Upper Gastrointestinal Events Research Articles

A Nationwide Study of Mortality Associated with Hospital Admission Due to Severe Gastrointestinal Events and Those Associated with Nonsteroidal Antiinflammatory Drug Use

The worst outcome of gastrointestinal complications is death. Data regarding those associated with nonsteroidal antiinflammatory drug (NSAID) or aspirin use are scarce. To determine mortality associated with hospital admission due to major gastrointestinal (GI) events and NSAID/aspirin use. The study was based on actual count of deaths from two different data sets from 2001. Study 1 was carried out in 26 general hospitals serving 7,901,198 people. Study 2 used a database from 197 general hospitals, representative of the 269 hospitals in the Spanish National Health System. Information regarding gastrointestinal complications and deaths was obtained throughout the Minimum Basic Data Set (CIE-9-MC) provided by participating hospitals. Deaths attributed to NSAID/aspirin use were estimated on the basis of prospectively collected data from hospitals of study 1. The incidence of hospital admission due to major GI events of the entire (upper and lower) gastrointestinal tract was 121.9 events/100,000 persons/year, but those related to the upper GI tract were six times more frequent. Mortality rate was 5.57% (95% CI = 4.9-6.7), and 5.62% (95% CI = 4.8-6.8) in study 1 and study 2, respectively. Death rate attributed to NSAID/aspirin use was between 21.0 and 24.8 cases/million people, respectively, or 15.3 deaths/100,000 NSAID/aspirin users. Up to one-third of all NSAID/aspirin deaths can be attributed to low-dose aspirin use. Mortality rates associated with either major upper or lower GI events are similar but upper GI events were more frequent. Deaths attributed to NSAID/ASA use were high but previous reports may have provided an overestimate and one-third of them can be due to low-dose aspirin use.

Validation of ICD-9 Codes Used for the Diagnosis of Upper Gastrointestinal Events (UGIE) Following NSAID Prescription

Aim: To determine if diagnostic and procedural codes can accurately diagnose an upper gastrointestinal event (UGIE) following NSAID prescription. Methods: A retrospective cohort study at the Houston VA. Administrative databases were reviewed for ICD-9 codes 531-534 or 578 that overlapped with NSAID prescription (01/01/01-12/31/02). The medical record was reviewed to confirm UGIE based on surgery, endoscopy, radiology, or autopsy notes or evidence of a 20% drop in hemoglobin or hematocrit. Sensitivity, specificity, positive predictive value, and negative predictive value for the ICD-9 codes were determined, using the medical chart as the gold standard.

A Comparison of Reported Gastrointestinal and Thromboembolic Events Between Rofecoxib and Celecoxib Using Observational Data

Rofecoxib, a selective cyclo-oxygenase (COX)-2 inhibitor, was a widely marketed drug that was used for relief of pain and inflammation in arthritic conditions. It was withdrawn from the market worldwide in September 2004 because of an increased risk of cardiovascular events. Celecoxib, which belongs to the same class of drugs, is now under scrutiny for the risk of similar events. The objective of our study was to compare the incidence of gastrointestinal (GI) [symptomatic and complicated upper GI] events and thromboembolic (cardiovascular, cerebrovascular and peripheral venous) events reported for patients prescribed rofecoxib or celecoxib in primary care. A retrospective analysis of selected events was conducted using data collected from previously conducted prescription-event monitoring (PEM) studies for rofecoxib and celecoxib. PEM is an observational cohort technique. Exposure data were derived from dispensed prescriptions for rofecoxib (July-November 1999) and celecoxib (May-December 2000) that were written by primary care general practitioners in England. Outcome data were clinical events and information on potential risk factors reported on simple questionnaires (posted to prescribers approximately 9 months after the date of the first prescription). Incidence rates of the first event during treatment within each thromboembolic and GI group were calculated during the 270 days after the patient started receiving either of the drugs; crude and adjusted rate ratios (RR) were calculated for rofecoxib compared with celecoxib using Poisson regression modelling. The rofecoxib and celecoxib PEM cohorts contained 15 268 and 17 458 patients, respectively. For the GI event groups, the adjusted RRs for rofecoxib compared with celecoxib were: 1.21 (95% CI 1.09, 1.36) for symptomatic upper GI events and 1.60 (95% CI 0.95, 2.70) for complicated upper GI conditions. For the thromboembolic event groups, the adjusted RRs were: 1.04 (95% CI 0.50, 2.17) for cardiovascular thromboembolic events; 1.43 (95% CI 0.86, 2.38) for cerebrovascular thromboembolic events; and 0.36 (95% CI 0.01, 1.34) for peripheral venous thromboembolic events. This study was a retrospective comparison of PEM studies conducted for rofecoxib and celecoxib. For symptomatic upper GI events, a 21% increase in the relative rate was found for rofecoxib users compared with celecoxib users after adjusting for identified risk factors. For complicated upper GI events, no statistically significant difference in the incidence was observed between rofecoxib and celecoxib users after adjusting for identified risk factors. For the three thromboembolic event groups, no evidence of a statistically significant difference between rofecoxib and celecoxib users was found after adjusting for identified risk factors. This study contributes to the understanding of the association between COX-2 inhibitors and thromboembolic events. However, it should be borne in mind that we had information on only a limited number of confounding variables for thromboembolic events. Further research is required to fully understand the risks and benefits of using celecoxib and other COX-2 inhibitors. Meanwhile, doctors should be cautious when prescribing these products, particularly to patients with risk factors for developing thromboembolic events.

Assessing the cost-effectiveness of COX-2 specific inhibitors for arthritis in the Veterans Health Administration

ABSTRACTObjective: This study was designed to assess the cost-effectiveness of cyclooxygenase-2 specific (COX-2) inhibitors (rofecoxib and celecoxib) over nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in high-risk arthritis patients from the perspective of the Veterans Health Administration (VA).Methods: This literature-based economic analysis (with data summarized from MEDLINE-indexed and other published sources, FDA reports, and data on file at VA San Diego Healthcare System) compared rofecoxib and celecoxib to NSAIDS in two arthritis patient populations considered at higher risk of developing clinically significant upper gastrointestinal events (CSUGIEs): (1) patients of any age with previous medical history of perforation/ulcer/bleed (PUB); and (2) patients 65 years and older (regardless of history of PUB). Two outcome measures were reported: (1) incremental cost per CSUGIE averted over 1 year; and (2) incremental cost per quality-adjusted life-year (QALY) gained, considering both the mortality and morbidity associated with gastrointestinal (including CSUGIEs) and cardiovascular-related adverse events. When possible, costs were modeled to reflect the VA perspective. Sensitivity analyses were conducted to test the robustness of the analysis.Results: Compared to NSAIDS, rofecoxib and celecoxib increased costs but reduced the incidence of CSUGIE. Cost per CSUGIE avoided were $7476 and $16,379 (in patients with a PUB history) and $14,294 and $18,376 (in patients aged ≥ 65 years) for celecoxib and rofecoxib, respectively. In both populations, celecoxib was associated with a cost per QALY less than $50,000. In contrast, rofecoxib was found to cost more and result in a net QALY loss, due in particular to the increase in the risk of cardiovascular complications, and was therefore considered cost-ineffective. Results were most dependent on assumptions about the incidence of cardiovascular events and CSUGIE and the COX-2 inhibitors‚ acquisition price.Conclusions: This analysis suggests that COX-2 inhibitors may be cost-effective from the perspective of the VA. However, cost-effectiveness appears to depend less on the specific characteristics of the high-risk target population considered but more on the agent evaluated. Celecoxib appears to be an alternative to traditional NSAIDs in the patient populations studied.

Risk of serious upper gastrointestinal and cardiovascular thromboembolic complications with meloxicam

Purpose To assess the risk of serious gastrointestinal and thromboembolic complications with approved doses of meloxicam. Methods We pooled data from clinical trials of meloxicam at doses of 7.5 or 15 mg/d. A blinded gastrointestinal adjudication committee used prespecified criteria to identify gastric or duodenal perforation, gastric outlet obstruction, or hemodynamically important upper gastrointestinal bleeding. For analysis of thromboembolic complications, investigator-reported events were analyzed without adjudication. Results We analyzed data from 24,196 patients from 28 trials, most of whom had been followed for up to 60 days. Of these patients, 13,118 received meloxicam (10,158 received a daily dose of 7.5 mg and 2960 received 15 mg), 5283 were treated with diclofenac 100 mg, 181 received diclofenac 150 mg, 5371 were treated with piroxicam 20 mg, and 243 received naproxen 500 mg twice daily. Patients who received 7.5 mg of meloxicam daily had a 0.03% risk of serious upper gastrointestinal events, which was significantly lower than the risk in those who received diclofenac, naproxen, or piroxicam ( P <0.02). With the 15 mg daily dose of meloxicam, this risk was significantly different only when compared with piroxicam ( P = 0.03). The risk of thromboembolic events in patients treated with meloxicam at either dose was lower than with diclofenac, but similar to that observed with piroxicam and naproxen. Conclusion This pooled analysis of 24,196 patients demonstrates that meloxicam has a favorable gastrointestinal and thromboembolic safety profile. However, only a small number of patients were followed for more than 60 days, and meaningful comparisons were not possible in this subgroup.

COX-2 inhibition, H. pylori infection and the risk of gastrointestinal complications.

Current data on the gastric safety of cyclooxygenase-2 (COX-2) inhibitors in the presence of H. pylori infection are largely derived from animal experiments and indirect clinical evidence. In animal models of H. pylori gastritis, COX-2 inhibitors suppressed prostaglandin synthesis and aggravated mucosal damage. In the human stomach, COX-1 appears to be the predominant source of prostaglandins despite the fact that COX-2 is upregulated in H. pylori gastritis. There are conflicting data on whether H. pylori alters the risk of ulcer in patients receiving COX-2 inhibitors. Among patients with H. pylori infection, rofecoxib reduced the risk of complicated gastric but not duodenal ulcers as compared to naproxen. The advantage of rofecoxib over naproxen also disappeared in patients with H. pylori infection and prior upper gastrointestinal events. In contrast, pooled data suggested that H. pylori increases the risk of ulcer in patients receiving nonselective nonsteroidal anti-inflammatory drugs but not in patients receiving celecoxib. In rodent gastric ulcers, COX-2 was upregulated in the granulation tissue and ulcer margin. Inhibition of COX-2 delayed healing of experimental gastric ulcer. Limited data showed that COX-2 expression was also increased in human gastric ulcer regardless of the H. pylori status. The functional significance of COX-2 in human gastric ulcer is unknown.

Pharmacoepidemiology and rheumatic diseases: 2001-2002.

Pharmacoepidemiology is the branch of epidemiology that focuses on medications and their outcomes, including both adverse events and intended consequences. Such studies have become more prominent in rheumatology as the number of new medications has grown and prescribing databases have become more available. In the past year, the potential cardiovascular complications associated with selective COX-2 inhibitors have become an important concern. A number of pooled analyses suggest the possibility of an increased risk of acute myocardial infarction, and studies of naproxen have found a possible protective effect. Accumulating evidence supports the contention that early initiation of disease modifying antirheumatid drug therapy improves outcomes of patients with rheumatoid arthritis. Open-label extensions of biologic therapies found continued benefits extending several years with the TNF-alpha antagonists, but concerns have arisen regarding tuberculosis and central nervous system demyelination with these agents. Data continue to be published quantifying the risk of osteoporosis associated with glucocorticoids, and the association between biphosphonate therapy and upper gastrointestinal events appears to be less of a concern that originally described.

Upper gastrointestinal event risk with COX-2 inhibitors depended on known risk factors

Source Citation Laine L, Bombardier C, Hawkey CJ, et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheu...

Non-steroidal anti-inflammatory induced upper gastrointestinal event rates in patients awaiting joint replacement in the United Kingdom. An epidemiologically-based burden of disease model

SUMMARYObjective: To quantify the likely morbidity associated with upper gastrointestinal (GI) ulceration associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients awaiting hip and knee replacement surgery.Method: A burden of disease model was constructed, using Hospital Episode Statistics from the Department of Health in England, selected patient cohorts drawn from a pooled anonymised general practice database (MediPlus) and NSAID risk assessments from the published literature. Based on mean derived waiting times from the point of referral to admission for procedure and estimates of both patient exposure to NSAIDs, and the age-specific risk associated with this treatment, the excess risk associated with NSAIDs was then calculated.Results: In 2001-2, there were approximately 109000 hip and knee replacements carried out in the UK. The mean waiting time for hip and knee replacement, measured from the point of first referral by the GP, was found to be 443 days (95% CI 419-467). 73% (95% CI 72-74) of patients were found to be taking NSAIDs, equating to a total risk exposure of ∼ 96000 patient years. By applying known age-specific bleeding risks it was estmated that there were around 637 upper GI bleeds directly attributable to NSAID treatment in this cohort, with between 51 and 89 deaths resulting.Conclusions: In order to improve outcomes in this high-risk patient group, action must continue to reduce overall waiting times, while simultaneously adopting treatment regimes that are inherently less likely to cause upper gastrointestinal bleeding.

Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors.

Short-term endoscopic studies of the highly selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) rofecoxib and celecoxib have shown that these agents are well tolerated and have efficacy equivalent to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) with fewer adverse effects on the upper gastrointestinal (GI) tract. These studies are limited, however, as the detection of endoscopic lesions is not well correlated with symptomatic ulcers and ulcer complications. Outcomes studies of the GI safety are, therefore, essential to understanding how coxibs are likely to perform in a clinical practice setting. Four large outcomes studies (Vioxx Gastrointestinal Outcomes Research, VIGOR; Assessment of Difference Between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness trial, ADVANTAGE; Celecoxib Long-term Arthritis Safety Study, CLASS; and the Successive Celecoxib Efficacy and Safety Studies, SUCCESS) examined the GI safety of rofecoxib and celecoxib in over 39,000 patients with osteoarthritis or rheumatoid arthritis. Results of these studies showed that patients taking a supratherapeutic dose of rofecoxib or celecoxib had significantly lower rates of GI-related adverse events than those taking a nonselective NSAID (naproxen, ibuprofen, or diclofenac). Reduced risk of upper GI events was seen in patients with multiple risk factors and in patients using low-dose aspirin and corticosteroids concomitantly with a coxib. Results of large outcomes studies provide support for the COX-2 hypothesis and demonstrate the long-term safety and tolerability of coxibs.

Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms

Background: There have been reports from physicians in clinical practice that up to 30% of patients taking bisphosphonate therapy develop upper gastrointestinal (UGI) symptoms, many or most of which they assume to be related to the drug. However, in several large placebo-controlled clinical trials of bisphosphonates, the incidence of UGI symptoms has been ≥30%, even among patients receiving placebo, perhaps reflecting a high background incidence of UGI events in osteoporotic patients. Objective: To assess the relationship between alendronate treatment and UGI complaints in patients who had discontinued treatment with alendronate in clinical practice because of UGI symptoms, we compared the incidence of such events on rechallenge with alendronate or placebo. Methods: This was a multicenter, double-blind trial in which postmenopausal women with osteoporosis who had previously discontinued alendronate therapy because of a UGI adverse experience were randomized to daily treatment with either alendronate 10 mg or matching placebo (1:1 ratio) for 8 weeks. The primary end point was the cumulative incidence of discontinuations due to any UGI adverse experience. Secondary end points were the incidence of any clinical adverse experiences and the percentage change from baseline in urinary N-telopeptide adjusted for urinary creatinine at week 8. Results: A total of 172 women were included in the study. They were a mean of 20.9 years past menopause, ranging in age from 41 to 90 years (mean, 67.0 years); 90.7% were white. On rechallenge, 14.8% ( 13 88 ) of patients in the alendronate group and 16.7% ( 14 84 ) in the placebo group discontinued treatment because of UGI adverse experiences. Conclusion: The results of this study suggest that many UGI adverse experiences reported during therapy with alendronate may reflect a high background incidence of UGI complaints and an increased sensitivity to detection of such complaints, rather than a causal relationship to therapy.

Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study

Objectives: To determine the profile of risk of upper gastrointestinal toxicity during continuous treatment with, and after cessation of, non-steroidal anti-inflammatory drugs.Design: Cohort study with a prospectively constructed, population based,...

Meta-analysis of risk factors for peptic ulcer. Nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking.

Attributable risk models describe the role of three risk factors for peptic ulcer and related serious upper gastrointestinal (GI) events. The factors-nonsteroidal antiinflammatory drugs (NSAIDs), Helicobacter pylori, and cigarette smoking-have been identified as major risk factors for peptic ulcer in numerous clinical and epidemiologic studies. Overall risk ratios for each risk factor were based on meta-analyses of English-language studies of risk for peptic ulcer-related GI events. Exposure estimates for factors used data from North American populations. Summary risk and exposure values were computed for the general population, males and females separately, and the elderly. Hypothetical models of multiple factor attributable risks were developed using population attributable risk percent calculated from these summary values. General population attributable risk percent were as follows: 24%, NSAIDs; 48%, H. pylori; and 23%, cigarette smoking. Based on these numbers, the "no interaction" attributable risk model estimates that 95% of total peptic ulcer related risk is attributable to these factors in the general population. The "interaction" model attributes 89% of cases to these risk factors: 24%, NSAIDs alone; 31%, H. pylori alone; 34%, H. pylori/smoking combined. Between 89% and 95% of peptic ulcer-related serious upper GI events may be attributed to NSAID use, H. pylori infection, and cigarette smoking.

New exposure to NSAIDS and hospitalisation for upper gastro-intestinal events and haemorrhage: A record-linkage study in the population of Tayside, Scotland

New exposure to NSAIDS and hospitalisation for upper gastro-intestinal events and haemorrhage: A record-linkage study in the population of Tayside, Scotland

Extra-articular manifestations of rheumatoid arthritis: risk factors for serious gastrointestinal events.

Serious upper gastrointestinal events are an important threat to patients with arthritis who are treated with non-steroidal anti-inflammatory drugs (NSAIDs). In this study risk factors for serious upper gastrointestinal events are identified in patients with possible or definite rheumatoid arthritis (RA). A retrospective analysis of factors that might contribute to the risk of serious upper gastrointestinal events was performed in a cohort of 2315 consecutive patients with possible or definite RA. The relative influences of disease severity, drug treatment, particularly with corticosteroids, and history of peptic ulceration were analysed with a conditional logistic regression model for the 106 patients with serious upper gastrointestinal intestinal events and for an equal number of control patients who were matched for age, gender, number of criteria for RA, and disease duration. The incidence rate for serious upper gastrointestinal events was 4.0/1000 patients in each year. The study reconfirmed that age over 60 years, history of peptic ulceration, and use of corticosteroids are risk factors. The presence of extra-articular manifestations of RA was associated with a two to 11-fold increase in the risk for serious upper gastrointestinal events. This risk was independent of the use of corticosteroids. Disease severity, in particular the presence of extra-articular features, may be an important factor in the pathogenesis of upper gastrointestinal ulceration in patients with RA who are treated with NSAIDs.