Best Practice & Research Clinical Gastroenterology 26 (2012) 141–151
`
`Contents lists available at SciVerse ScienceDirect
`
`Best Practice & Research Clinical
`Gastroenterology
`
`4 G
`
`astrointestinal lesions and complications of low-dose
`aspirin in the gastrointestinal tract
`Carlos Sostres, MD a,b, *, Carla J. Gargallo, MD, Research Fellow a
`a Service of Digestive Diseases, University Hospital Lozano Blesa, Zaragoza, Spain
`b CIBERehd, Aragon Health Sciences Institute, Zaragoza, Spain
`
`Keywords:
`Low-dose aspirin
`Gastrointestinal bleeding
`Mortality
`Time trends
`
`Low dose aspirin (ASA) use has been associated with a wide range
`of adverse side effects in the upper gastrointestinal (GI) tract, which
`range from troublesome symptoms without mucosal lesions to
`more serious toxicity, including ulcers, GI bleeding, perforation and
`even death. Upper GI symptoms in low dose ASA users are common
`but often careless or misinterpreted and they are not always related
`to the presence of mucosal injury. Usually, low dose ASA related
`ulcers are reasonably small and asymptomatic, and probably heal
`over a period of weeks to a few months. But, the real clinical
`problem occurs when the ulcer results in a GI complication (mostly
`bleeding). The estimated average excess risk of symptomatic or
`complicated ulcer related to low dose ASA is five cases per 1000
`ASA users per year. Death is the worst outcome of GI complications
`in low dose ASA users, but data about this aspect are scarce. Current
`evidence indicates that low dose ASA can damage the lower GI tract
`also, but the real size of the problem is still unknown.
`Ó 2012 Elsevier Ltd. All rights reserved.
`
`Introduction
`
`Low dose ASA, commonly defined as 75–325 mg daily, is one of the most widely used drugs in the
`world and the mainstay of therapy for cardiovascular disease [1]. One survey suggested that over
`one-third of the US adult population (including 80% of those with known cardiovascular disease) use
`low dose ASA regularly [2]. In England in 2007, over 30 million primary care prescriptions were issued
`
`* Corresponding author. Servicio de Aparato Digestivo, Hospital Clínico Universitário Lozano Blesa, c/Domingo Miral s/n, 5009
`Zaragoza, Spain.
`E-mail address: carlossostres@gmail.com (C. Sostres).
`
`1521-6918/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved.
`doi:10.1016/j.bpg.2012.01.016
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`for ASA [3]. Low dose ASA is associated with GI injury, and this damage may be different according to
`dose, concomitant medication use and patient risk profiles. Guidance from the American College of
`Cardiology Foundation Task Force on Clinical Expert Consensus Documents state that low dose ASA is
`associated with a two to four fold increase in GI events, increasing with concomitant medication use
`[4–6]. In this review we are going to summarize the most important points about GI symptoms and
`complications derived from the use of low dose ASA.
`
`Upper gastrointestinal symptoms
`
`Low dose ASA use has been associated with a wide range of adverse side effects in the upper GI
`tract, range from troublesome symptoms without mucosal lesions to more serious toxicity, including
`ulcers, GI bleeding, perforation and even death. [Fig. 1] [7]. Upper GI symptoms in low dose ASA
`users are common but often careless or misinterpreted. Gastro-oesophageal reflux (regurgitation
`and/or heartburn) and dyspeptic symptoms (including bloating, belching, epigastric discomfort,
`early satiety and postprandial nauseas) seem to be the most frequent and can be present in up to 15–
`20% of low dose ASA takers [5,8]. The study called “The UGLA survey” showed that 15.4% of low dose
`ASA users quoted upper GI symptoms, 70% gastroesophageal reflux, and that these symptoms had a
`negative impact on treatment compliance in 12% of patients. In addition, they also reported that a
`prior history of dyspeptic symptoms was predictive of low dose ASA related upper GI symptoms
`onset.
`The onset of these symptoms is important because it may lead to poor adherence or even
`discontinuation of low dose ASA treatment. Despite the strong evidence supporting the protective
`effects of low dose ASA, discontinuation rates of around 50% have been reported in patients who have
`been taking this medication for several years [9]; this is disturbing as interruption is associated with
`increased risk of major cardiovascular events including cardiovascular mortality [Fig. 2]. Cessation of
`treatment with oral antiplatelet agents (including aspirin and thienopyridines) has been shown to be
`an independent predictor of an increase in mortality after acute coronary syndromes [10], and
`multivariate analysis has shown an increased risk of transient ischaemic attack in the four weeks after
`discontinuation of ASA [11]. A systematic review of actual literature to date showed that withdrawal of
`low dose ASA is associated with a threefold increase in the risk of adverse cardiovascular events [12].
`
`Death
`
`Complications
`
`Symptomatic
`
`ulcer
`
`Ulcer
`
`Erosions
`
`Rare
`
`Infrequent
`
`Frequent
`
`Prostaglandin inhibition
`
`Always
`
`Fig. 1. Biologic progression of gastrointestinal damage associated with low dose aspirin [7].
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`Poor adherence
`
`discontinuation
`
`High-risks CV events
`
`GI symptoms
`
`Non-fatal myocardial
`
`infarction
`
`Therapeutic effect?
`
`Forget to take it
`
`Safety concerns
`
`Transient ischemic
`
`attack
`
`Correct adherence
`
`Low-risk CV events
`
`Fig. 2. Main causes and effects of low-dose aspirin poor adherence or discontinuation [13].
`
`Patients might not adhere to treatment because they forget to take it, because they do not perceive that
`it has therapeutic benefit, or because of adverse events not well discussed with their physician [13].
`On the other hand, and unfortunately, symptoms are not clearly predictive of the presence of
`mucosal injury. Holtmann et al have shown in their study that asymptomatic patients taking low dose
`ASA elevate their gastric sensory and they do not experience dyspepsia although acute mucosal injury
`was present [14].
`Reducing the number of low dose ASA users who discontinue treatment could therefore have
`a major impact on the benefit obtained with low dose ASA in the general population. New studies
`with this objective are now needed to evaluate whether efforts to encourage patients to continue
`prophylactic treatment with low dose ASA will result in a decrease in non-fatal myocardial infarction.
`
`Low dose aspirin related upper gastrointestinal injury
`
`Patients who take ASA could develop acute mucosal injury, and even at very low dose (10 mg daily).
`The whole gut tract can be damaged, but low dose ASA related mucosal lesions developed especially in
`upper GI tract. Antrum and particularly the pre-pyloric area are the most frequent locations. This harm
`includes petechiaes, ecchymosis, erosions and ulcers [15]. Damage may be different according to dose,
`concomitant medication use and patient risk profiles. Geall et al demonstrated for years that every
`dose of ASA causes some superficial loss of cells from the gastric mucosa in most people [16]. Much of
`this superficial damage is not visible macroscopically but, in areas where the repair process fails,
`luminal acid and pepsin aggravate and deep the damage. Thus, deeper lesions still confined to the
`mucosa develop focally and are visible endoscopically as acute erosions.
`
`Mechanisms of low dose ASA gastrointestinal damage
`Injury to the GI tract attributable to NSAIDs occurs on a nearly daily basis in patients who are
`taking these drugs [18]. The mechanisms responsible for ASA-induced ulcerative lesions of the GI tract
`are not yet completely understood, particularly with respect to lesions in the small and large intestine
`[17,18]. However, it is known that aspirin damages the gut by causing topical injury to the mucosa and
`by the systemic effect associated with mucosal prostaglandin depletion as a result of (cyclooxygenase)
`COX inhibition. Whether a low dose ASA also has a systemic damaging effect in the GI tract that is
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`based on inhibition of COX1 is uncertain, as most of the antiplatelet effects seen with low dose ASA
`occur in the portal system, and the amount of drug and the time available in the systemic circulation
`is rather limited [19].
`NSAIDs can be grouped on the basis of their pharmacodynamic features, for example COX1 or COX2
`selectivity [20]. ASA has >10 times greater selectivity for COX1 than COX2 [21]. By inhibiting both COX
`isoforms, ASA, as with other NSAIDs, is an effective pain reliever at doses >325 mg. At low doses (75–
`325 mg daily), ASA predominantly inhibits the COX1 isoform, thereby inhibiting the synthesis of
`platelet thromboxane A2.
`Topical injury: Direct contact of ASA with the gastroduodenal mucosa can induce damage by dis-
`rupting the gastric epithelial cell barrier [22]. However, clinical experience, including meta-analysis,
`with enteric-coated versus ‘uncoated’ ASA formulations, does not support the notion that ASA has
`predominantly local effects in causing gastroduodenal injury [23–27]. ASA is weakly acidic (pKa 3.5)
`and, therefore, is retained in its nonionized form in the aqueous, low-pH environment of the gastric
`lumen [23]. The pKa of ASA is among the lowest of the NSAIDs and, therefore, it confers a high
`propensity for gastroduodenal injury. ASA is able to penetrate the phospholipid membrane of gastric
`epithelial cells because of its lipophilicity (log P ¼ 1.15) [28]. The ability of ASA to decrease epithelial
`surface hydrophobicity [29] probably increases the susceptibility of the gastric mucus–bicarbonate
`barrier to injury [30].
`Systemic effects: Indirect toxicity via systemic inhibition of cyclooxygenase (COX)-1-mediated
`prostaglandin synthesis may be the main mechanism by which ASA causes damage to the upper GI
`mucosa [29,31,32]. However, the inhibition of COX-1 is not the only cause of gastric injury, since ASA
`induces gastric damage both in COX-1-deficient and COX-2-deficient mice [29]. COX-1 is expressed in
`many cells throughout the body and the activity of ASA at cells in the gastric mucosa, where prosta-
`glandins play an important role in maintenance of the gastric mucus–bicarbonate barrier, can result in
`gastroduodenal toxicity [33,34].
`The main difference between ASA and other NSAIDs in terms of systemic activity lies in the irre-
`versible nature of ASA–COX-1 binding in platelets [31], the effects of which are maintained for the
`duration of the platelet life-span (i.e. eight to ten days). It is important because the prevalence of
`gastroduodenal erosions with long-term ASA therapy is relatively high [5,35,36], and therefore
`bleeding may develop even when the dose of ASA is low or when the lesion is small or superficial. The
`differential effects of ASA versus other NSAIDs might have relevant implications in clinical practice,
`because in concomitant administration of non-ASA NSAIDs can interfere with the cardioprotection
`conferred by low dose ASA [37]. The platelet COX-1 binding site is temporarily occupied by the non-
`ASA NSAID [38,39] thereby preventing ASA binding. For example, ibuprofen administered before
`low dose ASA may block its antiplatelet effect [40].
`Endoscopically-controlled studies have shown that the prevalence of erosions in gastroduodenal
`mucosa in low dose ASA users is about 60% [41,42]. Hart et al in their study examined the potential risk
`factors for development of these lesions in patients taking low dose ASA [43]. They concluded that
`Helicobacter pylori infection may be a protector factor for gastric erosions and age is not an important
`risk factor, in contrast to the known increased risk for NSAID induced gastric ulcer with advancing age.
`Presumably, the aged mucosa is not more susceptible to ASA injury, but is less capable of healing the
`erosions that result from initial damage. Some erosions might progress into ulcers and/or associated
`complications.
`The most important lesion, of course, is a frank ulcer by definition, a lesion that extends through the
`whole thickness of the mucosa into the submucosa or deeper layers. One recent study of 187 patients
`taking low dose ASA without gastroprotective drugs showed that ulcer prevalence was 11% (95%
`confidence interval 6.3–15.1%) and ulcer incidence in patients followed for 3 months was 7% (95% CI
`2.4–11.8%) [5], that is identical to ulcer incidence found by Laine et al in patients who were taking
`enteric-coated low dose ASA [44]. If we assumed a linear rate of ulcer development, this translates to an
`annual ulcer incidence of 28%. In this study only 20% of patients with endoscopic evidence of an ulcer
`had epigastric symptoms [5], that is similar to the incidence of dyspeptic symptoms reported by
`patients without ulcer.
`There is some controversy about if ulcers develop in low dose ASA users who do not have other risk
`factor (such a H. pylori infection or concomitant use with NSAIDS). It seems that H. pylori infection
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`increases the risk of duodenal ulcer in ASA users, but the relationship with gastric ulcer has been highly
`controversial [5,45].
`The clinical significance of these endoscopic findings is unclear, as the incidence of detected ulcers is
`higher that actual incidence of upper GI complications in clinical practice and the correlation between
`symptoms and mucosal damage is scarce. A recent review of available literature suggested, however,
`that endoscopic ulcers could be a possibly surrogate endpoint for upper GI harm [46].
`
`Low dose aspirin related lower gastrointestinal injury
`
`It was generally believed that low dose ASA did not cause any small bowel damage since the drug is
`largely absorbed before reaching the intestine, and this would limit the topical action on the intestinal
`mucosa. Growing evidence indicates that ASA can damage the GI tract below the angle of Treitz. Long-
`term ASA users can suffer small bowel bleeding and protein loss that might contribute to iron defi-
`ciency anaemia and hypoalbuminemia [47]. The mechanisms of damage and the real clinical impact of
`most observations are, however, far from being completely understood. GI injury by ASA therapy is the
`result of both topical and systemic effects produced by a decrease in mucosal COX-1 derived prosta-
`glandins. Prostaglandin inhibition attributable to inhibition of COX by ASA use is present in all
`segments of the digestive tract. Very little evidence on this issue it is available so far.
`A systematic review found a small increase of fecal blood loss (0.5–1.5 ml per day) in low dose ASA
`users (<325 mg) [48]. This amount increased up to 10 ml per day in some individuals, especially in
`those taking 1800 mg daily. A recent study by Smecuol et al has evaluated the effect of low-dose
`enteric-coated ASA on the small bowel. Twenty healthy volunteers underwent videocapsule endos-
`copy (VCE), fecal calprotectin and permeability tests before and after ingestion of 100 mg of enteric-
`coated ASA daily for 14 days. Half of the healthy volunteers showed some degree of mucosal damage in
`the VCE studies, including erosions and two ulcers in one patient [49]. The median baseline of
`permeability test increased after ASA use and the post-ASA ratio was above the upper end of normal in
`10 out of 20 volunteers. The median baseline fecal calprotectin concentration also increased signifi-
`cantly after ASA use, although only three patients had values above the cutoff (>50 mg/g). These data
`should be taken with care since the clinical significance of this is uncertain. It must be remembered that
`low dose ASA is associated with acute gastric damage, but very few patients develop serious adverse
`events. However, the data show that low dose enteric-coated ASA may induce damage to the small
`bowel and could well be the responsible agent in some patients with anaemia or GI obscure bleeding.
`Further studies should validate these data and determine the clinic relevance of them.
`
`Gastrointestinal complications (GI bleeding, ulcer perforation and obstruction)
`
`Upper GI tract complications
`Most of ulcers are asymptomatic and reasonably small, and probably heal over a period of weeks to
`a few months. The real clinical problem occurs when an ulcer erodes a vessel or, less commonly,
`perforates.
`American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents
`state that low dose ASA is associated with a 2–4 fold increase in symptomatic or complicated ulcer,
`increasing with concomitant medication use [4–6]. The estimated average excess risk of symptomatic
`or complicated ulcer related to low dose ASA is five cases per 1000 ASA users per year [50].
`There are some factors that put patients on low dose ASA treatment at increased risk of upper GI
`complications. These risk factors that are thought to be important include a history of an ulcer, a history
`of a bleeding ulcer, age >70 years, H. pylori infection and concomitant drug therapy with NSAIDs,
`cyclooxygenase-2 (COX-2) inhibitors, other antiplatelet agents (clopidogrel) or anticoagulants [51,52].
`Multiple risk factors have a cumulative effect on complications; not all patients who take ASA are at the
`same risk of upper GI bleeding [Table 1].
`A recent meta-analysis of 61controlled-randomized trial [53] estimated that the risk of major GI
`bleeding increases in patients treated with low dose ASA alone (OR, 1.55; 95% CI, 1.27–1.90), compared
`with inert control reagents. The risk increased further when ASA was combined with clopidogrel or
`anticoagulants, compared with ASA alone (OR, 1.86; 95% CI, 1.49–2.31 and OR, 1.93; 95% CI, 1.42–2.61,
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`Table 1
`Estimated incidence of gastrointestinal complications associated with low-dose aspirin
`use according to risk factor [7].
`
`Risk factor
`
`History of ulcer bleeding
`NSAID use plus aged ≥ 70
`years
`Prior ulcer plus aged ≥ 70 years
`Prior ulcer
`Age
`
`≥ 70 years
`< 70 years
`
`Estimated incidence
`( per 1,000 patient-years)
`140
`57
`
`50
`32
`
`22
`7
`
`respectively), However, low dose ASA alone decreased the risk for all-cause mortality (RR 0, 93 95% CI),
`largely due to effects in secondary cardiovascular prevention. [Table 2] Observational studies have
`reported higher risk estimates of major GI bleeds and any GI bleeds, than this meta-analysis [27,45,46].
`A possible explanation for this is that treatment and observation of patients in controlled randomized
`trial actively seek out adverse events and reduce the probability of self-reporting bias, thus partici-
`pating in clinical trials may allow greater sensitivity [54].
`In an interesting a cohort study performed in 903 patients taking low dose ASA; patients were
`followed up for an average of 45 months after discharge from hospital. Telephone interviews were
`conducted to establish whether there was a major upper GI bleed, that requiring hospitalization,
`during the follow-up period. In the 41 patients who had been hospitalized because of upper GI
`bleeding, 12 (29%) had a bleeding gastric ulcer, 10 (24%) a bleeding duodenal ulcer, and 19 (46%) had
`acute gastroduodenal mucosal lesions. Overall, the rate of major upper GI bleeding was 4.5%, which
`translates into an incidence 1.2 per 100 patient-years [55].
`In the other hand, meta-analyses have been contradictory in demonstrating a significant difference
`in the risk of GI bleeding according to the range of the low dose ASA used [23,56], but dose reduction
`does not appear to reduce cardiovascular effect of this drug. Because of that the American College of
`Gastroenterology and American Heart Association recommend lowering the dose from 325 mg to
`81 mg among patients with a high risk of upper GI events [6]. About this issue, the recent published
`study CURRENT-OASIS 7 is interesting [57]. In this randomized trial 25,086 individuals with acute
`coronary syndromes were randomly assigned to double-dose versus standard-dose clopidogrel, and
`high-dose (300–325 mg daily) versus low dose (75–100 mg daily) ASA. There was no significant
`difference between different doses of ASA with respect to cardiovascular death, myocardial infarction,
`or stroke, but neither with respect to the incidence of major bleeding.
`Perforation is an ulcer complication less common than ulcer bleeding. A vast majority of perforating
`ulcers developed in the duodenum. The incidence and early mortality of peptic ulcer perforation are
`
`Table 2
`Gastrointestinal bleeding with LDA treatment (alone or with other compounds) [54].
`
`Endpoint
`Major GI bleeds
`
`Treatment
`LDA alone
`LDA þ clopidogrel
`LDA þ anticoagulants
`LDA alone
`LDA þ clopidogrel
`LDA þ anticoagulants
`NNH Number needed to harm. OR Odds ratio.
`
`Any GI bleeds
`
`Control
`No treatment
`LDA alone
`LDA alone
`No treatment
`LDA alone
`LDA alone
`
`OR (95% CI)
`1.55 (1.27–1.90)
`1.86 (1.49–2.31)
`1.93(1.42–2.61)
`1.31 (1.21–1.42)
`NA
`1.81 (1.32–2.49)
`
`NNH (95% CI)
`500 (334–1000)
`90(45–inf)
`125 (91–250)
`166(125–250)
`NA
`13(7–inf)
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`associated with old age, intake of low dose ASA and co-morbidity. The annual incidence of perforation,
`in subjects aged >65 years, was 32.7 per 100.000 of the age-specific population, of whom 10.7 per
`100.000 were taking low dose ASA [58].
`Moreover, the use of enteric-coated or buffered preparations do not reduce the risk of upper GI
`complications [25,59]. This suggests that severe side effects of ASA are the result of a systemic rather
`than a local or topical effect [60].
`
`Lower GI tract complications
`There is evidence that NSAIDs and/or ASA are associated with complications from the lower GI tract
`since early 90’s [61–63]. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding
`and perforation to a similar extent that seen in the upper GI tract, but data about lower GI effects of low
`dose ASA are scant. One study evaluated both non-ASA NSAIDs and ASA use in all consecutive patients
`admitted to hospital because of GI bleeding and in addition to clinical history, ASA use was assayed by
`estimating platelet COX activity and ASA plasma levels [62]. The study found that 86% of patients with
`lower GI bleeding had evidence of recent ASA or NSAID use. Other studies [63,64], confirmed later that
`the risk of developing a lower GI bleeding event is increased with NSAID use. Using a similar meth-
`odology to that commented above [61], a similar picture was found later for intestinal perforations
`[63]; 75% of patients with a perforation in the lower GI tract had evidence of ASA or NSAID use. The
`proportion of perforations resulting in death is high (around 30%) when compared to other NSAID-
`associated side effects [61,63,65].
`A recent study (Health Professionals Follow-up Study) have investigated the relation between ASA
`use and diverticulitis and diverticular bleeding risk and concluded that regular ASA use was associated
`with a significantly relative risk increase of both events [66]. Another recent prospective, population-
`based cohort study evaluated long term use of ASA and gastrointestinal bleeding and showed an
`increased relative risk of upper and lower GI bleeding (RR 1.74 and 1.21, respectively IC 95%) [67].
`
`Mortality
`Death is the worst outcome of GI complications, but mortality data associated with low dose ASA
`use are scarce. The Spanish Mortality Study collected information on GI complications and deaths
`occurring in 2001 attributed to NSAIDs/ASA use in two sets of data provided by 26 general hospitals
`serving 7,901,198 people and by 197 hospitals representative of the 269 hospitals in the Spanish health
`system [66]. In 2001, about 5% of the Spanish was taking low dose ASA for secondary cardiovascular
`protection [7]. Upper GI tract complications predominated. For 8.2–12.2% of inpatients, that developed
`a bleeding ulcer confirmed by endoscopy and who subsequently died, they could be linked to low dose
`ASA use. Among the patients who died, about 50% had a history of GI disease (peptic ulcer, upper GI
`bleeding or dyspepsia). Extrapolating these data, in Spain, annually there are 321 major upper GI
`bleeding and 18 deaths per 100,000 users of low dose ASA.
`The incidence of non-variceal upper GI bleeding has decreased and the associated mortality has also
`declined over the past 10 years [68,69]. But, the case fatality rate has remained constant in this period
`[69]. This reduction in the total number of deaths because of GI events is because of the declined
`number of events [70,71]. And it is probably related to our ability to prevent them, but not to our
`capacity to improve the outcome of the GI event, in spite of advances in endoscopic and medical
`treatments for ulcer bleeding [72,73]. The most current data showed that ulcer bleeding linked deaths
`are because of non-ulcer bleeding causes and are associated with non-GI risk factors like multi-organ
`failure, cardiopulmonary conditions or terminal malignancy [74].
`There are only a few studies of the association between genetic polymorphisms and the risks of
`ASA-induced ulcers or its complications. A recent published study showed that carriage of the IL-1b-
`511 T allele was significantly associated with peptic ulcer among low dose ASA takers. Anyway, data
`on which polymorphisms could be significant risk factor for GI event in low dose ASA users are still
`scarce and further clinical studies are needed [75].
`
`New aspirin compounds
`New agents are being developed to reduce the GI damage associated with low dose ASA and to
`suppress platelet activation more effectively than ASA. NO–ASA compounds like NCX-4016 (an ASA
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`compounds with an NO moiety that is released upon absorption) has been shown to be less gastrotoxic
`than plain ASA, at any dose, and could have a superior antithrombotic activity [76]. However, more
`studies are necessary to confirm these preliminary data. The aspirin–phosphatidylcholine complex
`(PL2200) that were developed to reduce the acute and topical effects of ASA that changed the normal
`hydrophobic biophysical properties of the mucus gel layer produces fewer erosions and ulcers than
`ASA in healthy volunteers and could be used either alone or in addition to a PPI in patients who are at
`risk of ASA-related complications [77,78].
`
`Practice points
` Low dose ASA prevents cardiovascular morbidity and mortality in at-risk patients with
`a history of cardiovascular disease, but can increase the risk of upper and lower GI
`complications.
` The use of enteric-coated or buffered ASA preparations does not reduce the risk of GI
`complications. Antiplatelet therapy with non-ASA preparations also increases the risk of GI
`bleeding complications.
` The onset of GI symptoms in low dose ASA users are common; dyspepsia and gastroesoph-
`ageal reflux are the most frequent.
` The presence of dyspepsia is not clearly predictive of the appearance of GI complications,
`more than a half of patients with GI complications will not have warming signs or symptoms,
`and conversely, as many as 50% of patients with dyspepsia have normal-appearing mucosa.
` ASA-induced GI damage can be reduced by the use of co-therapy with antisecretory agents,
`especially PPIs.
` The incidence of mortality from cardiovascular disease far exceeds that associated with GI
`haemorrhage; however, the benefits of ASA may be reduced in patients with a high risk of GI
`complications.
`
`Summary
`
`Aspirin is being used as an effective analgesic and anti-inflammatory agent at high doses
`(>325 mg), but low dose aspirin (75–325 mg) is considered the “key and reference” antiplatelet drug at
`the present time. The problem is that, even at low dose, aspirin use has been associated with adverse
`side effects in throughout the entire GI tract, but particularly in the gastroduodenal area. The range of
`GI effects is wide, range from troublesome symptoms without mucosal lesions to more serious toxicity,
`including ulcers, GI bleeding, perforation and even death. Upper GI symptoms can be present in up to
`15–20% of low dose ASA takers, being gastro-oesophageal reflux and dyspepsia the most frequently
`reported. These symptoms have a negative impact on treatment compliance and are not clearly
`predictive of the presence of mucosal injury. Even very low dose of ASA can produce acute mucosal
`injury. Endoscopically-controlled studies have shown that the prevalence of erosions and ulcer in these
`patients are about 60% and 10%, respectively. The clinical significance of these endoscopic findings is
`unclear, as the incidence of detected ulcers is much higher that actual incidence of upper GI compli-
`cations in clinical practice. The real clinical problem occurs when the ulcer results in a GI bleeding or,
`much less frequently, perforation. The risk of GI complications varies, depending on the presence of GI
`risk factors. The estimated average excess risk of symptomatic or complicated ulcer related to low dose
`ASA is five cases per 1000 ASA users per year. It is important to note that although it is estimated that
`the risk of major GI bleeding increases in low dose ASA users, low dose ASA decreases the risk for all-
`cause mortality, due to effects in secondary cardiovascular prevention. In addition, growing evidence
`indicates that ASA can damage the GI tract below the angle of Treitz. However, this evidence is still
`scant and further studies are necessary to validate data and determine the real clinical impact of lower
`GI damage associated with low dose ASA. Death is the worst outcome of GI complications, but
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`CFAD v. Pozen
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`C. Sostres, C.J. Gargallo / Best Practice & Research Clinical Gastroenterology 26 (2012) 141–151
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`149
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`mortality data associated with low dose ASA use are scarce. According to data of Spanish Mortality
`Study, in Spain, annually there are 18 deaths per 100,000 users of low dose ASA. New ASA compounds
`are being developed to reduce GI damage and provide the same or better cardiovascular protection.
`Current strategies to reduce this GI risk associated with low dose aspirin are effective.
`
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