Gastropathy in the elderly (Helicobacer pylori or/and NSAID)

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Specifics of Helicobacter pylori Infection/NSAID Effects in the Elderly Mladen Davidovic, Petar Svorcan, Pavle Milanovic, Aleksandr Antovic, Dragoslav Milosevic Geriatric Clinic KBC Zvezdara, Beograd, Serbia and Montenegro

Abstract The prevalence of Helicobacter pylori (HP) infection increases with age worldwide. Unlike in younger patients, the presentation of peptic disease in the elderly population is subtle and atypical, and thus leads to a delay of diagnosis. Due to comorbidities and advanced age, it results in increased complications, morbidity and mortality. Bleeding and perforation are frequent complications and therefore peptic ulcer in adult patients represents a serious disease. The relationship between the infection caused by HP and the use of non-steroidal anti-inflammatory drugs (NSAID) in the pathogenesis of peptic ulcer disease is still controversial. However these two factors, independently or in synergy, represent the principal cause of peptic ulcer development in the adult population. In patients diagnosed with peptic ulcer caused by HP, more than half take medications containing aminosalicylic acid. Helicobacter pylori infection in elderly NSAID users is associated with an increased ulcer incidence, but not with an increased prevalence of upper digestive tract bleeding. Helicobacter pylori and NSAID consumption are independent and unrelated risk factors for upper gastrointestinal tract bleeding. Eradication of HP is recommended before the initiation of a long-term aspirin administration in elderly patients. Low aspirin dosages are associated with a high risk of ulcer bleeding. The risk of upper gastrointestinal bleeding in elderly patients is significantly higher in the cases of acute abuse of NSAIDs relative to its chronic use. The simultaneous use of NSAID or aspirin and selective serotonin reuptake inhibitors – antidepressants, increases the risk of upper gastrointestinal bleeding. Peptic ulcer disease in the adult population, if Romanian Journal of Gastroenterology September 2005 Vol.14 No.3, 253-258 Address for correspondence: Professor Mladen Davidovic Geriatric Clinic KBC Zvezdara,11050 Beograd Rifata Burdzevica 31 Serbia and Montenegro E-mail:[email protected]

combined with old age, presence of serious and/or lifethreatening diseases, as well as repeated ulcer bleedings, shows a high mortality rate.

Key words Elderly – gastropathy - Helicobacter pylori - NSAID peptic ulcer

Rezumat Prevalenþa infecþiei cu Helicobacter pylori (Hp) creºte cu vârsta. Spre deosebire de pacienþii tineri, la vârstnici simptomatologia bolii peptice este discretã ºi atipicã, conducând la întârziere în diagnostic. Datoritã comorbiditãþilor ºi vârstei înaintate creºte numãrul complicaþiilor, morbiditatea ºi mortalitatea. Hemoragia ºi perforaþia reprezintã complicaþii frecvente, ulcerul peptic putând avea o evoluþie severã. Relaþia dintre infecþia cu Hp ºi antiinflamatoarele non-steroidiene (AINS) în patogeneza ulcerului peptic este încã controversatã. Totuºi, aceºti doi factori, acþionând independent sau sinergic, reprezintã cauza principalã a ulcerului peptic la adulþi. Mai mult de jumãtate dintre pacienþii diagnosticaþi cu ulcer peptic Hp pozitiv au folosit medicamente ce conþin acid aminosalicilic. Infecþia cu Helicobacter pylori la pacienþii vârstnici care folosesc AINS se coreleazã cu creºterea incidenþei ulcerului dar nu se coreleazã cu prevalenþa crescutã a hemoragiilor la nivelul tractului digestiv superior. Helicobacter pylori ºi consumul de AINS reprezintã factori de risc independenþi pentru hemoragiile la nivelul tractului digestiv superior. Se recomandã eradicarea infecþiei cu Hp înaintea instituirii terapiei cu aspirinã pe termen lung la pacienþii vârstnici. Administrarea de doze mici de aspirinã se asociazã cu creºterea riscului de ulcer hemoragic. Riscul de hemoragie digestivã superioarã la pacienþii vârstnici este semnificativ crescut în cazul unui abuz acut de AINS pe fondul unei administrãri cronice. Folosirea simultanã de AINS sau aspirinã ºi inhibitori selectivi ai recaptãrii serotoninei - antidepresive, creºte riscul de hemoragie digestivã superioarã.

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Hemoragiile repetate sau asocierea ulcerului peptic cu vârsta înaintatã ºi comorbiditãþi severe prezintã o ratã crescutã a mortalitãþii

Introduction Peptic disease in elderly patients is relatively frequent and recently has increased in prevalence (1). The high incidence of gastric and duodenal ulcer in geriatric patients suggests that the pathophysiological mechanisms of its development differ from those in the younger population. The immune deficit, due both to age and to accompanying diseases, is an important factor (2). Equally responsible are the infections caused by Helicobacter pylori (HP) and the broad unselective use of non-steroidal anti-inflammatory drugs (NSAID). NSAIDs and/or aspirin use is very high in the elderly outpatient population. The use of these drugs is associated significantly with a greater number of upper gastrointestinal (GI) symptoms and prescriptions for GI drugs (2,3). The prevalence of HP infection worldwide increases with age. Asymptomatically it exists in 40-60% of elderly patients, and in more than 70% of elderly patients with gastroduodenal diseases (4,5). There is a strong correlation between the duration of time in a nursing home and the prevalence of HP infection (6). It was suggested that any relationship between poor oral health of investigated persons and seropositivity for Hp may be due to both loss of teeth and HP colonization being associated with socioeconomic status and related factors (7).

The relationship between infection caused by Helicobacter pylori and use of NSAID Peptic ulcer in the elderly is primarily caused by HP and the use of NSAIDs, which are counted as aggressive factors. Altered defensive mechanisms at the level of gastric mucosa are another cause of peptic ulcer in the elderly. Secretion of protective prostaglandins in the elderly is decreased, while the secretion of neutral glycoprotein and N-acetylneuraminic acid is increased in patients with peptic ulcer (8). Basal acid output, pentagastrin stimulated acid, pepsin, pepsinogen and gastrin output are not changed in the elderly (8). Prostaglandin (PG) inhibition, as measured by changes in PG concentrations, correlated significantly with NSAID concentrations in plasma and differed significantly between high and low NSAID doses. Measurement of PG plasma concentrations appears to be a promising marker for the estimation of relative potency of NSAIDs (9). Acid secretion plays a pivotal role, not only in the pattern of HP induced gastritis and its consequences but also in NSAID induced gastropathies. It was proposed that the lack of antisecretory effect of PGE2 observed in C57BL/6 mice could reflect the extent of HP induced inflammation and status of acid secretion in response to NSAIDs (10).

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The main component of mucosa defense is its hydrophobicity and it is decreased in NSAID users and in HP infection. Hydrophobicity is also decreased in elderly patients regardless of HP status (11). In the elderly, peptic ulcer heals slower compared with younger patients. Responsible factors are pulmonary and cardiovascular diseases, use of NSAID, cardiovascular drugs and antidepressants. Smoking is another important factor that slows the healing of peptic ulcer (12). There is strong evidence of an altered eicosanoid pattern generated by leukocytes in gastroduodenal ulcer patients, which becomes obvious with in vitro modulation by arachidonic or acetylsalicylic acid. The phenomenon of an abnormal eicosanoid pattern in gastroduodenal ulcer is yet not fully understood, but may have implications in pathophysiology and diagnostics (13). Table I Gastroduodenal diseases in the elderly. Pathogenetic facts Increased (Ref.)

Decreased (Ref.)

The prevalence of Helicobacter pylori (4,5).

Secretion of protective prostaglandins (5).

Secretion of neutral glycoprotein and N-acetylneuraminic acid in patients with peptic ulcer (5).

Hydrophobicity in NSAID users and in HP infection (6).

The risk of upper gastrointestinal bleeding in case of simultaneous use of NSAIDs or aspirin and selective serotonin reuptake inhibitors - antidepressants (16) . Statistical important correlation between increased thickening of intima and atheromatous plaque with HP infection (18).

Mucosa defense (2).

Significantly lower levels of ferritin are found in HP positive female patients taking low-dose aspirin, while such effects were not documented in male patients (34)

Mucosa barrier in the elderly can be damaged by gastric stasis, biliary reflux and ischemia. Vitamin C deficiency may result in gastric mucosa atrophy (14). HP infection, especially cagA+ trait, negatively correlates with vitamin C levels (15). Sometimes, Candida albicans can be found in peptic ulcers (16). The relationship between the infection caused by HP and the use of NSAID in the pathogenesis of peptic ulcer disease is still controversial (17). However these two factors, independently or in synergy, represent the principal cause of peptic ulcer development in the adult population. In patients diagnosed with peptic ulcer caused by HP, more than half take medications containing aminosalicylic acid. The use of these drugs has no significant influence on ulcer localization as has been suggested in earlier studies. NSAIDs cause gastrointestinal damage primarily due to the inhibition of prostaglandin synthesis in gastric mucosa, which is an important factor in mucosa protection (18).

Gastropathy in the elderly (Helicobacer pylori or/and NSAID)

Clinical features Peptic ulcer disease is one of the rare illnesses where symptoms are mitigated in elderly patients. Unlike in younger patients, the presentation of peptic disease in the elderly population is subtle and atypical, and this leads to a delay in diagnosis. Together with the co-morbidities and the advanced age, it results in increased complications, morbidity and mortality (19). Table II Gastroduodenal diseases in the elderly. Clinical facts Incidence

Gastric vs duodenal ulcer 1:7 rate in younger population; in elderly the rate is 1.7:1.

Pilotto (4,5)

Mortality

Mortality is in 90% of cases connected with advanced age Mortality has increased since 1988, when it was 80%.

Linder (19)

Hospitalizations

In the USA the number of hospitalized patients with DU increased from 27% to 36% and for GU from 40% to 48% during a period of 8 years.

Uccheddu (23)

Prevalence of HP infection in elderly

Prevalence of HP infection in the elderly free of GI symptoms is 40-60%; in patients with GI symptoms it reaches 70%.

Pilotto (4,5)

However, the clinical presentation of ulcer in elderly patients has certain differences compared to younger patients. In the elderly, over 65 years, duodenal ulcer is rare, characteristic epigastric pain is also rare, but bleeding is often the first sign of an ulcer (20). Also it has been shown that the duration of symptoms related to misuse of NSAIDs in the elderly is shorter and localization of ulcer is more often atypical. The reason for this may be the fact that HP infection is not so frequent as in the young population. Though the most frequent cause of ulcer in elderly patients is NSAID use, the clinical picture has some particularities and it is not always due to misuse of NSAID. Anemia can be the only sign of the disease. Pain is usually not a dominant symptom even in very large ulcers. Typically, ulcers in the elderly are gastric ulcers, located high in the corpus, not infrequently larger than 3 cm (gastric) or 2 cm (duodenal). Gastric ulcers are more frequent than duodenal ulcers in the elderly, in a rate of 1.7:1. The same study showed that duodenal ulcers heal more slowly in the elderly than in the younger population during the first 4 weeks of treatment, but the difference disappears after 8 weeks of treatment (21). Peptic ulcer complications in the elderly are more frequent and more severe. In patients 70 years or older, bleeding ulcer mortality in internal medicine departments is 31% and 16% in surgical departments, supporting the fact that elective surgery should be considered early in the course of the disease in these patients (22). It is a fact that patients in “internal medicine” wards

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tend to have more co-morbidities and are sicker. Generally, the number of patients hospitalized due to peptic ulcer disease has decreased since 1950 up to the mid-eighties, but the number of hospitalizations due to bleeding or perforation has increased especially in older women, probably due to increased NSAID consumption (23,24). Ulcer perforation is a more frequently observed complication in the elderly than in younger patient (8). The same applies to mortality. Rebleeding is more frequent in very old (older than 80 years), and prognostic factors for rebleeding are ulcer size (larger than 2cm) and deranged liver function tests (25). The etiology of acute upper gastrointestinal bleeding (UGIB) has changed during the last 15 years probably due to the better therapeutic approach to chronic duodenal ulcer and increasing use of NSAIDs in the elderly (26). On the other hand, it seems that endoscopic hemostasis for peptic ulcer bleeding in patients aged 80 years or older is safe and effective. The rebleeding rate was not significantly different between the oldest group and the patients under 55 yrs (1). Bleeding and perforation are frequent complications and therefore peptic ulcer in adult patients represents a serious disease (27). Peptic ulcer disease in the adult population shows a high mortality level if combined with old age, the presence of serious and/or life-threatening diseases, as well as repeated ulcer bleedings (28).

Helicobacter pylori infection in elderly NSAID users. Treatment suggestions Close to one half of the patients with bleeding from peptic ulcer were using nonsteroidal anti-inflammatory drugs or aspirin. Rebleeding (22% vs 20%) and mortality (15% vs 14%) did not differ between the 1993/1994 and 2000. Increasing age, presence of severe and life-threatening comorbidity, and rebleeding were associated with higher mortality (28). Upper gastrointestial bleeding risk appears to correlate with clinical characteristics of the patient: it increases with age, comorbidity, and smoke and alcohol consumption. Among drugs, NSAIDs are associated with the highest UGIB risk, while nitrates have a reduced risk. a. Treatment and prevention of gastrointestinal bleeding in the elderly who use NSAID Helicobacter pylori infection in elderly NSAID users is related to increased ulcer incidence, but not with increased prevalence of bleeding from upper parts of the gastrointestinal tract (29). HP and NSAID are independent and unrelated risk factors for UGIB. It is possible that the elderly are more sensitive to NSAIDs, because bleeding occurs 7 times more frequently than in the younger NSAID users (30). Misoprostol can be used for prevention of NSAID ulcers (31), but its cost and side effects, pain and diarrhea make it unsuitable for ulcer disease prevention (32). Most recently, Japanese authors (33) suggest that deficiency of PG in the mucosa is a more important cause than HP infection of poor

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quality of ulcer healing. Therefore, a PG analogue may be a most reasonable tool for treatment of HP-negative peptic ulcers including NSAIDs ulcer, but it is often poorly tolerated because of diarrhea and abdominal pain. Elderly patients often have a tendency of constipation and lowest possibility of pregnancy. A PG-analogue may be not only safe but also favorable for such patients. Proton pump inhibitors (PPIs) are as efficient as misoprostol, while H2 receptor antagonists proved to be completely inefficient in ulcer and NSAID gastropathy prevention (32) . Significantly lower doses of ferritin are found in HP positive female patients taking low-dose aspirin and, while such effect was not documented in male patients (34). Given the small number of patients in that study, the results are not conclusive and prevention of NSAID gastropathy cannot be recommended in these patients. Prophylaxis of NSAID gastropathy is mandatory only in high-risk patients such as patients with a positive history of ulcer disease or concomitant corticosteroid and/or anticoagulant therapy. Prophylaxis should be instituted in these patients before long-term NSAID treatment is started (35). b. Risk factors other and in addition to H. pylori of upper gastrointestinal bleeding CagA positive HP infection is associated with an increased risk of ulcer bleeding. The risk from non-aspirin NSAIDs is even higher, but is less in HP infected people (36). Suprisingly, the HP prevalence , especially in older peptic ulcer patients using NSAID, is significantly lower in perforated and bleeding compared to that in noncomplicated ulcer, and this could be explained by direct suppression of HP by NSAID used by these patients (37). On the other hand, HP infection was associated with increased COX-2 expression in gastric antral mucosa for both NSAID users and nonusers, but not in gastric ulcer, where the effect of NSAID inhibition plays a major role. With these observations, we can interpret indirectly that HP eradication does not interfere with gastric ulcer healing in NSAID users (38). Low-dose aspirin is now commonly associated with ulcer bleeding (13). Minidose aspirin treatment is associated with a high prevalence of ulcerations of the stomach and duodenum. Esophagogastroduodenoscopy revealed ulcer or erosions in 47.8% of the patients (39). The most common cause of bleeding was peptic ulcer in 51 patients (45%) receiving anticoagulants compared to patients not receiving warfarin 59% (40). The simultaneous use of NSAID or aspirin and selective serotonin reuptake inhibitors – antidepressants, increases the risk of UGIB. The selective serotonin reuptake inhibitors themselves also contribute to the risk of UGIB, but their effect is moderate and equal to the small dosages of ibuprofen (41). c. Measures to reduce the risk of gastrointestinal bleeding There are a lot of possible methods to reduce the risk of GI bleeding.

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HP infection played a role in the pathogenesis of idiopathic thrombocytopenic purpura in approximately 30% of all patients assessed and in 45% of the patients with HP infection. Eradication of HP in idiopathic thrombocytopenic purpura patients led to improved disease evolution (42). Aspirin and clopidogrel are used for the secondary prevention of atherosclerotic events. What about the patients who are unable to take aspirin because of hypersensitivity and major gastrointestinal intolerance? The American College of Cardiology/American Heart Association guidelines state: “Clopidogrel should be administered to hospitalized patients” (43), but there is much research that suggests: “aspirin plus omeprazole was superior to clopidogrel in the prevention of recurrent ulcer bleeding” (44-47). We can add that the average cost of 30 tablets of clopidogrel is about 100 Euros; in comparison, a bottle of over-the-counter aspirin and a box of over-thecounter omeprazole together cost less than 20 Euros. The risk of UGIB is significantly higher in elderly acute vs chronic users of NSAIDs or regular-dose aspirin. In acute NSAID or aspirin users, co-treatment with PPIs, but not with H2-blockers, may reduce the risk of bleeding compared with non-users (48). d. The use of COX-2 inhibitors and prevention of gastrointestinal bleeding It is advisable, especially in elderly patients, as a prophylaxis of NSAID gastropathy and/or ulcer disease, to use selective COX-2 inhibitors such as celecoxib, rofecoxib or valdecoxib (49). COX-2 inhibitors cost less than PPI + diclofenac combination (50). The risk for the chronic use of H2 blocker or PPIs can be vitamin B12 deficiency in older adults (51), or an increased risk for acute myocardial infarction in current users of rofecoxib among elderly persons with no history of myocardial infarction. This risk appears greater at higher doses (52). Patients taking warfarin concomitantly with selective COX-2 inhibitors have an increased risk of hospitalization for UGIB. The risk appears similar to that of patients simultaneously taking warfarin and nonselective NSAIDs (53). Costs arising from NSAID-induced GI toxicity are considerable and primarily associated with conventional NSAIDs. COX2-selective NSAIDs could decrease this economic burden (54).

References 1. Yamaguchi Y, Yamato T, Katsumi N et al. Endoscopic hemostasis: safe treatment for peptic ulcer patients aged 80 years or older? J Gastroenterol Hepatol 2003;18:521-525 2. Uribe A, Ankarberg R, Vaara V. High incidence of gastroduodenal ulcers of unknown origin in elderly patients. Gut 2003;52 (Suppl VI): A61 3. Graham DY, Opekun AR, Willingham FF, Qureshi WA. Visible small-intestinal mucosal injury in chronic NSAID users. Clin Gastroenterol Hepatol 2005;3:55-59 4. Pilotto A, Malfertheiner P. Review article: an approach to

Gastropathy in the elderly (Helicobacer pylori or/and NSAID) Helicobacter pylori infection in the elderly. Aliment Pharmacol Ther 2002;16:683-691 5. Pilotto A, Salles N. Helicobacter pylori infection in geriatrics. Helicobacter 2002;7(Suppl 1):56-62 6. Regev A, Fraser GM, Braun M, Eran M, Lebovici ML, Niv Y. Seroprevalence of Helicobacter pylori and length of stay in a nursing home. Helicobacter 1999;4:89 7. Pearce MS, Steele, Campbell DI, Thomas JE. Tooth loss and Helicobacter pylori seropositivity: the Newcastle thousand families cohort study at age 49-51 Years. Helicobacter 2005; 59:475-480 8. Pilotto A. Gastric ulcer in the elderly. Ital J Gastroentrol 1994; 26:10-15 9. Giagoudakis G, Markantonis SL. Relationships between the concentrations of prostaglandins and the nonsteroidal antiinflammatory drugs indomethacin, diclofenac, and ibuprofen. Pharmacotherapy 2005;25:18-25 10. Padol IT, Hunt R. H-Host specific differences in the physiology of acid secretion related to prostaglandins may play a role in gastric inflammation and injury. Am J Physiol Gastrointest Liver Physiol 2005; 288:G1110-1117 11. Hackelsberger A, Platzer U, Nilius M et al. Age and Helicobacter pylori decrease gastric mucosal surface hydrophobicity independently. Gut 1998;42:465-469 12. Di Mario F, Leandro G, Battaglia G et al. Do concomitant diseases and therapies affect the persistence of ulcer symptoms in elderly? Dig Dis Sci 1996;41:17-21 13. Baenkler H, Zeus J, Schenk J, Schäfer D. Abnormal eicosanoid pattern by blood leukocytes in gastroduodenal ulcer. Med Sci Monit 2004;10:CR557-562 14. Sasazuki S, Sasaki S, Tsubono Y et al. The effect of 5-year vitamin C supplementation on serum pepsinogen level and Helicobacter pylori infection. Cancer Sci 2003;94:378-382 15. Simon JA, Hudes ES, Perez-Perez GI. Relation of serum ascorbic acid to Helicobacter pylori serology in US adults. The Third National Health and Nutrition Examination Survey. J Am Coll Nutr 2003;22:283-289 16. Davidovic M, Bojic B, Sabati IA. Peptic ulcer in the elderly. Rom J Gerontol Geriatrics 1997;19:45-50 17. Huang JQ, Sridhar S, Hunt RH. Role of Helicobacter pylori infection and non–steroidal anti–inflammatory drugs in peptic – ulcer disease: a meta–analysis. Lancet 2002;359:14-22 18. Watanabe T, Chiba T. Pathogenesis of gastric and duodenal ulcer in the elderly. Nippon Rinsho 2002;60:1515-1520 19. Linder JD, Wilcox CM. Acid peptic disease in the elderly. Gastroenterol Clin North Am 2001;30:363–376 20. Kemppainen H, Raiha I, Sourander L. Clinical presentation of peptic ulcer in the elderly. Gerontology 1997;43:283-288 21. Koop H, Arnold R, Classen M et al. Healing and relapse of duodenal ulcer during ranitidine therapy in the elderly. The RUDER Study Group. J Clin Gastroenterol 1992;15:291-295 22. Higham J, Kang JY, Majeed A. Recent trends in admissions and mortality due to peptic ulcer in England, increasing frequency of haemorrhage among older subjects. Gut 2003;50:460464 23. Uccheddu A, Floris G, Altane ML et al. Surgery for perforated peptic ulcer in the elderly. Evaluation of factors influencing prognosis. Hepatogastroenterology 2003;50:1956-1958 24. Chow LW, Gertsch P, Poon RT et al. Risk factors for rebleeding and death from peptic ulcer in the very elderly. Br J Surg 1998; 85:121-124 25. Imhof M, Schroders C, Ohmann C et al. Impact of early

257 operation on the mortality from bleeding peptic ulcer – ten years experience. Dig Surg 1998;15:308-314 26. Thomopoulos KC, Vagenas KA, Vagianos CE, et al. Changes in aetiology and clinical outcome of acute upper gastrointestinal bleeding during the last 15 years. Eur J Gastroenterol Hepatol 2004;16:177-182 27. Watanabe T, Chiba T. Clinical features of peptic ulcer disease in the elderly. Nippon Rinsho 2002; 60: 1499 – 1503. 28. Van Leerdam ME, Vreeburg EM, Rauws EA et al. Acute upper GI bleeding : did anything change? Time trend analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000. Am J Gastroenterol 2003; 98: 14941499. 29. Pilotto A. The effect of Helicobacter pylori infection on NSAID related gastro duodenal damage in the elderly. Eur J Gastroentrol Hepatol 1997;9:951-956 30. Roth SH. From peptic ulcer disease to NSAID gastropathy. An evolving nosology. Drugs Aging 1995;6:358-367 31. McKenna F. Efficacy and gastro duodenal safety of a fixed combination of diclofenac and misoprostol in the treatment of arthritis. Br J Rheumatol 1995;34:11-18 32. Gabriel SE, Jaakkimainen RL, Bombardier C. The cost effectivness of misoprostol for nonsteroidal antiinflammatory drug-associated adverse gastrointestinal events. Arthritis Rheum 1993;36:447-459 33. Arakawa T, Higuchi K, Fujiwara Y et al. Prostaglandin derivatives - indication and critical points. Nippon Rinsho 2002;60:16181625 34. Kaffes A, Cullen J, Mitchell H et al. Effect of Helicobacter pylori infection and low-dose aspirin use on iron stores in the elderly. J Gastroenterol Hepatol 2003;18:1024-1028 35. Limmer S, Ittel TH, Wietholtz H. Secondary and primary prophylaxis of gastropathy associated with nonsteroidal antiinflammatory drugs or low-dose aspirin: a review based on four clinical scenarios. Z Gastroenterol 2003;41:719-728 36. Stack WA, Atherton JC, Hawkey GM et al. Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding. Aliment Pharmacol Ther 2002;16: 497–506 37. Bobrzynski A, Konturek PC, Konturek SJ, Plonka M, Bielanski W, Karcz D. Helicobacter pylori and nonsteroidal antiinflammatory drugs in perforations and bleeding of peptic ulcers. Med Sci Monit 2005;11:CR132-135 38. Wu CY, Wu MS, Chen CJ, Li MC, Lin JT,Chen GH. The interaction of H. pylori infection and NSAIDs in cyclooxygenase-2 mRNA expression in gastric antral, corpus mucosa, and gastric ulcer. J Clin Gastroenterol 2005;39:50-55 39. Niv Y, Battler A, Abuksis G, Gal E, Sapoznikov B, Vilkin A. Endoscopy in asymptomatic minidose aspirin consumers.Dig Dis Sci 2005;50:78-80 40. Thomopoulos KC, Mimidis KP, Theocharis GJ, Gatopoulou AG, Kartalis GN, Nikolopoulou VN. Acute upper gastrointestinal bleeding in patients on long-term oral anticoagulation therapy: endoscopic findings, clinical management and outcome. World J Gastroenterol 2005;11:1365-1368 41. de Abajo FJ, Rodrigez LA, Montero D. Association between selective serotonin reuptake inhibitors and upper gastrointestinal bleeding: population based case-control study. BMJ 1999;319:1106–1109 42.. Inaba T, Mizuno M, Take S et al. Eradication of Helicobacter pylori increases platelet count in patients with idiopathic thrombocytopenic purpura in Japan. Eur J Clin Invest 2005; 35:214-219

258 43. Braunwald E, Antman EM, Beasley JW et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2002;40:1366-1374 44..Chan FKL, Ching JYL, Hung LCT et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005;352:238-244 45. Cryer B. Reducing the risks of gastrointestinal bleeding with antiplatelet therapies. N Engl J Med 2005;352:287-289 46. Kubler PA, Pillans PI, Marrinan MC, Frogley M. Concordance between clopidogrel use and prescribing guidelines. Intern Med J 2004;34:663-667 47. Leontiadis GI, Sharma VK, Howden CW. Systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding. BMJ 2005;330:568-568 48. Pilotto A, Franceschi M, Leandro G et al. The risk of upper gastrointestinal bleeding in elderly users of aspirin and other non-steroidal anti-inflammatory drugs: the role of gastroprotective drugs. Aging Clin Exp Res 2003;15:494-499 49. Pavelka K, Recher DP, Verburg KM. Valdecoxib is as effective as diclofenac in the management of rheumatoid

Davidovic et al arthritis with a lower incidence of gastroduodenal ulcers: results of 26 week trial. Rheumatology 2003;42:12071215 50. Lee KK, You JH, Ho JT et al. Economic analysis of celecoxib versus diclofenac plus omeprazole for the treatment of arthritis in patients at risk of ulcer disease. Aliment Pharmacol Ther 2003;18:217-222 51. Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol 2004; 57:422428. 52. Levesque LE, Brophy JM, ZhangB. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med 2005;142:I45 53. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med 2005;165:189-192 54. Delco F, Michetti P, Beglinger C, Fried M, Szucs TD.. Health care resource utilization and costs of NSAID-induced gastrointestinal toxicity. A population-based study in Switzerland. Digestion 2004;69:10–19 55. Schneider JP. Chronic pain management in older adults. With coxibs under fire, what now? Geriatrics 2005;60:26-31