archived

Evidence Summary: NSAIDs

Aspirin/NSAIDs for Prevention of Colorectal Cancer: Preventive Medication

March 15, 2007

Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Alaa Rostom, M.D., M.Sc.a; Catherine Dubé, M.D., M.Sc.a; Gabriela Lewin, M.D.b; Alexander Tsertsvadze, M.D., M.Sc.b; Nicholas Barrowman, Ph.D.b; Catherine Code, M.D.c; Margaret Sampson, M.L.I.S.b; and David Moher, Ph.D.b


The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the U.S. Agency for Healthcare Research and Quality (AHRQ) or the U.S. Department of Health and Human Services.

Address correspondence to: Alaa Rostom M.D., M.Sc (Epi), FRPC, Division of Gastroenterology, University of Calgary Medical Clinic, 3330 Hospital Drive, NW G176, Calgary, Alberta, Canada T2N 4N1, E-mail: arostom@calgary.ca

This systematic review was first published in the Annals of Internal Medicine. Select for copyright and source.

Return to Table of Contents

Purpose: To examine the benefits and harms of nonaspirin (non-ASA) nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX-2) inhibitors for the prevention of colorectal cancer (CRC) and adenoma.

Data Sources: MEDLINE® (1966 to 2006), EMBASE (1980 to 2006), Cochrane Central Register of Controlled Trials, Cochrane Collaboration's registry of clinical trials, Cochrane Database of Systematic Reviews.

Study Selection: Randomized, controlled trials and case-control and cohort studies of the effectiveness of NSAIDs for the prevention of CRC and colorectal adenoma were identified by multilevel screening by 2 independent reviewers. Systematic reviews of harms were sought.

Data Extraction: Data abstraction, checking, and quality assessment were completed in duplicate.

Data Synthesis: A single cohort study showed no effect of non-ASA NSAIDs on death due to CRC. Colorectal cancer incidence was reduced with non-ASA NSAIDs in cohort studies (relative risk, 0.61 [95% CI, 0.48 to 0.77]) and case-control studies (relative risk, 0.70 [CI, 0.63 to 0.78]). Colorectal adenoma incidence was also reduced with non-ASA NSAID use in cohort studies (relative risk, 0.64 [CI, 0.48 to 0.85]) and case-control studies (relative risk, 0.54 [CI, 0.4 to 0.74]) and by COX-2 inhibitors in randomized, controlled trials (relative risk, 0.72 [CI, 0.68 to 0.77]). The ulcer complication rate associated with non-ASA NSAIDs is 1.5% per year. Compared with non-ASA NSAIDs, COX-2 inhibitors reduce this risk but, in multiyear use, have a higher ulcer complication rate than placebo. Cyclooxygenase-2 inhibitors and nonnaproxen NSAIDs increase the risk for serious cardiovascular events (relative risk, 1.86 [CI, 1.33 to 2.59] for COX-2 inhibitors vs. placebo).

Limitations: Heterogeneity in the dose, duration and frequency of use necessitated careful grouping for analysis.

Conclusions: Cyclooxygenase-2 inhibitors and NSAIDs reduce the incidence of colonic adenomas. Nonsteroidal anti-inflammatory drugs also reduce the incidence of CRC. However, these agents are associated with important cardiovascular events and gastrointestinal harms. The balance of benefits to risk does not favor chemoprevention in average-risk individuals.

Return to Table of Contents

In the United States, cancer is the second leading cause of death after heart disease and is the leading cause of death in persons younger than 65 years of age. Colorectal cancer (CRC) is the second and third leading cause of cancer-related deaths in men and women, respectively, and overall, is the third most common type of cancer in men and women. In 2006, it was estimated that 148,610 new cases of CRC occurred and that 51,170 patients died of the disease.1, 2

The U.S. Preventive Services Task Force (USPSTF) strongly recommends screening for men and women 50 years of age or older for CRC ("A" recommendation).3 Biannual fecal occult blood testing can reduce CRC-related death by 21%, and it has been reported that flexible sigmoidoscopy reduces death by 60% for lesions within reach of the instrument. Further, data suggest that sigmoidoscopy followed by colonoscopy when polyps are found could decrease CRC incidence by up to 80%.4 Despite evidence of the effectiveness of several screening methods, adoption of routine CRC screening by eligible individuals, using any method, continues to be low in the United States.5-8

A CRC chemoprophylactic strategy may be used as a complement to or instead of a screening strategy. Several basic science, population-based, and experimental studies have suggested a protective effect of aspirin (ASA) and non-ASA nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase (COX)-2 inhibitors, on colorectal adenomas and CRC. However, 2 long-term, randomized, controlled trials, the Physicians' Health Study9 and the Women's Health Study,10 did not show a beneficial effect of low-dose ASA on CRC incidence. Furthermore, these agents are not without harms. Clinically significant gastrointestinal hemorrhage can occur with all of these agents, although it is substantially lower with COX-2 inhibitors.

More recently, interest has focused on a potentially prothrombotic effect of selective COX-2 inhibitors and nonnaproxen NSAIDs. In fact, during the conduct of our systematic review, 2 COX-2 inhibitors (rofecoxib and valdecoxib) were withdrawn from the U.S. market because of concerns about their cardiovascular toxicity, leaving only celecoxib remaining and uncertainty about the future of others, such as lumiracoxib and etoricoxib. These developments have resulted in uncertainty about the safety of COX-2 inhibitors and non-ASA NSAIDs when used longterm, such as in the setting of CRC prevention.11

At the request of the Agency for Healthcare Research and Quality (AHRQ), the Centers for Disease Control and Prevention (CDC), and the USPSTF, we conducted a systematic review to ascertain the effectiveness of non-ASA NSAIDs and COX-2 inhibitors in the chemoprevention of colorectal adenomas, CRC, and CRC-related death in average- to higher-risk individuals. We also examined the harms associated with these agents.

Return to Table of Contents

We developed the search strategy in MEDLINE® and modified it for other databases. The search was limited to English-language reports of human studies. We searched the following databases: MEDLINE® (1966 to December [week 4] 2006), EMBASE (1980 to the 14th week of 2005 publication years 2003 to 2005), Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Library Issue 4, 2004. Beyond these dates, we surveyed several sources to ascertain additional potentially eligible studies. PubMed Cancer subset was searched for non-MEDLINE® material.

Search terms were derived from the National Cancer Institute (NCI) Cancer topic searches for "colorectal cancer" and "adenomatous polyps." We derived a comprehensive retrieval strategy from the indexing in MEDLINE® and EMBASE, investigator-nominated terms, and previous reviews.12-14

We developed a search strategy in MEDLINE® (2003 to the third week of December 2006) to detect recent systematic reviews that appeared to address the harms of non-ASA NSAIDs and COX-2 inhibitors. We implemented a weekly monitoring strategy to detect emerging information on cardiovascular harms associated with COX-2 inhibitors. We also monitored the U.S. Food and Drug Administration News Digest and Health Canada's Health Product Information mailing list for announcements related to COX-2 inhibitors and cardiovascular harms (monitoring dates, 14 January 2005 to 26 May 2005). Beyond these dates, we surveyed several sources to ascertain additional potentially eligible studies.

Study Selection

Citation records were screened to identify potentially relevant articles and retained records were assessed for relevance to identify articles meeting inclusion criteria. A third screening phase was included to discriminate between the different study designs. At each screening stage, 2 members of the review team selected articles for inclusion after an initial calibration exercise. Conflicts were resolved by consensus.

We considered randomized, controlled trials (RCTs); controlled, clinical trials; and observational studies (cohort and case-control studies) of the efficacy of non-ASA NSAIDs and COX-2 inhibitors for inclusion if they fulfilled the population and outcome criteria.

We considered studies for inclusion if participants were at average risk for CRC (that is, no known risk factors for colorectal adenoma or CRC, other than age). We also considered studies of higher-risk individuals with a personal or family history of colorectal adenoma or a family history of sporadic CRC. Included studies addressed the incidence of colorectal adenomas, CRC, or both and CRC-related death or overall death. We excluded studies of high-risk patients with familial adenomatous polyposis or hereditary nonpolyposis colon cancer syndromes (Lynch I or II) and secondary prevention studies of patients with a personal history of CRC.

We sought existing systematic reviews to address the gastrointestinal, cardiovascular, and renal harms associated with the use of non-ASA NSAIDs and COX-2 inhibitors considering the number of reviews already done on these topics.

Data Extraction and Quality Assessment

Several members of the team extracted data independently by using a Web-based system (SRS 4.0, TrialStat Corp., Ottawa, Ontario, Canada). We extracted data by using the PICOS (participant, intervention and exposure, comparator, outcome, and study design) approach.

We used predefined criteria from the USPSTF to assess the quality of included systematic reviews, clinical trials, and observational studies, which we rated as good, fair, or poor.11 This scale relies on 4, 6, 7, and 7 criteria for systematic reviews, case-control studies, cohort studies, and RCTs, respectively. A good rating was given when all criteria were met; a fair rating when at least 80% were met and the study had no fatal flaws; and a poor rating when less than 80% of the criteria were met, when there was a fatal flaw, or both.

Data Synthesis and Analysis

We used an analytical framework to facilitate study grouping and subsequent data analysis in an effort to minimize clinical heterogeneity. We initially grouped studies by disorder (that is, colorectal adenoma or CRC), study design, study population, and medication exposure and subsequently subcategorized studies based on measures of dose effect, duration of exposure, and secondary outcomes (when reported). Definition of categories, such as "regular use," can be found elsewhere.11

We summarized and presented harms data from the included systematic reviews as a qualitative synthesis. We combined results numerically only if clinically and statistically appropriate. We chose relative risk as the effect measure. In case-control studies, a direct estimate of the relative risk is not possible. However, when event rates are low, as was the case in our review, the odds ratio provides a close approximation of the relative risk. In what follows, we simply refer to the relative risk. We assessed heterogeneity by using the I2 statistic. We combined studies when I2 was 50% or less.15 We directly abstracted point estimates of the adjusted relative risks and their 95% CIs from the reports of primary studies. One source of heterogeneity may be study-to-study variation in the method of selecting confounders for which to adjust and the final set of confounders chosen.

In Appendix Tables 1 and 2, we summarize these characteristics for each study. Further, a detailed discussion of the methodological considerations is presented in the USPSTF report.11 We computed standard errors by dividing the CI width by 2 X 1.96. We conducted quantitative synthesis by using inverse variance weighting and a random-effects model.17

Role of the Funding Sources

The evidence synthesis on which this article was based was funded by the CDC, AHRQ, and the USPSTF. Its design, conduct, and reporting was based on specific directives from these agencies.

Return to Table of Contents

Study Selection

Our literature search yielded 1790 potentially relevant bibliographic records that addressed the use of ASA, COX-2 inhibitors, and other non-ASA NSAIDs.11 For non-ASA NSAIDS, we retrieved 364 articles for relevance assessment, and 29 studies met final inclusion criteria. One study of rofecoxib18 and 2 studies of celecoxib19, 20 were published after completion of the task force report.11 and we include them herein.

A CRC-related death in 1 cohort study21 was reported. The chemoprophylaxis of CRC was addressed in 10 case-control studies22-31 and 3 cohort studies.32-34 The chemoprophylaxis of colorectal adenoma was addressed in 10 case-control studies,31, 35-43 1 cohort study,44 and 4 RCTs.18-20, 45

The Figure46, 47 describes the flow of reports through our review, and Appendix Tables 3, 4, and 5 describe the included studies. A table of duplicate and companion articles is available in the AHRQ report.11

Study Quality and Methodological Considerations

The understanding of the important sources of heterogeneity among the included observational studies is key to interpreting the results of this review and the ASA review,11 also in this issue of Annals of Internal Medicine. This was discussed in detail elsewhere,11 and we present it here in brief. We produced an a priori, hierarchical framework that identified key characteristics that were expected to be common to all the included studies. We used this framework to facilitate study grouping and subsequent data analysis.

We anticipated certain key characteristics, such as the dose across studies, to show important heterogeneity. Measuring the dose effect depended on the intervention dose, the frequency and duration of use, and whether the use was current and ongoing or had occurred at some time in the past. For example, some studies defined specific dose levels, whereas in other studies, researchers reported dose effect in terms of frequency of use, such as number of pills per week or prescription refills in a given time period, thereby combining the effects of dose and duration. One way to handle this inconsistency across studies was to define regular use and specific duration intervals in the developed framework11 to group studies with similar dose effects. Other sources of inconsistency also existed, such as the methods and timing of ascertainment of exposure (for example, questionnaires, patient records, and databases) and outcome (for example, colonoscopy, patient records, and databases). Lastly, the type of NSAIDs used varied among studies between non-ASA NSAIDs alone, ASA included among NSAIDs (herein referred to as "any NSAIDs"), and COX-2 inhibitors alone. We analyzed the data separately for each of these 3 types of exposures. In some situations, individual study differences precluded statistical pooling.

The quality of the included studies was good for 3 of the 4 RCTs, good to fair for the 5 cohort studies, and fair for most of the case-control studies (5 good,11 fair, and 4 poor).

Colorectal Cancer Mortality

A single cohort study of fair quality assessed the effect of ibuprofen on CRC mortality.21 The study used an administrative database to identify11 3,538 participants who filled at least 1 ibuprofen prescription over a 6-year period. A statistically significant increase in all-cause mortality was observed with ibuprofen, but no effect on death due to bowel or rectal cancer was observed (Table 1).

Colorectal Cancer Incidence

Table 1 summarizes the effects of regular use of non-ASA NSAIDs on CRC incidence. The available data are limited to observational studies.

Cohort Studies

Three cohort studies assessed the effect of non-ASA NSAIDs on CRC incidence.32-34 The Nurses' Health Study34 was a large, good-quality, 20-year prospective followup of average-risk U.S. women.34 It showed a statistically significant dose-dependent protective effect of non-ASA NSAIDs on CRC. The magnitude of the relative risk reduction was up to 30% in colon cancer, whereas no benefit was observed for rectal cancer alone. When specific dose subgroups were analyzed, patients receiving less than 6 tablets per week or those receiving non-ASA NSAIDs irregularly did not seem to show a reduction in CRC incidence. Two other large administrative database studies of fair quality showed a statistically significant protective effect of regular non-ASA NSAIDs on the incidence of CRC.32, 33

Case-Control Studies

The regular use of non-ASA NSAIDs and of any NSAIDs was associated with statistically significant reductions in CRC frequency in the pooled analyses (relative risk, 0.70 for non-ASA NSAIDs22, 23, 25, 49 vs. 0.57 for any NSAIDs26-29, 31). Two other case-control studies (1 large prescription database study of good quality30 and 1 study of fair quality24) demonstrated statistically significant reductions in CRC frequency, but their method of quantifying regular NSAID use prevented statistical pooling with the other studies.

Dose and Duration of Use

In cohort studies33, 34 and case-control studies22, 30, 31 higher dose levels of any NSAIDs were generally associated with statistically significant relative risk reductions in CRC frequency, whereas lower dose levels were not (Tables 2 and 3 ). Two studies of fair quality25, 28 demonstrated inconsistent dose effects, which may be due to underpowered subgroup analyses.

Similarly, longer durations of non-ASA NSAID use (that is, beyond 2 to 5 years) generally resulted in statistically significant reductions in risk for CRC, whereas lower durations of use did not.22, 25, 26, 30 The largest and best-quality study in the group demonstrated a statistically significant reduction in risk for CRC with non-ASA NSAID use of at least 11 years but not for shorter durations.30 Small studies of poor quality did not demonstrate a consistent duration effect.27,31

Colorectal Adenoma

Randomized, Controlled Trials

In patients with a history of colorectal adenomas, 3 recent, good-quality RCTs on COX-2 inhibitor (celecoxib19, 20 and rofecoxib18) demonstrated statistically significant reductions in the incidence of all adenomas and advanced adenomas over a 3-year followup (pooled relative risk, 0.72 [95% CI, 0.68 to 0.77] vs. 0.56 [CI, 0.42 to 0.75], respectively) (Table 1). A nonsignificant trend was observed toward a greater relative risk reduction in advanced versus all adenomas for celecoxib.19 However, patients with advanced adenoma seemed to derive less benefit from rofecoxib than those without advanced adenomas.18 Patients also seemed to have a reduced benefit with rofecoxib over time. Further, in a small subgroup of randomly assigned patients who agreed to undergo colonoscopy in year 4 post-study completion, patients in the rofecoxib group had a higher risk for adenomas than those in the placebo group, suggesting a possible rebound effect.18

Another small RCT45 of fair quality found that 4 months of sulindac, 30 mg/d (non-ASA NSAID), did not cause a statistically significant regression of colorectal adenomas (.1.0 cm), which were initially identified by using flexible sigmoidoscopy.

Cohort Studies

In a single cohort study of good quality,44 regular use of any NSAID significantly reduced the incidence of colorectal adenomas in patients with a history of colorectal adenoma (relative risk, 0.64 [CI, 0.48 to 0.85).

Case-Control Studies

The regular use of non-ASA NSAIDs36, 38, 50, 51 and any NSAID31, 36, 41-43 in average-risk individuals was associated with statistically significant reductions in frequency of colorectal adenoma (relative risk, 0.54 [CI, 0.4 to 0.74] vs. 0.57 [CI, 0.46 to 0.71], respectively).

Dose and Duration of Use

A nonstatistically significant trend for greater reduction in adenoma incidence was observed with celecoxib, 800 mg/d, compared with celecoxib, 400 mg/d, in 1 RCT.19 In 3 case-control studies,31, 37, 42 higher NSAID doses were associated with statistically significant reductions in frequency of colorectal adenoma, whereas lower doses were not (Table 2).

The use of any NSAID had less consistent duration effects on adenoma prevention than on CRC prevention. Two studies36, 39 demonstrated statistically significant reductions in adenoma frequency with the use of any NSAID for at least 5 years, whereas another study42 demonstrated a nonsignificant trend toward greater adenoma reduction with more than 19 years of use of any NSAID compared with fewer than 10 years of use of any NSAID. The remaining studies31, 38, 41 demonstrated inconsistent results mostly because of underpowered subgroup analyses (Table 3).

Harms Due to Non-ASA NSAIDs and COX-2 Inhibitors

All-Cause Mortality

Three reviews52-54 reported no statistically significant differences in all-cause mortality between different NSAIDs or between NSAIDs and placebo. Compared with placebo, neither less selective COX-2 inhibitors (etodolac, meloxicam, nabumetone, or nimesulide) used in 51 RCTs (relative risk, 0.68 [CI, 0.3 to 1.6]) nor selective COX-2 inhibitors (celecoxib and rofecoxib) used in 17 RCTs (relative risk, 1.02 [0.6 to 1.9]) were associated with a difference in mortality.52 No deaths were reported in 3 RCTs comparing celecoxib with placebo or other NSAIDs,53 and mortality rates were similar between rofecoxib (0.5%) and naproxen (0.4%) in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial54 and between rofecoxib (0.93%) and placebo (0.92%) in the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial18 However, 1 administrative database study of fair quality21 and a systematic review using a biologic progression model55 found a small, statistically significant increase in all-cause mortality with non-ASA NSAIDs.

Cardiovascular Harms

Eight systematic reviews53, 54, 56-61 addressed the magnitude of cardiovascular harms associated with the use of COX-2 inhibitors. They reported on RCT data, thereby providing high-level evidence, and 1 review59 also included observational studies. Two of the reviews56, 59 extracted cardiovascular harms of non-ASA NSAIDs. Cardiovascular events reported across the systematic reviews included death due to such events, serious cardiovascular events (overall), acute myocardial infarction (MI), acute stroke, arterial hypertension, congestive heart failure, edema, and thrombotic events (Table 4).

Four reviews found no significant differences in death due to cardiovascular events with the use of a COX-2 inhibitor compared with placebo, nonnaproxen NSAIDs, or naproxen.53, 54, 56, 59

Three reviews56, 58, 59 reporting overall serious cardiovascular events consistently demonstrated an excess risk for these events with the use of COX-2 inhibitors compared with use of placebo or naproxen. The risk for cardiovascular events was greatest in patients at high risk for such events (patients for whom aspirin is indicated).58 The risk associated with the use of nonnaproxen non-ASA NSAIDs (mostly high-dose diclofenac and ibuprofen) seemed similar to that shown with the use of COX-2 inhibitors.

Six reviews54, 56, 58-61 reported on the risk for acute MI in patients taking COX-2 inhibitors or non-ASA NSAIDs. The results consistently demonstrated statistically significant increases in the relative risk for MI with the use of COX-2 inhibitors compared with placebo or naproxen. High-dose, nonnaproxen, non-ASA NSAIDs (mostly diclofenac and ibuprofen) seemed to have a similar risk for MI as that of COX-2 inhibitors.56 One of the identified reviews59 showed a statistically significant protective effect of naproxen on MI; however, that analysis demonstrated significant heterogeneity.

Five reviews reported on acute stroke.54, 56, 58, 59, 61 The results consistently showed no statistically significant increased risk for stroke with COX-2 inhibitors compared with placebo, nonnaproxen NSAIDs, or naproxen. One high-quality review56 demonstrated a statistically significant lower risk for acute stroke with COX-2 inhibitors than nonnaproxen NSAIDs in an analysis primarily driven by the effect of high-dose diclofenac.

The risks for hypertension and renal toxicity may also be elevated with COX-2 inhibitors and are reported elsewhere.62

Gastrointestinal Harms

The included systematic reviews of the gastrointestinal harms of NSAIDs summarized data from RCTs,12, 50, 55, 63, 64 cohort studies,[[55, 65, 66]] and case-control studies.55, 63, 65 Two of the systematic reviews of RCTs12, 52 focused primarily on prevention of NSAID-induced upper gastrointestinal toxicity through the use of prophylactic agents or the use of COX-2 inhibitors. One of these12 reported the rate of gastrointestinal complications in patients taking NSAIDs. Twelve systematic reviews assessed COX-2 inhibitors with data on celecoxib,12, 52, 53, 66-69 rofecoxib,12, 50, 54, 57, 61 valdecoxib,60, 70, 71 and meloxicam.12, 50, 72 Rostom and colleagues12 updated their COX-2 inhibitor review to include data for lumiracoxib, valdecoxib, and etoricoxib. The updated review is currently in press, and the pooled estimates remain similar to those presented here.

All of the included studies reported an increased risk for peptic ulceration and gastrointestinal hemorrhage with non-ASA NSAID use. The risk for complicated peptic ulcers (perforation, obstruction, or bleeding) in those receiving NSAIDs compared with those who were not was elevated in pooled analyses for RCTs (odds ratio, 5.36 [CI, 1.79 to 16.1]), cohort studies (relative risk, 2.7 [CI, 2.1 to 3.5]), and case-control studies (odds ratio, 3.0 [CI, 2.5 to 3.7]).63 The best RCT evidence of the risk for perforation, obstruction, or bleeding with NSAIDs was derived from the original Misoprostol Ulcer Complications Outcome Safety Assessment (MUCOSA) study12, 13, 73 and corroborated with recent data from the NSAID groups of the COX-2 inhibitor trials.12, 74-76 A risk for perforation, obstruction, and bleeding of approximately 1.5% to 2% per year was observed in average-risk individuals taking standard non-ASA NSAIDs. The risk for perforation, obstruction, or bleeding can reach 10% or more in higher-risk individuals, including those who have had previous peptic ulcers; who are older; and who have comorbid conditions, such as cardiovascular disease.12, 13, 70, 74

We estimated the absolute risk difference of perforation, obstruction, or bleeding for patients taking NSAIDs compared with those not taking NSAIDs to be 0.48% for the included RCTs and 0.22% for the included cohort studies.

The risk for upper gastrointestinal toxicity due to non-ASA NSAID use can be reduced through the use of a concomitant gastroprotective agent. Misoprostol was associated with a statistically significant 40% relative risk reduction in clinical ulcer complications due to combined NSAID use.12, 13,73 Histamine-2-receptor antagonists (H2RAs) and proton-pump inhibitors have only been evaluated in endoscopic ulcer studies.12, 13 Double-dose H2RAs (equivalent to ranitidine, 300 mg twice daily) and standard dose proton-pump inhibitors were associated with statistically significant reductions in the risk for NSAID-induced duodenal and gastric ulcers. Standard-dose H2RAs were not effective at reducing the risk for NSAID-induced gastric ulcers.12, 13

The use of a COX-2 inhibitor compared with a non-ASA NSAID (ibuprofen, diclofenac, or naproxen) results in statistically significant relative risk reductions for the following: the incidence of endoscopically detected gastroduodenal ulcers by approximately 75%;12, 52-54, 61, 66, 67 clinically significant ulcer complication (perforation, obstruction, or bleeding and symptomatic ulcers) by 40% to 60%;12, 52- 54, 61, 66, 67, 70, 72 and gastrointestinal symptoms, such as dyspepsia.12, 52, 61, 67, 71 The effects were similar when non-ASA NSAIDs were pooled and when each was compared separately with COX-2 inhibitors.12

In several systematic reviews, no statistically significant difference in gastrointestinal bleeding or ulceration was reported when COX-2 inhibitors were compared with placebo.12, 53, 54, 60, 67, 70 However, 1 review66 showed that patients receiving celecoxib, 200 mg/d, were not at an increased risk for endoscopic ulcers compared with those receiving placebo but patients receiving celecoxib, 400 mg/d, were at increased risk (relative risk, 2.35; CI, 1.02 to 5.38).66 Compared with placebo, rofecoxib was associated with a statistically significant increased risk for total adverse events (relative risk, 1.32 [CI, 1.11 to 1.56]) and total gastrointestinal events accrued at 6 weeks (relative risk, 3.39 [CI, 1.47 to 7.84]).61 The APPROVe study found that the risk for symptomatic ulcer, bleeding, perforation or obstruction was higher with rofecoxib than with placebo over a 3-year followup period (relative risk, 4.9 [CI, 1.98 to 14.5]).

The Celecoxib Long-term Arthritis Safety Study (CLASS),74 Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) (lumiracoxib),76 and the valdecoxib trial70 assessed the use of a COX-2 inhibitor in a subgroup of patients receiving ASA. In patients taking ASA the frequency of clinically important ulcer complications was not different in those who received COX-2 inhibitors or non-ASA NSAIDs. The combination of ASA and celecoxib resulted in a 4-fold increase in ulcer complications over celecoxib alone,12, 74 and the combination of valdecoxib and ASA resulted in a 9-fold increase in ulcer complications over valdecoxib alone.70 Although the data for these estimates were derived from post hoc subgroup analyses and may be subject to important bias, one needs to keep them in mind when considering a strategy for combining a COX-2 inhibitor with ASA for cardioprotection.

Return to Table of Contents

Colorectal cancer is an important burden on the U.S. population. The use of NSAID chemoprophylaxis, alone or in combination with a recommended screening program, is 1 strategy to reduce the incidence of colorectal adenomas, CRC, and CRC-related death.

The results of our systematic review suggest that the use of non-ASA NSAIDs for CRC chemoprevention is effective at reducing the incidence of colorectal adenomas and CRC. Cyclooxygenase-2 inhibitors seem to be effective at reducing the incidence of colorectal adenoma in patients with previous adenomatous polyps. Higher doses and longer durations of use of non-ASA NSAIDs seem to be associated with greater protection from CRC and adenomas. We found the magnitude of the relative risk reduction for CRC incidence to be approximately 30% to 40% in the pooled analyses.

We found no observational data on the effect of COX-2 inhibitors on CRC incidence or CRC-related death, although a single cohort study showed no effect of the non-ASA NSAID ibuprofen on CRC death but demonstrated a small statistically significant increase in allcause mortality.21 Further, no RCT data exist on CRC incidence with the long-term use of COX-2 inhibitors or non-ASA NSAIDs that are similar to data from the ASA-based Physicians' and Women's Health studies.9, 10

The use of non-ASA NSAIDs and COX-2 inhibitors are each associated with important harms. Non-ASA NSAIDs are associated with an increased risk for ulcers and clinically important ulcer complications, such as hemorrhage, perforation, or pyloric obstruction. Cyclooxygenase-2 inhibitors are associated with fewer gastrointestinal symptoms, endoscopic ulcers, and clinically important ulcer complications than non-ASA NSAIDs. However, data from the APPROVe study18 demonstrated that over a 3-year period, COX-2 inhibitors were associated with a statistically significant increased risk for clinical ulcer complications compared with placebo.18 Although these data are in keeping with improved gastrointestinal safety of COX-2 inhibitors over non-ASA NSAIDs, the gastrointestinal safety of COX-2 inhibitors is not equivalent to that seen with placebo, as has been suggested in the past. On the other hand, COX-2 inhibitors are associated with an increased risk for adverse cardiovascular outcomes.56

During the conduct of our systematic review, rofecoxib was withdrawn from the market because of the results of the polyp prevention APPROVe study,78 which demonstrated an excess risk for cardiovascular events (16 per 1000 events) with the use of rofecoxib, confirming the suspicions reported by the VIGOR investigators.76 Subsequently, celecoxib was also found to have an excess risk for cardiovascular events (13 to 21 per 1000 events) in another polyp prevention study (Adenoma Prevention with Celecoxib [APC]).79 Valdecoxib was also withdrawn because of excess risk for cardiovascular events in 2 short-term cardiac surgery pain studies (Coronary Artery Bypass Graft [CABG] 1 and 2) and because of a rare dermatologic toxicity.80, 81

A systematic review of the cardiovascular harms of rofecoxib and non-ASA NSAIDs59 suggested a small cardiovascular protective effect of naproxen, although the included studies were heterogeneous. Naproxen's relatively long half-life of 14 hours makes a twice-daily dosing schedule theoretically capable of consistently blocking COX-1 and potentially providing some degree of cardioprotection. Clinical trial data of the quality comparable to data available for the COX-2 inhibitors is not available for non-ASA NSAIDs. However, a recent meta-analysis56 using an extensive set of RCT data derived from published and unpublished studies suggests that, as a group, COX-2 inhibitors are associated with an increased risk for adverse cardiovascular outcomes (predominantly MI) when compared with placebo or naproxen but not when compared with nonnaproxen, non-ASA NSAIDs. These data, and evidence from some population-based studies,82-84 suggest that the increased risk for cardiovascular harms with COX-2 inhibitors is shared by nonnaproxen, non-ASA NSAIDs (higher doses of ibuprofen and diclofenac).56

Although it is tempting to consider adding ASA to a COX-2 inhibitor for cardioprotection, there seems to be an attenuation of the gastrointestinal safety of COX-2 inhibitors with this strategy. However, it should be noted that these observations were derived from post hoc subgroup analyses.

Non-ASA NSAIDs and COX-2 inhibitors are used for longer durations for a variety of arthritic and inflammatory conditions.12 Although their use for these conditions is more easily justified, it is much more difficult to make a case for their use for the chemoprevention of adenomas and CRC in average-risk individuals or even in individuals with a history of polyps. In light of the cardiovascular and gastrointestinal toxicity of these agents when used in a multiyear setting, the demonstration of the chemopreventive efficacy may be a "pyrrhic victory" as stated by Lynch85 in his editorial on the APPROVe trial. Furthermore, considering the newly identified risks for cardiovascular events associated with these agents, the cost-effectiveness of a chemopreventive strategy for CRC needs to be fully evaluated, particularly because a screening strategy alone appears to be effective.4 In a simplified risk-benefit analysis, assuming that CRC incidence can be reduced by 50% with COX-2 inhibitor use, Psaty and Potter86 suggested that significantly more cardiovascular events would occur than cases of CRC prevented. However, the balance of benefits and risks in high-risk patients, such as those with familial adenomatous polyposis and nonpolyposis syndromes and those with a history of CRC, may be quite different from that detailed here for average- to higher-risk individuals. A role for COX-2 inhibitors continues to be evaluated in the setting of these high-risk patients.86

Although ASA seems to be an attractive candidate for CRC chemoprophylaxis, the apparent need for doses higher than that used for cardiovascular protection represents a crucial drawback.48 Likewise, the improved gastrointestinal safety profile of COX-2 inhibitors over non-ASA NSAIDs made COX-2 inhibitors an attractive candidate until their cardiovascular toxicity came to light. Nonnaproxen, non-ASA NSAIDs seem to be the least attractive option because they are associated with both gastrointestinal and cardiovascular toxicity.

In conclusion, non-ASA NSAIDs seem to be effective at reducing the incidence of colorectal adenomas and CRC in observational studies. Good-quality RCT data suggest that COX-2 inhibitors are effective at reducing the incidence of colorectal adenomas in patients with previous adenomas. However, positive data on the reduction of death is lacking for both non-ASA NSAIDs and COX-2 inhibitors.

No quantitative data exist on the risk for gastrointestinal or cardiovascular harms associated with daily, multiyear use of non-ASA NSAIDs. Available data on COX-2 inhibitors suggest that absolute risk increases of over 1% for cardiovascular events and for clinically important gastrointestinal complications can be anticipated after only 2 to 3 years of use, and higher risks may accrue over longer periods. Furthermore, the cost-effectiveness of chemoprevention needs to be considered carefully and compared with other strategies, such as colorectal cancer screening alone. Therefore, the balance of benefits and risks does not appear to favor chemoprevention with non-ASA NSAIDs or COX-2 inhibitors in average-risk individuals or in those with a history of colorectal adenomas.

Return to Table of Contents

1. Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8-29. [PMID: 14974761]
2. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56:106-30. [PMID: 16514137]
3. 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;136:161-72. [PMID: 11790072]
4. Thiis-Evensen E, Hoff GS, Sauar J, Langmark F, Majak BM, Vatn MH. Population-based surveillance by colonoscopy: effect on the incidence of colorectal cancer. Telemark Polyp Study I. Scand J Gastroenterol 1999;34:414-20. [PMID: 10365903]
5. Centers for Disease Control and Prevention. Trends in screening for colorectal cancer—United States, 1997 and 1999. MMWR Morb Mortal Wkly Rep 2001;50:162-6. [PMID: 11393486]
6. Centers for Disease Control and Prevention. Trends in screening for colorectal cancer—United States, 1997 and 1999. JAMA 2001;285:1570-1. [PMID: 11302136]
7. Centers for Disease Control and Prevention. Colorectal cancer test use among persons aged > or = 50 years—United States, 2001. MMWR Morb Mortal Wkly Rep 2003;52:193-6. [PMID: 12653456]
8. Seeff LC, Nadel MR, Klabunde CN, Thompson T, Shapiro JA, Vernon SW, et al. Patterns and predictors of colorectal cancer test use in the adult U.S. population. Cancer 2004;100:2093-103. [PMID: 15139050]
9. 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;85:1220-4. [PMID: 8331682]
10. Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, 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. [PMID: 15998890]
11. Rostom A, Dube´ C, Lewin G, Tsertsvadze A, Barrowman N, Code C, et al. Use of aspirin and NSAIDs to prevent colorectal cancer. Evidence synthesis prepared by the University of Ottawa Evidence-based Practice Center under contract no. 290-02-0021. Rockville, MD: Agency for Healthcare Research and Quality; 2006.
12. Rostom A, Dube´ C, Jolicoeur E, Boucher M, Joyce J. Gastroduodenal ulcers associated with the use of non-steroidal anti-inflammatory drugs: a systematic review of preventative pharmacological interventions. Ottawa, Canada: Canadian Coordinating Office for Health Technology Assessment; 2004. Technology report no. 38.
13. Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002:CD002296. [PMID: 12519573]
14. Asano TK, McLeod RS. Non steroidal anti-inflammatory drugs (NSAID) and Aspirin for preventing colorectal adenomas and carcinomas. Cochrane Database Syst Rev 2004:CD004079. [PMID: 15106236]
15. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60. [PMID: 12958120]
16. Paganini-Hill A. Aspirin and colorectal cancer: the Leisure World cohort revisited. Prev Med 1995;24:113-5. [PMID: 7597009]
17. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88. [PMID: 3802833]
18. Baron JA, Sandler RS, Bresalier RS, Quan H, Riddell R, Lanas A, et al. A randomized trial of rofecoxib for the chemoprevention of colorectal adenomas. Gastroenterology 2006;131:1674-82. [PMID: 17087947]
19. Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim K. et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006;355:873-84. [PMID: 16943400]
20. Arber N, Eagle CJ, Spicak J, Racz I, Dite P, Hajer J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006;355:885-95. [PMID: 16943401]
21. Lipworth L, Friis S, Blot WJ, McLaughlin JK, Mellemkjaer L, Johnsen SP, et al. A population-based cohort study of mortality among users of ibuprofen in Denmark. Am J Ther 2004;11:156-63. [PMID: 15133529]
22. García-Rodríguez LA, Huerta-Alvarez C. Reduced risk of colorectal cancer among long-term users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs. Epidemiology 2001;12:88-93. [PMID: 11138826]
23. Kune GA, Kune S, Watson LF. Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study. Cancer Res 1988;48:4399-404. [PMID: 3390835]
24. Juarranz M, Calle-Puro´n ME, González-Navarro A, Regidor-Poyatos E, Soriano T, Martínez-Hernandez D, et al. Physical exercise, use of Plantago ovata and aspirin, and reduced risk of colon cancer. Eur J Cancer Prev 2002;11:465-72. [PMID: 12394244]
25. Reeves MJ, Newcomb PA, Trentham-Dietz A, Storer BE, Remington PL. Nonsteroidal anti-inflammatory drug use and protection against colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 1996;5:955-60. [PMID: 8959316]
26. Slattery ML, Samowitz W, Hoffman M, Ma KN, Levin TR, Neuhausen S. Aspirin, NSAIDs, and colorectal cancer: possible involvement in an insulin-related pathway. Cancer Epidemiol Biomarkers Prev 2004;13:538-45. [PMID: 15066917]
27. Muscat JE, Stellman SD, Wynder EL. Nonsteroidal antiinflammatory drugs and colorectal cancer. Cancer 1994;74:1847-54. [PMID: 8082089]
28. Shaheen NJ, Silverman LM, Keku T, Lawrence LB, Rohlfs EM, Martin CF, et al. Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J Natl Cancer Inst 2003;95:154-9. [PMID: 12529348]
29. Coogan PF, Rosenberg L, Louik C, Zauber AG, Stolley PD, Strom BL, et al. NSAIDs and risk of colorectal cancer according to presence or absence of family history of the disease. Cancer Causes Control 2000;11:249-55. [PMID: 10782659]
30. Collet JP, Sharpe C, Belzile E, Boivin JF, Hanley J, Abenhaim L. Colorectal cancer prevention by non-steroidal anti-inflammatory drugs: effects of dosage and timing. Br J Cancer 1999;81:62-8. [PMID: 10487613]
31. Peleg II, Lubin MF, Cotsonis GA, Clark WS, Wilcox CM. Long-term use of nonsteroidal antiinflammatory drugs and other chemopreventors and risk of subsequent colorectal neoplasia. Dig Dis Sci. 1996;41:1319-26. [PMID: 8689906]
32. Sørensen HT, Friis S, Nørgärd B, Mellemkjaer L, Blot WJ, McLaughlin JK, et al. Risk of cancer in a large cohort of nonaspirin NSAID users: a population-based study. Br J Cancer 2003;88:1687-92. [PMID: 12771981]
33. Smalley W, Ray WA, Daugherty J, Griffin MR. Use of nonsteroidal antiinflammatory drugs and incidence of colorectal cancer: a population-based study. Arch Intern Med 1999;159:161-6. [PMID: 9927099]
34. 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;294:914-23. [PMID: 16118381]
35. Bigler J, Whitton J, Lampe JW, Fosdick L, Bostick RM, Potter JD. CYP2C9 and UGT1A6 genotypes modulate the protective effect of aspirin on colon adenoma risk. Cancer Res 2001;61:3566-9. [PMID: 11325819]
36. Logan RF, Little J, Hawtin PG, Hardcastle JD. Effect of aspirin and nonsteroidal anti-inflammatory drugs on colorectal adenomas: case-control study of subjects participating in the Nottingham faecal occult blood screening programme. BMJ 1993;307:285-9. [PMID: 8374373]
37. Boyapati SM, Bostick RM, McGlynn KA, Fina MF, Roufail WM, Geisinger KR, et al. Calcium, vitamin D, and risk for colorectal adenoma: dependency on vitamin D receptor BsmI polymorphism and nonsteroidal anti-inflammatory drug use? Cancer Epidemiol Biomarkers Prev 2003;12:631-7. [PMID: 12869402]
38. García Rodríguez LA, Huerta-Alvarez C. Reduced incidence of colorectal adenoma among long-term users of nonsteroidal antiinflammatory drugs: a pooled analysis of published studies and a new population-based study. Epidemiology 2000;11:376-81. [PMID: 10874542]
39. Breuer-Katschinski B, Nemes K, Rump B, Leiendecker B, Marr A, Breuer N, et al. Long-term use of nonsteroidal antiinflammatory drugs and the risk of colorectal adenomas. The Colorectal Adenoma Study Group. Digestion 2000; 61:129-34. [PMID: 10705177]
40. Sandler RS, Galanko JC, Murray SC, Helm JF, Woosley JT. Aspirin and nonsteroidal anti-inflammatory agents and risk for colorectal adenomas. Gastroenterology 1998;114:441-7. [PMID: 9496933]
41. Martínez ME, McPherson RS, Levin B, Annegers JF. Aspirin and other nonsteroidal anti-inflammatory drugs and risk of colorectal adenomatous polyps among endoscoped individuals. Cancer Epidemiol Biomarkers Prev 1995;4:703-7. [PMID: 8672985]
42. Lieberman DA, Prindiville S, Weiss DG, Willett W. Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals. JAMA 2003;290:2959-67. [PMID: 14665657]
43. Martin C, Connelly A, Keku TO, Mountcastle SB, Galanko J, Woosley JT, et al. Nonsteroidal anti-inflammatory drugs, apoptosis, and colorectal adenomas. Gastroenterology 2002;123:1770-7. [PMID: 12454832]
44. Tangrea JA, Albert PS, Lanza E, Woodson K, Corle D, Hasson M, et al. Non-steroidal anti-inflammatory drug use is associated with reduction in recurrence of advanced and non-advanced colorectal adenomas (United States). Cancer Causes Control 2003;14:403-11. [PMID: 12946034]
45. Ladenheim J, Garcia G, Titzer D, Herzenberg H, Lavori P, Edson R, et al. Effect of sulindac on sporadic colonic polyps. Gastroenterology 1995;108:1083-7. [PMID: 7698575]
46. Giovannucci E, Egan KM, Hunter DJ, Stampfer MJ, Colditz GA, Willett WC, et al. Aspirin and the risk of colorectal cancer in women. N Engl J Med 1995;333:609-14. [PMID: 7637720]
47. Chan AT, Giovannucci EL, Schernhammer ES, Colditz GA, Hunter DJ, Willett WC, et al. A prospective study of aspirin use and the risk for colorectal adenoma. Ann Intern Med 2004;140:157-66. [PMID: 14757613]
48. Dubé C, Rostom A, Lewin G, Tsertsvadze A, Barrowman N, Code C, et al. The use of aspirin for the primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med 2007:146;365-75.
49. Friedman GD, Coates AO, Potter JD, Slattery ML. Drugs and colon cancer. Pharmacoepidemiol Drug Saf 1998;7:99-106. [PMID: 15073733]
50. Morimoto LM, Newcomb PA, Ulrich CM, Bostick RM, Lais CJ, Potter JD. Risk factors for hyperplastic and adenomatous polyps: evidence for malignant potential? Cancer Epidemiol Biomarkers Prev 2002;11:1012-8. [PMID: 12376501]
51. Hauret KG, Bostick RM, Matthews CE, Hussey JR, Fina MF, Geisinger KR, et al. Physical activity and reduced risk of incident sporadic colorectal adenomas: observational support for mechanisms involving energy balance and inflammation modulation. Am J Epidemiol 2004;159:983-92. [PMID: 15128611]
52. Hooper L, Brown TJ, Elliott R, Payne K, Roberts C, Symmons D. The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review. BMJ 2004; 329:948. [PMID: 15475342]
53. Garner S, Fidan D, Frankish R, Judd M, Shea B, Towheed T, et al. Celecoxib for rheumatoid arthritis. Cochrane Database Syst Rev 2002: CD003831. [PMID: 12519610]
54. Garner SE, Fidan DD, Frankish RR, Judd MG, Towheed TE, Wells G, et al. Rofecoxib for rheumatoid arthritis. Cochrane Database Syst Rev 2005: CD003685. [PMID: 15674912]
55. Tramèr MR, Moore RA, Reynolds DJ, McQuay HJ. Quantitative estimation of rare adverse events which follow a biological progression: a new model applied to chronic NSAID use. Pain 2000;85:169-82. [PMID: 10692616]
56. 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;332:1302-8. [PMID: 16740558]
57. Gomez Cerezo J, Lubomirov Hristov R, Carcas Sansuán AJ, Vázquez Rodríguez JJ. Outcome trials of COX-2 selective inhibitors: global safety evaluation does not promise benefits. Eur J Clin Pharmacol 2003;59:169-75. [PMID: 12698301]
58. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001;286:954-9. [PMID: 11509060]
59. Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004;364: 2021-9. [PMID: 15582059]
60. Edwards JE, McQuay HJ, Moore RA. Efficacy and safety of valdecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. Pain 2004;111:286-96. [PMID: 15363872]
61. Garner SE, Fidan DD, Frankish R, Maxwell L. Rofecoxib for osteoarthritis.Cochrane Database Syst Rev 2005:CD005115. [PMID: 15654705]
62. Zhang J, Ding EL, Song Y. Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events: meta-analysis of randomized trials. JAMA 2006; 296:1619-32. [PMID: 16968832]
63. Ofman JJ, MacLean CH, Straus WL, Morton SC, Berger ML, Roth EA, et al. A metaanalysis of severe upper gastrointestinal complications of nonsteroidal antiinflammatory drugs. J Rheumatol 2002;29:804-12. [PMID: 11950025]
64. Ofman JJ, Maclean CH, Straus WL, Morton SC, Berger ML, Roth EA, et al. Meta-analysis of dyspepsia and nonsteroidal antiinflammatory drugs. Arthritis Rheum 2003;49:508-18. [PMID: 12910557]
65. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002;359:14-22. [PMID: 11809181]
66. Ashcroft DM, Chapman SR, Clark WK, Millson DS. Upper gastroduodenal ulceration in arthritis patients treated with celecoxib. Ann Pharmacother 2001;35:829-34. [PMID: 11485128]
67. Deeks JJ, Smith LA, Bradley MD. Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials. BMJ 2002;325:619. [PMID: 12242171]
68. Rigau J, Piqué JM, Rubio E, Planas R, Tarrech JM, Bordas JM. Effects of long-term sulindac therapy on colonic polyposis. Ann Intern Med 1991;115: 952-4. [PMID: 1659272]
69. Tsujii M, Kawano S, Tsuji S, Sawaoka H, Hori M, DuBois RN. Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell 1998;93:705-16. [PMID: 9630216]
70. Goldstein JL, Eisen GM, Agrawal N, Stenson WF, Kent JD, Verburg KM. Reduced incidence of upper gastrointestinal ulcer complications with the COX-2 selective inhibitor, valdecoxib. Aliment Pharmacol Ther 2004;20:527-38. [PMID: 15339324]
71. Eisen GM, Goldstein JL, Hanna DB, Rublee DA. Meta-analysis: upper gastrointestinal tolerability of valdecoxib, a cyclooxygenase-2-specific inhibitor, compared with nonspecific nonsteroidal anti-inflammatory drugs among patients with osteoarthritis and rheumatoid arthritis. Aliment Pharmacol Ther 2005;21: 591-8. [PMID: 15740543]
72. Schoenfeld P. Gastrointestinal safety profile of meloxicam: a meta-analysis and systematic review of randomized controlled trials. Am J Med 1999;107:48S-54S. [PMID: 10628593]
73. Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995;123:241-9. [PMID: 7611589]
74. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000;284:1247-55. [PMID: 10979111]
75. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343:1520-8, 2 p following 1528. [PMID: 11087881]
76. Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004;364: 665-74. [PMID: 15325831]
77. Singh G, Fort JG, Goldstein JL, Levy RA, Hanrahan PS, Bello AE, et al. Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study. Am J Med 2006; 19:255-66. [PMID: 16490472]
78. Topol EJ. Failing the public health—rofecoxib, Merck, and the FDA. N Engl J Med 2004;351:1707-9. [PMID: 15470193]
79. Topol EJ. Arthritis medicines and cardiovascular events—"house of coxibs" [Editorial]. JAMA 2005;293:366-8. [PMID: 15623849]
80. Health Canada. Advisory Committee Briefing Document. Celecoxib Valdecoxib Cardiovascular Safety. Accessed at www.hc-sc.gc.ca/dhp_mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/sap_report_gcs_rappurt_cox2_e.pdf on 20 January 2005.
81. U.S. Food and Drug Administration. Arthritis & Drug Safety and Risk Management Advisory Committee Briefing Package. Accessed at www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4090b1-01.htm on 20 January 2005.
82. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005;330:1366. [PMID: 15947398]
83. Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002;162:1105-10. [PMID: 12020179]
84. Ray WA, Stein CM, Hall K, Daugherty JR, Griffin MR. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002;359:118-23. [PMID: 11809254]
85. Lynch PM. Is the demonstration of adenoma reduction with rofecoxib a pyrrhic victory? [Editorial]. Gastroenterology 2006;131:2003-5. [PMID: 17188962]
86. Psaty BM, Potter JD. Risks and benefits of celecoxib to prevent recurrent adenomas [Editorial]. N Engl J Med 2006;355:950-2. [PMID: 16943408]

Return to Table of Contents

This document is in the public domain within the United States.

Requests for linking or to incorporate content in electronic resources should be sent via the USPSTF contact form.

Source: Rostom A, Dubé C, Lewin G, Tsertsvadze A, Barrowman N, Code C, Sampson M, Moher D. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: Systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2007;146:376-89.

Acknowledgments: The investigators thank Mary White, Sc.D., Chief Epidemiology and Applied Research Branch (CDC); Patrik Johansson, M.D., Medical Officer (AHRQ); Therese Miller, Dr.P.H., Task Order Officer (AHRQ); Janelle Guirguis-Blake, M.D., USPSTF Program Director; and Elizabeth A. Edgerton, M.D., M.P.H., Director of Clinical Prevention. They also thank members of the USPSTF who served as leads for the project: Ned Calonge, M.D., M.P.H.; Michael LeFevre, M.D., M.S.P.H.; Carol Loveland-Cherry, Ph.D., R.N.; and Al Siu, M.D., M.S.P.H. They thank Nav Saloojee, M.D., for helping in the selection of relevant reports; Tiffany Richards for assisting with the evidence tables; Raymond Daniel for retrieving the full reports; Chantelle Garritty for helping to coordinate the process; and Isabella Steffensen and Christine Murray for dedicating many long hours to editing the report and its appendix tables.

Notes

Author Affiliation:

a. Drs. Dubé and Rostom: Division of Gastroenterology, University of Calgary Medical Clinic, Calgary, Alberta, Canada.
b. Drs. Lewin, Tsertsvadze, Barrowman, Sampson, and Moher: Chalmers Research Group, CHEO Research Institute, Ottawa, Ontario Canada.
c. Dr. Code: Division of Internal Medicine, The Ottawa Hospital—Civic Site, Ottawa, Ontario Canada.

Return to Table of Contents

Text Description is shown below

Studies not shown but included were acetylsalicylic acid (ASA) studies or studies that considered more than 1 intervention, outcome, or both. The Nurses' Health Study (NHS) represents an initial publication46 and a followup publication34 for colorectal cancer (CRC) and a separate publication for colorectal adenoma (CRA).47 Three cyclooxygenase (COX)-2 inhibitor polyp studies and a systematic review were added after we submitted our report to the U.S. Preventive Services Task Force and the Agency for Health Research and Quality.
*11 of these considered harms of ASA.
CV = cardiovascular; NSAID = nonsteroidal anti-inflammatory drug; RCT = randomized, controlled trial.

Text Description.

Two diagrams depict the flow of reports through the review process for this article.

The first diagram depicts the flow of Studies of Efficacy and Cost-Effectiveness of Nonsteroidal Anti-inflammatory Drugs (NSAIDS). The uppermost box in the diagram reads "Records identified with bibliographic databases and reviewer nomination (n = 1790)." Two arrows point down from this box to two other boxes beneath it; one reads "Records excluded from further review because of lack of relevance (n = 1426)" and the other reads "Records retrieved for relevance assessment (n = 364)"

From "Records retrieved for relevance assessment (n = 364)," two arrows point down to two more boxes; one reads:

"Records excluded (n = 296):

  • No relevant population = 111.
  • No relevant intervention = 31.
  • No relevant outcome = 17.
  • Not an eligible study design = 135.
  • Unable to obtain = 2."

The second box reads:

"Studies included in the 68 reports that entered qualitative synthesis and were eligible for meta-analysis (n = 35):

  • RCTs (NSAID: 1 adenoma, 0 CRC): 1.
  • Cohort studies (NSAID: 1 adenoma, 4 CRC): 5.
  • Case-controlled studies (10 CRA, 10 CRC): 20.
  • Cost-effectiveness analysis (COX-2 inhibitor: 3): 3.

Included RCTs on COX-2 inhibitor use and adenoma published after review: (n = 3)."

The second diagram depicts the flow of Studies of Harms of NSAIDS. The uppermost box in the diagram reads "Records identified with bibliographic databases and reviewer nomination (n = 560)." Two arrows point down from this box to two other boxes beneath it; one box reads "Records excluded from further review because of lack of relevance (n = 442)" and the other reads "Records retrieved for relevance assessment (n = 118)"

From "Records retrieved for relevance assessment (n = 118)," two arrows point down to two more boxes; one reads:

"Records excluded (n = 90):

  • Inclusion criteria not met = 88.
  • Did not address relevant harm = 1.
  • Unable to obtain = 1."

The second box reads:

"Systematic reviews that entered qualitative synthesis (n = 28).*
Included systematic review on CV harms of COX-2 inhibitors published after review: (n = 1)."

 

Return to Table of Contents
Study, Year
(Reference)
Participants, n Quality Score Population Dose and Duration Relative Risk
(95% CI)
Effects on Mortality
Cohort study (n = 1)
North Jutland Population Database; Lipworth, et al., 200421 113,538 Fair Average-risk men and women Ibuprofen for ≥5 y All-cause: 1.11 (1.05-1.16)b
Bowel cancer: 0.93 (0.6-1.3)b
Rectal cancer: 1.46 (0.9-2.3)b
Effects on the Incidence of CRC
Cohort studies (n = 3)
Nurses' Health Study; Chan, et al., 200534 82,911 Good Average-risk women ≥2 tablets of non-ASA NSAIDs per wk for 20 y CRC overall: 0.79 (0.64-0.97)
Colon cancer: 0.71 (0.56-0.91)
Rectal cancer: 1.04 (0.72-1.52)
North Jutland Population Database; Sørensen, et al., 200332 183,693 Fair Average-risk men and women ≥10 prescriptions for non-ASA NSAIDs over 9 y Colon cancer: 0.7 (0.6-0.9)c
Rectal cancer: 0.6 (0.4-0.9)c
Tennessee Medicaid Program; Smalley et al., 199933 104,217 Fair Elderly men and women Regular use of non-ASA NSAIDs for ≥1 y 0.61 (0.48-0.77)
Case-controlled studies (n = 8)
García-Rodríguez and Huerta-Alvarez, 200122 12,002 Good Average-risk men and women Regular use of non-ASA NSAIDs for ≥1 y 0.7 (0.63-0.78)
Slattery, et al., 200426 4,403 Fair Average-risk men and women Regular use of non-ASA NSAIDs for ≥1 y 0.7 (0.6-0.8)
Kune et al., 198823 1,442 Fair Average-risk men and women Regular use of non-ASA NSAIDs for ≥1 y 0.77 (0.6-1.01)
Reeves et al., 199625 447 Fair Average-risk women Regular use of non-ASA NSAIDs for ≥1 y 0.43 (0.2-0.89)
Summary for the regular use of non-ASA NSAIDs         0.7 (0.63-0.78)
Coogan, et al., 200029 11,754
(in 4 separate studies)
Fair Average-risk men and women Regular use any NSAID for ≥1 y 0.4 (0.2-0.9); 0.5 (0.4-0.7); 0.5 (0.3-0.9); and 0.7 (0.6-0.9)
Slattery, et al., 200426 2,157 Fair Average-risk men and women Regular use any NSAID for ≥1 y 0.8 (0.6-1.1)
Shaheen et al., 200328 1,308 Fair Average-risk men and women Regular use any NSAID for ≥1 y 0.54 (0.39-0.75)
Peleg, et al., 199631 505 Poor Average-risk men and women Regular use any NSAID for ≥1 y 0.34 (0.12-0.94)
Muscat, et al., 199427 1,011 Poor Average-risk men and women Regular use any NSAID for ≥1 y Men: 0.64 (0.42-0.97)
Women: 0.32 (0.18-0.57)
Summary for the regular use of any NSAID         0.57 (0.47-0.68)
Effects on the Incidence of Colorectal Adenomas
Randomized controlled trials (RCTs) (n = 3)
PreSAP; Arber, et al., 200620 933 vs. 628 Good Higher risk (previous adenoma) Celecoxib, 400 mg/d, for 3 y Any adenoma: 0.64 (0.56-0.75)
Advanced adenoma: 0.49 (0.33-0.73)
APC; Bertagnolli, et al., 200619 685 vs. 671 vs. 679 Good Higher risk (previous adenoma) Celecoxib, 400 mg/d, for 3 y
Celecoxib, 800 mg/d, for 3 y
Any adenoma: 0.67 (0.59-0.77)
Advanced adenoma: 0.45 (0.33-0.63)
Any adenoma: 0.43 (0.31-0.61)
Advanced adenoma: 0.34 (0.24-0.50)
APPROVe; Baron et al., 200618 1158 vs. 1218 Good Higher risk (previous adenoma) Rofecoxib, 25 mg/d, for 3 y Any adenoma: 0.76 (0.69-0.83)
Advanced adenoma: 0.70 (0.58-0.86)
Summary for celecoxib, 400 mg/d, or rofecoxib, 25 mg/d         Any adenoma: 0.72 (0.68-0.77)
Advanced adenoma: 0.56 (0.42-0.75)
Cohort study (n = 1)
Polyp Prevention Study; Tangrea, et al., 200344 1,905 Good Higher risk (previous adenoma) Any NSAID use for 4 y 0.64 (0.48-0.85)
Case-controlled studies (n = 8)
García-Rodríguez and Huerta-Alvarez, 200038 11,864 Good Average-risk men and women Regular use of non-ASA NSAIDs for ≥1 y 0.7 (0.3-1.5)
Bigler, et al., 200135 1,502 Fair Average-risk men and women Regular use of non-ASA NSAIDs for ≥1 y 0.4 (0.2-0.7)
Logan, et al., 199336 300 Fair Average-risk men and women Regular use of non-ASA NSAIDs for ≥1 y 0.56 (0.3-1.2)
Boyapati, et al., 200337 4405 Poor Average-risk men and women Regular use of non-ASA NSAIDs for ≥1 y 0.4 (0.2-0.7)
Summary for the regular use of non-ASA NSAIDs         0.55 (0.4-0.76)
Martin, et al., 200243 719 Good Average-risk men and women Regular use any NSAID for ≥1 y 0.5 (0.3-0.8)
Martínez, et al., 199541 637 Good Average-risk men and women Regular use any NSAID for ≥1 y 0.46 (0.29-0.75)
Lieberman, et al., 200342 1,770 Fair Average-risk men and women Regular use any NSAID for ≥1 y 0.67 (0.5-0.89)
Logan, et al., 199336 300 Poor Average-risk men and women Regular use any NSAID for ≥1 y 0.33 (0.1-1.4)
Peleg, et al., 199631 525 Poor Average-risk men and women Regular use any NSAID for ≥1 y 0.56 (0.2-1.52)
Summary for the regular use of any NSAID         0.57 (0.46-0.71)

Notes:

a. Any NSAIDs include non-ASA NSAIDs and ASA. APC = Adenoma Prevention with Celecoxib; APPROVe = Adenomatous Polyp Prevention on Vioxx; ASA = acetylsalicylic acid; CRC = colorectal cancer; PreSAP = Prevention of Colorectal Sporadic Adenomatous Polyps; RCT = randomized, controlled trial.
b. Data are standardized mortality ratios (95% CI).
c. Data are standardized incidence ratios (95% CI).

Return to Table of Contents
Study, Year
(Reference)
Participants, n Quality Score NSAID Dosage Relative Risk
(95% CI)
P value for dosage (trend)
Incidence of CRC
Cohort studies
Nurses' Health Study; Chan, et al., 200534 82,911 Good 0.5-1.5 tablets/wk 1.00 (0.82-1.21)  
2-5 tablets/wk 0.91 (0.69-1.19)
6-14 tablets/wk 0.69 (0.51-0.95)
P value for dosage (trend)   <0.001
Tennessee Medicaid Program; Smalley et al., 199933 104,217 Fair Low average dosage over 5 y 0.53 (0.26-1.08)  
Medium average dosage over 5 y 0.59 (0.45-0.77)
High average dosage over 5 y 0.77 (0.41-1.45)
Case-controlled studies
Collet, et al., 199930 19,217 Good Highest dosage over >10 y Colon cancer: 0.57 (0.36-0.89);
Rectal cancer: 0.26 (0.11-0.61)
Colon cancer: 0.01;
Rectal cancer: <0.001
Lowest dosage over <10 y Colon cancer 1.01 (0.88-1.15);
Rectal cancer: 0.80 (0.66-0.98)
García-Rodríguez and Huerta-Alvarez, 200122 12,002 Good Low-medium daily dosage 0.7 (0.5-1.1)  
High daily dosage 0.4 (0.3-0.7)
Shaheen et al., 200328 1,308 Fair Low average dosage 0.54 (0.39-0.75)  
Medium average dosage 0.80 (0.59-1.01)
High average dosage 0.49 (0.34-0.71)
Reeves et al., 199625 447 Fair <7 doses/wk 0.5 (0.2-1.2)  
7-14 doses/wk 0.6(0.2-1.2)
>14 doses/wk 0.7 (0.3-1.5)
Peleg, et al., 199626 505 Poor Low cumulative dosage 0.58 (0.26-1.32)  
Moderate cumulative dosage 0.19 (0.09-0.52)
High cumulative dosage 0.22 (0.09-0.56)
Incidence of Colorectal Adenomas
Randomized controlled trial (RCT)
APC; Bertagnolli, et al., 200619 685 vs. 671 vs. 679 >Good Celecoxib, 400 mg/d, for 3 y Any adenoma: 0.67 (0.59-0.77)
Advanced adenoma: 0.45 (0.33-0.63)
 
Celecoxib, 800 mg/d, for 3 y Any adenoma: 0.43 (0.31-0.61)
Advanced adenoma: 0.34 (0.24-0.50)
Case-controlled studies
García-Rodríguez and Huerta-Alvarez, 200038 11,864 Good Low-medium daily dosage 0.7 (0.4-1.3)  
High daily dosage 0.6 (0.4-0.9)
Lieberman, et al., 200342 1,770 Fair <Daily 0.71 (0.49-1.01)  
≥Daily 0.65 (0.48-0.89)
Peleg, et al., 199631 525 Poor Low cumulative dosage 0.59 (0.23-1.48)  
Moderate cumulative dosage 0.56 (0.20-1.52)
High cumulative dosage 0.31 ( 0.11-0.84)

Notes:

a Any NSAIDs include non-ASA NSAIDs and ASA. APC = Adenoma Prevention with Celecoxib; APPROVe = Adenomatous Polyp Prevention on Vioxx; ASA = acetylsalicylic acid; CRC = colorectal cancer; PreSAP = Prevention of Colorectal Sporadic Adenomatous Polyps; RCT = randomized, controlled trial.

Return to Table of Contents
Study, Year
(Reference)
Participants, n Quality Score Duration of Regular NSAID Use, y Relative Risk
(95% CI)
Incidence of CRC in case-control studies
Collet, et al., 199930 19,217 Good 2-5 (at highest dosage) Colon cancer: 0.97 (0.76-1.24);
rectal cancer: 1.29 (0.94-1.78)
6-10 (at highest dosage) Colon cancer: 0.94 (0.71-1.24);
rectal cancer: 0.77 (0.5-1.18)
11-15 (at highest dosage) Colon cancer: 0.57 (0.36-0.89);
rectal cancer: 0.26 (0.11-0.61)
García-Rodríguez and Huerta-Alvarez, 200122 12,002 Good 1 0.6 (0.3-1.2)
1-2 0.4 (0.2-0.7)
>2 0.6 (0.4-0.8)
Slattery, et al., 200426 4,403 Fair 1-5 0.7 (0.6-1.0)
>5 0.6 (0.5-0.9)
Reeves et al., 199625 447 Fair <2 0.7 (0.4-1.3)
2-5 0.3 (0.2-0.7)
>5 1.1 (0.6-2.0)
Muscat, et al., 199427 1,011 Poor 1-4 0.77 (0.34-1.75)
5-9 0.93 (0.45-1.97)
>9 0.47(0.21-0.94)
Peleg, et al., 199631 505 Poor 1 0.34 (0.12-0.94)
2 0.09 (0.02-0.35)
4 0.14 (0.02-0.90)
≥5 0.12 (0.04-0.39)
Incidence of colorectal adenomas in case-control studies
García-Rodríguez and Huerta-Alvarez, 200038 11,864 Good 1 0.9 (0.5-1.6)
2-3 0.4 (0.2-0.8)
>3 0.7 (0.5-1.1)
Martínez, et al., 199541 637 Good <5 0.39 (0.21-0.71)
5-40 0.6 (0.32-1.14)
Lieberman, et al., 200342 1,770 Fair <10 0.71 (0.52-0.96)
10-19 0.63 (0.41-0.99)
>19 0.49 (0.3-0.8)
Breuer-Katschinski, et al., 200039 542 Fair ≤5 0.65 (0.31-1.34)
≥5 0.21 (0.04-0.99)
Logan, et al., 199336 300 Poor ≤5 0.74 (0.2-2.3)
≥5 0.21 (0.1-0.8)
Peleg, et al., 199631 525 Poor 1 0.59 (0.22-0.63)
2 0.24 (0.07-0.83)
3 0.26 (0.07-1.0)
3 0.24 (0.06-0.95)
≥5 0.25 (0.08-0.79)

Notes: a NSAIDs may include non-acetylsalicylic acid NSAIDs or acetylsalicylic acid plus non-acetylsalicylic acid NSAIDs.

Return to Table of Contents
Outcome Naproxen Non-Naproxen, Non-ASA NSAIDs COX-2 Inhibitors
All-cause mortality NA No difference52-54 to increased21,55 (all non-ASA NSAIDs): SMR, 1.11 (1.05-1.16)21 and 3.4 (1.3-8.7)55 No difference52: 1.02 (0.6-1.9) vs. placebo
Cardiovascular mortality No difference56: 1.47 (0.90-2.40) for COX-2 inhibitors vs. naproxen No difference56 (similar to COX-2): 0.67 (0.43-1.06) for COX-2 inhibitors vs. non-naproxen NSAIDs No difference53,54,56,59: 1.49 (0.97-2.29) vs. placebo56 and 0.79 (0.29-2.19)59
Serious cardiovascular events Neutral or reduced56: 0.92 (0.67-1.26) vs. placebo or 1.57 (1.21-2.03) for COX-2 inhibitors vs. naproxen Increased56: 1.51 (0.96-2.37) for ibuprofen vs. placebo; 1.63 (1.12-2.37) for diclofenac vs. placebo; similar to COX-2, 0.88 (0.69-1.12) for COX-2 inhibitors vs. nonnaproxen NSAIDs Increased56,58,59: 1.42 (1.13-1.78) vs. placebo56; 1.55 (0.05-2.29)59; 1.89 (1.03-3.45)58; 4.89 (1.41-16.88) for high-risk patients58; 1.57 (1.21-2.03) for COX-2 inhibitors vs. naproxen56
Myocardial infarction Neutral or reduced56,59: 0.86 (0.75-0.99) (heterogeneity)59 or 2.04 (1.41 to 2.96) for COX-2 inhibitors vs. naproxen56 Increased (similar to COX-2 inhibitors)56,59: 1.20 (0.85-1.68) for COX-2 inhibitors vs. nonnaproxen NSAIDs56 and 1.55 (0.55-4.36) for rofecoxib vs. nonnaproxen NSAIDs59 Increased54,56,58,61: 1.86 (1.33-2.59) for COX-2 inhibitors vs. placebo56; 2.04 (1.41-2.96) for COX-2 inhibitors vs. naproxen56; 2.93 (1.36-6.33) for rofecoxib vs. naproxen59; 5.0 (1.5-13.2) for rofecoxib vs. naproxen54; 2.83 (1.24-6.43) for high-dose rofecoxib59; 2.17 (1.03-4.59) for rofecoxib .6 mo59
Stroke No difference56,61: 0.08 (0.00-1.36) vs. rofecoxib61 and 1.10 (0.73-1.65) for COX-2 inhibitors vs. naproxen56 No difference56,59: 0.62 (0.41-0.95) for COX-2 inhibitors vs. NSAIDs56 and 1.02 (0.54-1.93) for rofecoxib vs. NSAIDs59 No difference54,56,58-59,61: 1.02 (0.71-1.47) for COX-2 vs. placebo56; 1.10 (0.73-1.65) for COX-2 vs. naproxen56; 1.02 (0.54-1.93) for rofecoxib vs. NSAIDs59; 1.12(0.43-2.91) for rofecoxib vs. NSAIDs54; 1.43 (0.99-2.07) for rofecoxib vs. celecoxib58

Notes:

a Data reported are relative risks (95% CIs), unless otherwise noted. NA = not applicable; SMR = standardized mortality ratio.

Return to Table of Contents
Study, Year
(Reference)
Source of Abstracted Data Methods for Selecting Confounders Confounders Individual Study Estimate RR
(95% CI)
Index of Heterogeneity and Pooled Estimate; RR
(95% CI)
Recent Use (e.g., current use) I2 = 0; 0.78 (0.66-0.92)
García-Rodríguez and Huerta-Alvarez, 200138 Table 4 Stepwise model-based selectionb Age, sex, constipation 0.80 (0.70-1.00)  
Hauret, et al., 200451 Table 2 A priori and stepwise model-based selectionb Age, sex, family history of CRC, pack-years of smoking, BMI, waist-hip ratio, height, physical activity levels, total energy intake, dietary intake of calcium and sucrose 0.62 (0.36-1.07)  
Regular Use I2 = 0; 0.56 (0.40-0.76)
Morimoto, et al., 200250 Table 3 Backwards stepwise model-based selectionb Age, sex, BMI, HRT, pack-years of smoking, alcohol consumption 0.40 (0.20-0.70)  
Hauret, et al., 200451 Table 2 A priori and stepwise model-based selectionb Age, sex, family history of CRC, pack-years of smoking, BMI, waist-hip ratio, height, physical activity levels, total energy intake, dietary intake of calcium and sucrose 0.62 (0.36-1.07)  
García-Rodríguez and Huerta-Alvarez, 200138 Table 6
for ibuprofen
Stepwise model-based selectionb Age, sex, constipation 0.70 (0.30-1.50)  
Logan, et al., 199336 Table 2
(p. 286)
A priori and stepwise model-based selectionb Age- and sex-matched cases and controls (adjusted for social class) 0.56 (0.30-1.20)  
Regular Use I2 = 0; 0.54 (0.40-0.74)
Morimoto, et al., 200250 Table 3 Backwards stepwise model-based selectionb Age, sex, BMI, HRT, pack-years of smoking, alcohol consumption 0.40 (0.20-0.70)  
Hauret, et al., 200451 Table 2 A priori and stepwise model-based selectionb Age, sex, family history of CRC, pack-years of smoking, BMI, waist-hip ratio, height, physical activity levels, total energy intake, dietary intake of calcium and sucrose 0.62 (0.36-1.07)  
García-Rodríguez and Huerta-Alvarez, 200138 Table 6
for diclofenac
Stepwise model-based selectionb Age, sex, constipation 0.60 (0.30-1.00)  
Logan, et al., 199336 Table 2 A priori and stepwise model-based selectionb Age- and sex-matched cases and controls (adjusted for social class) 0.56 (0.30-1.20)  

Notes:
aBMI = body mass index; CRC = colorectal cancer; HRT = hormone replacement therapy; RR = relative risk.
b Multiple logistic regression model.

Return to Table of Contents
Study, Year
(Reference)
Source of Abstracted Data Methods for Selecting Confounders Confounders Individual Study Estimate RR
(95% CI)
Index of Heterogeneity and Pooled Estimate; RR
(95% CI)
Nonaspirin NSAID use for <5 y I2 = 0; 0.43 (0.26-0.70)
Peleg, et al., 199631 Table 4 A priorib Age, sex, cumulative years of nonaspirin NSAID use 0.26 (0.07-1.00)  
Logan, et al., 199336 Table 2 A priori and stepwise model-based selectionb Age- and sex-matched cases and controls (adjusted for social class) 0.80 (0.30-2.50)  
Martínez, et al., 199541 Table 2 A priori and stepwise model-based selectionb Age, sex, race, cigarette smoking, family history of CRC, BMI, dietary fiber and alcohol consumption 0.39 (0.21-0.71)  
Nonaspirin NSAID use for ≥5 y I2 = 0; 0.56 (0.39-0.77)
Peleg, et al., 199631 Table 4 A priorib Age, sex, cumulative years of nonaspirin NSAID use 0.25 (0.08-0.79)  
Logan, et al., 199336 Table 2 A priori and stepwise model-based selectionb Age- and sex-matched cases and controls (adjusted for social class) 0.33 (0.10-1.40)  
Martínez, et al., 199541 Table 2 A priori and stepwise model-based selectionb Age, sex, race, cigarette smoking, family history of CRC, BMI, dietary fiber and alcohol consumption 0.60 (0.32-1.14)  
Lieberman et al., 200342 Table 1 A priorib Age 0.63 (0.41-0.99)  
Regular use of nonaspirin NSAID I2 = 0; 0.57 (0.46-0.71)
Martin, et al., 200243 Table 2 A priori and stepwise model-based selectionb Age, sex, race, BMI 0.50 (0.30-0.80)  
Martínez, et al., 199541 Table 2 A priori and stepwise model-based selectionb Age, sex, race, cigarette smoking, family history of CRC, BMI, dietary fiber and alcohol consumption 0.46 (0.29-0.75)  
Lieberman et al., 200342 Table 1 A priorib Age 0.67 (0.50-0.89)  
Logan, et al., 199336 Table 2 A priori and stepwise model-based selectionb Age- and sex-matched cases and controls (adjusted for social class) 0.33 (0.10-1.40)  
Peleg, et al., 199631 Table 2 A priorib Age, sex, cumulative years of nonaspirin NSAID use 0.56 (0.20-1.52)  

Notes:

aBMI = body mass index; CRC = colorectal cancer; HRT = hormone replacement therapy; RR = relative risk.
b Multiple logistic regression model.

Return to Table of Contents
Study, Year
(Reference)
Location Treat- ment/Placebo, n/n Dur- ation Population Control Group Exposure
(Ascertain- ment)
Outcomes Assessed Quality Score
Chemoprevention of colonic adenomas (3 RCTs)
Arber, et al., 200620 Multinational 933/628 3 yr Inclusion criteria: age >30 y; colonoscopy within 3 mo of enrollment showing 1 adenoma ≥6 mm or 2 to 10 adenomas of any size; documented clean colon postpolypectomy; 80% drug adherence during run-in period.

Exclusion criteria: nonstudy COX-2 inhibitor or NSAID use; ASA, .162.5 mg/d or 325 mg every 2 days; FAP; HNPCC; IBD; invasive cancer; colonic resection; renal, hepatic, or bleeding disorder; study or related drug hypersensitivity
Placebo Celecoxib, 400 mg/d Primary end point: ≥1 adenoma at year 1, 3, or both Good
Bertagnolli, et al., 200619 Multinational 1356/679 3 yr Inclusion criteria: full colonoscopy and polypectomy within 6 mo; ≥1 confirmed adenoma; history of adenoma ≥5 mm or multiple adenoma.

Exclusion criteria: nonstudy COX-2 inhibitor or NSAID use; ASA > "low dose"; FAP; HNPCC; IBD; invasive cancer; colonic resection; renal, hepatic, or bleeding disorder; study or related drug hypersensitivity; PUD
Placebo Celecoxib, 200 mg BID;
Celecoxib, 400 mg BID
Primary end point: adenoma at colonoscopy

Secondary end points: adenoma ≥1.0 cm (villous or tubulovillous histology); high-grade dysplasia; intramucosal carcinoma or invasive cancer; number of adenomas; size of largest adenoma; adenoma burden (the sum of the diameter of all adenomas; cardiovascular outcomes and adverse events
Good
Baron, et al., 200618 Multinational 1293/1277 3 yr Inclusion criteria: age >40 y; colonoscopy within 12 wk; biopsy-proven adenoma; no polyps remaining.

Exclusion criteria: FAP or HNPCC; polyps at age <35 y; bowel resection; IBD; cancer; hypertension, MI, heart failure, stroke, TIA, or coronary revascularization within 2 years; need for long-term NSAID or ASA therapy; ASA rule relaxed to allow up to 20% using ASA ≤100 mg
Placebo Rofecoxib, 25 mg/d Primary end point: ≥1 adenoma at year 1 or 3 on colonoscopy

Secondary end points: number of adenomas; advanced adenoma (tubulovillous or villous histology, adenoma >1 cm, high-grade dysplasia, invasive cancer); death; cardiovascular and gastrointestinal events
Good
Regression of colonic adenomas (1 RCT)
Ladenheim, et al., 199545 United States 44/40 4 mo Inclusion criteria: adults age >50 y; with routine screening flexible sigmoidoscopy; polyps ≤1 cm.

Exclusion criteria: history of gastrointestinal bleeding, CRF, PUD, underlying malignant condition, long-term OTC or prescription NSAID use (except ASA); decompensated pulmonary or cardiac disease; polyps >1 cm
Placebo Sulindac, 150 mg orally BID for 4 mo
(n = 22)
Primary end point: percentage of patients for whom all polyps either disappeared or regressed Fair

Notes:
a ASA = acetylsalicylic acid; BID = twice daily; COX-2 = cyclooxygenase-2; CRF = chronic renal failure; FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis colorectal cancer; IBD = inflammatory bowel disease; MI = myocardial infarction; OTC = over the counter; PUD = peptic ulcer disease; RCT = randomized, controlled trial; TIA = transient ischemic attack.

Return to Table of Contents

Study, Year
(Reference)
Location Partici- pants, n Dur- ation, y Population Cohort Name Exposure
(Ascertainment)
Quality Score
Chemoprevention of colonic adenomas (1 study)
Tangrea, et al., 200344 United States 1905 4 Inclusion criteria: Enrollees of the Polyp Prevention Trial (1991) age ≥35 y with ≥1 histologically confirmed colorectal adenoma.

Exclusion criteria: History of CRC, surgical resection of adenomas, IBD, or FAP
Polyp Prevention Study Any NSAIDs (questionnaire) Good
Chemoprevention of CRC mortality (1 study)
Lipworth, et al., 200421 Denmark 113,538 7 Inclusion criteria: Patients with ≥1 ibuprofen prescription between 1989 and 1995.

Exclusion criteria: NR
North Jutland Population Database Ibuprofen (prescription database) Fair
Chemoprevention of CRC (3 studies)
Chan, et al., 200534 United States 82,911 20 Inclusion criteria: Female registered nurses age 30-55 y.

Exclusion criteria: Baseline cancer; did not complete questionnaire
Nurses' Health Study Non-ASA NSAIDs (mailed questionnaire) Good
Sørensen, et al., 200332 Denmark, United States, and Sweden 183,693 9 Inclusion criteria: Patients with prescribed non-aspirin NSAIDs.

Exclusion criteria: Occurrence of cancer excluding nonmelanoma skin cancer before the date of first recorded prescription; end of followup: cancer diagnosis, death, emigration, or reaching study end date (1 December 1997)
North Jutland Population Database Non-ASA NSAIDs (prescription database) Fair
Smalley, et al., 199933 United States 104,217 13 Inclusion criteria: Enrollees of the Tennessee Medicaid program, age >65 y, with 5 y medical history available.

Exclusion criteria: Incident CRC, death, loss of eligibility, or the end of the study (December 1992)
Tennessee Medicaid Program Non-ASA NSAIDs (prescription database) Fair

a Any NSAIDs include non-ASA NSAIDs and ASA.
ASA = acetylsalicylic acid; FAP = familial adenomatous polyposis; IBD = inflammatory bowel disease; NR = not reported.

Return to Table of Contents

Study, Year
(Reference)
Location Cases/ Controls, n/n Dur- ation Cases Controls Exposure
(Ascertainment)
Quality Score
Chemoprevention of colonic adenomas (10 studies)
García-Rodríguez and Huerta-Alvarez, 200038 Spain 1864/10,000 5 y, 8 mo Biopsy-proven adenoma on medical records database Randomly selected age- and sex-matched persons from database; absence of adenoma Non-ASA NSAIDs (prescription database) Good
Martínez, et al., 199541 United States 157/480 About 19 mo First pathologic diagnosis of colorectal adenoma and/or hyperplastic polyps Colonoscopy-negative patients Any NSAIDs (questionnaire) Good
Martin, et al., 200243 United States 226/493 2 y First colonoscopic diagnosis of colorectal adenoma Colonoscopy-negative patients Any NSAIDs (questionnaire) Good
Lieberman, et al., 200342 United States 329/1441 3 y Villous adenoma; high-grade dysplasia, including carcinoma in situ and intramucosal cancer; invasive cancer Colonoscopy-negative patients Any NSAIDs (questionnaire) Fair
Bigler, et al., 200135 United States 474/563 3 y First colonoscopic diagnosis of colorectal adenoma Colonoscopy-negative patients Non-ASA NSAIDs (questionnaire) Fair
Logan, et al., 199336 United Kingdom 147/153 7 y Patients with positive FOBT result and first colonoscopic diagnosis of colorectal adenoma Negative control patients: age- and sex-matched patients with negative FOBT results; positive control patients: age- and sex-matched patients with positive FOBT results and no polyp or mass on sigmoidoscopy and barium enema Non-ASA NSAIDs (questionnaire) Fair
Breuer-Katschinski, et al., 200039 Germany 182/360 3.5 y First pathologic diagnosis of colorectal adenoma Hospital control patients: age- and sex-matched patients with negative colonoscopy; nonhospital (community) control patients: age- and sex-matched inhabitants of Essen, Germany Any NSAIDs, non-ASA NSAIDs (questionnaire) Fair
Sandler, et al., 199840 United States 142/169 3 y First colonoscopic diagnosis of colorectal adenoma Colonoscopy-negative patients Any NSAIDs, non-ASA NSAIDs (questionnaire) Fair
Boyapati, et al., 200337 United States 177/228 1 y First colonoscopic diagnosis of colorectal adenoma Colonoscopy-negative patients Non-ASA NSAIDs (questionnaire) Poor
Peleg, et al., 199631 United States 113/226 2.5 y First colonoscopic diagnosis of colorectal adenoma Hospital patient without cancer, born in 1948, with regular followups at GMH for the same duration as the case at the same time Any NSAIDs (prescription database) Fair
Chemoprevention of CRC (10 studies)
Collet, et al., 199930 Canada Colon Cancer Study, 3844/ 15,373;
Rectal Cancer Study, 1971/ 7882
NR Saskatchewan Prescription Drug Plan member patients with histologically proven CRC Age- and sex-matched Saskatchewan Prescription Drug Plan members age >35 y; without CRC and other cancer except nonmelanoma and carcinoma in situ of cervix Any NSAIDs (prescription database) Good
García-Rodríguez and Huerta-Alvarez, 200122 Spain 2002/ 10,000 3 y Participants age 40-79 y with an incident diagnosis of biopsy-proven CRC Randomly selected age- and sex-matched participants age 40-79 y without CRC at the index date of case No-ASA NSAIDs (prescription database) Good
Coogan, et al., 200029 United States 1526/ 10,228 13 y Primary CRC diagnosis <6 mo (tumor registry of hospitals, state cancer registry) Cancer control: diagnosis of lung or other respiratory malignant melanoma, prostate, bladder, kidney, ovary, uterus, and other cancer diagnosis <6 mo; noncancer control: patients admitted for trauma or acute infection with no history of cancer Any NSAIDs (questionnaire by nurse interviewers) Fair
Slattery, et al., 200426 United States 952/1205 5 y, 2 mo English-language speakers; mentally competent to complete the interview; age 30-79 y; first primary tumor in the rectosigmoid junction or rectum; May 1997-May 2001 Matched by sex and by 5-y age groups, patients age >65 y who were randomly selected from Health Care Financing Administration lists, patients age <65 y who were selected from driver's license lists Non-ASA NSAIDs (questionnaire) Fair
Kune, et al., 198823 Australia 715/727 1 y New diagnosis of CRC between April 1980 and April 1981 Age- and sex-matched participants Non-ASA NSAIDs (questionnaire) Fair
Shaheen, et al., 200328 United States 475/833 4 y Patients age 40-79 y with first-time diagnosis of colon cancer Race-, age-, and sex-matched from general population Any NSAIDs (questionnaire) Fair
Juarranz et al., 200224 Spain 196/228 NR Participants with laboratory-confirmed colon cancer between January 1995 and December 1996 who resided in Madrid Age- and sex-matched participants without neoplasm or severe digestive disease at enrollment Non-ASA NSAIDs (questionnaire) Fair
Reeves, et al., 199625 United States 184/293 1 y Women age 40-74 y; local residents with new diagnosis of invasive cancer of the colon or rectum; listed telephone number Patients with listed telephone number and either a current Wisconsin driver's license (age <65 y) or a Medicare card (age >65 y) Any NSAIDs, non-ASA NSAIDs (questionnaire) Fair
Muscat, et al., 199427 United States 511/500 3 y Patients with histologically confirmed CRC Patients matched by sex, race, hospital, age (±5 y), and mo of interview; conditions unrelated to NSAID use Any NSAIDs (questionnaire) Poor
Peleg, et al., 199631 United States 93/186 5.5 y Incident CRC Hospital patient without cancer, born in 1948, with regular hospital followups for the same duration as the case at the same time Any NSAIDs (prescription database) Poor

a Any NSAIDs include non-ASA NSAIDs and ASA.
ASA = acetylsalicylic acid; CRC = colorectal cancer; FOBT = fecal occult blood test; GMH = germinal matrix hemorrhage; NR = not reported.

Return to Table of Contents