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Jitters over Celebrex as more cardiac concerns arise
 
 
  01/09/2006
www.pharmatimes.com
 
Pfizer's one-time blockbuster painkiller Celebrex (celecoxib) is an effective treatment for preventing colorectal polyps, a precancerous condition, but the looming spectre of its effect on the heart has raised its ugly head again and the researchers say the potential for cardiovascular events outweigh the benefits in this patient population and should not be used routinely in this indication.
 
In two studies in yesterday's New England Journal of Medicine enrolling more than 3,500 patients, investigators set out to determine whether inhibition of the COX-2 receptor using Celebrex prevented the re-appearance of polyps in patients who had previously had growths removed, and followed up with colonoscopies at year one and year three. Results were significantly in favour of Celebrex, with just 34%-43% of patients given the active therapy going on to develop polyps over the study period versus 49%-60% of those in the placebo group.
 
But there was a big jump in the risk of serious cardiovascular problems, with 2.5% of subjects in the Celebrex group experiencing a heart attack, stroke or heart failure versus 1.9% of those given dummy pills. Researchers say the drug should not be routinely used to prevent colon cancer: "The cardiovascular risks far outweigh even the most optimistic estimates of the potential benefit on colorectal cancer," commented Bruce Psaty, who wrote an accompanying editorial for the studies, reported by Bloomberg.
 
Merck & Co pulled its COX-2 offering Vioxx (rofecoxib) from the global marketplace in 2004 after a similar study showed a doubling in the risk of heart attack and stroke in patients given the drug for 18 months or longer. And Pfizer has struggled to keep its once $3 billion drug going, particularly after dosing in two trials of Celebrex was stopped later that year because of a raised cardiovascular event risk. Then it was given a black box warning by the US Food and Drug Administration and saw sales in the fourth quarter of 2005 halved. But it has been making gains again, with revenues boosted 17% in the second quarter of this year to $471 million - and is still a big selling drug for the firm.
 
The dose used in colorectal trials is greater than that used in arthritis patients, so the impact on this patient group is unknown. Pfizer is gambling on a 20,000-patient study that it hopes will prove once and for all that Celebrex is effective and no more likely to cause cardiovascular side effects than the older non-steroidal anti-inflammatory drugs ibuprofen and naproxen.
 
Study 1
 
Celecoxib for the Prevention of Colorectal Adenomatous Polyps

 
NEJM Aug 31, 2006
 
Nadir Arber, M.D., Craig J. Eagle, M.D., Julius Spicak, M.D., Istvn Rcz, M.D., Petr Dite, M.D., Jan Hajer, M.D., Miroslav Zavoral, M.D., Maria J. Lechuga, M.D., Paola Gerletti, B.Sc.D., Jie Tang, M.S., Rebecca B. Rosenstein, Ph.D., Katie Macdonald, Ph.D., Pritha Bhadra, Ph.D., Robert Fowler, M.S., Janet Wittes, Ph.D., Ann G. Zauber, Ph.D., Scott D. Solomon, M.D., Bernard Levin, M.D., for the PreSAP Trial Investigators
 
ABSTRACT
Background: Overexpression of cyclooxygenase 2 (COX-2) has been associated with colorectal adenomatous polyps and cancer, prompting researchers to propose its inhibition as a chemopreventive intervention.
 
Methods: The Prevention of Colorectal Sporadic Adenomatous Polyps trial was a randomized, placebo-controlled, double-blind study of the COX-2 inhibitor celecoxib given daily in a single 400-mg dose. At 107 centers in 32 countries, we randomly assigned 1561 subjects who had had adenomas removed before enrollment to receive celecoxib (933 subjects) or placebo (628 subjects) daily, after stratification according to the use or nonuse of low-dose aspirin. The primary outcome was detection of adenomas at either year 1 or year 3 by colonoscopy and was compared among the groups with the use of the Mantel-Cox test.
 
Results: Colonoscopies were performed at year 1 on 88.7 percent of the subjects who had undergone randomization and at year 3 on 79.2 percent. Of the 557 subjects in the placebo group and the 840 subjects in the celecoxib group who were included in the efficacy analysis, 264 and 270, respectively, were found to have at least one adenoma at year 1, at year 3, or both. The cumulative rate of adenomas detected through year 3 was 33.6 percent in the celecoxib group and 49.3 percent in the placebo group (relative risk, 0.64; 95 percent confidence interval, 0.56 to 0.75; P<0.001). The cumulative rate of advanced adenomas detected through year 3 was 5.3 percent in the celecoxib group and 10.4 percent in the placebo group (relative risk, 0.49; 95 percent confidence interval, 0.33 to 0.73; P<0.001). Adjudicated serious cardiovascular events occurred in 2.5 percent of subjects in the celecoxib group and 1.9 percent of those in the placebo group (relative risk, 1.30; 95 percent confidence interval, 0.65 to 2.62).
 
Conclusions: The use of 400 mg of celecoxib once daily significantly reduced the occurrence of colorectal adenomas within three years after polypectomy. (ClinicalTrials.gov number, NCT00141193 [ClinicalTrials.gov])
 
Colorectal cancer, the second most prevalent cancer in the developed world and the third most prevalent in developing nations,1 is responsible worldwide for more than a million new cases of cancer and half a million deaths annually.2 Recent annual reductions of 1.8 percent in the incidence in the United States are credited, in part, to increased screening and the removal of adenomatous polyps (adenomas).3 Most cases of colorectal cancer are preceded by adenomas, which are characterized by an early accumulation of gene mutations.4
 
The regression and prevention of adenomas have become primary aims of investigators, who have used nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin, to reduce the incidence and recurrence of adenomas.5,6,7 Since being identified as distinct from the ubiquitous cyclooxygenase (COX) 1 isoform,8 COX-2 has been shown to be overexpressed in colorectal cancers and adenomas in humans9,10 and was demonstrated in knockout mice to be a controlling factor in the formation of adenomas.11 Researchers have therefore sought to assess the effects of such selective COX-2 inhibitors as celecoxib on the formation of adenomas in hopes that these agents could overcome the gastrointestinal adverse events of nonselective NSAIDs that placed limits on effective therapy.
 
Three international, multicenter studies of the use of COX-2 inhibitors to prevent sporadic adenomas, including the present study, were launched in 1999 and 2000.12,13 The randomized Adenoma Prevention with Celecoxib (APC) trial included 2035 patients in a study of two twice-daily doses of celecoxib, and the randomized Adenomatous Polyp Prevention on Vioxx (APPROVe) trial included 2586 patients in a study of rofecoxib. We undertook a randomized, placebo-controlled, double-blind study of 400 mg of celecoxib once daily in subjects who had undergone colonoscopy and polypectomy at baseline.
 
Results
 
Baseline Characteristics

Baseline demographic characteristics, colonoscopic findings, cardiovascular risk factors, and body-mass index were similar in the groups (Table 1). The proportion of subjects with a history of cardiovascular events (atherosclerotic or cerebrovascular disease) was 11.1 percent in the placebo group and 13.7 percent in the celecoxib group.
 
Subject Disposition
Of 1738 subjects screened for eligibility, 1561 underwent randomization, 628 to the placebo group and 933 to the celecoxib group; 107 (17.0 percent) in the placebo group and 160 (17.1 percent) in the celecoxib group took low-dose aspirin. In the placebo group, 554 subjects (88.2 percent) completed the colonoscopy at year 1 and 498 (79.3 percent) completed the colonoscopy at year 3; in the celecoxib group, 831 subjects (89.1 percent) completed the year 1 colonoscopy and 739 (79.2 percent) completed the year 3 colonoscopy (Figure 1). In all, 495 subjects in the placebo group (78.8 percent) and 727 in the celecoxib group (77.9 percent) received the study medication for 80 percent or more of the study period. Forty-two percent of subjects who underwent colonoscopy at year 3 did so after administration of the drug was suspended on December 17, 2004; 93 percent of those colonoscopies were performed within three months after suspension. Total treatment exposure was 2331 patient-years (mean, 2.49 years) for celecoxib and 1570 patient-years (mean, 2.50 years) for placebo, reflecting the 3:2 ratio of randomization.
 
Efficacy
Of the 557 subjects in the placebo group and the 840 subjects in the celecoxib group who were included in the efficacy analysis, 264 and 270, respectively, were found to have at least one adenoma at year 1, at year 3, or both (Table 2). Overall, the three-year estimated cumulative rate of adenomas, calculated on the basis of the Mantel-Cox method, was 33.6 percent for subjects receiving celecoxib and 49.3 percent for subjects receiving placebo (relative risk, 0.64; 95 percent confidence interval, 0.56 to 0.75; P<0.001) (Table 2). The results were similar for subjects taking low-dose aspirin at baseline (relative risk, 0.61; 95 percent confidence interval, 0.43 to 0.88; P=0.007), as well as for those not taking low-dose aspirin at baseline (relative risk, 0.65; 95 percent confidence interval, 0.55 to 0.76; P<0.001). Fifty-six subjects in the placebo group and 42 in the celecoxib group were found to have advanced adenomas as follows: 40 in the placebo group and 25 in the celecoxib group at year 1, and 16 in the placebo group and 17 in the celecoxib group at year 3. The estimated cumulative proportion of subjects with advanced adenomas at year 3 was 5.3 percent in the celecoxib group and 10.4 percent in the placebo group (relative risk, 0.49; 95 percent confidence interval, 0.33 to 0.73; P<0.001). Among subjects who had any new adenoma detected, the mean size of the largest adenoma and the mean adenoma burden were significantly lower in the celecoxib group than in the placebo group; the difference in the mean number of adenomas was not significant (Table 2).
 
Safety
In the placebo group, the only adverse events related to colonoscopy were three cases of bleeding and one case of hypotension. All four occurred at baseline. Adverse events related to colonoscopy reported in the celecoxib group were 10 cases of bleeding, 2 perforations, 3 cardiovascular complications (tachycardia and bradycardia), and 1 vasovagal episode. Eleven occurred at baseline, four at year 1, and one at year 3.
 
Investigator-reported serious adverse events occurred in less than 20 percent of either group (Table 3). Thirty-five subjects died of cardiovascular causes or had myocardial infarction, stroke, or congestive heart failure adjudicated by the cardiovascular safety committee; these consisted of 2.5 percent of the celecoxib group (23 of 933) and 1.9 percent of the placebo group (12 of 628) (relative risk, 1.30; 95 percent confidence interval, 0.65 to 2.62), with estimated rates of 9.4 and 7.2 events per 1000 patient-years for celecoxib and placebo, respectively. Of these 35 subjects, 12 came from a subgroup of 198 with a history of cardiovascular or cerebrovascular events (relative risk, 1.55; 95 percent confidence interval, 0.42 to 5.76), and 23 from a subgroup of 1363 without a medical history of cardiovascular or cerebrovascular events (relative risk, 1.14; 95 percent confidence interval, 0.49 to 2.65; P for interaction=0.59), indicating no significant difference in relative risk between subjects with and those without a history of previous cardiovascular events.
 
Three quarters of all subjects who received at least one dose of study medication had at least one adverse event (74.0 percent in the placebo group and 77.1 percent in the celecoxib group) (Table 3). Investigator-reported renal and hypertensive adverse events were more common in the celecoxib group than in the placebo group (relative risk, 1.35; 95 percent confidence interval, 1.08 to 1.69) overall. Of investigator-reported adverse events occurring in 5 percent or more of subjects, only hypertension was significantly more common in the celecoxib group than in the placebo group (15.5 percent vs. 10.7 percent of subjects; relative risk, 1.45; 95 percent confidence interval, 1.11 to 1.91). Nevertheless, mean (±SE) systolic and diastolic blood pressures fell slightly in both treatment groups from baseline to the end of treatment for all subjects (systolic, -2.3±0.78 mm Hg in the placebo group and -1.9±0.64 mm Hg in the celecoxib group; diastolic, -1.5±0.49 mm Hg in the placebo group and -1.5±0.38 mm Hg in the celecoxib group) and in both aspirin strata.
 
Investigator reports of gastrointestinal ulceration or hemorrhage were similar (celecoxib group, 12.1 percent; placebo group, 10.4 percent), and no significant difference was seen in hemoglobin and hematocrit laboratory values over the three-year period (mean hematocrit values in the placebo and the celecoxib groups were 43.9 and 43.8, respectively, at year 1, and 44.2 and 44.1, respectively, at year 3) (see Supplementary Appendix 1, available with the full text of this article at www.nejm.org).
 
A summary of the number of patients with serious adverse events categorized by the MedDRA systems organ class is provided in Supplementary Appendix 2. Those systems organ classes with the most patients were gastrointestinal disorders; cardiac disorders; benign, malignant, and unspecified neoplasms; surgical and medical procedures; and nervous system disorders. Within the systems organ classes, there were no significant differences in incidence between the celecoxib and the placebo groups.
 
In this randomized, placebo-controlled, double-blind clinical trial, 400 mg of celecoxib once daily was associated with a relative risk of 0.64 for adenomas detected during a three-year period. A reduced risk was apparent at the first follow-up colonoscopy (year 1) and persisted at the second (year 3). Likewise, the cumulative rate of detection of advanced adenomas was lower in the celecoxib group, which had a relative risk of 0.49. The size of the largest adenoma and the adenoma burden were significantly lower in the celecoxib group, but the mean number of adenomas among those with any adenoma was not significantly different between the groups. The relative risk of adenomas during the three years among subjects who took low-dose aspirin was 0.61, which was similar to the relative risk among all subjects.
 
Celecoxib may be effective against existing adenomas perhaps missed on an index colonoscopy and against the formation of new adenomas, as evidenced by reductions in the newly diagnosed adenomas at year 1 and year 3. This effect is consistent with experimental evidence in animals and humans and with epidemiologic data.
 
The study did not directly address whether celecoxib affects the risk of a first adenoma or progression to invasive cancer. Colorectal cancer was diagnosed in six subjects in the celecoxib group (0.6 percent) and one subject in the placebo group (0.2 percent) (Table 3). Because five of these seven cases were diagnosed at the year 1 colonoscopy (stage 0 in two subjects and stage 1 in three), these five cases might represent either incomplete excision or disease that was undetected at the index colonoscopy. The remaining two cases of colorectal cancer were diagnosed at year 3 (stage 2A and stage 4). Three of the seven cases were in subjects whose mothers had colorectal cancer.
 
Delineation of clinical benefit requires further research. As the type of adenoma that responds to celecoxib becomes characterized, treatment with celecoxib may be found to reduce the frequency of colonoscopy necessary in certain subjects prone to adenomas. Also, determining the persistence of the effect of celecoxib on the prevention of adenomas and advanced adenomas is expected to be an especially important aspect of the follow-up of these subjects. Celecoxib may also have effects on other enzymes, such as 15-lipoxygenase-1,21 which could mediate its biologic effects. Further assessment of the relative risks and benefits of celecoxib in patients with adenomas is expected not only to promote greater safety for patients but also to encourage greater patient-physician dialogue, thus improving overall patient care.
 
Neither gastrointestinal adverse events nor changes in the laboratory values of hemoglobin were significantly different between groups. Cardiovascular safety results, however, need to be considered with those previously reported for the APC trial.13 A significant increase in adjudicated serious cardiovascular events with the use of celecoxib in the APC trial (an increase in risk by a factor of two or three for a composite end point of myocardial infarction, stroke, congestive heart failure, or cardiovascular-related death)13 prompted suspension of the administration of celecoxib in both the APC trial and our study. In our study, the relative risk of such events with the use of celecoxib as compared with placebo was 1.30 (95 percent confidence interval, 0.65 to 2.62).
 
The relative risk of renal or hypertensive adverse events associated with celecoxib was 1.35 (95 percent confidence interval, 1.08 to 1.69). Nevertheless, once-daily celecoxib was not associated with an increase in mean blood pressure, a finding in contrast to the results in the APC trial reported by Bertagnolli et al. elsewhere in this issue of the Journal.22
 
In our study, subjects came from six continents and the study protocol required photographic documentation of polyp size and cecal intubation to ensure conformity across clinical sites. The simplicity of once-daily dosing may have promoted enrollment and sustained adherence to the regimen of study medication. Subjects required documentation of adenomas at baseline and were at high risk for further adenomatous polyps. Because this study included a diverse population, our findings probably have broad applicability.
 
In conclusion, we found that celecoxib significantly reduced the risk of colorectal adenomas. These findings, which are consistent with other evidence linking COX-2 with colorectal neoplasia, indicate that selective inhibition of COX-2 may reduce colorectal tumorigenesis. Deriving specific recommendations for the clinical use of this treatment approach requires further investigation.
 
Supported by Pfizer, which also provided celecoxib and matching placebo.
 
Dr. Arber reports having served as a consultant to, owning stock in, and having received lecture fees and grant support from Pfizer. Dr. Levin reports having served as a consultant to Pfizer and having received consulting fees from Enterix and grant support from Pfizer for this study. Drs. Lechuga, Gerletti, Macdonald, Eagle, Bhadra, and Rosenstein and Ms. Tang report being employees of Pfizer. No other potential conflict of interest relevant to this article was reported.
 
Discussion
 
Study 2
 
Celecoxib for the Prevention of Sporadic Colorectal Adenomas

 
NEJM Aug 31, 2006
 
Monica M. Bertagnolli, M.D., Craig J. Eagle, M.D., Ann G. Zauber, Ph.D., Mark Redston, M.D., Scott D. Solomon, M.D., KyungMann Kim, Ph.D., Jie Tang, M.S., Rebecca B. Rosenstein, Ph.D., Janet Wittes, Ph.D., Donald Corle, M.S., Timothy M. Hess, M.S., G. Mabel Woloj, Ph.D., Frdric Boisserie, William F. Anderson, M.D., M.P.H., Jaye L. Viner, M.D., M.P.H., Donya Bagheri, M.S., D.A.B.T., John Burn, M.D., Daniel C. Chung, M.D., Thomas Dewar, M.D., T. Raymond Foley, M.D., Neville Hoffman, M.D., Finlay Macrae, M.D., Ronald E. Pruitt, M.D., John R. Saltzman, M.D., Bruce Salzberg, M.D., Thomas Sylwestrowicz, M.D., Gary B. Gordon, M.D., Ph.D., Ernest T. Hawk, M.D., M.P.H., for the APC Study Investigators
 
ABSTRACT
Background: Studies showing that drugs that inhibit cyclooxygenase-2 (COX-2) reduce the number of colorectal adenomas in animals and patients with familial adenomatous polyposis suggest that COX-2 inhibitors may also prevent sporadic colorectal neoplasia.
 
Methods: We randomly assigned patients who had adenomas removed before study entry to receive placebo (679 patients) or 200 mg (685 patients) or 400 mg (671 patients) of celecoxib twice daily. Randomization was stratified for the use of low-dose aspirin. Follow-up colonoscopies were performed at one and three years after randomization. The occurrence of newly detected colorectal adenomas was compared among the groups with the life-table extension of the Mantel-Haenszel test.
 
Results: Follow-up colonoscopies were completed at year 1 in 89.5 percent of randomized patients, and at year 3 in 75.7 percent. The estimated cumulative incidence of the detection of one or more adenomas by year 3 was 60.7 percent for patients receiving placebo, as compared with 43.2 percent for those receiving 200 mg of celecoxib twice a day (risk ratio, 0.67; 95 percent confidence interval, 0.59 to 0.77; P<0.001) and 37.5 percent for those receiving 400 mg of celecoxib twice a day (risk ratio, 0.55; 95 percent confidence interval, 0.48 to 0.64; P<0.001). Serious adverse events occurred in 18.8 percent of patients in the placebo group, as compared with 20.4 percent of those in the low-dose celecoxib group (risk ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.5) and 23.0 percent of those in the high-dose group (risk ratio, 1.2; 95 percent confidence interval, 1.0 to 1.5; P=0.06). As compared with placebo, celecoxib was associated with an increased risk of cardiovascular events (risk ratio for the low dose, 2.6; 95 percent confidence interval, 1.1 to 6.1; and risk ratio for the high dose, 3.4; 95 percent confidence interval, 1.5 to 7.9).
 
Conclusions: These findings indicate that celecoxib is an effective agent for the prevention of colorectal adenomas but, because of potential cardiovascular events, cannot be routinely recommended for this indication. (ClinicalTrials.gov number, NCT00005094 [ClinicalTrials.gov])
 
Colorectal cancer is a common malignant condition, responsible for approximately 150,000 new patients and approximately 55,000 deaths per year in the United States alone.1 Despite these statistics, colorectal cancer is one of the most preventable cancers. Most colorectal cancers develop from precursor adenomas, which can be identified and removed during a screening colonoscopy. This procedure may lower the rates of death due to colorectal cancer by as much as 30 to 40 percent.2 The aim of chemoprevention is to use pharmacologic agents to augment the benefits of colonoscopic polypectomy by inhibiting early stages of tumorigenesis, thereby preventing malignant transformation of precursor adenomas.
 
A remarkable concordance of data from more than 40 observational studies suggests that nonsteroidal antiinflammatory drugs (NSAIDs) reduce the incidence of colorectal adenomas, colorectal cancer, and deaths from colorectal cancer.3 The effects of NSAIDs have been confirmed in randomized trials showing that aspirin has a modest chemopreventive effect on sporadic colorectal adenomas.4,5,6 A leading hypothesis explaining this result is based on the presence of tumorigenic cyclooxygenase-2 (COX-2) within adenomas but not in normal intestinal tissue. COX-2 mediates the production of prostaglandin E2 (PGE2) in epithelial tissues, resulting in activation of signaling pathways that promote cell proliferation and inhibit cell death.7,8 Selective COX-2 inhibitors, such as celecoxib, were originally developed for the treatment of pain and inflammation. In patients with familial adenomatous polyposis, celecoxib (Celebrex) also showed antitumor activity.9 We conducted a randomized trial to determine whether celecoxib also prevents sporadic colorectal adenomas.
 
Results
 
Baseline variables were similar across all treatment groups (Table 1). Risk factors for adverse events, such as a history of cardiovascular disease, smoking, or diabetes, were also balanced among treatment groups. Colonoscopic end points were assessed in 1822 of 2035 patients who had undergone randomization (89.5 percent); 1541 patients (75.7 percent) completed the examination at year 3 (Figure 1). Before assessment of the end points, 10.5 percent of the patients withdrew from the study. This includes 1.2 percent of patients who had undergone randomization but were lost to follow-up before a study colonoscopy was performed. Patients who did not complete the study were relatively evenly distributed among the treatment groups (Figure 1).
 
Patients who did not adhere to the use of the study drug for any reason remained in the study until the scheduled completion time for the determination of the end points, in keeping with the intention-to-treat principle. Approximately two thirds of participants adhered to the treatment regimen at least 80 percent of the time, with no significant difference among the treatment groups (Figure 1). Because of an increased incidence of cardiovascular events in the two groups treated with celecoxib, use of the study medication by patients who had undergone randomization was discontinued on December 17, 2004, in compliance with the recommendations of the data and safety monitoring board. At that time, 1762 patients (86.6 percent) had completed three years of treatment. Of the 273 patients who still had one to three months remaining of planned use of the study drug, 199 (72.9 percent) underwent study colonoscopy at year 3, and these data were used in the primary efficacy analyses.
 
The primary efficacy analysis considered adenomas detected at any time after randomization (Table 2). A small percentage of polyps removed (1.4 percent) were not retrieved and could not be examined. In the placebo group, 354 patients had at least one adenoma, as did 252 patients in the group receiving 200 mg of celecoxib twice daily, and 213 patients in the group receiving 400 mg of celecoxib twice daily. The estimated cumulative incidence of the detection of one or more adenomas was 60.7 percent in the placebo group, 43.2 percent in the group receiving 200 mg of celecoxib twice daily, and 37.5 percent in the group receiving 400 mg of celecoxib twice daily. This corresponds to a risk ratio of 0.67 (95 percent confidence interval, 0.59 to 0.77) in the 200-mg group and 0.55 (95 percent confidence interval, 0.48 to 0.64) in the 400-mg group.
 
Celecoxib therapy was associated with a reduced number of advanced adenomas; 99 patients in the placebo group had at least one advanced adenoma during the three-year period, as compared with 44 patients in the group receiving 200 mg of celecoxib twice daily and 35 patients in the group receiving 400 mg of celecoxib twice daily. The estimated cumulative incidence of advanced adenomas was 17.2 percent for patients receiving placebo, 7.8 percent for those treated with 200 mg of celecoxib twice daily, and 6.3 percent for those treated with 400 mg of celecoxib twice daily, corresponding to a risk ratio of 0.43 (95 percent confidence interval, 0.31 to 0.61) in the 200-mg group and 0.34 (95 percent confidence interval, 0.24 to 0.50) in the 400-mg group. Subgroup analyses according to the use or nonuse of low-dose aspirin yielded similar results (Table 2).
 
During the three-year study, the adenoma burden was smaller among patients given celecoxib than among those given placebo. Patients receiving placebo had a mean (±SE) adenoma burden of 1.3±0.1 cm, as compared with 1.0±0.1 cm among patients receiving 200 mg of celecoxib twice daily (P=0.004) and 0.9±0.1 cm among those receiving 400 mg of celecoxib twice daily (P=0.002) (Figure 2).
 
Clinical variables measured during physical examinations during the study showed increased blood pressure among patients in the celecoxib groups, with a change from baseline to year 3 in mean blood pressure of -1.6/-3.0 mm Hg in the placebo group, +1.0/-1.2 mm Hg in patients assigned to 200 mg of celecoxib twice daily, and +3.6/-1.0 mm Hg in patients assigned to 400 mg of celecoxib twice daily (P<0.001 and P=0.01 for the comparison of the combined celecoxib groups with the placebo group for systolic and diastolic blood pressure, respectively). No drug-associated change was observed in serum levels of creatinine, alanine aminotransferase, or hemoglobin.
 
At least one adverse event was reported in 617 patients in the placebo group (91.3 percent), 645 of those receiving 200 mg of celecoxib twice daily (94.4 percent), and 635 of those receiving 400 mg of celecoxib twice daily (94.9 percent) (Table 3). At least one serious adverse event was reported in 18.8 percent of the patients in the placebo group, as compared with 20.4 percent of those receiving 200 mg of celecoxib twice daily (risk ratio, 1.1; 95 percent confidence interval, 0.9 to 1.3; P=0.5), and 23.0 percent of those receiving 400 mg of celecoxib twice daily (risk ratio, 1.2; 95 percent confidence interval, 1.0 to 1.5; P=0.06) (Table 3 and Supplementary Appendix, available with the full text of this article at www.nejm.org). One patient in the placebo group had grade 3 bleeding after the polypectomy - a serious complication resulting from a study colonoscopy.
 
Nonadjudicated investigator-reported renal and hypertensive disorders, gastrointestinal ulceration and hemorrhage, and cardiovascular disorders were analyzed separately. No consistent dose-related trend toward an increased incidence of renal and hypertensive disorders or gastrointestinal ulceration and hemorrhage was observed, although aspirin users assigned to receive celecoxib showed a trend toward increased gastrointestinal ulceration and hemorrhage.
 
Cardiovascular adverse events among participants in the APC trial have been reported previously, according to a prespecified analysis of adjudicated serious adverse events,10 and were updated with the final study data (Table 3). This analysis indicated an increased risk of serious cardiovascular complications (i.e., death from cardiovascular causes, nonfatal myocardial infarction, stroke, or heart failure) among those receiving celecoxib, with risk ratios of 2.6 (95 percent confidence interval, 1.1 to 6.1) and 3.4 (95 percent confidence interval, 1.5 to 7.9) for the low-dose and high-dose cohorts, respectively. The absolute magnitude of risk was greatest for patients with a history of cardiovascular events at baseline, although no relation between cardiovascular events at baseline and during the study was observed in patients receiving celecoxib. Patients who entered the study with a history of myocardial infarction, stroke, congestive heart failure, or angina had a 3.0 percent incidence of serious cardiovascular events if they took placebo and an 8.8 percent incidence if they took celecoxib at either dose (risk ratio for the comparison with placebo, 3.0; 95 percent confidence interval, 0.9 to 10.4). Among patients without these risk factors at baseline, 0.7 percent of those in the placebo group had a serious cardiovascular event, as compared with 2.1 percent of those in either celecoxib group (risk ratio, 3.0; 95 percent confidence interval, 1.0 to 8.7). The adjudicated analysis of data pertaining to serious adverse events agreed substantially with nonadjudicated investigator reports of serious adverse events related to cardiovascular disorders.
 
Discussion
 
Previous attempts to modify the risk of sporadic adenomas through dietary interventions have been largely unsuccessful,16,17 although calcium and vitamin D supplementation demonstrated a slight benefit.18,19,20 Randomized trials of aspirin showed a more substantial chemopreventive effect, with reductions of approximately 20 percent among patients in whom recurrent adenomas developed.4,5,6 These findings are tempered somewhat by the observation in one study that low-dose, but not high-dose, aspirin had an antitumor effect.4 We studied a cohort at high risk for colorectal tumors, as evidenced by a 60.7 percent incidence of newly detected adenomas in the placebo group during the three-year period and a 17.2 percent incidence of advanced lesions. Treatment with a 400-mg dose of celecoxib twice daily for three years reduced the incidence of recurrent adenomas of any type by 45 percent and of high-risk lesions by 66 percent. The effect was confirmed by a similarly designed independent study, the PreSAP Trial, described by Arber et al. elsewhere in this issue of the Journal.21 Patients in the APC trial who took aspirin in addition to celecoxib did not show greater chemopreventive benefit than those who took celecoxib alone.
 
We did not directly assess the effect of celecoxib on colorectal cancer. In the context of a program of surveillance colonoscopy to detect and remove premalignant adenomas, the benefit of celecoxib in the prevention of colorectal cancer is still unknown, and further research is necessary to develop a successful chemopreventive regimen. To optimize the benefit, studies should focus on persons who are at the highest risk for colorectal cancer, since celecoxib was particularly effective in preventing advanced lesions. Colorectal cancer takes many years to develop, and celecoxib causes regression, in addition to suppression, of established adenomas.9 Thus, additional investigations should address the value of various dosing schedules, considering the dose-related effects on the prevention of adenomas and on adverse events.
 
Selective COX-2 inhibitors were developed as a safer alternative to nonselective NSAIDs, with respect to gastrointestinal bleeding. These agents preferentially inhibit COX-2, an inducible enzyme mediating inflammation and tumorigenesis, and not COX-1, the constitutively expressed enzyme responsible for protective mechanisms in the gastric mucosa and renal vasculature. Selective COX-2 inhibitors have fewer effects on gastric mucosa or platelet function than do the nonselective NSAIDs and, as a result, may be associated with fewer ulcers and hemorrhagic complications.22 In general, our results are consistent with these assertions, although the combination of aspirin and celecoxib may be associated with more gastrointestinal ulceration and hemorrhagic events than is placebo.
 
Previously, we reported the results of a cardiovascular analysis conducted of the APC trial while the treatment portion of the study was still under way.10 The data were analyzed on an intention-to-treat basis and included adjudicated serious cardiovascular events, and the analysis revealed an increased risk among patients taking celecoxib of a combined end point including myocardial infarction, stroke, congestive heart failure, or death due to cardiovascular disease. The updated adjudicated analysis reported here, which includes one additional event in the low-dose celecoxib group, also shows a dose-related increased cardiovascular risk associated with celecoxib. Not surprisingly, subgroup analyses suggested that the absolute risk of cardiovascular events was greatest among patients with a history of cardiovascular events at baseline, but the risk ratio did not differ significantly among those with and those without cardiovascular events at baseline. In addition, blood pressure increased with the use of celecoxib, suggesting that changes in vascular tone may predispose patients to cardiovascular events.
 
In summary, the use of celecoxib by patients at high risk for colorectal neoplasia significantly reduced the proportion of patients with adenomas detected during a three-year study. This trial documented prevention of premalignant adenomas with celecoxib but was not designed to assess effectiveness of the drug for the prevention of colorectal cancer, and no claims about its use in this regard can be made from our data. Safety analyses confirmed previous reports of an increased incidence of serious cardiovascular events. If future study of celecoxib for the chemoprevention of colorectal cancer is pursued, the potential addition of this drug to an optimal endoscopic surveillance program must be weighed against the known risk of serious cardiovascular events.
 
Supported by the National Cancer Institute (N01-CN-95015) and Pfizer.
 
Drs. Bertagnolli and Redston report having received grant support for the APC trial from Pfizer under a clinical trials agreement with Brigham & Women's Hospital. Dr. Macrae reports having received grant support for clinical trials from Pfizer. Drs. Eagle, Rosenstein, Woloj, and Ms. Tang report being employees of Pfizer. Drs. Eagle, Rosenstein, Gordon, and Ms. Tang report owning stock in Pfizer. Dr. Kim reports being a member of a legal-defense team for Merck. No other potential conflict of interest relevant to this article was reported.
 
 
 
 
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