Factors associated with treatment delays in pediatric refractory convulsive status epilepticus.

OBJECTIVE: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). METHODS: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. RESULTS: We studied 219 patients (53% males) with a median (25th-75th percentiles [p25-p75]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25-p75) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. CONCLUSION: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Cyclo-oxygenase-2 inhibitors or nonselective NSAIDs plus gastroprotective agents: what to prescribe in daily clinical practice?

BACKGROUND: Two strategies for prevention of upper gastrointestinal (UGI) events for nonselective nonsteroidal anti-inflammatory drug (nsNSAID) users are replacement of the nsNSAID by a cyclo-oxygenase-2-selective inhibitor (coxib) or co-prescription of a gastroprotective agent (GPA). AIM: To identify whether and in whom either of these strategies should be preferred in daily practice. METHODS: A nested case-control study was conducted using three European primary care databases. We selected a cohort including all naive nsNSAID+GPA (≥80% GPA adherence) and coxib users (without GPA use) aged ≥50 years. Cases with an UGI event (i.e. symptomatic UGI ulcer or bleeding) were matched to cohort members without an UGI event on age, sex and number of individual UGI risk factors (i.e. UGI event history, age ≥65 years, concomitant use of anticoagulants, antiplatelets, or glucocorticoids) and calendar time. Conditional logistic regression analysis was used to calculate odds ratios (ORs) with 95% CI, while adjusting for potential confounders. RESULTS: Within the NSAID cohort (n = 617,220), 398 UGI cases were identified. The risk of UGI events was equivalent for coxib and nsNSAID+GPA (≥80% adherence) users (OR: 1.02; 95%CI: 0.77-1.37). In concurrent glucocorticoid users, the risk of UGI events was significantly elevated for nsNSAID+GPA (≥80% adherence) compared with coxib users (OR: 9.01; 95%CI: 1.61-50.50). CONCLUSIONS: The risk of UGI events was similar in nsNSAID+GPA (≥80% adherence) and coxibs users. In patients concurrently using glucocorticoids, a significant increase in the risk of UGI events for nsNSAID+GPA users was observed and coxibs should be preferred.

Risk factors associated with a decrease ≥2 g/dL in haemoglobin and/or ≥10% haematocrit in osteoarthritis patients taking celecoxib or a nonselective NSAID plus a PPI in a large randomised controlled trial (CONDOR).

BACKGROUND: Nonsteroidal anti-inflammatory drugs are associated with gastrointestinal (GI) damage. The Celecoxib vs. Omeprazole and Diclofenac for At-Risk Osteoarthritis and Rheumatoid Arthritis Patients (CONDOR) trial showed that a haemoglobin drop ≥2 g/dL adjudicated as either of defined or presumed GI origin was the most frequent component/event for the composite GI primary end point. This adverse event is potentially clinically relevant in long-term NSAID treatment. AIM: To define potential risk factors associated with a decrease in haemoglobin/haematocrit. METHODS: Post hoc analysis of the CONDOR trial was conducted in the intention-to-treat population. Clinically significant blood loss was defined as: (i) a haemoglobin drop ≥2 g/dL and/or a haematocrit drop ≥10%; and (ii) blood loss adjudicated as either of defined or presumed GI origin. Fifteen risk factors were evaluated by stepwise logistic regression. Each factor had to be significant at <0.20 α to be included in the model. RESULTS: A total of 64/3774 (1.7%) osteoarthritis (OA) patients had decreased haemoglobin/haematocrit and were adjudicated to the GI endpoint. Significant risk factors, at the 0.20 α level found to be associated with clinically significant blood loss in OA patients included [odds ratio (80% CI)] baseline C-reactive protein (CRP) levels [2.27 (1.46-3.53)], history of gastritis and history of GI intolerance [1.55 (1.06-2.28)], positive Helicobacter pylori at screening [1.54 (1.07-2.22)], increasing age [1.17 (1.04-1.32)] and body mass index [BMI; 1.03 (1.00-1.06)]. CONCLUSIONS: Monitoring for decreases in haemoglobin should be considered for all OA patients and especially those with an increased age, BMI, history of gastritis and GI intolerance, CRP levels >1 mg/dL and/or positive H. pylori status, as this may affect their clinical management.

Does concomitant use of paracetamol potentiate the gastroduodenal mucosal injury associated with aspirin? A prospective, randomised, pilot study.

BACKGROUND: Paracetamol is commonly prescribed for first-line symptomatic treatment in patients with osteoarthritis and aspirin is often co-administered for cardiovascular prophylaxis. It is not known if an interaction exists between aspirin and paracetamol in regards to gastroduodenal mucosal injury. AIM: To investigate whether or not co-administered aspirin with paracetamol results in an increased rate of endoscopic gastroduodenal mucosal injury as compared to either agent alone. METHODS: In this prospective, double-blind, randomised, three-arm, placebo- and active-controlled, parallel-group pilot study healthy adult subjects (18-75 years old) with a normal baseline trans-nasal oesophagogastroduodenoscopy (TN-EGD), received oral paracetamol 4000 mg q.d.s. (n = 21), aspirin 325 mg q.d.s. (n = 19) or paracetamol 4000 mg q.d.s. and aspirin 325 mg q.d.s. (n = 20). Upper gastrointestinal mucosal injury was evaluated after 7 days of treatment with TN-EGD. RESULTS: The rate of gastric ulcers in subjects receiving paracetamol (0/21, 0%) alone or aspirin (3/19, 16%) or both (2/20, 10%) was not different. There were, however, significantly more subjects with one or more lesions (erosion or ulcer) per subject in the paracetamol and aspirin (16/20, 80%) treated subjects as compared to the aspirin (8/19, 42%, P < 0.001) or the paracetamol (3/21, 14%, P < 0.01) exposed subjects. The mean number of lesions per subject was also greater (7.9 vs. 0.7, P < 0.01) in those treated with aspirin and paracetamol compared to paracetamol alone. CONCLUSIONS: Co-administration of paracetamol and aspirin was not associated with a significant difference in endoscopic ulcer rates compared to either drug alone. There was a strong signal for increased endoscopic erosions and ulcers in the combined group compared to either aspirin or paracetamol alone.

Vertebral fracture efficacy during risedronate therapy in patients using proton pump inhibitors.

UNLABELLED: Recent evidence suggests that proton pump inhibitor (PPI) use may affect fracture risk, an important issue for patients being concurrently treated for osteoporosis. The results of our post hoc analysis showed that, regardless of PPI concomitant use, risedronate significantly reduced the risk of new vertebral fractures compared with placebo. INTRODUCTION: Recent evidence suggests that PPI use may affect fracture risk, an important issue for patients being concurrently treated for osteoporosis. Moreover, data suggest that concomitant use of PPIs may wane the anti-fracture effect of bisphosphonates. We explored the relationship between concomitant use of PPIs and incident vertebral fractures among patients treated with risedronate or placebo. Bone mineral density (BMD) and upper gastrointestinal (UGI) adverse events (AEs) were also assessed. METHODS: This study is a post hoc analysis of a subset of patients participating in three prospective, randomized, placebo-controlled clinical trials, with durations of up to 3 years, which evaluated the efficacy of risedronate in reducing fracture risk: Vertebral Efficacy with Risedronate Trial-MultiNational (VERT-MN); Vertebral Efficacy with Risedronate Trial-North America (VERT-NA); and the risedronate Hip Intervention Program (HIP). RESULTS: Total enrollment included 2,729 risedronate and 2,725 placebo patients. Concomitant acid-suppressing drugs were used by 8.8% of the total population (n = 482). Regardless of PPI concomitant use, risedronate significantly reduced the risk of new vertebral fractures compared with placebo (risk reduction: PPI users 57%, p = 0.009; PPI non-users 38%, p < 0.001). BMD increased with risedronate, independent of PPI use. PPI users were at a 2.5-fold greater risk of experiencing at least one UGI AE compared with non-users. CONCLUSIONS: Risedronate significantly reduced the risk of new vertebral fractures compared with placebo, regardless of PPI concomitant use.

Haemoglobin decreases in NSAID users over time: an analysis of two large outcome trials.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with clinically significant decreases in haemoglobin dependent and independent of acute bleeding events. AIM: To evaluate the incidence and time to a clinically meaningful decrease in haemoglobin in two double-blind, prospective randomised clinical trials comparing NSAIDs in patients with osteoarthritis (OA) or rheumatoid arthritis (RA). METHODS: In CLASS, patients with OA/RA who were aged ≥ 18 years and required continuous NSAID treatment were included; patients who were Helicobacter pylori positive and/or using aspirin were not excluded. In contrast, in the CONDOR trial, comparing celecoxib alone to diclofenac sustained release (plus omeprazole), patients were aged ≥ 60 years or ≥ 18 years with a history of gastroduodenal ulcer and were H. pylori negative; aspirin or other anti-platelet users were excluded. To make a parallel post hoc analysis we limited our study to 6 months and the populations to only the non-aspirin users in CLASS and those patients receiving either celecoxib or diclofenac. A decrease in haemoglobin of ≥ 2 g/dL defined the primary end point. RESULTS: At 6 months, in the CLASS and CONDOR trials, 1.9% and 2.0% of patients treated with celecoxib and 3.3% and 5.7% of patients treated with diclofenac developed a ≥ 2 g/dL decrease in haemoglobin, respectively, [CLASS: odds ratio (OR) 1.80 (95% confidence interval (CI), 1.22-2.65) and CONDOR: OR 2.93 (95% CI, 2.06-4.15), respectively]. CONCLUSION: IN these two large, independent trials, clinically-meaningful decreases in haemoglobin ≥ 2 g/dL occurred in a relatively similar fashion over time despite differences in trial designs.

Surviving starvation: essential role of the ghrelin-growth hormone axis.

After brief starvation, vertebrates maintain blood glucose by releasing fatty acids from adipose tissue. The fatty acids provide energy for gluconeogenesis in liver and are taken up by muscle, sparing glucose. After prolonged starvation, fat stores are depleted, yet blood glucose can be maintained at levels sufficient to preserve life. Using a new mouse model, we demonstrate that survival after prolonged starvation requires ghrelin, an octanoylated peptide hormone that stimulates growth hormone (GH) secretion. We studied wild-type mice and mice lacking ghrelin as a result of knockout of GOAT, the enzyme that attaches octanoate to ghrelin. Mice were fed 40% of their normal intake for 7 d. Fat stores in both lines of mice became depleted after 4 d. On day 7, mice were fasted for 23 h. In wild-type mice, ghrelin and GH rose massively, and blood sugar was maintained at ~60 mg/dL. In Goat(-/-) mice, ghrelin was undetectable and GH failed to rise appropriately. Blood sugar declined to ~20 mg/dL, and the animals were moribund. Infusion of ghrelin or GH prevented hypoglycemia. Our results support the following sequence: (1) Starvation lowers blood glucose; (2) glucose-sensing neurons respond by activating sympathetic neurons; (3) norepinephrine, released in the stomach, stimulates ghrelin secretion; (4) ghrelin releases GH, which maintains blood glucose. Thus, ghrelin lies at the center of a hormonal response that permits mice to survive an acute fast superimposed on chronic starvation.

Clinical trial: endoscopic evaluation of naproxen etemesil, a naproxen prodrug, vs. naproxen - a proof-of-concept, randomized, double-blind, active-comparator study.

BACKGROUND: Nonsteroidal anti-inflammatory drugs are associated with upper gastrointestinal mucosal injury. Naproxen etemesil is a lipophilic, non-acidic, inactive prodrug of naproxen that is hydrolysed to pharmacologically active naproxen once absorbed. We hypothesized that with lesser topical exposure to naproxen from the prodrug, there would be reduced gastroduodenal mucosal injury compared with naproxen. AIM: To compare the degree of endoscopic mucosal damage of naproxen etemesil vs. naproxen. METHODS: This multicentre, randomized, double-blind, double-dummy trial compared oral naproxen etemesil 1200 mg twice daily (n = 61) with naproxen 500 mg twice daily (n = 59) for 7.5 days in 120 healthy subjects (45-70 years; mean 51 years; 58% female) with baseline total modified gastroduodenal Lanza score ≤ 2 (no erosions/ulcers) on endoscopy. The primary endpoint was mean total modified gastroduodenal Lanza score on day 7. A secondary endpoint was incidence of gastric ulcers. RESULTS: The day 7 mean total modified gastroduodenal Lanza score was 2.8 ± 1.7 for naproxen etemesil vs. 3.5 ± 2.0 for naproxen (P = 0.03), and significantly fewer naproxen etemesil-treated subjects (3.3%) developed gastric ulcers compared with naproxen-treated subjects (15.8%) (P = 0.02). CONCLUSION: In this first proof-of-concept study, naproxen etemesil was associated with significantly lower gastroduodenal mucosal injury compared with naproxen after 7 days of exposure ( CLINICAL TRIAL NUMBER: NCT00750243).

Clinical trial: the incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone.

BACKGROUND: Gastroprotective co-therapy may reduce the risk of nonsteroidal anti-inflammatory drug (NSAID)-associated gastric ulcers, but adherence is suboptimal. AIM: To compare the incidence of gastric ulcers with PN 400 [enteric-coated (EC) naproxen 500 mg and immediate-release esomeprazole 20 mg], or EC naproxen. METHODS: Two randomized, double-blind, multicentre studies (PN400-301, PN400-302). Patients [stratified by low-dose aspirin (< or =325 mg) use] aged > or =50 years or 18-49 years with a history of ulcer, received PN 400 BID (301, n = 218; 302, n = 210) or EC naproxen 500 mg BID (301, n = 216; 302, n = 210) for 6 months. The primary endpoint was the cumulative incidence of endoscopic gastric ulcers. RESULTS: The cumulative incidence of gastric ulcers was significantly lower with PN 400 vs. EC naproxen (301: 4.1% vs. 23.1%, P < 0.001; 302: 7.1% vs. 24.3%, P < 0.001). PN 400 was associated with a lower combined incidence of gastric ulcers vs. EC naproxen in low-dose aspirin users (n = 201) (3.0% vs. 28.4%, P < 0.001) and non-users (n = 653) (6.4% vs. 22.2%, P < 0.001). The incidence of, and discontinuations due to, upper gastrointestinal (UGI) AEs was significantly lower with PN 400 relative to EC naproxen (P < 0.01, both studies). CONCLUSIONS: PN 400 significantly reduces the incidence of gastric ulcers, regardless of low-dose aspirin use, in at-risk patients, and is associated with improved UGI tolerability relative to EC naproxen (ClinicalTrials.gov, NCT00527782).

Clinical trial: gastric acid suppression in Hispanic adults with symptomatic gastro-oesophageal reflux disease - comparator study of esomeprazole, lansoprazole and pantoprazole.

BACKGROUND: Hispanic-Americans are a rapidly growing population in the United States, yet gastro-oesophageal reflux disease (GERD) is not well studied in this population. AIM: To compare the efficacy of esomeprazole, lansoprazole and pantoprazole in suppressing gastric acid, including the area of the 'acid pocket,' in Hispanics with GERD. METHODS: In this open-label, 3-way crossover study, 83 Hispanics with symptomatic GERD were randomized to 1 of 6 possible treatment sequences of three 5-7-day dosing periods with esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg daily separated by 10-17-day washout periods. Intragastric pH was measured for 24 h using dual probes with a distal and proximal (area of the 'acid pocket') electrode. RESULTS: Esomeprazole suppressed intragastric acid (pH >4.0) significantly longer over 24 h (primary end point) compared with lansoprazole and pantoprazole (P < 0.0001), and proximal gastric acid (pH >4.0) significantly longer over 24 h compared with lansoprazole (P < 0.05) and pantoprazole (P < 0.0001). CONCLUSIONS: Esomeprazole was more effective than lansoprazole and pantoprazole in suppressing gastric acidity at both intragastric distal and proximal (area of the acid pocket) sites in Hispanics with GERD. Future studies are warranted to understand better the role of the acid pocket in GERD (Clinical trial numbers: D9612L00106; ClinicalTrials.gov: NCT00410592).

Clinical trial: healing of NSAID-associated gastric ulcers in patients continuing NSAID therapy - a randomized study comparing ranitidine with esomeprazole.

BACKGROUND: The use of non-steroidal anti-inflammatory drugs (NSAID) is associated with an increased risk of gastric ulcer (GU) development. METHODS: This multicentre, randomized, double-blind, parallel-group trial compared endoscopic healing rates at 4 and 8 weeks after treatment with oral esomeprazole 40 or 20 mg once daily, or ranitidine 150 mg twice daily, in patients with 1 baseline GU > or = 5 mm but no GUs or duodenal ulcers >25 mm in diameter who received continued cyclooxygenase-2-selective or non-selective NSAID therapies. The primary outcome was the percentage of patients in each treatment group who had no GUs at week 8. RESULTS: Four hundred and forty patients were randomized to treatment. At week 8, GU healing rates (95% CI) with esomeprazole 40 mg, esomeprazole 20 mg and ranitidine were 85.7 (79.8-91.7)%, 84.8 (78.8-90.8)% and 76.3 (69.2-83.3)%, respectively; between-group differences were not statistically significant. Week-4 GU healing rates were 70.7 (62.9-78.4)% and 72.5 (65.0-79.9)% with esomeprazole 40 and 20 mg, respectively, and were significantly higher (P < 0.01 for both doses) than those with ranitidine [55.4 (47.1-63.7)%]. CONCLUSION: In patients who require continued NSAID therapy, GU healing rates at 8 weeks numerically favoured esomeprazole but were not significantly different from ranitidine.

Small bowel mucosal injury is reduced in healthy subjects treated with celecoxib compared with ibuprofen plus omeprazole, as assessed by video capsule endoscopy.

BACKGROUND: Small bowel mucosal injury associated with non-selective non-steroidal anti-inflammatory drugs is being increasingly recognized. AIM: To evaluate the incidence of small bowel injury in healthy subjects receiving celecoxib or ibuprofen plus omeprazole using video capsule endoscopy (VCE). METHODS: Subjects with normal baseline VCE were randomly assigned to receive celecoxib 200 mg b.d., ibuprofen 800 mg t.d.s. plus omeprazole 20 mg o.d. or placebo for 2 weeks. The primary end point was mean number of small bowel mucosal breaks per subject. Secondary end points included correlation of faecal calprotectin levels with the primary outcome. RESULTS: After treatment, the mean number of small bowel mucosal breaks per subject and the percentage of subjects with mucosal breaks were 0.7/25.9% for ibuprofen/omeprazole compared with 0.2/6.4% for celecoxib and 0.1/7.1% placebo (both comparisons P < 0.001). There were no significant differences between celecoxib and placebo in any measure. Mean increases in faecal calprotectin levels were higher in subjects receiving ibuprofen/omeprazole compared with celecoxib (P < 0.001), but no correlation was determined between these levels and small bowel mucosal breaks. CONCLUSIONS: Among healthy subjects with no baseline endoscopic lesions, celecoxib was associated with significantly fewer small bowel mucosal breaks than ibuprofen/omeprazole as assessed by VCE.

Efficacy of esomeprazole for resolution of symptoms of heartburn and acid regurgitation in continuous users of non-steroidal anti-inflammatory drugs.

BACKGROUND: The use of non-steroidal anti-inflammatory drugs (NSAIDs) is often associated with upper gastrointestinal symptoms such as heartburn and acid regurgitation. AIM: To assess the efficacy of esomeprazole 20 and 40 mg for resolution of heartburn and acid regurgitation in continuous NSAIDs. METHODS: A post hoc analysis of five clinical trials was performed. Two identically designed, placebo-controlled, 4-week studies (NASA1, SPACE1) enrolled non-ulcer, NSAIDs-treated patients with upper abdominal pain, discomfort or burning. PLUTO and VENUS were identically designed, placebo-controlled, 6-month studies that enrolled patients at risk of NSAIDs-induced ulcers. Study 285 was an 8-week comparative study with ranitidine (300 mg/day) in patients with NSAIDs-induced gastric ulcers. Resolution of investigator-assessed heartburn and acid regurgitation was defined as symptom severity of 'none' in the last 7 days. RESULTS: In NASA1/SPACE1, heartburn resolved in 61% and 62% of patients taking esomeprazole 20 and 40 mg, respectively (vs. 36% on placebo, P < 0.001), and acid regurgitation resolved in 65% and 67% (vs. 48%, P < 0.001). Resolution of both symptoms was greater with esomeprazole than with placebo in PLUTO/VENUS (P

The impact of low-dose aspirin on endoscopic gastric and duodenal ulcer rates in users of a non-selective non-steroidal anti-inflammatory drug or a cyclo-oxygenase-2-selective inhibitor.

BACKGROUND: The effect of low-dose aspirin on endoscopic ulcer incidence in cyclo-oxygenase-2-selective inhibitor or non-selective non-steroidal anti-inflammatory drug users remains controversial. AIM: To compare prospectively the incidence of endoscopic ulcers in healthy subjects receiving low-dose aspirin plus celecoxib or naproxen. METHODS: In this double-blind, placebo-controlled, 1-week study, subjects (50-75 years) were randomized to receive aspirin 325 mg o.d. plus either celecoxib 200 mg o.d., naproxen 500 mg b.d., or placebo. Baseline and end of study endoscopies were performed. The primary end point was incidence of one or more gastric and duodenal ulcers. RESULTS: A lower incidence of gastric and duodenal ulcers was seen in celecoxib/aspirin-treated subjects (19%) vs. naproxen/aspirin (27%; RR: 0.63, 95% CI: 0.44-0.92). Both naproxen/aspirin and celecoxib/aspirin groups demonstrated a higher incidence of gastric and duodenal ulcers vs. placebo/aspirin (8%; RR: 3.7, 95% CI: 1.8-7.6 and RR: 2.6, 95% CI: 1.2-5.8, respectively). CONCLUSIONS: Fewer endoscopic ulcers were observed in patients treated with celecoxib/aspirin vs. naproxen/aspirin. However, celecoxib/aspirin was associated with a significantly higher incidence of gastric and duodenal ulcers than aspirin alone. Further studies are required to determine the generalizability of these findings in the aspirin users and to determine the appropriate strategy to minimize risk in susceptible patients.

Intragastric acid control in non-steroidal anti-inflammatory drug users: comparison of esomeprazole, lansoprazole and pantoprazole.

BACKGROUND: Studies to date have not directly compared the pharmacodynamic efficacies of different proton pump inhibitors in controlling intragastric acidity in patients treated with non-steroidal anti-inflammatory drugs. AIM: To compare acid suppression with once-daily esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg in patients receiving non-selective or cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drug therapy. METHODS: In this multicentre, open-label, comparative, three-way crossover study, adult patients (n = 90) receiving non-steroidal anti-inflammatory drugs were randomized to one of six treatment sequences. At the study site, patients were administered esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg for 5 days each, with a washout period of > or =10 days between each treatment. Twenty-four-hour pH testing was performed on day 5 of each dosing period. RESULTS: The mean percentage of time during the 24-h pH monitoring period that gastric pH was >4.0 was significantly greater with esomeprazole (74.2%) compared with lansoprazole (66.5%; P < 0.001) and pantoprazole (60.8%; P < 0.001), and significantly greater with esomeprazole (P < 0.05) than with the comparators regardless of whether using non-selective vs. cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drugs. CONCLUSIONS: At the doses studied, esomeprazole treatment provides significantly greater gastric acid suppression than lansoprazole or pantoprazole in patients receiving non-selective or cyclo-oxygenase-2-selective non-steroidal anti-inflammatory drugs.

Meta-analysis: upper gastrointestinal tolerability of valdecoxib, a cyclooxygenase-2-specific inhibitor, compared with nonspecific nonsteroidal anti-inflammatory drugs among patients with osteoarthritis and rheumatoid arthritis.

AIM: To compare the incidence of abdominal pain, dyspepsia and/or nausea associated with valdecoxib, nonspecific nonsteroidal anti-inflammatory drugs and placebo in patients with rheumatoid arthritis and osteoarthritis. METHODS: Data from five randomized, double-blind 12-week trials were pooled. Independent risk factors for abdominal pain, dyspepsia and/or nausea were also determined. RESULTS: The final analysis consisted of 4394 patients. Nonspecific nonsteroidal anti-inflammatory drug users (n = 1185) received naproxen 1000 mg/day (n = 766), ibuprofen 2400 mg/day (n = 207) or diclofenac sodium 150 mg/day (n = 212). Valdecoxib users received 10 mg/day (n = 955), 20 mg/day (n = 851) or 40 mg/day (n = 430). A total of 973 patients received placebo. The nonspecific nonsteroidal anti-inflammatory drug group was most likely to report abdominal pain or dyspepsia, while the placebo group reported the highest incidence of nausea. The most important risk factors for abdominal pain, dyspepsia and/or nausea were nonspecific nonsteroidal anti-inflammatory drug use, gastrointestinal history of nonspecific nonsteroidal anti-inflammatory drug-related intolerance or gastroduodenal ulcers, osteoarthritis diagnosis, female gender and age <65 years. CONCLUSION: This pooled analysis demonstrates a clear decrease in dyspepsia and an improvement in upper gastrointestinal tolerability for patients with osteoarthritis and rheumatoid arthritis taking valdecoxib, even at supratherapeutic doses, compared with those taking nonspecific nonsteroidal anti-inflammatory drugs over 12 weeks.

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. METHODS: In randomized, controlled trials, 7434 osteoarthritis and rheumatoid arthritis patients received placebo (n = 973), valdecoxib 5-80 mg daily (n = 4362), or a non-selective non-steroidal anti-inflammatory drug (naproxen, ibuprofen or diclofenac; n = 2099) for 12-26 weeks. In long-term, open-label trials, 2871 patients received valdecoxib 10-80 mg daily for up to 1 year. All potential events were reviewed by a blinded, independent review committee based on a priori definitions of ulcer complications (perforations, obstructions, bleeds). RESULTS: In randomized, controlled trials, 19 of 955 potential events were adjudicated to be ulcer complications. Valdecoxib was associated with a significantly lower ulcer complication rate than non-selective non-steroidal anti-inflammatory drugs (0.68% vs. 1.96%, all patients; 0.29% vs. 2.08%, non-aspirin users; P < 0.05). In long-term, open-label trials, seven of 310 potential events were adjudicated to be ulcer complications; the annualized incidence for valdecoxib was 0.39% (seven of 1791 patient-years) for all patients and 0.2% (three of 1472 patient-years) for non-aspirin users. CONCLUSIONS: Valdecoxib, including above recommended doses, is associated with a significantly lower rate of upper gastrointestinal ulcer complications than therapeutic doses of non-selective non-steroidal anti-inflammatory drugs.

Application of a propensity score to adjust for channelling bias with NSAIDs.

PURPOSE: To compare the relative risks of upper GI haemorrhage (UGIH) in users of Newer versus Older, non-specific NSAIDs when adjusted for channelling bias by regression on individual covariates, a propensity score and both. METHODS: Cohort study of patients prescribed NSAIDs between June 1987 and January 2000. Exposure to Newer and Older non-specific NSAIDs was identified, and risk factors evaluated for each patient. Results of multiple covariate analyses and the propensity scoring technique to assess potential channelling bias in comparisons between Newer and Older non-specific NSAIDs were compared. RESULTS: This study included 7.1 thousand patient years (tpy) exposure to meloxicam, 1.6 tpy exposure to coxibs, and 628 tpy exposure to Older non-specific NSAIDs. Patients receiving Newer NSAIDs were older, more likely to have a history of GI symptoms, and at higher risk for GI complications. Adjusting for these risk factors reduced the relative risks of UGIH on meloxicam and coxibs versus Older non-specific NSAIDs to 0.84 (95%CI 0.60, 1.17) and 0.36 (0.14, 0.97) respectively. CONCLUSIONS: Channelling towards high GI risk patients occurred in the prescribing of Newer NSAIDs. Propensity scores highlighted the markedly different risk profiles of users of Newer and Older non-specific NSAID. Correcting for channelling bias, coxib exposure, but not meloxicam exposure, was associated with less UGIH than Older non-specific NSAID exposure. In the present study, corrections made by regression on a propensity score and on individual covariates were similar.

Adherence to proton pump inhibitors or H2-receptor antagonists during the use of non-steroidal anti-inflammatory drugs.

BACKGROUND: The efficacy of proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) prescribed as prophylaxis for NSAID-related upper gastrointestinal (UGI) toxicity is dependent upon patient adherence. AIM: To describe patient adherence to prophylactically prescribed PPIs and H2RAs in the clinical setting. METHODS: We conducted a retrospective observational cohort study using the Integrated Primary Care Information Project database. The study population consisted of incident non-specific NSAID users prescribed a PPI or H2RA specifically as prophylaxis for NSAID-related UGI toxicity. Patients were classified as non-adherent if < 75% of days of NSAID use were covered by one of these agents, and as continuing users after discontinuation of NSAID use if they had a renewed prescription for these agents after their last NSAID prescription. RESULTS: The study cohort comprised 784 patients: 374 with H2RAs, 405 with PPIs, and 5 with both PPI and H2RA. Eighty-five percent of H2RA users and 7% of PPI users were prescribed these drugs at doses below the minimum recommended/effective dose for NSAID-associated gastroduodenal ulcer prophylaxis. Thirty-seven percent of patients were non-adherent. The lowest rate of non-adherence was associated with the first NSAID prescription (9%), increasing to 61% for patients with >/= 3 prescriptions. In a cohort of subjects who stopped their NSAID and were followed for up to 2 years (n = 711), there was significant persistent use of acid suppressive agents; 40% of patients had at least one additional prescription for the acid suppressive agent after stopping NSAIDs, and> 30% received enough drug to cover a period longer than 2 months after stopping their NSAID. CONCLUSIONS: The pattern of PPI and H2RA prescriptions, when prescribed as prophylactic strategy, does not correspond with the pattern of NSAID use. Physicians should consider the medical impact of non-adherence with dual therapies and the impact of prolonged use of GPAs on treatment cost.