Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine

Transcription

1 Br. J. clin. Pharmac. (1989), 28, Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine G. K. KITCHINGMAN, P. J. PRICHARD, T. K. DANESHMEND, R. P. WALT & C. J. HAWKEY Department of Therapeutics, University Hospital. Nottingham, NG7 2UH 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,u 10 min-1 (95% confidence limits ,u1 10 min-') to 2.8,lI 10 min-' ( pu1 10 min-', P < 0.01) after 5 days of aspirin. Adaptation did not occur and the gastric bleeding rates remained elevated at 3.4 RI 10 min-' ( ,ul 10 min-) after 12 days of aspirin consumption (P < 0.01). 2 Coadministration of ranitidine significantly raised intragastric ph and reduced aspirin induced bleeding to 1.5,ul 10 min- 1 ( pl1 10 min-') after 5 days and 1.6 ( RI 10 min-') after 12 days (P < 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. Keywords aspirin ranitidine gastric bleeding Introduction The increasing use of low doses of aspirin for primary and secondary prophylaxis in cardiovascular diseases is based on the observation that such doses achieve a maximum differential effect on thromboxane and prostacyclin synthesis (Hanley et al., 1981; Patrono et al., 1985; Pedersen et al., 1984), leading to prolongation of the bleeding time (Boss et al., 1984). One of the most important adverse consequences of treatment with aspirin or other non-steroidal anti-inflammatory drugs, however, is the development of bleeding from peptic ulceration, with a relative risk in the elderly of about three (Armstrong & Blower, 1987; Coggon et al., 1982; O'Brien & Burnham, 1985; Somerville et al., 1985). Usage of low dose aspirin is still too uncommon in the community for such case control studies to establish a specific association. However, in many instances presentation with bleeding peptic ulcers has followed periods of brief or light intake of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) (Coggon et al., 1982; Somerville et al., 1985, 1988). Moreover, we have shown that doses of aspirin as low as 75 mg day- 'taken for 5-28 days double the rate of spontaneous bleeding from the gastric mucosa (Prichard et al., 1989). In the recently published study of aspirin 500 mg day- ' as prophylaxis in British doctors there was a significant increase in peptic ulceration and gastrointestinal bleeding in treated subjects compared with controls (Peto et al., 1988). We have therefore assessed the short term effects of aspirin 300 mg day-' on bleeding from the gastric mucosa and investigated possible protective effects of acid inhibition by ranitidine. Correspondence: Dr C. J. Hawkey, Department of Therapeutics, University Hospital, Nottingham NG7 2UH 581

2 582 G. K. Kitchingman et al. Methods Subjects We studied 30 healthy volunteers (15 male, 15 female, aged years) who were nonsmokers, with no significant history of gastrointestinal or other disease, no history of dyspepsia, easy bruising or bleeding, aspirin or ranitidine intolerance, and whose pre-study blood (and platelet) counts, prothrombin time and APTT were normal. The subjects took no drugs during the study and were asked to refrain from drinking alcohol during treatment periods. All subjects gave informed consent to participate in the study, which was approved by the Nottingham Medical School Ethics Committee. Study design The study was randomised and double-blind, with intrasubject comparisons. Subjects received plain aspirin 300 mg (Evans Medical) at h daily for two treatment periods of 12 days duration. During one treatment period they also received ranitidine 150 mg at h, and during the other an identical placebo for ranitidine. The two treatment periods were separated by a washout period of at least 2 weeks. Fifteen subjects took aspirin with ranitidine during the first treatment period and aspirin with placebo during the second treatment period; for the other fifteen subjects this order was reversed. Gastric mucosal injury was quantified as the rate of gastric mucosal bleeding. This was measured five times in each subject, on the fifth and twelfth day of each treatment period and also under basal conditions. Collection of samples Bleeding was measured over timed periods using the technique of gastric washing. Details have been published previously (Hawkey et al., 1986, 1988). Briefly, subjects fasted from h on the evening prior to the experiment. On each study day at h (90 min after the final dose of aspirin) they swallowed a Salem sump orogastric tube, French gauge 16, as far as the 55 cm mark. They lay on their left side in order to reduce pyloric loss of gastric contents. The pre-collection stomach contents were aspirated and the ph measured. The position of the tube was checked and the stomach washed of debris by three rapid washes of 100 ml water. Three consecutive timed collections were then made. To compensate for pyloric loss of blood during the collections, 2 mg of phenol red in 15 ml water (total) was introduced into the stomach after 5 min, to act as a marker for recovery. On each occasion the subjects rested for 9 min then drank 100 ml of water which was dispersed around the stomach, aspirated by 10 min and saved for assay. Two further consecutive timed collections were carried out in a similar manner, each preceded by two rapid washes performed to remove residual marker dye. Whenever liquids were introduced into the stomach a short standard exercise activity was performed in order to ensure contact of the liquid with the whole stomach surface. Assays Concentrations of blood in aliquots of the three timed washes were assayed on the day of the experiment for haemoglobin by the orthotolidine method using the subject's own blood for the preparation of standards. This method depends upon the peroxidase activity of haemoglobin which liberates oxygen from hydrogen peroxide and oxidises orthotolidine to a blue colour. Details of the method have been described previously (Fisher & Hunt, 1976; Hawkey et al., 1986, 1988; Hunt & Franz, 1981). The ph of the pre-collection aspirate and of the three timed washes was measured using a glass electrode (Corning). Phenol red recovery of each wash was evaluated spectrophotometrically at 560 nm, after adjusting to ph 10.5 with ammonium hydroxide (Hawkey et al., 1986, 1988; Hunt & Franz, 1981). The proportion of phenol red recovered in the first wash at the end of each treatment period was used to adjust the measurement of blood in the washings to allow for losses through the pylorus or by failure of reaspiration. This adjustment assumes that losses of blood and phenol red are similar, and occur at a roughly constant rate (Hawkey et al., 1986, 1988; Hunt & Franz, 1981). Statistical analysis A factorial analysis of variance was carried out for the influence of ranitidine and duration of treatment on gastric mucosal bleeding, corrected for phenol red recovery. The data were logarithmically transformed prior to computation in order to approximate a normal distribution. Results were expressed as geometric mean with 95% confidence limits. Data for phenol red recovery were analysed similarly but without prior logarithmic transformation, since they were

3 normally distributed without transformation. Friedman two way analysis of variance by ranks was used to determine the significance of changes in ph values of the pre-collection aspirate and timed washes. Results were expressed as medians with interquartile ranges. Results Under baseline conditions the rate of bleeding (geometric means and 95% confidence limits) was 0.5 ( ),u 10 min-' (Table 1). After 5 days of aspirin it rose to 2.8 ( ) pul 10 min-' and, after 12 days, 3.4 ( ,u1 10 min-' (P < 0.01 compared with baseline; comparison of 5 and 12 days-no significant difference). Co-administration of ranitidine reduced these values to 1.5 ( ) RI 10 min-' and 1.6 ( ) RI 10 min-' respectively (P < 0.01 for effect of ranitidine; no significant difference between days 5 and 12). These changes were accompanied by significant elevations of intragastric ph measured in both pre-collection samples and washings after ranitidine treatment (Table 1). Discussion These data confirm that even low doses of aspirin increase gastric mucosal bleeding substantially. Microscopic bleeding has been shown to correlate with endoscopic signs of acute gastric mucosal injury (Daneshmend et al., 1988; Fellows et al., 1989; Sharma et al., 1989). Our data show that the injury caused by aspirin 300 mg is considerably reduced by anti-secretory Table 1 The results of the study Aspirin, ranitidine and gastric bleeding doses of ranitidine, as is the case with higher doses of aspirin (Daneshmend et al., 1988; Hawkey et al., 1986, 1988; Hunt & Franz, 1981; Prichard et al., 1988). Previous studies have shown that the gastric mucosa adapts to continued high dose aspirin after the first week of ingestion (Graham & Smith, 1986; Shorrock & Rees, 1987) but we found no effect of time and in particular no suggestion of a reduction in bleeding between 5 and 12 days, with this lower dose of aspirin. There is growing clinical evidence that these short term findings are reflected in the long term development of clinically important end points. In trials of aspirin in daily doses of 900 mg or more there seems little doubt that there is an increased rate of presentation with dyspepsia or peptic ulceration and its consequences (Aspirin Myocardial Infarction Study Research Group, 1980; Cairns et al., 1985; Coronary Drug Project Research Group, 1976; Elwood & Sweetham, 1979; ESPS Study Group, 1987; Persantin-Aspirin Reinfarction Study Research Group, 1980). Hitherto there have been few data on lower doses of aspirin. In the recently reported trial of aspirin 500 mg day- ' as primary vascular prevention in British doctors, there was a significant increase (by 50%) in peptic ulceration and in non fatal gastrointestinal bleeding in those taking aspirin compared with controls (Peto et al., 1988). Gastrointestinal bleeding led to withdrawal of 2.2% of those taking aspirin (Peto et al., 1988). In the UK TIA study (UK-TIA Study Group, 1988), dyspepsia and gastrointestinal bleeding were also significantly increased in subjects taking aspirin 300 mg or 1200 mg day-'. This study was not large enough to evaluate the risk of aspirin 300 mg alone but rates for all of the Aspirin 300 mg daily and ranitidine Aspirin 300 mg daily 150 mg twice daily Control Day 5 Day 12 Day 5 Day 12 Blooda t 3.4t 1.5* 1.6* (ull 10 min ') ( ) ( ) ( ) ( ) ( ) Phenol reda (% recovery) (52-62) (5342) (55-67) (53-63) (54-64) Initial ph" t 6.82t ( ) ( ) ( ) ( ) ( ) Washings pht t 6.13t ( ) ( ) ( ) ( ) ( ) 'Mean and 95% confidence limits. "Mcdian and interquartile range tp < 0.01 compared with control. *P < 0.05 compared with aspirin 583

4 584 G. K. Kitchingman et al. individually reported gastrointestinal problems were numerically higher than in the placebo group. Case control studies suggest that the absolute risk of presenting with a peptic ulcer complication in elderly patients taking aspirin or NSAIDs at any dose is somewhere in the range 1: patient years (Armstrong & Blower, 1987; O'Brien & Burnham, 1985; Somerville et al., 1985, 1988). The non-significant difference in rates of serious gastrointestinal bleeding (1.5% vs 0.9%) between patients taking aspirin 300 mg and those taking placebo in the UK TIA study is compatible with a similar rate for low dose aspirin, but a much larger study would be required to evaluate the precise magnitude of this risk. At variance with these British studies is the US Physicians Health Study, whose interim report failed to show a significant increased incidence of dyspepsia or gastrointestinal bleeding in subjects receiving aspirin 325 mg on alternate days (The Steering Committee of the Physicians' Health Study Research Group, 1988). However, this apparently lower risk may not relate to the dose of aspirin, since the study specifically excluded patients who were found to be intolerant of aspirin during a pre-randomization treatment period. Taken together these studies suggest aspirin mg day-' is associated with an increased incidence of peptic ulceration and gastrointestinal haemorrhage. Moreover, since none of them involved systematic evaluation of these end points, such risks are likely to have been underestimated. Neither these nor published case control studies identify the precise nature of the risk which may involve either ulcerogenesis or induction of bleeding (and therefore, presentation) in pre-existing silent ulcers. Whilst our data suggest that co-administration of ranitidine protects human gastric mucosa against aspirin 300 mg, bleeding rates still appeared to be somewhat higher than control values. It is likely that meal stimulated acid was not suppressed as much as that recorded under fasting conditions in this study and it is possible that a greater benefit would accrue from more profound acid inhibition (Daneshmend et al., 1988). In addition our study covers only a relatively short time and relates to acute injury rather than chronic ulceration. However, we have shown that there is a difference in the response to low doses of aspirin compared with that reported for higher doses (Graham & Smith, 1986; Shorrock & Rees, 1987) in that no adaptation occurs. Thus it seems likely that the changes identified in our study would continue with long term ingestion and that coadministration of ranitidine could prevent some of the clinically significant consequences of long term low dose aspirin ingestion. Protection against aspirin induced gastric mucosal injury is in contrast to the results of two recent studies showing that misoprostol protected against NSAID induced gastric ulceration (but not obviously duodenal ulceration) whilst ranitidine protected against duodenal ulceration (but not obviously gastric ulceration) (Ehsanhullah et al., 1988; Graham et al., 1988). However, the situation in respect of low dose aspirin may differ. Firstly aspirin and other salicylates contrast with most non aspirin NSAIDs in damaging the gastric mucosa by a topical action not mediated by prostaglandins (Chvasta & Cooke, 1972). Secondly ph is of particular importance in determining passive absorption of aspirin by the gastric mucosa (Spenney & Marshall, 1983). Thirdly aspirin may promote gastrointestinal bleeding by its ability to acetylate platelets and cause a 6-fold increase in rates of gastric bleeding (Daneshmend et al., 1989). Such an action is likely to be of importance with the doses of aspirin we have used. Intragastric fibrinolysis has been shown to be ph dependent (Green et al., 1978). Acid inhibition may thus be of clinical benefit to patients taking low doses of aspirin either by preventing mucosal injury and ulceration or by reducing intragastric bleeding. References Armstrong, C. P. & Blower, A. I. (1987). Nonsteroidal anti-inflammatory drugs and life threatening complications of peptic ulceration. Gut, 28, Aspirin Myocardial Infarction Study Research Group (1980). A randomized, controlled trial of aspirin in persons recovered from myocardial infarction. J. Am. med. Ass., 243, Boss, A. H., Boysen, G. & Olsen, J. S. (1984). Bleeding time, thromboxane production and platelet aggregation in stepwise increment of acetylsalicylic acid. Acta Neurol. Scand., 69 (Suppl. 98), Cairns, J. A., Gent, M. & Singer, J. (1986). Aspirin, sulfinpryazone, or both in unstable angina. Results of a Canadian Multicenter Trial. New Engl. J. Med., 313, Chvasta, T. E. & Cooke, A. R. (1972). The effect of several ulcerogenic drugs on the canine gastric mucosal barrier. J. lab. clin. Med., 79,

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