there was no effect, somesuggested that the risk was increased only at high doses, andothers indicated a possible increase in the risk of cardiovascularevents at standard or unspecified doses.6,9,11,18,19,20,21
The Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial wasdesigned to evaluate the hypothesis that three years of treatmentwith rofecoxib would reduce the risk of recurrent adenomatouspolyps among patients with a history of colorectal adenomas.Potential thrombotic events were adjudicated by an independentcommittee, and all safety data were monitored by an externalsafety-monitoring committee. We report the cardiovascular findingsfrom the study.
Methods
Design of the Trial
Enrollment occurred from February 2000 to November 2001 at 108centers in 29 countries. Participating investigators are listedin the Appendix. Men and women who were at least 40 years oldwere eligible if they had had at least one histologically confirmedlarge-bowel adenoma removed within 12 weeks before study entryand were not anticipated to need long-term NSAID therapy (includinghigh-dose aspirin) during the study. Initially, patients whowere taking low-dose aspirin (no more than 100 mg daily) wereexcluded from the study. However, in May 2000, after the resultsof the Vioxx Gastrointestinal Research (VIGOR) trial13 had becomeavailable, the protocol was amended to allow randomized subjectsto take low-dose aspirin (no more than 100 mg daily) for cardiovascularprotection. The proportion of subjects taking low-dose aspirinat enrollment was capped at 20 percent because of the possiblechemopreventive effects of the drug.22 Exclusion criteria wereevidence of uncontrolled hypertension (defined by a blood pressureof more than 165/95 mm Hg); angina or congestive heart failure,with symptoms evoked by minimal activity; myocardial infarction,coronary angioplasty, or coronary-artery bypass grafting withinthe preceding year; or stroke or transient ischemic attack withintwo years before screening.
Written informed consent was obtained from all patients. Theinstitutional review board at each center approved the study.
Treatment
The randomized treatment period was preceded by a six-week,single-blind, placebo run-in period to assess patients' compliance.Patients who took at least 80 percent of their tablets duringthe placebo run-in period were randomly assigned to receiveeither one 25-mg tablet of rofecoxib per day (the maximal recommendedlong-term daily dose) or one identical-appearing placebo tabletper day for three years. The computer-derived randomizationwas stratified according to the clinical center and the useor nonuse of low-dose aspirin, with blocks of 2. Patients, investigators,and sponsor personnel who monitored the study, other than theunblinded study statistician, were unaware of the treatmentassignments.
Patients were evaluated clinically at randomization and at weeks4, 17, 35, 52, 69, 86, 104, 121, 138, 156, and 158 or afterthe discontinuation of treatment. Vital signs, including bloodpressure obtained while the patient was seated, were measuredat each clinic visit during the study according to the usualclinical practice. Adverse events occurring during the studywere recorded and evaluated in a blinded fashion by the investigators.Follow-up of the patients for one year after the discontinuationof treatment is ongoing.
Cardiovascular Events
Monitoring and analysis of the cardiovascular events in thetrial were part of a planned assessment of the cardiovascularsafety of rofecoxib. Data presented include events occurringduring treatment and up to 14 days after the last dose of thestudy drug. Serious vascular events were reviewed in a blindedfashion by adjudication committees, which confirmed events thatmet prespecified case definitions for two sets of events. Thromboticevents included fatal and nonfatal myocardial infarction, unstableangina, sudden death from cardiac causes, fatal and nonfatalischemic stroke, transient ischemic attack, peripheral arterialthrombosis, peripheral venous thrombosis, and pulmonary embolism.The end point used in the Antiplatelet Trialists' Collaboration(APTC) study23 was also analyzed: the combined incidence ofdeath from cardiovascular, hemorrhagic, and unknown causes;nonfatal myocardial infarction; and nonfatal ischemic and hemorrhagicstroke. Other relevant but not independently adjudicated eventswere also analyzed, including hypertension-related events, edema-relatedevents, and the combined end point of congestive heart failure,pulmonary edema, or cardiac failure.
The procedure for confirming cardiovascular events was prespecifiedin the protocol. All serious adverse events were identifiedand recorded by the clinical investigators. Potential thromboembolicevents, components of the APTC end point, and all deaths (regardlessof cause) were prespecified as eligible for adjudication accordingto standard procedures for rofecoxib studies initiated by thesponsor in 1998. For each eligible event, source documents werecollected and sent to the cardiac, cerebrovascular, or peripheralvascular adjudication committee. Decisions were made on thebasis of majority rule with the use of prespecified criteria.
Statistical Analysis
An independent, external safety-monitoring board met periodicallyto review safety data provided by a statistician who was awareof patients' study-group assignments. No formal stopping rulewas specified for terminating the study.
Data were collected and held by the sponsor. The investigatorshad full and unfettered access to the data. A statistician whowas aware of patients' study-group assignments but who was nototherwise involved in the study analyzed the data using SASsoftware (version 8.2). All patients who underwent randomizationand took at least one dose of study medication were includedin the analyses. For confirmed serious thrombotic events andthe APTC end point, event rates were determined and relativerisks (with 95 percent confidence intervals) were calculatedwith the use of Cox proportional-hazards models. However, ifthere were fewer than 11 events in either group, the rate ratiowas computed with the use of the binomial distribution.24 Atest of the proportional-hazards assumption was specified inthe cardiovascular-analysis plan. This was accomplished by evaluatingthe interaction between the logarithm of time and the assignedtreatment in the Cox proportional-hazards model. Kaplan–Meierestimates of the cumulative event rates over time were alsomade.
Several exploratory analyses were performed to delineate therelation between mean arterial pressure and the study findings.One analysis summarized the relative risk of confirmed seriousthrombotic adverse events according to the quartiles of changein mean arterial pressure at week 4. This time was chosen becausetreatment-based differences in mean arterial pressure occurredearly and remained constant throughout the treatment periodand because only two confirmed serious thrombotic events hadoccurred by week 4 (one in each group). The second analysisincluded changes from baseline in mean arterial pressure asa time-varying covariate in a Cox proportional-hazards modelin which treatment was the main effect. This model was usedto investigate the association of the change in blood pressureover time with the occurrence of confirmed serious thromboticevents.
The data reported here are those available to the authors asof February 14, 2005.
Results
Participants
A total of 3260 patients were screened for the study, of whom2586 were deemed to be eligible; 1287 of the eligible patientswere randomly assigned to receive rofecoxib, and 1299 to receiveplacebo (Figure 1). The two groups were generally similar withregard to baseline characteristics, including age, sex, useor nonuse of low-dose aspirin, and cardiovascular-risk status(Table 1). Concomitant medications used at some time duringthe study included low-dose aspirin (in 20 percent of the rofecoxibgroup and 19 percent of the placebo group, P=0.52), antihypertensivedrugs (44 percent and 36 percent, respectively; P<0.001),lipid-lowering agents (31 percent and 28 percent, respectively;P=0.09), antiplatelet agents such as clopidogrel (4 percentand 2 percent, respectively; P=0.003), insulin (3 percent and2 percent, respectively; P=0.10), and oral hypoglycemic agents(13 percent and 11 percent, respectively; P=0.12).
Figure 1. Enrollment, Randomization, and Outcomes.
The original study design included a group assigned to receive 50 mg of rofecoxib per day; 26 patients had been assigned to this treatment before it was decided not to proceed with this group.
Table 1. Baseline Characteristics of the Patients.
The study was terminated on September 30, 2004, approximatelytwo months ahead of the planned date of completion, at the recommendationof the external safety-monitoring board and the steering committee.At the time of termination, a total of 877 patients in the rofecoxibgroup and 980 patients in the placebo group had completed thescheduled three years of treatment. The mean duration of treatmentwas 2.4 years in the rofecoxib group and 2.6 years in the placebogroup.
Before September 30, 2004, more patients discontinued rofecoxibtreatment than placebo (32 percent vs. 25 percent) (Figure 1).The main reason for discontinuation was an adverse clinicalevent. The three most common adverse events resulting in thediscontinuation of treatment were hypertension (25 patientsin the rofecoxib group and 7 patients in the placebo group),increased blood pressure (6 in the rofecoxib group and 1 inthe placebo group), and peripheral edema (7 in the rofecoxibgroup and 1 in the placebo group).
Incidence of Thrombotic Events and the APTC End Point
A total of 121 patients had investigator-reported serious thromboticevents (77 in the rofecoxib group and 44 in the placebo group).A total of 46 patients in the rofecoxib group had confirmed(i.e., adjudicated) thrombotic events during 3059 patient-yearsof follow-up (1.50 events per 100 patient-years), and 26 patientsin the placebo group had such events during 3327 patient-yearsof follow-up (0.78 event per 100 patient-years). As comparedwith the placebo group, the rofecoxib group had an increasedrisk of confirmed thrombotic events (relative risk, 1.92; 95percent confidence interval, 1.19 to 3.11). The types of confirmedserious thrombotic events are shown in Table 2. The differencebetween the two groups was mainly due to an increased numberof myocardial infarctions and strokes in the rofecoxib group.There were 10 deaths in each group. Myocardial infarction wasthe cause of death in two patients in the rofecoxib group andthree in the placebo group, sudden death from cardiac causesoccurred in three patients in the rofecoxib group and one inthe placebo group, ischemic stroke was the cause of death inone patient in the rofecoxib group, and hemorrhagic stroke wasthe cause of death in one patient in the placebo group.
Table 2. Incidence of Adjudicated Thrombotic Adverse Events.
In a post hoc analysis, the difference between the two groupsin the incidence of thrombotic events was evident in the second18 months of the study, whereas the event rates were similarfor the first 18 months (Figure 2 and Table 3). The changingpattern of the treatment effect over time was confirmed by afailed test for proportionality of hazards (P=0.01). Findingsfor the APTC end point were similar (Table 3).
Table 3. Summary of Rates and Relative Risks of Confirmed Serious Thrombotic Events and the APTC End Point.
There were no significant interactions between treatment groupand subgroups (P>0.10 for all comparisons) for confirmedserious thrombotic events in subgroup analyses based on country(United States vs. other); age; sex; use or nonuse of antihypertensivedrugs at baseline, low-dose aspirin at baseline, or low-doseaspirin for more than 50 percent of follow-up; presence or absenceof a history of hypertension, hypercholesterolemia, or ischemicheart disease; presence or absence of current cigarette use;or presence or absence of a high cardiovascular risk. A highcardiovascular risk was defined by a history of symptomaticatherosclerotic cardiovascular disease or the presence of atleast two of the following risk factors for coronary arterydisease: a history of hypertension, a history of hypercholesterolemia,a history of diabetes, or current cigarette use. However, pointestimates for the relative risk in the rofecoxib group as comparedwith the placebo group were particularly high among patientswith a history of symptomatic atherosclerotic cardiovasculardisease (9.59; 95 percent confidence interval, 1.36 to 416)relative to those without such a clinical history (1.58; 95percent confidence interval, 0.95 to 2.64; P for interaction= 0.096). Also, the relative risk in the rofecoxib group ascompared with the placebo group was 6.10 among patients witha history of diabetes (95 percent confidence interval, 1.36to 56.1), in contrast to a relative risk of 1.55 among patientswith no history of diabetes (95 percent confidence interval,0.92 to 2.61; P for interaction = 0.091).
Nonadjudicated Cardiovascular Events
As compared with the placebo group, the rofecoxib group hadhigher percentages of patients with hypertension-related eventsand edema-related events. The Kaplan–Meier curves forthe cumulative incidence of congestive heart failure, pulmonaryedema, and cardiac failure (Figure 3) showed early separationof the two groups (at approximately five months), with no significantdepartures from proportional hazards over time and a hazardratio of 4.61 for the comparison of the rofecoxib group withthe placebo group (95 percent confidence interval, 1.50 to 18.83).The hazard ratios for edema and hypertension were lower thanthose for the combined end point of congestive heart failure,pulmonary edema, or cardiac failure (Table 4), but the eventcurves showed an early separation similar to that for the combinedend point (data not shown).
Table 4. Incidence of Nonadjudicated Cardiovascular Adverse Events.
During the trial, the rofecoxib group had mean (±SE)increases of 3.4±0.4 mm Hg in systolic blood pressureand 0.9±0.2 mm Hg in diastolic blood pressure, as comparedwith respective changes of –0.5±0.3 mm Hg and –0.8±0.2mm Hg in the placebo group (P<0.01 for the comparison betweenthe two groups). Blood-pressure effects were seen by four weeksand remained relatively constant throughout the study. To investigatethe relation between changes in blood pressure and confirmedthrombotic events, we categorized patients according to thechange from baseline in mean arterial pressure at four weeks.The relative risks of a confirmed thrombotic event in the rofecoxibgroup, as compared with the placebo group, were broadly similaracross quartile categories of the change in blood pressure (datanot shown). The mean arterial pressure throughout the study,included as a time-varying covariate, did not materially modifythe treatment effect (relative risk for the comparison of therofecoxib group with the placebo group, 1.87; 95 percent confidenceinterval, 1.14 to 3.06).
Discussion
COX-2 inhibitors have been widely used as antiinflammatory andpain-relief agents and may hold promise as chemopreventive agentsfor a variety of epithelial cancers. In this randomized, placebo-controlled,double-blind trial, we found that long-term use of the COX-2inhibitor rofecoxib was associated with an increased risk ofcardiovascular events. In post hoc analyses, the increased relativerisk of adjudicated thrombotic events was first observed afterapproximately 18 months of treatment. The overall risk did notappear to be significantly influenced by baseline or subsequentuse of low-dose aspirin. In addition, there was an increasedfrequency of investigator-reported events, such as hypertension,edema, and congestive heart failure, which occurred much earlierin the study.
Thromboxane A2, a major COX-1–mediated product of arachidonicacid metabolism, causes irreversible platelet aggregation, vasoconstriction,and smooth-muscle proliferation, whereas prostacyclin is aninhibitor of platelet aggregation, a vasodilator, and an inhibitorof smooth-muscle proliferation. COX-2 is the chief source ofsystemic prostacyclin synthesis,25 and COX-2 inhibitors mayincrease the cardiovascular risk by shifting the functionalbalance of these vasoactive eicosanoids toward the promotionof thrombosis or atherogenesis. COX-2 inhibition combined withthromboxane-receptor antagonism may also lead to the destabilizationof atheromatous plaque.12 In addition, COX-2 plays a role inangiogenesis.1 How these pharmacologic observations relate tothe clinical cardiovascular findings with COX-2 inhibition isunknown. It is also not clear whether the partial inhibitionof COX-1 by various nonselective NSAIDs offsets any adversecardiovascular effects of COX-2 inhibition, since this possibilityhas not been evaluated explicitly in trials.
The VIGOR study13 compared 50 mg of rofecoxib daily with 500mg of naproxen twice daily in patients with rheumatoid arthritisand found rofecoxib to be associated with a higher incidenceof myocardial infarction. It was unclear how much of the increasein risk was due to a deleterious effect of high-dose rofecoxib,a protective effect of naproxen, chance, or a combination ofthese factors.26 A recent meta-analysis21 suggested that themagnitude of any cardioprotective effect of naproxen is unlikelyto account entirely for these findings.
In aggregate, previous randomized, controlled trials comparingrofecoxib with placebo or conventional NSAIDs other than naproxenhave not demonstrated an increased cardiovascular risk associatedwith rofecoxib use. Analysis of a database including 5435 patientswith osteoarthritis in eight double-blind, placebo-controlled,phase 2B or phase 3 trials reported similar rates of thromboticcardiovascular adverse events with rofecoxib, placebo, and variousnonselective NSAIDs.5 A pooled analysis of data from more than28,000 patients with various diseases (representing more than14,000 patient-years at risk) from 23 previous trials of rofecoxib(phase 2B through phase 5), including patients from the VIGORtrial, also did not demonstrate a significant increase in cardiovascularrisk for rofecoxib as compared with placebo or NSAIDs otherthan naproxen.4 This analysis used the APTC end point we evaluated.An updated analysis that included data from various placebo-controlledstudies investigating rofecoxib for the treatment or preventionof Alzheimer's disease did not demonstrate an excess of cardiovascularevents associated with rofecoxib therapy.5 A recent meta-analysiscomparing cardiovascular risk in trials that included variousdoses of rofecoxib suggested an increased relative risk amongpatients taking rofecoxib, as compared with those taking naproxen,but not placebo.22 Differences between our results and theseearlier clinical-trial data may be related to differences indefined end points or the duration of treatment, a possibilitysupported by the apparent absence of a difference in adjudicatedthrombotic events during the first 18 months of our study.
Observational studies have provided conflicting data on thecardiovascular safety of rofecoxib. A Canadian retrospectivecohort study did not demonstrate an increased risk of myocardialinfarction among new users of rofecoxib as compared with controlsubjects,18 but a case–control study of patients 65 yearsof age or older suggested a dose-dependent elevation in therelative risk of acute myocardial infarction with rofecoxibtherapy.7 Unlike the findings in the current study, this riskwas elevated during the first 90 days of use, but not thereafter.A retrospective cohort study that assessed the occurrence ofserious coronary heart disease among NSAID users19 showed anelevated cardiovascular risk associated with the use of high-doserofecoxib, but no increased risk with the use of doses of 25mg or less.
In our randomized, placebo-controlled trial, we found an increasedrisk of confirmed thrombotic events associated with the long-termuse of rofecoxib. The increase in adjudicated thrombotic eventsassociated with rofecoxib therapy was not evident during thefirst 18 months of the trial. Other investigator-reported cardiovascularevents known to be associated with NSAID use, such as congestiveheart failure and pulmonary edema, although less well defined,occurred earlier (at approximately five months) and at a higherrate among patients taking rofecoxib than among those takingplacebo.
Patients in the rofecoxib group had increases in systemic arterialpressure during the trial, a finding that is consistent withthe previously reported renovascular effects of NSAIDs. Thesechanges in blood pressure were observed early in the study,along with investigator-reported edema and congestive heartfailure. Mean arterial pressure did not appear to have a significantassociation with confirmed thrombotic events, however, accordingto an assessment of changes from baseline to four weeks andan analysis that included mean arterial pressure as a time-varyingcovariate in a model of treatment effects. On the basis of thesefindings, it is unlikely that changes in blood pressure werethe explanation for the excess cardiovascular risk in our study.However, hemodynamic changes could have contributed to a degreethat is difficult to determine from the available data.
It is unclear whether the results seen with rofecoxib representa general effect of COX-2 inhibitors or a specific effect ofrofecoxib. A recent case–control study27 suggested thatthe odds of nonfatal myocardial infarction differ between patientswho take rofecoxib and those who take celecoxib, and a nestedcase–control study20 also suggested that there are differencesin the risk of serious coronary heart disease between the twoagents. Elsewhere in this issue of the Journal, Nussmeier etal. report that patients who received parecoxib and valdecoxibfor pain in the first 10 days after coronary-artery bypass graftinghad an increased risk of cardiovascular events during 30 daysof follow-up.28 Also in this issue, Solomon et al. report thatan ongoing safety review of the Adenoma Prevention with CelecoxibTrial revealed that the risk of fatal or nonfatal cardiovascularevents was increased by a factor of 2.3 among patients who wererandomly assigned to receive celecoxib, as compared with thosewho were assigned to receive placebo,29 leading the NationalCancer Institute to suspend the trial. The possibility thatconventional NSAIDs may have similar effects also has to beconsidered. Possible cardiovascular effects will need to betaken into account in an assessment of the potential abilityof any of these drugs to prevent neoplasia in the large boweland other organs.
Funded by Merck Research Laboratories.
Drs. Bresalier, Sandler, Riddell, Morton, Lanas, and Baron reporthaving received consulting fees from Merck Research Laboratories.Dr. Baron also reports having served as an unpaid consultantto Bayer. Dr. Konstam reports having received consulting feesfrom Merck. Mr. Bolognese and Drs. Quan, Oxenius, Horgan, andLines are employees of Merck, and Drs. Quan, Oxenius, Horgan,and Lines and Mr. Bolognese own equity in the company.
* The members of the APPROVe Trial are listed in the Appendix.
Source Information
From the Department of Gastrointestinal Medicine and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston (R.S.B.); the Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill (R.S.S.); Merck Research Laboratories, West Point, Pa. (H.Q., J.A. Bolognese, B.O., K.H., C.L.); the Department of Pathology, Mount Sinai Hospital, Toronto (R.R.); the Department of Surgery, University of Birmingham, Birmingham, United Kingdom (D.M.); the Department of Medicine, Clinic University Hospital, Zaragoza, Spain (A.L.); the Department of Medicine, Tufts–New England Medical Center, Boston (M.A.K.); and the Departments of Medicine and Community and Family Medicine, Dartmouth Medical School, Hanover, N.H. (J.A. Baron). This article was published at www.nejm.org on February 15, 2005.
Address reprint requests to Dr. Bresalier at the Department of Gastrointestinal Medicine and Nutrition, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030-4009, or at rbresali{at}mdanderson.org.
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Appendix
The following persons and institutions participated in the APPROVeTrial: Steering Committee — J.A. Baron (chair), R.S. Bresalier,R.S. Sandler, R. Riddell, D. Morton, A. Lanas, B. Oxenius (nonvotingmember), J.A. Bolognese (nonvoting member), K. Horgan (nonvotingmember); External Safety Monitoring Board — J. Neaton(chair), M.A. Konstam, D. Bjorkman, R. Logan, H. Quan (nonvotingmember); Adjudication Committees — Cardiology: L.S. Dreifus,G. Vetrovec, B. Chaitman; Neurology: H. Adams, J.P. Mohr, J.Zivin; Peripheral Vascular: J. Ginsberg, C. Kearon, T. Rooke;Gastrointestinal: M. Griffin, M. Langman, D. Jensen; Investigators— M. Aguilar, Clinica Aguilar Bonilla, San Jose, CostaRica; P. Angus, Austin & Repatriation Medical Centre, Heidelberg,Australia; N. Arber, Tel Aviv Sourasky Medical Center, Tel Aviv;J.M.P. Badia, Hospital Clinic I Provincial, Barcelona, Spain;R.D. Baerg, Tacoma Digestive Disease Center, Tacoma, Wash.;H. Baistrocchi, Unidad de Aparato Digestivo Julio Dante Baistrocchi,Cordoba, Argentina; M.L. Barclay, Christchurch Hospital, Christchurch,New Zealand; C. Beglinger, University of Basel, Basel, Switzerland;G. Bianchi-Porro, Ospedale Luigi Sacco, Milan; T. Bolin, Princeof Wales Hospital, Randwick, Australia; R.M. Bostick, PalmettoHealth South Carolina Cancer Center, Columbia; R.S. Bresalier,A.A. Dekovich, T. Ben-Menachem, S.K. Batra, Henry Ford Hospital,Detroit; E. Bruun, J. Christiansen, Amtssygehuset i Herlev,Herlev, Denmark; C. Burke, Cleveland Clinic Foundation, Cleveland;E. Butruk, Akademia Medyczna w Warszawie, Warsaw; L. Capurso,Azienda Ospedaliera San Filippo, Rome; J.P. Cello, San FranciscoGeneral Hospital, San Francisco; S. Chaussade, Hospital CochinSaint-Jacques, Paris; D.P. Cleland, Montreal General Hospital,Montreal; G. Costamagna, Universita Cattolica del Sacro Cuore,Rome; P. Crone, Kobenhavns Amtssygehus i Glostrup, Glostrup,Denmark; E.V. Cutsem, Universitaire Ziekenhuizen, Leuven, Belgium;G.R. D'Haens, Imeldaziekenhuis, Bon Heiden, Belgium; W. Dekker,J. Ferwerda, Kennemer Gasthuis, Haarlem, the Netherlands; E.Dominguez-Munoz, Hospital de Conxo, La Coruna, Spain; D.S. Eskreis,R.E. Tepper, Long Island Clinical Research Associates, GreatNeck, N.Y.; R. Estela, Hospital Clinico San Borja-Arriaran,Santiago, Chile; M. Färkkilä, University Central Hospital,Helsinki; G.M. Fugarolas, J.F. deDios, Hospital UniversitarioReina Sofia, Cordoba, Spain; A. Giacosa, Instituto NazionalePer La Ricerca Sul Cancro, Genoa, Italy; M.J. Goldstein, LongIsland Gastro Intestinal Research Group, Great Neck, N.Y.; F.Gomollon-Garcia, Hospital Universitario Miguel Servet, Zaragoza,Spain; P. Gandrup, Aalborg Syenhus, Aalborg, Denmark; A. Habr-Gama,Hospital das Clinicas da Faculdade de Medicina da Universidadede São Paulo, São Paulo; M. Haque, S. Parry, MiddlemoreHospital, Auckland, New Zealand; R. Hardi, Metropolitan GastroenterologyGroup, Chevy Chase, Md.; W. Harford, Veterans Affairs MedicalCenter, Dallas; S.M. Harris, N.B. Vakil, Aurora Sinai MedicalCenter, Milwaukee; P.R. Holt, D.P. Kotler, Saint Luke's–RooseveltHospital, New York; P.A. Holt, Endoscopic Microsurgery Associates,Towson, Md.; R.W. Hultcrantz, Karolinska Universitetssjukhuset-Solna,Stockholm; S.H. Itzkowitz, Mount Sinai Medical Center, New York;R.F. Jacoby, University of Wisconsin Medical School, Madison;K.E.J. Jensen, Centralsygehuset Esbjerg Varde, Esbjerb, Denmark;J.F. Johanson, Rockford Gastroenterology Associates, Rockford,Ill.; P.W. Jørgensen, Bispebjerg Hospital, Copenhagen;K.E. Kim, University of Chicago Medical Center, Chicago; P.Knoflach, AKH Barmherzige, Schwestern vom heiligen Kreuz, Wels,Austria; M. Koch, Capital Gastroenterology Consultants, SilverSpring, Md.; B. Koch, St. Vincenz Krankenhaus, Datteln, Germany;A. Lanas, University Clinical Hospital, Zaragoza, Spain; M.R.Lane, Auckland City Hospital, Auckland, New Zealand; T.R. Liebermann,Radiant Research, Austin, Tex.; M. Lukas, Univerzita Karlova,Prague; C.M. Schmitt, Southern Clinical Research, Chattanooga,Tenn.; F. Macrae, Cabrini Hospital, Malvern, Australia; E.E.Maiza, Hospital Jose Joaquin Aguirre, Santiago, Chile; N.E.Marcon, Toronto; R.D. Marks, Alabama Digestive Research Center,Alabaster; C.E. Martinez, Hospital Militar Central, Bogota,Colombia; R. McLeod, Mount Sinai Hospital, Toronto; K.R. McQuaid,Veterans Affairs Medical Center, San Francisco; G. Minoli, OspedaleValduce Reparto, Como, Italy; M. Montoro, Hospital San Jorge,Huesca, Spain; A. Montoya, Clinica Shaio, Bogota, Colombia;G. Morelli, Optimum Clinical Research, Montreal; D.G. Morton,Queen Elizabeth Hospital, Edgbaston, United Kingdom; T.J. Myrhoj,J.R. Andersen, Hvidovre Hospital, Hvidovre, Denmark; A. Nakad,Hospital Notre Dame, Tournai, Belgium; V. Narayen, GastrointestinalDiagnostic Center, Baltimore; Y. Niv, Rabin Medical Center,Petah Tikva, Israel; P.M. Pardoll, S. Scheinert, Center forDigestive Diseases, St. Petersburg, Fla.; C. Phino, J.M. Soares,Celestial Ordem Terceira da Santissima, Porto, Portugal; I.Pokorny, Prerov, Czech Republic; J. Ponce-Garcia, Hospital UniversitariLa Fe Valencia, Valencia, Spain; T. Ponchon, Hospital EdouardHerriot, Lyon, France; J.H. Pressman, San Diego Digestive DiseaseConsultants, San Diego, Calif.; V. Prochazka, Fakultni NemocniceOlomouc, Olomouc, Czech Republic; J.M. Provenza, Louisiana ResearchCenter, Shreveport; W.S. Putnam, Seattle Gastroenterology Associates,Seattle; E. Quintero-Carrion, Hospital Universitario De CanariasTenerife, Santa Cruz de Tenerife, Spain; J.P. Raufman, V. Raj,University of Arkansas for Medical Sciences, Little Rock; D.K.Rex, Indiana University Hospital, Indianapolis; F.P. Rossini,M. Spandre, Azienda Sanitaria Ospedaliera, Turin, Italy; R.I.Rothstein, Dartmouth Hitchcock Medical Center, Lebanon, N.H.;A.K. Rustgi, University of Pennsylvania, Philadelphia; R. Sandler,University of North Carolina at Chapel Hill, Chapel Hill; B.Schmeizer, Sunninghill Clinic, Sandton, South Africa; R.E. Schoen,University of Pittsburgh Medical Center, Pittsburgh; T.T. Schubert,Allenmore Medical Center, Tacoma, Wash.; H.I. Schwartz, MiamiResearch Associates, Miami; E. Segal, Hospital General de AgudosCarlos G. Durand, Buenos Aires; F. Seow-Choen, K.W. Eu, SingaporeGeneral Hospital, Singapore; N.R. Shah, Philip J. Bean MedicalCenter, Hollywood, Md.; N. Skandalis, Peripheral General Hospital,Athens; P.L. Szego, Royal Victoria Hospital, Montreal; N. Toribara,University of Colorado Health Sciences Center, Denver; J. Torosis,Gastrointestinal Research, Redwood City, Calif.; D.K. Turgeon,University of Michigan, Ann Arbor; S.W. Van der Merwe, Pretoria,South Africa; R. VanStolk, C.W. Howden, Northwestern University,Chicago; P. Vergauwe, Algemeen Ziekenhuis Groeninge, Kortrijk,Belgium; B. Vergeau, C. Nizou, Hopital d'Instruction des Armees,Paris; G. Winde, Klinikum Kreis Herford, Herford, Germany; J.Wolosin, M.W. Swaim, Regional Research Institute, Jackson, Tenn.;J.C. Wolper, P.L. Yudelman, Digestive Health Physicians, FortMyers, Fla.; B.C.Y. Wong, University of Hong Kong Queen MaryHospital, Hong Kong; J.P. Wright, Kinsbury Hospital, Claremont,South Africa; A. Zambelli, Ospedale Maggiore Azienda Ospedaliera,Crema, Italy.
Adverse Cardiovascular Effects of Rofecoxib
Nissen S. E., Furberg C. D., Bresalier R. S., Baron J. A.
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N Engl J Med 2006;
355:203-205, Jul 13, 2006;
published at www.nejm.org on Jun 26, 2006 (10.1056/NEJMc066260).
Correspondence
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A correction has been published: N Engl J Med 2006;355(2):221.
65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002;90:959-963. [CrossRef][Web of Science][Medline]
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