Drugs 1997 Jan; (1): 1-5

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Gastric Toxicity of Antiplatelet

Therapy with Low-Dose Aspirin
Mario Guslandi
Gastroenterology Unit,S Raffaele Hospital, Milan, Italy

Summary Low-dose aspirin is widely employed as antiantiplate1et

platelet therapy for cardiovascu-
lar disorders. However, even in the dosages usually employed for that purpose
(75 to 325mg daily), the drug maintains its ability to damage the gastric mucosa
by inducing bleeding ulcers and/or erosions. Pharmacological protection is there-
fore necessary. Specific long term studies with histamine H2 receptor antagonists
or sucralfate are lacking, but data from trials on the prevention of gastric damage
by other nonsteroidal anti-inflammatory drugs (NSAIDs) are discouraging.
discouraging. Re-
cent preliminary data suggest that misoprostol, in keeping with its ability to
protect both gastric and duodenal mucosa from long term NSAID treatment, treatment,
seems to be effective also against long term low-dose aspirin therapy in this
setting.

Aspirin (acetylsalicylic acid) is widely em-
ployed as an antiplatelet drug in the secondary pre-
vention of arterial occlusive disease and, to a lesser
extent, also in the primary prevention of cardiovas-
cular disorders.[1-3]
disorders)I-3] The dosages usually adminis-
tered for that purpose range from 75 to 325 mg/day.
Aspirin is known to be harmful to the gastric mu-
cosa, to increase the incidence of mucosal lesions
(erosions, ulcers or both) and to promote gastric
bleeding.[4-6]
bleeding. 14 -6] Quite often (up to 60% of cases) as-
pirin-induced lesions are asymptomatic, especially
in the elderly who are, unfortunately, the major
long term users of the drug. The absence of symp-
toms encourages continuous aspirin intake with in-
large muIticentre trials carried out in the UK have
shown that the relative risk of hospitalisation for
bleeding peptic ulcer in patients taking aspirin 300
mg/day is around 3.6 to 3.9.[8,9] Even lower doses,
despite a slight reduction in risk (3.2 with 150
mg/day and 2.3 with 75 mg/day) can induce gastric
injury, regardless of sex, age and previous history
dyspepsial9 ] (table I). It appears
of peptic ulcer or dyspepsia[9]
that in the UK 17% of patients aged 60 and over
with bleeding ulcers are receiving anti platelet ther-
antiplatelet
apy with low-dose aspirin, and that a daily dose of
only 75mg would reduce the risk by only 40% com-
pared with the 300 mg/day dosage and by 30%
compared with the 150 mg/day dosage.1
dosage.[9]9]

creased risk of sudden, massive haemorrhages. Is
long term therapy with low dose aspirin still harm-
ful to the gastroduodenal mucosa?
One study[7] failed to detect any difference be-
tween aspirin 325 mg/day and placebo in the oc-
currence of dyspeptic symptoms and ulcer de devel-
vel-
opment,[7] but patients potentially at risk of
opment,l7]
gastroduodenal lesions were excluded during a
preliminary run-in period. On the other hand, 2
These data are consistent with previous obser-
vations that long term aspirin users have a relative
risk for gastric bleeding of 3.1 with dosages of 250
mg/day or less,[IO] and indicate that there seems to
be no 'safe' dosage of aspirin between 75 and 300
mg/day in terms of gastric toxicity. A double-blind,
placebo-controlled study in a healthy population of
patients aged 70 years or more taking aspirin 100
mg/day for 12 months reported that the incidence
2 Guslandi
Table I. Relationship between low-dose aspirin and hospitalisation
for bleeding peptic ulcers l8 ,91
Aspirin dosage ...:.O...:.d"--ds...:.r...:.a_tio_(:..,-95;;;;O,i_o_C-'-I)_--:-:-:--::------:-;;;;-_ _
(mg/day) Slattery et al. 181
75
150
300 3.6 (0.7-17.2)
of gastrointestinal symptoms was only slightly
higher with aspirin (18 vs 13%), but that both overt
bleeding and chronic blood loss as assessed by
mean haemoglobin levels were significantly
greater in the aspirin group,lll] Even at a dosage of
30 mg/day, aspirin appears to promote gastrointes-
tinal bleeding to the same extent as at 283
mg/day.[12]
A recent meta-analysis has reviewed the trials
employing aspirin at dosages ranging from 75 to
325 mg/day,l13] Nine studies were included for a
total of more than 14 000 patients taking low-dose
aspirin. Compared with placebo, the occurrence of
peptic ulcer bleeding was 1.5 times higher with as-
pirin (p < 0.001). The figures are markedly lower
than those reported in case-control studies in un-
selected populations, since in the examined pro-
spective trials patients with previous ulcer history
had not been included.
According to a study in healthy volunteers, dos-
ages of aspirin lower than 30 mg/day still retain the
ability to reduce serum thromboxane B2 and to in-
hibit platelet function without decreasing the gas-
tric output of cytoprotective prostaglandins. [14]
However, whether such dosages of aspirin can ac-
tually be effective as antiplatelet therapy in clinical
practice remains to be determined.
1. General Preventive Measures
In order to determine possible ways to minimise
or prevent the untoward gastric effects of antiplate-
let treatment, it is necessary to briefly review the
mechanisms through which aspirin harms the gas-
tric mucosa. Nonsteroidal anti-inflammatory drugs
(NSAIDs), including aspirin, are known to exert
their gastric toxicity by means of a dual mecha-
nism,l15] When administered by the oral route they
© Adis International Limited. All rights reserved.
can injure the mucosa by direct contact. With aspi-
rin the effect is pH-dependent. At low intragastric
pH values aspirin is in nonionised form and, be-
Weil et al. 191
cause of its lipophilic properties, is able to pene-
2.3 (1.2-4.4)
3,2 (1,7-6,5) trate into the epithelial cells. There, because of the
3,9 (2.5-6.3) higher pH, the drug becomes ionised and remains
trapped inside the cell, thus altering cellular perme-
ability and promoting back-diffusion of hydrogen
ions with consequent tissue damage.[15]
The other damaging mechanism is systemic and
it occurs when the drug enters the general circula-
tion, no matter what route of administration has
been chosen. Inhibition of cyclo-oxygenase with
reduced production of intragastric prostaglandins
leads to a general failure of the mucosal defensive
factors (mucus and bicarbonate secretion, mucosal
blood flow) and an impairment of the substances
involved in tissue repair and ulcer healing such
as epidermal growth factor.[16] Cyclo-oxygenase
inhibition by aspirin might also enhance gastric
lipoxygenase activity, with increased production of
cytotoxic and vasoconstrictor leukotrienes,[15]
endothelial neutrophil infiltration and further mu-
cosal damage resulting from local ischaemia and
overproduction of toxic free radicals.[17,18]
Gastric adaptation to repeated aspirin adminis-
tration can occur[19,20] because of enhanced mitotic
activity, reduced neutrophil infiltration and re-
stored local blood flow.[20] Unfortunately, aspirin
adaptation, which is still a controversial issue,l21,22j
appears to take place only in a limited number of
patients[23] and even so does not reduce chronic
micro bleeding during long term low-dose aspirin
therapy.[21]
The possible development of gastric adaptation
to aspirin is unpredictable. Elderly people, whose
tissue repair mechanisms are slower and whose
microcirculation is already compromised, are less
likely to develop adaptation and, unfortunately, are
also the patients more often receiving antiplatelet
therapy with aspirin. Furthermore, according to a
recent study, cardiovascular disorders are an inde-
pendent risk factor for peptic ulcer complications
during therapy with NSAIDsJ24] As observed in
endoscopic studies, the use of 'buffered' aspirin
Drugs 1997 Jan; 53 (1)
 Gastric Toxicity of Low-Dose Aspirin
does not reduce the gastric toxicity of the drug)2S.26]
whereas enteric-coated preparations may offer
substantial benefits during short term administra-
tion[27.28] by avoiding direct contact of the drug
with the gastric mucosa. However, in view of more
recent observations[29.30] it is unlikely that they
could abolish long term untoward effects due to
persistence of cyclo-oxygenase inhibition by the
systemic route. Pharmacological prevention is
therefore necessary.
2. Pharmacological Prophylaxis
The drugs that can theoretically be employed to
prevent aspirin-induced gastric injury are either
gastric acid inhibitors or gastroprotective agents.
Endoscopic studies in healthy volunteers during a
few days of aspirin intake show that both types of
drugs are more effective than placebo, but these
data can hardly apply to long term aspirin treat-
ment.
Studies specifically designed to ascertain the
possible effectiveness of histamine H2 receptor
antagonists in preventing gastric injury by long
term aspirin intake are lacking. However, long
term trials employing other NSAIDs have shown
that ranitidine, while significantly effective in pre-
venting NSAID-induced duodenal ulcers, is no
better than placebo in protecting against the devel-
opment of gastric injuries,[IS.31] by far the most fre-
quent gastrointestinal lesions caused by aspirin.
Long term studies with proton pump inhibitors are
also unavailable.
Sucralfate, in spite of its remarkable gastro-
protective properties, has provided conflicting
and, all in all, poor results. In particular, a compar-
ative short term study versus misoprostol in aspi-
rin-treated volunteers has shown that the prosta-
glandin derivative is significantly superior in the
prevention of gastric ulcers,[32] a finding which is
in keeping with the results of a long term compar-
ative trial of the 2 drugs in NSAID-treated pa-
tientsJ33] Since a substantial portion of the protec-
tive effects of sucralfate relies upon stimulation of
local prostaglandins, it is possible that suppression
of gastric prostaglandin synthesis by aspirin is re-
© Adis International Limited. All rights reserved,
3
sponsible for the poor activity of the drug in this
context.
Misoprostol, an alprostadil (prostaglandin E 1,
PGEl) derivative, has been found to be signifi-
cantly superior to both placebo and sucralfate in
preventing gastric injuries caused by short term in-
take of high-dose aspirin.[33-3S] In long term studies
the drug was significantly better than ranitidine or
sucralfate in preventing NSAID-induced gastric
ulcers, and as effective as ranitidine in the case of
duodenal ulcersJls.36.37] In most studies, and in a
recent muIticentre trial carried out in the US,L38] a
dosage of only 200llg twice daily was employed,
which greatly reduces the rate of intestinal adverse
effects due to misoprostol.
The issue of misoprostol protection against long
term aspirin treatment has recently been addressed
in a double-blind UK study, the results of which
are still to be published as a full paper. Single daily
doses of either placebo or misoprostol 100ug in
healthy volunteers taking aspirin 300 mg/day for 4
weeks have been compared.[39] Endoscopic evalu-
ation has shown a significantly lower incidence of
bleeding or nonbleeding gastric erosions in the
misoprostol group. For instance, in the misoprostol
group the number of individuals with haemor-
rhagic lesions was 4 times lower and the average
number of erosions per individual was reduced
more than 8-fold (p < 0.001). The trial indicates
that even a dosage of misoprostol as low as IOOllg
daily is sufficient to protect the gastric mucosa
against aspirin injury at least during medium term
treatment.
3. Conclusions
The data available from both case-control and
prospective studies clearly show that aspirin, even
in low dosages such as those usually employed as
antiplatelet therapy, exerts harmful effects on the
gastroduodenal mucosa. Compared with dosages
of 150 to 300 mg/day, a dosage of 75 mg/day ap-
pears to be associated with a comparatively minor
risk of adverse gastrointestinal effects and should
therefore be preferred, but it has been clearly dem-
onstrated that there is no 'safe' therapeutic dose of
Drugs 1997 Jan; 53 (1)
 4 Guslandi
aspirin as regards the development of gastric in-
jury. Enteric-coated formulations have been shown
to reduce the gastric toxicity of aspirin only during
short term administration. Their benefits in the
long run remain unproven.
Pharmacological prevention of aspirin-induced
gastric lesions is feasible (since major interactions
between aspirin and antiulcer agents can be ex-
cluded[l5 1) and necessary.
Gastric acid inhibitors such as ranitidine can
prevent development of NSAID-induced duodenal
ulcers, but are unable to protect the gastric mucosa
effectively. On the other hand, misoprostol is
known to prevent both gastric and duodenal
NSAID-induced ulcers and, in particular, appears
to protect the gastric mucosa against a 4-week
treatment with low-dose aspirin. Dosages between
100 and 400 Ilg/day seem to be sufficient to pro-
vide gastric protection with a minimal incidence of
untoward intestinal effects.[l5,37,38.40]
Physicians who need to prescribe anti platelet
therapy with aspirin and who are worried about
possible gastric adverse effects should bear the~e
data in mind when considering pharmacological
prevention.
Two questions remain unanswered: should all
patients receiving antiplatelet therapy with aspirin
be protected with misoprostol, and for how long?
From a theoretical point of view, all patients should
be put on misoprostol and, since antiplatelet ther-
apy is usually lifelong, prophylaxis should be con-
tinued indefinitely. For practical purposes this is
unlikely, especially for economic reasons. How-
ever, at least patients with major risk factors such
as elderly individuals with a previous history of
ulcer must receive concomitant misoprostol treat-
ment. The risk of gastric toxicity is higher during
the first 3 months - hence prophylaxis should last
no less than that - but lack of gastric adaptation in
elderly patients also maintains the risk after that
period.
For the time being we have no proof that very
long term misoprostol treatment is mandatory. Evi-
dence that the drug is effective as a preventive
agent against NSAIDs is limited to 12 months (and
© Adis International Limited. All rights reserved.
this could be, at present, the suggested length of
therapy) but long term studies, focused on aspirin
only, are required to reconfirm the efficacy of the
drug in this respect after the first 4 weeks.
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Correspondence and reprints: Dr Mario Guslandi, Gastro-
enterology Unit, S Raffaele Hospital, Via Olgettina 60, 20132
Milan, Italy.
Drugs 1997 Jan; 53 (1)