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BACKGROUND - Although joint use of nonsteroidal anti-inflammatory drugs (NSAIDs) and oral anticoagulants may increase the risk of gastrointestinal tract hemorrhage in elderly persons, no epidemiologic studies have been performed to quantify this risk.
METHODS - We performed a retrospective cohort study of Tennessee Medicaid enrollees aged 65 years or older from 1984 through 1986. A total of 103,954 individuals contributed 209,066 person-years of follow-up, including 2203 person-years of current oral anticoagulant use, to the study.
RESULTS - Of the cohort members, 1371 had confirmed hospitalizations for peptic ulcer disease. Of these, 661 (48%) presented with frank hematemesis or melena and thus met the definition for hemorrhagic peptic ulcer disease. Among current users of oral anticoagulants, the adjusted incidence of hospitalization for peptic ulcer disease was 14.3 per 1000 person-years, and the adjusted incidence of hospitalization for hemorrhagic peptic ulcer disease was 10.2 per 1000 person-years. Compared with nonusers, current anticoagulant users were at increased risk for hospitalization for ulcer disease (relative risk, 2.2; 95% confidence interval, 1.6 to 3.1), primarily due to the increased risk of hospitalization for hemorrhagic ulcers (relative risk, 3.3; 95% confidence interval, 2.3 to 4.9). Compared with nonusers of either drug, the relative risk of hemorrhagic peptic ulcer disease among current users of both anticoagulants and NSAIDs was 12.7 (95% confidence interval, 6.3 to 25.7). However, the prevalence of NSAID use among anticoagulant users was 13.5%, the same as in those who were not using anticoagulants.
CONCLUSIONS - The nearly 13-fold increase in the risk of developing hemorrhagic peptic ulcer disease in concurrent users of oral anticoagulants and NSAIDs suggests that NSAIDs should be prescribed with extreme caution in patients undergoing anticoagulation therapy.
Approximately 50% of Helicobacter pylori strains produce a cytotoxin, encoded by vacA, that induces vacuolation of eukaryotic cells. Analysis of a clinically isolated tox- strain (Tx30a) indicated secretion of a 93-kDa product from a 3933-base pair vacA open reading frame. Characterization of 59 different H. pylori isolates indicated the existence of three different families of vacA signal sequences (s1a, s1b, and s2) and two different families of middle-region alleles (m1 and m2). All possible combinations of these vacA regions were identified, with the exception of s2/m1 (p < 0.001); this mosaic organization implies that recombination has occurred in vivo between vacA alleles. Type s1/m1 strains produced a higher level of cytotoxin activity in vitro than type s1/m2 strains; none of 19 type s2/m2 strains produced detectable cytotoxin activity. The presence of cagA (cytotoxin-associated gene A) was closely associated with the presence of vacA signal sequence type s1 (p < 0.001). Among patients with past or present peptic ulceration, 21 (91%) of 23 harbored type s1 strains compared with 16 (48%) of 33 patients without peptic ulcers; only 2 (10%) of 19 subjects harboring type s2 strains had past or present peptic ulcers (p < 0.005). Thus, specific vacA genotypes of H. pylori strains are associated with the level of in vitro cytotoxin activity as well as clinical consequences.
CD44, an integral membrane glycoprotein expressed by many cell types, serves as the principal transmembrane hyaluronate receptor and may be a determinant of metastatic and invasive behavior in carcinomas. The expression of CD44 in 23 gastric adenocarcinoma and 12 peptic ulcer disease (PUD) resection specimens and gastric carcinoma cell lines HS746t and KATO III was examined by immunohistochemistry using the murine monoclonal antibody A3D8 on formalin-fixed, paraffin-embedded tissue or cells. Western blot analysis of whole cell lysates of KATO III and HS746t cells showed protein bands at 85 to 90 kd with KATO III cells expressing an additional band at 145 kd. In normal stomach gastric epithelium was negative. In PUD foveolar epithelium was focally positive, but staining did not correlate with the extent of gastritis. In carcinoma cases intensity of staining was progressively stronger comparing intestinal metaplasia with dysplasia with intramucosal carcinoma. Invasive carcinoma was invariably more strongly positive than dysplasia or intramucosal carcinoma. Twelve adenocarcinomas were weakly positive and 11 were strongly positive. The staining intensity of metastases (12 cases) was the same or weaker than the primary tumor. For the 12 patients whose carcinomas were weakly positive, mean length of survival for the six who died was 23.3 months. Five of the 11 patients whose carcinomas strongly expressed CD44 died within the study period with a mean length of survival of 11.0 months. A key consequence of CD44 overexpression in gastric carcinomas may be development of the invasive phenotype and strong expression may indicate a poorer prognosis.
STUDY OBJECTIVE - To determine the association between current non-aspirin nonsteroidal anti-inflammatory drug (NSAID) use and fatal peptic ulcers or upper gastrointestinal hemorrhage.
DESIGN - Nested case control study using a linked Medicaid-death certificate database.
SETTING - Tennessee Medicaid enrollees aged 60 and greater from 1976 to 1984.
PATIENTS - One hundred twenty-two patients, "the cases," had a terminal hospitalization and a peptic ulcer or upper gastrointestinal hemorrhage confirmed by hospital chart review. Population controls (n = 3897) were matched to potential cases by age, sex, race, calendar year, and nursing home status.
MEASUREMENTS AND MAIN RESULTS - "Cases" more frequently filled a prescription for an NSAID within 30 days before onset of illness than controls (34% compared with 11%; adjusted odds ratio, 4.7; 95% CI, 3.1 to 7.2). This association between fatal ulcer disease and current NSAID use was consistent in three age groups, women and men, whites and nonwhites, and community and nursing home dwellers. There was no significant association between case status and previous NSAID use (adjusted odds ratio, 1.9; 95% CI, 0.7 to 4.7).
CONCLUSIONS - The findings of this study add to the growing evidence that NSAIDs can increase the risk for clinically serious peptic ulcer disease in the elderly.
A community-based group of gastroenterologists examined 623 patients (541 prospectively and 82 retrospectively) with endoscopically diagnosed gastric ulcer disease during a 12-month period. Patients averaged 60 years of age; the majority were women (62%). Women were less likely to smoke, abuse alcohol, and were more likely to present with abdominal pain (p less than 0.05). Whereas patients presenting with bleeding or requiring transfusion were less likely to complain of pain (p less than 0.05), they were more likely to be taking aspirin or nonsteroidal anti-inflammatory drugs and have prior history of bleeding (p less than 0.05). Patients with a prior history of ulcer disease were more likely to smoke, present with pain and use acetaminophen (p less than 0.05). Patients with large ulcers were more likely to bleed, present with pain, and obstruct (p less than 0.05). Multiple gastric ulcers were seen in patients taking aspirin or nonsteroidal anti-inflammatory drugs (p less than 0.05).
Helicobacter pylori infection is strongly associated with histologic gastritis and peptic ulcer disease. Broth culture supernatants from a subset of H. pylori strains induce vacuolization in cultured cells, a phenomenon that has been attributed to cytotoxin activity. Concentrated culture supernatants from 15 of 28 (53.6%) H. pylori strains tested induced vacuolization in HeLa cells in titers ranging from 1:10 to 1:180. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and silver staining of supernatants from these 28 strains and 2 control strains demonstrated an 82-kilodalton (kDa) protein band in 3 of 16 supernatants with vacuolizing activity, but in none of 14 supernatants without vacuolizing activity. By immunoblotting with human sera, a 128-kDa band was recognized in all 16 supernatants with vacuolizing activity, compared with 9 of 14 (64%) supernatants without vacuolizing activity (P = 0.014). Serologic recognition of the 128-kDa band in H. pylori culture supernatants was more prevalent among persons infected with vacuolizing H. pylori strains than among persons infected with nonvacuolizing strains, but the difference was not statistically significant (80 versus 45%; P = 0.079); human serologic recognition of the 82-kDa band was less common. The 128-kDa band was recognized by 100% of 31 serum samples from H. pylori-infected patients with duodenal ulcer disease, compared with 60.8% of 74 serum samples from H. pylori-infected persons without peptic ulcer disease (P = 0.0001). These data indicate that antigenic 128- and 82-kDa proteins are present in H. pylori broth culture supernatants with vacuolizing activity and that serologic responses to the 128-kDa protein are more prevalent among H. pylori-infected persons with duodenal ulceration than among infected persons without peptic ulceration.
OBJECTIVE - To estimate the relative risk for peptic ulcer disease that is associated with the use of oral corticosteroids.
DESIGN - A nested case-control study.
SETTING - Tennessee Medicaid program.
PARTICIPANTS - The case patients (n = 1415) were hospitalized between 1984 and 1986 for gastric or duodenal ulcer or for upper gastrointestinal hemorrhage of unknown cause. The controls (n = 7063) were randomly selected from Medicaid enrollees not meeting the study criteria for inclusion as case patients.
MEASUREMENTS AND MAIN RESULTS - The estimated relative risk for the development of peptic ulcer disease among current users of oral corticosteroids was 2.0 (95% CI, 1.3 to 3.0). However, the risk was increased only in those who concurrently received nonsteroidal anti-inflammatory drugs (NSAIDs); these persons had an estimated relative risk associated with current corticosteroid use of 4.4 (CI, 2.0 to 9.7). In contrast, the estimated relative risk for those corticosteroid users not receiving NSAIDs was 1.1 (CI, 0.5 to 2.1). Persons concurrently receiving corticosteroids and NSAIDs had a risk for peptic ulcer disease that was 15 times greater than that of nonusers of either drug.
CONCLUSION - Discrepant findings among earlier studies regarding steroids and the risk for peptic ulcer disease could in part be due to differences in the use of NSAIDs among study participants. The high risk for peptic ulcer disease associated with combined use of NSAIDs and corticosteroids indicates the need to prescribe this drug combination cautiously.
OBJECTIVE - To evaluate the relative risk for peptic ulcer disease that is associated with the use of nonaspirin nonsteroidal anti-inflammatory drugs.
DESIGN - Nested case-control study.
SETTING - Tennessee Medicaid program.
PARTICIPANTS - Medicaid enrollees 65 years of age or older were included in the study. The 1415 case patients had been hospitalized for confirmed peptic ulcer disease at some point from 1984 through 1986. The 7063 control persons represented a stratified random sample of other Medicaid enrollees.
MEASUREMENTS AND MAIN RESULTS - The estimated relative risk for the development of peptic ulcer disease among current users of nonaspirin nonsteroidal anti-inflammatory drugs, compared with that among nonusers, was 4.1 (95% CI, 3.5 to 4.7). For current users, the risk increased with increasing dose, from a relative risk of 2.8 (CI, 1.8 to 4.3) for the lowest to a relative risk of 8.0 (CI, 4.4 to 14.8) for the highest dose category. The risk was greatest in the first month of use (relative risk, 7.2; CI, 4.9 to 10.5). If the association is fully causal, 29% of peptic ulcers in the study sample resulted from the use of these drugs, and the excess risk associated with such use was 17.4 hospitalizations for ulcer disease per 1000 person-years of exposure.
CONCLUSIONS - These data support other findings indicating that a clinically significant risk for serious ulcer disease is associated with the use of nonaspirin nonsteroidal anti-inflammatory drugs. The data show that this risk increases with dose and recency of use and that use of these drugs may be responsible for a large proportion of peptic ulcer disease among elderly persons.
Helicobacter pylori infection is now recognized as the primary cause of active chronic gastritis in humans. Most infected persons remain asymptomatic, but are at increased risk for the development of peptic ulcer disease and possibly gastric cancer. The pathogenesis of this infection is not well understood, but motility and urease activity are virulence factors in an animal model. The eradication of H. pylori infection is associated with resolution of gastritis and a decreased rate of duodenal ulcer recurrence.