Aspirin Use in Secondary Cardiovascular Protection and the Development of Aspirin-Associated Erosions and Ulcers.

Aspirin for secondary cardiovascular disease prevention is well established, but treatment discontinuation, often because of gastrointestinal mucosal injury or symptoms, can lead to increased risk for cardiovascular events. Proton pump inhibitor therapy is recommended for aspirin-treated patients at gastrointestinal risk. PA32540 [enteric-coated aspirin (EC-ASA) 325 mg + immediate-release omeprazole 40 mg] was compared with EC-ASA 325 mg alone once daily for 6 months in 2 duplicate, randomized double-blind trials in gastrointestinal-risk patients taking aspirin for ≥3 months for secondary prevention. In this post hoc analysis, we determined the prevalence of endoscopic upper gastrointestinal ulcers at screening and whether baseline endoscopic gastric erosions impacted subsequent ulcer development. At the screening endoscopy, 6% of subjects had upper gastrointestinal ulcers (not eligible for randomization) and 40% had gastric erosions. Conditional logistic regression modeling showed that baseline gastric erosions are significantly associated with endoscopic gastric ulcer development (OR = 2.12, 95% confidence interval, 1.26-3.57). In subjects with baseline gastric erosion, 4.2% of PA32540-treated versus 13.0% of EC-ASA-treated subjects (P = 0.001) subsequently developed endoscopic gastric ulcers. These data suggest that gastric injury predisposes to gastric ulcer development when taking EC-ASA, and exposure to immediate-release omeprazole in the presence of aspirin therapy significantly reduces the likelihood of progressing to gastric ulcers.

PA32540 (a coordinated-delivery tablet of enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) versus enteric-coated aspirin 325 mg alone in subjects at risk for aspirin-associated gastric ulcers: results of two 6-month, phase 3 studies.

BACKGROUND: Discontinuations and/or interruptions in aspirin therapy for secondary cardioprotection due to upper gastrointestinal (UGI) complications or symptoms have been shown to increase the risk for subsequent cardiovascular events. PA32540 is a coordinated-delivery, combination tablet consisting of enteric-coated aspirin (EC-ASA) 325 mg and immediate-release (IR) omeprazole 40 mg. METHODS: Two identically-designed, 6-month, randomized, double-blind trials evaluated PA32540 vs. EC-ASA 325 mg in a secondary cardiovascular disease prevention population taking aspirin 325 mg daily for ≥3 months and at risk for ASA-associated gastric ulcers (GUs). The combined study population was 1049 subjects (524 randomized to PA32540, 525 to EC-ASA 325 mg). The primary endpoint was the occurrence of endoscopically-determined gastric ulceration over 6 months. Safety outcomes included the rates of major adverse cardiovascular events (MACE) and UGI symptoms. RESULTS: Significantly fewer PA32540-treated subjects (3.2%) developed endoscopic GUs vs. EC-ASA 325 mg-treated subjects (8.6%) (P < .001). Overall occurrence of MACE was low (2.1%), with no significant differences between treatments in types or incidence of MACE. PA32540-treated subjects had significantly fewer UGI symptoms (P < .001) and significantly fewer discontinuations due to pre-specified UGI adverse events (1.5% vs. 8.2%, respectively; P < .001). CONCLUSIONS: PA32540 reduced the incidence of endoscopic GUs compared to EC-ASA 325 mg, but with a similar cardiovascular event profile. Due to fewer UGI symptoms, continuation on aspirin therapy was greater in the PA32540 treatment arm.

Spaced administration of PA32540 and clopidogrel results in greater platelet inhibition than synchronous administration of enteric-coated aspirin and enteric-coated omeprazole and clopidogrel.

BACKGROUND: A common regimen for patients requiring dual-antiplatelet therapy who are at risk for gastrointestinal complications is the synchronous administration of enteric-coated (EC) aspirin, a proton pump inhibitor, and clopidogrel, although proton pump inhibitors have the potential for pharmacodynamic interaction with clopidogrel. Spaced administration of a clopidogrel and a single-tablet formulation of aspirin and immediate-release omeprazole (PA32540) was considered as an alternative that might reduce this potential pharmacodynamic interaction. METHODS AND RESULTS: A randomized, open-label, crossover study was conducted in healthy subjects (n = 30). Two 7-day treatments were separated by 14-day washout periods: (a) PA32540 + clopidogrel (300 mg loading/75 mg maintenance) 10 hours later and (b) synchronous dosing of clopidogrel + EC aspirin (81 mg) + EC omeprazole (40 mg). The primary end point was the inhibition of platelet aggregation (20 µM adenosine diphosphate, maximal extent) after 7 days. CYP2C19 and ABCB1 genotypes were determined. Inhibition of platelet aggregation was greater with spaced PA32540 + clopidogrel therapy vs synchronous clopidogrel + EC aspirin + EC omeprazole therapy (P = .004). There was no difference in day 7 arachidonic acid-induced aggregation. The effect of spacing on pharmacodynamics was independent of genotype. CONCLUSIONS: PA32540 and clopidogrel spaced 10 hours apart had greater antiplatelet effects than did synchronously administered EC aspirin (81 mg), clopidogrel (75 mg), and EC omeprazole in healthy volunteers. These finding are directly relevant to the treatment for patients with high gastrointestinal risk who require dual-antiplatelet therapy and gastroprotection.

The budget impact of using enteric-coated aspirin 325 mg + immediate-release omeprazole 40 mg to prevent recurrent cardiovascular events.

OBJECTIVE: Aspirin (acetylsalicylic acid; ASA) is commonly used for secondary prevention of cardiovascular (CV) events, but may be associated with gastrointestinal (GI) adverse events, which can reduce adherence. Use of ASA co-therapy with proton pump inhibitors in patients at risk may be suboptimal. PA32540 (Yosprala™) is a coordinated-delivery tablet combining EC-ASA 325 mg and immediate-release omeprazole 40 mg. The objective of this flexible budget impact model was to project the financial consequences of introducing PA32540 325 mg/40 mg to prevent recurrent CV events, while reducing ASA-associated GI events in US adults. METHODS: A Markov Model was employed to estimate health state transitions associated with ASA 75-325 mg, ASA 75-325 mg + generic delayed-release omeprazole 40 mg, PA32540, or clopidogrel 75 mg to prevent recurrent CV events. Health states included ulcers, GI bleeding, CV events, and death. Model inputs included demographics, treatment dosages, treatment costs, adverse GI and CV events, and premature death. Data from peer-reviewed literature and censuses enabled appropriate allocation of CV and GI disease prevalence and mortality. The PA32540 non-adherence rate was conservatively set at 20%. PA32540 market share was set to 50%. RESULTS: The model projected annual savings of $81.0 million to $190.9 million within 1-5 years after PA32540 introduction to the plan, which included 134,558 members at risk for recurrent CV events. These values translate into savings of $602 (year 5) to $1,419 (year 1) per patient per year, and $81 (year 5) to $191 (year 1) per member per year. These values were robust to variations in parameters under a deterministic sensitivity analysis. CONCLUSION: PA32540 use to prevent recurrent CV events was associated with cost reductions in each year examined with the model. From a health plan perspective, PA32540 is likely to have a net overall effect, resulting in significant cost savings.

A double-blind, randomized, placebo-controlled phase III study of the safety of alvimopan in patients who undergo simple total abdominal hysterectomy.

OBJECTIVE: The purpose of this study was to investigate the safety and efficacy of alvimopan, a novel peripherally acting mu-opioid receptor antagonist, in patients who undergo simple total abdominal hysterectomy. STUDY DESIGN: Women (n = 519) were randomized (4:1) to receive alvimopan 12 mg (n = 413) or placebo (n = 106) > or = 2 hours before the operation then twice daily for 7 days (hospital and home). Adverse events were monitored up to 30 days after the last dose of study drug was administered. Efficacy was assessed for 7 postoperative days. RESULTS: Overall, the most common adverse events were nausea, vomiting, and constipation; < 5% of patients discontinued use because of adverse events. Alvimopan significantly accelerated the time to first bowel movement (hazard ratio, 2.33; P <.001). Average time to first bowel movement was reduced by 22 hours, with more frequent bowel movement and better bowel movement quality found in the treatment cohort. CONCLUSION: Alvimopan has a safety profile that is similar to that of placebo and provides significantly improved lower gastrointestinal recovery in women who undergo simple total abdominal hysterectomy.

The Effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 (COX-2) inhibitors may attenuate the efficacy of antihypertensive agents in high-risk patients. Therefore, we conducted a double-blind, randomized trial to evaluate the effects of celecoxib, rofecoxib, and naproxen on 24-hour blood pressure (BP) in patients with type 2 diabetes, hypertension, and osteoarthritis. METHODS: Patients were randomly assigned to treatment with 200 mg of celecoxib once daily (n = 136), 25 mg of rofecoxib once daily (n = 138), or 500 mg of naproxen twice daily (n = 130) for 12 weeks. Twenty-four-hour ambulatory BP monitoring and validated arthritis efficacy assessments were conducted at randomization and at weeks 6 and 12 of treatment. The primary end point was the mean change from baseline in average 24-hour systolic BP at week 6. RESULTS: Reductions in osteoarthritis symptoms, including pain, mobility, and stiffness, were similar in all treatment groups. The mean +/- SE 24-hour systolic BP following 6 weeks of therapy was increased significantly by rofecoxib (from 130.3 +/- 1.2 to 134.5 +/- 1.4 mm Hg; P < .001) but not by celecoxib (132.0 +/- 1.3 to 131.9 +/- 1.3 mm Hg; P = .54) or naproxen (133.7 +/- 1.5 to 133.0 +/- 1.4 mm Hg; P = .74). The BP difference between rofecoxib and celecoxib was 3.78 mm Hg (95% confidence interval, 1.18-6.38; P = .005); between rofecoxib and naproxen, 3.85 mm Hg (95% confidence interval, 1.15-6.55; P = .005). The proportion of patients with controlled hypertension at baseline who developed ambulatory hypertension by week 6 (24-hour systolic BP>135 mm Hg) was significantly greater with rofecoxib (30%) than with celecoxib (16%) (P = .05) but not significantly greater than with naproxen (19%). CONCLUSIONS: At equally effective doses for osteoarthritis management, treatment with rofecoxib but not celecoxib or naproxen induced a significant increase in 24-hour systolic BP. However, destabilization of hypertension control occurred to some extent in all 3 treatment groups; this phenomenon was seen more often in patients treated with rofecoxib than with the other therapies.

Long-Term Safety of a Coordinated Delivery Tablet of Enteric-Coated Aspirin 325 mg and Immediate-Release Omeprazole 40 mg for Secondary Cardiovascular Disease Prevention in Patients at GI Risk.

INTRODUCTION: In two, 6-month, randomized, double-blind Phase 3 trials, PA32540 (enteric-coated aspirin 325 mg and immediate-release omeprazole 40 mg) compared to aspirin alone was associated with fewer endoscopic gastric and duodenal ulcers in patients requiring aspirin therapy for secondary cardiovascular disease (CVD) prevention who were at risk for upper gastrointestinal (UGI) events. AIMS: In this 12-month, open-label, multicenter Phase 3 study, we evaluated the long-term cardiovascular and gastrointestinal safety of PA32540 in subjects who were taking aspirin 325 mg daily for ≥ 3 months for secondary CVD prevention and were at risk for aspirin-associated UGI events. Enrolled subjects received PA32540 once daily for up to 12 months and were assessed at baseline, month 1, month 6, and month 12. RESULTS: The overall safety population consisted of 379 subjects, and 290 subjects (76%) were on PA32540 for ≥ 348 days (12-month completers). Adverse events (AEs) caused study withdrawal in 13.5% of subjects, most commonly gastroesophageal reflux disease (1.1%). Treatment-emergent AEs occurred in 76% of the safety population (11% treatment-related) and 73% of 12-month completers (8% treatment-related). The most common treatment-related AE was dyspepsia (2%). One subject had a gastric ulcer observed on for-cause endoscopy. There were five cases of adjudicated nonfatal myocardial infarction, one nonfatal stroke, and one cardiovascular death, but none considered treatment-related. CONCLUSIONS: Long-term treatment with PA32540 once daily for up to 12 months in subjects at risk for aspirin-associated UGI events is not associated with any new or unexpected safety events.

Onset and durability of pain relief in knee osteoarthritis: Pooled results from two placebo trials of naproxen/esomeprazole combination and celecoxib.

OBJECTIVE: To further characterize time-to-first pain relief, effect size, correlations between various outcome measures and durability of relief for single-tablet naproxen 500 mg/esomeprazole 20 mg (NAP/ESO) given twice daily and celecoxib (CEL) (200 mg) given once daily versus placebo in knee osteoarthritis (OA). METHODS: Unpublished data from two double-blind, double-dummy, placebo-controlled trials in which patients aged ≥ 50 years with knee OA were randomized to NAP/ESO (n = 487), CEL (n = 486) or placebo (n = 246) were pooled (NCT00664560 and NCT00665431). Acute response endpoints: 1) Time to first significant pain response, 2) Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain subscale and 3) American Pain Society Patient Outcome Questionnaire (APS-POQ) scores. Sustainability endpoints: 1) Routine Assessment of Patient Index Data (RAPID3) and 2) WOMAC Stiffness, Pain and Total scores; and Patient Global Assessment (PGA) at 6 and 12 weeks. Effect sizes for all measures were calculated. Rescue pain medication use also was analyzed, as was the correlation of WOMAC to RAPID3. RESULTS: NAP/ESO produced statistically significant decreases in WOMAC Pain on Days 2-7 and at Weeks 6 and 12 (all p < 0.05); most APS-POQ pain assessments with NAP/ESO were significantly improved on Days 2-7 compared with placebo (all p < 0.05). A good or excellent response occurred in a median of 6 days. RAPID3 and WOMAC total/stiffness/function/PGA scores decreased significantly at Weeks 6 and 12 (all p < 0.05). Placebo-adjusted WOMAC pain effect sizes were 0.44, 0.34 and 0.25 at Day 7, week 6 and week 12, respectively. RAPID3 to WOMAC total and WOMAC pain to RAPID3: Pain scores were highly correlated at 6 and 12 weeks (correlation coefficients >0.80). No significant differences in overall responses were found between CEL and NAP/ESO. CONCLUSION: Naproxen/esomeprazole produced a significant absolute moderate early pain response, which was maintained for 12 weeks. RAPID3 was found to be highly correlated with the typical OA measure (WOMAC) and might be a useful clinical tool for measuring NSAID response. NCT00664560: https://clinicaltrials.gov/ct2/show/NCT00664560, NCT00665431: https://www.clinicaltrials.gov/ct2/show/NCT00665431.

Onset and durability of pain relief in knee osteoarthritis: pooled results from two placebo trials of naproxen/esomeprazole combination and celecoxib.

OBJECTIVE: To further characterize time-to-first pain relief, effect size, correlations between various outcome measures and durability of relief for single-tablet naproxen 500 mg/esomeprazole 20 mg (NAP/ESO) given twice daily and celecoxib (CEL) (200 mg) given once daily versus placebo in knee osteoarthritis (OA). METHODS: Unpublished data from two double-blind, double-dummy, placebo-controlled trials in which patients aged ≥50 years with knee OA were randomized to NAP/ESO (n = 487), CEL (n = 486) or placebo (n = 246) were pooled (NCT00664560 and NCT00665431). Acute response endpoints: 1) Time to first significant pain response, 2) Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain subscale and 3) American Pain Society Patient Outcome Questionnaire (APS-POQ) scores. Sustainability endpoints: 1) Routine Assessment of Patient Index Data (RAPID3) and 2) WOMAC Stiffness, Pain and Total scores; and Patient Global Assessment (PGA) at 6 and 12 weeks. Effect sizes for all measures were calculated. Rescue pain medication use also was analyzed, as was the correlation of WOMAC to RAPID3. RESULTS: NAP/ESO produced statistically significant decreases in WOMAC Pain on Days 2-7 and at Weeks 6 and 12 (all p < 0.05); most APS-POQ pain assessments with NAP/ESO were significantly improved on Days 2-7 compared with placebo (all p < 0.05). A good or excellent response occurred in a median of 6 days. RAPID3 and WOMAC total/stiffness/function/PGA scores decreased significantly at Weeks 6 and 12 (all p < 0.05). Placebo-adjusted WOMAC pain effect sizes were 0.44, 0.34 and 0.25 at Day 7, week 6 and week 12, respectively. RAPID3 to WOMAC total and WOMAC pain to RAPID3: Pain scores were highly correlated at 6 and 12 weeks (correlation coefficients >0.80). No significant differences in overall responses were found between CEL and NAP/ESO. CONCLUSION: Naproxen/esomeprazole produced a significant absolute moderate early pain response, which was maintained for 12 weeks. RAPID3 was found to be highly correlated with the typical OA measure (WOMAC) and might be a useful clinical tool for measuring NSAID response. NCT00664560: https://clinicaltrials.gov/ct2/show/NCT00664560, NCT00665431: https://www.clinicaltrials.gov/ct2/show/NCT00665431.

Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or =65 years of age with systemic hypertension and osteoarthritis.

Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs), including the cyclooxygenase-2 (COX-2) specific inhibitors, with antihypertensive medication is common practice for many patients with arthritis. This study evaluated the effects of celecoxib 200 mg/day and rofecoxib 25 mg/day on blood pressure (BP) and edema in a 6-week, randomized, parallel-group, double-blind study in patients > or =65 years of age with osteoarthritis who were treated with fixed antihypertensive regimens. One thousand ninety-two patients received study medication (celecoxib, n = 549; rofecoxib, n = 543). Significantly more patients in the rofecoxib group compared with the celecoxib group developed increased systolic BP (change >20 mm Hg plus absolute value > or =140 mm Hg) at any time point (14.9% vs 6.9%, p <0.01). Rofecoxib caused the greatest increase in systolic BP in patients receiving angiotensin-converting enzyme inhibitors or beta blockers, whereas those on calcium channel antagonists or diuretic monotherapy receiving either celecoxib or rofecoxib showed no significant increases in BP. Clinically significant new-onset or worsening edema associated with weight gain developed in a greater percentage of patients in the rofecoxib group (7.7%) compared with the celecoxib group (4.7%) (p <0.05). Thus, in patients with controlled hypertension on a fixed antihypertensive regimen, careful monitoring of BP is warranted after the initiation of celecoxib or rofecoxib therapy.

Efficacy of celecoxib versus ibuprofen in the treatment of acute pain: a multicenter, double-blind, randomized controlled trial in acute ankle sprain.

Ankle sprain is a common acute soft-tissue injury that often results in pain, inflammation, and ecchymosis. In this multicenter, double-blind, randomized parallel-group study, 445 adult patients received celecoxib 400 mg/day, ibuprofen 2,400 mg/day, or placebo for 10 days. Patients had experienced grade 1 or 2 ankle sprains within 48 hours and had moderate to severe ankle pain. Patient's Global Assessment of Ankle Injury responses, given on days 4 and 8, showed that the celecoxib group improved significantly more than the placebo group did, with 67% of the celecoxib group versus 55% of the placebo group improving at day 4 (P < .05). Patient's Assessment of Ankle Pain Visual Analog Scale on Weight Bearing responses, also given on days 4 and 8, showed that celecoxib was as efficacious in the treatment of ankle sprain as the maximum therapeutic dosage of ibuprofen and that, compared with placebo, it reduced pain significantly more (P < .05). The celecoxib group recovered and returned to function earlier (after 5 days) than did either the placebo group (8 days) or the ibuprofen group (6 days); the celecoxib-placebo difference was significant. Celecoxib, a cyclo-oxygenase-2-specific inhibitor with platelet-function-sparing properties, may be useful as a multimodal adjuvant in the treatment of ankle sprain.

Long-term safety of naproxen and esomeprazole magnesium fixed-dose combination: phase III study in patients at risk for NSAID-associated gastric ulcers.

OBJECTIVE: To evaluate long-term safety of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg fixed-dose combination (FDC) in patients at risk of NSAID-associated upper gastrointestinal (UGI) ulcers. RESEARCH DESIGN AND METHODS: In this open-label, multicenter, phase III study, Helicobacter pylori-negative patients aged ≥50 years or 18-49 years with history of uncomplicated ulcer within the past 5 years, who had osteoarthritis, rheumatoid arthritis, or other condition requiring daily NSAIDs for ≥12 months received naproxen/esomeprazole twice daily for 12 months. CLINICAL TRIAL REGISTRATION: NCT00527904. MAIN OUTCOME MEASURES: Adverse events (AEs), vital signs, physical examination, and laboratory tests. Subgroup analyses included age and low-dose aspirin (LDA) use. Predefined NSAID-associated UGI and cardiovascular AEs were analyzed. RESULTS: Of 239 patients treated (safety population), 135 completed ≥348 treatment days (12-month completers). AE incidence was approximately 70%; dyspepsia, constipation, upper respiratory tract infection, nausea, back pain, and contusion were most frequent (≥5% patients, either population). Treatment-related AEs occurred in 28.0% and 23.7% of patients in the safety and 12-month completer populations, respectively; 18.8% of patients withdrew due to AEs (safety population). Few serious AEs and no deaths occurred. In the safety population, AE incidence was 71.4% and 76.9% in patients aged <65 years (n = 161) and ≥65 years (n = 78), respectively, and 67.6% and 75.8% in LDA users (n = 74) and non-users (n = 165), respectively. Predefined UGI and cardiovascular AEs were observed in 18.8% and 6.3% of patients, respectively, in the safety population, and 16.3% and 5.2%, respectively, in 12-month completers. Dyspepsia and hypertension were most common. Additional assessments showed no unexpected findings. CONCLUSIONS: Based on these outcome measures, long-term treatment with FDC naproxen/esomeprazole is not associated with any new safety issues, including predefined UGI and cardiovascular AEs, in patients requiring NSAID therapy who are at risk of UGI complications.

Fixed-dose combination of enteric-coated naproxen and immediate-release esomeprazole has comparable efficacy to celecoxib for knee osteoarthritis: two randomized trials.

OBJECTIVE: To demonstrate that a fixed-dose combination of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg has comparable efficacy to celecoxib for knee osteoarthritis. RESEARCH DESIGN AND METHODS: Two randomized, double-blind, parallel-group, placebo-controlled, multicenter phase III studies (PN400-307 and PN400-309) enrolled patients aged ≥50 years with symptomatic knee osteoarthritis. Following an osteoarthritis flare, patients received naproxen/esomeprazole magnesium twice daily, celecoxib 200 mg once daily, or placebo for 12 weeks. CLINICAL TRIAL REGISTRATION: NCT00664560 and NCT00665431. MAIN OUTCOME MEASURES: Three co-primary efficacy endpoints were mean change from baseline to week 12 in Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain and function subscales, and Patient Global Assessment of osteoarthritis using a visual analog scale (PGA-VAS). RESULTS: In Study 307, 619 patients were randomized and 614 treated. In Study 309, 615 patients were randomized and 610 treated. Both naproxen/esomeprazole magnesium and celecoxib were associated with improvements (least squares mean change from baseline to week 12) in WOMAC pain (Study 307: -42.0 and -41.8, respectively; Study 309: -44.2 and -42.9, respectively), WOMAC function (Study 307: -36.4 and -36.3, respectively; Study 309: -38.9 and -36.8, respectively), and PGA-VAS (Study 307: 21.2 and 21.6, respectively; Study 309: 29.0 and 25.6, respectively). A prespecified non-inferiority margin of 10 mm between naproxen/esomeprazole magnesium and celecoxib was satisfied for each co-primary endpoint at week 12 in both studies. Significant improvements were observed with naproxen/esomeprazole magnesium versus placebo in both studies (p < 0.05). Celecoxib was significantly different from placebo in Study 307 (p < 0.05); however, the improvements were not significant in Study 309. Acetaminophen use and patient expectation of receiving active treatment (80% probability) may have contributed to a high placebo response observed. CONCLUSIONS: Naproxen/esomeprazole magnesium has comparable efficacy to celecoxib for the management of pain associated with osteoarthritis of the knee over 12 weeks.

A fixed-dose combination of naproxen and esomeprazole magnesium has comparable upper gastrointestinal tolerability to celecoxib in patients with osteoarthritis of the knee: results from two randomized, parallel-group, placebo-controlled trials.

BACKGROUND. Non-steroidal anti-inflammatory drugs are associated with poor upper gastrointestinal (UGI) tolerability and increased ulcer risk, but patient adherence to gastroprotective co-therapy is frequently inadequate. A fixed-dose combination of enteric-coated naproxen 500 mg and immediate-release esomeprazole magnesium 20 mg was evaluated: efficacy is reported by Hochberg et al. (Curr Med Res Opin 2011;27:1243-53); tolerability findings are reported here. PATIENTS AND METHODS. In two 12-week double-blind, placebo-controlled, multicenter, phase III studies (PN400-307 and PN400-309), patients aged ≥ 50 years with symptomatic knee osteoarthritis randomly (2:2:1) received naproxen/esomeprazole magnesium BID, celecoxib 200 mg QD, or placebo. Tolerability end-points included: modified Severity of Dyspepsia Assessment (mSODA); heartburn severity; and UGI adverse events (AEs). RESULTS. Overall, 619 (PN400-307) and 615 (PN400-309) patients were randomized; mSODA scores improved (baseline to week 12) in each group, with no significant treatment differences between naproxen/esomeprazole magnesium and celecoxib (95% CIs: PN400-307: -0.4, 1.9; PN400-309: -1.8, 0.6). Naproxen/esomeprazole magnesium-treated patients reported significantly more heartburn-free days versus celecoxib (95% CIs: PN400-307: 2.1, 12.7; PN400-309: 2.5, 13.4). UGI AE incidence (PN400-307: 17.3%; PN400-309: 20.3%) was similar between treatment groups. UGI AEs resulted in few discontinuations (< 4%, either study). CONCLUSIONS. Naproxen/esomeprazole magnesium has comparable UGI tolerability to celecoxib in patients with osteoarthritis.

Gastrointestinal tract recovery in patients undergoing bowel resection: results of a randomized trial of alvimopan and placebo with a standardized accelerated postoperative care pathway.

OBJECTIVE: To investigate the efficacy and safety of alvimopan, 12 mg, administered orally 30 to 90 minutes preoperatively and twice daily postoperatively in conjunction with a standardized accelerated postoperative care pathway for managing postoperative ileus after bowel resection. DESIGN, SETTING, AND PATIENTS: This multicenter, randomized, placebo-controlled, double-blind, phase 3 trial enrolled adult patients undergoing partial bowel resection with primary anastomosis by laparotomy and scheduled to receive intravenous, opioid-based, patient-controlled analgesia. A standardized accelerated postoperative care pathway including early ambulation, oral feeding, and postoperative nasogastric tube removal was used to facilitate gastrointestinal (GI) tract recovery in all of the patients. MAIN OUTCOME MEASURES: The primary end point was time to GI-2 recovery (toleration of solid food and first bowel movement). Secondary end points included time to GI-3 recovery (toleration of solid food and first flatus or bowel movement), hospital discharge order written, and actual hospital discharge. Postoperative length of hospital stay based on calendar day of hospital discharge order written, opioid consumption, and overall postoperative ileus-related morbidity were recorded. RESULTS: Alvimopan, 12 mg, was well tolerated and significantly accelerated GI-2 recovery, GI-3 recovery, and actual hospital discharge compared with a standardized accelerated postoperative care pathway alone (hazard ratio = 1.5, 1.5, and 1.4, respectively; P < .001 for all). Time to hospital discharge order written as measured by hazard ratio (1.4) and by postoperative calendar days (mean for alvimopan, 5.2 days; mean for placebo, 6.2 days) was also accelerated. Opioid consumption was comparable between groups, and alvimopan was associated with reduced postoperative ileus-related morbidity compared with placebo. CONCLUSIONS: Alvimopan, 12 mg, administered 30 to 90 minutes before and twice daily after bowel resection is well tolerated, accelerates GI tract recovery, and reduces postoperative ileus-related morbidity without compromising opioid analgesia.

The rate of NSAID-induced endoscopic ulcers increases linearly but not exponentially with age: a pooled analysis of 12 randomised trials.

The risk of major ulcer complications on treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is known to increase exponentially with age. However, in a pooled analysis of 12 trial arms, the incidence of endoscopic ulcers on treatment with NSAID was found to increase with age in a roughly linear fashion. Thus, it is concluded that increasing age is associated with both more frequent and more serious NSAID gastropathy.

Alvimopan, for postoperative ileus following bowel resection: a pooled analysis of phase III studies.

OBJECTIVE: To obtain further analysis regarding specific outcomes and alvimopan doses in bowel resection (BR) patients. SUMMARY BACKGROUND DATA: Although postoperative ileus (POI) is common after BR, there is currently no recognized treatment or prevention available. Alvimopan, a novel, peripherally active mu-opioid receptor antagonist, accelerated GI recovery after BR or hysterectomy in 3 phase III trials. METHODS: A pooled retrospective subset analysis of BR patients in alvimopan phase III trials was performed. Randomized BR patients received alvimopan 6 mg (n = 397), 12 mg (n = 413), or placebo (n = 402) >or=2 hours before surgery and twice daily until hospital discharge for

Celecoxib versus naproxen and diclofenac in osteoarthritis patients: SUCCESS-I Study.

PURPOSE: To evaluate the efficacy and upper gastrointestinal (UGI) safety of celecoxib, compared with nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs), among patients with osteoarthritis. METHODS: A total of 13274 osteoarthritis patients from 39 countries were randomly assigned to double-blind treatment with either celecoxib 100 mg twice daily (BID), celecoxib 200 mg BID, or nonselective NSAID therapy (diclofenac 50 mg BID or naproxen 500 mg BID) for 12 weeks. Standard validated measures were used to assess osteoarthritis efficacy. Serious UGI events were evaluated by 2 blinded, independent, gastrointestinal events committees. RESULTS: Results from all primary efficacy assessments showed that both dosages of celecoxib were as effective as NSAIDs in treating osteoarthritis. Significantly more ulcer complications occurred within the nonselective NSAID group (0.8/100 patient-years) compared with the celecoxib group (0.1/100 patient-years) (odds ratio = 7.02; 95% confidence interval [CI], 1.46 to 33.80; P =.008). There were fewer ulcer complications in the celecoxib group compared with the NSAID group, both in patients taking concomitant aspirin and those not taking aspirin, but the difference reached statistical significance only in the latter comparison. The number of cardiovascular thromboembolic events was low and not statistically different between the groups (eg, myocardial infarction rates: celecoxib 10 events [0.55/100 patient-years] vs NSAIDs 1 event [0.11/100 patient-years], (P =.11), but the study was not powered to detect such differences. CONCLUSIONS: In the treatment of osteoarthritis, celecoxib is as effective as the nonspecific NSAIDs naproxen and diclofenac, but has significantly fewer serious upper gastrointestinal events.

Cyclooxygenase-2 specific inhibitors and upper gastrointestinal tolerability in patients with osteoarthritis receiving concomitant low dose aspirin: pooled analysis of 2 trials.

OBJECTIVE: To evaluate the relative gastrointestinal (GI) tolerability of celecoxib and rofecoxib in elderly hypertensive patients with osteoarthritis (OA) with or without coadministration of low dose aspirin (ASA) (< or = 325 mg daily). METHODS: Two independently conducted, multicenter, double blind, randomized controlled trials designed to evaluate GI tolerability, in addition to cardiorenal study endpoints, in patients randomized to celecoxib 200 mg once daily (qd; n = 960) or rofecoxib 25 mg qd (n = 942) were analyzed. GI tolerability was assessed using investigator-reported GI symptoms, prespecified as abdominal pain, dyspepsia, and nausea. The pooled incidences of the 3 reported GI symptoms, regardless of severity (mild and moderate to severe), and the incidences of mild or moderate to severe GI symptoms individually were evaluated. RESULTS: In the pooled population, the incidence of the 3 GI symptoms, regardless of severity, was not significantly different for patients receiving celecoxib or rofecoxib. In contrast, the aggregate incidence of moderate to severe GI symptoms for patients receiving rofecoxib (5.2%) was significantly greater than for those receiving celecoxib (3.2%; p < 0.05). Notably, the significant difference between the 2 arms was more pronounced in the population of patients receiving concomitant low dose ASA (rofecoxib 9.7% vs celecoxib 1.5%; p < 0.001). The incidence of moderate to severe GI symptoms was similar with rofecoxib (3.3%) and celecoxib (3.9%; p = 0.564) treatment in patients who did not receive low dose ASA. CONCLUSION: While the GI tolerability was similar in the 2 arms of the entire pooled population, celecoxib 200 mg qd was associated with a significantly lower incidence of moderate to severe GI symptoms than rofecoxib 25 mg qd in patients receiving concomitant low dose ASA.