False-positive fecal immunochemical test results in colorectal cancer screening and gastrointestinal drug use.

PURPOSE: The study aimed to determine the influence of drug treatments (proton pump inhibitors [PPIs] combined with other drugs) on the false-positive (FP) rate in the fecal immunochemical test (FIT). METHODS: Patients undergoing colonoscopy in the setting of a CRC screening program due to a positive FIT result were included prospectively. Demographic data and drug intake of PPIs, antiplatelet therapy (APA), anticoagulants, selective serotonin reuptake inhibitors (SSRIs), and nonsteroidal anti-inflammatory drugs (NSAIDs) were collected. An FP FIT result was considered normal colonoscopy or with nonneoplastic pathology (NNP). Logistic regression models were used to evaluate the effect of these drugs on the rate of FP FIT results. RESULTS: We included 515 patients, and 59% (304/515) were males. The rate of FP FIT results was 48% (249/515). Study drug use was higher in patients > 60 years old and females than in those < 60 years old and males (p < 0.001 and p = 0.049, respectively). Multivariate logistic regression revealed that female sex (OR = 2.7 95% CI 1.9-3.9), NNP (OR = 1.5 95% CI 1.1-2.2), and the use of any of the study drugs (OR = 1.4 95% CI 0.9-2.0) were independent risk factors for FP FIT results. The risk of FP FIT results was significantly higher in PPI users than in nonusers (OR = 1.8 95% CI 1.1-2.9), specifically when PPIs were combined with other drugs (OR = 2.01 95% CI 1.1-3.6) only in men. CONCLUSION: Female sex, NNP, and PPIs combined with other drugs in males were identified as independent risk factors for FP FIT results.

Quantitative analysis of p16 methylation in Barrett's carcinogenesis.

p16 hypermethylation in Barrett's carcinogenesis has been evaluated in studies which did not take into account sample heterogeneity and yielded qualitative (methylated/unmethylated) instead of accurate quantitative (percentage of CpG methylation) data. We aimed to measure the degree of p16 methylation in pure samples representing all the steps of Barrett's tumorogenesis and to evaluate the influence of sample heterogeneity in methylation analysis. METHODS: 77 paraffin-embedded human esophageal samples were analyzed. Histological grading was established by two pathologists in: negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia and adenocarcinoma. Areas of interest were selected by laser-capture microdissection. p16 methylation was quantified by pyrosequencing. An adjacent section of the whole sample was also analyzed to compare methylation data. RESULTS: After microdissection, we obtained 15 samples of squamous epithelium, 36 non-dysplastic Barrett's esophagus, 3 indefinite for dysplasia, 24 low-grade dysplasia, 4 high-grade dysplasia and 12 adenocarcinoma. Squamous epithelium showed the lowest methylation rates: 6% (IQR 5-11) vs. 11%(7-39.50) in negative/indefinite for dysplasia, p<0.01; 10.60%(6-24) in low-grade dysplasia, p<0.05; and 44.50%(9-66.75) in high-grade dysplasia/adenocarcinoma, p<0.01. This latter group also exhibited higher methylation rates than Barrett's epithelium with and without low-grade dysplasia (p<0.05). p16 methylation rates of microdissected and non-microdissected samples did not correlate unless the considered histological alteration comprised >71% of the sample. CONCLUSIONS: p16 methylation is an early event in Barrett's carcinogenesis which increases with the severity of histological alteration. p16 methylation rates are profoundly influenced by sample heterogeneity, so selection of samples is crucial in order to detect differences.

Peptic Ulcer Bleeding Risk. The Role of Helicobacter Pylori Infection in NSAID/Low-Dose Aspirin Users.

OBJECTIVES: Helicobacter pylori (H. pylori) infection and NSAID/low-dose aspirin (ASA) use are associated with peptic ulcer disease. The risk of peptic ulcer bleeding (PUB) associated with the interaction of these factors remains unclear. The objective of this study was to determine the risk of PUB associated with the interaction between H. pylori infection and current nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose ASA use. METHODS: This was a case-control study of consecutive patients hospitalized because of PUB. Controls were matched by age, sex, and month of admission. H. pylori infection status was determined in all cases and controls by serology. Drug use was determined by structured questionnaire. Adjusted relative risk (RR) associated with different factors, and the interaction between NSAID/ASA and H. pylori infection was estimated by logistic regression analysis. RESULTS: The study included 666 cases of PUB and 666 controls; 74.3% cases and 54.8% controls (RR: 2.6; 95% confidence interval (CI): 2.0-3.3) tested positive for H. pylori infection; 34.5% of cases had current NSAID use compared with 13.4% of controls (RR: 4.0; 95% CI: 3.0-5.4). Respective proportions for low-dose ASA use were 15.8 and 12%, respectively (RR: 1.9; 95% CI: 1.3-2.7). The RR of PUB for concomitant NSAID use and H. pylori infection suggested an additive effect (RR: 8.0; 95% CI: 5.0-12.8), whereas no interaction was observed with ASA use (RR: 3.5; 95% CI: 2.0-6.1). CONCLUSIONS: NSAID, low-dose ASA use, and H. pylori infection are three independent risk factors for the development of PUB, but there were differences in the interaction effect between low-dose ASA (no interaction) or NSAID (addition) use and H. pylori infection, which may have implications for clinical practice in prevention strategies.

Effect of oral anticoagulants on the outcome of faecal immunochemical test.

BACKGROUND: We aimed to evaluate whether oral anticoagulants (OACs) alter faecal immunochemical test (FIT) performance in average-risk colorectal cancer (CRC) screening. METHODS: Individuals aged 50-69 years were invited to receive one FIT sample (cutoff 75 ng ml(-1)) between November 2008 and June 2011. RESULTS: Faecal immunochemical test was positive in 9.3% (21 out of 224) of users of OAC and 6.2% (365 out of 5821) of non-users (P-trend=0.07). The positive predictive value (PPV) for advanced neoplasia (AN) in non-users was 50.4% vs 47.6% in users (odds ratio, 0.70; 95% CI, 0.3-1.8; P=0.5). The PPV for AN in OAC more antiplatelets (aspirin or clopidogrel) was 75% (odds ratio, 2; 95% CI, 0.4-10.8; P=0.4). CONCLUSIONS: Oral anticoagulant did not significantly modify the PPV for AN in this population-based colorectal screening program. The detection rate of advanced adenoma was higher in the combination OAC more antiplatelets.

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.

BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14-1·66; p=0·0009) or diclofenac (1·41, 1·12-1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31-2·37; p=0·0001; diclofenac 1·70, 1·19-2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10-4·48; p=0·0253), but not major vascular events (1·44, 0·89-2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69-1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00-2·49; p=0·0103) and diclofenac (1·65, 0·95-2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56-6·41; p=0·17), but not by naproxen (1·08, 0·48-2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17-2·81, p=0·0070; diclofenac 1·89, 1·16-3·09, p=0·0106; ibuprofen 3·97, 2·22-7·10, p<0·0001; and naproxen 4·22, 2·71-6·56, p<0·0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation.

Gastroprotection in low-dose aspirin users for primary and secondary prevention of ACS: results of a cost-effectiveness analysis including compliance.

PURPOSE: Low-dose aspirin (ASA) increases the risk of upper gastrointestinal (GI) complications. Proton pump inhibitors (PPIs) reduce these upper GI side effects, yet patient compliance to PPIs is low. We determined the cost-effectiveness of gastroprotective strategies in low-dose ASA users considering ASA and PPI compliance. METHODS: Using a Markov model we compared four strategies: no medication, ASA monotherapy, ASA+PPI co-therapy and a fixed combination of ASA and PPI for primary and secondary prevention of ACS. The risk of acute coronary syndrome (ACS), upper GI bleeding and dyspepsia was modeled as a function of compliance and the relative risk of developing these events while using medication. Costs, quality adjusted life years and number of ACS events were evaluated, applying a variable risk of upper GI bleeding. Probabilistic sensitivity analyses were performed. RESULTS: For our base case patients using ASA for primary prevention of ACS no medication was superior to ASA monotherapy. PPI co-therapy was cost-effective (incremental cost-effectiveness ratio [ICER] €10,314) compared to no medication. In secondary prevention, PPI co-therapy was cost-effective (ICER €563) while the fixed combination yielded an ICER < €20,000 only in a population with elevated risk for upper GI bleeding or moderate PPI compliance. PPI co-therapy had the highest probability to be cost-effective in all scenarios. PPI use lowered the overall number of ACS. CONCLUSIONS: Considering compliance, PPI co-therapy is likely to be cost-effective in patients taking low dose ASA for primary and secondary prevention of ACS, given low PPI prices. In secondary prevention, a fixed combination seems cost-effective in patients with elevated risk for upper GI bleeding or in those with moderate PPI compliance. Both strategies reduced the number of ACS compared to ASA monotherapy.

A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22.

BACKGROUND: Colorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22-31, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24. METHODS: CRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24. RESULTS: None of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk. CONCLUSIONS: TOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts.

Risk factors for advanced lesions undetected at prior colonoscopy: not always poor preparation.

BACKGROUND AND STUDY AIM: Colonoscopy is regarded as the gold standard for diagnosis of colonic lesions. However, adenoma miss rates in tandem colonoscopy studies vary from 2 % to 26 %. We aimed to investigate the rates of advanced neoplasia in patients with a prior normal colonoscopy in an outpatient endoscopy unit. METHODS: Review of reports for colonoscopies performed in our Endoscopy Unit from 2000 to 2005. Undetected lesions were defined as advanced adenoma or colorectal cancer (CRC) not reported in a colonoscopy performed in the previous 2 or 3 years, respectively. Patients with hereditary nonpolyposis CRC (HNPCC) and familial adenomatous polyposis (FAP) were excluded. RESULTS: Between 2002 and 2005, 795 patients were diagnosed with at least one advanced adenoma and 386 with CRC. Among these, 107/795 patients (13.5 %) had advanced adenoma that had been undetected in a previous colonoscopy (39 % [53/135 lesions] in the right colon); 92/107 (86 %) had an undetected advanced adenoma ≥ 10 mm. Previously undetected CRCs were found in 27/386 patients (6.7 %), located in the left colon in 21/27 (78 %); in 7 the area had not been reached in the previous colonoscopy. Risk factors for undetected advanced adenoma were advanced age, male gender, the presence of another advanced adenoma at first colonoscopy, and history of advanced neoplasia. CONCLUSIONS: Failure to detect advanced neoplasia is common in a community-based endoscopy facility. Previously undetected advanced lesions are more frequently found in the left colon and rectum. Risk factors for non-detection of advanced adenoma are similar to those for advanced neoplasia recurrence. Lowering non-detection rates is crucial for correct follow-up recommendations. Patients should be aware of rates of detection of advanced neoplasia after previous normal colonoscopic findings.

Effects of long-term cyclo-oxygenase 2 selective and acid inhibition on Barrett's oesophagus.

BACKGROUND: There is an overexpression of cyclo-oxygenase 2 (COX-2) in Barrett's oesophagus (BO). AIM: To determine the long-term effect of a COX-2 inhibitor on cellular mechanisms involved in BO. METHODS: A randomized controlled trial was conducted in BO patients allocated to continue the usual proton pump inhibitor (PPI) alone treatment, or PPI combined with rofecoxib (25 mg/day) for 6 months. Cell proliferation index and COX-2 expression in BO glands was determined in biopsy specimens at baseline and after treatment. Cell apoptosis, cyclin D1, p53 and vascular endothelial growth factor (VEGF) expression was also explored in a subset of patients. Student-t test and the U-Mann-Whitney test were used for quantitative and ordinal variables. RESULTS: Of 62 patients, 58 completed the study. A higher proportion of patients on rofecoxib + PPI exhibited a decrease in COX-2 expression compared to those treated with PPI alone, but cell proliferation index was not affected. Unlike PPI alone, rofecoxib + PPI was associated with an increase in the apoptotic cell index, a decrease in p53 cell staining and VEGF expression in mucosal vessels. No effect on low-grade dysplasia or cyclin D1 was observed. CONCLUSIONS: The addition of rofecoxib to PPI therapy does not affect cell proliferation index in BO cells after 6 months of therapy, but does reduce COX-2 and VEGF expression and increases cell apoptosis.

Low-Dose Aspirin Acetylates Cyclooxygenase-1 in Human Colorectal Mucosa: Implications for the Chemoprevention of Colorectal Cancer.

The mechanism of action of low-dose aspirin in the prevention of colorectal cancer (CRC) remains largely hypothetical. We aimed to compare the effects of low-dose aspirin (100 mg/day for 7 days) given to 40 individuals undergoing CRC screening on the extent of cyclooxygenase (COX)-1 acetylation at serine-529 (AceCOX-1), in blood platelets vs. colorectal mucosa, at 7 (group 1) and 24 h (group 2) after dosing. A significantly (P < 0.01) lower %AceCOX-1 was detected in colonic and rectal mucosa (average 64%) vs. platelets (average 75%) in both groups. This effect was associated with an average 46% (P < 0.01) and 35% (P < 0.05) reduction in prostaglandin (PG) E2 levels and phosphorylated S6 (p-S6) levels, respectively. Rectal mucosal levels of p-S6/S6 significantly (P < 0.01) correlated with PGE2 . These findings demonstrate that low-dose aspirin produces long-lasting acetylation of COX-1 and downregulation of p-S6 in human colorectal mucosa, an effect that may interfere with early colorectal carcinogenesis.

Systematic review: the safety and tolerability of pharmacological agents for treatment of irritable bowel syndrome--a European perspective.

AIM: To use an evidence-based approach to evaluate the safety and tolerability of the treatments available for irritable bowel syndrome (IBS), or in clinical development, in Europe. A separate review appraises the evidence for the efficacy of these therapies. METHODS: A literature search (for 1980 to 2005) was completed for all relevant clinical trial data and other articles which included safety information on the use of pharmacological IBS therapies. Clinical trials were scored according to the level of safety information, and adverse event incidence reported when possible. RESULTS: The tolerability of many of the agents used to treat IBS in Europe is poorly understood. However, serotonergic agents, such as tegaserod and alosetron, which are currently unavailable in Europe, have undergone rigorous assessment in IBS and their benefits have been established. Following initial marketing of alosetron for use in patients with IBS with diarrhoea, concerns about severe constipation and ischaemic colitis resulted in restriction of its use to women with severe IBS symptoms. This highlights the importance of post-marketing surveillance and post-marketing studies in refining the therapeutic indication of new IBS therapies, which will help to identify appropriate recipients for the drug and establish the impact of adverse reactions in clinical practice. CONCLUSIONS: There is a significant lack of data on the safety and tolerability of the therapies currently used routinely to treat IBS in Europe. The newer agents have undergone rigorous assessment, such that their benefits and risks in treating IBS are established. Defining their place among the spectrum of available therapies remains challenging when the benefits and risks of the older treatments are so poorly characterized.

NSAIDs-induced gastrointestinal damage. Review.

Non-steroidal anti-inflammatory drugs (NSAIDs), along with analgesics, are the most widely prescribed medication in the world. However, NSAIDs cause numerous side effects, being the gastrointestinal (GI) events the most common ones with an increase of risk of serious GI complications between 2.5- and 5-fold, as compared with individuals not taking NSAIDs. Factors that increase the risk for serious events in NSAID-using patients include a history of ulcer or ulcer complications, advanced age (=or>65 years), the use of high-dose NSAIDs, more than one NSAID, anticoagulants or corticosteroid therapy. If NSAID therapy is required, we must balance GI and cardiovascular risk and the therapy should be prescribed at the lowest possible dose and for the shortest period of time. The use of NSAID without gastroprotective co-therapy is considered appropriate in patients<65 years, not taking aspirin and having no GI history. In patients with GI risk factors, but no cardiovascular risk, coxibs or NSAIDs plus proton pump inhibitor (PPI) or misoprostol are valid options. Patients with a history of ulcer bleeding should receive coxib plus PPI therapy and should be tested and treated for Helicobacter pylori infection. Coxib therapy has better GI tolerance than traditional NSAIDs and PPI therapy is effective both in treatment and prevention of NSAID-induced dyspepsia and should be considered in patients who develop dyspepsia during NSAID or coxib therapy.

Clinical trends in ulcer diagnosis in a population with high prevalence of Helicobacter pylori infection.

BACKGROUND: It is unknown whether the incidence of peptic ulcer changes in areas with a high prevalence of Helicobacter pylori infection. AIM: To determine trends in peptic ulcer complications in a community with a high prevalence of H. pylori infection. METHODS: New endoscopic diagnoses of peptic ulcers and their complications from 1985 to 2000 were obtained. H. pylori infection in the adult population, the number of prescriptions for anti-secretory drugs and non-steroidal anti-inflammatory drugs were also evaluated. RESULTS: Although the global prevalence of H. pylori infection remains high in this population (>60%), a 41.4 to 25.4% decrease in the incidence of peptic ulcers and ulcer complications was observed. This was associated with a decrease in the prevalence of H. pylori infection in people under 65 years of age, a 3.5-fold increase in the number of prescriptions of proton-pump inhibitors and an increase in the number of prescriptions of non-steroidal anti-inflammatory drugs, especially coxibs. CONCLUSIONS: In an area with a high prevalence of H. pylori infection, the incidence of peptic ulcer and associated complications is declining rapidly. This was associated with a reduction of the prevalence of H. pylori infection in the young and a widespread use of proton-pump inhibitors. The increase in the use of non-steroidal anti-inflammatory drugs, especially coxibs, has not changed the tendency.

Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin.

BACKGROUND: Aspirin is valuable for preventing vascular events, but information about ulcer frequency is necessary to inform risk-benefit decisions in individual patients. AIM: To determine ulcer prevalence and incidence in a population representative of those given aspirin therapy and evaluate risk predictors. METHODS: Patients taking aspirin 75-325 mg daily were recruited from four countries. Exclusions included use of gastroprotectant drugs or other non-steroidal anti-inflammatory drugs. We measured point prevalence of endoscopic ulcers, after quantitating dyspeptic symptoms. Incidence was assessed 3 months later in those eligible to continue (no baseline ulcer or reason for gastroprotectants). RESULTS: In 187 patients, ulcer prevalence was 11% [95% confidence interval (CI) 6.3-15.1%]. Only 20% had dyspeptic symptoms, not significantly different from patients without ulcer. Ulcer incidence in 113 patients followed for 3 months was 7% (95% CI 2.4-11.8%). Helicobacter pylori infection increased the risk of a duodenal ulcer [odds ratio (OR) 18.5, 95% CI 2.3-149.4], as did age >70 for ulcers in stomach and duodenum combined (OR 3.3, 95% CI 1.3-8.7). CONCLUSIONS: Gastroduodenal ulcers are found in one in 10 patients taking low-dose aspirin, and most are asymptomatic; this needs considering when discussing risks/benefits with patients. Risk factors include older age and H. pylori (for duodenal ulcer).

The effects of proton pump inhibition on patient-reported severity of dyspepsia when receiving dual anti-platelet therapy with clopidogrel and low-dose aspirin: analysis from the Clopidogrel and the Optimization of Gastrointestinal Events Trial.

BACKGROUND: Dual anti-platelet therapy with clopidogrel and low-dose aspirin increases the risk for gastrointestinal clinical events. Omeprazole has been shown to significantly reduce these events without compromising cardiovascular safety in patients treated with dual anti-platelet therapy. Whether or not omeprazole improves patient-reported outcomes is undetermined. AIM: To assess the impact of prophylactic omeprazole with background dual anti-platelet therapy on patient-reported symptoms of dyspepsia compared to placebo. METHODS: We analysed results of the Severity of Dyspepsia Assessment questionnaires collected in the Clopidogrel and the Optimization of Gastrointestinal Events Trial. RESULTS: Patient-reported outcome data from 3759 subjects were available for analysis. At 4 weeks, the mean scores of pain intensity and nonpain symptoms were lower in the omeprazole group (5.61 ± 0.17 vs. 6.40 ± 0.17, P = 0.001, and 10.61 ± 0.07 vs. 11.00 ± 0.07, P < 0.001 respectively). These differences were maintained at 24 weeks (5.91 ± 0.35 vs. 7.10 ± 0.37, P = 0.020 for pain intensity; 10.36 ± 0.12 vs. 10.93 ± 0.13, P = 0.001 for nonpain symptoms). After adjusting for covariates there were no statistically significant differences between the groups in the percent of patients with dyspepsia during follow-up. CONCLUSIONS: In addition to reducing the risk of gastrointestinal bleeding, statistically significant benefits with prophylactic omeprazole use on both pain and nonpain symptoms were evident at 4 weeks and sustained through 24 weeks. The clinical significance of these overall results is unclear, but greater in patients with pain at baseline.

Gastroesophageal reflux disease (GERD): current agents and future perspective.

The objectives of medical treatment of patients with gastroesophageal reflux disease (GERD) are relief of symptoms and healing of esophagitis, which can be achieved, at least in part, by drugs which suppress acid secretion. In patients with GERD symptoms and/or mild esophagitis, the best and most cost-effective therapeutic strategy is to start with a proton pump inhibitor with subsequent trial of step down of the intensity of therapy (e.g. H2-receptor antagonists). In patients with moderate or severe esophagitis, proton pump inhibitors are the mainstay of treatment and the most effective in preventing symptoms and esophagitis. In patients with mild disease, the recurrence of symptoms is less frequent and many patients may not need continuous maintenance therapy or may require treatment with either low dose proton pump inhibitors, H2-receptor antagonists or cisapride only. H. pylori eradication might be needed in GERD patients on long-term treatment with proton pump inhibitors, but the benefit of this strategy has not yet been adequately demonstrated. Antireflux surgery is a maintenance option for the young patient on long-term medical therapy. Improved medical therapy for GERD might depend on future agents with different therapeutic targets, including GABA inhibitors and nitric oxide modulating drugs in the control of the lower sphincter esophagus and in motility disorders, free radical scavengers in the prevention of mucosal damage and COX-2 specific inhibitors in the prevention of the progression of Barret's esophagus to adenocarcinoma. Finally, the modulation of some growth factors might have a potential role in delayed esophageal ulcer healing, refractory esophagitis and in Barrett's esophagus.

COX-2 inhibition in esophagitis, Barrett's esophagus and esophageal cancer.

There is extensive evidence that cyclooxygenase-2 (COX-2) plays a significant role in the process of carcinogenesis in different tumors. Although most of these evidences derive from studies in colorectal cancer, data obtained from recent studies strongly suggest that COX-2 might play an important role in the neoplastic transformation of esophageal epithelium. NSAIDs use is associated with a reduction of the risk of developing esophageal cancer, including adenocarcinoma. Up-regulation of COX-2 has been reported in different stages of the carcinogenic sequence leading to esophageal adenocarcinoma. Treatment with selective COX-2 inhibitors has been shown to reduce the damage induced by acid and pepsin in the esophageal mucosa of rabbits, the incidence of tumors in an animal model of esophageal adenocarcinoma and to decrease proliferation and induce apoptosis in both Barrett's epithelial and adenocarcinoma cells. The first clinical study has shown that selective inhibition of COX-2 is followed by a significant decrease of cell proliferation in human Barrett's metaplasia. Clinical trials have begun in order to assess the efficacy of selective COX-2 inhibitors to prevent the progression of Barrett's esophagus to adenocarcinoma. Bile salts and acid are likely to early induce COX-2 in this sequence, although other factors, such as proinflammatory cytokines, inducible nitric oxide synthase and growth factors such as TGF-beta, are potential COX-2 inducers in the esophagus. Further studies are necessary in order to better understand factors involved in COX-2 up-regulation and mechanisms of COX-2 associated tumorigenesis in the esophagus.

Current approaches to reducing gastrointestinal toxicity of low-dose aspirin.

Use of low-dose aspirin is associated with gastroduodenal mucosal damage and increased risk of upper gastrointestinal (GI) bleeding. Many patients on low-dose aspirin should receive prophylactic treatment, because they often present several risk factors that may lead to upper GI complications in nonsteroidal anti-inflammatory drug (NSAID) users. It is reasonable to assume that effective therapy (e.g., omeprazole, misoprostol, and high-dose famotidine) in the prevention of NSAID-induced gastroduodenal ulcers will also be effective in this setting. However, the best therapeutic approach to reducing GI toxicity in low-dose aspirin users is not defined, because only a few studies have focused on this problem. Omeprazole seems very effective in reducing both acute gastroduodenal mucosal damage and upper GI bleeding in the high-risk patient taking low-dose aspirin, but data with other antiulcer agents are lacking (misoprostol) or inconsistent (ranitidine) at present. No data are available on the effect of these drugs on dyspepsia or chronic gastroduodenal ulcers in the long-term use of low-dose aspirin. The role of Helicobacter pylori is controversial, but it may increase mucosal damage and the risk of upper GI bleeding in these patients. More data are needed to define the best therapeutic regimen in patients taking low-dose aspirin.

Economic analysis of strategies in the prevention of non-steroidal anti-inflammatory drug-induced complications in the gastrointestinal tract.

BACKGROUND: It is unclear what the best therapeutic approach is in patients who require non-steroidal anti-inflammatory drugs. In clinical practice, choice of prescriptions are often based on drug costs. AIM: To evaluate costs per upper gastrointestinal bleeding avoided with different prevention strategies. METHODS: Two major strategies have been considered (coxibs vs. non-steroidal anti-inflammatory drugs plus generic/brand gastroprotective agent). The number of patients needed to treat to prevent a bleeding event, the cost of the drug and duration of treatment were used to estimate costs. RESULTS: Based on hospitalization costs of a bleeding event, no therapeutic strategy is cost-effective in patients without risk factors. All strategies (including omeprazole + coxib) are cost-effective in patients with bleeding ulcer history. With other risk factors, all strategies are cost-effective but prevention of events is twice as expensive in patients <75 years of age. No strategy shows superiority unless the cheapest generics are prescribed or a 50% reduction in the incidence of lower gastrointestinal complications with coxibs is confirmed. CONCLUSIONS: Current prevention strategies to reduce serious non-steroidal anti-inflammatory drug-associated gastrointestinal events are only cost-effective in patients with risk factors. No strategy shows superiority, but coxib strategy would be more cost-effective if it were associated with a reduction of events of the lower gastrointestinal tract.