Search

Background: The Helicobacter Eradication Aspirin Trial (HEAT) is a multicentre, double blind, randomised controlled trial investigating whether Helicobacter (H.) pylori eradication reduces hospitalisation for peptic ulcer bleeding. Recruited participants were aged 60 and over and taking aspirin (≤325 mg daily) for at least four months prior to consent. Based on results of a pilot study, a sample size calculation predicted 6600 H. pylori-positive randomised participants would be required, from 33,000 volunteers, recruited from 170,000 invited patients. Methodology was therefore designed for recruitment of large numbers of patients from primary care using a novel electronic search tool, automated mail-out and electronic follow-up. Recruitment started in 2012 and completed in 2017., Methods: All participants were recruited from GP practices, with assistance from the UK Clinical Research Network (UKCRN). H. pylori-positive participants were randomised to one week of eradication treatment or placebo. Recruitment was managed using a bespoke web-based database that communicated directly with a programmed search tool downloaded at participating practices. The primary endpoint is hospitalisation due to peptic ulcer bleeding. The trial will end when 87 adjudicated events have occurred, identified from searches of GP databases, review of secondary care admission data and mortality data, and reported events from randomised participants and GPs., Results: HEAT has recruited participants from 1208 GP practices across the UK. Of the 188,875 invitation letters sent, 38,771 returned expressions of interest. Of these, 30,166 patients were consented to the trial, of whom 5355 H. pylori-positive participants (17.8% of those consented) were randomised. Mean age at consent was 73.1 ± 6.9 (SD) years and 72.2% of participants were male. Of the randomised (H. pylori-positive) participants, 531 have died (as of 17 Sep 2020); none of the deaths was due to trial treatment., Conclusion: The HEAT trial methodology has demonstrated that recruitment of large numbers of patients from primary care is attainable, with the assistance of the UKCRN, and could be applied to other clinical outcomes studies., Trial Registration: ClinicalTrials.gov ; registration number NCT01506986 . Registered on 10 Jan 2012., (© 2022. The Author(s).)

Background: Clinical trials measuring the effect of an intervention on clinical outcomes are more influential than those investigating surrogate measures but are costly. We developed methods to reduce costs substantially by using existing data in primary care systems, to ask whether Helicobacter pylori eradication would reduce the incidence of hospitalisation for ulcer bleeding in aspirin users., Methods: The Helicobacter Eradication Aspirin Trial (HEAT) is a National Institute of Health Research-funded, double-blind placebo controlled randomised trial of the effects of H. pylori eradication on subsequent ulcer bleeding in infected individuals taking aspirin daily, conducted in practices across the whole of England, Wales and Northern Ireland. A bespoke web-based trial management system developed for the trial (and housed within the secure NHS Data Network) communicates directly with the HEAT Toolkit software downloaded at participating practices, which issues queries searching entry criteria (≥ 60 years, on chronic aspirin ≤ 325 mg daily, not on anti-ulcer therapy or non-steroidal anti-inflammatory drugs) for GP review of eligibility. Trial participation is invited using a highly secure automated online mail management system. Interested patients are seen once for consent and breath testing. Those with a positive test are randomised to eradication treatment (lansoprazole, clarithromycin, metronidazole) or placebo, with drug sent by post. Events are tracked by upload of accumulating information in the GP database, patient contact, review of National Hospital Episode Statistics and Office of National Statistics data., Results: HEAT is the largest Clinical Research Network-supported drug trial, with 115,660 invitation letters sent from 850 practices, 22,922 volunteers, and 3038 H. pylori positive patients randomised to active or placebo treatment after 2.5 years of recruitment. 178 practices have performed their first follow-up data search to identify 21 potential endpoints to date., Discussion: HEAT is important medically, because aspirin is so widely used, and methodologically, as a successful trial would show that large-scale studies of important clinical outcomes can be conducted at a fraction of the cost of those conducted by industry, which in turn will help to ensure that trials of primarily medical rather than commercial interest can be conducted successfully in the UK.

Background: Gastroduodenal ulcers are common in patients taking low-dose aspirin. However, the factors predisposing to mucosal erosions, the precursor lesions, are not well known., Aims: To examine the potential risk factors for the development of erosions in patients chronically taking low-dose aspirin., Methods: Patients included were taking aspirin 75-325 mg daily for >28 days. Exclusion criteria included use of nonsteroidal anti-inflammatory and ulcer-healing drugs. Demographic data were collected at baseline, prior to endoscopy to determine the frequency and number of erosions and Helicobacter pylori status. In those without ulcer or other exclusions, endoscopy was repeated at 3 months., Results: Fewer patients had gastric erosions if they were H. pylori +ve (48.5% vs. 66.4% in H. pylori-ve patients at baseline, P = 0.17; 40.0% vs. 64.1% at 3 months, P = 0.029). If gastric erosions were present, they were also less numerous in H. pylori +ve patients (3.61 +/- 0.83 vs. 4.90 +/- 0.53 at baseline, P = 0.026; 2.17 +/- 0.68 vs. 5.68 +/- 0.86 at 3 months, P = 0.029). There was a trend (0.1 > P > 0.05) for more gastric erosions in those taking >100 mg/day aspirin. Males had more duodenal erosions at baseline (25.2% vs. 7.5%, P = 0.016). Patient age did not affect the presence or number of erosions. H. Pylori was not significantly associated with duodenal erosion numbers., Conclusions: Helicobacter pylori infection may partially protect against low-dose aspirin-induced gastric erosions; damage to the stomach appears weakly dose-related; and older age does not increase the risk of erosions.

Background: Low-dose acetylsalicylic acid (ASA; aspirin; 75-325 mg/day) is effective for the prevention of cardiovascular events, and its use in this indication is rapidly increasing. However, the use of ASA and, indeed, other non-steroidal anti-inflammatory drugs (NSAIDs) is limited by the incidence of adverse gastroduodenal events. OBJECTIVES AND SCOPE: To review the clinical evidence for, and the pharmacodynamic basis of, ASA-induced gastroduodenal toxicity in comparison with NSAIDs, and address the question of whether low-dose ASA is 'safe' from a gastroduodenal perspective. This was a narrative, descriptive review, rather than a formal systematic review., Findings: Adverse gastroduodenal effects, which are well known to occur with NSAIDs, are also prevalent in patients receiving low-dose ASA for cardiovascular protection even at doses as low as 75 mg/day. The risk of gastroduodenal toxicity is particularly high among 'at-risk' low-dose ASA patients (aged >70 years, previous ulcer or upper gastrointestinal bleeding and users of antiplatelets or NSAIDs). There are important differences in the mechanism of ASA-induced gastroduodenal toxicity, relative to NSAIDs. These differences include the effects on the cyclooxygenase (COX)-1 isoenzyme, local effects on the gastroduodenal mucosa specific to ASA and a reduction in platelet aggregation., Conclusion: Data suggest that ASA causes significant gastroduodenal damage even at the low doses used for cardiovascular protection. These effects (both systemic and possibly local) may be pharmacodynamically distinct from the gastroduodenal toxicity seen with NSAIDs. Studies are required to establish strategies for improving the tolerability of low-dose ASA, allowing patients to continue to benefit from the cardiovascular protection associated with such therapy.

Aims: Selective cyclooxygenase (COX)-2 inhibitors have recently been implicated as enhancing risk of myocardial infarction (MI). Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are also effective COX-2 inhibitors, so we investigated the hypothesis that they too increase risk of MI., Methods: We conducted a case-control study with direct structured interview of cases and controls. Cases were all subjects (N = 205) with a first nonfatal MI who had no previously recognized cardiovascular disease. Community controls (N = 258) were randomly selected from the same practice as the index case. Hospital controls (N = 205) were those admitted at the same time as index cases for nonmyocardial conditions not influenced by NSAID use. The effects of aspirin, NSAIDs and previously recognized influences on MI were investigated by unconditional logistic regression analysis., Results: NSAID use was associated with an increase risk of MI with an odds ratio of 1.77 (1.03, 3.03) vs. community controls and 2.61 (1.38, 4.95) vs. hospital controls. These values were 5.00 (1.18, 21.28) and 7.66 (0.87, 67.48), respectively, in aspirin users. Results were similar when naproxen was grouped with aspirin. Odds ratios for smoking and for use of antidiabetic medication were 3.91 (2.52, 6.04) and 3.92 (1.25, 12,33), respectively, vs. community controls., Conclusions: Like selective COX-2 inhibitors, non-selective NSAIDs [corrected] are associated with an increased risk of MI. The extent to which this reflects interference with aspirin warrants further investigation.

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).

Despite great proven and potential benefits, aspirin also has adverse side effects on all parts of the gastrointestinal tract including ulceration, bleeding, perforation, and stenosis. Because of widespread and growing use, there is a need to understand and, if possible, prevent the adverse effects of aspirin while maintaining its benefits. This article is part of a report from a consensus meeting in 1999 on nonsteroidal anti-inflammatory drugs, and examines possible mechanisms of each of the risks of normal and low-dose aspirin use including areas of uncertainty. Based on these issues, we recommend studies that would further clarify the actions of aspirin. We also examine various strategies that might be used to prevent or mitigate adverse effects. Finally, we propose future research prospects in the search for a safer aspirin.

Introduction: The harmful effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastric mucosa and the prophylactic effects of misoprostol are both dose-dependent., Aim: To investigate whether a low-dose of misoprostol is sufficient to prevent gastric mucosal injury caused by low-dose aspirin., Methods: We conducted a double-blind placebo controlled parallel group endoscopic study in 32 evaluable volunteers. The main outcome measure was erosive injury (ulcers and superficial erosions) in the gastric mucosa over 28 days., Results: Most subjects developed erosions on aspirin 300 mg daily. This was significantly reduced by misoprostol 100 microg daily. (Odds ratio 0.18, 95% CI: 0.07-0.48). There were no drug-related or gastrointestinal adverse events in subjects receiving misoprostol., Conclusion: Misoprostol 100 microg daily can prevent low-dose aspirin induced gastric mucosal injury without causing identifiable adverse effects.

Background: Gastric ulceration induced by aspirin and by non-steroidal anti-inflammatory drugs (NSAIDs) is a major clinical problem. The mechanism of injury is unclear. There is evidence that NSAID-induced injury may cause endothelin activation. Endothelin-induced vasoconstriction has been shown to be capable of causing gastric ulceration., Aim: To investigate whether acute gastroduodenal injury induced in humans by aspirin can be prevented by the endothelin-1 antagonist, bosentan., Methods: Eighteen healthy volunteers each received 5 x 900 mg aspirin every 12 h on three separate occasions (with either placebo, bosentan 700 mg or misoprostol 400 mg). Treatment order was randomized by Latin square design. Subjects were endoscoped and erosions counted before and 90 min after the first and last dose of aspirin. Plasma concentrations of bosentan were measured up to 5 h post-dose., Results: There was a significant reduction in the mean number of erosions in the aspirin plus bosentan and aspirin plus misoprostol groups after the first dose of aspirin, compared with controls (aspirin plus placebo) (P<0.05). This was not sustained after the fifth dose of aspirin in the aspirin plus placebo and aspirin plus bosentan groups, but was still present in the aspirin plus misoprostol group. The mean plasma concentration of bosentan measured 3.5 h post-dose fell from 4510 (95% CI: 2791-6230) ng/mL after the 1st dose to 2508 (95% CI: 1733-3283) ng/mL after the 5th dose (P = 0.02)., Conclusion: Endothelin receptor antagonism by bosentan can protect the gastric mucosa against aspirin damage. After five doses, bosentan levels fell, possibly because of enzyme induction, and protection was no longer evident. Further investigation is needed to assess whether higher doses would be effective.

Background: Aspirin is widely used for cardiovascular prophylaxis., Aim: To compare the effectiveness of two widely-used strategies-dose reduction and enteric coating-for the minimization of gastric mucosal injury or toxicity., Methods: Twelve healthy volunteers were studied. On four separate occasions each received, under blinded conditions, five daily doses of plain aspirin 300 mg, plain aspirin 75 mg, enteric-coated aspirin 300 mg or placebo. Ex vivo prostaglandin E2 synthesis was stimulated by the vortex mixing of gastric mucosal biopsies in Tris saline and measured by radioimmunoassay. Mucosal injury was quantified both by counting erosions and with a visual analogue scale., Results: All three preparations reduced prostaglandin E2 synthesis by day five, by (median) 84% for plain aspirin 300 mg, by 80% for enteric coated aspirin 300 mg and by 63% for plain aspirin 75 mg. There was little mucosal injury prior to the start of each dose and period and no significant change with placebo. Plain aspirin caused a dose-dependent mucosal injury, with two (median, IQR 0-7) gastric erosions after five days of plain aspirin 75 mg, and 18 (2-26) after five days of plain aspirin 300 mg. With enteric-coated aspirin 300 mg there were 0 (0-1) gastric erosions (P = 0.003 compared to plain aspirin 300 mg P = 0.11, compared to plain aspirin 75 mg)., Conclusion: Enteric coated aspirin reduces acute gastric mucosal injury to placebo levels, despite its inhibition of prostaglandin synthesis. Enteric coating is an appropriate strategy for the prevention of gastric mucosal damage induced by low-dose aspirin, which warrants systematic clinical evaluation.

Background: Sucralfate does not have potent anti-ulcerogenic actions in users of non-steroidal anti-inflammatory drugs (NSAIDs). However, sucralfate may influence intragastric haemostasis favourably., Aim: To investigate separately the effects of sucralfate on acute gastric and duodenal injury and on changes in intragastric bleeding induced by aspirin., Method: On three occasions, 24 healthy volunteers received three days' treatment with aspirin 900 mg twice daily together with placebo, sucralfate 2 g twice daily or sucralfate 1 g four times daily. Injury was assessed endoscopically and bleeding by spontaneous and biopsy induced bleeding intragastric washings. Ex vivo prostaglandin E2 (PGE2) synthesis and serum thromboxane were measured by using radioimmunoassay., Results: Aspirin significantly inhibited ex vivo gastric mucosal PGE2 synthesis, reduced serum thromboxane, caused gastric erosions, and increased spontaneous and biopsy induced bleeding. Sucralfate had no significant effects on endoscopic injury but sucralfate 1 g four times daily significantly reduced spontaneous and biopsy induced bleeding. Similar trends were seen with sucralfate 2 g twice daily but the results were less consistent., Conclusion: Sucralfate does not affect aspirin induced acute gastric mucosal injury but reduces aspirin associated intragastric bleeding.

Background: The mechanisms of aspirin induced gastroduodenal injury are not fully understood. Aspirin induces the release of reactive oxygen metabolites in animal models, which may contribute to mucosal injury., Aims: To investigate the effects of aspirin administered with placebo or antioxidants on gastric mucosal reactive oxygen metabolite release and gastroduodenal injury in human volunteers., Subjects: Fourteen healthy volunteers participated in the study (seven male; mean age 27 years, range 20-40)., Methods: In a double blind, randomised, crossover study, volunteers received aspirin 900 mg twice daily and either placebo, allopurinol 100 mg twice daily, sulphasalazine 1 g twice daily or vitamin C 1 g twice daily for three days. Injury was assessed endoscopically and by quantifying mucosal reactive oxygen metabolite release by measuring chemiluminescence before and after each treatment. The effect on prostanoids was determined by measuring ex vivo antral prostaglandin E2 (PGE2) synthesis and serum thromboxane B2 (TXB2)., Results: No drug reduced any parameter of gastric injury but vitamin C reduced duodenal injury assessed by Lanza score (p < 0.005). Chemiluminescence increased after aspirin both with placebo (p < 0.05) and vitamin C (p < 0.05). Post-treatment chemiluminescence was lower in subjects taking allopurinol (p < 0.05) or sulphasalazine (p < 0.005) than in those taking placebo with aspirin., Conclusions: In this study, aspirin induced gastric injury was associated with reactive oxygen metabolite release. This was reduced by sulphasalazine and allopurinol, although macroscopic injury was not affected. Vitamin C, however, was shown to have a previously unrecognised protective effect against aspirin induced duodenal injury.

Calcium carbasalate is a therapeutically active salicylate which seems to cause less gastroduodenal mucosal damage than aspirin in laboratory animals. This endoscopist-blinded, randomised, cross over trial aimed to compare acute gastric mucosal damage in 20 healthy volunteers treated with acetyl salicylic acid (ASA) (650 mg three times daily) and effervescent calcium carbasalate (ECC) (826.8 mg three times daily) bioequivalent to 650 mg ASA over a five day period. Endoscopy was performed immediately before treatment and on day 5 of each treatment. Serum salicylate, thromboxane B2, and gastric mucosal prostaglandin E2 (PGE2) concentrations were measured after endoscopy. ECC caused fewer gastric mucosal erosions than ASA. The total number of gastric erosions was 23.8 (16.1) in the ASA treated subjects compared with 9.1 (8.7) in ECC treated subjects (p = 0.004). Differences between ASA and ECC were significant for both the gastric antrum and body, and for both haemorrhagic and non-haemorrhagic erosions. The mean gastric body Lanza score for mucosal damage was lower after ECC than ASA (p = 0.003). The visual analogue score for gastric body damage was lower for ECC (16.9 mm (15.9)) than for ASA (32.7 mm (20.8)), p = 0.008. Serum salicylate concentrations were similar after both preparations (ASA: 66 (23) mg/l, versus ECC: 58 (17) mg/l, NS). Serum thromboxane B2 was similarly reduced using both preparations-97.2 (3.5)% inhibition with ASA, 95.2 (5.5)% inhibition with calcium carbasalate (NS). Suppression of gastric mucosal PGE2 synthesis was similar with both preparations (ASA: 83.4 (17.1)%; ECC 84.3 (12.9)%; NS). It is concluded that ECC causes significantly less gastroduodenal mucosal damage than ASA administered at bioequivalent doses as judged by serum salicylate, serum thromboxane, and mucosal PGE2 values. ECC may therefore be a less harmful alternative treatment to plain ASA.

Aim: To investigate the degree and selectivity of rectal thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet thromboxane to rectal thromboxane., Methods: The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B4 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of thromboxane B2, leukotriene B4, prostaglandin E2, and serum thromboxane B2 were measured by radioimmunoassay., Results: Dialysate thromboxane B2 levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95% CI: 0.79-1.43 ng/ml) on placebo, by 29% (95% CI: 11-40%) to 0.75 ng/ml (0.56-1.01 ng/ml) (P = 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E2 was 1.47 ng/ml (0.97-2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leukotriene B4 was 0.45 ng/ml (0.34-0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95% by plain aspirin 300 mg, and by 82% by enteric coated aspirin 300 mg, respectively (P < 0.01). These results show that 29% of the rectal thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4 is inhibited by low dose aspirin. We infer that 34% of the rectal thromboxane B2 is platelet-derived in our volunteers., Conclusion: Low dose aspirin will selectively inhibit a proportion of rectal thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.

Many animal and human studies have shown aspirin to cause gastric mucosal erosions and enhanced spontaneous microbleeding. Chronic use is associated with uncomplicated gastric ulcer (but not clearly with uncomplicated duodenal ulcer) and with presentation with haematemesis and melaena. Sub-group analysis suggests that the risks of bleeding duodenal ulcer as well as bleeding gastric ulcer (and possibly non-ulcer bleeding) are increased. These data imply that an anti-haemostatic as well as an ulcerogenic effect contributes to such presentation and acute data support this proposition. A broken mucosa and inhibition of thromboxane synthesis both appear to be necessary for bleeding to occur. Aspirin enhances the bleeding associated with mucosal biopsy analogous to its prolongation of the skin bleeding time. Anti-haemostatic properties could account for the apparent increase in presentation with haematemesis and melaena in patients taking low doses of aspirin for cardiovascular prophylaxis. However, acute studies also show aspirin 300 mg to cause a level of mucosal injury which is substantial, though significantly less than with aspirin 600 mg q.d.s. The risk attached to aspirin consumption needs to be kept in perspective. It can be calculated that aspirin use is associated with approximately 700 bleeds per annum in the UK. The relative risk for upper gastrointestinal bleeding is roughly similar to that for non-aspirin non-steroidal anti-inflammatory drugs but those affected are generally younger, in an age group where death from upper gastrointestinal bleeding is very uncommon. In keeping with this and in contrast to non-aspirin non-steroidal anti-inflammatory drugs, no study has shown increased mortality from aspirin-related upper gastrointestinal complications.

The aim of this study was to investigate the protective action of a new compound, ranitidine bismuth citrate, in the prevention of aspirin-induced acute mucosal injury to the upper gastrointestinal tract of healthy human volunteers. In a double-blind randomized three-way cross-over study 24 male volunteers received placebo, 900 mg aspirin or 900 mg aspirin and 800 mg ranitidine bismuth citrate at 12-h intervals for nine doses with a 2-week wash-out period between each treatment. The median (interquartile range) number of erosions seen at endoscopy when ranitidine bismuth citrate was given with aspirin (1 [0-4]) was significantly lower than aspirin alone (24 [16-32]) (P < 0.001) and not significantly different from either baseline or placebo (0 [0-2]). These findings were similarly reflected in the effects on microbleeding following the ninth dose: 12.1 (7.1-21.0) microL/10 min following aspirin alone compared to levels with placebo of 1.2 (0.4-2.9), and with aspirin and ranitidine bismuth citrate of 1.6 (0.8-2.6) (P < 0.005). Ranitidine bismuth citrate conferred substantial protection from aspirin-induced injury to the gastric and duodenal mucosa as determined by both endoscopic assessment and microbleeding rates, reducing injury to placebo levels.

This study investigated the influence of ranitidine on mucosal injury and gastric bleeding in 20 normal volunteers taking 600 mg aspirin q.d.s. This study was a double-blind placebo controlled crossover study comparing ranitidine, as 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. with placebo. Gastric mucosal injury was assessed at unsedated endoscopy by counting haemorrhagic and non-haemorrhagic erosions; bleeding was measured in gastric washings. Aspirin alone increased mucosal injury from 0 to 11.4 erosions (mean, P < 0.01) and bleeding from 1.77 to 9.11 microliters blood/10 min (mean P < 0.001). Ranitidine prophylaxis reduced bleeding to 5.34, 3.18 and 3.47 microliters/10 min with 150 mg b.d., 300 mg q.d.s. and 600 mg b.d. respectively (overall effect of ranitidine P < 0.001) and also reduced haemorrhagic erosions though it had no effect on the total number of erosions. Ranitidine is effective at reducing aspirin-induced gastric bleeding and whilst not reducing aspirin-induced gastric erosions, it does reduce the number that appear haemorrhagic. Ranitidine may have a role in the prophylaxis of aspirin-induced gastric bleeding.

1. An increasing body of data suggests that the antihaemostatic as well as the ulcerogenic actions of aspirin and other non-steroidal anti-inflammatory drugs may be operative when patients present with haematemesis and melaena. 2. We therefore developed methods to allow separate evaluation of the erosive and anti-haemostatic actions of aspirin in the human gastric mucosa. Volunteer subjects took 300 mg of aspirin daily in the morning or 600 mg of aspirin four times a day for 5 days under blinded randomized conditions. Changes in spontaneous gastric microbleeding, endoscopic signs of injury, spontaneous bleeding per gastric erosion, biopsy-induced bleeding and eicosanoids were studied. 3. Both doses of aspirin significantly inhibited gastric mucosal synthesis of prostaglandin E2 and reduced the serum thromboxane concentration. Erosions developed and regressed rapidly; compared with baseline 300 mg of aspirin daily in the morning caused substantial numbers of gastric erosions to develop (mean 5.3, 95% confidence limits 2.7-10.2) but this was significantly less than that caused by 600 mg of aspirin four times a day (10.9, 7.2-16.5, P less than 0.05). The presence of erosions was associated with enhanced spontaneous bleeding, but only during aspirin administration. 4. Aspirin significantly increased bleeding induced by mucosal biopsy and was associated with significant enhancements in the rate of bleeding per gastric erosion. Bleeding rate per erosion but not biopsy-induced bleeding showed a significant dose-related increase with 600 mg of aspirin four times a day. Enteric coating reduced endoscopic signs of injury, but did not affect the impaired haemostasis caused by aspirin.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Gastric damage induced by low-dose aspirin and the protective effect of enteric-coating was assessed in healthy volunteers in a double-blind placebo-controlled cross-over trial using Latin square design. Each was administered placebo, plain aspirin 300 mg daily, plain aspirin 600 mg four times daily, enteric-coated aspirin 300 mg daily, or enteric-coated aspirin 600 mg four times daily for 5 days. Gastric damage was assessed endoscopically, and gastric mucosal bleeding measured. 2. Aspirin 300 mg daily and 600 mg four times daily caused significant increases in gastric injury compared with placebo. Gastric mucosal bleeding was significantly more with the high dose, with a trend towards increased gastric erosions, compared with the low dose. 3. Enteric-coating of aspirin eliminated the injury caused by low dose aspirin and substantially reduced that caused by the higher dose. 4. All dosages and formulations caused similar inhibition of gastric mucosal prostaglandin E2 synthesis. 5. Serum thromboxane levels were suppressed equally with plain and enteric-coated aspirin. 6. In this short-term study in healthy volunteers, gastric toxicity from aspirin was largely topical, independent of inhibition of prostaglandin synthesis, and could be virtually eliminated by the use of an enteric-coated preparation.

This study investigates whether aspirin injury to the human gastric mucosa can be prevented by profound acid suppression with omeprazole, in a randomised, double blind, crossover design according to latin square. It was concluded that profound acid suppression can prevent aspirin induced gastric mucosal injury in normal subjects. This approach may prevent the development of peptic ulcers and their complications in patients taking aspirin and other non-steroidal anti-inflammatory drugs.

Aspirin almost invariably causes acute mucosal injury to the stomach or duodenum as evidenced by erosions seen endoscopically, extensive surface cell disruption on histology, reduced mucosal potential difference and increased gastric bleeding. This injury is usually minor and transient, and not associated with symptoms. However, in the elderly recent aspirin intake may be associated with bleeding peptic ulcer, and along with other NSAIDs, may be causal in a third of cases. Regular chronic aspirin intake may also be associated with gastric ulceration. Such ulceration, however, although seemingly capable of healing despite continued aspirin or other NSAID use, may take longer to do so. Although aspirin and other NSAIDs have a strong connection with gastroduodenal problems the risk in an individual needs to be balanced by the likelihood of such events. Given their widespread use, the serious side effects of these drugs occur in only a small proportion of users. This, however, does not mitigate against careful prescription.

The ability of ranitidine to protect the human gastric mucosa against aspirin-induced damage was investigated by timed measurements of blood loss collected by gastric washing. Ranitidine (150 mg) 1 h or 5 h before 900 mg aspirin (5 doses of each) over 48 h reduced subsequent mean bleeding from 7.7 microliters/10 min to 2.6 microliters/10 min or 3.4 microliters/10 min, respectively. Both regimens were antisecretory at the time of aspirin administration, as judged by a rise in the pH of the aspirated washings. The prolonged protection against aspirin-induced bleeding achieved with twice daily dosing with ranitidine has clinical potential in the management of patients taking anti-inflammatory drugs.

1. We evaluated injury to the human gastric mucosa caused by low doses of aspirin and its prophylaxis by ranitidine. On two separate occasions, 30 subjects took aspirin 300 mg daily for 12 days either with or without ranitidine 150 mg, 30 min before aspirin. This dose of aspirin caused more than a 5 fold increase in gastric bleeding, from control values of 0.5 microliters 10 min-1 (95% confidence limits 0.3-0.8 microliters 10 min-1) to 2.8 microliters 10 min-1 (1.9-4.1 microliters 10 min-1, P less than 0.01) after 5 days of aspirin. Adaptation did not occur and the gastric bleeding rates remained elevated at 3.4 microliters 10 min-1 (1.9-6.1 microliters 10 min-1) after 12 days of aspirin consumption (P less than 0.01). 2. Coadministration of ranitidine significantly raised intragastric pH and reduced aspirin induced bleeding to 1.5 microliters 10 min-1 (1.0-2.3 microliters 10 min-1) after 5 days and 1.6 (1.0-2.5 microliters 10 min-1) after 12 days (P less than 0.05). 3. Although these values were higher than control levels our results raise the possibility that coadministration of ranitidine may reduce the incidence of peptic ulceration and gastrointestinal haemorrhage which is increasingly reported in some subjects taking low dose aspirin for vascular prophylaxis.

1. We investigated the effect of the haemostatic agent ethamsylate on aspirin-induced gastric mucosal bleeding. 2. Eighteen healthy subjects were studied three times: at the end of 48 h periods of treatment with (a) placebo, (b) aspirin 600 mg four times daily, (9 doses) and (c) aspirin 600 mg four times daily with each dose preceded by ethamsylate 500 mg. 3. At the end of each treatment period gastric mucosal bleeding into timed gastric washings was quantified using the orthotolidine reaction. 4. Aspirin increased bleeding from a rate on placebo of 1.2 microliters 10 min-1 geometric mean (95% confidence limits) (0.7-1.8) microliters 10 min-1 to 20.0 (11.6-34.2) microliters 10 min-1, (P less than 0.01). The rate of bleeding after aspirin preceded by ethamsylate [14.1 (8.5-23.4) microliters 10 min-1] was not significantly different from that after aspirin alone. 5. We conclude that ethamsylate does not reduce acute aspirin-induced gastric mucosal bleeding in healthy humans.

1. We have compared acute gastric bleeding caused by a new slow release preparation of indomethacin (indomethacin Continus) with that caused by aspirin and other indomethacin preparations. 2. In a randomized crossover study, blood loss into timed gastric aspirates was determined in 20 healthy volunteers after receiving, over 96 h, either placebo, aspirin (600 mg four times daily; 17 doses) indomethacin BP (50 mg three times daily; 13 doses), Indocid-R (75 mg twice daily; 9 doses) or indomethacin Continus (75 mg twice daily; 9 doses). A venous blood sample was also taken during each treatment period for subsequent determination of alpha 1-glycoprotein, and for drug assay. 3. Gastric bleeding on placebo was 1.4 (0.7-2.8) microliters 10 min-1 (mean, 95% confidence interval). Both aspirin and the indomethacin preparations caused significantly more bleeding (P less than 0.05). Rates of bleeding after aspirin, indomethacin BP, Indocid-R, and indomethacin Continus were respectively 22.0 (10.7-47.2) microliters 10 min-1, 4.4 (2.2-9.1) microliters 10 min-1, 10.8 (5.3-22.3) microliters 10 min-1, and 5.1 (3.0-10.6) microliters 10 min-1. 4. Rates of bleeding after indomethacin BP and indomethacin Continus, but not Indocid-R, were significantly less than after aspirin (P less than 0.01). 5. Salicylate or indomethacin was detectable in the plasma of all subjects after the active treatment periods, except for one instance involving a subject allocated indomethacin BP. Indomethacin levels were significantly higher 2 h after Indocid-R than with indomethacin BP or indomethacin Continus. 6. alpha 1-acid glycoprotein levels were not significantly affected by prior treatment with aspirin or indomethacin.

Prostaglandins protect the gastric mucosa in animals, but the evidence of an effect independent of pH changes in man is not overwhelming. Gastrointestinal bleeding because of non-steroidal anti-inflammatory drugs is a major clinical problem, which we have investigated in a model system measuring bleeding rates caused by short-term administration of aspirin. Of the various strategies tested, only those that elevated intra-gastric pH reduced aspirin-induced bleeding.

Objective: To investigate the suitability of treatment with low dose aspirin or warfarin, or both, as possible prophylaxis against cardiovascular disease by determining the effect on gastric mucosal bleeding., Design: Randomised crossover trial., Setting: Academic department of therapeutics., Subjects: Twenty healthy male volunteers aged 19-22., Interventions: On separate occasions and in randomised order all subjects received aspirin 75 mg, warfarin, or aspirin 75 mg combined with warfarin. Each treatment was given for 12 days or (when warfarin was used) for longer if necessary until the international normalised ratio of the prothrombin time was stable at 1.4-1.6., End Point: Loss of blood over 10 minutes into gastric washings., Measurements and Main Results: Bleeding over 10 minutes into gastric washings under baseline conditions and after five days, and at end of each regimen of treatment. Aspirin 75 mg increased bleeding from 0.60 (95% confidence interval 0.36 to 0.99) microliters/10 minutes to 1.26 (0.71 to 2.25) microliters/10 minutes at five days, with no evidence of either progressive change or adaptation thereafter. Warfarin had no effect on bleeding either alone or when combined with aspirin., Conclusions: Aspirin 75 mg causes gastric mucosal bleeding. Low dose warfarin neither induces gastric mucosal bleeding nor enhances that caused by aspirin.