Colorectal Cancer Prevention (PDQ®): Prevention - Health Professional Information [NCI] - Description of the Evidence
Nonselective COX inhibitors include indomethacin (Indocin); sulindac (Clinoril); piroxicam (Feldene); diflunisal (Dolobid); ibuprofen (Advil, Motrin); ketoprofen (Orudis); naproxen (Naprosyn); and naproxen sodium (Aleve, Anaprox). Selective COX-2 inhibitors include celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra). Rofecoxib and valdecoxib are no longer marketed because of an associated increased risk of serious cardiovascular events.
Both celecoxib and rofecoxib have been associated with serious cardiovascular events including dose-related death from cardiovascular causes, myocardial infarction, stroke, or heart failure.[39,40,41,42] Four trials that demonstrated this increased risk are summarized in the Table. In addition, a network meta-analysis of all large scale (RCTs) comparing any NSAID to any other NSAID or placebo found that there is little evidence to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful.
Cardiovascular Risks Associated With Celecoxib and Rofecoxib Dose/Drugs
|bid = twice a day; qd = every day; CI = confidence interval; HR = hazard ratio; OR = odds ratio; RR = relative risk.|
|||Rofecoxib <25 mg/qd; rofecoxib >25 mg/qd||OR = 1.47 (0.99–2.17) 3 vs. 58 (1.27–10.17)||Nested case-control study all users|
|||Celecoxib 200 mg/qd vs. 400 mg bid||3.4%; HR = 3.4 (95% CI, 1.4–7.8)||Sporadic adenoma prevention trial (N = 2,035)|
|||Rofecoxib 25 mg/qd||RR = 1.92 (95% CI, 1.19–3.11;P = .008)||Chemoprevention sporadic adenoma|
|||Rofecoxib 25 mg/qd||RR (estimated) = 2.66 (95% CI, 1.03–6.86;P = .04)||Chemoprevention sporadic adenoma median study Rx 7.4 months|
Other major harms from all NSAIDs are gastrointestinal bleeding and renal impairment. The incidence of reported major gastrointestinal bleeding events appears to be dose-related.
Celecoxib reduces the incidence of adenomas; however, celecoxib does not have a clinical role in reducing the risk of sporadic CRC. Its long-term efficacy in preventing CRC has not been shown due to increased risk of cardiovascular events, and because there are other effective ways, such as screening to reduce CRC mortality. A population-based retrospective cohort study of nonaspirin NSAID use among individuals aged 65 years and older was associated with lower risk of CRC, particularly with longer durations of use.
Several studies conducted in a rigorous manner have demonstrated the effectiveness of sulindac in reducing the size and number of adenomas in familial polyposis.[47,48] In a randomized, double-blind, placebo-controlled study of 77 patients with familial adenomatous polyposis, patients receiving 400 mg of celecoxib twice a day had a 28.0% reduction in the mean number of colorectal adenomas (P = .003 for the comparison with placebo) and a 30.7% reduction in the polyp burden (sum of polyp diameters; P = .001) as compared with reductions of 4.5% and 4.9%, respectively, in the placebo group. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9% (P = .33 for the comparison with placebo) and 14.6% (P = .09), respectively. The incidence of adverse events was similar among the groups.