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Medicines Q&As
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
Before using this Q&A, read the disclaimer at https://www.sps.nhs.uk/articles/about-ukmi-medicines-qas/
Date prepared: 31/3/2016
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 (COX), an enzyme which
controls the conversion of arachadonic acid to prostaglandins and thromboxanes. In platelets, this will
reduce the formation of thromboxane A2 (TBX2), 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 anti-aggregant (2).
Dyspepsia, gastrointestinal (GI) 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 was developed and marketed in an effort to reduce GI
adverse effects associated with aspirin therapy. EC aspirin has an outer layer designed 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 EC aspirin is being prescribed
in the belief that it will help reduce GI side effects in patients.
There are reports however, that EC 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 anti-platelet 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 on the use
of EC aspirin to prevent GI damage, and also the effect of the enteric coating on the anti-platelet
effect of aspirin.
Answer
Evidence surrounding the use of EC aspirin to reduce GI effects
According to a Clinical Knowledge Summary (CKS) on anti-platelet therapy, available evidence does
not demonstrate that EC preparations of aspirin reduce the risk of GI bleeding when compared to
standard formulations (4).
Walker et al. (2007) reviewed the published literature and identified one review, three large case
control and cohort studies and five randomised controlled trials in healthy volunteers. Patients were
randomised to either plain or EC aspirin (one study randomised to either EC, plain, or buffered
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aspirin). Outcome measures included assessing mucosal damage by endoscopy, or incidences of GI
bleeding. They concluded that overall the data were not robust enough to indicate a clinical benefit
with regards to reduction of GI side effects with the use of EC aspirin (5). The review also concluded
that the use of EC aspirin was associated with less mucosal damage. However, limitations of this
research included only using a Medline search, 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. Doses used were also
much higher than that used in cardiovascular disease (CVD). The incidence of GI side effects with
long term use of aspirin could therefore not be assessed from these trials.
Additional studies have been identified that were not included in Walker et al 2007 literature review
but these are also 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. These
studies indicated reduced blood loss or decreased GI ulceration with EC aspirin. However, these
findings are based on weak evidence that cannot be used to definitively demonstrate the gastroprotective effects of EC aspirin. It should be borne in mind that EC 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.
Evidence surrounding the anti-platelet 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.
The evidence for this issue consists of small randomised controlled trials conducted over 7-14 days
and larger cohort studies. 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.
Haastrup et al recently reviewed evidence from 7 articles: 4 studies compared EC with plain aspirin; 2
studies looked at responses following EC aspirin administration (no comparator); and 1 study
compared EC with plain or with combination dypridamole + plain aspirin. Outcome measures were
reductions in COX activity (namely by measuring TXB2 levels). There were 2 pharmacokinetic
focused studies, one of which looked at plasma concentrations of aspirin and another looking at the
acetylation of COX alongside TXB2 levels. Haastrup et al concluded that EC formulations can
decrease the anti-platelet activity/effect of aspirin. They suggested that the formulation may also
affect its pharmacokinetics. The potential pharmacokinetic pseudoresistance can mean it is necessary
to administer higher doses of EC aspirin (in comparison to plain aspirin) over a longer duration to
achieve sufficient and comparable effects (18). Limitations of Haastrup et al review were differences
in populations studied (5 trials used healthy volunteers, 2 trials used patients with stable CVD) and
differing definitions of insufficient anti-platelet effect with regards to COX inhibition. All studies
included were short term studies (up to 2 weeks of treatment) and 3 of the studies had relatively small
study populations (n=<25).
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A summary of the studies on EC aspirin can be found in Tables 1 and 2. In addition, the clinical
significance of these surrogate markers assessed are unknown.
Summary




Low dose EC aspirin tablets were developed and marketed in an effort to reduce the incidence of
GI side effects in patients using it for prevention of CVD.
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 gastro-protective role of EC aspirin
compared to standard release (plain) aspirin.
There is speculation that enteric coating reduces the anti-platelet effect of aspirin, and thus its
efficacy in the prevention of cardiovascular events. The available evidence for this is however
conflicting. There is a theory of pseudoresistance reflecting delayed and reduced drug absorption
with EC aspirin over normal plain aspirin. Additionally the studies employed the use of surrogate
rather than clinical outcome measures to evaluate the anti-platelet 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
Savon JJ et al. 7
Patient group
Intervention
Measurement of GI blood loss
by obtaining 24 hour stool
collections and measuring
chromium-51 labelled
erythrocyte loss.
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.
Outcome measures were not correlated to actual clinical
outcomes of the participants.
20 volunteers (aged
20-29)
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
Gastric damaged assessed
endoscopically, and GI mucosal
bleeding measured.
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.
Small sample size and short follow up period.
Volunteers were healthy and young.
19 healthy male
volunteers
Plain vs EC aspirin at a dose
of 2.925g/day in divided
doses.
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.
Blood loss lower with EC aspirin use compared
to plain aspirin 1.54ml vs 4.33ml, respectively.
Small sample size of healthy volunteers only. Short term
follow up (7 days). Outcome measures were not
correlated to actual clinical outcomes of the participants.
High dose aspirin used.
1991
RCT
1984
Study Weaknesses
Plain aspirin (325mg) vs EC
aspirin
RCT
Robbins DC et
al.8
Key results
47 healthy volunteers
1995
Hawthorne AB et
al.9
Outcome measures
RCT
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Table 2: Evidence for anti-platelet effectiveness
Study
Grosser et al.19
2013
Interventional
Phase 1 study
Patient group
400 healthy
volunteers aged
18-55 years
(median 26
years)
Intervention
Phase 1: Single dose 325mg EC aspirin
vs single dose of 325mg plain aspirin.
Phase 2: 14 day washout period, then
repeat single dose test.
Outcome measures
Key results
Study Weaknesses
>50% reduction in COX activity (TXB2
levels and arachadonic acid induced
platelet aggregation) – measured 4
and 8 hours post-dose administration.
83% had sufficient responses after singledose 325 mg EC Aspirin (apparent resistance)
vs 100% after single-dose 325 mg plain
aspirin. After 1 week of treatment, 98% had a
sufficient response in individuals previously
not responding to single-dose treatment.
Healthy, relatively young volunteers.
Limited drug exposure in vivo (single dose
administration; phase 3 one week
exposure): unreliability of basing a
diagnosis of “aspirin resistance” on a single
measurement of platelet aggregation.
Phase 3: Non-responders for both
phases, given repeated low-dose 81mg
EC aspirin or 75mg clopidogrel for 1 week
(cross-over design).
EC aspirin “non-responders” after 4 hours:
49%, 8 hours: 17%.
Pseudoresistance shown rather than a true
drug resistance reflecting delayed and
reduced drug absorption with EC aspirin over
normal plain aspirin.
Peace et al.20
2010
Cohort
(Prospective)
Cox D et al.10
2006
RCT
Karha J et al. 2
236 patients
with stable CVD
(mean age
65yrs; mean
weight 80kg)
EC 75mg (n=148) vs plain 75mg aspirin
(n=88). EC non-responders trialled on
plain aspirin. If still non-responsive, doses
were increased to 150mg.
COX activity: TXB2 levels (goldstandard) and arachadonic acid
induced platelet aggregation
Observational study. Non-probability
sampling method. Short follow up time of 14
days for each treatment group. Compliance
issues.
71 healthy
volunteers aged
20-50 years
Each volunteer took 2 different aspirin
preparations. Five preparations in total: 3
different EC formulations, dispersible and
combined aspirin with dipyridamole
TXB2 levels and arachadonic acid
induced platelet aggregation.
Treatment failure classified as <95%
serum inhibition TXB2
Dispersible aspirin superior to other
preparations in inhibiting TXB2. Treatment
failure occurred in 3% of EC preparations, but
not with dispersible aspirin
Healthy, young volunteers used. Short
follow up time of 14 days. No indication of
actual clinical outcomes of participants. Low
numbers of volunteers.
50 healthy
volunteers > 18
7 day course of standard aspirin followed
by 7 day course of EC aspirin (separated
Platelet function using optical
No difference in platelet inhibition between
Excluded patients with cardiovascular
disease, hypertension and hyperlipidaemia.
4.2% in the EC aspirin group had insufficient
responses. Of these patients, once switched
to plain aspirin, 70% showed responses.
2 weeks treatment in each group
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Overall, 44/236 (19%), were found to have an
inadequate responses (defined by
insufficiently reduced TBX2 levels) to aspirin
(both plain and EC).
Medicines Q&As
2006
years
by 3 week washout period).
aggregometry.
standard and EC aspirin.
No indication of actual clinical outcomes of
participants.
36 healthy male
volunteers
Comparison of 40mg plain aspirin, 100mg
plain aspirin, 100mg EC aspirin.
Platelet aggregation, platelet TXB2
release, serum TXB2, 6-keto-PGF1
alpha levels at baseline and 7 days
after each medication
Plain and EC 100mg tablets are equally
effective in inhibition of platelet aggregation
Small numbers of healthy volunteers used..
Short study time. No indication of actual
clinical outcomes of participants.
10 volunteers
EC aspirin vs. normal aspirin
Bleeding times 4 hours after ingestion.
Defined >8 minutes as abnormal
bleeding time
10% of EC group developed abnormal
bleeding times vs. 80% of normal aspirin.
Low participant numbers. No indication of
actual clinical outcomes of participants.
40 healthy male
participants
Standard and EC aspirin at doses of
81mg and 325mg.
Adenosine diphosphate and
epinephrine induce platelet
aggregation at rest and after exercise.
Measurements taken at baseline and 7
days post therapy.
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.
12 healthy
volunteers aged
20-32 years
Plain aspirin 300mg vs. plain aspirin 75mg
vs. EC aspirin 300mg
Measurement of platelet aggregation
in response to different agonists
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.
Small sample size of young, healthy
volunteers. Short follow up time. No
indication of actual clinical outcomes of
participants
22 healthy
volunteers
100mg alternate day dosing of plain
aspirin vs. EC aspirin
Platelet aggregation induced by
arachadonic acid, adenosine
diphosphate and epinephrine over 2
No difference found between regular and EC
formulations
Small sample size and short follow up time.
No indication of actual clinical outcomes of
participants.
RCT
Bode-Boger et
a.l11
1998
RCT
Gantt AJ et al. 12
1998
RCT
Feng D et al. 13
1997
RCT
May JA et al. 16
1997
RCT
Ridiker P et al. 15
1996
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Medicines Q&As
RCT
weeks
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
No significant difference between bleeding
times of EC aspirin and plain aspirin
No indication of actual clinical outcomes of
participants
Stampfer MJ et
al.14
33 volunteers
Randomised to plain aspirin 325mg, one
of two EC aspirin preparations 325mg, or
placebo. Tablets were taken every other
day
Bleeding times, platelet aggregation
and TXA2 levels before and after a
single dose, and after seven alternateday doses
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
1986
RCT
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Limitations
The majority of the included trials involved 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. In addition, evidence is conflicting
between studies for anti-platelet efficacy. Furthermore, the data analysed came only from studies
using plain aspirin as a comparator and not other formulations (i.e. buffered aspirin). A definitive
conclusion therefore cannot be made from the available data regarding the GI safety of EC
formulations compared to standard release aspirin
References
1. Joint Formulary Committee. British National Formulary. [60th] ed. London: British Medical
Association and Royal Pharmaceutical Society; [2016]
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. Anti-platelet 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_anti-platelet_treatment#-385356 on
09/02/2016
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 anti-platelet activity of low-dose
aspirin in healthy volunteers. British Journal of Clinical Pharmacology 1991; 32: 77-83.
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.
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Medicines Q&As
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
18. Haastrup P.F, Gronlykke T, Jarbol D.E. Enteric coating can lead to reduced anti-platelet effect of
low-dose acetylsalicylic acid. Basic and Clinical Pharmacology and Toxicology 2015; 116/3: 212215
19. Grosser T, Fries S, Lawson J et al. Drug resistance and pseudoresistance: An unintended
consequence of enteric coating aspirin. Circulation 2013; 127/3: 377-385
20. Peace A, McCall M, Tedesko T et al. The role of weight and enteric coating on aspirin response in
cardiovascular patients. Journal of Thrombosis and Haemostasis 2010; 8/10: 2323-2325
Quality Assurance
Prepared by
Reshma Chhana, Medicines Information, Guy’s and St Thomas’ Hospital, London
Date Prepared
31/03/2016
Checked by
Yuet Wan, Medicines Information, Guy’s and St Thomas’ Hospital, London
Date of check
1/4//2016
Search strategy

British National Formulary 70, Sept 2016 Online
Edition: 70 September 2016, 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 August 2011. accessed online via
www.emc.medicines.org.uk

Micromedex accessed online via http://www.thomsonhc.com
Available through Specialist Pharmacy Service at
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Medicines Q&As








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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