Risks and Benefits of Celecoxib to Prevent Recurrent Adenomas
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《新英格兰医药杂志》
In late September 2004, the cardiovascular risks identified in a placebo-controlled adenoma-prevention trial that was terminated early precipitated the voluntary withdrawal from the market of the cyclooxygenase-2 (COX-2) inhibitor rofecoxib.1 Later that year, in another adenoma-prevention trial, the COX-2 inhibitor, celecoxib, was also associated with an increase in the risk of cardiovascular events.2 For this reason, on December 17, 2004, the data and safety monitoring boards of two celecoxib trials recommended stopping drug administration in the trials.2,3 Articles describing the cardiovascular risks seen in the two adenoma prevention trials were published rapidly.1,4 However, in the absence of evidence about the primary outcome, the occurrence of metachronous adenomas, it was not possible to assess the overall risks and benefits of COX-2 inhibitors in patients with colonic adenomas.5 In this issue of the Journal, the publication of the primary results of the Adenoma Prevention with Celecoxib (APC) and the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials provides new evidence about the efficacy and the safety profile associated with the use of celecoxib in patients with adenomas.2,3
Nonsteroidal antiinflammatory drugs (NSAIDs) vary in the degree to which they inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The COX-2 selectivity of celecoxib, for instance, is similar to that of diclofenac and sulindac and less pronounced than that of rofecoxib or valdecoxib.6 Early on, the biology of prostaglandins and their COX-dependent synthesis suggested that the selective COX-2 inhibitors might avert the gastrointestinal bleeding complications associated with traditional NSAIDs.7 In colon cancers and adenomas, the high levels of expression of COX-2 and the potential cancer-promoting role of its product, prostaglandin E2, in epithelial tissue identified COX-2 inhibitors as potentially valuable chemopreventive agents.8 Inhibition of the production of prostacyclin, which is derived from COX-2, was also hypothesized to have several cardiovascular effects, including the promotion of platelet aggregation, vasoconstriction, and atherosclerosis.7 Information about the biologic mechanisms of COX-2 inhibition suggests several types of benefits or risks, but obtaining estimates of their magnitude requires studies in human populations.
The placebo-controlled APC and PreSAP trials were well designed and well conducted and had many design features in common, including the age of the patients, the exclusion criteria, the sample size, and the duration of the run-in phase to assess adherence. Patients qualified for entry into these trials only if they had had an adenoma removed during a recent colonoscopy. Both trials planned a three-year duration of the active treatments, and colonoscopies were repeated at one and three years in the two trials. In both trials, the occurrence of any metachronous adenoma was the primary outcome and the occurrence of advanced adenomas was a secondary outcome. The trial designs differed primarily in dosing regimens. Approximately equal numbers of patients in the APC trial were randomly assigned to one of the following three treatments: 200 mg of celecoxib twice daily, 400 mg of celecoxib twice daily, or placebo. Patients in the PreSAP trial were randomly assigned in a 3:2 ratio to receive 400 mg of celecoxib or placebo once daily.
For efficacy outcomes, the results were similar. Treatment with celecoxib as compared with placebo in both trials was associated with a pronounced reduction in the risk of metachronous adenomas and advanced adenomas. For instance, the relative risk of an advanced adenoma among patients who took 200 mg of celecoxib twice daily in the APC trial (0.43; 95 percent confidence interval, 0.31 to 0.61) was similar to that among patients who took 400 mg of celecoxib once daily in the PreSAP trial (0.49; 95 percent confidence interval, 0.33 to 0.73). Although the number of colorectal cancers was small in both trials, the incidence was slightly higher among those receiving celecoxib than among those receiving placebo (a meta-analysis across the two trials showed a relative risk of 1.5; 95 percent confidence interval, 0.5 to 4.7).
These trials together provide convincing evidence that, as compared with placebo, celecoxib prevents metachronous adenomas in patients with a history of adenomas. These findings are consistent with the results of placebo-controlled trials of aspirin for the prevention of adenomas,9 as well as with a large body of observational evidence suggesting that the use of one of a variety of NSAIDs may reduce the incidence of colorectal cancer by about 50 percent.8 Although metachronous adenomas are thought to be an excellent surrogate end point for the incidence of colorectal cancer, large trials of aspirin that lasted 5 to 10 years and involved men and women have not provided evidence of a reduced risk of colorectal cancer.10,11 Additional treatment or follow-up time may be necessary. Observational studies, for instance, suggest that the duration of treatment with NSAIDs may need to exceed 10 years.12 Finally, large clinical trials with active controls to compare COX-2 inhibitors and traditional NSAIDs have not been done at all.
In both trials, celecoxib, as compared with placebo, was associated with an increased risk of cardiovascular events. The risk associated with high-dose celecoxib in the APC trial was pronounced (relative risk, 3.4; 95 percent confidence interval, 1.5 to 7.9). For the dose of 200 mg twice daily in the APC trial, the relative risk of 2.6 (95 percent confidence interval, 1.1 to 6.1) was higher than the relative risk of 1.3 (95 percent confidence interval, 0.6 to 2.6) for 400 mg of celecoxib once daily in the PreSAP trial (P for the difference between relative risks, 0.2). Combined data from the APC and PreSAP trials, which have been included in a recent meta-analysis,13 suggest an increase by a factor of about two in cardiovascular risk associated with celecoxib as compared with placebo (Table 1).
Table 1. Hypothetical Risk–Benefit Analyses for Celecoxib and Low-Dose Aspirin over a Period of Three Years in 1000 Patients with Colonic Adenomas.
Among patients who have had an adenoma removed, repeated colonoscopy is now generally recommended at intervals of three to five years, depending on pathology-defined risk.16 Although colonoscopy itself carries risks, an adenoma that is removed does not develop into cancer. The purpose of evaluating a chemopreventive agent such as celecoxib in clinical trials is not to preclude a repeated colonoscopy but to provide evidence about the potential risks and benefits of lengthening the interval between colonoscopies. Table 1 summarizes one hypothetical three-year risk–benefit analysis — a virtual clinical trial — that compares the use of celecoxib with no treatment and with the use of low-dose aspirin.
Because celecoxib, in comparison with traditional NSAIDs, was not associated with a health benefit in terms of the risk of complicated gastrointestinal events at one year,17,18 the dominant clinical events in this analysis are colorectal cancer and cardiovascular disease, devastating clinical conditions that, here, are assumed to carry equal weight. The event rates for colorectal cancer and cardiovascular disease in the control groups from the two trials are similar to estimates from epidemiologic data. Applying clinical-trial risk reductions for advanced adenomas to the incidence of colorectal cancer suggests that celecoxib for the treatment of 1000 patients for three years has a slight advantage over low-dose aspirin (1.6 fewer colorectal-cancer events for celecoxib vs. 1.2 fewer for aspirin). Cardiovascular events were, however, almost five times as common as colorectal cancer (Table 1). Because aspirin decreases the risk of coronary disease (4.4 fewer events in 1000 patients followed for three years), and because celecoxib increases the risk of coronary disease (12.7 extra events), the use of celecoxib in 1000 patients for three years, under the assumptions of this simple risk–benefit analysis, results in 16.7 more colorectal-cancer and cardiovascular events than treatment with low-dose aspirin and in 11.1 more events than no treatment at all.
According to evidence from the Preventive Services Task Force, low-dose aspirin is likely to be associated with 3 (95 percent confidence interval, 2 to 4) major gastrointestinal bleeding events among 1000 patients who are followed for five years.14 Other reasonable estimates of the incidence and the risks of serious gastrointestinal bleeding, colorectal cancer, and cardiovascular events, as well as other reasonable weights assigned to the two dominant clinical events in this hypothetical analysis, are unlikely to alter substantially the projected three-year risk–benefit profile associated with celecoxib. Although the prevention of colorectal cancer in patients with adenomas may require treatment or follow-up for more than three years, established practice guidelines for patients with adenomas limit the available duration of treatment to the interval between repeated colonoscopies.16
In summary, these two trials provide strong evidence that among patients with colonic adenomas, the use of celecoxib for up to three years reduces the risk of metachronous adenoma. These placebo-controlled trials were too small to evaluate the role of celecoxib in preventing colorectal cancer. Nevertheless, in these same studies, significant cardiovascular risks were demonstrated. In patients with adenomas who undergo repeated colonoscopies, the increase in cardiovascular events caused by celecoxib outweighs what may be an optimistic projection of its potential benefit in decreasing colorectal-cancer events. It is reasonable to conclude that celecoxib has no role as a chemopreventive agent either in patients with nonfamilial colonic adenomas or in the general population.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Cardiovascular Health Research Unit, Departments of Medicine (B.M.P.), Epidemiology (B.M.P., J.D.P.), and Health Services (B.M.P.), University of Washington; and the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center (J.D.P.) — both in Seattle.
References
Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-1102.
Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006;355:873-884.
Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006;355:885-895.
Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-1080.
Psaty BM, Furberg CD. COX-2 inhibitors -- lessons in drug safety. N Engl J Med 2005;352:1133-1135.
Warner TD, Mitchell JA. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 2004;18:790-804.
Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006;116:4-15.
Ulrich CM, Bigler J, Potter JD. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 2006;6:130-140.
Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003;348:891-899.
Gann PH, Manson JE, Glynn RJ, Buring JE, Hennekens CH. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst 1993;85:1220-1224.
Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005;294:47-55.
Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Curhan GC, Fuchs CS. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 2005;294:914-923.
Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302-1308.
Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;136:161-172.
Ridker PM, Cook NR, Lee I-M, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293-1304.
Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. CA Cancer J Clin 2006;56:143-159.
Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA 2000;284:1247-1255.
Hrachovec JB, Mora M. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. JAMA 2001;286:2398-2398.(Bruce M. Psaty, M.D., Ph.)
Nonsteroidal antiinflammatory drugs (NSAIDs) vary in the degree to which they inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The COX-2 selectivity of celecoxib, for instance, is similar to that of diclofenac and sulindac and less pronounced than that of rofecoxib or valdecoxib.6 Early on, the biology of prostaglandins and their COX-dependent synthesis suggested that the selective COX-2 inhibitors might avert the gastrointestinal bleeding complications associated with traditional NSAIDs.7 In colon cancers and adenomas, the high levels of expression of COX-2 and the potential cancer-promoting role of its product, prostaglandin E2, in epithelial tissue identified COX-2 inhibitors as potentially valuable chemopreventive agents.8 Inhibition of the production of prostacyclin, which is derived from COX-2, was also hypothesized to have several cardiovascular effects, including the promotion of platelet aggregation, vasoconstriction, and atherosclerosis.7 Information about the biologic mechanisms of COX-2 inhibition suggests several types of benefits or risks, but obtaining estimates of their magnitude requires studies in human populations.
The placebo-controlled APC and PreSAP trials were well designed and well conducted and had many design features in common, including the age of the patients, the exclusion criteria, the sample size, and the duration of the run-in phase to assess adherence. Patients qualified for entry into these trials only if they had had an adenoma removed during a recent colonoscopy. Both trials planned a three-year duration of the active treatments, and colonoscopies were repeated at one and three years in the two trials. In both trials, the occurrence of any metachronous adenoma was the primary outcome and the occurrence of advanced adenomas was a secondary outcome. The trial designs differed primarily in dosing regimens. Approximately equal numbers of patients in the APC trial were randomly assigned to one of the following three treatments: 200 mg of celecoxib twice daily, 400 mg of celecoxib twice daily, or placebo. Patients in the PreSAP trial were randomly assigned in a 3:2 ratio to receive 400 mg of celecoxib or placebo once daily.
For efficacy outcomes, the results were similar. Treatment with celecoxib as compared with placebo in both trials was associated with a pronounced reduction in the risk of metachronous adenomas and advanced adenomas. For instance, the relative risk of an advanced adenoma among patients who took 200 mg of celecoxib twice daily in the APC trial (0.43; 95 percent confidence interval, 0.31 to 0.61) was similar to that among patients who took 400 mg of celecoxib once daily in the PreSAP trial (0.49; 95 percent confidence interval, 0.33 to 0.73). Although the number of colorectal cancers was small in both trials, the incidence was slightly higher among those receiving celecoxib than among those receiving placebo (a meta-analysis across the two trials showed a relative risk of 1.5; 95 percent confidence interval, 0.5 to 4.7).
These trials together provide convincing evidence that, as compared with placebo, celecoxib prevents metachronous adenomas in patients with a history of adenomas. These findings are consistent with the results of placebo-controlled trials of aspirin for the prevention of adenomas,9 as well as with a large body of observational evidence suggesting that the use of one of a variety of NSAIDs may reduce the incidence of colorectal cancer by about 50 percent.8 Although metachronous adenomas are thought to be an excellent surrogate end point for the incidence of colorectal cancer, large trials of aspirin that lasted 5 to 10 years and involved men and women have not provided evidence of a reduced risk of colorectal cancer.10,11 Additional treatment or follow-up time may be necessary. Observational studies, for instance, suggest that the duration of treatment with NSAIDs may need to exceed 10 years.12 Finally, large clinical trials with active controls to compare COX-2 inhibitors and traditional NSAIDs have not been done at all.
In both trials, celecoxib, as compared with placebo, was associated with an increased risk of cardiovascular events. The risk associated with high-dose celecoxib in the APC trial was pronounced (relative risk, 3.4; 95 percent confidence interval, 1.5 to 7.9). For the dose of 200 mg twice daily in the APC trial, the relative risk of 2.6 (95 percent confidence interval, 1.1 to 6.1) was higher than the relative risk of 1.3 (95 percent confidence interval, 0.6 to 2.6) for 400 mg of celecoxib once daily in the PreSAP trial (P for the difference between relative risks, 0.2). Combined data from the APC and PreSAP trials, which have been included in a recent meta-analysis,13 suggest an increase by a factor of about two in cardiovascular risk associated with celecoxib as compared with placebo (Table 1).
Table 1. Hypothetical Risk–Benefit Analyses for Celecoxib and Low-Dose Aspirin over a Period of Three Years in 1000 Patients with Colonic Adenomas.
Among patients who have had an adenoma removed, repeated colonoscopy is now generally recommended at intervals of three to five years, depending on pathology-defined risk.16 Although colonoscopy itself carries risks, an adenoma that is removed does not develop into cancer. The purpose of evaluating a chemopreventive agent such as celecoxib in clinical trials is not to preclude a repeated colonoscopy but to provide evidence about the potential risks and benefits of lengthening the interval between colonoscopies. Table 1 summarizes one hypothetical three-year risk–benefit analysis — a virtual clinical trial — that compares the use of celecoxib with no treatment and with the use of low-dose aspirin.
Because celecoxib, in comparison with traditional NSAIDs, was not associated with a health benefit in terms of the risk of complicated gastrointestinal events at one year,17,18 the dominant clinical events in this analysis are colorectal cancer and cardiovascular disease, devastating clinical conditions that, here, are assumed to carry equal weight. The event rates for colorectal cancer and cardiovascular disease in the control groups from the two trials are similar to estimates from epidemiologic data. Applying clinical-trial risk reductions for advanced adenomas to the incidence of colorectal cancer suggests that celecoxib for the treatment of 1000 patients for three years has a slight advantage over low-dose aspirin (1.6 fewer colorectal-cancer events for celecoxib vs. 1.2 fewer for aspirin). Cardiovascular events were, however, almost five times as common as colorectal cancer (Table 1). Because aspirin decreases the risk of coronary disease (4.4 fewer events in 1000 patients followed for three years), and because celecoxib increases the risk of coronary disease (12.7 extra events), the use of celecoxib in 1000 patients for three years, under the assumptions of this simple risk–benefit analysis, results in 16.7 more colorectal-cancer and cardiovascular events than treatment with low-dose aspirin and in 11.1 more events than no treatment at all.
According to evidence from the Preventive Services Task Force, low-dose aspirin is likely to be associated with 3 (95 percent confidence interval, 2 to 4) major gastrointestinal bleeding events among 1000 patients who are followed for five years.14 Other reasonable estimates of the incidence and the risks of serious gastrointestinal bleeding, colorectal cancer, and cardiovascular events, as well as other reasonable weights assigned to the two dominant clinical events in this hypothetical analysis, are unlikely to alter substantially the projected three-year risk–benefit profile associated with celecoxib. Although the prevention of colorectal cancer in patients with adenomas may require treatment or follow-up for more than three years, established practice guidelines for patients with adenomas limit the available duration of treatment to the interval between repeated colonoscopies.16
In summary, these two trials provide strong evidence that among patients with colonic adenomas, the use of celecoxib for up to three years reduces the risk of metachronous adenoma. These placebo-controlled trials were too small to evaluate the role of celecoxib in preventing colorectal cancer. Nevertheless, in these same studies, significant cardiovascular risks were demonstrated. In patients with adenomas who undergo repeated colonoscopies, the increase in cardiovascular events caused by celecoxib outweighs what may be an optimistic projection of its potential benefit in decreasing colorectal-cancer events. It is reasonable to conclude that celecoxib has no role as a chemopreventive agent either in patients with nonfamilial colonic adenomas or in the general population.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Cardiovascular Health Research Unit, Departments of Medicine (B.M.P.), Epidemiology (B.M.P., J.D.P.), and Health Services (B.M.P.), University of Washington; and the Division of Public Health Sciences, Fred Hutchinson Cancer Research Center (J.D.P.) — both in Seattle.
References
Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-1102.
Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006;355:873-884.
Arber N, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006;355:885-895.
Solomon SD, McMurray JJV, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-1080.
Psaty BM, Furberg CD. COX-2 inhibitors -- lessons in drug safety. N Engl J Med 2005;352:1133-1135.
Warner TD, Mitchell JA. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J 2004;18:790-804.
Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest 2006;116:4-15.
Ulrich CM, Bigler J, Potter JD. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 2006;6:130-140.
Baron JA, Cole BF, Sandler RS, et al. A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 2003;348:891-899.
Gann PH, Manson JE, Glynn RJ, Buring JE, Hennekens CH. Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst 1993;85:1220-1224.
Cook NR, Lee IM, Gaziano JM, et al. Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA 2005;294:47-55.
Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Curhan GC, Fuchs CS. Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 2005;294:914-923.
Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302-1308.
Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002;136:161-172.
Ridker PM, Cook NR, Lee I-M, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med 2005;352:1293-1304.
Winawer SJ, Zauber AG, Fletcher RH, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. CA Cancer J Clin 2006;56:143-159.
Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. JAMA 2000;284:1247-1255.
Hrachovec JB, Mora M. Reporting of 6-month vs 12-month data in a clinical trial of celecoxib. JAMA 2001;286:2398-2398.(Bruce M. Psaty, M.D., Ph.)