Protection of human gastric mucosa against aspirinðenteric coating or dose reduction?

Transcription

1 Aliment Pharmacol Ther 1999; 13: 187±193. Protection of human gastric mucosa against aspirinðenteric coating or dose reduction? A. T. COLE*, N. HUDSON*, L. C. W. LIEW*, F. E. MURRAY*, C. J. HAWKEY* & S. HEPTINSTALL *Division of Gastroenterology, Division of Cardiovascular Medicine, University Hospital, Nottingham, UK Accepted for publication 23 October 1998 SUMMARY Background: Aspirin is widely used for cardiovascular prophylaxis. Aim: To compare the effectiveness of two widely-used strategiesðdose reduction and enteric coatingðfor the minimization of gastric mucosal injury or toxicity. Methods: Twelve healthy volunteers were studied. On four separate occasions each received, under blinded conditions, ve daily doses of plain aspirin 300 mg, plain aspirin 75 mg, enteric-coated aspirin 300 mg or placebo. Ex vivo prostaglandin E 2 synthesis was stimulated by the vortex mixing of gastric mucosal biopsies in Tris saline and measured by radioimmunoassay. Mucosal injury was quanti ed both by counting erosions and with a visual analogue scale. Results: All three preparations reduced prostaglandin E 2 synthesis by day ve, 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 signi cant change with placebo. Plain aspirin caused a dose-dependent mucosal injury, with two (median, IQR 0±7) gastric erosions after ve days of plain aspirin 75 mg, and 18 (2±26) after ve days of plain aspirin 300 mg. With enteric-coated aspirin 300 mg there were 0 (0±1) gastric erosions (P ˆ compared to plain aspirin 300 mg P ˆ 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. INTRODUCTION Aspirin is increasingly used for cardiovascular prophylaxis in a daily dose range of between 75 and 300 mg daily. 1 Along with the bene ts of low dose aspirin there are hazards. Aspirin predisposes to both peptic ulceration, ulcer bleeding, anaemia and the need for transfusion, 1, 2 even at low doses. 3 Strategies for protection of the gastric mucosa include using the lowest effective dose of aspirin or using an enteric coated preparation. The enteric coating of Correspondence to: Prof. C. J. Hawkey, Division of Gastroenterology, University Hospital, Nottingham, NG7 2UH, UK. cj.hawkey@nottingham.ac.uk aspirin, when it is given at higher doses, is known to protect the gastroduodenal mucosa. 4, 5 However, it is not clear from current studies whether daily doses of aspirin lower than 300 mg are associated with fewer gastrointestinal adverse effects compared with conventionally formulated and enteric coated aspirin. Ideally, the drug regimen should provide an effective inhibition of platelet function with minimum gastric damage. We therefore carried out an investigation in which we compared the effects of once daily doses of plain aspirin 300 mg, plain aspirin 75 mg, enteric coated (EC) aspirin 300 mg and placebo on gastric mucosal prostaglandin (PG) E 2 synthesis and acute gastroduodenal damage. Ó 1999 Blackwell Science Ltd 187

2 188 A. T. COLE et al. METHODS Study design The study was an investigator blinded, placebo controlled study comparing plain aspirin 300 mg daily (Wallace Laboratories, UK) plain aspirin 75 mg daily (Evans, Horsham, UK), EC aspirin 300 mg daily (Nuseals, Eli Lilly, UK), and placebo. The order in which subjects received the different treatment regimens was randomized in blocks of four by the Latin square design. Each treatment period was for ve daily doses of medication taken at hours. There was a washout period of 16 days between treatment periods. Previous studies have shown that acute aspirin induced lesions and changes in prostaglandin synthesis resolve within 48 h. Subjects We studied 12 healthy volunteers, seven male, ve female, age range 20±32 years. All subjects considered for entry into the study had a screening endoscopy and were excluded if they had any erosions or ulcers. The study was approved by the University of Nottingham Ethics Committee and all volunteers gave written informed consent. Endoscopy Subjects underwent unsedated endoscopy, using an Olympus XP10 endoscope. Mucosal injury was quanti- ed by counting the number of erosions in the oesophagus, the stomach as a whole, in the body, antrum separately and in the duodenal bulb. 6 An erosion was de ned as a break in the mucosa 3 mm or less in diameter, less than 1 mm deep. Larger or deeper erosions were classi ed as ulcers. Mucosal injury in the gastric body, antrum and duodenum was also quanti- ed on a 10-cm visual analogue scale as previously described. 5 Prostaglandin E 2 synthesis Two pairs of mucosal biopsy specimens were taken, at 50 cm from the teeth from a standardized point on the greater curve. Each pair was transferred to 1 ml of Tris saline (0.15 M, ph 7.4) in separate polypropylene Eppendorf vials at room temperature and washed twice by vortex mixing for 6 s on a bench mixer (Whirlimixer, Fisons plc, UK). Three hundred microlitres of fresh Tris saline were then added and the tubes were vortexed for 1 min, before centrifugation for 10 s. Supernatants were removed and stored at )40 C until radioimmunoassay. 6, 7 Statistics The primary gastric end-points, stated prior to the start of the study, were changes in ex vivo prostaglandin (PGE 2 ) synthesis and the total number of gastric erosions. Overall differences at day 5 were examined by Friedman two-way analysis of variance. Comparisons between the effect of individual drugs were analysed using the Wilcoxon rank sign test. Data are presented as median and interquartile range. All tests were two-tailed and a P-value of 0.05 was taken as signi cant. RESULTS Prostaglandin E 2 synthesis Analysis of variance showed no signi cant difference in baseline values before each of the four treatment periods. However, changes due to aspirin were highly signi cant and there were signi cant differences between the different preparations of aspirin (P ˆ 0.003). As shown in Figure 1a, placebo did not signi cantly affect PGE 2 synthesis. With plain 300 mg aspirin there was an 84.5% (62.0±91.1%) reduction in PGE 2 synthesis, from 94.5 pg/mg (median, IQR: 50.5±183.1 pg/mg) before treatment to 11.8 (7.8±35.7) pg/mg on day 5 (P ˆ compared with placebo). Plain aspirin 300 mg signi cantly inhibited prostaglandin synthesis within 90 min of the rst dose, and there was no further depression by day 5 (Figure 1b). Plain aspirin 75 mg reduced PGE 2 synthesis by 63.4% (41.8±90.7%) from (53.8±293.1) pg/mg before treatment to 26.5 (13.8±108.4) pg/mg on day 5 (P ˆ compared to placebo). This was signi cantly less than the inhibition seen with plain aspirin 300 mg (P ˆ compared to plain aspirin 300 mg). Plain aspirin 75 mg also signi cantly inhibited PGE 2 synthesis after one dose (P ˆ 0.023), with no further depression by day 5 (Figure 1c). EC aspirin 300 mg reduced PGE 2 synthesis by 79.8% (48.3±92.4%) from (25.6 ±211.5) pg/ mg before treatment, to 14.9 (10.2±38.1) pg/mg by day 5 (P ˆ 0.004), although no inhibition was evident after

3 ASPIRIN AND THE GASTRIC MUCOSA 189 Figure 1. Gastric mucosal prostaglandin E 2. Individual data are shown for each treatment (panels a±d) and for each time point (day 0: pre-treatment) day 1 ˆ 90 min post rst dose, day 5 ˆ after ve daily doses: paired data are shown connected by lines. Vertical axis ˆ pg/mg tissue wet weight. the rst dose. Mucosal PGE 2 levels after 5 days of EC aspirin tended to be lower than those with aspirin 75 mg (P ˆ 0.117) and were not signi cantly different from plain aspirin 300 mg. Mucosal injury Erosions. At baseline there were 0(0±0) erosions Figure 2). Analysis of variance showed signi cant overall differences in total gastric erosions between aspirin preparations during treatment (P ˆ 0.01). There were 18 (2±26) erosions with plain aspirin 300 mg (P ˆ compared to placebo) and 2(0±7) with plain aspirin 75 mg (P ˆ compared to placebo). With EC aspirin 300 mg there were 0(0±1) erosions at day 5. This was not signi cantly different from placebo values and signi cantly less than plain aspirin 300 mg (P ˆ 0.003). There was a trend to fewer erosions with enteric coated aspirin 300 mg compared to plain aspirin 75 mg, although this did not achieve statistical signi cance (P ˆ 0.11). A similar pattern of differences between aspirin treatments was seen when erosions in the gastric body and antrum were counted individually. There was little duodenal injury and no signi cant differences between the groups in this respect. After 5 days treatment there were 0(0±1) duodenal erosions with plain aspirin 300 mg, 0(0±0.5) with plain aspirin 75 mg, 0(0±1) with enteric coated aspirin 300 mg and 0(0±10) on placebo. In one subject on plain aspirin 75 mg there were 16 duodenal erosions. No ulcers were seen on any treatment. Visual analogue scores. Quanti cation of injury using visual analogue scores gave similar ndings to the erosion counts (Table 1). At baseline, the median scores were all 0. After 5 days of treatment with aspirin 300 mg the score was 16 (0.5±40.3) mm for body

4 190 A. T. COLE et al. Figure 2. Gastric erosion Individual data are shown for each treatment (panels a±d) and for each time point (day 0 ˆ pretreatment) day 1±90 min post rst dose, day 5 ˆ after ve daily doses: paired data are shown connected by lines. Vertical axis ˆ number of gastric erosions. (P ˆ compared with placebo) and 14.5 (5.3± 33.8) mm for antrum (P ˆ 0.01 compared with placebo). With plain aspirin 75 mg the visual analogue scores were 3.5(0±16) mm for body (P ˆ 0.21 compared with placebo, P ˆ compared to plain aspirin 300 mg) and 6(0±19.5) for antrum (P ˆ compared with placebo, P ˆ 24 compared to plain aspirin 300 mg). Injury scores with EC aspirin 300 mg were 0(0±1.5) for body (P ˆ 0.05 compared with plain aspirin 75 mg, P ˆ compared with plain aspirin 300 mg) and 1(0±9.3) for antrum (P ˆ 0.31 compared with placebo, P ˆ 0.20 compared with plain aspirin 75 mg, P ˆ compared with plain aspirin 300 mg). Safety and tolerability Few new symptoms were recorded during the study. Two subjects reported abdominal pain that they specifically related to air insuf ation at endoscopy. Mild epigastric pain was recorded in one subject following a single dose of placebo, in one subject following a single dose of plain aspirin 300 mg, and in one subject during treatment with plain aspirin 75 mg. Severe epigastric pain was recorded in the one subject following a single dose of EC aspirin 300 mg. None of these subjects had recurrent pain with subsequent doses of the same preparations, required any drug therapy or withdrew from the study. DISCUSSION In this study the effects of three aspirin preparations on gastric mucosal prostaglandin synthesis and gastroduodenal mucosal injury were compared directly. Each of the three formulations of aspirin signi cantly inhibited ex vivo gastric mucosal PGE 2 synthesis, although the plain aspirin 75 mg preparation was signi cantly less effective than the 300 mg preparations. There was a slower onset of action for EC aspirin. However, there

5 ASPIRIN AND THE GASTRIC MUCOSA 191 Table 1. Erosions: visual analogue scores Plain aspirin EC aspirin Plain aspirin Placebo 75 mg 300 mg 300 mg Body Day 0 0(0±0) O(0) 0(0±1) 0(0±0.8) Day 1 6.5(0±11) 0(0±19.8) 0.5(0±7) 13.5(0.3±7.3) Day 5 1.5(0±12.5) 3.5(0±16) 0(0±1.5) 16(0.5±40.3) Antrum Day 0 0(0±0.8) 0(0±0.75) 0(0±0) 0(0±1) Day 1 0(0±0.8) 0(0±11.5) 0(0±0.8) 11.5(0±18) Day 5 0.5(0±4.2) 6(0±19.5) 1(0±9.3) 14.5(5.3±33.8) Duodenum Day 0 0(0±0) 0(0±0) 0(0±0) 0(0±0) Day 1 0(0±0) 0(0±0) 0(0±0.75) 0(0±1.8) Day 5 0(0±0) 0(0±2.8) 0(0±0) 3(0±8.5) All data are given as median and interquartile ranges of the visual analogue score in mm (100 mm maximum). were marked differences in the amount of mucosal injury seen with the different formulations of aspirin. Plain aspirin caused signi cant dose-related increases in mucosal injury whether measured by mucosal lesion counts, or the visual analogue score. Elsewhere we have reported that EC aspirin was as effective as the same dose of plain aspirin in its effects on a variety of measures of platelet function. 8 We have previously reported a comparison of higher doses of both aspirin 2.4 g daily and 300 mg daily between plain and enteric coated preparations and found similar results to those presented here. Enteric coating gave almost complete protection against gastric erosion formation. Other authors have also demonstrated protection with higher doses of enteric coated aspirin. 4 Our data show that EC aspirin 300 mg caused the least gastric injury of the three preparations tested. This occurred despite reductions in the ex vivo synthesis of PGE 2 to levels which were comparable to those seen with plain aspirin and bio-equivalence of their effects on platelet function. 8 Reduced mucosal injury in the face of reduced prostaglandin synthesis supports the idea that there is a topical component to the injury caused by plain aspirin and that abrogation of this topical injury is the basis of the protection associated with enteric coating of aspirin. Topical injury with aspirin may arise by a number of mechanisms. Aspirin accumulates in the gastric mucosa when absorbed from an acidic milieu and may interfere with metabolic processes which include oxidative phosphorylation. 9 Aspirin also associates with hydrophobic phospholipids in the gastric mucus and surface mucosal layer, so impairing the function of the mucus and mucosal barriers. 10 Plain aspirin dissolves in the stomach and may in part affect mucosal prostaglandin synthesis as a result of luminal delivery. By contrast, the inhibition of prostaglandin synthesis by enteric coated aspirin is likely to have occurred because of systemic delivery of aspirin to the gastric mucosa. Lower doses of aspirin have been shown to acetylate platelet cyclo-oxygenase in the pre-systemic circulation and before elimination by rst pass metabolism by the liver. It is therefore possible that enteric coated aspirin in very low doses might achieve both the bene ts of aspirin on platelets without any exposure at all of the gastric mucosa to aspirin, and it would seem that this would be worth investigating. Although our study has covered short-term changes in young healthy volunteers, it is likely that similar relationships would be seen for longer ingestion by older patients. Acute studies of protective strategies have shown that normal doses of H 2 antagonists do not prevent gastric erosions, 11, 12 whilst higher doses, 12 proton pump inhibitors 13 and misoprostol 14, 15 do. These results have been replicated in clinical studies of patients with arthritis taking NSAIDs on a long-term basis. 15±24 Moreover, when old and young subjects have been compared, there were no differences in acute mucosal injury. 25 Epidemiological studies have found that use of enteric coating or non-oral routes of administration are still associated with an increased tendency to upper gastrointestinal bleeding. 26 However,

6 192 A. T. COLE et al. these results may be confounded by dose and multiple drug use and do not apply speci cally to aspirin. Our data con rm that the enteric coating of aspirin is one way of protecting the stomach from aspirin, while at the same time allowing the complete suppression of eicosanoid-dependent platelet function. 7 Other prophylactic strategies to protect the stomach and duodenum against the ulcerogenic action of nonsteroidal antiin ammatory drugs may be used, including the use of ulcer healing drugs 24 and mucosal protection agents such as misoprostol. 15±24 In the future, inhibitors of the inducible cyclo-oxygenase (COX-2) pathway 8, 25 or 26, 27 nitric oxide donating NSAIDs may prove safer than existing agents. However, COX-2 inhibitors do not affect platelet function and will have no utility as cardiovascular prophylaxis. Strategies which employ co-prescription are not proven by long-term studies for aspirin users. 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