Prevention Of Adenomatous Polyps Research Articles

Disconnect between COX-2 selective inhibition and cardiovascular risk in preclinical models

IntroductionSecondary pharmacology profiling is routinely applied in pharmaceutical drug discovery to investigate the pharmaceutical effects of a drug at molecular targets distinct from (off-target) the intended therapeutic molecular target (on-target). Data from a randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX, rofecoxib) trial, raised significant concerns about COX-2 inhibition as a primary or secondary target, shaping the screening and decision-making processes of some pharmaceutical companies. COX-2 is often included in off-target screens due to cardiovascular (CV) safety concerns about secondary interactions with this target. Several potential mechanisms of COX-2-mediated myocardial infarctions have been considered including, effects on platelet stickiness/aggregation, vasal tone and blood pressure, and endothelial cell activation. In the present study, we focused on each of these mechanisms as potential effects of COX-2 inhibitors, to find evidence of mechanism using various in vitro and in vivo preclinical models. MethodsCompounds tested in the study, with a range of COX-2 selectivity, included rofecoxib, celecoxib, etodolac, and meloxicam. Compounds were screened for inhibition of COX-2 vs COX-1 enzymatic activity, ex vivo platelet aggregation (using whole blood from multiple species), ex vivo canine femoral vascular ring model, in vitro human endothelial cell activation (with and without COX-2 induction), and in vivo cardiovascular assessment (anesthetized dog). ResultsThe COX-2 binding assessment generally confirmed the COX-2 selectivity previously reported. COX-2 inhibitors did not have effects on platelet function (spontaneous aggregation or inhibition of aggregation), cardiovascular parameters (mean arterial pressure, heart rate, and left ventricular contractility), or endothelial cell activation. However, rofecoxib uniquely produced an endothelial mediated constriction response in canine femoral arteries. ConclusionOur data suggest that rofecoxib-related cardiovascular events in humans are not predicted by COX-2 potency or selectivity. In addition, the vascular ring model suggested possible adverse cardiovascular effects by COX-2 inhibitors, although these effects were not seen in vivo studies. These results may also suggest that COX-2 inhibition alone is not responsible for rofecoxib-mediated adverse cardiovascular outcomes.

Pharmacologically pertinent period of effect (PPPE).

BackgroundThe period of time during which a patient is exposed to a drug does not necessarily correspond to the period during which the drug produces the adverse effect under consideration. We propose the term Pharmacologically pertinent period of effect (PPPE) to address this time window. We explored the PPPE in light of the rofecoxib saga.MethodsWe identified the observational database studies of rofecoxib at doses 25 and 50 mg daily and thromboembolic events. We also obtained the Kaplan‐Meier curves of Vioxx Gastrointestinal Outcomes Research trial (VIGOR) and Adenomatous Polyp Prevention on Vioxx (APPROVE) trials.ResultsWe found seven observational studies with nine analyses. All the studies only looked at current exposure. At the dose of 25 mg, only three of nine analyses were barely statistically significant. At the dose of 50 mg, the risk ratios were much higher. The visual inspection of the Kaplan‐Meier curves shows that in the APPROVE trial (25 mg), the placebo and rofecoxib curves start separating to become statistically significantly different only after 36 months. In contrast the VIGOR (50 mg), curves start separating very early and the divergence increases after 8 months.DiscussionThe 50 mg observational studies, looking at current exposure, correctively identified the almost immediate increase in risk evident in the VIGOR Kaplan‐Meier curves. The absence of an immediate increase in risk shown by the APPROVE trial was also correctively identified by most observational 25 mg studies. To our knowledge no observational study was done on the long‐term cardiac toxicity of the 25‐mg dose. It would thus appear that the two doses of rofecoxib have different PPPEs.

Abstract 1266: Downregulation of PD-L1 by NSAID administration augments the effects of a multi-antigen vaccine for the prevention of adenomatous polyps in APC(Min/+) mice

Abstract Introduction: We have shown that treatment of APC(Min/+) mice with NSAIDs will inhibit development of adenomatous polyps and induce significant levels of polyp-infiltrating CD8 T-cells. We sought to identify the mechanism of NSAID induced immune stimulation and questioned whether administration of NSAIDs concurrent with vaccination could further reduce polyp formation. Methods: PD-L1 expression and T-cell infiltrates were assessed by IHC and flow cytometry. MC38 and RKO (murine/human colorectal carcinoma cell lines) were treated with naproxen (200uM-1000 uM) and harvested at 24, 48 and 72h. At 4-6 weeks, APC(Min/+) mice were given a multi-antigen peptide vaccine (COX2, CDC25B, EGFR) with CFA/IFA or adjuvant alone. Two groups received 400ppm naproxen orally 7d/wk for 18 weeks. Polyps were quantified at ≤24 weeks. Spleens and polyps were collected for IFN-gamma ELISPOT, flow cytometry, and IHC. Results: Polyps from the APC(Min/+) mouse and both cancer cell lines highly express PD-L1. PD-L1 expression was significantly decreased in MC38 (p<0.01) and RKO (p<0.01) as compared to control after incubation with naproxen at all doses. The inhibitory effect of NSAIDs on PD-L1 expression was both time and dose dependent. We evaluated the in vivo effect of combination immunoprevention in the APC(Min/+). Animals receiving vaccine alone showed a 33% inhibition of polyp formation while naproxen alone showed 54% inhibition (p<0.0001) compared to adjuvant alone. Combination treatment demonstrated significantly greater inhibition of polyps than either modality (p<0.001), 81% inhibition vs. adjuvant. Antigen specific T-cells could be detected at higher levels than control antigen in both the vaccine alone (p=0.0001) and combination-treated animals (p<0.0001). The antigen specific responses seen in combination treated animals were nearly two-fold that of vaccine alone (p=0.008). No antigen specific immunity was detected in naproxen and adjuvant only treated mice. The magnitude of the immune response was significantly correlated with lower polyp counts, with a Pearson correlation coefficient of -0.55 (p=0.0014). Detailed immunologic analysis of tumors will be presented. Conclusions: NSAIDs, via modulation of PD-L1, synergize with vaccines to increase immunogenicity and enhance influx of polyp infiltrating lymphocytes. This synergy results in superior prevention of polyp formation compared to treatment with NSAID or vaccine alone and has high potential for clinical application. Citation Format: Mary L. Disis, Lauren R. Corulli, Clinton Grubbs, Ronald A. Lubet, Paul Cowan, Ekram Gad. Downregulation of PD-L1 by NSAID administration augments the effects of a multi-antigen vaccine for the prevention of adenomatous polyps in APC(Min/+) mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1266.

English

Non Steroidal anti-inflammatory Drugs (NSAIDs) are most commonly prescribed drugs constituting more than 20% of all drug prescriptions. Prescription pattern study of NSAID was conducted in Medicine OPD of a rural teaching hospital with the objective of analyzing prescribing trend of NSAIDs, to evaluate co-prescription of Gastro-protective agents (GPAs) with NSAIDs and to determine number of prescribed NSAIDs falling within Drug utilization (DU) 90% segment. Overall 200 NSAID prescriptions were analysed. Prevalence of NSAID prescription was 25.71%. Paracetamol (36%) was the commonest drug prescribed. In general non-selective NSAIDs were more commonly prescribed (79.5%) and selective COX-2 inhibitors were least prescribed (1%). High prevalence of nimesulide prescription (19.5%) was a significant finding. Co-prescription of GPAs was high (61%). Four drugs (paracetamol, diclofenac, nimesulide and aceclofenac) fall within DU90% segment. In general prescription pattern requires further rationalization of NSAID usage as more number of drugs constitutes DU90% segment. KEY WORD: Prescription pattern, NSAID, DU90%, GPAs co-prescription. INTRODUCTION: The treatment of pain and inflammation is an important area of therapeutics. Over the past two decades, non steroidal anti-inflammatory drugs (NSAIDs) have played a central role in these indications. NSAIDs constitute the largest single group of drugs used worldwide, constituting more than 20% of all drug prescriptions 1 . In India over 400 formulations of NSAIDs are marketed, resulting in wide spread exposure of patients to this class of drugs and its adverse effects 2 . For all these reasons, studies that evaluate the pattern, extent and frequency of NSAID prescriptions are valuable. The demonstration of two unique isoforms of cyclooxygenase (designated as COX-1 and COX- 2) has led to a greater understanding of the mechanisms of action of NSAIDs and their toxicity 3 . The beneficial anti-inflammatory effect of the NSAIDs had been attributed to inhibition of COX-2, while the gastrointestinal (GI), renal and anti-platelet adverse effects were attributed to COX-1 inhibition 4 . Prescription pattern of NSAID changed frequently over a period of time. With the introduction of the selective COX-2 inhibitors, it has been suggested that they may be more cost-effective because of their improved GI tolerability and a reduction in concomitant prescription of antiulcer agents. This has led to an increase of almost 50% in the total number of NSAID prescriptions dispensed, with COX-2 drugs accounting for two thirds of this increase 3 . Before withdrawal of Rofecoxib, the prescriptions of COX-2 selective inhibitors had accounted for 37% of the total NSAID prescriptions dispensed. After its withdrawal in 2004, following the emergence of evidence of increased cardiovascular morbidity in the APPROVe (Adenomatous Polyp Prevention on Vioxx) study, COX-2 inhibitors represented less than 16% of the

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.

Statin polyp prevention trial in patients with resected colon cancer: NSABP protocol P-5.

TPS1615 Background: HMG-CoA reductase inhibitors (statins) are effective lipid-lowering agents that are used for treating hyperlipidemia. Results from cell culture, animal experiments, and epidemiologic studies indicate that statins may be active chemopreventive agents against colorectal cancer (CRC). However, the clinical studies come largely from retrospective, observational studies originally designed to investigate lipid-lowering or cardiovascular endpoints rather than tumor endpoints. Methods: NSABP P-5 is a randomized, prospective placebo-controlled, double-blind study of rosuvastatin (10 mg per day x 5 years) or placebo for the prevention of adenomatous polyps of the colon or rectum, metachronous colorectal carcinoma, and colon cancer recurrence. Additional secondary endpoints include the size, number and features of the colorectal adenomas as well as health-related quality of life and self-reported symptoms. Selected Eligibility: (1) Patients who have undergone complete resection of AJCC Stage I or II colon cancer within 1 year before randomization. (2) Colonoscopy within 180 days before randomization. Selected Ineligibility: (1) Hyperlipidemia, (2) Familial Adenomatous Polyposis, (3) Lynch Syndrome. Sample Size:1,740 patients will be entered, and as of January 23, 2012, 163 (9.37%) have been randomized. The study is open at NSABP and CTSU sites in North America. Funded by NCI PHS grants U10-CA-37377 and U10-CA-6974, with additional funding from AstraZeneca Pharmaceuticals, LP.

Progress in COX-2 Inhibitors: A Journey So Far

The non-steroidal anti-inflammatory drugs (NSAIDs) are diverse group of compounds used for the treatment of inflammation, since the introduction of acetylsalicylic acid in 1899. Traditional (first generation) NSAIDs exert antiinflammatory, analgesic, and antipyretic effects through the blockade of prostaglandin synthesis via non-selective inhibition of cyclooxygenase (COX-1 and COX-2) isozymes. Their use is associated with side effects such as gastrointestinal and renal toxicity. A number of selective (second generation) COX-2 inhibitors (rofecoxib, celecoxib, valdecoxib etc.) were developed as safer NSAIDs with improved gastric safety profile. Observation of increased cardiovascular risks in APPROVe (Adenomatous Polyp Prevention on Vioxx) study sent tremors and led to voluntary withdrawn of Vioxx (rofecoxib) by Merck from the market in September 2004 followed by Bextra (valdecoxib) in 2005 raising a question on the safety of selective COX-2 inhibitors. This leads to the belief that these effects are mechanism based and may be class effect. However, some studies suggested association of traditional NSAIDs with similar effects requiring a relook into the whole class of NSAIDs rather than simply victimizing the selective COX-2 inhibitors. Recognition of new avenues for selective COX-2 inhibitors such as cancer, Alzheimer's disease, Parkinson's disease, schizophrenia, major depression, ischemic brain injury and diabetic peripheral nephropathy has kindled the interest in these compounds. This review highlights the various structural classes of selective COX-2 inhibitors developed during past seven years (2003-2009) with special emphasis on diaryl-hetero/carbo-cyclic class of compounds. Molecular modeling aspects are also briefly discussed.

Loss of 15-Hydroxyprostaglandin Dehydrogenase Expression Contributes to Bladder Cancer Progression

Prostaglandin E2, which is known to contribute to cancer progression, is inactivated by the catabolic enzyme, 15-hydroxyprostaglandin dehydrogenase (PGDH), which has tumor-suppressor activity in lung, colon, breast, and gastric cancers. Therefore, we evaluated the expression of PGDH in human bladder cancer tissue specimens and cell lines. Immunoperoxidase staining of bladder cancer tissues demonstrated that (1) PGDH is highly expressed by normal urothelial cells but (2) reduced in many low stage (Ta/Tis) bladder cancers, and (3) PGDH is completely lost in most invasive bladder cancers. Of eight cancer cell lines tested, only two relatively well-differentiated bladder cancer cell lines, RT4 and UM-UC9, expressed PGDH. Moreover, inhibition of PGDH expression in well-differentiated RT4 cells using small inhibitory RNA or short hairpin RNA resulted in a more aggressive phenotype with increased motility and anchorage-independent growth. Additionally, PGDH knockdown affected prostaglandin E2 signaling as measured by cAMP generation. These data indicate that loss of PGDH expression contributes to a more malignant bladder cancer phenotype and may be necessary for bladder cancer development and/or progression.

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Cardiovascular Safety of Celecoxib on Top of Dual Antiplatelet Therapy

Rofecoxib increased risk of CV events in patients with history of colorectal adenomas ⩾1 year after stopping treatment

### Design: randomised controlled trial (RCT) (The Adenomatous Polyp Prevention on Vioxx [APPROVe] study). ClinicalTrials.gov NCT0282386. ### Allocation: unclear.* ### Blinding: blinded (patients, clinicians, and outcome assessors).* ### Setting: 108...

Non‑steroidal anti‑inflammatory drugs and the risk of cardiovascular diseases: are we going to see the revival of cyclooxygenase‑2 selective inhibitors?

The use of non-steroidal anti-inflammatory drugs (NSAID) is associated with a number of gastrointestinal and other adverse effects. Introduction of selective cyclooxygenase-2 (COX-2) inhibitors at the end of the 20th century raised hopes for a substantial reduction in the rate of serious events such as upper gastrointestinal ulcers, bleeding and perforations. In 2004 and 2005, predictions of some pharmacologists were confirmed when the Adenomatous Polyp Prevention on VIOXX trial (APPROVE) and other randomized, double-blind, placebo-controlled trials with COX-2 inhibitors showed an increased rate of thrombotic vascular events, including myocardial infarction, in patients treated with coxibs. So far, only limited long-term data on cardiovascular risk associated with non-selective NSAID have been available; however, some studies have suggested that both selective COX-2 inhibitors and traditional NSAID increase the risk of cardiovascular events. For patients at high cardiovascular risk, contradictory warnings and recommendations have been published recently by the American Heart Association, Food and Drug Administration, and by independent experts. The current paper reviews these recommendations and discusses the therapeutic challenge to minimize the risk of serious adverse events associated with the use of NSAID.

Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial

Selective inhibition of cyclo-oxygenase-2 has been associated with an increased risk of cardiovascular events in several clinical trials. The Adenomatous Polyp Prevention on Vioxx (APPROVe) study assessed the effect of 3-year treatment with a cyclo-oxygenase-2 inhibitor, rofecoxib (25 mg), on recurrence of neoplastic polyps of the large bowel. We report the cardiovascular outcomes of a long-term follow-up of participants in the trial. The APPROVe study is a multicentre, randomised, placebo-controlled, double-blind trial. 2587 patients with a history of colorectal adenomas were recruited at 108 centres worldwide during 2000 and 2001. Participants were followed for adverse events while on treatment and during the following 14 days. However, after early termination of treatment because of cardiovascular toxicity, we attempted to follow up all randomised patients for at least 1 year after stopping study treatment. External committees blindly assessed potential serious cardiovascular events. The focus of the analysis was the combined incidence of non-fatal myocardial infarction, non-fatal stroke, and death from cardiovascular, haemorrhagic, and unknown causes (Antiplatelet Trialists' Collaboration [APTC] combined endpoint). We used Cox proportional hazards regression to calculate endpoint hazard ratios. The study is registered with ClinicalTrials.gov, number NCT0282386. We obtained extended post-treatment cardiovascular follow-up data from 84% of participants, and extended mortality follow-up from 95%. In total, 59 individuals had an APTC endpoint in the rofecoxib group and 34 in the placebo group (hazard ratio 1.79, 95% CI 1.17-2.73; p=0.006). In the first year after cessation of treatment, there was a non-significant increase in the risks of APTC endpoints. The APTC hazard ratio did not substantially change over time. Use of rofecoxib is associated with increased rates of APTC events. Study data are compatible with an early increase in risk that persists for one year after stopping treatment.

Selective COX-2 inhibitors: where do we go from here?

The results of the Adenomatous Polyp Prevention On Vioxx (APPROVe) trial were first announced in September, 2004, after concerns about cardiovascular toxicity with rofecoxib prompted the data monitoring committee to recommend termination about 2 months before the scheduled study end. Rofecoxib was immediately withdrawn from the market and the cardiovascular safety of other selective inhibitors of cyclo-oxygenase 2 (coxibs) and traditional non-steroidal anti-inflammatory drugs (NSAIDs) came under intense scrutiny.

Cyclooxygenase-2 (COX-2) in Carcinogenesis and Selective COX-2 Inhibitors for Chemoprevention in Gastrointestinal Cancers

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to have a property to inhibit tumor development in some cancers while it shows various side effects such as gastrointestinal bleeding and renal disorder. Selective cyclooxygenase (COX)-2 inhibitors (coxibs) were originally developed as one of anti-inflammatory drugs to avoid side effect of NSAIDs. Fortunately, the coxibs was also proved to have an inhibiting effect on tumorigenesis by many experimental studies using cell lines and animal models like NSAIDs. Since a randomized study for polyp chemoprevention by celecoxib in familial adenomatous polyposis (FAP) patients demonstrated a significant reduction in the number of colorectal polyps, the clinical use of celecoxib was approved for FAP patients. Three large trials using celecoxib (the Adenoma Prevention with Celebrex and the Prevention of Spontaneous Adenomatopus Polyps) or refecoxib (the Adenomatous Polyp Prevention on Vioxx) for the recurrence of colorectal polyps in patients with a history of colorectal adenoma polypectomized confirmed chemopreventive effects on colorectal adenoma but two of three trails alerted us a hazard of cardiovascular (CV) events. Thereafter, some coxibs were withdrawn from the market because they showed to increase risk of serious CV events including heart attacks and strokes. But recent reports concluded that a merit of the reduction in gastrointestinal events by coxibs exceeded a demerit of the increase in serious CV events. In this review, a role of COX-2 in carcinogenesis of gastrointestinal tract and a future of coxibs for chemoprevention are discussed.

Cerebrovascular Events After Discontinuation of Rofecoxib Treatment

The pain-relieving nonsteroidal antiinflammatory drugs (NSAIDs) exhibit different degrees of selectivity for the isoforms COX-1 and COX-2 which differ substantially in their localization and function. While COX-1 plays an important role in the cytoprotection of the gastric mucosa, in platelet activation, and in other homeostatic processes, COX-2 is thought to largely account for prostaglandin formation at the site of tissue injury [1]. With the objective of treating pain and inflammation without affecting gastric mucosa, COX-2 selective NSAIDs (“Coxibs”) were developed and introduced on the market. The finding of an excess of thrombotic cardiovascular events, primarily of myocardial infarction, in the VIGOR trial [2 ]r aised concern about the cardiovascular safety of rofecoxib, and also of COX-2 inhibitors in general. The relative risk (RR) of myocardial infarction was 5.00 (95% confidence interval (CI) 1.68–20.13) for patients treated with rofecoxib as compared with naproxen [3]. The proportion of patients with ischemic stroke was similar in both treatment groups (0.2%). The randomized placebo-controlled Adenomatous Polyp Prevention On Vioxx (APPROVe) trial [4] conducted to demonstrate preventive effects of rofecoxib on development of colorectal adenomas ultimately lead to marketing withdrawal of rofecoxib in 2004, since it showed a nearly 2-fold increased risk of confirmed thrombotic events compared with the placebo group. This was statistically significant for cardiac events including myo

Chemoprevention of Colorectal Cancer: Two Steps Forward, One Step Back?

Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality in the Western world. The poor survival rate has prompted the emphasis on prevention of this disease. Removal of adenomas at colonoscopy is highly effective and is the cornerstone of screening/surveillance strategies. However, screening efforts have had limited impact owing to low compliance with guidelines. Chemoprevention aims to prevent the development or recurrence of precancerous lesions and cancers with the use of compounds that block the carcinogenic process. A major advantage was the establishment and understanding of the multistage process of CRC carcinogenesis. Progress has been remarkable because of the availability of reliable animal models and clinical studies using colonic adenomas as a reliable and economic target for testing chemopreventive agents. Nonsteroidal anti-inflammatory drugs have drawn the most attention. Sulindac and celecoxib were shown to be effective in promoting polyp regression in high-risk individuals with familial adenomatous polyposis. In the more common sporadic setting, the Adenomatous Polyp PRevention On Vioxx (rofecoxib), Adenoma Prevention with Celecoxib and Prevention of Sporadic Adenomatous Polyps (celecoxib) trials have demonstrated a significant reduction in adenoma recurrence, but important concerns were raised regarding cardiovascular toxicity associated with selective cyclo-oxygenase-2 inhibitors. These landmark studies are very important, as they are a proof-of-concept that we can prevent CRC. More clinical studies are required to better select high-risk patients with safer regimens. Potential advantage versus risk for a given chemopreventive agent will have to be assessed on an individual basis. Currently, the only approved agent for chemoprevention is celecoxib in high-risk individuals with familial adenomatous polyposis.

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.

Parecoxib – getting to the heart of the matter

Parecoxib – getting to the heart of the matter

Lapses at the New England Journal of Medicine

Lapses at the New England Journal of Medicine