Clinical aspects of upper gastrointestinal bleeding associated with the use of nonsteroidal antiinflammatory drugs

Objective: The aim of this study was to compare the clinical features of major upper gastrointestinal bleeding among patients exposed to nonsteroidal antiinflammatory drugs (NSAID) and those not taking these drugs.
Methods: Using data from a multicenter international case-control study designed to evaluate the role of drugs in the etiology of major upper gastrointestinal bleeding (UGIB), patients with a confirmed first episode of major UGIB were divided into two groups: those exposed to NSAIDs during the week before the onset of bleeding, and those not exposed. The groups were compared according to age and sex, clinical appearance and site of the bleeding, preceding symptoms, and requirement for transfusion and acute surgery.
Results: The median age was significantly higher and the proportion of women was slightly higher among the NSAID users. There was no significant difference between users and nonusers according to the clinical presentation, the site of the bleeding, or the frequency of preceding symptoms. Forty percent in each group had no symptoms before the onset of bleeding. Slightly more NSAID users received blood transfusions, although the same median amount of blood per transfusion was given in both groups. There was no difference in the frequency of surgical intervention.
Conclusions: There are no important differences in the clinical presentation of major UGIB according to whether or not an individual is an NSAID user. An important finding is the frequent absence of preceding symptoms in patients with major UGIB, regardless of NSAID use.     

Outcome of peptic ulcer bleeding, nonsteroidal anti-inflammatory drug use, and Helicobacter pylori infection.

BACKGROUND & AIMS: NSAIDs and Helicobacter pylori are risk factors for the development of peptic ulcers. A prospective study was conducted to determine prevalence of NSAID use, H pylori infection, and outcome of peptic ulcer bleeding. METHODS: In 2000, data of all 361 patients presenting with peptic ulcer bleeding were prospectively collected in a defined geographical area, including 14 hospitals, and serving a catch area of 1.68 million persons. Follow-up data after a mean of 31 months were obtained from 211 patients. RESULTS: The overall incidence was 21.5 cases per 100,000 persons. Mean age of the group was 70.9 years, 55% were male, and 41% had severe or life-threatening comorbidity. NSAIDs were used by 52%, and in only 17% concomitant acid suppressive therapy was given. H pylori infection was tested in 64%. Of the patients tested for H pylori, 43% were positive. Twenty-three percent were H pylori negative and not using NSAIDs. Rebleeding during initial admission occurred in 19%. Mortality during initial admission was 14%. During follow-up mortality was high, 29%. CONCLUSIONS: Half of all ulcer bleeding was associated with NSAID use. Only a minority of NSAID users used concomitant acid suppressive therapy. H pylori is not assessed systematically in all patients with ulcer bleeding. Almost a quarter of the ulcers were associated with neither H pylori infection nor NSAID use. Mortality, both during hospitalization and follow-up, was substantial.     

30-day mortality after peptic ulcer perforation among users of newer selective COX-2 inhibitors and traditional NSAIDs: a population-based study

OBJECTIVES: Nonsteroidal anti-inflammatory drug (NSAID) use is a strong risk factor for peptic ulcer perforation, yet little is known about the outcome of this condition among NSAID users. We examined 30-day mortality after peptic ulcer perforation associated with the use of traditional NSAIDs and newer selective cyclo-oxygenase-2 (COX-2) inhibitors. METHODS: We conducted a cohort study of patients with the first hospitalization for peptic ulcer perforation, identified in discharge registries of three Danish counties between 1991 and 2003. Data on preadmission NSAID use, other ulcer-related drugs, and comorbidity were likewise from population-based registries. Mortality was ascertained from the Civil Registration System. We compared 30-day mortality in NSAID users and nonusers while adjusting for age, gender, comorbidity, previous uncomplicated peptic ulcer, and ulcer medication use. RESULTS: Of the 2,061 patients hospitalized with peptic ulcer perforation, 38% were current NSAID users. The 30-day mortality was 25% overall, and 35% among current NSAID users. Compared with never-use, the adjusted 30-day mortality rate ratios (MRRs) were 1.8 (95% CI 1.4-2.3) for current use of NSAIDs alone and 1.6 (95% CI 1.2-2.2) for current use combined with other ulcer-associated drugs. The mortality increase associated with the use of COX-2 inhibitors was similar to that of traditional NSAIDs: adjusted MRR for users of COX-2 inhibitors alone and in combination, 2.0 (1.3-3.1) and 1.4 (0.8-2.5), and for users of traditional NSAIDs alone or in combination, 1.7 (1.3-2.3) and 1.6 (1.2-2.3). CONCLUSION: Current use of NSAIDs, including COX-2 inhibitors, is associated with a poor prognosis for patients hospitalized with peptic ulcer perforation.     

NSAID use and BP in treated hypertensives: a retrospective controlled observational study

The objective of this study was to investigate the association between NSAID use and blood pressure (BP) among a sample of treated hypertensive patients. A controlled observational study was designed in UK primary care setting. Patients with diagnosed hypertension and currently being prescribed antihypertensive medication registered with four general practices, comparing patients also prescribed NSAIDs (exposed) to those not prescribed NSAIDs (unexposed). Majority of the patients were elderly. Systolic and diastolic pressure were the outcome measures. Data were collected for 184 NSAID users and 762 nonusers with a mean age of 68 years. There was no difference in either systolic (adjusted difference 1.9 mmHg, 95% CI -0.7 to 4.5, P=0.15) or diastolic (adjusted difference 1.0 mmHg, 95% CI -0.3 to 2.3, P=0.15) blood pressure. There was no evidence of any interactions according to categories of age, sex, or number of antihypertensive drugs prescribed. Among NSAID users, there was no evidence of any differences in blood pressure according to NSAID type or dose. In conclusion we found no evidence for an association between NSAID usage and BP control in known hypertensive patients receiving antihypertensive medication in primary care. The reported association between NSAID use and BP control appears much less substantial than has been previously suggested.     

Impact of discontinuing non-steroidal antiinflammatory drugs on long-term recurrence in colonic diverticular bleeding

AIM: To determine the effect of discontinuing nonsteroidal antiinflammatory drugs(NSAIDs) on recurrence in long-term follow-up patients with colonic diverticular bleeding(CDB).METHODS: A cohort of 132 patients hospitalized for CDB examined by colonoscopy was prospectively enrolled. Comorbidities, lifestyle, and medications(NSAIDs, low-dose aspirin, antiplatelet agents, anticoagulants, acetaminophen, and corticosteroids) were assessed. After discharge, patients were requested to visit the hospital on scheduled days during the followup period. The Kaplan-Meier method was used to estimate recurrence.RESULTS: Median follow-up was 15 mo. The probability of recurrence at 1, 6, 12, and 24 mo was 3.1%, 19%, 27%, and 38%, respectively. Of the 41 NSAID users on admission, 26(63%) discontinued NSAID use at discharge. Many of the patients who could discontinue NSAIDs were intermittent users, and could be switched to alternative therapies, such as acetaminophen or an antiinflammatory analgesic plaster. The probability of recurrence at 12 mo was 9.4% in discontinuing NSAID users compared with 77% in continuing users(P < 0.01, log-rank test). The hazard ratio for recurrence in the discontinuing NSAIDs users was 0.06 after adjusting for age > 70 years, right-sided diverticula, history of hypertension, and hemodialysis. No patients developed cerebrocardiovascular events during follow-up.CONCLUSION: There is a substantial recurrence rate after discharge among patients hospitalized for diverticular bleeding. Discontinuation of NSAIDs is an effective preventive measure against recurrence. This study provides new information on risk reduction strategies for diverticular bleeding.     

Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti-inflammatory drugs: a case-control study.

BACKGROUND & AIMS: Peptic ulcer complications related to use of nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common serious adverse drug reactions. Whether Helicobacter pylori infection potentiates this gastrointestinal toxicity of NSAIDs is still unresolved. In this study, we investigated the role of H. pylori as a cause of bleeding peptic ulcer among NSAID users. METHODS: A case-control study of current users (n = 132) of NSAIDs (including acetylsalicylic acid), admitted because of bleeding peptic ulcer, was performed. Controls were 136 NSAID users without gastrointestinal complications. H. pylori was diagnosed by either increased levels of serum immunoglobulin G or by 13C-urea breath test. RESULTS: Fifty-eight (44%) case subjects had a bleeding gastric ulcer, 54 (41%) had a bleeding duodenal ulcer, 12 (9%) had both gastric and duodenal ulcers, and 8 (6%) had hemorrhagic gastritis. H. pylori was present in 75 (57%) cases compared with 59 (43%) controls. The adjusted odds ratio of bleeding peptic ulcer among NSAID users associated with H. pylori infection was 1.81 (95% confidence interval, 1.02-3.21). H. pylori accounted for approximately 24% of bleeding peptic ulcers among elderly NSAID users. CONCLUSIONS: NSAID users infected with H. pylori have an almost twofold increased risk of bleeding peptic ulcer compared with NSAID users without H. pylori.     

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.     

Visible small-intestinal mucosal injury in chronic NSAID users.

BACKGROUND & AIMS: Patients who regularly take nonsteroidal anti-inflammatory drugs (NSAIDs) have an increased risk for small-intestinal mucosal ulceration and bleeding, which may present as anemia of undetermined gastrointestinal origin or protein loss. The prevalence and severity of small-intestinal lesions remains unclear. Our aim was to assess the frequency of NSAID-induced small-bowel injury among chronic NSAID users. METHODS: Ambulatory patients with various types of arthritides who took NSAIDs daily (>3 mo duration) or took either acetaminophen alone or nothing were enrolled in the study. All patients fasted overnight and underwent wireless video capsule endoscopy. Two investigators, blind to therapy, reviewed each video beginning after the pylorus. Lesions were scored as normal, red spots, small erosions, large erosions, or ulcers. An ulcer was defined as a larger lesion with apparent depth and a definite rim. RESULTS: Forty-one patients, 36 men and 5 women, ages ranging from 22 to 66 years (mean age, 49.8 y) were analyzed including 21 chronic NSAID users and 20 control patients. Small-bowel injury was seen in 71% of NSAID users compared with 10% of controls (P < .001). Injury was mild (few or no erosions, absence of large erosions/ulcers) in 10 NSAID users compared with 2 controls. Five NSAID users had major (>4 erosions or large ulcers/ulcers) damage compared with none in the control group. There were no complications or problems with the capsule endoscopy procedure. CONCLUSIONS: Endoscopically evident small-intestinal mucosal injury is very common among chronic NSAID users. The role of endoscopically evident injury in unexplained iron-deficiency anemia and hypoalbuminemia among chronic NSAID users remains undetermined.     

Primary non-variceal upper gastrointestinal bleeding in NSAID and low-dose aspirin users: development and validation of risk scores for either medication in two large Dutch cohorts

Background

Non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose acetylsalicylic acid (ASA) have several adverse gastrointestinal (GI) effects, including upper GI bleeding. We aimed to develop a simple risk score to identify high risk NSAID and ASA users for primary upper GI bleeding.

Methods

Using data from two large anonymized health insurance databases, we defined a development and validation cohort with NSAID and ASA users which were followed-up for the occurrence of a primary upper GI bleeding. Cox regression analyses identified risk factors which were combined into simple risk scores. C-statistics were used to evaluate the discriminative ability of these scores in a validation cohort.

Results

In total, 421 cases of upper GI bleeding were identified in the initial cohort of 784,263 NSAID users (incidence rate 54.2 per 10,000 person-years), while 1,295 cases of upper GI bleeding were identified in 235,531 ASA users (incidence rate 37.9 per 10,000 person-years). The risk of upper GI bleeding increased with a higher risk score, which for NSAID users included age, male gender, anemia and concomitant use of ASA or anticoagulants. For ASA users, age, anemia, diabetes and concomitant use of other antiplatelet drugs or anticoagulants were included in the risk score. The C-statistics in the validation cohort were 0.68 and 0.63 or NSAID and ASA users, respectively.

Conclusion

Risk factors for primary upper GI bleeding are to a large extent similar for NSAID and ASA users. Using a risk score based on these risk factors, patients at the highest risk can be identified with moderate accuracy.     

Utilization of nonsteroidal anti-inflammatory drugs and antisecretory agents: a managed care claims analysis

PURPOSE: To describe patients initiating nonsteroidal anti-inflammatory drug (NSAID) therapy with regard to gastrointestinal and cardiac risks and patterns of antisecretory agent use, and to explore the relation between therapy type and subsequent outcomes. METHODS: We studied patients aged 18 years or older who had continuous coverage from 1998 to 2001 and who had initiated treatment with cyclooxygenase-2 (COX-2) selective inhibitors or nonselective NSAIDs. Patients were categorized with respect to gastrointestinal and cardiac risk profiles. Proton pump inhibitor use within 15 days of initiating NSAID therapy was considered prophylactic. Logistic regression analysis was used to evaluate associations between treatment and hospitalization events, cardiac events, and health care costs. RESULTS: We identified 106,564 eligible NSAID initiators: 65.2% used COX-2 inhibitors and 34.8% used traditional NSAIDs. Users of COX-2 inhibitors were more likely to be at higher risk of gastrointestinal bleeding and cardiac events than were NSAID users. Proton pump inhibitor prophylaxis was most common among users of COX-2 inhibitors, but was only 11% in patients at high risk of gastrointestinal bleeding. There were no differences among treatment groups in terms of gastrointestinal or cardiac events. Initiation of COX-2 inhibitor therapy was associated with greater total health care costs. CONCLUSION: Although we found that COX-2 inhibitors were used more frequently than were traditional NSAIDs in certain groups of patients with varying cardiac or gastrointestinal risk, we did not find that their use resulted in reductions in clinical events, cotherapy with proton pump inhibitors, or costs, suggesting that a better understanding of the relation between NSAID treatment strategies and outcomes in patients with differing risk characteristics is needed.     

Risk of peptic ulcer hospitalizations in users of NSAIDs with gastroprotective cotherapy versus coxibs

BACKGROUND & AIMS: The primary strategies to reduce the risk of serious gastropathy caused by traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are use of a coxib or concurrent use of a proton pump inhibitor or double-dose histamine-2 receptor antagonist. However, the relative clinical effectiveness of these therapeutic alternatives is understudied. METHODS: We studied peptic ulcer hospitalizations in a cohort of Tennessee Medicaid enrollees between 1996 and 2004. To decrease potential "channeling" bias, the study included only new episodes of prescribed NSAID or coxib use and controlled for multiple baseline risk factors for upper gastrointestinal disease. There were 234,010 and 48,710 new episodes of NSAID and coxib use, respectively, with 363,037 person-years of follow-up and 1223 peptic ulcer hospitalizations. RESULTS: Current users of NSAIDs with no gastroprotective cotherapy had an adjusted incidence of peptic ulcer hospitalizations of 5.65 per 1000 person-years, 2.76 (95% confidence interval, 2.35-3.23) times greater than that for persons not currently using either NSAIDs or coxibs. This risk was reduced by 39% (16%-56%, 95% CI) for current users of NSAIDs with gastroprotective cotherapy and 40% (23%-54%) for current users of coxibs without such cotherapy. Concurrent users of NSAIDs and proton pump inhibitors had a 54% (27%-72%) risk reduction, very similar to the 50% (27%-66%) reduction for concurrent users of proton pump inhibitors and coxibs. CONCLUSIONS: These findings suggest that coprescribing a proton pump inhibitor with an NSAID is as effective as use of a coxib for reducing the risk of NSAID-induced gastropathy.     

Health care resource utilization and costs of NSAID-induced gastrointestinal toxicity. A population-based study in Switzerland

BACKGROUND AND AIMS: The well-recognized gastrointestinal toxicity of NSAIDs ranges from mild symptoms to severe complications requiring medical attention and leading to work loss. The present study evaluates the economic burden derived from health care resource utilization and work loss caused by NSAID-induced gastrointestinal toxicity in the Swiss population. The costs induced by conventional and COX2-selective NSAIDs were calculated separately, and the results were then extrapolated for the United States. METHODS: A computer-generated random sampling of the Swiss population (n = 6,118) was administered a questionnaire by phone. Questions investigated NSAID intake, occurrence of adverse effects, consumption of gastroprotective drugs, health care resource utilization and work loss. Country-specific direct and indirect costs associated with NSAID-induced gastrointestinal toxicity were calculated according to current reimbursement costs in Switzerland and the United States. Medication expenses were used to compute separate iatrogenic cost factors for conventional and COX2-selective NSAIDs. The ability of demographic variables and symptoms to predict resource utilization was analyzed by univariate and multivariate analyses. RESULTS: From among the 6,085 responders (99.5% response rate), 294 subjects had gastrointestinal adverse effects associated with NSAID intake. The annual amount spent on NSAID-related adverse effects was CHF 432.2 million for Switzerland and USD 7,425.7 million for the United States. This amount corresponded to CHF 581 and USD 272 per NSAID user, and was primarily due to costs derived from work loss. For Switzerland, 91.1% of total costs were associated with the use of conventional NSAIDs and could be saved by using COX2-NSAIDs instead. While additional 13% of the medication purchase costs are spent for gastrointestinal adverse effects among COX2-selective NSAID users, additional 315% are spent for the same reason among conventional NSAID users. Thus, given similar efficacy and purchase costs in the two drug groups, COX2-selective NSAIDs are 25.1 times more cost-effective than conventional NSAIDs. Language region, place of residence, nationality, marital status, epigastric pain, diarrhea, hematemesis and melena predicted resource utilization. CONCLUSIONS: Costs arising from NSAID-induced gastrointestinal toxicity are considerable and primarily associated with conventional NSAIDs. COX2-selective NSAIDs could decrease this economic burden.     

Underutilization of gastroprotective measures in patients receiving nonsteroidal antiinflammatory drugs

OBJECTIVE: To determine the frequency of use of recommended gastroprotective strategies in a cohort of patients receiving recurrent treatment with nonsteroidal antiinflammatory drugs (NSAIDs). METHODS: A cross-sectional study was performed using administrative data from the Tennessee Medicaid (TennCare) program. The study population consisted of 76,765 recurrent recipients of NSAIDs (NSAID users), comprising 24% of the 319,402 persons ages 50 years or older enrolled in the TennCare program from January 1999 through June 2000. Frequency of use of either of 2 recommended gastroprotective strategies, involving either traditional NSAIDs combined with recommended anti-ulcer cotherapy or use of a selective cyclooxygenase 2-inhibiting drug (coxib), was measured and categorized by risk for ulcer complication. RESULTS: Among this cohort of recurrent NSAID users, 16% received 1 of the 2 recommended gastroprotective therapies: 10% received traditional NSAIDs along with antiulcer drugs at the recommended doses and 6% received coxibs. Among those patients with > or=2 risk factors for ulcer complications (age 75 years or older, peptic ulcer or gastrointestinal bleeding in the past year, or concurrent use of oral anticoagulants or corticosteroids), 30% received such gastroprotective therapy. CONCLUSION: Use of recommended strategies to decrease ulcer complications in vulnerable populations is relatively uncommon.     

L’ulcère bulbaire hémorragique et les anti-inflammatoires non stéro?diens : quelle gravité de l’accident hémorragique ?

Introduction

Non steroidal anti inflammatory drugs (NSAIDs) are among the most prescribed and used drugs, because of their therapeutic efficacy in multiple epidemiological indication. Severity of the bleeding in the case of duodenal ulcer would be different between the group of patients taking NSAIDs and those not taking NSAIDs before bleeding complication.

Materials and methods

We propose to study the group of patients admitted for bleeding peptic ulcer (BPU) with NSAIDs and to compare it to the group without NSAIDs. Four hundred and twenty eight patients were admitted during this period for bleeding duodenal ulcer.

Results

The NSAID previous hemorrha 29.5% of patients (n=126). There was no statistically significant difference between the group taking NSAID (n=126) and NSAIDs negative (n=302) in terms of average age (45.4 vs 45 respectively). There is a clear male predominance compared in the 2 groups. There was no statistically significant difference in terms of average rate of Hte, endoscopic data (seat of the ulcer, stage Forrest, endoscopic hemostasis). The surgery was no more frequent in cases of BPU associated with NSAID Furthermore, patients who used NSAIDs had more frequent initial hemodynamic instability (4 patients vs 1, p=0.01), recurred more frequently (8.7% vs 4%, p=0.04) and there was trend to more death in the group with NSAID.

Conclusion

The episode of bleeding from peptic ulcer associated with NSAID use was more severe     

Risk of ulcer bleeding in patients infected with Helicobacter pylori taking non-steroidal anti-inflammatory drugs

OBJECTIVE: To determine whether Helicobacter pylori is an independent risk factor for bleeding peptic ulcer in users of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin. DESIGN: A prospective matched case-control study. SETTING: Odense University Hospital, Denmark. SUBJECTS: 132 patients with a bleeding peptic ulcer (n=124) or haemorrhagic gastritis (n=8) at endoscopy who had taken an NSAID in the previous week and 136 controls who had taken NSAIDs without gastrointestinal complications. The controls were recruited from rheumatology and geriatric outpatient clinics. MEASUREMENTS: H pylori status assessed by serology and 13C-urea breath test and regarded as positive if either test was positive. Data on potential confounding factors including smoking and alcohol were collected by interview. MAIN RESULT: H pylori was present in 57% of cases and 43% of controls. The adjusted odds ratio of bleeding from a peptic ulcer owing to H pylori infection in NSAID users was 1.81 (95% CI 1.02 to 3.21) and was similar in aspirin and non-aspirin NSAID users. Peptic ulcer bleeding was also statistically significantly associated with a history of previous ulcer bleeding, dyspepsia within the previous 3 months, drinking alcohol but not with smoking. About 16% of bleeding peptic ulcers in NSAID users could be attributed to H pylori infection. CONCLUSION: NSAID users infected with H pylori have an almost doubled risk of bleeding peptic ulcer compared with uninfected NSAID users.