Editorial How safe is low d o s e aspirin in clinical practice? R L Satarasinghe*, P D Duane** Journal of the Ceylon College of Physicians, 2000 , 33 , 2-4 (Key words: NSAIDs - Non Steroidal Anti inflammatory Drugs; PUD - Peptic Ulcer Disease; GU - Gastric Ulcer; DU - Duodenal Ulcer) Abstract Objective: To study the safety of low dose aspirin on the upper gastrointestinal tract. Design and Setting: Endoscopy findings of 993 patients who had gastroscopies done for any reason in the Department of Medicine - Withybush District General Hospital in Pembrokeshire from 14-08-92 to 01-08-94 were re-examined. The notes of any pa­ tient who had clinical evidence of upper gastrointesti­ nal damage and had been on low dose aspirin, were reviewed. Results: Total number on low dose aspirin - 4 1 . Age range 40 - 90 yrs. Majority: 50 - 70 age group. Male: Female = 30 : 11. Profile of clinical presentat ions: Malaena (15), Dyspepsia (12), Haemetemesis (10), Vomiting (5). Endoscopy Finding: GU in 17, DU in 8, erosions alone in 7, Oesophagitis in 3, overlaps in 8. Types of aspirin used: Soluble aspirin in 25; dose range: 75 mg in 6 , 1 5 0 mg in 10, 300 mg in 9; Enteric coated aspirin in 16; dose range: 75mg in 9, 150 mg in 7. Duration of aspirin therapy: > 2 yrs - 10, 2 yrs to 1 yr - 1 3 , 6 m - 9, < 6m - 9. Indications: Cardiovascular events -15, Cerebrovascular events - 20, Prophylactic - 6. The clinical implications are discussed in the text. Conclusions: 1. Low dose aspirin too causes con­ siderable gastrointestinal morbidity. 2. There s e e m s to be no great safety with enteric-coated types, a s well. 3 . Risk - Benefit evaluation is essential, prior to prescription of low dose aspirin with adequate preven­ tive measures . Introduction The number of reported beneficial effects of low dose aspirin (< 325 mg daily) continue to increase. Used a s secondary prevention, low dose aspirin re­ duces the incidence of myocardial infarction, strokes * Consultant Physician, Base Hospital, Panadura. ** Consultant Physician Gastroenterology, Withybush District General Hospital, Pembrokeshire, Wales. and vascular deaths by about 25%' . Evidence is also accumulating that regular aspirin use reduces the risk of developing colo-rectal cancer, the commonest cause of nonsmoking cancer related dea ths 2 . The studies are also in progress with regard to effect of low dose aspirin on vascular dementias. With all these 'positive' results, it s e e m s that the general public is of the opin­ ion that, 'as aspirin a day keeps doctor away'. With this background, it is not surprising that many young adults and elderly will be inclined to use low dose a s ­ pirin indiscriminately a s a primary prophylactic agent against the above disease. Kelly et a l 3 reported that in the USA 9% of healthy control subjects with a median age of 60 years were taking low dose aspirin regularly, at least every other day. A similar UK b a s e d c a s e control study found that 8% of the hospital and 6% community controls were consuming < 300 mg aspi­ rin at least 5 days per week 4 . With this background a retrospective study was - designed to evaluate the safety of low dose aspirin on the upper Gl tract including the enteric coated varieties. Objective To study the safety of low dose aspirin on upper gastrointestinal tract. Design and Setting Endoscopy findings of 993 patients who had gas ­ troscopies done for any reason in the Department of Medicine - Withybush District General Hospital in Prembrokeshire from 14-08-92 to 01-08-94 were re­ examined. The notes of patients who had evidence of Upper Gl damage and had been on low dose aspirin, were reviewed. Duration of aspirin therapy: > 2 yrs 10 2 yrs ~ 1 yr 13 1 yr - 06 months 09 < 06 months 09 How safe is low dose aspirin in clinical practice? Indications for aspirin therapy: Cerebrovascular events 20 Cardiovascular events 15 Prophylactic 06 Discussion It has been proved beyond doubt that NSAIDs are a potent cause of upper Gl morbidity and mortal­ ity5'7. Aspirin too is a NSAID which is now a days used in small doses in secondary prevention of cardiovas­ cular and cerebrovascular d isease . Its major indica­ tion to be used in larger doses is rheumatic arthritis, which Is relatively a d isease of the developing coun­ tries in the modern era. Several hypothetical mechanisms by which aspi­ rin could bring about Upper Gl bleeding have been pro­ p o s e d 8 4 . The back diffusion of acid into the gastric mucosa could occur due to local irritation thus dam­ aging the mucosal cells and submucosal capillaries with an e n d resu l t of n e c r o s i s a n d b l e e d i n g . Cyclooxygenase which catalises the synthesis of gas­ tric prostaglandins PG12 and PGE2 are inhibited by aspirin. These prostoglandins inhibit acid secretion and enhance synthesis of cyto-protective mucus. Impair­ ment of platelet aggregation may increase the ten­ dency to bleed. An aspirin tablet coated with a combi­ nation of silicon, cellulose or other inactive ingredi­ ents has resistance to disintegrate in the stomach. This feature allows the drug to dissolve in the neutral to alkaline medium in the duodenum 1 0 . The safety of this type of product h a s been confirmed by several endoscopic studies comparing plain aspirin with en­ teric coated preparations o n 1 " 3 healthy volunteers. Less gastric erosion and micro bleeding were noted with enteric coated preparations. Buffering agents lowered hydrogen ion concentration in the microenvironment of aspirin particles, thus resulting in a reduce contact time between aspirin particles and gastric mucosa and enhance the gastrointestinal solubility of aspirin 8 ' 9- 1 2. However the belief that buffering would reduce the gas­ tric damage has been largely unsupported by endo­ scopic s tud i e s 1 1 1 2 . Recently Kelly et al reported that the use of low dose of enteric coated or buffered aspi­ rin carries a three fold increase in the risk of major upper Gl bleeding 3. Therefore the assumption that those formulations are less harmful than plain aspirin may be mistaken. Results Total number of patients on low dose asprin: 41 3 Age range: Yrs. No. 4 0 - 5 0 - 05 5 1 - 6 0 - 12 6 1 - 7 0 - 17 7 1 - 8 0 - 06 8 1 - 9 0 - 01 Sex distribution: Male: Female: 30:11 Profile of clinical presentations: Malena - 15 Dyspepsia - 12 Haematemes is - 10 Vomiting - 05 Endoscopy findings: GU - 17 DU - 08 Erosions alone - 07 Oesophagitis - 03 Overlaps - 08 Types of aspirin used: Soluble asprin - 25 Enteric coated - 16 Dose range: 75 mg - 06 150 mg - 07 300 mg • 09 dose range in enteric coated type: 75 mg - 09 150 mg - 07 In the study 16 were on enteric coated aspirin with a dose range of 75-150 mg daily. There were no patients on buffered aspirin. Doses a s minimum a s 75mg has caused upper Gl bleeding. Studies show that doses of aspirin even a s low a s 75mg a day are harmful, though to a lesser extent than 300 mg daily 1 4. The risks and benefits of aspirin therapy need to be a s se s sed for each patient. For example, the attribut- Vol. 33, No. 1, 2000 4 R L Satarasinghe, P D Duane able risk of haematemesis is 0.2 to 1.0 per 1000 per­ son-years of exposure 4 , whereas in a patient with a history of myocardial infarction the absolute reduction in vascular events is 40 per 1000 patients treated 1 . It is a l s o worth explor ing t h e p ro tec t ive effect of misoprostol and stroke or H2 antagonists in patients at high risk of Gl bleeding, who needs aspirin prophy­ laxis. In rheumato id d i s e a s e , co-prescr ip t ion of misoprostol with NSAIOs reduces the frequency of up­ per Gl ulceration, perforation and obstruction by 04% to 50% 1 5 , but not the frequency of haematamesis . One should also discourage the indiscriminate use of aspi­ rin, a s it has no proven value in primary prevention of cerebrovascular and cardiovascular even t s 1 . In the study 06 patients were on prophylactic aspirin. It is also equally important to use the minimum effective dose . Several s tudies have shown that the desired benefit could be achieved with doses of 75mg daily or l e s s . In conclusion, the physicians who recommend aspirin whether enteric coated or buffered, should not a s s u m e that these forms are less harmful to the Gl tract and individuals who use these preparations in the belief that they are safer than plain aspirin, still subject themselves to a significant risk of major upper gastrointestinal bleed. References 1. Anti-platelet Trialists Collaboration - Collaborative overview of randomised trails of anti platelet therapy - 1 . Prevention of death, myocardial infarction and stroke by prolonged anti platelet therapy in various categories of patients. BMJ1994; 308:81-106. 2. Giovannuci E, Egan KM, Hunter DJ, et al. Aspirin and the risk of colorectal cancer in women. En Engl J Med 1995; 333: 609-14. 3. Kelley JP, Kaufman DW, Gurgelon JM et al. Risk of aspirin associated major upper gastrointestinal bleeding with enteric coated or buffered products. Lancet 1996;348: 1413-16. 4. Roderick PJ, Wilkes HC, Meade TW. The gastrointestinal tox­ icity of aspirin. An overview of randomised controlled trails. BrJ Cin Pharmacol 1993; 35:241 -49. 5. Kaufman DW, Kelley JP, Sheehan JE, et al. Nonsteroidal anti-inflammatory drug use in relation to major upper gas­ trointestinal bleeding. Clin Pharmacol 77>er1993; 53:485- 94. 6. Holovet J, Terriere L, Van Hee W, et al. Relation of upper gastrointestinal bleeding to nonsteroidal anti-inflammatory drugs and aspirin. A case control study. Girt 1991; 32:730- 34. 7. Levy M, Muller O, Kaufman OW, et al. Major upper gas­ trointestinal bleeding and the use of aspirin and other non narcotic analgesics. Arch Intern Med1988; 148:281-85. 8. Graham DY, Smith JL. Aspirin and the stomach. Ann Inter Med1986; 104:990-98. 9. Gilman AG, Rail TW, Niles AS, eds. Goodman & Gilman's The pharmacological basis of therapeutics 8th ed. New York: Pergaman Press 1990; 644-53. 10. Physician's Desk Reference, 49th ed. Montyale, New Jer­ sey. Medical Economics Data Production Company, 1995. 11. Hoftiezre JW, Silvoso GR, Burks M, Ivey KJ. Comparison of the effect of regular and enteric coated aspirin on gas- troduodenal mucosa of man. Lancet 1980; 2:609-12. 12. Lanza FL, Royer GL Jr, Nelson RS. Endoscopic Evaluation of the effects of aspirin, buffered aspirin and enteric coated aspirin on gastric and duodenal mucosa. New EnglJ Med 1980;303:136-38. 13. Hawthorne AB, Mahida YR, Cole AT, Hawkey CJ. Aspirin induced gastric mucosal damage: prevention by enteric coat­ ing and relation to prostoglandin synthesis. Br J Clin Pharmacol 1991; 22: 77-83. 14. Richard PJ, Kitchingman GK, Walt RP, et al. Human gastric mucosal bleeding induced by low dose aspirin, but not war­ farin. BMJ 1989; 298: 493-96. 15. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflam­ matory drugs. Ann Intern Med 1995; 123: 214-49. Journal of the Ceylon College of Physicians