Naurang M. Agrawal

Reduced risk of upper gastrointestinal ulcer complications with celecoxib, a novel COX-2 inhibitor.

OBJECTIVE:The aim of this study was to assess the rate of upper gastrointestinal (UGI) ulcer complications (bleeding, perforation, or gastric outlet obstruction) associated with celecoxib, a specific COX-2 inhibitor, compared with the rate associated with nonspecific, nonsteroidal anti-inflammatory drugs (NSAIDs).METHODS:A pooled analysis was conducted of 14 multicenter, double-blind, randomized, controlled trials (RCTs) and a separate analysis of one long-term open label trial that assessed the efficacy and safety of celecoxib for symptomatic treatment of arthritis. The RCTs enrolled 11,008 patients with osteoarthritis or rheumatoid arthritis treated for 2–24 wk; the long-term open label trial enrolled 5,155 patients receiving celecoxib for a maximum of 2 yr. In the RCTs, patients were randomly assigned to receive placebo (n = 1,864; 208 patient-years), celecoxib 25–400 mg b.i.d. (n = 6,376; 1,020 patient-years), or a comparator NSAID (n = 2,768; 535 patient-years); NSAIDs were naproxen 500 mg b.i.d., diclofenac 50 or 75 mg b.i.d., or ibuprofen 800 mg t.i.d.). In the long-term, open-label trial, patients received celecoxib 100–400 mg b.i.d. for up to 2 yr (n = 5,155; 5,002 patient-years). The principal outcome measure of this analysis was development of a UGI ulcer complication, which was prospectively defined as bleeding, perforation, or gastric outlet obstruction. Ulcer complications were assessed and adjudicated by persons blinded to the patients treatment assignment or the study in which the patient participated.RESULTS:In the RCTs, UGI ulcer complications occurred in no placebo patients (0 of 1,864 patients), in 2 of 6,376 celecoxib patients (0.03%), and in 9 of 2,768 patients receiving an NSAID (0.33%), corresponding to annual incidences of 0.20% for celecoxib (p > 0.05vs placebo) and 1.68% for NSAIDs (p = 0.002vs celecoxib and placebo). In the long-term open-label trial, nine UGI ulcer complications occurred, for an incidence of 0.17% and an annualized incidence of 0.18%.CONCLUSIONS:The incidence of UGI ulcer complications associated with celecoxib was 8-fold lower than with nonspecific NSAIDs. The incidence of ulcer complications observed in celecoxib-treated patients was similar to that in patients receiving placebo in the RCTs, and to that in non-NSAID users reported in the literature.

Incidence of gastroduodenal ulcers associated with valdecoxib compared with that of ibuprofen and diclofenac in patients with osteoarthritis.

Objective To determine whether valdecoxib, at chronic arthritis doses, has the characteristics of a cyclo-oxygenase 2 (COX-2) specific inhibitor, as measured by a reduced incidence of upper-gastrointestinal ulceration compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Methods This double-blind, multicentre, placebo-controlled, parallel-group study compared the incidence of gastroduodenal ulcers associated with valdecoxib 10 mg daily (q.d.) and 20 mg q.d. with that of ibuprofen 800 mg three times daily (t.i.d.) or diclofenac 75 mg twice daily (b.i.d.) when administered over a 12-week period. The incidence of gastroduodenal ulcers was assessed by upper-gastrointestinal endoscopy, performed at baseline and again at the end of week 12 (or at early study termination). Efficacy assessments were performed at baseline and at weeks 2, 6 and 12 using Patients and Physicians Global Assessments of Arthritis. Results A total of 1052 osteoarthritis patients were enrolled into the trial. The incidence of gastroduodenal ulcers over 12 weeks was 5% in patients receiving valdecoxib 10 mg q.d., 4% in patients receiving valdecoxib 20 mg q.d., 7% in patients receiving placebo, 16% in patients receiving ibuprofen 800 mg t.i.d. (P < 0.05 v. placebo), and 17% in patients receiving diclofenac 75 mg b.i.d. (P < 0.05 v. placebo). The incidence of gastroduodenal ulcers at week 12 seen in the ibuprofen 800 mg t.i.d. and diclofenac 75 mg b.i.d. groups was significantly higher than that in the valdecoxib 10 mg q.d. and valdecoxib 20 mg q.d. groups (P < 0.05). The incidence rates of gastroduodenal ulcers were not significantly different between the valdecoxib treatment groups or between valdecoxib- and placebo-treated patients. Efficacy responses to valdecoxib 10 mg and 20 mg q.d. were significantly greater than placebo and comparable with both ibuprofen 800 mg t.i.d. and diclofenac 75 mg b.i.d. Conclusions The results of the study demonstrate that valdecoxib has an upper-gastrointestinal safety profile typical of a COX-2 specific inhibitor. Overall, the data indicate that administration of valdecoxib offers similar efficacy for the treatment of osteoarthritis but improved upper-gastrointestinal safety compared with the conventional NSAIDs, ibuprofen and diclofenac, based on the significantly lower incidence of gastroduodenal ulcers detected by endoscopy.

Reduced incidence of upper gastrointestinal ulcer complications with the COX-2 selective inhibitor, valdecoxib.

Aim : In a predefined analysis, data were pooled from eight blinded, randomized, controlled trials, and separately from three long‐term, open‐label trials to determine the rate of upper gastrointestinal ulcer complications with the cyclo‐oxygenase‐2 selective inhibitor, valdecoxib, vs. non‐selective non‐steroidal anti‐inflammatory drugs.

Comparison of the upper gastrointestinal safety of arthrotec® 75 and nabumetone in osteoarthritis patients at high risk for developing nonsteroidal anti-inflammatory drug-induced gastrointestinal ulcers

A 6-week, multicenter, double-masked, placebo-controlled, parallel-group study compared the upper gastrointestinal (UGI) safety of Arthrotec 75 (diclofenac sodium 75 mg-misoprostol 200 microg; G.D. Searle & Co., Skokie, Illinois) administered twice daily with that of nabumetone 1500 mg administered once daily in 1203 patients with symptomatic osteoarthritis (OA) of the hip or knee. All patients had a documented clinical history of endoscopically confirmed gastric, pyloric-channel, or duodenal ulcer or > or = 10 erosions in the stomach or duodenum. UGI endoscopy was performed at baseline and again at week 6 or early withdrawal. Treatment with Arthrotec 75 resulted in a significantly lower combined incidence of endoscopically confirmed gastric and duodenal ulcers compared with nabumetone (4% vs 11%), and its rate of endoscopically confirmed ulceration was equivalent to that of placebo. The incidence of gastric ulcers alone was also significantly lower with Arthrotec 75 than with nabumetone (1% vs 9%). The incidence of duodenal ulcer with Arthrotec 75 was not significantly different from that with nabumetone (4% vs 3%). Types of adverse events were similar for all treatment groups, with GI adverse events predominating. Arthrotec 75 was well tolerated by the majority of patients. The results of this study demonstrate that Arthrotec 75 has a superior UGI safety profile, causing significantly fewer UGI ulcers, in comparison with nabumetone in patients with symptomatic OA and a documented history of ulcers or > or = 10 erosions.

M1333 Irritable Bowel Syndrome and the Association With Small Intestinal Bacterial Overgrowth: Putting the Concept in Perspective

Aim: To explore triggers and warning sensations that precede diarrhea and how individuals make use of these. Methods: 579 individuals (68.6% female; ages 19-71, mean=30.5) with recurring diarrhea completed an internet survey including the Rome III diagnostic functional bowel disorders modules and a detailed questionnaire asking about diarrhea history, triggers, warning sensations and self-management. Individuals with inflammatory bowel disease, celiac disease, lactose intolerance or GI surgery history were excluded. Results: Most respondents (90.7%) had diarrhea at least 2-3 times per month. 23.7% had consulted health care providers about diarrhea. 70.5% met Rome III irritable bowel syndrome criteria but only 0.3% met functional diarrhea criteria. Diarrhea was self-defined by survey respondents, and typically considered to be characterized by loose/watery stools (92.5%), urgency (56.4%), pain/ discomfort (40.2%) and frequent stools (35.3%). 79.8% of subjects reported specific diarrhea triggers (i.e., actions or experiences they knew might result in diarrhea), and 44.0% stated that diarrhea resulted half or more of the times that these triggers occurred. Most common triggers were specific foods or drinks (72.3% of subjects), especially high-fat or spicy foods or caffeine beverages; stress/anxiety (49.7%); and large meals (25.2%). 83% of subjects with triggers rated stress/anxiety as the most frequent trigger. Nearly all subjects (95.6%) reported one or more types of physical warning sensations in advance of diarrhea, usually the same in nature for each subject and generally first occurring 10-25 minutes before diarrhea. The earliest warnings were typically either pain/discomfort (44.6%) or rumbling/bowel sounds (29.1%). 84.9% reported doing nothing to prevent or diminish diarrhea after warning sensations, but 15.1% used anti-diarrheal or antispasmodic drugs to counter the anticipated diarrhea. 74.4% used no medication once diarrhea started, 9.9% took medication early after onset, and 13.3% only later if it did not stop on its own. Warning sensations preceded at least half of all diarrhea bowel movements for 84.5% of subjects. Conclusions: Recognizable triggers and warning sensations precede diarrhea in most individuals, but few make efforts to prevent anticipated diarrhea. [Supported by McNeil Consumer Healthcare and R24 DK067674]

Celecoxib is associated with fewer gastrointestinal (GI) symptoms than nonsteroidal anti-inflammatory drugs (NSAIDs): implications for ulcer complications

Celecoxib is associated with fewer gastrointestinal (GI) symptoms than nonsteroidal anti-inflammatory drugs (NSAIDs): implications for ulcer complications