Medicines Q&As
Q&A 285.1
Is there Evidence to Support the use of Enteric Coated (EC) Aspirin to
Reduce Gastrointestinal Side Effects in Cardiovascular Patients?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date prepared:19th March 2011
Background
The use of low dose aspirin is part of the standard management plan for the prevention of
cardiovascular events (1). Aspirin irreversibly inhibits cyclo-oxygenase, an enzyme which controls the
conversion of arachadonic acid to prostaglandins and thromboxanes. In platelets, this will reduce the
formation of thromboxane A2, which is a vasoconstrictor and platelet aggregant. It also reduces the
formation of prostacyclin in the vascular endothelium which acts as a potent vasodilator and antiaggregant (2).
Dyspepsia, gastrointestinal ulceration and haemorrhage are known adverse effects of aspirin therapy,
potentially through a combination of direct damage and inhibition of prostaglandin synthesis in the gut
mucosa (2).
The enteric coated (EC) formulation of aspirin has been developed and marketed in an effort to
reduce gastrointestinal adverse effects associated with aspirin therapy. EC aspirin has an outer layer
aimed to prevent aspirin from dissolving in the acidic environment of the stomach, but instead
releasing its contents in the higher pH of the duodenum. Theoretically this should help protect the
gastric mucosa from local irritation (although damage to the duodenum can still occur) (2). Thus
enteric coated aspirin is being prescribed in the belief that it will help reduce gastrointestinal side
effects in patients.
There are reports however, that enteric coating does not significantly reduce the risk of GI bleeding
when compared to standard formulations of aspirin. There is also speculation that enteric coating may
reduce the antiplatelet effect of aspirin due to a reduction in bioavailability, thereby reducing its clinical
efficacy in prevention of cardiovascular events (3). This Q&A reviews the evidence surrounding the
use of enteric coated aspirin to prevent gastrointestinal damage, and also the effect of enteric coating
on the antiplatelet effect of aspirin therapy.
Answer
Evidence surrounding the use of EC aspirin to reduce GI effects
According to a Clinical Knowledge Summary (CKS) on antiplatelet therapy, available evidence does
not demonstrate that enteric coated preparations of aspirin reduce the risk of GI bleeding when
compared to standard formulations (4).
Walker et al. (2007) reviewed the evidence (including a systematic review, three large case control
and cohort studies and five randomised controlled trials) and concluded that overall it was not robust
enough to indicate a clinical benefit with regards to reduction of GI side effects with the use of EC
aspirin (5). The systematic review within this analysis was the only piece of evidence concluding that
use of enteric coated aspirin was associated with less mucosal damage. However limitations of this
research included no reported search strategy, no details given of the papers reviewed, and no
attempt to aggregate data. The RCT’s reviewed by Walker et al. were small scale studies conducted
in healthy volunteers, with study observation times ranging from 5 days to a maximum of 3 months,
thus not directly applicable to the real life situation. The incidence of GI side effects with long term use
of aspirin could therefore not be assessed from these trials.
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Medicines Q&As
Additional studies identified were small scale trials conducted in healthy volunteers, with short
observation periods. Outcome measures included estimation of faecal blood loss by measurement of
radio-labelled erythrocytes within the faeces, or observation of the mucosal state using endoscopic
methods. The studies indicated reduced blood loss or decreased gastrointestinal ulceration with the
be definitively demonstrated. It should be borne in mind that enteric coating will not protect against the
systemic effect that aspirin has on prostaglandin synthesis, which increases the risk of gastric
mucosal damage and ulceration irrespective of the formulation used.
A summary of the evidence found surrounding the effectiveness of EC aspirin in reducing GI side
effects can be found in Table 1.
Evidence surrounding the effectiveness of EC aspirin compared to standard release
Enteric coating of aspirin tablets delays the absorption time across the GI tract (6), and there is
speculation that the bioavailability of EC aspirin is reduced compared to standard release tablets,
resulting in reduced efficacy of the medication.
The evidence for this issue (Table 2) consisted solely of small randomised controlled trials conducted
over 7-14 days. Participants were in the most part healthy volunteers, and outcome measures
consisted of in vitro measurement of the bleeding times, extent of platelet aggregation, or inhibition of
chemical mediators such as thromboxane and PGI2. Results of these studies were conflicting; with
some showing that standard and EC formulations of aspirin were equally efficacious, and others
showing the EC formulation to be less effective than standard release aspirin.
Summary
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Low dose EC aspirin tablets have been developed and marketed in an effort to reduce the
incidence of gastrointestinal side effects in patients using it for primary or secondary prevention
of cardiovascular disease.
Enteric coating prevents aspirin from dissolving in the stomach, which is instead released in the
higher pH of the duodenum, theoretically protecting the gastric mucosa from local irritation
The available evidence is not robust enough to support a gastroprotective role of EC aspirin
compared to standard release aspirin.
There is speculation that enteric coating reduces the anti-platelet effect of aspirin, subsequently
reducing its efficacy in the prevention of cardiovascular events. However, the available evidence
surrounding this theory consists of small scale trials which demonstrate conflicting results.
Additionally the studies employed the use of surrogate rather than clinical outcome measures to
evaluate the antiplatelet efficacy of standard and EC formulations and the significance of these
findings in practice is thus not known.
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Table 1: Evidence surrounding use of EC aspirin to reduce GI symptoms
Author , Date and Study
type
Walker et al. 5
2007
Review
Patient group
Intervention
Outcome measures
Key results
Study Weaknesses
Review of 1 systematic
review, 3 cohort
studies,and 5 RCTs in
healthy volunteers
47 healthy volunteers
Randomised to either plain or
enteric coated aspirin (one study
randomised to either EC, plain, or
buffered aspirin).
Plain aspirin (325mg) vs EC aspirin
Mucosal damage assessed
by endoscopy, or incidence
of GI bleeding
Use of enteric coated aspirin shows
reduction in gastric mucosal injury
Robbins DC et al. 8
1984
RCT
19 healthy male
volunteers
Plain vs EC aspirin at a dose of
2.925g/day in divided doses.
GI blood loss 1.12 ml (+/- 0.31)/ day
with EC aspirin vs 2.6ml (+/- 0.68)/
day with plain aspirin. Reduced GI
blood loss with EC compared to
plain aspirin
Blood loss lower with EC aspirin use
compared to plain aspirin 1.54ml vs
4.33ml
Hawthorne AB et al.9
1991
RCT
20 volunteers (aged 2029)
Each volunteer received 5 different
treatments separated by a 10 day
washout period: plain aspirin 300mg
OD, EC aspirin 300mg daily, plain
aspirin 600mg QDS, EC aspirin
600mg QDS
Measurement of GI blood
loss by obtaining 24 hour
stool collections and
measuring chromium-51
labelled erythrocyte loss.
Estimation of faecal blood
content by measurement of
sodium chromate radioactive
labelled RBC in stools.
Measurement made prior to
drug administration, then
through days 4-7 of aspirin
administration
Gastric damaged assessed
endoscopically, and GI
mucosal bleeding measured
Trials conducted in healthy volunteers. Short term
studies ranging between 5 days to 3 months. Doses
much higher than that used for CVD.
Only used a Medline search to retrieve evidence.
Outcome measures were not correlated to actual clinical
outcomes of the participants.
Savon JJ et al. 7
1995
RCT
No gastric mucosal injury seen with
300mg EC aspirin, and less GI
mucosal injury seen with 600mg
QDS EC aspirin compared to high
dose plain aspirin
From the National Electronic Library for Medicines. www.nelm.nhs.uk
Small population sample of healthy volunteers used.
Short term follow up (7 days). Outcome measures were
not correlated to actual clinical outcomes of the
participants. High dose aspirin used.
Small sample size and short follow up period.
Volunteers were healthy and young.
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Table 2: Evidence for antiplatelet effectiveness
Study
Cox D et al.10
2006
RCT
Patient group
71 healthy
volunteers aged
20-50 years.
50 healthy
volunteers > 18
years
Intervention
Each volunteer took 2 different aspirin
preparations. Five preparations in total: 3
different EC formulations, dispersible and
combined aspirin with dipyridamole
7 day course of standard aspirin followed
by 7 day course of EC aspirin (separated
by 3 week washout period).
Outcome measures
TXB2 levels and arachadonic acid
induced platelet aggregation.
Treatment failure classified as <95%
serum inhibition TXB2
Platelet function using optical
aggregometry.
Key results
Dispersible aspirin superior to other
preparations in inhibiting TXB2. Treatment
failure occurred in 3% of EC preparations, but
not with dispersible aspirin
No difference in platelet inhibition between
standard and EC aspirin.
Karha J et al. 2
2006
RCT
Bode-Boger et
a.l11
1998
RCT
Gantt AJ et al. 12
1998
RCT
Feng D et al. 13
1997
RCT
36 healthy male
volunteers
Comparison of 40mg plain aspirin, 100mg
plain aspirin, 100mg EC aspirin.
Plain and EC 100mg tablets are equally
effective in inhibition of platelet aggregation
10 volunteers
EC aspirin vs. normal aspirin
40 healthy male
participants
Standard and EC aspirin at doses of 81mg
and 325mg.
Platelet aggregation, platelet TXB2
release, serum TXB2, 6-keto-PGF1
alpha levels at baseline and 7 days
after each medication
Bleeding times 4 hours after ingestion.
Defined >8 minutes as abnormal
bleeding time
Adenosine diphosphate and
epinephrine induce platelet
aggregation at rest and after exercise.
Measurements taken at baseline and 7
days post therapy.
Stampfer MJ et
al.14
1986
RCT
Ridiker P et al. 15
1996
RCT
33 volunteers
Randomised to plain aspirin 325mg, one
of two EC aspirin preparations 325mg, or
placebo. Tablets were taken every other
day
100mg alternate day dosing of plain
aspirin vs. EC aspirin
May JA et al. 16
1997
RCT
12 healthy
volunteers aged
20-32 years
Plain aspirin 300mg vs. plain aspirin 75mg
vs. EC aspirin 300mg
Bleeding times, platelet aggregation
and TXA2 levels before and after a
single dose, and after seven alternateday doses
Platelet aggregation induced by
arachadonic acid, adenosine
diphosphate and epinephrine over 2
weeks
Measurement of platelet aggregation
in response to different agonists
Gow JA et al. 17
1993 RCT
52 healthy male
volunteers
80mg or 325 mg of plain aspirin daily, or
325mg EC aspirin daily.
Bleeding times prior to therapy, day 1
and day 14 of aspirin therapy
22 healthy
volunteers
Study Weaknesses
Healthy, young volunteers used. Short
follow up time of 14 days. No indication of
actual clinical outcomes of participants .
Low numbers of volunteers
Excluded patients with cardiovascular
disease, hypertension,, hyperlipidaemia. No
indication of actual clinical outcomes of
participants.
Small numbers of healthy volunteers used..
Short study time. No indication of actual
clinical outcomes of participants.
10% of EC group developed abnormal
bleeding times vs. 80% of normal aspirin.
Low participant numbers. No indication of
actual clinical outcomes of participants.
Equal inhibition of adenosine diphosphate and
epinephrine induce platelet aggregation by
standard and EC preparations. EC
preparations caused less inhibition of 6-ketoprostaglandin F1 alpha.
Short study time of 7 days. No indication of
actual clinical outcomes of participants.
Plain and EC aspirin were equally efficacious
in prolonging bleeding time, inhibition of
platelet aggregation and suppression of TXA2.
Short study time of 7 days. Alternate day
dosing used. No indication of actual clinical
outcomes of participants
No difference found between regular and EC
formulations
Small sample size and short follow up time.
No indication of actual clinical outcomes of
participants.
Plain aspirin achieved its maximal effect after
one dose. EC aspirin produced a sub maximal
effect after one dose. No difference in extent
of platelet after 2 doses.
No significant difference between bleeding
times of EC aspirin and plain aspirin
Small sample size of young, healthy
volunteers. Short follow up time. No
indication of actual clinical outcomes of
participants
No indication of actual clinical outcomes of
participants
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Medicines Q&As
Limitations
Limitations common to the majority of the reviewed trials included recruitment of small numbers of
subjects, use of healthy volunteers (some studies actively excluded patients with risk factors for
cardiovascular disease), short study observation periods, and the use of surrogate outcome
measures. A definitive conclusion therefore cannot be made from the available data regarding the
efficacy of EC formulations compared to standard release aspirin.
Disclaimer
 Medicines Q&As are intended for healthcare professionals and reflect UK practice.
 Each Q&A relates only to the clinical scenario described.
 Q&As are believed to accurately reflect the medical literature at the time of writing.
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must use your judgement to determine the accuracy and relevance of the information they
contain.
 See NeLM for full disclaimer.
References
1. Joint Formulary Committee. British National Formulary. [60th] ed. London: British Medical
Association and Royal Pharmaceutical Society; [2010]
2. Anon. Which Prophylactic Aspirin? Drugs and Therapeutics Bulletin 1997 Vol 35;1
3. Karha J, Rajagopal V, Kottke-Marchant K et al. Lack of effect of enteric coating on aspirin-induced
inhibition of platelet aggregation in healthy volunteers. American Heart Journal 2006; 151/5
(976.e7-11).
4. Antiplatelet treatment (Management) How should I manage someone at high risk of gastrointestinal
bleeds? CKS [Clinical knowledge Summaries] last revised July 2009, accessed online via
http://www.cks.nhs.uk/antiplatelet_treatment/management/quick_answers/scenario_antiplatelet_treatmen
t#-385356 on 03/02/2011
5. Walker J, Robinson J, Stewart J et al. Does enteric-coated aspirin result in a lower incidence of
gastrointestinal complications compared to normal aspirin? Interactive Cardiovascular & Thoracic Surgery
2007; 6: 519-22.
6. Drugdex® Consults, Non-steroidal anti-inflammatory agents effects on platelet function (2005).
Thomson Micromedex, Greenwood village, Colorado USA. Accessed online via www.thomsonhc.com on
03/02/2011.
7. Savon JJ, Allen ML, DiMarino AJ Jr. et al. Gastrointestinal blood loss with low dose (325 mg) plain and
enteric-coated aspirin administration. American Journal of Gastroenterology 1995; 90: 581-5.
8. Robbins DC, Schwartz RS, Kutny K et al. Comparative effects of aspirin and enteric-coated aspirin on
loss of chromium 51-labeled erythrocytes from the gastrointestinal tract. Clinical Therapeutics 1984; 6:
461-6.
9. Hawthorne A.B., Mahida Y.R., Cole A.T et al. Aspirin-induced gastric mucosal damage: Prevention by
enteric-coating and relation to prostaglandin synthesis. British Journal of Clinical Pharmacology 1991; 32:
77-83.
10. Cox D, Maree AO, Dooley M et al. Effect of enteric coating on antiplatelet activity of low-dose aspirin
in healthy volunteers. British Journal of Clinical Pharmacology 1991; 32: 77-83.
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As
11. Bode-Boger SM, Boger RH, Schubert M, et al. Effects of very low dose and enteric-coated
acetylsalicylic acid on prostacyclin and thromboxane formation and on bleeding time in healthy subjects.
European Journal of Clinical Pharmacology 1998; 54: 707-14.
12. Gantt AJ, Gantt S. Comparison of enteric-coated aspirin and uncoated aspirin effect on bleeding time.
Catheterization & Cardiovascular Diagnosis 1998; 45: 396-9.
13. Feng D, McKenna C, Murillo J et al. Effect of aspirin dosage and enteric coating on platelet reactivity.
American Journal of Cardiology 1997; 80: 189-93.
14. Stampfer MJ, Jakubowski JA, Deykin D, et al. Effect of alternate-day regular and enteric-coated
aspirin on platelet aggregation, bleeding time, and thromboxane A2 levels in bleeding-time blood.
American Journal of Medicine 1986; 81: 400-4.
15. Ridker P.M., Hennekens C.H., Tofler G.H et al. Anti-platelet effects of 100 mg alternate day oral
aspirin: A randomized, double-blind, placebo-controlled trial of regular and enteric coated formulations in
men and women. Journal of Cardiovascular Risk 1996; 3:209-212.
16. May JA, Heptinstall S, Cole AT et al. Platelet responses to several agonists and combinations of
agonists in whole blood: a placebo controlled comparison of the effects of a once daily dose of plain
aspirin 300 mg, plain aspirin 75 mg and enteric coated aspirin 300 mg, in man. Thrombosis
Research1997; 88: 183-92.
17. Gow JA, Ebbeling L, Gerrard JM. The effect of regular and enteric-coated aspirin on bleeding time,
thromboxane, and prostacyclin. Prostaglandins Leukotrienes & Essential Fatty Acids 1993; 49: 515-20,
Quality Assurance
Prepared by
Sonal Patel, Medicines Information, Guy’s and St Thomas’ Hospital, London
Date Prepared
19/03/2011
Checked by
Yuet Wan, Medicines Information, Guy’s and St Thomas’ Hospital, London
Date of check
24/06/2011
Search strategy
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British National Formulary 60, Sept 2010 Online
Edition: 60 September 2010, accessed online via www.bnf.org/bnf/bnf/current/104945.htm
Summary of Product Characteristics. Boots Aspirin 75mg enteric coated Tablets, Boots
Company PLC. Date of Revision June 2009. accessed online via www.emc.medicines.org.uk
Micromedex accessed online via http://www.thomsonhc.com
Martindale, the Complete Drug reference. Accessed online via www.medicinescomplete.com
NICE accessed online via www.nice.org.uk
Clinical Knowledge Summaries (CKS) accessed online via www.cks.nhs.uk
Scottish Intercollegiate Guideline Network (SIGN) accessed online via www.sign.ac.uk
The Cochrane Library accessed via www.library.nhs.uk
National Electronic Library for Medicines accessed online via www.nelm.nhs.uk
MEDLINE search: exp TABLETS, ENTERIC-COATED/ [Limit to: Humans and English
Language]; AND exp *ASPIRIN/ [Limit to: Humans and English Language]
EMBASE Search: exp *ACETYLSALICYLIC ACID/ [Limit to: Human and English Language]
AND *ENTERIC COATED TABLET/ [Limit to: Human and English Language]
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