Risk Of Peptic Ulcer Research Articles

Renin-Angiotensin System Associated with Risk of Upper GI Mucosal Injury Induced by Low Dose Aspirin

We have previously shown that co-treatment of angiotensin type 1 receptor (AT1R) blocker (ARB) or angiotensin converting enzyme (ACE) inhibitor seem to reduce peptic ulcer among patients taking low dose aspirin. It is reported that a series of renin-angiotensin system (RAS) gene polymorphisms significantly influence the rate of the gene transcription. The aim of this study was to examine the genotypes of RAS genes related to the risk of peptic ulcer and ulcer bleeding among patients taking low dose aspirin. Patients taking 100mg of aspirin who were planning to undergo endoscopy for surveillance or who had history of recent upper GI ulcer bleeding were included. ACE (Ins/Del), angiotensinogen (AGT; G-217A, A-20C, A-6G, T174M, M235T), and AT1R (T-713G, C-521T, A1166C) genotypes were determined by PCR or PCR-RFLP. Four hundred twenty-five patients were enrolled including 68 patients with peptic ulcer and 20 patients with ulcer bleeding. Co-treatment of ARB was significantly associated with peptic ulcer and ulcer bleeding. AGT-20 CC (adjusted OR 4.94, 95% CI 1.21-20.2) was significantly associated with ulcer bleeding. The CC genotype of AT1R-521 was significantly associated with peptic ulcer only in the subgroup taking neither ACE inhibitor nor ARB. Co-treatment of ARB reduces peptic ulcer and bleeding among patients taking low dose aspirin. RAS may play an important role in the development of upper GI mucosal injury induced by low dose aspirin.

Critical appraisal of a fixed combination of esomeprazole and low dose aspirin in risk reduction

Low dose aspirin (</=325 mg) is routinely used for primary and secondary prophylaxis of cardiovascular and cerebrovascular events. The use of low dose aspirin is associated with two- to four-fold greater risk of symptomatic or complicated peptic ulcers. Risk factors associated with low dose aspirin induced gastrointestinal toxicity includes prior history of ulcer or upper gastrointestinal (GI) bleeding, concomitant use of other nonsteroidal anti-inflammatory drugs, corticosteroid or warfarin, dual antiplatelet therapy, Helicobacter pylori (H. pylori) infection, and advanced age. Esomeprazole, like other proton pump inhibitors (PPIs) is very effective in decreasing the risk of aspirin induced gastrointestinal toxicity. Although evidence to support esomeprazole or other PPIs for primary prophylaxis in aspirin induced gastrointestinal toxicity is limited, its role in secondary prophylaxis is well established.

Time trends in incidence of peptic ulcer bleeding and associated risk factors in Norway 1985&amp;ndash;2008

The aim of this study was to examine time trends in the incidence of peptic ulcer bleeding and risk factors in a defined geographical area in Norway. Retrospective data were collected for 306 patients with bleeding peptic ulcers admitted to one hospital during the 1985-1986, 1995-1996, and 2007-2008 periods. The incidence in 1985-1986 was 52/100,000 and in 2007-2008 was 45/100,000. In the group aged 20-75 years, the incidence decreased by 54% from 54/100000 in 1985-1986 to 25/100000 in 2007-2008 (P = 0.001) and increased by 49% in the group aged >75 years from 272/100000 to 406/100000 (P = 0.0001). The use of aspirin or nonsteroidal anti-inflammatory steroid drugs (NSAIDs) was 31% in 1985-1986 and increased to 67% in 2007-2008 (P = 0.004). In patients using aspirin or NSAIDs, Helicobacter pylori was present in 73% in 1995-1996 and in 51% in 2007-2008. H. pylori infection declined from 84% to 52% between 1995-1996 and 2007-2008. The incidence rate of peptic ulcer bleeding did not change between 1985-1986 and 2007-2008, but decreased in the age group ≤75 years and increased in the age group >75 years. The use of low-dose aspirin and NSAIDs increased substantially over time, and H. pylori infection was still present in 51% of these patients in 2007-2008.

Reflux Disease, Gastrointestinal Ulcer or Weight Loss in Patients with COPD

ABSTRACTPeptic ulcer disease, gastro-oesophageal reflux disease (GORD) and weight loss have been associated with chronic obstructive pulmonary disease (COPD). Many studies, especially on peptic ulcer and weight loss, are cross-sectional or were done back in the 1960s or 1970s. Our purpose was to learn more about GORD, ulcer, and weight loss in relation to COPD during long-term follow-up in recent years. We conducted a case-control and a follow-up study using the UK-based General Practice Research Database to assess and compare the prevalence and incidence of GORD, peptic ulcer and weight loss in patients with COPD and in COPD-free patients during the period 1995–2005. We identified 35,772 patients with COPD and the same number of COPD-free patients. Incidence rates of GORD, peptic ulcer and weight loss in COPD patients were 59.2, 14.8 and 134.0 per 10,000 person years, respectively. The risk of weight loss was increased in patients with COPD compared to COPD-free patients (1.81, 95% CI 1.61–2.02), while the risk of GORD (OR 1.19, 95% CI 1.00–1.40) or peptic ulcer (OR 1.24, 95% CI 0.92–1.66) were similar in both groups. The results provide further evidence that COPD is associated with weight loss, while there is no materially increased risk for ulcer or GORD associated with COPD.

Helicobacter pylori CagA Phosphorylation Status Determines the gp130-activated SHP2/ERK and JAK/STAT Signal Transduction Pathways in Gastric Epithelial Cells

The Helicobacter pylori protein CagA may undergo tyrosine phosphorylation following its entry into human gastric epithelial cells with downstream effects on signal transduction. Disruption of the gp130 receptor that modulates the balance of the SHP2/ERK and JAK/STAT pathways enhanced peptic ulceration and gastric cancer in gp130 knock-out mice. In this study, we evaluated the effect of translocated CagA in relation to its tyrosine phosphorylation status on the gp130-mediated signal switch between the SHP2/ERK and JAK/STAT3 pathways. We showed that in the presence of CagA, SHP2 was recruited to gp130. Phosphorylated CagA showed enhanced SHP2 binding activity and ERK1/2 phosphorylation, whereas unphosphorylated CagA showed preferential STAT3 activation. These findings indicate that the phosphorylation status of CagA affects the signal switch between the SHP2/ERK and JAK/STAT3 pathways through gp130, providing a novel mechanism to explain H. pylori signaling.

774 Renin-Angiotensin System and Risk of Peptic Ulcer and Ulcer Bleeding Induced by Low Dose Aspirin

774 Renin-Angiotensin System and Risk of Peptic Ulcer and Ulcer Bleeding Induced by Low Dose Aspirin

T1149 Risk of Upper Gastrointestinal Bleeding in Clopidogrel and Aspirin Users Receiving Concomitant Proton Pump Inhibitors

Background and aims: Clopidogrel and aspirin (ASA) are wildly used in the prevention of cardiovascular and embolic events. However, these combined medications cause significant risk of peptic ulcers and bleeding complications. This case-control study was designed to evaluate the risk of upper gastrointestinal bleeding (UGIB) in clopidogrel and aspirin users who continue receiving standard dose of proton pump inhibitors (PPI). . Methods: Data for clinical information and endoscopic findings were collected during January 2009 and November 2009 from patients who used clopidogrel and/or ASA and continue receiving standard dose of PPI. Patients with history of prior UGIB or abdominal surgery were excluded. Clopidogrel or ASA user was defined as consumption of clopidogrel or ASA for at least 7 days period preceding the episode of bleeding. The UGIB was defined as overt bleeding (hematemesis, positive nasogastric aspirate, and melena) or fall in baseline hematocrit ≥ 5 points within 24 hours of admission. Ulcer was defined at endoscope by breaking mucosa > 3mm in diameter. Results:A total of 175 patients (82 men and 93 women, mean age of 65.3 years) were evaluated in this study including 54 patients (30.9%) with UGIB and 121 patients (69.1%) with dyspeptic symptoms. Male were significantly more common than female patients in bleeding group (61.1 % vs 38.9%: P=0.01). However, the underlying diseases of the patients including cardiovascular diseases, rheumatological diseases and diabetes mellitus were not different between these 2 groups. UGIB was significantly higher in current ASA (325mg) plus clopidogrel user than non-user (16.7% vs 5.8%; P=0.02). The multivariable model suggested that the probability of UGIB event increased with current ASA (325mg) plus clopidogrel use (OR= 2.3, 95%CI =1.2-3.9) in the patients receiving concomitant PPI. Summary: Risk of UGIB events still occur in ASA and clopidogrel users in spite of receiving concomitant PPI. Lower dose of ASA, concomitant higher dose PPI and carefully monitoring of UGIB should be considered in combined ASA and clopidogrel user patients.

T1150 Role of Cyclooxygenase-2 in Cancer Stem Cell Biology and Effect of COX-2 Inhibitors in Anti-Cancer Therapy Targeting Cancer Stem Cells

Background and aims: Clopidogrel and aspirin (ASA) are wildly used in the prevention of cardiovascular and embolic events. However, these combined medications cause significant risk of peptic ulcers and bleeding complications. This case-control study was designed to evaluate the risk of upper gastrointestinal bleeding (UGIB) in clopidogrel and aspirin users who continue receiving standard dose of proton pump inhibitors (PPI). . Methods: Data for clinical information and endoscopic findings were collected during January 2009 and November 2009 from patients who used clopidogrel and/or ASA and continue receiving standard dose of PPI. Patients with history of prior UGIB or abdominal surgery were excluded. Clopidogrel or ASA user was defined as consumption of clopidogrel or ASA for at least 7 days period preceding the episode of bleeding. The UGIB was defined as overt bleeding (hematemesis, positive nasogastric aspirate, and melena) or fall in baseline hematocrit ≥ 5 points within 24 hours of admission. Ulcer was defined at endoscope by breaking mucosa > 3mm in diameter. Results:A total of 175 patients (82 men and 93 women, mean age of 65.3 years) were evaluated in this study including 54 patients (30.9%) with UGIB and 121 patients (69.1%) with dyspeptic symptoms. Male were significantly more common than female patients in bleeding group (61.1 % vs 38.9%: P=0.01). However, the underlying diseases of the patients including cardiovascular diseases, rheumatological diseases and diabetes mellitus were not different between these 2 groups. UGIB was significantly higher in current ASA (325mg) plus clopidogrel user than non-user (16.7% vs 5.8%; P=0.02). The multivariable model suggested that the probability of UGIB event increased with current ASA (325mg) plus clopidogrel use (OR= 2.3, 95%CI =1.2-3.9) in the patients receiving concomitant PPI. Summary: Risk of UGIB events still occur in ASA and clopidogrel users in spite of receiving concomitant PPI. Lower dose of ASA, concomitant higher dose PPI and carefully monitoring of UGIB should be considered in combined ASA and clopidogrel user patients.

Host-Interactive Genes in AmerindianHelicobacter pyloriDiverge from Their Old World Homologs and Mediate Inflammatory Responses

Helicobacter pylori is the dominant member of the gastric microbiota and has been associated with an increased risk of gastric cancer and peptic ulcers in adults. H. pylori populations have migrated and diverged with human populations, and health effects vary. Here, we describe the whole genome of the cag-positive strain V225d, cultured from a Venezuelan Piaroa Amerindian subject. To gain insight into the evolution and host adaptation of this bacterium, we undertook comparative H. pylori genomic analyses. A robust multiprotein phylogenetic tree reflects the major human migration out of Africa, across Europe, through Asia, and into the New World, placing Amerindian H. pylori as a particularly close sister group to East Asian H. pylori. In contrast, phylogenetic analysis of the host-interactive genes vacA and cagA shows substantial divergence of Amerindian from Old World forms and indicates new genotypes (e.g., VacA m3) involving these loci. Despite deletions in CagA EPIYA and CRPIA domains, V225d stimulates interleukin-8 secretion and the hummingbird phenotype in AGS cells. However, following a 33-week passage in the mouse stomach, these phenotypes were lost in isolate V225-RE, which had a 15-kb deletion in the cag pathogenicity island that truncated CagA and eliminated some of the type IV secretion system genes. Thus, the unusual V225d cag architecture was fully functional via conserved elements, but the natural deletion of 13 cag pathogenicity island genes and the truncation of CagA impaired the ability to induce inflammation.

Preventing Recurrence of Aspirin-Related Peptic Ulcers

Patients who use low-dose aspirin for cardiovascular and neurovascular prophylaxis are at elevated risk for developing peptic ulcers. Famotidine, a

Relevance of Helicobacter pylori genotypes in gastric pathology and its association with plasma malondialdehyde and nitric oxide levels

Persistent infection with Helicobacter pylori confers an increased risk of peptic ulceration and gastric adenocarcinoma. Reactive oxygen and nitrogen species play a crucial role in the progression from normal gastric mucosa to cancer. The aim of the present study was to investigate the plasma malondialdehyde and nitric oxide levels in H. pylori related gastroduodenal diseases and associate their levels with gastric pathology and genotypes of H. pylori. Malondialdehyde and nitric oxide levels in plasma samples of 250 subjects were spectrophotometrically determined. Subsequently, genotypic and histopathological assessment was performed in gastric biopsies obtained during endoscopy. The levels of MDA and NO exceeded in subjects infected with genotype-1 of Hp than those with other genotypes suggesting more precise interaction of highly virulent strains of Hp in eliciting severe tissue damage. In conclusion, the study demonstrates close relationship between the plasma malondialdehyde and nitric oxide levels, gastric histopathology and genotypes of H. pylori.

Influence of interleukin polymorphisms on development of gastric cancer and peptic ulcer

Pro-inflammatory cytokines are produced in the gastric mucosa by inflammatory cells activated by chronic Helicobacter pylori (H. pylori) infection. Polymorphisms of these cytokine genes are associated with individual differences in gastric mucosal cytokine mRNA level, which result in differences in gastric mucosal inflammation, acid inhibition and gastroduodenal disease risk in response to H. pylori infection. Although polymorphisms of interleukin (IL)-1B, IL-1RN and TNF-A have been reported to relate well with gastric cancer and peptic ulcer risk, those of IL-2, IL-4, IL-6 and IL-8 genes are unclear. In combined analyses using data from previous studies, we found that the risk of gastric non-cardia cancer development was significantly associated with IL-4-168 C allele (OR: 0.81, 95% CI: 0.69-1.00) and IL-4-590 T allele carrier status (0.61, 0.53-0.73), and IL-6-174 G/G genotype (2.02, 1.31-3.10). In peptic ulcer development, IL-2-330 G and IL-4-590 T allele carriers had a significantly decreased risk (0.37, 0.27-0.50 and 0.58, 0.34-0.99, respectively). Moreover, IL-2, IL-4, IL-6 and IL-8 gene genotypes prevalence differs among populations. The inflammatory cytokine gene polymorphisms (e.g. IL-4-590 and IL-6-572 for gastric cancer, and IL-4-590, IL-6-572 and IL-8-251 for peptic ulcer) have a more potent influence on development of gastroduodenal diseases in Western than East Asian populations. These cytokine gene polymorphisms, as well as those of IL-1B, IL-1RN and TNF-A, may be used to identify groups at higher risk of gastric cancer and peptic ulcer, and those suitable for their prevention by H. pylori eradication therapy in Western populations.

Coadaptation of Helicobacter pylori and humans: ancient history, modern implications

Humans have been colonized by Helicobacter pylori for at least 50,000 years and probably throughout their evolution. H. pylori has adapted to humans, colonizing children and persisting throughout life. Most strains possess factors that subtly modulate the host environment, increasing the risk of peptic ulceration, gastric adenocarcinoma, and possibly other diseases. H. pylori genes encoding these and other factors rapidly evolve through mutation and recombination, changing the bacteria-host interaction. Although immune and physiologic responses to H. pylori also contribute to pathogenesis, humans have evolved in concert with the bacterium, and its recent absence throughout the life of many individuals has led to new human physiological changes. These may have contributed to recent increases in esophageal adenocarcinoma and, more speculatively, other modern diseases.

OL-017 Relationship between Helicobacter pylori vacA genotypes status and risk of peptic ulcer in Saudi patients

OL-017 Relationship between Helicobacter pylori vacA genotypes status and risk of peptic ulcer in Saudi patients

The association of vacA genotypes and Helicobacter pylori-related gastroduodenal diseases in the Middle East

The variations in the three regions of the Helicobacter pylori vacA gene, the signal (s1 and s2), intermediate (i1 and i2) and middle regions (m1 and m2), are known to cause the differences in vacuolating activities. However, it was unclear whether these vacA genotypes are associated with the development of gastric cancer and peptic ulcer in the Middle East. The aim was to identify the prevalence of vacA genotypes in the Middle East and the association with gastroduodenal diseases. We investigated the relationship of vacA genotypes to H. pylori-related disease development by meta-analysis using previous reports of 1,646 patients from the Middle East. The frequency of the vacA s1, m1 and i1 genotypes in the Middle Eastern strains was 71.5% (1,007/1,409), 32.8% (427/1,300) and 40.7% (59/145), respectively. Importantly, the frequency of vacA s- and m-region genotypes significantly differed between the north and south parts of the Middle East countries (P < 0.001). The vacA genotypes significantly increased the risk of gastric cancer (odds ratio [OR]: 4.02, 95% confidence interval [CI]: 1.98-8.14 for the s1 genotype; 2.50, 1.62-3.85 for m1; 5.27, 1.97-14.1 for s1m1; 15.03, 4.69-48.17 for i1) and peptic ulcers (OR: 3.07, 95% CI: 2.08-4.52 for s1; 1.81, 1.36-2.42 for m1). The cagA-positive genotype frequently coincided with the s1, m1 and i1 genotypes. The vacA s- and m-region genotypes may be useful risk factors for gastrointestinal diseases in the Middle East, similar to European and American countries. Further studies will be required to evaluate the effects of the i-region genotype.

Applicability of a Monoclonal Antibody-Based Stool Antigen Test to Evaluate the Results of &lt;i&gt;Helicobacter pylori&lt;/i&gt; Eradication Therapy

The 13C-urea breath test (UBT) is widely used to examine the results of eradication therapy for Helicobacter pylori. We examined whether a stool antigen test can be used as efficiently as UBT. (i) Ninety-four patients infected with H. pylori underwent eradication therapy. Six or eight weeks after the completion of treatment, the results were evaluated by UBT and a stool antigen test (TPAg). In 77 out of 78 patients who had negative UBT results, the TPAg results were also negative. Among the 16 UBT-positive patients, 12 were also positive by TPAg. Agreement of UBT and TPAg was 94.7%. (ii) Twenty-two patients with peptic ulcers in the active stage also received eradication therapy followed by proton pump inhibitor (PPI) administration. TPAg and UBT were performed to examine the results of eradication therapy at the end of PPI administration and at least 7 days after its discontinuation. Of the 22 patients taking PPIs, TPAg evaluated the results of eradication therapy accurately in 21 patients. TPAg appears to be an accurate test for evaluating the results of H. pylori eradication therapy, and to be as efficient as 13C-UBT. Use of the stool antigen test should be considered as an alternative, particularly in patients who have to take PPIs in order to avoid the risk of peptic ulcers.

Blood group O and vWf expression may be involved in development of peptic ulcer disease secondary to Helicobacter pylori infection

Helicobacter pylori is a gram negative organism involved in peptic ulcer disease and has been linked to a number of extra-intestinal diseases. There is a large body of evidence describing the link between blood group O/non-secretor phenotypes with H. pylori infection and the risk of peptic ulcer disease. Blood group O individuals also have a higher risk of bleeding disorders due to low levels of the circulating plasma protein von Willebrand factor (vWf). vWf is one of the main proteins that binds platelets during platelet activation and aggregation. The mechanisms of how ulcers develop during H. pylori infection are not fully understood. There is however recent evidence of vWf involvement in platelet aggregation in H. pylori infection. Our new hypothesis states that H. pylori bacteria present in blood group O/non-secretor individuals are binding the available vWf to promote adhesion and subsequent platelet aggregation within the microvasculature. This in turn may deplete any available vWf for wound repair to take place leading to an increased risk of peptic ulceration and bleeding and eventually leading to an ulcer.

Helicobacter pylori in Health and Disease

Helicobacter pylori is highly adapted for colonization of the human stomach and is present in about half of the human population. When present, H pylori is usually the numerically dominant gastric microorganism. H pylori typically does not cause any adverse effects, but it is associated with an increased risk of noncardia gastric adenocarcinoma, gastric lymphoma, and peptic ulcer. Disorders such as esophageal diseases and childhood-onset asthma were recently reported to occur more frequently in individuals who lack H pylori than in H pylori-positive persons. In this review, we discuss biologic factors that allow H pylori to colonize the human stomach, mechanisms by which H pylori increases the risk of peptic ulcer disease and noncardia gastric adenocarcinoma, and potential benefits that H pylori might confer to humans.

The association of vacA genotype and Helicobacter pylori-related disease in Latin American and African populations

In the populations of Western countries, particular genotypes of the vacuolating cytotoxin gene, vacA (vacA s, signal region variants; vacA m, middle region variants) of Helicobacter pylori are believed to be risk factors for the development of peptic ulcers and gastric cancer. However, it was unclear whether these vacA gene variants are associated with the development of gastrointestinal diseases in developing nations. The relationship between vacA genotypes and H. pylori-related disease development in Latin American and African populations was investigated using meta-analysis of 2612 patients from Latin America (2285 strains) and 520 patients from Africa (434 strains). The frequencies of vacA s and m genotypes differed between strains from Latin America (77.2% for s1 and 68.1% for m1) and Africa (83.9% for s1 and 56.7% for m1). Latin American strains with s1 and m1 genotypes increased the risk of gastric cancer (OR 4.17, 95% CI 2.49-6.98 for s1, and 3.59, 2.27-5.68 for m1) and peptic ulcers (e.g. 1.73, 1.37-2.20 for s1). African strains with the s1 or m1 genotypes also increased the risk of peptic ulcers (8.69, 1.16-64.75 for s1) and gastric cancer (10.18, 2.36-43.84 for m1). The cagA-positive genotype frequently coincided with s1 and m1 genotypes in both populations. Overall, the vacA s and m genotypes were related to gastric cancer and peptic ulcer development and might be useful markers of risk factors for gastrointestinal disease, especially in Latin America. Further studies will be required to evaluate the effects of vacA genotypes in African populations because of the small sample number currently available.

The Impact of Occult Haemorrhage in Asymptomatic Endoscopic Peptic Ulcers On Long-Term Concomitant Use of NSAID and Low-Dose Aspirin

Purpose: Patients with rheumatoid arthritis(RA) display some of the risk factors for peptic ulcer(PU), and also have a high risk of cardiovascular disease. Therefore, determining the risk of PU induced by non-steroidal anti-inflammatory drugs(NSAIDs) alone or in combination with low-dose aspirin(L-aspirin) in the daily clinical setting of RA patients is essential. The primary objective of this study was to elucidate the risk of PU induced by concomitant L-aspirin in Japanese RA outpatients on long-term NSAID treatment. Although endoscopic PU(EPU) has been defined as an excavated mucosal break 3 mm in diameter in most studies, the clinical implications of EPUs are unclear. A secondary objective was thus to evaluate whether EPUs induced by NSAID/L-aspirin are associated with anemia, implying bleeding from PUs. Methods: This retrospective cohort study enrolled consecutive RA outpatients with a recorded medical history of >3 months. These patients underwent esophagogastroduodenoscopy. Subjects receiving PPI or prostaglandin E1 analog co-therapy or who displayed any changes in medication within the preceding 3 months were excluded from this investigation. Patients were then divided into 4 groups according to the pattern of NSAID/L-aspirin administration: controls(n=25); NSAID group(n=174); NSAID+Aspirin group(n=11); and NSAID+NSAID group(n=22). Hemoglobin level(Hb) and mean corpuscular volume(MCV) were used as biomarkers for potential bleeding. [Results]Ulcer incidence was 0% in the control group, 19.5% in the NSAID group, 18.2% in the NSAID+Aspirin group, and 45.5% in the NSAID+NSAID group. Ulcer incidence was higher in the NSAID group than in the control group(P=0.010), and ulcer incidence was higher in the NSAID+NSAID group than in the control or NSAID groups(P=0.010 and P=0.012, respectively). Conversely, no significant differences were seen in biomarkers for potential bleeding among the four groups. To clarify the association of EPUs with potential bleeding, each group was divided into two subgroups: with EPU; and without EPU. In subgroups with EPU, Hb was lower in the NSAID+Aspirin group than in the NSAID group or NSAID+NSAID group(P=0.010 and P=0.010, respectively). Furthermore, only in the NSAID+Aspirin group, Hb and MCV in the subgroup with EPU was lower in the subgroup with EPU than in the subgroup without EPU(P=0.055 and P=0.029). [Conclusions] Non-aspirin NSAID-duplicated therapy has a higher risk of EPU compared with NSAID alone, but L-aspirin-NSAID combination therapy does not. Nevertheless, EPUs with combined NSAID/L-aspirin therapy, but not in the other groups, seem to have a risk of potential bleeding, even if the EPUs are asymptomatic.