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Three Part Question

In [patients post CABG] [EC aspirin vs aspirin] [lower incidence of gastrointestinal complications]

Clinical Scenario

You have performed a coronary artery bypass graft on a 72 year recent ex-smoker with triple vessel disease and hypercholestrolaemia, who has done very well post-operatively. You usually prescribe dispersible aspirin on discharge, but this gentleman has taken enteric-coated aspirin for 3 years and he tells you that he got terrible indigestion with dispersible aspirin but that the enteric-coated aspirin tablets were no problem at all. You wonder if you should prescribe enteric-coated aspirin to all your patients if it is so 'good to your stomach' instead of your usual dispersible aspirin.

Search Strategy

Medline 1950 to week 2 February 2007 using the OVID interface.[exp Aspirin/ OR aspirin.mp] AND [exp tablets, enteric-coated/ OR enteric coat$.mp]
[exp Aspirin/ OR aspirin.mp] AND [exp tablets, enteric-coated/ OR enteric coat$.mp]

Search Outcome

340 papers were found in MEDLINE. Nine were deemed to be relevant. Two systematic reviews and a guideline that considered these papers were included. These are summarised in the table

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Cole et al, 1999, UK	12 healthy volunteers screened before trial by endoscope. Randomized to 5 daily doses of plain Aspirin 300mg , plain aspirin 75mg, enteric-coated aspirin 300mg, placebo 7 male 5 female, age range 20-32.	Randomised control trial (Level 1b)	Erosion occurrence in healthy volunteer	Erosions caused after 5 days: Plain aspirin 75mg 2 gastric erosions Plain aspirin 300mg 18 gastric erosions Enteric coated aspirin No erosions	Small trial, short period of time. Young healthy volunteers, very different to our own group of interest
			Prostaglandin E2 reduction	Plain aspirin 300mg 84% reduction Plain aspirin 75mg Enteric coated aspirin 300mg 80%
Damman et al, 1999,	Study 1: 18 volunteers receiving either 100mg enteric coated aspirin or placebo for 15 days. Study 2: 41 volunteers 100mg enteric coated aspirin or 100mg plain aspirin for 7 days	Randomised control trial (level 1b )	Gastric Mucosal damage occurrence in healthy volunteer	Study 1: no significant difference in lesion scores Study 2: significantly higher mucosal lesion scores with plain aspirin: Plain : 3.95+/- 3.38 Coated: 1.43 +/- 1.91	Small study size
Blondon et al, 2000,	Single blinded RCT of 24 volunteers, concluded healthy by endocopic examination, 8 day trial of ASA 300mg, ECA or placebo then repeat examination by endoscopy.	Randomised control trial (level 1b )	Gastric Mucosal damage occurrence	Lanza score: Placebo 0.29 +/- 0.62. Enteric coated aspirin 0.75 +/- 0.99. Plain aspirin 1.17 +/- 1.37 ASA vs placebo = 1.17 vs 0.29 (p=0.01) ECA vs placebo = 0.75 vs 0.29 (p=0.11)	Small study size. No clear statistically significant improvement between formulations.
Hawthorne et al, 1991,	double blinded RCT of 20 volunteers determined as healthy by endoscopic examination and biopsy, 5 day trial of ASA 300mg od ASA 600mg qds, ECA 600mg qds or placebo. Examined by endoscopy and biopsy	Randomised control trial ( level 1b)	Gastric Mucosal damage occurrence	Haemorrhagic erosion score: Placebo = 0 (0-0.25) ASA 300mg = 2 (0-5). ASA 600mg qds = 4 (0.5-8.5). ECA 600mg qds = 0 (0-1.5	Small study size
Petroski, 1993	Single blinded RCT of 80 volunteers, determined as healthy by endoscopic examination 3 month trial 325mg o.d. of either ASA, buffered aspirin, ECA or placebo. Examination by endoscopy at 4, 8 and 12 weeks.	Randomised control trial (level 1b)	Gastric Mucosal damage.	Mean score of patients with gastric mucosal injury Placebo = 0.72 (sd = 1.07). ASA= 2.33 (sd = 1.06). Buffered Aspirin =1.60 (sd = 1.43). ECA =0.90 (sd = 1.26)
Kelly et al, 1996, UK	550 cases of patients admitted with melaena or haematemesis, confirmed by endoscopy, versus 1202 control identified from census	Multicentre case control study ( level 3b )	calculation of relative risk of GI bleed	Relative risk of UGIB with 325mg or less :Plain aspirin 2.6 Buffered aspirin 2.7 Enteric coated aspirin 3.1 P=NS	No significant differences between groups
De Abajo et al, 2001,	2105 cases of Upper Gastrointestinal complications from general practice research data base, compared to 11,500 controls from 1993 to 1998. 13% of cases and 7% of controls were exposed to aspirin.	Case control Study ( level 3b )	Increased Relative risk of bleeding with aspirin	Enteric-coated aspirin 2.3 (1.6 – 2.3) Plain aspirin 1.9 ( 1.6 – 2.3)	Only 287 of cases had recent aspirin and only an estimated 47% of these were for the indication of cardiovascular disease prevention.
Takada et al, 2004, Japan	The frequency of antisecretory drugs ( PPI or H2 antagonist) for patients being prescribed buffered or enteric coated aspirin on the National cardiovascular centre prescription database. ( A single hospital's database)	Retrospective Cohort study (Level 2b)	Frequency of antisecretory drug prescriptions	2451-3533 aspirin prescription per month Prescription for H2-antagonists in patient with prescriptions for Buffered aspirin 18.4%. E-coated aspirin 19.4% PPI prescriptions Buffered aspirin 0.31% E-coated aspirin 0.47%	Patient demographics not described. No idea of the types of patients that these are. No weighting for risk factors for GI complications Difficult to make any meaningful conclusions from the results of this study
Banoob et al, 2002, USA	Medline search of papers published from 1980 to 1998 discussing enteric coated aspirin and GI bleeding 8 studies found	Review (level 2a)	Effect of aspirin on mucosal lining	Conclusion is that most of the studies suggest that the use of enteric coated aspirin was associated with less mucosal damage.	Search strategy not reported. No tabulated summary of papers, or attempt to aggregate data.

Comment(s)

The evidence surrounding enteric-coated aspirin (ECA) falls into two clear categories. Some studies selected random volunteers, confirmed good gastric-health via endoscopy and administered ECA or ASA (acetylsalicylic acid) for a period of time before repeat endoscopy. A third category of studies looked retrospectively at patients with gastric complications. Cole performed endoscopy on 12 healthy volunteers after randomizing to various preparations of aspirin. 18 gastric erosions were found in patients taking 300mh of plain aspirin, 2 erosions in patients taking 75mg of plain aspirin and no erosions in the enteric coating groups. Dammann performed endoscopy on 59 healthy volunteers in 2 study arms. In one arm the patients were randomized to plain aspirin 100mg and had a three-fold increase in mucosal lesions compared to patients having enteric-coated aspirin 100mg for 7 days. Blondon performed endoscopy on 24 healthy volunteers 8 days after 300mg of enteric coated aspirin, plain aspirin or placebo. There was a non-statistically significant improvement in gastrointestinal tolerance with enteric coating versus plain aspirin. Hawthorne performed endoscopy on volunteers who were randomized to plain aspirin 300mg, plain aspirin 300mg 4-times daily(qds), enteric-coated aspirin 300mg, and enteric-coated aspirin 300mg qds for 5 days. The enteric coating resulted in substantially reduced gastric erosion scores and mucosal bleeding scores compared to plain aspirin. Petroski performed endoscopy in 80 volunteers who received placebo, or325mg of plain aspirin, or buffered aspirin, or enteric-coated aspirin for 3 months. Enteric-coated aspirin produced significantly reduced gastric mucosal damage compared to aspirin and the score was identical to placebo. Strengths of these studies include the random design and the sensitivity and good reproducibility of endoscopy as an outcome measure. However healthy volunteers taking aspirin for 5 days to 3 months often in doses much higher than our own patients are clearly very different to patients post-cardiac surgery. Also no correlation with adverse clinical outcomes are shown by these studies. Of the studies considering adverse clinical outcomes, Kelly et al performed a case-control study, taking 550 patients admitted with GI bleed confirmed on endoscopy and comparing then to 1202 normal controls. They found a 3 fold increase in the risk of GI bleed with all preparations of Aspirin but no differences between the different types of preparation. This study was large but did not account for other possible causes of a GI bleed, long-term exposure to aspirin or concomitant use of non-steroid anti-inflammatory drugs (NSAIDS). De Abajo et al looked at a general practice databases and identified cases of upper GI bleeds (n=2105) and compared this group to a control group (n=11500). 287 of these cases had been exposed to aspirin. No relative risk reduction was seen with enteric coating compared to plain aspirin, but the number of patients in both plain and the coated groups were small. Takada et al, looked at prescription in patients with prescriptions for ASA or ECA. They found more H2-antagonist and proton pump inhibitor use in enteric-coated aspirin patients. However it is impossible to interpret these results as there is no information on any patient demographics and the reasons for prescribing differences are unknown. Banoob et al carried out a systematic review in 2002. Possible faults were highlighted in previous studies, such as not accounting for influential factors in GI complications (i.e. tobacco use, chronic alcohol use and drug abuse). They concluded that ECA could offer a safer alternative to ASA but called for further research in this area. Of interest in the UK the British National Formulary (www.bnf.org) lists the price of a 28 tablet pack of non-proprietary aspirin to be 87p and Caprin, a brand of enteric-coated aspirin to be £1.55.

Clinical Bottom Line

5 randomised controlled trials of healthy volunteers undergoing endoscopy after a period of either enteric-coated aspirin or plain aspirin administration all demonstrated a clear reduction of gastric mucosal injury. However these trials on healthy volunteers taking short term aspirin have not been supported by clinical studies in older age-group adults taking lower doses of aspirin for long periods. No clinical benefits in terms of reduction of gastrointestinal bleeding or ulceration with enteric coating have therefore been successfully demonstrated, although the endoscopic studies show that potentially these benefits could exist.

References

1. Cole AT, Hudson N, Liew LC, Murray FE, Hawkey CJ, Heptinstall S. Protection of human gastric mucosa against aspirin-enteric coating or dose reduction? Alimentary Pharmacology & Therapeutics 13(2):187-93, 1999.
2. Dammann HG, Burkhardt F, Wolf N. Enteric coating of aspirin significantly decreases gastroduodenal mucosal lesions. Alimentary Pharmacology & Therapeutics 13(8):1109-14, 1999.
3. Blondon H, Barbier JP, Mahe I, Deverly A, Kolsky H, Bergmann JF. Gastroduodenal tolerability of medium dose enteric-coated aspirin: a placebo controlled endoscopic study of a new enteric-coated formulation versus regular formulation in healthy volunteers. Fundamental & Clinical Pharmacology 14(2):155-7, 2000;-Apr.
4. Hawthorne AB, Mahida YR, Cole AT, Hawkey CJ. Aspirin-induced gastric mucosal damage: prevention by enteric-coating and relation to prostaglandin synthesis. British Journal of Clinical Pharmacology 32(1):77-83, 1991.
5. Petroski D. Endoscopic comparison of three aspirin preparations and placebo. Clinical Therapeutics . 15(2):314-20, 1993;-Apr.
6. Kelly JP, Kaufman DW, Jurgelon JM, Sheehan J, Koff RS, Shapiro S. Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product.[see comment]. Lancet 348(9039):1413-6, 1996.
7. de Abajo FJ, Garcia Rodriguez LA. Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as plain and enteric-coated formulations. BMC Clinical Pharmacology 1:1, 2001.
8. Takada M, Fukumoto K, Shibakawa M. Concomitant use of buffered and enteric-coated low-dose aspirin products and antisecretory drugs. Journal of Clinical Pharmacy & Therapeutics 29(2):183-7, 2004.
9. Banoob DW, McCloskey WW, Webster W. Risk of gastric injury with enteric- versus nonenteric-coated aspirin. Annals of Pharmacotherapy 36(1):163-6, 2002.