Adenoma Prevention With Celecoxib Research Articles

First person profile: Monica Bertagnolli, MD: An international oncology leader and noted surgical oncologist, Dr. Monica Bertagnolli has forged her own path.

First person profile: Monica Bertagnolli, MD: An international oncology leader and noted surgical oncologist, Dr. Monica Bertagnolli has forged her own path.

Chemopreventive Efficacy of the Cyclooxygenase-2 (Cox-2) Inhibitor, Celecoxib, Is Predicted by Adenoma Expression of Cox-2 and 15-PGDH.

Background: The Adenoma Prevention with Celecoxib (APC) Trial showed that cyclooxygenase-2 (Cox-2) inhibitor, celecoxib, decreased adenoma development in patients at high risk for colorectal cancer. A prospectively planned analysis of the APC Trial tested the hypothesis that expression of target enzymes in adenomas removed before beginning study treatment would identify individuals at high risk of adenoma development, and/or predict response to Cox-2 inhibition.Methods: Pre-treatment adenomas were examined using immunohistochemistry to assess expression of Cox-2 (high vs. low) and 15-prostaglandin dehydrogenase (15-PGDH, presence vs. loss). The Mantel-Cox test evaluated whether these markers predicted benefit from celecoxib for reduction of adenoma detection.Results: Patients whose pre-treatment adenomas demonstrated elevated Cox-2 achieved the greatest adenoma reduction with celecoxib treatment [RR, 0.37; 95% confidence interval (CI), 0.22-0.61; P = 0.0001]. This reduction was less in the low Cox-2 category (RR, 0.64; 95% CI, 0.56-0.73). Patients whose pre-treatment adenomas showed 15-PGDH loss had a similar treatment-associated reduction in adenoma detection (RR, 0.60; 95% CI, 0.52-0.69; P < 0.0001). In contrast, patients with intact tumor 15-PGDH expression did not significantly benefit from celecoxib (RR, 0.73; 95% CI, 0.47-1.12; P = 0.15). However, subset analysis suggested that this lack of response to celecoxib was confined to those patients with 15-PGDH intact tumors who were also using cardioprotective aspirin.Conclusions: The expression of Cox-2 and 15-PGDH in pre-treatment adenomas provides predictive information in patients treated with celecoxib for prevention of colorectal adenomas.Impact: The results of this study show that Cox-2 and 15-PGDH are characteristics of colorectal adenomas that may be used to predict nonsteroidal anti-inflammatory drug chemoprevention efficacy. Cancer Epidemiol Biomarkers Prev; 27(7); 728-36. ©2018 AACR.

Germline variants and advanced colorectal adenomas: adenoma prevention with celecoxib trial genome-wide association study.

Identification of single-nucleotide polymorphisms (SNP) associated with development of advanced colorectal adenomas. Discovery phase: 1,406 Caucasian patients (139 advanced adenoma cases and 1,267 controls) from the Adenoma Prevention with Celecoxib (APC) trial were included in a genome-wide association study (GWAS) to identify variants associated with postpolypectomy disease recurrence. Genome-wide significance was defined as false discovery rate less than 0.05, unadjusted P = 7.4 × 10(-7). Validation phase: results were further evaluated using 4,175 familial colorectal adenoma cases and 5,036 controls from patients of European ancestry [COloRectal Gene Identification consortium (CORGI), Scotland, Australia, and VQ58]. Our study identified eight SNPs associated with advanced-adenoma risk in the APC trial (rs2837156, rs7278863, rs2837237, rs2837241, rs2837254, rs741864 at 21q22.2, and rs1381392 and rs17651822 at 3p24.1, at P < 10(-7) level with OR > 2). Five variants in strong pairwise linkage disequilibrium (rs7278863, rs2837237, rs741864, rs741864, and rs2837241; r(2) = 0.8-1) are in or near the coding region for the tight junction adhesion protein, IGSF5. An additional variant associated with advanced adenomas, rs1535989 [minor allele frequency, 0.11; OR, 2.09; 95% confidence interval (CI), 1.50-2.91], also predicted colorectal cancer development in a validation analysis (P = 0.019) using a series of adenoma cases or colorectal cancer (CORGI study) and 3 sets of colorectal cancer cases and controls (Scotland, VQ58, and Australia; N = 9,211). Our results suggest that common polymorphisms contribute to the risk of developing advanced adenomas and might also contribute to the risk of developing colorectal cancer. The variant at rs1535989 may identify patients whose risk for neoplasia warrants increased colonoscopic surveillance.

Much of the Genetic Risk of Colorectal Cancer Is Likely to Be Mediated Through Susceptibility to Adenomas

Several single-nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) susceptibility. Most CRCs arise from adenomas, and SNPs therefore might affect predisposition to CRC by increasing adenoma risk. We found that 8 of 18 known CRC-associated SNPs (rs10936599, rs6983267, rs10795668, rs3802842, rs4444235, rs1957636, rs4939827, and rs961253) were over-represented in CRC-free patients with adenomas, compared with controls. Ten other CRC-associated SNPs (rs6691170, rs6687758, rs16892766, rs7136702, rs11169552, rs4779584, rs9929218, rs10411210, rs4813802, and rs4925386) were not associated significantly with adenoma risk. Genetic susceptibility to CRC in the general population is likely to be mediated in part by predisposition to adenomas.

Abstract 1521: Expression of the tight junctions protein IGSF5 in the colorectal adenoma-carcinoma sequence

Abstract Patients with advanced adenomas are at high risk for the development of colorectal cancer, but predictors of disease progression remain elusive. Genome wide association study (GWAS) data from the Adenoma Prevention with Celecoxib (APC) Trial identified six germline single nucleotide polymorphisms (SNPs) that predicted advanced adenoma recurrence. These SNPs are located in tight linkage disequilibrium on chromosome 21 in or around the coding sequence for Immunoglobulin Superfamily Member 5 (IGSF5). This transmembrane protein localizes to tight junctions and modulates cell adhesion with its binding partner MAGI-1. We examined the expression of IGSF5 in normal colon tissue, adenomas and adenocarcinomas. By immunohistochemistry, IGSF5 was expressed in both crypt cells and stromal cells of normal human colon. With progression to adenoma and adenocarcinoma, IGSF5 expression became more membranous and diffuse in comparison to normal colon. Immunofluorescence histochemistry (IF) showed co-localization of IGSF5 with BMI-1 in normal colon crypt cells, indicating that intestinal stem cells express IGSF5. Pericryptal stromal cells expressing IGSF5 included both mesenchymal stem cells and hematopoietic stem cells, but not myofibroblasts, as indicated by IF colocalization with CD73 and CD34 but not αSMA, respectively. These results suggest that IGSF5 expression is altered in the progression from colorectal adenoma to carcinoma, and may exert its effects through stem cell modulation of intestinal homeostasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1521. doi:1538-7445.AM2012-1521

Statin Use and Colorectal Adenoma Risk: Results from the Adenoma Prevention with Celecoxib Trial

Statins are widely prescribed for cardiovascular disease prevention and also commonly used in patients at high risk for colorectal cancer. We report the results of a planned secondary analysis of the relationship between statin use and colorectal adenoma risk in a large chemoprevention trial. The Adenoma Prevention with Celecoxib (APC) trial randomized 2,035 adenoma patients to receive placebo (679 patients), 200 mg celecoxib twice daily (bid; 685 patients), or 400 mg celecoxib bid (671 patients). The study collected complete medical history and medication use data and performed colonoscopic surveillance to 5 years after study enrollment. The effects of statin use on newly detected adenomas and cardiovascular adverse events were analyzed as time-dependent variables by multivariable Cox regression. Statins were used by 36% (n = 730) of APC trial participants. When adjusted for covariates including cardioprotective aspirin use, age, and sex, participants on the placebo arm who used statins at any time had no benefit over 5 years compared with never users (risk ratio, 1.24; 95% confidence interval, 0.99-1.56; P = 0.065). Statin use for >3 years increased adenoma risk over 5 years (risk ratio, 1.39; 95% confidence interval, 1.04-1.86; P = 0.024). For all comparisons of patients treated with celecoxib, adenoma detection rates for statin users and nonusers were equivalent. Consistent with their use in patients at high risk, cardiovascular serious adverse events were more common among statin users. For patients at high risk of colorectal cancer, statins do not protect against colorectal neoplasms and may even increase the risk of developing colorectal adenomas.

M1177 Risk of Colorectal Adenoma Recurrence Due to Red Blood Cell Folate Level in the Post Folate Fortification Era: Results From the Adenoma Prevention With Celecoxib (APC) Trial

M1177 Risk of Colorectal Adenoma Recurrence Due to Red Blood Cell Folate Level in the Post Folate Fortification Era: Results From the Adenoma Prevention With Celecoxib (APC) Trial

Abstract LB-173: Statin use and colorectal adenoma risk: Results from the Adenoma Prevention with Celecoxib (APC) trial

Abstract Discussant: John A. Baron, Dartmouth Medical School, Lebanon, NH. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-173.

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Aberrant Crypt Foci in the Adenoma Prevention with Celecoxib Trial

Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients randomized to placebo (n = 17), celecoxib (200 mg twice daily; n = 15), or celecoxib (400 mg twice daily; n = 13) in the Adenoma Prevention with Celecoxib (APC) trial. Magnification chromoendoscopy was done to identify, count, and biopsy ACF within the rectum at baseline and after 8 to 12 months of treatment. A total of 655 ACF were identified in 45 patients. We examined 70 of these ACF histologically, and all 70 were nondysplastic. Cohort characteristics and APC trial treatment results for substudy patients were similar to those of the overall APC trial. There was no significant modulation of ACF by celecoxib (versus placebo; P = 0.77). Immunohistochemical comparison of ACF with adjacent normal mucosa showed that ACF had an increased proliferative index as determined by Ki-67 (P < 0.0001), but lacked other features of neoplasia such as increased cyclooxygenase-2 expression and microvessel density, nuclear localization of beta-catenin, or decreased expression of the tumor suppressors SMAD4, Estrogen Receptor alpha, or MGMT. Only baseline SMAD4 expression in ACF correlated with posttreatment adenoma recurrence (independent of treatment arm; P = 0.01). The presence or number of nondysplastic ACF did not correlate with a higher risk of synchronous advanced or recurrent adenomas. Our overall results indicated that nondysplastic ACF were not accurate surrogate endpoint biomarkers of recurrent colorectal adenomas in the APC trial.

Drugs To Prevent Colon Cancer Show Promise, But Hurdles Remain for Chemoprevention

A low-dose combination of sulindac and difluoromethylornithine (DFMO) reduced the risk of recurrent colorectal adenomas by 70% and high-risk adenomas by 92% compared with placebo in a randomized controlled trial, researchers reported in April at the annual meeting of the American Association for Cancer Research (AACR). Also, 5-year follow-up data from the Adenoma Prevention with Celecoxib (APC) trial showed that individuals who took celecoxib during the trial continued to be at lower risk of developing adenomas 2 years after they stopped taking the drug, compared with participants who took a placebo. These results could fundamentally change chemoprevention, experts agree. The magnitude of the benefi t in the sulindac – DFMO trial was larger than expected for any type of chemoprevention. (As designed, the trial would have been deemed a success if the combination had reduced the risk by 50%.) And the trial is the fi rst to show that a combination of chemoprevention drugs is effective and safe. The APC data show that the use of nonsteroidal antiinfl ammatory drugs, specifi cally a cyclooxygenase-2 (COX-2) inhibitor, reduces the development of adenomas instead of just masking the presence of lesions. “The fi eld of [nonsteroidal antiinfl ammatory drugs] and COX-2 inhibitors — and in some people’s minds, the entire concept of chemoprevention — was in ashes when the COX-2 selective inhibitor [toxicity] reports came out in 2005,” said Scott Lippman, M.D. , professor and chair of thoracic and head and neck medical oncology at the University of Texas M. D. Anderson Cancer Center in Houston. Those reports, showing that celecoxib and rofecoxib (Vioxx) increased the risk of cardiovascular disease and death, garnered so much attention that when researchers reported the initial effi cacy data from the APC trial in 2006, few noticed. “I think what we are seeing now in these two very important trials is that the phoenix is rising,” Lippman said.

Abstract LB-141: The Adenoma Prevention with Celecoxib (APC) trial: Five-year efficacy and safety results

Abstract The APC Trial was a placebo-controlled randomized study of celecoxib for prevention of sporadic adenomas in high risk patients. This study showed that, after 3 years of treatment, patients taking 200 mg of celecoxib bid had 33% fewer adenomas and 57% fewer advanced lesions, and patients taking 400 mg of celecoxib bid had 45% fewer adenomas and 66% fewer advanced lesions. This study also found that celecoxib use was associated with a small but significant increase in cardiovascular risk. After completing the 3 year treatment study, APC trial enrollees were offered participation in a 2 year off treatment observational study during which additional safety and efficacy data were collected. Colonoscopies at 5 years after initiating study treatment were performed on 639 patients, and showed a cumulative advanced adenoma incidence of 0.125 in patients taking 200 mg bid celecoxib, and 0.158 in patients taking 400 mg celecoxib bid, compared to 0.212 for patients on placebo (41% and 25% reductions, respectively, P&amp;lt;0.0001). Investigator reported, non-adjudicated selected cardiovascular events occurred 35 times in 676 patients randomized to placebo, 45 times in 683 patients randomized to celecoxib 200 mg bid, and 46 times in 669 patients randomized to 400 mg celecoxib bid. This selected category of events included all reports of myocardial infarction or ischemia, death from any cause, cerebrovascular disease, cardiovascular therapeutic procedures, or venous thrombosis or thromboembolism. One third of APC Trial participants used cardioprotective aspirin, and year 5 colonoscopy data showed increased adenoma incidence and severity in this subset, suggesting the presence of more aggressive disease in aspirin users. These data, together with additional new placebo-controlled analyses of celecoxib cardiovascular safety, suggest that chemoprevention with celecoxib may be safe and effective for some high risk colorectal adenoma patients.

Abstract LB-242: Aberrant crypt foci (ACF) are not surrogate biomarkers of sporadic adenoma prevention with celecoxib: Results from the Adenoma Prevention with Celecoxib (APC) trial

Abstract Aberrant crypt foci (ACF) are the earliest visible neoplastic lesions in the colorectum. The natural history of these lesions and their role in the adenoma-carcinoma sequence are unknown. We studied ACF in a subset of patients enrolled in the Adenoma Prevention with Celecoxib (APC) Trial to determine whether the presence of ACF in the rectum correlated with that of adenomas in the entire large intestine. Participants were randomized to placebo (n=17), celecoxib 200 mg bid (n=15), or celecoxib 400 mg bid (n=13). Magnification chromoendoscopy (MCE) was performed to identify and biopsy ACF within the rectum at baseline and after 8-12 months of medication use. A total of 670 ACF were identified in 45 patients, and 70 of these were examined histologically. All of the ACF examined were non-dysplastic. Analysis showed no differences in ACF number between baseline and post-treatment studies (8.3±1.0 vs. 6.3±1.1) and no modulation by treatment (celecoxib vs placebo; p=0.77). Immunohistochemical studies showed that ACF contained cells exhibiting increased proliferation, but lacked other features of neoplasia such as increased Cox-2 expression and microvascular density, nuclear localization of β-catenin, or decreased expression of the tumor suppressors SMAD4, estrogen receptor (ERα) or MGMT. Of the secondary markers assessed at baseline, only SMAD4 expression correlated with post-treatment adenoma recurrence. Taken together, these data showed that non-dysplastic ACF are not accurate surrogate endpoint biomarkers of colorectal adenoma risk or NSAID chemoprevention response.

Adjudication of GI Events from Long-Term Placebo-Controlled Trials Provides Evidence for GI Safety and Tolerability of Celecoxib vs Placebo

Purpose: To analyze incidence of clinically significant upper or lower gastrointestinal adverse events (CSULGIEs) of celecoxib vs placebo, using adjudicated gastrointestinal (GI) data from the Adenoma Prevention with Celecoxib (APC), and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) studies. Methods: In APC, 2035 subjects were randomized to celecoxib 200 mg BID, 400 mg BID, or placebo for 3 years. In PreSAP, 1561 subjects were randomized to 400 mg QD or placebo for 3 years. Adverse events (AEs), bleeds, perforations, obstructions or ulcers were evaluated up to 30 days last dose by a blinded GI Endpoint Adjudication Committee (GIEAC). Subjects with GI AEs, GI-related deaths, or Hb fall 3 g from baseline were included. Time between first dose and CSULGIE was analyzed by a Cox proportional hazards model, stratified by study, with aspirin as covariate. Age, gender, clinical history were also analyzed. Results: Of total population reporting AEs (N = 3588), 97 subjects met inclusion criteria and were reviewed by the GIEAC. 54 were adjudicated as having CSULGIEs (1.62% for celecoxib; 1.30% for placebo). Incidence of CSULGIEs was higher among aspirin-users in both groups (2.99% vs 1.17% celecoxib; 2.83% vs 0.81% placebo). No significant difference was shown in hazard ratio (HR) or relative risk (RR) of celecoxib vs placebo. HR of celecoxib vs placebo was 1.24 with upper 0.025 CI at 2.21 (rejects non-inferiority). There were no significant differences in RR of CSULGIEs between treatments in either aspirin (RR 1.06, 95% CI 0.48, 2.34, P= 0.894) or non-aspirin users (RR 1.44, 95% CI 0.64, 3.25, P= 0.374). Aspirin and age were significant contributors of toxicity. Conclusion: In this pooled analysis, testing for non-inferiority, incidence of CSULGIEs was equivalent for celecoxib and placebo. Importantly, there were few events and the analysis was underpowered. These findings support celcoxib's long-term GI safety and tolerability, and show long-term aspirin use is associated with significant GI toxicity.Table

Response to Letter Regarding Article, “Effect of Celecoxib on Cardiovascular Events and Blood Pressure in Two Trials for the Prevention of Colorectal Adenomas”

We thank Dr Cen for his thoughtful comments about our work.1,2 He suggests combining covariates from the Adenoma Prevention With Celecoxib (APC) and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) trials into a single Cox model and using the resulting hazard ratio to estimate the overall effect of celecoxib on cardiovascular end points. This approach treats the variable trial (APC or PreSAP) as 1 ingredient in a stew. We believe in maintaining the integrity of the ingredients as long as possible to allow the flavor of each trial to retain its unique contribution. …

Letter by Cen Regarding Article, “Effect of Celecoxib on Cardiovascular Events and Blood Pressure in Two Trials for the Prevention of Colorectal Adenomas”

To the Editor: I read with interest the paper by Solomon et al1 in which the authors have combined the analysis results of 2 independent trials, Adenoma Prevention With Celecoxib (APC)2 and Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP),3 in an attempt to estimate cardiovascular events (CVs) associated with celecoxib across 3 different dose regimens. I am concerned about the validity of their combined analysis and their conclusion that celecoxib at 200 or 400 mg twice daily (APC) or at 400 mg once daily (PreSAP) showed a nearly 2-fold increase in …

Use of Nonsteroidal Antiinflammatory Drugs

Clinical trial data have prompted questions about the degree to which patients and their physicians should consider an increased risk of cardiovascular or cerebrovascular events when selecting medications for pain relief. Since the 2005 publication of a Science Advisory on the use of nonsteroidal antiinflammatory drugs (NSAIDs) by the American Heart Association,1 several important events have occurred that have served as the catalyst for this update for clinicians. (1) Additional data from randomized controlled trials of cyclooxygenase (COX)-2–selective agents have been reported and summarized in meta-analyses, which has reinforced the concern about cardiovascular events with COX-2 inhibitors (coxibs; Figure 1). (2) Several reports have appeared that have identified an increased risk of cardiovascular events even with the nonselective NSAIDs, which has raised concern about the use of those agents as well (Table). (3) Regulatory authorities in several regions of the world have introduced warning statements and advisories to both healthcare professionals and the lay public about the use of various NSAIDs (Figures 2 and 3⇓). Figure 1. Comparison of effects of different selective COX-2 inhibitors vs placebo on myocardial infarction. Event numbers and person-years of exposure, with corresponding mean annual event rates in parentheses, are presented for patients allocated to selective COX-2 inhibitor or placebo. Event rate ratios for pooled data with 95% CIs are indicated by a diamond; rate ratios for individual selective COX-2 inhibitors, with 99% CIs, are indicated by a square and horizontal line. Diamonds to the right of the solid line indicate hazard with a selective COX-2 inhibitor compared with placebo. As noted, there was a significant increase in the rate ratio for myocardial infarction with COX-2 inhibitors compared with placebo. Similar analyses (data not shown) include rate ratios of 1.42 (1.13 to 1.78; P =0.003) for vascular events, 1.02 (0.71 to 1.47; P …

Cardiovascular and Cerebrovascular Events in the Randomized, Controlled Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT)

Objectives:The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) was designed to evaluate the conventional NSAID naproxen sodium and the selective COX-2 inhibitor celecoxib for primary prevention of Alzheimer's dementia (AD). On 17 December 2004, after the Adenoma Prevention with Celecoxib (APC) trial reported increased cardiovascular risks with celecoxib, the ADAPT Steering Committee suspended treatment and enrollment. This paper reports on cardiovascular and cerebrovascular events in ADAPT.Design:ADAPT is a randomized, placebo-controlled, parallel chemoprevention trial with 1–46 mo of follow-up.Setting:The trial was conducted at six field sites in the United States: Baltimore, Maryland; Boston, Massachusetts; Rochester, New York; Seattle, Washington; Sun City, Arizona; and Tampa, Florida.Participants:The 2,528 participants were aged 70 y and older with a family history of AD.Interventions:Study treatments were celecoxib (200 mg b.i.d.), naproxen sodium (220 mg b.i.d.), and placebo.Outcome measures:Outcome measures were deaths, along with nonfatal myocardial infarction (MI), stroke, congestive heart failure (CHF), transient ischemic attack (TIA), and antihypertensive treatment recorded from structured interviews at scheduled intervals. Cox proportional hazards regression was used to analyze these events individually and in several composites.Results:Counts (with 3-y incidence) of participants who experienced cardiovascular or cerebrovascular death, MI, stroke, CHF, or TIA in the celecoxib-, naproxen-, and placebo-treated groups were 28/717 (5.54%), 40/713 (8.25%), and 37/1070 (5.68%), respectively. This yielded a hazard ratio (95% confidence interval [CI]) for celecoxib of 1.10 (0.67–1.79) and for naproxen of 1.63 (1.04–2.55). Antihypertensive treatment was initiated in 160/440 (47.43%), 147/427 (45.00%), and 164/644 (34.08%). This yielded hazard ratios (CIs) of 1.56 for celecoxib (1.26–1.94) and 1.40 for naproxen (1.12–1.75).Conclusions:For celecoxib, ADAPT data do not show the same level of risk as those of the APC trial. The data for naproxen, although not definitive, are suggestive of increased cardiovascular and cerebrovascular risk.

Risk of Cardiovascular Events in Patients Receiving Celecoxib: A Meta-Analysis of Randomized Clinical Trials

Some nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 selective inhibitors, have been associated with increased cardiovascular (CV) events in recent clinical trials or observational studies. To determine whether the cyclooxygenase-2 selective inhibitor celecoxib affects CV risk, the incidence of CV events was analyzed in patients treated with celecoxib, placebo, or nonselective NSAIDs in the clinical trial database for celecoxib using defined Antiplatelet Trialists' Collaboration end points of nonfatal myocardial infarction, nonfatal stroke, and CV death. Patient data were derived from studies in osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, low back pain, and Alzheimer's disease. This meta-analysis included (1) 7,462 patients exposed to celecoxib 200 to 800 mg/day for 1,268 patient-years compared with 4,057 patients treated with placebo for 585 patient-years, and (2) 19,773 patients treated with celecoxib 200 to 800 mg/day for 5,651 patient-years compared with 13,990 patients treated with nonselective NSAIDs (diclofenac, ibuprofen, naproxen, ketoprofen, and loxoprofen) for 4,386 patient-years. CV events were adjudicated by a 3-member expert end point committee (WBW, JSB, PBG) blinded to treatment group and study. The incidence rates of the combined CV events were not significantly different between patients treated with celecoxib and placebo or between those treated with celecoxib and nonselective NSAIDs. Event rates were similar for adjudicated and nonadjudicated data. Dose of celecoxib, the use of aspirin, or the presence of CV risk factors did not alter these results. In conclusion, these analyses failed to demonstrate an increased CV risk with celecoxib relative to placebo and demonstrated a comparable rate of CV events with celecoxib treatment compared with nonselective NSAIDs.

Adjusted indirect comparison of celecoxib versus rofecoxib on cardiovascular risk

To compare the magnitude of celecoxib versus rofecoxib on the cardiovascular risk. We performed adjusted indirect comparison of celecoxib versus rofecoxib for cardiovascular events using two data on The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial and Adenoma Prevention with Celecoxib (APC) trial. Baseline characteristics of the patients and placebos were comparable in both trials, in terms of age, sex, hypertension, diabetes mellitus, smoking, and hypercholesterolemia. The overall incidence of cardiovascular events was similar in both groups (rofecoxib 48/1,287 versus celecoxib 48/1,356, p = 0.79). The relative risks (RRs) of all myocardial infarction or sudden death from cardiac causes were increased in both rofecoxib and celecoxib groups [rofecoxib versus placebo; RR 1.35, 95% confidence interval (CI) 1.07-1.69, p = 0.03, celecoxib versus placebo; RR 1.35, 95% CI 1.14-1.51, p = 0.01]. The RRs for cardiovascular events derived from the adjusted indirect comparisons of the two coxibs did not significantly differ from unity (celecoxib versus rofecoxib; RR 0.95, 95% CI 0.76-1.19, p = 0.67). The adjusted indirect comparison analysis shows that celecoxib and rofecoxib may have similarly effect of cardiovascular events when used for 3 years.