Dr John Wright

Gastroenterologist
MbChB MRCP(UK) PhD

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Low dose aspirin and gastrointestinal bleeding

Dr John P Wright
Updated: 14 February 2001

The use of low dose aspirin(<325mg daily) in preventing cardiovascular disease such as coronary heart disease, cerebrovascular disease and peripheral vascular disease, is well supported by the literature. A recent meta-analysis of 5 studies with 55580 subjects (21% women) showed that low dose aspirin significantly reduces first myocardial infarct rate by 32% and important vascular events by 15%. There were no significant beneficial effects on cerebrovascular accidents.

In another study of 39 876 female subjects low dose aspirin had no overall effect on the risk of myocardial infarction or on death from cardiovascular causes. In the subgroup of women aged 65 and over aspirin significantly decreased first myocardial infarctions by about 34% which was virtually identical to the 32% above. It is therefore apparent that low dose aspirin in men and at least older women is of benefit in protecting against cardiovascular disease.

Aspirin, at doses of 75 to 100mg a day, binds to and then irreversibly acetylates the catalytic site of cyclooxygenase(COX) in platelets. Normally cyclooxygenas metabolises arachidonic acid to PGH2 which, in platelets, is processed to thromboxane A2, a powerful promoter of platelet aggregation. At a dose of about 30 mg/day aspirin is a much more potent inhibitor of COX-1 than COX-2. This effect is so pronounced that higher doses of aspirin appear to yield little additional benefit and much higher doses have been postulated to be deleterious due to reversible inhibition of endothelial cell synthesis of prostacyclin (a vasodilator and inhibitor of platelet aggregation). The clinical relevance of this prostacyclin sparing has not been demonstrated as the benefits of aspirin are similar in doses from 75 mg to over 1000 mg daily. Side effects and in particular gastric mucosal damage may however be less in patients on the lower dose.

In order to avoid gastric damage the use of enteric-coated aspirin has become popular. These preparations have been shown to diminish endoscopic signs of gastroduodenal injury but do not appear to protect against the danger of gastrointestinal bleeding with a similar relative risk as plain aspirin. This in really not that surprising as it is the systemic rather than the local effect, that causes the ulceration and bleeding. This system effect is confirmed by the observation that buffered aspirin is no more effective than plain aspirin in preventing ulcer bleeding. Furthermore when NSAID are taken by injection or suppository mucosal damage is still a problem.

Aspirin damages gastric mucosa by inhibiting COX-1 which the gastric mucosa uses to generate mucosal-protective prostaglandins. Even at doses as low as 10 mg/day prostaglandin production is inhibited. This effect is long lasting with the mucosa taking 5 to 8 days to recover its COX-1 activity. This slow recovery is mirrored in the platelets, the primary target of low dose aspirin, which takes 14 days to recover from the aspirin effects.

All COX-1 inhibitors cause gastric damage similar to aspirin. The relative dangers vary between the different agents. A ranking of increasing risk has been found to be ibuprofen, fenoprofen, aspirin, diclofenac, sulindac, naproxen, indomethacin, tolmetin, piroxicam and ketoprofen.Furthermore if a patient is on one of these agents it may interfere with the action of aspirin on the platelet COX-1. This generally applies to the non-selective NSAIDs such as ibuprofen or naproxen but is not seen with diclofenac. In the case of the COX-2 inhibitors where the lack of COX-1 inhibition of platelets has led to increased cardiovascular events. Conversely COX-2 inhibitors do still cause gastric mucosal damage but less so than the non-selective agents.

In order to prevent the gastric damage associated with NSAIDs concomitant misoprostol or proton pump inhibitors may be used. Misoprostil 200mg 6 hourly has the added advantage or disadvantage of loosening bowel function. A slightly cheaper and possibly better alternative is the use of a proton pump inhibitor. In a study reported last year in 844 patients on NSAID of various varieties the rate of ulcer formation in the placebo group was 20.4%, in those on esomeprazole 20mg 5.3% and in those on 40mg, 4.7%. When just those on COX-2 inhibitors were analyzed the respective rates were 16.5%, 0.9% and 4.9%. This study therefore demonstrated that all NSIADs cause problems and a PPI albeit on full dose in some instances will prevent most of these.

The need for prophylactic therapy when only low dose aspirin is used is less clear. Gastric damage due to these agents is dose related. In those with previous peptic ulcers or if symptoms develop some form of prophylaxis should be used if the low dose aspirin needs to be continued. Another alternative would be to take a non-NSAID platelet inhibitor such as clopidogrel. It has a similar protective effect but is considerably more expensive.

In patients who have had an upper gastrointestinal bleed but still need anti-platelet medication it has been shown that restarting low-dose aspirin (50 - 100 mg/day) has a 14.8% rebleed rate. Substituting clopidogrel (75 mg/day) for low-dose aspirin has an 8.6% rate while if low-dose aspirin with a proton pump inhibitor is used the re-bleed rate is only about 1 %. Not surprisingly the use of low dose aspirin does not appear to cause increased intestinal bleeding but small-bowel injury was seen by capsule video endoscopy in 71% of NSAID users compared with 10% of controls.

Aspirin has widespread gastrointestinal effects. These are largely dose related but vary from insignificant erythema to large bleeding ulcers and perforation. When there is a past history of gastrointestinal peptic ulceration or compatible symptoms concurrent proton pump inhibitors should be considered. The traditional advice of taking enteric coated aspirin with meals probably has little merit and a pharmacological answer needs to be employed.