Celecoxib Long-term Arthritis Safety Study Research Articles

Gastrointestinal safety and efficacy of long-term GCSB-5 use in patients with osteoarthritis: A 24-week, multicenter study

Ethnopharmacology relevanceA previous study indicated non-inferiority of GCSB-5 to celecoxib regarding efficacy and safety in treating OA; however, the gastrointestinal (GI) safety data was limited to 12 weeks. Accordingly, a longer term study with a larger number of patients was necessary to establish the GI safety of GCSB-5. Aim of studyThe primary goal was to determine the safety and efficacy of 24-week use of GCSB-5. The secondary goal was to compare the GI safety data of GCSB-5 with that of the previously reported Celecoxib Long-term Arthritis Safety Study (CLASS). MethodThis was a 24-week, multicenter, single-arm phase IV Study for the safety and efficacy of GCSB-5. A total of 761 patients were enrolled and 756 patients received at least one dose of GCSB-5. Among them, 629 patients (82.7%) completed the 24 week follow up. The primary goal was to determine the safety and efficacy of GCSB-5 for 24 weeks. The secondary goal was to compare the GI safety data of GCSB-5 with that of the previously reported Celecoxib Long-term Arthritis Safety Study (CLASS). ResultsThe incidence of GI disorders of GCSB-5 was 23.7%. The annual rate of perforation, ulcer obstruction, or bleeding (PUB) incidence was 0.0%. The drop-out rate due to GI disorders following GCSB-5 use was 4.8%. Compared to celecoxib data from CLASS, the incidence of GI disorders (23.7% vs. 31.4%, p<0.001), annual rate of PUB and gastroduodenal ulcers (0.0% vs 2.2%, p=0.004), and drop-out rate due to GI disorders following GCSB-5 use were significantly low (4.8% vs 8.7%, p<0.001). Efficacy was proven by significant improvements in Western Ontario McMaster Questionnaire (WOMAC) scale, Korean Knee Score (KKS), 100-mm pain visual analogue scale (VAS), and physician's global assessments of patient's response to therapy (PGART). ConclusionsThe safety and efficacy profile of GCSB-5 are comparable to celecoxib. These results indicate GCSB-5 is safe for a long-term treatment of knee OA patients. Trial registrationClinicalTrials.gov (NCT01604239).

Credulous Fondness for Celecoxib

The American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication (PIM) Use in Older Adults1 lists “Non-Cox-selective NSAIDs [nonsteroidal anti-inflammatory drugs], oral.” The rationale focuses on risk of gastrointestinal (GI) bleeding, and the recommendation is to avoid chronic use. Perhaps the notorious Celecoxib Long-term Arthritis Safety Study (CLASS),2 whose authors were six employees of and 10 consultants for celecoxib's (Celebrex, Pfizer, New York, NY) vendor, persuaded the panelists. Submitted to JAMA as a 6-month trial, CLASS was the combination of results of a 12-month and a 15-month trial, each completed when CLASS was submitted to JAMA. Neither trial was disclosed to JAMA, nor the fact that CLASS was not actually a single trial. The authors also changed the outcomes and analysis for their report, without disclosing these changes. Almost all ulcer complications after the first 6 months occurred in the celecoxib groups.3 In participants taking aspirin, rates of ulcer complications and symptomatic ulcers were not different between celecoxib and standard NSAIDs. NSAIDs, including Celebrex, increase the risk of serious adverse GI events, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly adults are at high risk for serious GI events.4 Why not add celecoxib to the list of PIMs? Especially because its safety in chronic use is unlikely to be any better than that of conventional NSAIDs. The enduring credulous fondness for celecoxib is perplexing. Conflict of Interest: I, Thomas E. Finucane, MD, have no conflict of interest with regard to the contents of this letter. Author Contributions: TF is responsible for the entire content. Sponsor's Role: None.

Editorial: On the selective inhibitors of Cyclooxygenase-2: Do we have a last word?

The cardiovascular safety of selective inhibitors of cyclooxygenase 2 (COX-2) has received a great deal of attention since the withdrawal of rofecoxib and valdecoxib and recently with the non-approvable decisions for etoricoxib and lumiracoxib by the Food and Drug Administration (FDA). Numerous reviews and editorials have attempted to bring clarity to a very complicated issue. Differences among the individual COX-2 inhibitors have been suggested, but it is difficult to compare risk because of the lack of head-to-head trials and different comparators used in the key studies. Attempts have been made to determine difference in agents through comparison of the current published trials and through metaanalysis. These comparisons are challenging because of differing patient populations, risk profile of the patients, and different comparators used in the various trials. However, an evaluation of the literature can provide some relevant information. For example, comparisons of agents with similar selectivity, such as etoricoxib and diclofenac, did not show a difference in thrombotic events or complicated gastrointestinal (GI) events in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) program [Canon et al. 2006]. A difference was noted, however, with heart failure and hypertension with etoricoxib and uncomplicated GI events with diclofenac. Also, when the population is at low risk for cardiovascular disease, as in the Celecoxib Long-term Arthritis Safety Study (CLASS), no differences are seen. The cardiac safety of COX-2 inhibitors is a Correspondence to: Carlos M. Ferrario, MD Hypertension and Vascular Research Center Wake Forest University School of Medicine Winston Salem, North Carolina 27157, USA Tel: 336-716-5819 Fax: 336-716-6644 cferrari@wfubmc.edu complex issue that needs further evaluation to determine the risk of these agents in individual patients. Understanding the mechanism behind the cardiovascular effects is also critical to assist in patient selection and evaluation of an individual’s risk versus benefit. While many have attempted to present the mechanism simplistically, two possible mechanisms, as reviewed below, have garnered the most attention to date.

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 …

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.

Cardiorenal effects of celecoxib as compared with the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen

The cardiorenal safety database from the Celecoxib Long-term Arthritis Safety Study (CLASS) was analyzed to examine whether supratherapeutic doses of celecoxib are associated with decreased renal function and blood pressure (BP) effects compared with standard doses of diclofenac and ibuprofen in osteoarthritis (OA) and rheumatoid arthritis (RA) patients.In total, 8059 patients were enrolled; 7968 received at least one dose of study drug (RA: N = 2183; OA: N = 5785). Patients received celecoxib, 400 mg twice a day (b.i.d.). (N = 3987); ibuprofen, 800 mg three times a day. (N = 1985); or diclofenac, 75 mg b.i.d. (N = 1996). Effects measured included: investigator-reported hypertension, edema or congestive heart failure, clinically important BP elevations, incidence of patients starting new antihypertensive medication, and increases in serum creatinine or reductions in creatinine clearance. Celecoxib was associated with a similar incidence of hypertension or edema to diclofenac but significantly lower than ibuprofen. The celecoxib group had significantly fewer initiations of antihypertensives versus ibuprofen. Systolic BP increases of >20 mmHg and above 140 mmHg occurred significantly less often with celecoxib compared with ibuprofen or diclofenac. Changes in serum creatinine or estimated creatinine clearance occurred in a similar percentage of patients taking celecoxib or ibuprofen; modest differences were evident against diclofenac. In patients with mild prerenal azotemia, significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.7%), compared with diclofenac (7.3%; P < 0.05) and ibuprofen (7.3%; P < 0.05). A supratherapeutic dose of celecoxib was associated with an improved cardiorenal safety profile compared with standard doses of either ibuprofen or diclofenac.

Consensus Development Conference on the Use of Nonsteroidal Anti-Inflammatory Agents, Including Cyclooxygenase-2 Enzyme Inhibitors and Aspirin

Consensus Development Conference on the Use of Nonsteroidal Anti-Inflammatory Agents, Including Cyclooxygenase-2 Enzyme Inhibitors and Aspirin

Inconsistencies in cardiovascular data from COX-2 inhibitor trials--is it a class effect?

The recent editorials in the New England Journal of Medicine about inaccuracies in cardiovascular data in the publication of the VIGOR (Vioxx Gastrointestinal Outcomes Research) study1,2 has prompted us to report similar inaccuracies in the CLASS study (Celecoxib Long-term Arthritis Safety Study), which were identified during a systematic review of the cardiovascular effects of celecoxib.3 Like the VIGOR study, CLASS was designed primarily to compare the incidence of upper gastrointestinal adverse events resulting from a COX-2 specific inhibitor with those of conventional non-steroidal anti-inflammatory drugs (NSAIDs) in patients with arthritis. As with the VIGOR study, in CLASS there were also inconsistencies in the serious adverse cardiovascular events reported in the different published reports. The outcomes of CLASS have been reported in two peer-reviewed journals4,5 and in a number of documents posted on the Food and Drug Association website, of which the medical officer review is the most complete.6 We have reviewed the data from these three major publications.4-6 In September 2000 the initial 6-month data were published by Silverstein and colleagues in JAMA in which no cardiovascular deaths were reported (Table 1).4 Also in September 2000, the FDA medical officer review of celecoxib data supplied by GD Searle & Co, reported that in CLASS there were five and eight cardiovascular deaths in the celecoxib and NSAID groups, respectively, during the full 12-month study period or within the following 28 days (Table 1).6 In the subsequent 2002 American Journal of Cardiology publication of the cardiovascular events from CLASS, a total of 10 cardiovascular deaths were reported in each of the celecoxib and NSAID groups (Table 1).5 It is difficult to understand why all the cardiovascular deaths would have occurred after 6 months of treatment, and how there could be such major discrepancies between the two complete study reports for such a definite outcome measure as death. Table 1 Mortality data reported in the three CLASS (Celecoxib Longterm Arthritis Safety Study) publications Similarly, there were inconsistencies between the three sources of CLASS data in the reporting of myocardial infarction (Table 2). For example, in the publications of the entire CLASS data, one reported 26 myocardial infarctions in the celecoxib group and 15 in the NSAID group5, whereas the other reported 19 and 13 myocardial infarctions, respectively.6 Table 2 Myocardial infarction data reported in the three CLASS (Celecoxib Long-term Arthritis Safety Study) publications These findings add to the concerns previously expressed regarding the selective and partial reporting of the gastrointestinal side effects from the CLASS study and that the published CLASS study differs from the original protocol in primary outcomes, statistical analysis, trial duration and conclusions.7-10.7,8 Thus history appears to have repeated itself in two respects. First, in CLASS there were inconsistencies in the reporting of cardiovascular data. Of greater concern is the identification that in the two major safety studies of the most commonly used COX-2 specific inhibitors there were major inconsistencies in reporting of the cardiovascular events. Thus, there would seem to be a systemic problem in research conduct in this field. There are considerable public health, pharmaceutical, regulatory and clinical implications.

Cyclooxygenase-2 Inhibitors: A Painful Lesson

Non-steroidal anti-inflammatory drugs (NSAIDs) represent a clinically important class of agents. NSAIDs are commonly used in treatment of conditions such as headache, fever, inflammation and joint pain. Complications often arise from chronic use of NSAIDs. Gastrointestinal (GI) toxicity in the form of gastritis, peptic erosions and ulcerations and GI bleeds limit usage of NSAIDs. These toxicities are thought to be due to cyclooxygenase (COX)-1 blockade. COX-1 generates cytoprotective prostanoids such as prostaglandin (PG) E2 and prostacyclin (PGI2). COX-2 inhibitors, commonly referred to as coxibs, were developed to inhibit inflammatory prostanoids without interfering with production of COX-1 prostanoids. Concerns over cardiovascular safety, however, have evolved based on the concept of inhibition of COX-2-derived endothelial prostanoids without inhibition of platelet thromboxane A2, leading to increased cardiovascular risk. The Celecoxib Long-Term Arthritis Safety Study (CLASS) trial did not show a significant increase in cardiovascular risk for celecoxib (Celebrex), but results of the Vioxx Gastrointestinal Outcomes Research (VIGOR) study showed an increased cardiovascular risk with long-term daily usage of rofecoxib in patients with rheumatoid arthritis. The Adenomatous Poly Prevention on Vioxx (APPROVe) trial further evaluated cardiovascular effects of rofecoxib and recently led to removal of this drug from the marketplace. Coxibs affect renal function via blockade of normal COX-2 functions. COX-2 expression increases in high renin states and in response to a high-sodium diet or water deprivation. PGI2 and PGE2 are the most important renal prostanoids. PGI2 inhibition results in hyperkalemia. PGE2 inhibition results in sodium retention, which leads to hypertension, peripheral edema and potentially exacerbation of heart failure. This review article discusses beneficial and deleterious effects associated with prostanoids produced by COX-1 and COX-2 in various organs and how blockade of these products translates into clinical medicine.

COX-2 in Cardiovascular Disease

Prostanoids are a large family of lipid mediators derived from the arachidonic acid metabolites of the cyclooxygenase (COX) enzymes. Therapeutically, COX is the target of the nonsteroid antiinflammatory drugs (NSAIDs), a chemically diverse group that includes ibuprofen, naproxen, and diclofenac, among dozens of others. Inhibition of prostanoid production by traditional NSAIDs accounts for all their major therapeutic effects, such as the dampening down of inflammation and the reduction of fever, and their potentially severe adverse side effects, most commonly within the gastrointestinal tract.1,2 See page 1137 Since the early 1990’s it has been clear there are two distinct enzymes responsible for the production of prostanoids: a constitutive COX-1 found in all tissues and an inflammation-associated enzyme COX-2.1,2 COX-2 is constitutively expressed in only a few sites, such as parts of the kidney and central nervous system, but is highly upregulated and active at sites of inflammation. These findings led to the hypothesis that selective COX-2 inhibitors could be antiinflammatory without the major side effects associated with traditional NSAIDs. Against this background several COX-2–selective inhibitors have been produced and brought to market, the first two being celecoxib (Celebrex) and rofecoxib (Vioxx). Preclinical studies of these COX-2–selective inhibitors were extremely promising. In animal models, for example, they were demonstrated to be as efficacious as traditional NSAIDs but to be lacking their toxic actions on the gastrointestinal tract. Clinical trials have, however, been marred by controversy. The CLASS trial for celecoxib, a 12-month osteoarthritis study of celecoxib, demonstrated celecoxib to have improved safety relative to ibuprofen but not …

Selective Cyclooxygenase-2 Inhibitors Development in Cardiovascular Medicine

At the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. Since its approval in 1999, Vioxx, a selective cyclooxygenase-2 (COX-2) inhibitor, has been Merck & Co’s leading drug for control of acute pain and chronic pain associated with osteoarthritis, rheumatoid arthritis, and menstruation. Last year, worldwide sales of rofecoxib reached US $2.5 billion, and it is estimated that the drug was prescribed ≈10 million times per month in the United States.1 Thus, given the number of patients involved and the serious nature of the side effects, the withdrawal raised serious concerns about the safety of other selective COX-2 inhibitors, collectively called coxibs, that are on the market and those currently under development. Celecoxib (Celebrex) and rofecoxib were the first 2 coxibs approved by the US Food and Drug Administration (FDA) and launched in 1999 by Pfizer and Merck & Co, respectively. Since then, a second generation of these drugs has emerged onto the market. Valdecoxib (Bextra) was approved by the FDA and launched in 2002. In that same year, the European regulatory authority approved 2 other coxibs: etoricoxib (Arcoxia) and parecoxib sodium (Dynastat), the prodrug of valdecoxib. Today, etoricoxib and a fifth coxib, lumiracoxib (Prexige), are under consideration for FDA approval. In view of the rapid development in this area, the main concern is whether the reported cardiovascular effects of rofecoxib are a class effect applicable to all coxibs that were initially designed to reduce the gastric toxicity of nonselective COX inhibitors. Although most of the data accumulated so far would suggest a class effect related to the general mode of action of all coxibs and the physiological role of COX-2, recent in vitro data would theoretically support the hypothesis that the cardiovascular side …

To the Heart of the Matter

When cyclooxygenase (COX)-2–selective inhibitors (coxibs) first entered the market about 5 years ago, the major concern with regard to cardiovascular side effects related to their potential to increase blood pressure and cause salt and water retention, in a manner similar to conventional (nonselective) nonsteroidal antiinflammatory drugs (NSAIDs). In the short time since, wariness about these side effects has grown into widespread alarm about putative prothrombotic actions and generation of excess major cardiovascular events with these agents. See p 1024 In September 2004, safety findings of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study indicated an increase in risk for myocardial infarction and stroke among subjects randomized to rofecoxib compared with those randomized to placebo. This study had been designed to examine recurrent colonic polyps rather than cardiovascular disease end points and therefore could only be considered hypothesis generating. Subsequent data from a number of observational studies further implicated the drug’s association with arterial thromboembolic disease. As with APPROVe, no single study generated sufficiently robust attestation by itself, but they provided concordant signals, and the accumulating evidence eventually reached a critical mass. As the data on rofecoxib emerged, concerns about other COX-2–selective agents on the market also grew. This was based on the assumption of a “class effect” for an increase in risk of cardiovascular disease related to preferential inhibition of prostacyclin over thromboxane and thus a tendency toward prothrombosis. The results presented by McAdam and colleagues in this issue of Circulation 1 challenge our view with regard to this prostanoid hypothesis and raise new questions about the mechanisms underlying the potential cardiovascular side effects of coxibs and traditional NSAIDs. The authors hypothesized that the enhanced systemic biosynthesis of prostacyclin in smokers was dependent on COX-2 activity. They also sought to determine the functional importance of COX2–derived prostacyclin (PGI2) in limiting platelet activation in smokers in vivo. Contrary to the conventional wisdom of an expected increase in the biosynthesis of TxA2 (related to increased platelet activation via COX-1), the authors demonstrated the opposite finding—ie, that COX-2 contributed to, and a COX-2 inhibitor reduced, TxA2 biosynthesis in smokers.

Valdecoxib Withdrawal Leaves Pain Relief Treatment Gap

Valdecoxib Withdrawal Leaves Pain Relief Treatment Gap

Celecoxib associated with lower rate of renal dysfunction compared to nonspecific inhibitor NSAIDs

Both the COX-1 and COX-2 isoforms are expressed by the human kidney and vasculature. Therefore, it is important to evaluate the renovascular effects of COX-2 specific inhibitors and NSAIDs, particularly in patients with preexisting renal dysfunction. The Celecoxib Long-term Arthritis Safety Study (CLASS) assessed gastrointestinal outcomes associated with supratherapeutic doses of the COX-2 specific inhibitor celecoxib (400mg bid), and standard doses of NSAIDs, ibuprofen (800mg tid) and diclofenac (75mg bid), in patients with rheumatoid arthritis (RA) or osteoarthritis (OA). The trial's full database provided a large cardiorenal database for studying renal-related adverse events associated with nonspecific NSAIDs and celecoxib. Complete methods and gastrointestinal and cardiovascular results are published elsewhere. Enrolled patients had a serum creatinine ≤1.5mg/dL reflecting normal renal function. Renal function was assessed in all patients including those with mild prerenal azotemia defined by a baseline blood urea nitrogen (BUN) level of >20mg/dL. The renovascular effects measured in these patients were clinically important reductions in renal function (defined as an increase in serum creatinine >0.5mg/dL from baseline) and mean serum creatinine/estimated creatinine clearance. In patients with mild prerenal azotemia significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.4%) compared with either diclofenac (8.3%;P ≤0.05) or ibuprofen (7.7%;P ≤0.05). In patients with mild renal compromise, celecoxib was associated with a significantly lower rate of renal dysfunction at supratherapeutic doses compared with diclofenac and ibuprofen at standard doses. These data suggest that celecoxib may be a more suitable alternative to treat chronic pain and inflammation than nonspecific NSAIDs in patients with compromised renovascular function. (See Table) *P ≤ 0.05; ANCOVA, Fisher's exact test *P ≤ 0.05; ANCOVA, Fisher's exact test

Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo

Data indicate that cyclooxygenase-2-specific inhibitors cause less gastroduodenal mucosal damage than nonspecific NSAIDS, but their effects on the small bowel mucosa are less well recognized. In a multicenter, double-blind, placebo-controlled trial with video capsule endoscopy (VCE) we prospectively evaluated the incidence of small bowel injury in healthy subjects treated with celecoxib compared to naproxen plus omeprazole. We randomly assigned subjects with normal baseline VCEs to celecoxib 200 mg twice daily (n = 120), naproxen 500 mg twice daily plus omeprazole 20 mg once daily (n = 118), or placebo (n = 118) for 2 weeks. The primary end point was the mean number of small bowel mucosal breaks per subject. Baseline VCE found small bowel lesions in 13.8% (57/413) of screened subjects, who became ineligible for randomization. The mean number of small bowel mucosal breaks per subject and the percentage of subjects with these mucosal breaks were 2.99 +/- 0.51, 55% for naproxen/omeprazole compared to 0.32 +/- 0.10, 16% for celecoxib and 0.11 +/- 0.04, 7% for placebo (P < .001, both comparisons). The magnitude of the difference between celecoxib and placebo was small but statistically significant (P = .04). Among healthy subjects with lesion-free baseline VCEs, celecoxib was associated with significantly fewer small bowel mucosal breaks than naproxen plus omeprazole. This study also showed that the background incidence of small bowel lesions in healthy adults is not insignificant and should be considered in future trials with VCE.

Arthritis Medicines and Cardiovascular Events—“House of Coxibs”

PHYSICIANS, PATIENTS, AND THE GENERAL PUBLIC ARE confronted with an acute confusional state regarding the cardiovascular safety of medicines for arthritis. Since September 30, 2004, the day that rofecoxib was precipitously withdrawn, there has hardly been a day without significant news on the general topic of cyclooxygenase 2 (COX-2) inhibitors. On December 9, 2004, the US Food and Drug Administration (FDA) issued a black box warning for valdecoxib for life-threatening skin reactions and cardiovascular risk. Just over a week later, on December 17, 2004, the National Cancer Institute announced the premature cessation of a trial of celecoxib known as Adenoma Prevention with Celecoxib (APC) due to a significant excess of cardiovascular death, myocardial infarction (MI), and stroke. The principal cardiovascular event data for APC are summarized in the FIGURE. This was a trial of 2026 patients, with randomization to 1 of 3 groups: placebo; celecoxib, 200 mg twice daily; or celecoxib, 400 mg twice daily. The patients, each of whom had an adenomatous polyp removed before enrollment, were followed up for a mean of 33 months (of a planned 60 months) while taking the study drug, with the primary objective of limiting the development of colorectal cancer. A significant excess of major cardiovascular events was demonstrated, with a dose-response effect (odds ratio, 2.5 for celecoxib 400-mg dose, and 3.4 at the 800-mg dose, vs placebo) (Figure). The absolute excess of major cardiovascular events of 13/1000 patients at the 400-mg dose and 21/1000 patients at the 800-mg dose is similar in magnitude to the results of trials with rofecoxib and valdecoxib. However, it is not possible to meaningfully interpret interdrug differences because the patient populations in the various trials were different; the drug doses, strength, and duration of therapy were different; and each of the drugs in the coxib class are distinct molecules with specific biological properties. While celecoxib is the least COX-2 selective in the class of 5 agents that have gone through pivotal trials, lumiracoxib is the most selective. A trial of 18325 patients, the largest in the field, demonstrated only modest (not statistically significant) excess of cardiovascular risk when lumiracoxib was compared with naproxen, but not when compared with ibuprofen. Importantly, there have not been any direct comparative (head-to-head) trials of one of the agents vs another, which is the only way to definitively establish likeness or difference between the drugs. Notwithstanding these concerns, several epidemiologic studies have considered large populations of patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors. In general, these studies found an increased cardiovascular hazard for rofecoxib, especially at higher doses, but not for celecoxib. Some studies therefore concluded that celecoxib did not carry any risk for MI or stroke. But in randomized trials, a signal for potential cardiovascular risk with celecoxib was present. As my colleagues and I described in a 2001 review of the Celecoxib Long-term Arthritis Safety Study (CLASS), the MI rate was 1.6% in the celecoxib group (at a dosage of 400 mg twice per day) and 1.2% in the diclofenac or ibuprofen group for the 1739 patients taking low-dose aspirin. This numerical excess, albeit not statistically significant, was also found in the 6229 Figure. Event Rates of Cardiovascular Death, Myocardial Infarction, and Stroke in the Adenoma Prevention With Celecoxib (APC) Trial

Are All COX-2 Inhibitors Created Equal?

Prostaglandins (PGs) are biologically active lipids derived from the cyclooxygenase (COX)-mediated metabolism of arachidonic acid. They are constitutively produced in certain tissues (eg, brain, gut, and kidney), and their synthesis is increased at sites of inflammation. Prostanoids function as important mediators of inflammation and modulate a variety of physiological processes, including maintenance of gastric mucosal integrity, renal hemodynamic regulation, renin synthesis and release, and tubular reabsorption of salt and water.1 Cyclooxygenase, or PG synthase G2/H2, is the rate-limiting enzyme responsible for the initial conversion of arachidonic acid to PGG2 and subsequently to PGH2. PGH2 is then metabolized by tissue-specific isomerases to produce prostaglandins and thromboxanes. There are 2 distinct isoforms of cyclooxygenase, COX-1 and COX-2, which share 66% homology in amino acid sequence 2–4 but have different patterns of expression and regulation. COX-1, traditionally termed the “constitutive” enzyme, is widely distributed in tissues, and its level of activity is not dynamically regulated. COX-2, the glucocorticoid-sensitive “inducible” enzyme, is more restricted in its basal expression and is upregulated in response to inflammation, resulting in increased prostanoid production at the site of inflammation. NSAIDs, which block both isoforms COX-1 and COX-2, have been widely used in the treatment of inflammatory conditions. However, the adverse effects of NSAIDs, especially gastrointestinal toxicity, have limited their long-term use in clinical settings. The hypothesis that NSAID-induced gastrointestinal toxicity was related to the inhibition of gastric COX-1, whereas the anti-inflammatory properties caused by COX-2 inhibition5 led to the development of the new antiinflammatory agents, the coxibs, which were designed to inhibit COX-2 selectively. It was anticipated that these selective COX-2 inhibitors would be as effective as the nonselective NSAIDs in the treatment of inflammatory diseases but would be better-tolerated with fewer gastrointestinal side effects. Rofecoxib (Vioxx) and celecoxib (Celebrex) were the first COX-2–selective inhibitors to be marketed as effective antiinflammatory agents without serious gastrointestinal toxicity, based on the results of the VIoxx Gastrointestinal Outcomes Research (VIGOR) trial6 and the Celecoxib Long term Arthritis Safety Study (CLASS) trial, 7 respectively. The VIGOR trial reported that patients with rheumatoid arthritis receiving rofecoxib (50 mg daily) had fewer gastrointestinal events compared with those taking naproxen (500 mg twice daily) (2.1% versus 4.5%; P0.001), but there was similar efficacy between the drugs. However, the incidence of myocardial infarction was increased by a factor of 5 in the rofecoxib-treated group compared with the naproxen group. In the CLASS trial, celecoxib (400 mg twice daily) was compared with ibuprofen (800 mg thrice daily) or diclofenac (75 mg twice daily) in patients with osteoarthritis or rheumatoid arthritis. Celecoxib had a lower gastrointestinal side effect profile compared with other NSAIDs, and there was no difference in the incidence of cardiovascular events between celecoxib and NSAIDs regardless of aspirin use. Questions regarding the cardiovascular risk of the various coxibs remained, and on September 30, 2004 rofecoxib was withdrawn from the market based on the data from the Adenomatous Polyp PRevention On Vioxx (APPROVe) study. 8 This trial was prematurely discontinued after it was discovered that 3.5% of the patients treated with rofecoxib (25 mg once daily) had serious thromboembolic adverse events compared with 1.9% of patients in the placebo group (P0.001).8,9 The

Letters To The Editor

Journal of Pharmacy Practice and ResearchVolume 33, Issue 2 p. 157-160 LettersFree Access Letters To The Editor First published: 01 June 2003 https://doi.org/10.1002/jppr2003332157AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References 1Silverstein 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. 2Bombardier 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. 3Cutts C, LaCaze AB, Tett S. Audit of selective and non-selective non-steroidal anti-inflammatory drug use in rural general practice. J Pharm Pract Res 2003; 33: 70– 3. 4Slader CA, Welch SA. Audit of celecox.ib and rofecoxib use: St Vincent-s Public Hospital, Darlinghurst. J Pharm Pract Res 2003; 33: 74– 7. 5Graudins LV, Gazarian M. Celecoxib use and overuse-too much celebration? J Pharm Pract Res 2002; 32: 104– 7. 6New South Wales Therapeutic Assessment Group Incorporated. COX-2 inhibitors - the evidence. Position statement, Darlinghurst, New South Wales, January 2001, <www.clininfo.health.nsw.gov.au/nswtag/publications/>. 7Graudins LV. COX-2 Inhibitor use and overuse .. the DUE cycle turns. Proceedings of The Society of Hospital Pharmacists NSW Branch Conference; 2002 Oct 25–27; Leura, NSW. Sydney, NSW: The Society; 2002 . 8National Prescribing Service Ltd. NPS News 18. Osteoarthritis-have COX-2s changed its management? Surry Hills, NSW, October 2001 , <www.nps.org.au>. 9Victorian WorkCover Authority. Handling cytotoxic drugs in the workplac e. 1st edition. Melbourne: The Authority; 2003. 10Rodriquez P, Yap CY. Abnormal blood results found in pharmacists preparing cytotoxics. \Letter] Aust J Hosp Pharrn 1991; 21: 39. Volume33, Issue2June 2003Pages 157-160 ReferencesRelatedInformation

Breast cancer chemoprevention: additional observations

We would like to comment on Salih and Fentiman's considered and timely review of breast cancer chemoprevention.1 Firstly, the preliminary results of the International Breast Intervention Study-l (IBIS-l) have now been presented.2 With a median follow-up of 50 months, a 33% reduction in breast cancer incidence was observed in the tamoxifen-treated group. The greatest risk reduction was observed in patients with ductal carcinoma in situ and was confined to patients with oestrogen-receptor positive tumours. Tamoxifen use was associated with a significant increase in the incidence of venous thromboembolism and endometrial carcinoma, and a 2.5 fold increase in mortality from all causes. These results are of some concern, as apart from confirming the significant morbidity of tamoxifen therapy, they suggest that chemoprevention will need to be individualised to specific subgroups of patients. Lack of individualisation of therapy could explain the apparent non-significant effect observed during the fenretinide trial3 quoted by the authors. It is likely retinoids exert their anti-cancer activity by modifying the IGF-l/IGFBP-3 system.4 This effect may be genetically determined. AA-type individuals, for example, produce high levels of IGFBP-3 in response to retinoids,5 so it is possible that these women, who may have derived significant benefit from retinoids, were not represented with significant power in the Veronesi study. Regarding the newer candidates for chemoprevention, there is now considerable evidence to demonstrate overexpression of COX-2 in breast cancer, and a role for cyclo-oxygenase inhibitors in treatment.6, 7 A recent meta-analysis8 described a risk reduction in breast cancer incidence of 20% with the use of NSAIDs. While it might be attractive to minimise the adverse sequelae of COX-1 suppression by using selective COX-2 inhibition, concern has recently been raised regarding the toxicity profile of COX-2 inhibitors. Reappraisal of the original celecoxib long term arthritis safety study (CLASS) data uncovered flaws in the original study design.9 Revised data now indicate that COX-2 inhibitors may have a similar incidence of ulcer complications to traditional NSAIDs. COX-1 overactivity is also present in some breast cancers,10, 11 and experimental studies with COX-1 or COX-2 null cells have shown prostaglandin levels remain high in the cells, because of increased transcription of the remaining functional gene.12 Although there are many remaining questions regarding the application of COX-suppression in breast cancer, it is possible that some will be answered with carefully planned randomised controlled clinical trials. The significant challenge for the future will, however, reside in identifying chemoprevention strategies that will provide the most benefit for individual patients, particularly those with oestrogen-receptor negative disease.

Current perspective on the cardiovascular effects of coxibs.

Aspirin and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory and analgesic effects. In addition, aspirin is documented to reduce cardiovascular events in selected populations, presumably because of inhibition of platelet aggregation. Yet these drugs are not without toxicity, particularly adverse effects on the gastric mucosa. The gastrointestinal toxicity of nonselective NSAIDs and aspirin derives from the inhibition of the cyclooxygenase (COX) enzyme, COX-1, which synthesizes gastroprotective prostaglandins, while the anti-inflammatory and pain-relieving effects are largely derived from inhibition of COX-2-derived prostaglandins. Available data indicate that the harmful gastric effects of nonselective NSAIDs are reduced by substitution of agents that only inhibit the COX-2 protein. The COX-2-selective inhibitors, however, have also been shown to inhibit the production of vascular prostacyclin, which has vasodilatory effects and inhibits platelet aggregation; unlike nonselective NSAIDs, they do not inhibit the production of thromboxane, an eicosanoid that promotes platelet aggregation. Whether these effects could potentially contribute to a prothrombotic environment is the subject of current, intensive debate. In the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, there was a higher incidence of cardiovascular thrombotic events in the rofecoxib- vs the naproxen-treated group: 1.67 vs 0.70 per 100 patient years. However, in a pooled analysis of rofecoxib studies, the risk of sustaining a thrombotic cardiovascular event was similar when comparing patients receiving rofecoxib with those receiving placebo, or when comparing patients receiving rofecoxib with those receiving nonnaproxen nonselective NSAIDs. These findings are likely to result, at least in part, from the antiplatelet action of naproxen, which has been shown to be potent and sustained during a typical dosing regimen (500 mg twice daily in VIGOR). In contrast, the other NSAID comparators effect weaker and/or nonsustained antiplatelet action. In the Celecoxib Long-term Arthritis Safety Study (CLASS) trial, there was no difference between celecoxib and the nonselective NSAIDs explored (which did not include naproxen) in cardiovascular event rates. Unlike those in VIGOR, patients in the CLASS trial were allowed to take low-dose aspirin. Thus, despite concerns raised by results of VIGOR, other existing data, including those pooled from existing placebo-controlled trials, do not support a clinically relevant prothrombotic effect of the COX-2 inhibitors. Additional placebo-controlled data, from patients at both high and low risk for cardiovascular events, are warranted to clarify the cardiovascular effects of this class of agents.