Nonsteroidal Anti-inflammatory Drug Ulcers Research Articles

Is combined use of SSRIs and NSAIDs associated with an increased risk of starting peptic ulcer treatment?

De Jong et al. [1] reported that the combined use of nonsteroidal anti-inflammatory drugs (NSAIDs) with selective serotonin reuptake inhibitors (SSRIs) synergistically increased the risk of initiating a treatment course with peptic ulcer drugs as a proxy for gastrointestinal adverse effects. In an attempt to limit confounding by indication, tricyclic antidepressant (TCA) users were used as a control group. As the observed association was not adjusted for potential differences between TCA and SSRI users [1], unmeasured confounding may have affected the estimation of the adverse effects. We therefore addressed the association using another pharmacoepidemiological study design, a so-called prescription sequence symmetry design [2]. The main advantage of this design is that it controls for time-invariant (unmeasured) confounding, because the patient population serves as its own control group. We used data from the same pharmacy prescription database (IADB; http://www.IADB.nl) that de Jong et al. [1] used and applied similar inclusion and exclusion criteria. When assessing the association between initiating treatment A and B, the sequence ratio (SR) is calculated by dividing the number of individuals starting treatment A first and treatment B second by the number of individuals starting treatment B first and treatment A second. For the primary analysis, only patients with a time span between both incident prescriptions between 2 and 28 days were included to limit time-variant confounding. We adjusted for prescription time trends by dividing the crude SR by a null ratio, i.e. the SR obtained assuming no association between both drugs, based on overall prescription rates of both drugs in the total IADB population. We estimated 95% confidence intervals (CIs) of SRs using exact confidence intervals for binomial distributions using STATA 12 software (StataCorp LP, College Station, TX, USA). In total, 50 350 adult patients who initiated SSRI treatment were identified between July 1994 and December 2011. A peptic ulcer drug treatment course was started in 277 of them within a 4 week period of SSRI therapy initiation; 126 (45%) started SSRI therapy prior to peptic ulcer drug treatment, while 151 (55%) patients first started peptic ulcer drug treatment [adjusted (a)SR, 0.83; 95% CI, 0.65–1.06; Table ​Table1].1]. Concurrent use of SSRIs and NSAIDs was associated with a statistically nonsignificant increase in the risk of starting peptic ulcer drug treatment (aSR, 1.48; 95% CI, 0.90–2.49), which did not exceed the risk estimated for NSAID treatment alone (aSR, 2.50; 95% CI, 2.27–2.76). Similar results were obtained for TCA treatment alone and concurrent use of TCAs and NSAIDs (Table ​(Table11). Table 1 Symmetry analysis of selected drug therapy initiation within 4 weeks of peptic ulcer drug therapy initiation using a drug-free run-in period of half a year Given that we used the same database and similar inclusion and exclusion criteria as de Jong et al. [1], the main difference between their study and ours is that we used an alternative design that reduces time-invariant (unmeasured) confounding. In accordance with our results, Dall et al., who applied a case–control design in which they controlled for various potential confounders including alcohol abuse, did not observe an increased risk of uncomplicated peptic ulcers associated with combined use of SSRIs and NSAIDs [3]. As we restricted our analyses to relatively short time spans to reduce the potential influence of time-variant confounding, we could not detect a risk that develops later in the course of treatment. However, de Jong et al. found an increased risk for concomitant use of SSRIs and NSAIDs during an average follow-up of 21 days [1]. In addition, Dall et al. found that the risk of uncomplicated peptic ulcers is greatest during the first 30 days of SSRI treatment [3], indicating that our time span of 4 weeks should be long enough to capture potential drug-related increases in peptic ulcer drug prescribing. We could not capture peptic ulcer drug courses prescribed during hospitalization, measure gastrointestinal adverse effects that required hospitalization or measure over-the-counter NSAID and peptic ulcer drug use. However, de Jong et al. did previously find an increased risk in patients concurrently using SSRIs and NSAIDs, while coping with the same limitations [1]. Therefore, the lack of an increased risk associated with SSRI use, whether used concurrently with NSAIDs or not, is likely not to be related to these potential limitations. In conclusion, our results suggest that the observations reported by de Jong et al. [1] might, at least partly, be attributed to unmeasured confounding. Although comparison with a drug that is used to treat the same indication does limit confounding, it does not eliminate all potential confounders. Therefore, when limited data on potential confounders are available, a self-controlled design can have added value, because it eliminates all time-invariant confounders [4].

Retention of Capsule Endoscopy at the Site of NSAIDs-induced Intestinal Ulcer ―Lessons to Learn―

A 77-year-old man with a history of non-steroidal anti-inflammatory drugs (NSAID) use was admitted to our hospital due to anemia and hypoalbuminemia. Radioisotope scintigraphy indicated protein loss from the small intestine. The patient underwent capsule endoscopy, which was later found to be retained in the ileum. Double-balloon endoscopy showed multiple strictures with ulcers in the small intestine. The capsule was found in proximal to one of the stenosis, and was removed by doubleballoon enteroscopy. Based on endoscopic findings, NSAID-induced enteritis was diagnosed. Although anemia and hypoalbuminemia improved after discontinuing NSAID, the patient developed ileus and underwent partial resection of the ileum. Multiple diaphragm-like strictures were present in the resected intestine. The current case highlights the importance of screening for intestinal strictures when NSAID ulcer is suspected. ACTA MEDICA NAGASAKIENSIA 58: 135−138, 2014

Bleeding gastroduodenal ulcers in patients without Helicobacter pylori infection and without exposure to non-steroidal anti-inflammatory drugs

A high risk of bleeding in Helicobacter pylori (H. pylori)-negative, non-steroidal anti-inflammatory drugs (NSAID)-negative ulcers highlights the clinical importance of analysis of the changing trends of peptic ulcer disease. The aim of the study was to investigate the risk factors for ulcer bleeding in patients with non-H. pylori infection, and with no NSAIDs use. A prospective study included patients with endoscopically diagnosed ulcer disease. The patients were without H. pylori infection (verified by pathohistology and serology) and without exposure to NSAIDs and proton pump inhibitors (PPI) within 4 weeks before endoscopy. After endoscopy the patients were divided into 2 groups: the study group of 48 patients with bleeding ulcer and the control group of 47 patients with ulcer, but with no bleeding. Prior to endoscopy they had completed a questionnaire about demographics, risk factors and habits. The platelet function, von Willebrand factor (vWF) and blood groups were determined. Histopathological analysis of biopsy samples were performed with a modified Sydney system. The influence of bile reflux was analyzed by Bile reflux index (BRI). Age, gender, tobacco and alcohol use did not affect the bleeding rate. The risk of bleeding did not depend on concomitant diseases (p = 0.509) and exposure to stress (p = 0.944). Aspirin was used by 16/48 (33.3%) patients with bleeding ulcer, as opposed to 7/47 (14.9%) patients who did not bleed (p = 0.036). Abnormal platelet function had 12/48 (25.0%) patients who bled, as opposed to 2/47 (4.3%) patients who did not bleed (p = 0.004). Patients with BRI < 14 bled in 79.2%, and did not bleed in 57.4% of the cases (p = 0.023). There was no statistical difference between groups in regards to blood groups and range of vWF. Antrum atrophy was found in 14/48 (29.20%) patients with bleeding ulcer and in only 5/47 (10.6%) patients who had ulcer without bleeding (p = 0.024). Abnormal platelet function, aspirin use and antrum atrophy were the risk factors for ulcer bleeding in non-H. pylori, non- NSAIDs ulcer disease.

The use of prophylactic gastroprotective therapy in patients with nonsteroidal anti‐inflammatory drug‐ and aspirin‐associated ulcer bleeding: a cross‐sectional study

Poor adherence to gastroprotective agents (GPAs) is common among users of nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (ASA). There are little data on the utilization of GPAs among NSAID and ASA users complicated by ulcer bleeding. To study the utilization of GPA among NSAID and ASA ulcers before the onset of ulcer bleeding. We conducted a cross-sectional study to determine the exposure to NSAIDs, ASA, and GPAs within 4 weeks before endoscopically confirmed ulcer bleeding. Sensitivity analysis was performed to study how improving adherence to GPA use would reduce the risk of ulcer bleeding in high-risk users. Between 2000 and 2009, 1093 and 2277 patients had NSAID- and ASA-associated ulcer bleeding respectively. The incidence of NSAID-associated ulcer bleeding declined by 40%, whereas that of ASA-associated ulcer bleeding increased by 46%. Thirty-nine per cent of NSAID users and 75% of ASA users belonged to high ulcer risk category. Although GPA prescription rate has increased over time, only 41.6% and 30.6% of high-risk NSAID and ASA users received GPAs before ulcer bleeding respectively. Sensitivity analysis showed that if GPAs could reduce bleeding risk by 50%, improving adherence would prevent up to 35% of ulcer bleeding in high-risk users. A substantial proportion of high-risk NSAID and ASA users had not received prophylaxis with gastroprotective agents before ulcer bleeding. These bleeding episodes may be preventable with better adherence to gastroprotective agent use.

The Influence of Etiologic Factors on Clinical Outcome in Patients with Peptic Ulcer Bleeding

Peptic ulcer bleeding remains an important cause of morbidity and mortality. The aim of this study was to evaluate the prevalence of non-steroidal anti-inflammatory drugs (NSAID) use, Helicobacter pylori infection and non-H. pylori-non-NSAIDs causes of peptic ulcer bleeding and to identify the predictive factors influencing the rebleeding rate and in-hospital mortality in patients with bleeding peptic ulcer. A total of 1,530 patients with endoscopically confirmed peptic ulcer bleeding were evaluated consecutively between January 2005 and December 2009. The 30-day mortality and clinical outcome were related to patient's demographic data, endoscopic and clinical characteristics. The age-standardized 1-year cumulative incidence for peptic ulcer bleeding was 40.4 cases/100,000 people. The proportion of patients over 65 years increased from 45.7 % in 2005 to 61.4 % in 2009 (p = 0.007). Overall 30-day mortality rate was 4.6 %, not significantly different for conservatively and surgically treated patients (4.9 vs. 4.1 %, p = 0.87). Mortality was significantly higher in patients over 65 years of age and those with in-hospital bleeding recurrence. Patients with non-H. pylori-non-NSAID idiopathic ulcers had significantly higher 30-day mortality rate than those with H. pylori ulcers and NSAID-H. pylori ulcers (7.1 vs. 0 vs. 0.8 %, p = 0.001 and p = 0.007, respectively). There was no statistically significant difference between patients with NSAID ulcers and non-H. pylori-non-NSAID idiopathic ulcers in terms of 30-day mortality rate (5.3 vs. 7.1 %, p = 0.445). The incidence of peptic ulcer bleeding has not changed over a 5-year observational period. The overall 30-day mortality was positively correlated to older age, underlying comorbid illnesses, in-hospital bleeding recurrence and the absence of H. pylori infection.

Ulcère gastroduodénal : avant et après Helicobacter pylori

Before the discovery of Helicobacter pylori, ulcer disease was considered as the result of a conflict between gastric acid and pepsin, on one side, and protection afforded by gastric mucosal barrier, on the other side. The discovery of H. pylori by Marshall and Warren in 1982 overthrew this conception and revealed ulcer disease mainly as an infectious disease. H. pylori eradication with an appropriate triple therapy is now considered as the gold standard treatment of gastroduodenal ulcer. The pathogenic role of H. pylori lies far beyond ulcer disease since H. pylori is looked as involved in nonulcer dyspepsia, nonsteroidal anti-inflammatory drug ulcers, gastric cancer, MALT lymphoma and, eventually, oesophageal adenocarcinoma, and nondigestive diseases as cardiovascular diseases. The pandemic nature of the H. pylori infection, particularly within developing countries, combined with emerging resistances to antibiotics make the development of a vaccine a public health necessity. The relationships between the human host and the bacterium remains mostly unknown, some of which could be beneficial.

Helicobacter pylori and NSAID-induced gastric ulcer in a Japanese population

A recent meta-analysis by Huang et al. clarified that Helicobacter pylori infection and nonsteroidal antiinflammatory drugs (NSAIDs) are important factors for peptic ulcer. The results showed that the risk for ulcer in NSAID(+)/H. pylori(+) patients was 61.1 fold higher when compared with NSAID(-)/H. pylori(-) patients. Some gastric ulcers detected in patients on NSAID therapy may actually be caused by H. pylori, but it is difficult to differentiate NSAID-induced gastric ulcer from H. pylori-induced gastric ulcer. Several studies have investigated the effects of H. pylori eradication on ulcer healing. One study reported that H. pylori eradication actually lowered the healing rate of gastric ulcers. Because there have been no studies finding that H. pylori eradication facilitates healing, H. pylori eradication is not recommended for NSAID users. Concerning the efficacy of H. pylori eradication in the prevention of NSAID-induced gastric ulcer, a meta-analysis concluded that among all patients on NSAID therapy, H. pylori eradication lowered the prevalence of ulcer, which was particularly marked in NSAID-naïve patients. When compared with those of proton pump inhibitors (PPIs), the preventative effects of H. pylori eradication were inferior. In Japan, national health insurance does not cover procedures that prevent or lower the risk for NSAID-induced ulcer. When administering NSAID to patients with risk factors, it is desirable to administer antiulcer agents.

Outcomes of bleeding peptic ulcers: A prospective study

Bleeding peptic ulcers can be due to Helicobacter pylori (H. pylori) infection, use of non-steroidal anti-inflammatory drugs (NSAIDs), or idiopathic causes. The aim of this prospective study was to identify the clinical outcomes of bleeding peptic ulcers related to different causes. A total of 390 patients with bleeding ulcers were evaluated consecutively between June 2005 and August 2006. The diagnosis of H. pylori infection was made at index endoscopy, using histology and the rapid urease test. If both endoscopic diagnostic tests were not performed, a serological test was applied to detect the presence of H. pylori infection in a previously untreated patient. The prevalence and outcome of bleeding ulcers are related to H. pylori infection, NSAID use, and non-H. pylori idiopathic causes. The outcome between patients who were admitted for ulcer bleeding (outpatient bleeder) and those who bled while hospitalized (in-hospital bleeder) was also compared. NSAID ulcers were noted in 223 patients, H. pylori ulcers in 102, and non-H. pylori idiopathic ulcers in 65. In total, 298 patients had outpatient bleeders, and 92 had in-hospital bleeders. The overall 3-day rebleeding rate was 11.8% and the mortality rate was 5.4%. Eighteen of the 21 mortality cases died of their underlying comorbid illness. Patients with non-H. pylori idiopathic ulcers had a significantly higher mortality rate than NSAID and H. pylori ulcers (12.3% vs 4.5% vs 2.9%, P = 0.02). Patients with H. pylori ulcers had significantly favorable outcomes than patients with NSAID ulcers (less blood transfusion and a shorter hospital stay) and non-H. pylori idiopathic ulcers (shorter hospital stay and a lower mortality). Patients with in-hospital bleeders had an adverse outcome as compared to outpatient bleeders, including a 3-day rebleeding rate (25.0% vs 7.7%, P < 0.0001), 30-day rebleeding rate (32.6% vs 12.1%, P < 0.0001), and higher mortality rate (16.3% vs 2.0%, P < 0.0001). This study emphasizes the role of non-H. pylori idiopathic ulcers and in-hospital bleeders as the determining high-risk predictors for bleeding peptic ulcers.

Incremental cost effectiveness of proton pump inhibitors for the prevention of non-steroidal anti-inflammatory drug ulcers: a pharmacoeconomic analysis linked to a case-control study

IntroductionWe estimated the cost effectiveness of concomitant proton pump inhibitors (PPIs) in relation to the occurrence of non-steroidal anti-inflammatory drug (NSAID) ulcer complications.MethodsThis study was linked to a nested case-control study. Patients with NSAID ulcer complications were compared with matched controls. Only direct medical costs were reported. For the calculation of the incremental cost effectiveness ratio we extrapolated the data to 1,000 patients using concomitant PPIs and 1,000 patients not using PPIs for 1 year. Sensitivity analysis was performed by 'worst case' and 'best case' scenarios in which the 95% confidence interval (CI) of the odds ratio (OR) and the 95% CI of the cost estimate of a NSAID ulcer complication were varied. Costs of PPIs was varied separately.ResultsIn all, 104 incident cases and 284 matched controls were identified from a cohort of 51,903 NSAID users with 10,402 NSAID exposition years. Use of PPIs was associated with an adjusted OR of 0.33 (95% CI 0.17 to 0.67; p = 0.002) for NSAID ulcer complications. In the extrapolation the estimated number of NSAID ulcer complications was 13.8 for non-PPI users and 3.6 for PPI users. The incremental total costs were € 50,094 higher for concomitant PPIs use. The incremental cost effectiveness ratio was € 4,907 per NSAID ulcer complication prevented when using the least costly PPIs.ConclusionsConcomitant use of PPIs for the prevention of NSAID ulcer complications costs € 4,907 per NSAID ulcer complication prevented when using the least costly PPIs. The price of PPIs highly influenced the robustness of the results.

Ulcers and gastritis

Upper gastrointestinal bleeding (UGIB) remains a major problem worldwide. Over time the management issues have changed and a paradigm shift occurred when it became clearly established that eradication of Helicobacter pylori would ”cure” peptic ulcers, including the elimination of new ulcers, recurrent ulcers, and ulcer complications. The subsequent recognition that H. pylori infections increased the risk of complications from nonsteroidal anti-inflammatory drugs (NSAIDs) led to the recommendation to test NSAID and aspirin users for H. pylori, and to eradicate the infection whenever it is found. Unfortunately, eradication of H. pylori is no longer straightforward, as clinicians are facing the increasing challenge of resistant strains. Moreover, eradication of H. pylori alone will not solve the problem of NSAID ulcer complications because NSAIDs themselves increase the risk of UGIB. Unresolved issues include identification of the circumstances in which particular traditional NSAIDs or cyclo-oxygenase-2 (COX-2)-selective inhibitors are preferred, and the actual role for gastroprotective co-therapy.

Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to non-steroidal anti-inflammatory drugs: a nested case-control study

Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by gastrointestinal ulcer complications, such as ulcer bleeding and perforation. The efficacy of proton-pump inhibitors in the primary prevention of ulcer complications arising from the use of NSAIDs remains unproven. Selective cyclooxygenase-2 (COX-2) inhibitors reduce the risk for ulcer complications, but not completely in high-risk patients. This study determines which patients are especially at risk for NSAID ulcer complications and investigates the effectiveness of different preventive strategies in daily clinical practice. With the use of a nested case-control design, a large cohort of NSAID users was followed for 26 months. Cases were patients with NSAID ulcer complications necessitating hospitalisation; matched controls were selected from the remaining cohort of NSAID users who did not have NSAID ulcer complications. During the observational period, 104 incident cases were identified from a cohort of 51,903 NSAID users with 10,402 patient years of NSAID exposure (incidence 1% per year of NSAID use, age at diagnosis 70.4 ± 16.7 years (mean ± SD), 55.8% women), and 284 matched controls. Cases were characterised by serious, especially cardiovascular, co-morbidity. In-hospital mortality associated with NSAID ulcer complications was 10.6% (incidence 21.2 per 100,000 NSAID users). Concomitant proton-pump inhibitors (but not selective COX-2 inhibitors) were associated with a reduced risk for NSAID ulcer complications (the adjusted odds ratio 0.33; 95% confidence interval 0.17 to 0.67; p = 0.002). Especially at risk for NSAID ulcer complications are elderly patients with cardiovascular co-morbidity. Proton-pump inhibitors are associated with a reduced risk for NSAID ulcer complications.

Primary care physician perceptions of non‐steroidal anti‐inflammatory drug and aspirin‐associated toxicity: results of a national survey

To assess primary care physician perceptions of non-steroidal anti-inflammatory drug (NSAID) and aspirin-associated toxicity. A group of gastroenterologists and internal medicine physicians created a survey, which was administered via the Internet to a large number of primary care physicians from across the US. One thousand primary care physicians participated. Almost one-third of primary care physicians recommended 325 mg rather than 81 mg of aspirin/day for cardioprotection. Fifty-nine percent thought enteric-coated or buffered aspirin reduced the risk of upper gastrointestinal (GI) bleeding. Seventy-six percent believed that Helicobacter pylori infection increased the risk of NSAID ulcers but fewer than 25% tested NSAID users for this infection. More than two-thirds were aware that aspirin co-therapy decreased the GI safety benefits of the cyclo-oxygenase 2 selective NSAIDs. However, 84% felt that aspirin with a cyclo-oxygenase 2 selective NSAID was safer than aspirin with a non-selective NSAID. When presented a patient at high risk for NSAID-related GI toxicity, almost 50% of primary care physicians recommended a proton pump inhibitor and cyclo-oxygenase 2 selective NSAID. This survey has identified areas of misinformation regarding the risk-benefit of NSAIDs and aspirin and the utilization of gastroprotective strategies. Further education on NSAIDs for primary care physicians is warranted.

Long-term Outcome of Helicobacter pylori–Negative Idiopathic Bleeding Ulcers: A Prospective Cohort Study

Helicobacter pylori-negative idiopathic ulcers are increasingly recognized. The secular trend and long-term outcome of this condition are unknown. We prospectively studied consecutive patients with bleeding gastroduodenal ulcers from January to December 2000. The incidence and etiology of ulcers during this period were compared with that between September 1997 and August 1998. H. pylori-negative idiopathic ulcers were defined as negative tests for H. pylori, no exposure to analgesics within 4 weeks, and absence of other risk factors for ulcers. After the ulcers had healed, patients with H. pylori-negative idiopathic ulcers and patients with H. pylori ulcers who received eradication therapy were followed up for 12 months without anti-ulcer drugs. Six hundred thirty-eight patients had bleeding ulcers: 213 (33.4%) were H. pylori ulcers, and 120 (18.8%) were H. pylori-negative idiopathic ulcers (vs 480 [50.3%] H. pylori ulcers and 40 [4.2%] H. pylori-negative idiopathic ulcers in 1997-1998; P < .001). H. pylori-negative idiopathic ulcers accounted for 16.1% of patients who were admitted for bleeding and 42.4% of patients who bled while in the hospital (P < .0001); 28.3% of patients with H. pylori-negative idiopathic ulcers had histologic evidence of past H. pylori infection. The probability of recurrent ulcer complications in 12 months was 13.4% (95% CI: 7.3%-19.5%) in patients with H. pylori-negative idiopathic ulcers and 2.5% (95% CI: 0.4%-4.6%) in patients with H. pylori ulcers who received eradication therapy (P = .0002). The incidence of H. pylori-negative idiopathic bleeding ulcers is rising. These ulcers are prone to recurrent complications.

Ulcers and gastritis.

Significant advances continue to be made in the area of gastritis and ulcer disease. Studies to identify the most appropriate use of capsule endoscopy have now confirmed that it is superior to other methods for identifying small-bowel mucosal pathology and sites of obscure gastrointestinal bleeding. It has increasingly been recognized that the complications of ulcer disease are secondary to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and to interactions between NSAIDs and Helicobacter pylori. Effective prophylaxis for NSAID ulcers in H. pylori-negative individuals continues to be a challenge, as it has become clear that conclusions from studies focusing on "endoscopic ulcers" in patients whose H. pylori status was unknown provided a false sense of security. The concept of multifocal atrophic gastritis has been challenged. The precursor lesion to gastric cancer now appears to be a sheet of pseudopyloric metaplasia advancing into the gastric body with islands of intestinal metaplasia embedded within it. Multifactorial models such as those proposed for understanding periodontal disease, including the organism, environmental factors, and host factors, appear particularly applicable to understanding the pathogenesis of H. pylori-associated gastric cancer.

Management of peptic ulcer disease not related to Helicobacter.

Most peptic ulcers not due to Helicobacter pylori are caused by non-steroidal anti-inflammatory drugs (NSAID), among which an important subset are due to vascular protective ("low-dose") aspirin therapy. Non-steroidal anti-inflammatory drugs ulcers heal quite quickly when treated with a proton pump inhibitor (PPI), even though the NSAID is continued. If the NSAID can be stopped, the ulcers heal readily with either a PPI or a histamine H2-receptor antagonist (H2-RA). If anti-inflammatory treatment is still needed after ulcers are healed, prophylactic co-therapy with a PPI or misoprostol will reduce the risk of ulcer recurrence by about 60-80%. The alternative of switching to a highly selective cyclooxygenase-2 inhibitor has been shown to reduce the risk of a complicated ulcer by about 50-60%, unless low-dose aspirin treatment needs to be given as well for vascular disease. Idiopathic ulcers are becoming more frequent as H. pylori prevalence falls. Some may be sequelae of previous NSAID ulceration even though the NSAID has been ceased and the original ulcer had healed. These are best treated with an H2-RA or a PPI, followed by long-term maintenance with either of these (often in half the healing dosage) to prevent recurrence. Ulcers due to Zollinger-Ellison syndrome and other hypergastrinemia syndromes are rare, and largely beyond the scope of this review.

Treat H. Pylori Infection and Lower NSAID Ulcer Risk

H elicobacter pylori infection and nonsteroidal anti-inflammatory drugs (NSAIDs) have both been associated with increased risk for peptic-ulcer disease. Two recent studies explore the contribution of each, the interactions between them, and possible interventions to lessen risk for ulcers. In a double-blind, randomized, placebo-controlled trial, Chan and colleagues recruited NSAID-naive patients with positive H. pylori breath tests and a history of dyspepsia or peptic ulcers who required long-term NSAID therapy. Patients were randomized to receive omeprazole …

Helicobacter pylori infection and the use of NSAIDs

Helicobacter pylori infection and the use of non-steroidal anti-inflammatory drugs (NSAIDs) can each result in gastroduodenal ulcers and ulcer complications. Recent studies have suggested that there is an interaction between the two causes such that elimination of H. pylori before NSAID treatment decreases the occurrence of ulcers. This led to the conclusion of the Maastricht 2000 meeting that H. pylori eradication should be considered before embarking on long-term NSAID therapy. One of the main sources of confusion is related to the fact that prospective endoscopic studies testing various drugs for prevention of NSAID ulcers among chronic NSAID users are probably not directly applicable to problems of clinical ulcers and of ulcer complications. It has become clear that, to be interpretable clinically, such studies must provide separate analyses based on H. pylori status, history of ulcer, or an ulcer complication. Overall, the data strongly support the notion that eradication therapy is beneficial for primary prophylaxis. In contrast, one would expect little benefit when NSAIDs caused the clinical ulcer (secondary prevention) and, at best, H. pylori eradication has a modest effect on the prevention of recurrent ulcer bleeding in NSAID users who have suffered ulcer complications. The data support the notion that H. pylori eradication therapy should be given to all H. pylori -infected patients with peptic ulcers irrespective of whether or not they have used NSAIDs. Proton pump inhibitors are superior to placebo for the prevention of ulcer recurrence but are inferior to full-dose misoprostol for the prevention of ulcers among those with NSAID ulcers and no H. pylori infection. Selective COX-2 inhibitors appear to reduce markedly, but not eliminate, ulcer complications among chronic NSAID users.

Ulcer complications associated with anti‐inflammatory drug use. What is the extent of the disease burden?

Information on the intake of non-steroidal anti-inflammatory drugs (NSAIDs) and on aspirin taken regularly by patients with peptic ulcer bleeding aged 60 years and over was used in conjunction with data measuring the overall frequency of hospital admissions with ulcer bleeding in England and Wales to determine the annual burden of disease imposed by particular treatment strategies. Over 40% of the calculated 8528 episodes of ulcer bleeding in those aged 60 years and over, and over 40% of the estimated 981 deaths each year would seem to be causally related to the treatments. Substitution of the NSAID with the lowest associated risk would be expected to reduce the frequency of non-aspirin NSAID-associated episodes of ulcer bleeding, and deaths, each by over 70%. Use of the lowest conventional dose of regular prophylactic aspirin (75 mg) would also be expected to reduce the frequency of treatment-related episodes, and deaths, by nearly 30%. Both strategies employed together would be expected to reduce NSAID and regular aspirin-related bleeding ulcer admissions from 4121 to less than 2184, and deaths from 523 to less than 250. Substitution of completely safe anti-inflammatory analgesics and anti-platelet drugs would be expected to reduce admissions from 4121 to 1072, and deaths from 523 to 123.

Helicobacter pylori and nonsteroidal anti-inflammatory drugs: interaction with proton pump inhibitor therapy for prevention of nonsteroidal anti-inflammatory drug ulcers and ulcer complications—future research needs

Two recently reported studies of nonsteroidal anti-inflammatory drugs (NSAIDs), the Omeprazole versus Misoprostol for NSAID-induced Ulcer Management and the Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment studies, concluded that omeprazole was superior to a subtherapeutic misoprostol or an ineffective dose of ranitidine for the endpoint, prevention of gastroduodenal ulcers in chronic NSAID users. Helicobacter pyloristatus was collected prospectively but was not reported. We report separate analyses for patients with unequivocal NSAID ulcers ( H. pylori negative) and patients whose NSAID use was complicated by the presence of an active H. pylori infection. Omeprazole was superior to placebo for the prevention of ulcer recurrence in chronic NSAID users. However, omeprazole was not significantly better than a subtherapeutic dose of misoprostol for the prevention of gastroduodenal ulcers in chronic NSAID users. Misoprostol was superior to omeprazole for the prevention of gastric ulcers among those patients with unequivocal NSAID ulcers (8.2% vs 16.6%, respectively; P <0.05). Omeprazole was not statistically different from misoprostol for gastric ulcer prevention in those whose NSAID use was complicated by an active H. pylori infection. Ranitidine and omeprazole were also not statistically different for the prevention of unequivocal NSAID gastric ulcers (14.6% vs 11.6%, respectively; P = 0.56). That the Misoprostol Ulcer Complications Outcomes Safety Assessment (MUCOSA) trial found full-dose misoprostol to be more effective in ulcer prevention than it was in prevention of ulcer complications suggests that either many of the ulcer complications were related to H. pylori ulcers or that more antisecretory activity than can be provided with misoprostol is needed, or both. The question remains whether the combination of low-dose misoprostol plus an antisecretory drug (either an H 2-receptor antagonist or a proton pump inhibitor) would provide superior results compared with either alone. That omeprazole was not superior to one half the dose of misoprostol used in the ulcer complication prevention, or MUCOSA, study indicates that it would not be prudent to suggest that ulcer prevention with omeprazole alone would be able to provide similar protection to misoprostol.

Approaches to healing and prophylaxis of nonsteroidal anti-inflammatory drug–associated ulcers

Treating and preventing peptic ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDs) calls for clinical judgment. Physicians must weigh their patients’ need for anti-inflammatory therapy against their individual risks for ulcer development; their likelihood of coping with an ulcer complication if it should develop; and the economics, efficacy, and tolerability of various treatment and prevention options. This article considers some general strategies common to both treatment and prevention. Data from randomized trials that can guide clinicians and their patients as they attempt to heal an established NSAID ulcer or prevent one occurring in the future are also reviewed.