Chronic Nonsteroidal Anti-inflammatory Drug Therapy Research Articles

Impact of concomitant low-dose aspirin on the safety and tolerability of naproxen and esomeprazole magnesium delayed-release tablets in patients requiring chronic nonsteroidal anti-inflammatory drug therapy: an analysis from 5 Phase III studies

Patients receiving chronic nonsteroidal anti-inflammatory drugs (NSAIDs) and concomitant low-dose aspirin (LDA) are at increased risk of gastrointestinal (GI) toxicity. A fixed-dose combination of enteric-coated (EC) naproxen and immediate-release esomeprazole magnesium (NAP/ESO) has been designed to deliver a proton-pump inhibitor followed by an NSAID in a single tablet. To examine safety data from 5 Phase III studies of NAP/ESO in LDA users (≤ 325 mg daily, administered at any time during the study), and LDA non-users, data were analyzed from 6-month studies assessing NAP/ESO versus EC naproxen in patients with osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis (n = 2), 3-month studies assessing NAP/ESO vs celecoxib or placebo in patients with knee osteoarthritis (n = 2), and a 12-month, open-label, safety study of NAP/ESO (n = 1). In an analysis of two studies, incidences of endoscopically confirmed gastric ulcers (GUs) and duodenal ulcers (DUs) were summarized by LDA subgroups. In the pooled analysis from all five studies, incidences of treatment-emergent adverse events (AEs) (including prespecified NSAID-associated upper GI AEs and cardiovascular AEs), serious AEs, and AE-related discontinuations were stratified by LDA subgroups. Overall, 2,317 patients received treatment; 1,157 patients received NAP/ESO and, of these, 298 received LDA. The cumulative incidence of GUs and DUs in the two studies with 6-month follow-up was lower for NAP/ESO vs EC naproxen in both LDA subgroups [GUs: 3.0 vs 27.9%, respectively, for LDA users, 6.4 vs 22.4%, respectively, for LDA non-users (both P < 0.001); DUs: 1.0 vs 5.8% for LDA users, 0.6 vs 5.3% for LDA non-users]. The incidence of erosive gastritis was lower in NAP/ESO- vs EC naproxen-treated patients for both LDA users [18.2 vs 36.5%, respectively (P = 0.004)] and LDA non-users [19.8 vs 38.5%, respectively (P < 0.001)]. Among LDA users, incidences of NSAID-associated upper GI AEs were: NAP/ESO, 16.1%; EC naproxen, 31.7%; celecoxib, 22.1%; placebo, 23.2%. Among LDA non-users, incidences of NSAID-associated upper GI AEs were: NAP/ESO, 20. %; EC naproxen, 36.6%; celecoxib, 18.5%; placebo, 18.9%. For LDA users, incidences of cardiovascular AEs were: NAP/ESO, 3.0%; EC naproxen, 1.0%; celecoxib, 0%; placebo, 0%. For LDA non-users, incidences of cardiovascular AEs were: NAP/ESO, 1.0%; EC naproxen, 0.6%; celecoxib, 0.3%; placebo, 0%. NAP/ESO appears to be well-tolerated in patients receiving concomitant LDA. For LDA users, AE incidence was less than that observed for EC naproxen. For most AE categories, incidences were similar among NAP/ESO, celecoxib and placebo groups. The safety of NAP/ESO appeared similar regardless of LDA use.

Efficacy and tolerability of naproxen/esomeprazole magnesium tablets compared with non-specific NSAIDs and COX-2 inhibitors: a systematic review and network analyses.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as non-selective NSAIDs (nsNSAIDs) or selective cyclooxygenase-2 (COX-2) inhibitors, are commonly prescribed for arthritic pain relief in patients with osteoarthritis (OA), rheumatoid arthritis (RA), or ankylosing spondylitis (AS). Treatment guidelines for chronic NSAID therapy include the consideration for gastroprotection for those at risk of gastric ulcers (GUs) associated with the chronic NSAID therapy. The United States Food and Drug Administration has approved naproxen/esomeprazole magnesium tablets for the relief of signs and symptoms of OA, RA, and AS, and to decrease the risk of developing GUs in patients at risk of developing NSAID-associated GUs. The European Medical Association has approved this therapy for the symptomatic treatment of OA, RA, and AS in patients who are at risk of developing NSAID-associated GUs and/or duodenal ulcers, for whom treatment with lower doses of naproxen or other NSAIDs is not considered sufficient. Naproxen/esomeprazole magnesium tablets have been compared with naproxen and celecoxib for these indications in head-to-head trials. This systematic literature review and network meta-analyses of data from randomized controlled trials was performed to compare naproxen/esomeprazole magnesium tablets with a number of additional relevant comparators. For this study, an original review examined MEDLINE®, Embase®, and the Cochrane Controlled Trials Register from database start to April 14, 2009. Using the same methodology, a review update was conducted to December 21, 2009. The systematic review and network analyses showed naproxen/esomeprazole magnesium tablets have an improved upper gastrointestinal tolerability profile (dyspepsia and gastric or gastroduodenal ulcers) over several active comparators (naproxen, ibuprofen, diclofenac, ketoprofen, etoricoxib, and fixed-dose diclofenac sodium plus misoprostol), and are equally effective as all active comparators in treating arthritic symptoms in patients with OA, RA, and AS. Naproxen/esomeprazole magnesium tablets are therefore a valuable option for treating arthritic symptoms in eligible patients with OA, RA, and AS.

Methodology of a large prospective, randomised, open, blinded endpoint streamlined safety study of celecoxib versus traditional non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis: protocol of the standard care versus celecoxib outcome trial (SCOT)

IntroductionCyclooxygenase 2 (COX-2) inhibitors have less upper gastrointestinal toxicity than traditional non-steroidal anti-inflammatory drugs (NSAIDs). However, both COX-2 inhibitors and traditional NSAIDs may be associated with adverse cardiovascular side effects....

A Very High Rate of Inappropriate Use of Gastroprotection for Nonsteroidal Anti-inflammatory Drug Therapy in Primary Care

To assess the appropriateness of gastroprotection in nonsteroidal anti-inflammatory drug (NSAID) users by primary care physicians. A gastroprotective therapy is advised in NSAID users who are at a high risk for developing gastrointestinal side effects. However, an inappropriate (overuse/underuse) prescription of gastroprotection has been reported. This was a cross-sectional study in which a questionnaire was administered to consecutive NSAID users who visited routine primary care during a 1-week period. The presence of risk factors for NSAID-related gastrointestinal side effects and the eventual gastroprotective strategy used were registered. Gastroprotective therapy was considered appropriate/inappropriate according to the current guidelines. Overall, 869 (25.3%) of 3,433 patients were on chronic NSAID therapy. Gastroprotection was performed in 593 (68.2%) NSAID users, and it was appropriate in only 299 (34.4%) cases. Specifically, an underuse of gastroprotective therapy was observed in 30.6% of ≥65-year-old, whereas an overuse occurred in 57.5% of <65-year-old patients without any risk factor. Concomitant therapy with either steroids [odds ratio (OR): 4.3] or anticoagulants (OR: 3.9), and >72 years of age (OR: 1.67) were significant predictive factors of inappropriate gastroprotection. Appropriate use of gastroprotective therapy for NSAID users by primary care physicians needs to be promptly implemented, as its inappropriate use is noticeably increasing ethical and economic concerns.

Helicobacter pylori management in non-steroidal anti-inflammatory drug therapy patients in primary care

Non-steroidal anti-inflammatory drugs (NSAIDs) may cause gastroduodenal ulcers and its complications. Helicobacter pylori infection is recognized as an additional risk factor for ulcer development, its eradication in NSAIDs users being recommended. In this cross-sectional study, during a 1-week period, consecutive patients who were routinely visiting in 58 primary care clinics were enrolled. A questionnaire was used to collect clinical data on the patients who were chronically taking NSAIDs. Patients with age >65 years, a personal history of peptic ulcer, concomitant therapy with steroids, anti-coagulants, multiple NSAIDs, or relevant co-morbidities were considered at high risk for NSAIDs gastroduodenal complications. Data on H. pylori infection management were collected. Overall, H. pylori was searched for in 140 (16.1%) out of 869 patients receiving chronic NSAID therapy, and it was eventually cured in 43 (72.9%) of the infected cases. In detail, H. pylori status was not investigated in 670 (77.1%) of those patients at high risk of NSAID-related gastroduodenal lesions, including 516 patients ≥65 years old, and 154 younger, but with at least 1 adjunctive risk factor. In addition, 234 (35%) of these high-risk patients were not receiving any gastric mucosa protection. Our data find that H. pylori infection is investigated in fewer than one of every five NSAID-user patients in primary care. The low alertness towards such an infection in these patients suggests a need for prompt implementation of current guidelines.

Prevention of NSAID-Associated Gastric Ulcers: Comparison of PN 400 (Enteric-Coated Naproxen with Esomeprazole) versus Enteric-Coated Naproxen Alone

Practice PearlIn patients requiring chronic nonsteroidal antiinflammatory drug therapy, PN 400 (enteric-coated naproxen with esomeprazole) effectively reduces the risk of developing gastric and duodenal ulcers compared with enteric-coated naproxen alone.

Combining nitric oxide release with anti-inflammatory activity preserves nigrostriatal dopaminergic innervation and prevents motor impairment in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

BackgroundCurrent evidence suggests a role of neuroinflammation in the pathogenesis of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of basal ganglia injury. Reportedly, nonsteroidal anti-inflammatory drugs (NSAIDs) mitigate DAergic neurotoxicity in rodent models of PD. Consistent with these findings, epidemiological analysis indicated that certain NSAIDs may prevent or delay the progression of PD. However, a serious impediment of chronic NSAID therapy, particularly in the elderly, is gastric, renal and cardiac toxicity. Nitric oxide (NO)-donating NSAIDs, have a safer profile while maintaining anti-inflammatory activity of parent compounds. We have investigated the oral activity of the NO-donating derivative of flurbiprofen, [2-fluoro-α-methyl (1,1'-biphenyl)-4-acetic-4-(nitrooxy)butyl ester], HCT1026 (30 mg kg-1 daily in rodent chow) in mice exposed to the parkinsonian neurotoxin MPTP.MethodsAgeing mice were fed with a control, flurbiprofen, or HCT1026 diet starting ten days before MPTP administration and continuing for all the experimental period. Striatal high affinity synaptosomial dopamine up-take, motor coordination assessed with the rotarod, tyrosine hydroxylase (TH)- and dopamine transporter (DAT) fiber staining, stereological cell counts, immunoblotting and gene expression analyses were used to assess MPTP-induced nigrostriatal DAergic toxicity and glial activation 1-40 days post-MPTP.ResultsHCT1026 was well tolerated and did not cause any measurable toxic effect, whereas flurbiprofen fed mice showed severe gastrointestinal side-effects. HCT1026 efficiently counteracted motor impairment and reversed MPTP-induced decreased synaptosomal [3H]dopamine uptake, TH- and DAT-stained fibers in striatum and TH+ neuron loss in subtantia nigra pars compacta (SNpc), as opposed to age-matched mice fed with a control diet. These effects were associated to a significant decrease in reactive macrophage antigen-1 (Mac-1)-positive microglial cells within the striatum and ventral midbrain, decreased expression of iNOS, Mac-1 and NADPH oxidase (PHOX), and downregulation of 3-Nitrotyrosine, a peroxynitrite finger print, in SNpc DAergic neurons.ConclusionsOral treatment with HCT1026 has a safe profile and a significant efficacy in counteracting MPTP-induced dopaminergic (DAergic) neurotoxicity, motor impairment and microglia activation in ageing mice. HCT1026 provides a novel promising approach towards the development of effective pharmacological neuroprotective strategies against PD.

Gastrointestinal Bleeding in Children Following Ingestion of Low‐dose Ibuprofen

Gastrointestinal Bleeding in Children Following Ingestion of Low‐dose Ibuprofen

A Thrombelastograph whole blood assay for clinical monitoring of NSAID-insensitive transcellular platelet activation by arachidonic acid

Optical platelet aggregation (OPA) with platelet-rich plasma (PRP) was compared with a Thrombelastograph (TEG) whole blood assay for monitoring arachidonic acid (AA)-induced platelet activation. Assays were performed on 47 interventional cardiology and 24 general surgery patients receiving aspirin therapy for cardiovascular disease, as well as 48 volunteers asked to take nonsteroidal anti-inflammatory drugs (NSAIDs) or 12 volunteers on chronic NSAID therapy unrelated to diagnosed cardiovascular disease. Whole blood TEG monitoring of NSAID inhibition detected NSAID-insensitive AA activation of platelets in a significantly higher number of cardiology (23%) and surgery (25%) patients and normal volunteers on chronic NSAID (25%) therapy relative to normal subjects not on chronic NSAID therapy (0%). Whole blood NSAID insensitivity was observed with cyclooxygenase-I inhibitors, such as aspirin and ibuprofen; was not affected by Celebrex, a cyclooxygenase-II inhibitor; but was completely inhibited by thromboxane-receptor antagonists. This was not due to platelet NSAID insensitivity, because complete inhibition of AA-activation responses in PRP was observed with either TEG or OPA assays. We confirmed that thromboxane B(2) formation in PRP from NSAID-insensitive subjects was completely inhibited by NSAIDs. However, significant amounts were formed in whole blood from NSAID-insensitive subjects, but not in whole blood from NSAID-sensitive subjects. Thromboxane formation after AA addition was not found in washed blood cells with 90% reduced platelet counts or in leukocyte-rich buffy coat fractions, but could be restored by addition of PRP. NSAID-insensitive activation was inhibited by nordihydroguaiaretic acid, with an IC(50) of 30 micromol, implicating 12- and/or 15-lipoxygenases in this transcellular pathway.

Ulcer recurrence in high-risk patients receiving nonsteroidalanti-inflammatory drugs plus low-dose aspirin: results of a post HOC subanalysis

Background: Concomitant aspirin use is a risk factor for nonsteroidal anti-inflammatory drug (NSAID)-associatedupper gastrointestinal toxicity. In high-risk individuals, such as those with a history of NSAID-related gastric ulcer bleeding, gastroprotective therapy with a proton pump inhibitor has been reported to reduce the risk of recurrent aspirin-associated gastroduodenal ulcer bleeding. Objective: This analysis compared the efficacy of misoprostol, lansoprazole, and placebo in reducing the riskof gastric or duodenal ulcer recurrence in patients taking NSAIDs and low-dose aspirin. Methods: This post hoc subanalysis was based on a previous multicenter, prospective, randomized, double-blind, placebo-controlled, 12-week study in patients who had a history of gastric ulcer, were Helicobacter pylori negative, required chronic NSAID therapy, and were free of gastric or duodenal ulcer on baseline endoscopy. The study treatments were misoprostol 200 μg QID or lansoprazole 15 or 30 mg OD. The subanalysis included data from patients in the intent-to-treat cohort who took aspirin at an amount ≤325 mg/d. The end point was the cumulative rate of gastric ulcers, as assessed by serial endoscopy at 4, 8, and 12 weeks. Results: Of 535 intent-to-treat patients from the primary study, 70 (40 men, 30 women; mean [SD] age, 64.7 [10.0] years; age range, 40–83 years) met the criteria for inclusion in the subanalysis. The proportions of patients who were free of gastric ulcers at the end of 12 weeks were 96% in the misoprostol group, 93% in the lansoprazole 15-mg group, 100% in the lansoprazole 30-mg group, and 35% in the placebo group ( P ≤ 0.008, each active treatment vs placebo). Adverse events considered possibly or probably related to treatment occurred in 5 (20.0%) misoprostol recipients (4 episodes of diarrhea, 1 episode of abdominal pain), 1 (14.3%) recipient of lansoprazole 30 mg (1 episode of pharyngitis), and 3 (13.6%) placebo recipients (1 episode each of abdominal pain, palpitations, and dyspepsia). Conclusions: In this subgroup analysis in patients at high risk for recurrence of gastric ulcer, use of cotherapywith misoprostol 200 μg QID or lansoprazole 15 or 30 mg OD significantly lowered the risk for gastric ulcer recurrence.

The risk of upper gastrointestinal bleeding in elderly users of aspirin and other non-steroidal anti-inflammatory drugs: the role of gastroprotective drugs.

Although the administration of gastroprotective drugs may reduce the risk of gastrointestinal (GI) bleeding due to intake of non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin during chronic treatment, no consensus exists as to whether such co-therapy is effective in short-term prevention, particularly in old age. The aim of our study was to evaluate the risk of bleeding associated with acute and chronic NSAID or aspirin therapy in elderly subjects, and the influence of gastroprotective treatment on such a risk. The study included 467 elderly NSAID or aspirin users and 1784 non-users, who consecutively underwent upper GI endoscopy. The use of NSAIDs and/or aspirin as well as gastroprotective drugs (misoprostol, H2-blockers, proton pump inhibitors) was evaluated during a structured interview. Upper GI tract bleeding was diagnosed on the basis of symptoms and endoscopic signs of recent hemorrhage. 54.2% of patients were acute and 45.8% chronic users of NSAIDs or aspirin. The risk of bleeding was higher in acute [odds ratio (OR) 4.14, 95% CI 2.97-5.78] than chronic users (OR 1.71, 95% CI 1.1-2.67). The risk of bleeding, adjusted for age, gender, Helicobacter (H) pylori infection, and gastroprotective drug use were 7.87 (CI 4.90-12.60) in acute users and 3.97 (95% CI 2.27-6.96) in chronic users of NSAIDs and/or aspirin. The risk of bleeding was significantly associated with acute but not chronic use of regular-dose aspirin (OR 5.53, 95% CI 2.29-13.3), diclofenac (OR 4.44, 95% CI 2.21-8.93), ketorolac (OR 4.81, 95% CI 2.13-10.9), naproxen (OR 14.9, 95% CI 4.23-52.4) or nimesulide (OR 4.06, 95% CI 1.2-13.8). Piroxicam increased the risk of bleeding in both acute (OR 5.36, 95% CI 1.94-14.8) and chronic therapy (OR 5.53, 95% CI 1.23-24.9). In acute users, concomitant therapy with proton pump inhibitors reduced the risk of bleeding compared with non-users (OR 1.05, 95% CI 0.19-5.65), whereas co-treatment with H2-blockers was associated with a significantly higher risk of bleeding than in non-users (OR 3.40, 95% CI 1.28-9.02). Chronic users of NSAIDs or aspirin co-treated with proton pump inhibitors had a lower risk of bleeding (OR 1.12, 95% CI 0.21-6.07) than those treated with misoprostol (OR 1.91, 95% CI 0.33-10.9) or H2 blockers (OR 2.26, 95% CI 0.81-6.36). The risk of upper GI bleeding is significantly higher in elderly acute vs chronic users of NSAIDs or regular-dose aspirin. In acute NSAID or aspirin users, co-treatment with proton pump inhibitors, but not with H2-blockers, may reduce the risk of bleeding compared with non-users.

Gastrointestinal health care resource utilization with chronic use of COX-2-specific inhibitors versus traditional NSAIDs

Background & aims: Cyclooxygenase 2 (COX-2)-specific inhibitors (coxibs) decrease gastrointestinal (GI) events in controlled trials, but results in clinical practice are unknown. We assessed GI-related resource use and costs in patients switching from chronic nonsteroidal anti-inflammatory drug (NSAID) therapy to chronic coxib therapy and in patients starting chronic NSAID therapy vs. chronic coxib therapy in a U.S. administrative claims database of >8 million lives. Methods: “Switchers” (n = 2246) were assessed in the 12-month periods before and after switching from chronic NSAID therapy to coxib therapy. “New NSAID” (n = 25,989) and “new coxib” (n = 2125) groups were assessed for the 12-month periods before and after the initial prescription. Proportions of patients with GI resource use (odds ratio [OR] adjusted for relevant covariates) and costs were compared. Results: The adjusted OR for any GI resource use (coxib vs. NSAID period) among switchers was 0.86 (0.74–0.99). The decrease was due to less GI cotherapy (OR = 0.82 [0.69–0.97]). Costs were not significantly lower after switching to coxibs (mean difference, −$19; 95% CI: −$139, $55), although after adding NSAID/coxib costs, the total cost in the coxib period was significantly higher (mean increase, $377; $271, $488). Adjusted OR for GI resource use for new-coxib vs. new-NSAID was 1.04 (0.92–1.16), but GI costs were significantly lower in new-NSAID patients. Conclusions: Patients switching from chronic NSAID therapy to chronic coxib therapy had a slight decrease in the proportion using GI-related resources but not in GI costs. When NSAID/coxib drug costs were included, costs were significantly less with NSAIDs than with coxibs. The potential GI-related cost savings suggested in coxib clinical trials may not be fully realized in “real-world” settings.

Nitric oxide-releasing nonsteroidal anti-inflammatory drugs: novel gastrointestinal-sparing drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have unacceptable morbidity and mortality due to their gastrointestinal toxicity. Attempts so far to improve the safety profile of NSAIDs have met with limited clinical acceptance. Nitric oxide (NO) functions as an endogenous mediator of gastric mucosal health and defense. Recent medicinal chemistry approaches attempt to exploit the tissue-protective function of NO against NSAID-induced gastric injury. Both nitroxybutyl-ester and nitrosothiol NSAID derivatives have been synthesized. Profiling of these NO-donating NSAIDs in both the laboratory and the clinic suggests that they might offer a unique solution to the problem of NSAID-induced gastropathy without sacrificing the well-accepted pharmacological activity of these agents in the management of pain and inflammation.

Strategy for treatment of Helicobacter pylori infection in adults. I. Updated indications for test and eradication therapy suggested in 2000.

Since the report of culture of Helicobacter pylori in 1983, there has been increasing agreement that H. pylori infection is etiologically associated with a number of important diseases including chronic active gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, gastric polyps, gastric cancer, as well as suggestions that it may be involved in diseases outside the upper gastrointestinal tract. There have been a number of national and international consensus meetings to propose guidelines to treat H. pylori infection. The recommendations of these conferences are reviewed here and updated to include new indications and concepts regarding H. pylori eradication therapy. Eradication therapy is considered the standard of care for active or inactive peptic ulcer patients including those who use non-steroidal anti-inflammatory drugs (NSAIDs). Other strong indications include MALT lymphoma, hyperplastic polyps, hyperplastic gastropathy, post-endoscopic resection for gastric malignancy, and acute H. pylori gastritis. Other considerations include plan to use chronic NSAID therapy, plan for chronic anti-secretory therapy, and some extra-gastroduodenal diseases such as chronic ureterica. Non-investigated dyspepsia is an indication for diagnostic evaluation and eradication therapy for those with H. pylori infection, whereas non-ulcer dyspepsia (NUD) in which peptic ulcer disease has been excluded is not an indication for evaluation per se. Intervention studies are now in progress to test the hypothesis that prevention of gastric malignancy is an outcome of H. pylori eradication. Because the prevalence of H. pylori infection and the associated diseases such as peptic ulcer or gastric cancer differ among countries as well as different approvals for treatment are required by governments or insurance agencies, the acceptable indications of eradication therapy will, by necessity, vary among countries.

Non-Steroidal Antiinflammatory Drugs

1. Non-steroidal antiinflammatory drugs (NSAIDs) are among the most frequently prescribed medications and are used primarily to control pain, stiffness, and reduce inflammation. 2. One of the most common adverse effects of NSAID therapy is gastrointestinal (GI) problems, specifically indigestion, nausea, dyspepsia, diarrhea, constipation, and gastritis. 3. Considerations in chronic pain management include non-pharmacologic treatment options (i.e., physical therapy, behavioral therapy, etc.), use of misoprostol for clients at high risk for NSAID induced GI problems, and monitoring blood and urine every 3 months to 1 year with chronic NSAID therapy to detect liver, kidney, and hematologic problems. 4. Current research is focused on development of a prostaglandin H synthetase (PGHS-2) inhibitor which should offer efficacy equal to the most potent NSAIDs with minimal side effects, including gastric safety.

Prophylaxis Against Nonsteroidal Anti-inflammatory Drug–Associated Ulcers and Erosions: A Commentary on the New Data

Nonsteroidal anti-inflammatory drug (NSAID)associated injury to the gastrointestinal tract is now a well-established fact. Indeed, studies have shown a prevalence of peptic ulcer in 20 –25% of patients taking these agents. The incidence of gastrointestinal bleeding, perforation, or obstruction in these patients is 1–3%, indicating that approximately one out of every 10 NSAID-associated peptic ulcers becomes complicated (ie, development of hemorrhage, perforation, or obstruction). These complications occur most often in well-defined, high-risk patients, primarily those who are elderly, those who have a history of gastrointestinal disease, and those who are receiving high-dose or multiple-drug regimens. The evaluation of any mucosal-protective agent is extremely difficult. For example, what end-point should be measured to determine efficacy: hemorrhages and erosions in healthy volunteers, peptic ulcers in volunteers or patients, or complication rates in patients taking NSAIDs? It is now generally agreed by most investigators that hemorrhages seen in short-term healthy volunteer studies are of little use. In a study from our laboratory evaluating the ability of the H2-receptor antagonist cimetidine to prevent naproxen-induced gastric injury, it was shown that the antagonist prevented hemorrhages but had no effect on the occurrence of erosions or peptic ulcers. This finding suggests that hemorrhages are acid dependent and are unrelated to more important lesions. Erosions, on the other hand, are probably more significant lesions in short-term healthy volunteer studies, and trials evaluating the prevention of these lesions by various agents are often predictive of findings in arthritic patients during long-term studies. Erosions may therefore be useful as a positive screening mechanism for new prophylactic agents. Healthy volunteer studies have shown that sucralfate is generally ineffective in preventing erosions and ulcers, that H2-receptor antagonists prevent erosions and ulcers in the duodenum but not in the stomach, and that misoprostol prevents both gastric and duodenal erosions and ulcers. –7 Longer-term studies in arthritic patients using ulcer as the end point have demonstrated essentially the same findings. –13 The use of ulcer as an end-point in these longer-term patient studies is justified by the fact that the major complications of NSAID use are those associated with peptic ulcer disease; erosions are found in a high percentage of patients taking NSAIDs chronically, but they are not associated with complications. Studies evaluating sucralfate have shown that it is essentially ineffective in preventing any type of NSAID-associated peptic ulcer disease. Two large, multicenter studies evaluating the H2-receptor antagonist ranitidine, 150 mg twice daily, in the prevention of NSAID-associated peptic ulcer have shown that this agent is significantly better than placebo in the prevention of duodenal ulcer, whereas it has no effect on the prevention of gastric ulcer. However, a recent study has shown that the H2-receptor antagonist famotidine, in addition to preventing duodenal ulcer, significantly reduces the incidence of gastric ulcer when given at high dose in patients receiving chronic NSAID therapy, when compared with placebo. Finally, numerous studies in arthritic patients have shown that misoprostol prevents both gastric and duodenal ulcers in patients taking NSAIDs, –12 although the side-effects caused by misoprostol sometimes prevent its use.

Management of NSAID-induced gastropathy: an economic decision analysis

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a 2% to 4% annual incidence of serious gastrointestinal complications. These adverse clinical outcomes, and the strategies used to prevent their occurrence, translate into a significant economic burden. A decision-analysis model was constructed to contrast the 6-month costs associated with various approaches to preventing and managing NSAID-induced gastropathy and to evaluate the economic impact of two treatment regimens using fixed-dose formulations of diclofenac/misoprostol. After incorporating expected medical outcomes and predicted practice patterns, 6-month per-patient costs were derived from the model for each of five treatment regimens: (1) NSAID alone; (2) NSAID with a histamine 2-receptor antagonist; (3) NSAID with coprescribed misoprostol; (4) diclofenac/misoprostol 50 mg/200 μg TID/BID; and (5) diclofenac/misoprostol 75 mg/200 μg BID. The combined diclofenac/misoprostol regimens demonstrated an 18.6% per-patient cost advantage compared with the combined NSAID regimens. Based on a 6-month period, this cost savings translated into a $214.00 per-patient overall cost savings ($1153.00 per patient for NSAID regimens versus $939.00 for diclofenac/misoprostol regimens). The magnitude of this difference was verified by Monte Carlo simulation. Despite the considerable cost difference, sensitivity analyses revealed that our model was robust and that no single variation substantially influenced the results. Given the lack of long-term prospective, comparative clinical-outcomes studies in this area, this decision analysis provides guidance to clinicians in developing a rational and cost-effective approach to the treatment of patients requiring chronic NSAID therapy.

EFFICACY OF SUCRALFATE IN PREVENTING GASTROINTESTINAL SIDE EFFECTS OF NSAIDs

To find out the efficacy of sucralfate in preventing gastrointestinal side effects of non-steroidal anti-inflammatory drugs (NSAIDs) a prospective, randomised single blind study was conducted from 1989 to 1992. Patients with osteoarthritis, rheumatoid arthritis and other long standing painful conditions, who were expected to receive NSAIDs for over three months, were recruited into the study. All medicines were discontinued for a period of 10-15 days prior to initial endoscopic assessment. NSAID therapy was started and the patients were randomised to receive either placebo (group A) or sucralfate (group B) in addition. Patient were reassessed clinically every week and an endoscopic examination was repeated after 6-8 weeks of follow-up. A total of 176 patients were studied in group A (n=91) and group B (n=85). At the end of 8 weeks gastrointestinal symptoms were present in 30.6% and 26.4% patients of group A and B respectively. Endoscopic assessment showed superficial lesions in 36.5% and 18.7% while endoscopic ulcer in 2.4% and 1.1% patients of groups A and B respectively. Thus in patients receiving chronic NSAID therapy, simultaneous administration of sucralfate reduces the incidence of superficial gastric lesions but has no significant effect on symptoms or ulcer formation.

Misoprostol compared with sucralfate in the prevention of nonsteroidal anti-inflammatory drug-induced gastric ulcer

Objectives To compare the efficacy and frequency of adverse experiences of misoprostol and sucralfate in the prevention of gastric ulcers in patients receiving nonsteroidal anti-inflammatory drug (NSAID) therapy. Design A prospective, randomized, single-blind, multicenter trial. Patients Patients with osteoarthritis receiving treatment with ibuprofen, piroxicam, or naproxen and experiencing abdominal pain were eligible. Interventions Patients who were expected to receive at least 3 months of NSAID therapy and who did not have a gastric ulcer at the time of the initial screening endoscopy were randomized to receive misoprostol, 200 micrograms four times a day, or sucralfate, 1 g four times a day. A gastric ulcer was defined as a lesion of the gastric mucosa 0.3 cm or greater in diameter. Patients were followed clinically, and repeat endoscopies were performed after 4, 8, and 12 weeks. Main measurement The development of a gastric ulcer, which was regarded as a prophylaxis failure. Results Two hundred fifty-three patients were evaluable for efficacy analysis. A gastric ulcer developed in 2 of the 122 (1.6%, 95% CI, 0.3% to 6.4%) patients on misoprostol, compared with 21 of 131 patients on sucralfate (16%, CI, 10.4% to 23.7%). The difference in ulcer rates was 14.4% (CI, 10.4% to 19.5%; P less than 0.001). Conclusion In patients receiving chronic NSAID therapy for osteoarthritis, treatment with misoprostol for 3 months was associated with a significantly lower frequency of gastric ulcer formation, compared with treatment with sucralfate (P less than 0.001).

Misoprostol Compared with Sucralfate in the Prevention of Nonsteroidal Anti-inflammatory Drug-induced Gastric Ulcer

To compare the efficacy and frequency of adverse experiences of misoprostol and sucralfate in the prevention of gastric ulcers in patients receiving nonsteroidal anti-inflammatory drug (NSAID) therapy. A prospective, randomized, single-blind, multicenter trial. Patients with osteoarthritis receiving treatment with ibuprofen, piroxicam, or naproxen and experiencing abdominal pain were eligible. Patients who were expected to receive at least 3 months of NSAID therapy and who did not have a gastric ulcer at the time of the initial screening endoscopy were randomized to receive misoprostol, 200 micrograms four times a day, or sucralfate, 1 g four times a day. A gastric ulcer was defined as a lesion of the gastric mucosa 0.3 cm or greater in diameter. Patients were followed clinically, and repeat endoscopies were performed after 4, 8, and 12 weeks. The development of a gastric ulcer, which was regarded as a prophylaxis failure. Two hundred fifty-three patients were evaluable for efficacy analysis. A gastric ulcer developed in 2 of the 122 (1.6%, 95% CI, 0.3% to 6.4%) patients on misoprostol, compared with 21 of 131 patients on sucralfate (16%, CI, 10.4% to 23.7%). The difference in ulcer rates was 14.4% (CI, 10.4% to 19.5%; P less than 0.001). In patients receiving chronic NSAID therapy for osteoarthritis, treatment with misoprostol for 3 months was associated with a significantly lower frequency of gastric ulcer formation, compared with treatment with sucralfate (P less than 0.001).