Risk factors for gastrointestinal bleeding associated with low-dose aspirin

Best Practice & Research Clinical Gastroenterology 26 (2012) 125–140

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Risk factors for gastrointestinal bleeding associated with low-dose aspirin Vera E. Valkhoff, MD a, b, *, Miriam C.J.M. Sturkenboom, PharmD, Professor in Observational Data-analysis a, c,1, Ernst J. Kuipers, MD, Professor of Medicine b, d, 2 a

Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, The Netherlands Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands c Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands d Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands b

Keywords: Low-dose aspirin Gastrointestinal haemorrhage Gastrointestinal bleeding Peptic ulcer disease Risk factors Predictors Review

Low-dose aspirin use is associated with an increased risk for gastrointestinal ulceration and bleeding. At-risk low-dose aspirin users are therefore recommended to take proton-pump inhibitors. However, it is poorly understood which aspirin users are at risk to develop such complications. It is assumed that the known risk factors for NSAID-induced upper gastrointestinal events also apply to low-dose aspirin users. The conventional risk factors for upper gastrointestinal complications associated with aspirin therapy include: (1) a history of peptic ulcer disease or gastrointestinal bleeding, (2) older age, (3) concomitant use of NSAIDs, including coxibs, (4) concomitant use of anticoagulants or other platelet aggregation inhibitors, (5) the presence of severe co-morbidities, and (6) high aspirin dose. In patients with a history of peptic ulcer disease, Helicobacter pylori infection should be assessed and treated. This review focuses on the evidence for upper gastrointestinal risk factors in aspirin users. Ó 2012 Elsevier Ltd. All rights reserved.

* Corresponding author. Department of Medical Informatics, Ee-2159, Dr. Molewaterplein 50-60, 3015 GE Rotterdam, The Netherlands. Tel.: þ31 10 7044116; fax: þ31 10 7044722. E-mail addresses: [email protected] (V.E. Valkhoff), [email protected] (M.C.J.M. Sturkenboom), [email protected] (E.J. Kuipers). 1 Department of Medical Informatics, Ee-2104, Dr. Molewaterplein 50-60, 3015 GE Rotterdam, The Netherlands. Tel.: þ31 10 7043050; fax: þ31 10 7044722. 2 Department of Gastroenterology and Hepatology, HS-304, ’s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Tel.: þ31 10 7034681; fax: þ31 10 7034682, Postbus 2030, 3000 CA Rotterdam, The Netherlands. 1521-6918/$ – see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2012.01.011

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Introduction Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (aspirin; ASA), are among the world’s most frequently prescribed medications. The prevalence of aspirin use approximated on average 9.6% among adults in the UK in 2006, being low in younger subjects and increasing rapidly in the elderly to 35% above the age of 75 years [1]. Access to these drugs has expanded as both NSAIDs and aspirin are available on prescription as well as over-the-counter (OTC). NSAIDs and standard doses of aspirin of 500–1000 mg are mostly prescribed for inflammatory conditions and pain relief, whereas aspirin doses between 75 and 325 mg/day (referred as low-dose aspirin; LDA) are recommended for prevention of cardiovascular (CV) events. Although standard dose aspirin is still being used as an effective analgesic agent, its major indication is as anti-platelet therapy, most frequently in a 75–100 mg daily regimen. Cardiovascular disease is the leading cause of morbidity and mortality in Europe and North-America [2]. However, long-term use of LDA has been well established to reduce the risk of vascular events by about 25%, primarily by acting as platelet aggregation inhibitor [3–5]. LDA is mostly advised for secondary prevention [6], but is also considered beneficial for primary prevention of CV events in highrisk subjects, depending on the number of cardiovascular risk factors including age, sex, life-style and co-morbidities [7]. Despite the clear evidence for beneficial preventive effects and the growing burden of cardiovascular disease worldwide, aspirin has been reported to be underutilized in patients at high risk developing CV events [8]. Adverse events of aspirin Despite the reputation of aspirin as being a relatively harmless drug, some adverse events are reported. Amongst others, aspirin use has been associated with urticaria, tinnitus, Reye’s syndrome in children and adolescents with fever, prolonged bleeding, and seldom with pancytopenia. However, the most predominant side effects due to aspirin are related to the gastrointestinal (GI) tract. The effects range from mild upper GI complications (e.g. dyspepsia, petechiae, or erosions) to more severe events, such as peptic ulcer disease (PUD) and its complications (including upper GI bleeding (UGIB; Fig. 1), perforation or stricture formation, in particular gastric outlet syndrome as a result of pyloric narrowing after repeat ulceration). Of the described complications, UGIB is the most frequent and also most studied. In spite of the clear evidence of the risks related to aspirin in the upper gastrointestinal tract, its effect on the lower gastrointestinal tract is not well defined. However, growing evidence support the hypothesis that aspirin can also harm the gastrointestinal tract below the ligament of Treitz, injuring the small bowel and the colon [9]. This may lead to abdominal symptoms and iron deficiency anaemia [10]. Epidemiology of upper gastrointestinal complications in overall population Upper GI (UGI) complications commonly result in hospital admission, especially in the elderly, and have an estimated case fatality rate around 5–14% [11]. The incidence of these serious UGI adverse events is approximately one case per 1000 person years in the overall population [11,12], of which bleeding encompass the majority [12]. A few published meta-analyses demonstrated that use of LDA significantly increases the risk of upper GI complications compared with placebo or non-use, reporting the relative risk of gastrointestinal complications associated with aspirin at a range of 1.5–2.5 [13–19] in clinical trials, and 2.6 and 3.3 in observational studies [20,21]. The epidemiological dogma provides that a limited relative risk only results in many excess cases when the absolute incidence of the particular event is high in the general population. As described, upper gastrointestinal complications are quite rare with an incidence of one UGIB case per 1000 person years in the general population, resulting in the average incidence of two cases per 1000 person years for aspirin users. However, with tens of millions of aspirin users and a 35% prevalence of its use among elderly [1], a small but significant absolute excess risk of one case per 1000 persons using aspirin for

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Fig. 1. Multiple erosions in the duodenum of a recently admitted 85-year-old man with an upper gastrointestinal bleeding on longterm treatment of aspirin 80 mg/day, without gastro-prophylaxis, with a haemoglobin level of 3.0 mmol/l up on admission at the intensive care unit.

one year can have major implications for the overall incidence of upper gastrointestinal complications and therefore for public health and health care expenditures.

Practice points  The use of low-dose aspirin increases the risk of upper GI complications two-fold compared with non-use.  Low-dose aspirin is harmful for the entire GI tract, but data are sparse on lower GI complications attributable to aspirin.

Risk factors for UGI bleeding due to NSAIDs From NSAID studies it is well known that not every NSAID user is at the same risk of developing NSAID-related UGI complications. Particular UGI risk factors help to identify NSAID users as low, medium or high risk and determine the indication for treatment with gastroprotective agents (GPAs), in particular proton-pump inhibitors or misoprostol. Although different evidenced-based guidelines provide slightly different risk factor definitions of patients at risk to develop NSAID-induced UGI events, most designate advanced age, a medical history of UGI events, serious co-morbidity, and concurrent administration of anticoagulants or corticosteroids as relevant risk factors. For this review we will follow the risk factors reported in the American College of Gastroenterology guidelines for prevention of NSAID-related ulcer complications (Table 1) [22]. Risk factors for UGI bleeding due to aspirin in published guidelines or reviews Like NSAID users, the risk of developing upper gastrointestinal complications differs among aspirin users. However, in contrast to NSAID-related UGI risk factors, risk factors for aspirin users are less well

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Table 1 Risk factors discussed in this review and classified as definite, probable or controversial risk factor.

Patient-related risk factors P-1 History of peptic ulcer disease or history of gastrointestinal bleeding P-2 Older age P-3 Concomitant use with NSAIDs, including coxibs P-4 P-5 P-6 P-7 P-7 P-7 P-8 P-8 P-8 P-9 P-10

Concomitant use of anticoagulants and other platelet aggregation inhibitors The presence of severe co morbidities Male gender Excessive alcohol use Current smoking High body mass Concurrent use of corticosteroids Concurrent use of calcium channel blockers Concurrent use of selective serotonin receptors inhibitors History of dyspepsia H. pylori infection

Aspirin-related risk factors A-1 High aspirin dose A-2 Short aspirin duration A-3 Plain aspirin preparation A-4 Regular aspirin use

Identified as risk factor for UGIB due to aspirin (according to this review) Definite/Probable/Controversial/No

Identified as risk factor for UGIB due to NSAIDs (according to guidelines American College of Gastroenterology [22]) Yes or No

Definite

Yes

Controversial Definite

Probable

Yes Yes, concomitant use of other NSAIDs, including low-dose aspirin Yes

Controversial with the exception of patients with hypertension No Probable No Probable Controversial Probable

Yes, especially cardiovascular disease No No No No Yes No No

Probable Definite

No Yes

Probable Definite No Probable

Yes, high NSAID dose No No No

studied. It is generally believed that risk factors for NSAID-related UGI harm also pertain to aspirin users as the same mechanism of gastrointestinal damage are in place. The poor definition of risk factors for UGI complications during aspirin use is firstly due to the fact that very large studies (preferable well-conducted clinical studies) are needed in order to have sufficient power to address predictors of UGI bleeding during aspirin use. Secondly, the current literature when dealing with aspirin-related UGI risk factors mostly concerns secondary analyses, while the study of aspirin risk factors was not the primary goal of the study itself. Therefore, it is possible that more risk factors were examined, but those risk factors that were found not to be associated with the outcome under study (aspirin-related UGIB) were not deemed important to report, although information on negative risk factors in itself is considered valuable information. With these limitations, one guideline and a review did compose a list of risk factors which were considered specific for aspirin users. In a US guideline on prevention of GI risks of antiplatelet therapy, risk factors for UGI events during low-dose aspirin therapy were defined as a history of peptic ulcer disease, older age (>60 years), and concomitant use of NSAIDS or antithrombotic agents [23]. However, only one reference [24] was included in order to support the statements on the risk stratification of at-risk aspirin users, although the authors of the guideline did appreciate that risk factors for aspirin-related UGI events have been poorly characterized [23]. A more rigorous review of the literature aiming to present the current scientific evidence resulted in the following list of risk factors: (1) a history of peptic ulcer or bleeding ulcer, (2) older age (especially >70 years), (3) concomitant use of NSAIDs, other antiplatelet agents or anticoagulants, (4) the presence of severe co-morbidities, and (5) high aspirin dose [25].

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Possible other risk factors such as Helicobacter pylori infection (discussed in Chapter 7 of this issue by Francis Chan) or concurrent use of corticosteroids may play a role. In addition to the already mentioned risk factors, we will also discuss additional potential risk factors which have been considered at least once in other studies: male gender, excessive alcohol use, current smoking, high body mass, concurrent use of calcium channel blockers, history of dyspepsia, early onset of aspirin use, aspirin preparation and regimen of aspirin use.

Practice points  Aspirin-related UGI risk factors are poorly studied.  Risk factors for aspirin-related UGI events are not clearly specified in guidelines on prevention of GI complications with antiplatelet therapy.

Review of risk factors for UGI bleeding due to aspirin We will describe the evidence for the potential risk factors one by one. We will divide the risk factors as follows: (1) patient-related risk factors (i.e. age, gender, co-morbidity), and (2) aspirinrelated risk factors (i.e. dose, formulation). Patient-related risk factors (P-1) History of peptic ulcer disease or history of gastrointestinal bleeding Several studies reported a previous medical history of ulcer disease or gastrointestinal bleeding as the most important risk factor in low-dose aspirin users [26–31]. A study by Lanas et al. showed that low-dose aspirin users had a 2.4 fold increased risk to develop upper gastrointestinal bleeding compared to no aspirin users [26]. However, among patients taking low-dose aspirin, a history of ulcer disease increased the risk for upper gastrointestinal bleeding by 2.1 compared to aspirin users without such medical history. Among the same low-dose aspirin users, 13.5% of cases with an upper gastrointestinal bleeding reported a previous history of GI bleeding compared to only 2.3% of the patients without an UGI bleed, resulting in a reported adjusted OR of 6.5 (95% CI, 2.0–21.2) [26]. This study showed that previous complicated ulcer disease such as bleeding is more important as a risk factor for recurrent ulceration during aspirin use than previous uncomplicated ulcer disease. In contrast, one other study reported separately on a history of uncomplicated or complicated ulcer disease with smaller differences. In a cohort of low-dose aspirin users (75–300 mg/day) in the United Kingdom, patients with a history of uncomplicated ulcer disease had a relative risk of 4.2 (95% CI, 2.4–7.2) and patients with a history of complicated peptic ulcer disease had a relative risk of 5.7 (95% CI, 2.7–12.0) compared to patients without a previous episode of peptic ulcer disease [27]. Other studies supported the finding that the risk of upper gastrointestinal bleeding (UGIB) among low-dose aspirin users with a previous ulcer or UGIB is increased around three-fold [29–31]. One study reported a much higher bleeding risk among low-dose aspirin users with a previous history of ulcer disease (age and sexadjusted OR, 15.2; 95% CI, 3.8–60.1) [28]. (P-2) Age Although age is believed to be a risk factor of importance among aspirin users, not much supporting evidence is available. A systematic review of epidemiologic studies published between 1990 and 2001 showed that the relative risk associated with aspirin use was not significantly different for patients below or above 60 years of age [20]. Patients below the age of 60 years had an increased risk of 5.0 (95% CI, 4.1–6.1) and patients older than 60 years an increased risk of 4.0 (95% CI, 3.3–4.8) compared to nonaspirin users, after aggregating the results of four observational studies. This is in line with results of four studies published from 2001 onwards, in which no statistically significant association was reported between age and the risk of UGI complications during low dose

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aspirin use [28–31]. However, it should be noted that in one of these studies the risk of low-dose aspirin-associated UGIB increased non-significantly by 2.3% per each advanced age year (OR, 1.023; 95% CI, 0.991–1.055) [30]. (P-3) Concomitant use with non-steroidal anti-inflammatory drugs In patients taking low-dose aspirin, concurrent use of non-steroidal anti-inflammatory drugs is identified as important risk factor in developing aspirin-related UGIBs. The combined use of low-dose aspirin together with NSAIDs more or less doubles to triples the risk compared to patients on low-dose aspirin alone [26,27,29,32–35]. One of the earlier studies found that odds ratios were raised almost eightfold (OR, 7.7; 95% CI, 3.6–16.4) in those who took both daily aspirin together with non-aspirin non-steroidal anti-inflammatory drugs, and threefold for users of aspirin alone (OR, 3.3; 95% CI, 2.5– 4.4) compared to non-users [35]. A more recent case–control study investigated the difference between NSAIDs in general versus cyclooxygenase 2 (COX-2)-selective NSAIDs (coxibs) concurrently with low-dose aspirin use [33]. The risk of UGIB increased when low-dose aspirin was taken together with NSAIDs (OR, 12.7; 95% CI, 7.0– 23.0) compared with use of low-dose aspirin alone (OR, 3.9; 95% CI, 3.1–4.9). The risk of UGIB was also higher in patients taking coxibs and low-dose aspirin (OR, 14.5; 95% CI, 3.3–63.9) than in those taking low-dose aspirin alone (OR, 3.6; 95% CI, 2.9–4.5). It should be noted that the number of individuals taking low-dose aspirin and coxibs in this study was very small, which may have affected the power of the study. This shows that, although the risk of upper GI complications is lower with coxibs than with non-selective NSAIDs, there is no benefit from coxibs over conventional NSAIDs, when taken together with low-dose aspirin. (P-4) Concomitant use of anticoagulants and other platelet aggregation inhibitors Another factor that was studied as potential risk factor for aspirin-related UGIB was concomitant use of antithrombotic agents, both anticoagulants and platelet aggregation inhibitors. Anticoagulants. Warfarin is a widely-used anticoagulant and is indicated for prevention of stroke in patients with atrial fibrillation. Furthermore, warfarin and other anticoagulants are prescribed for a shorter period to treat patients with deep venous thrombosis or as prophylaxes for thrombosis in patients after surgery. Warfarin is frequently studied and often co-prescribed with low-dose aspirin in various cardiac conditions. In the Thrombosis Prevention Trial men aged between 45 years and 69 years at high risk of ischaemic heart disease were randomized to either warfarin and low-dose aspirin (n ¼ 1277) or to low-dose aspirin alone (n ¼ 1268) [36]. Seven of the 1277 patients (0.55%) on dual anticoagulant therapy compared to five of the 1268 patients (0.39%) on aspirin monotherapy developed a major, but non-fatal, upper gastrointestinal bleeding. This was a slight, but non-significant, increase of UGIB among users of combination therapy. These results contrasted with those of another trial which randomized patients with atrial fibrillation to either fixed dose warfarin (1.25 mg) plus low-dose aspirin (300 mg/day) or low-dose aspirin (300 mg/day) alone [37]. None of 171 patients in the dual anticoagulant therapy arm developed major upper gastrointestinal bleeding as compared to four of 169 patients (2.4%) randomized to low-dose aspirin alone. Two other studies did not specify the exact location of the occurred GI bleedings. In patients who had survived acute myocardial infarction, the reported absolute numbers on gastrointestinal bleeding (not specified to upper or lower bleeding) were six out of 1206 patients randomized to aspirin (160 mg/day) and 21 out of 1208 patients randomized to aspirin (75 mg/day) plus warfarin [38]. The second study reported that there were more gastrointestinal bleeds in the dual anticoagulant group compared to the aspirin only group. No relative risk estimates were provided due to small numbers [39]. In patients aged 40–79 years extracted from the General Practice Research Database in the United Kingdom, a small interaction was observed between low-dose aspirin and anticoagulants [32]. Two other observational studies were not able to show an interaction between low-dose aspirin and anticoagulants [29,30]. Other vitamin K antagonists such as fenprocoumon and acenocoumarol in combination with aspirin are not studied with regard to UGI bleeding. Recent developed antithrombotic agents (oral direct

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inhibitors of clotting factor IIa (thrombin) or clotting factor Xa) are more convenient in use than warfarin and show promising results with respect to stroke rates. We will need to await results considering their UGI risk associated with aspirin use. Other platelet aggregation inhibitors. Clopidogrel is an oral antiplatelet agent commonly used in addition to aspirin to reduce cardiovascular events, for example in patients with coronary artery stents. In a cohort of 38,077 individuals (aged 50–84 years) receiving low-dose ASA for secondary prevention of cardiovascular or cerebrovascular events, patients who received clopidogrel as dual antiplatelet therapy had a non-significant increased risk of UGIB when aspirin monotherapy was set as the reference (OR, 1.61; 95% CI, 0.85–3.05) [27]. These results are in line with those from another administrative database study in Canada, which found a similar elevated risk for bleeding in general (however, not restricted to the gastrointestinal tract) of 1.68 (95% CI, 1.02–2.77) among 21,443 elderly survivors of acute myocardial infarction receiving aspirin plus a thienopyridine derivative (antiplatelet combination) as compared to aspirin alone [40]. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial also showed that gastrointestinal bleeding was more common in the clopidogrel plus aspirin group (1.3% of 6259 clopidogrel plus aspirin users as compared with 0.7% of 6303 aspirin users only; relative risk not reported). No specification was provided whether these events are mostly upper or lower bleedings [41]. In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, the combination of aspirin and clopidogrel was compared with aspirin alone for a median follow-up of 28 months. The risk of moderate or severe bleeding was most pronounced during the first year and was significantly higher in the dual antiplatelet therapy group as compared to the aspirin alone group. Although the majority of bleedings was within the gastrointestinal tract, no hazard ratios were reported specifically for the GI tract and there was also no separation made into upper or lower GI tract bleedings [42]. Most data thus support the hypothesis that dual anticoagulant therapy (aspirin plus a vitamin K antagonist) as well as dual antiplatelet therapy (aspirin plus other platelet aggregation inhibitor) increases the risk of general bleeding (with the majority of bleedings developing within the gastrointestinal tract) to a higher degree than aspirin alone, however most papers did not specify the exact bleeding locations within the GI tract. (P-5) The presence of severe co-morbidities The presence of serious co-morbidity as risk factor for UGIB among NSAIDs and low dose aspirin users has been poorly defined and studied. The problem is that serious co-morbidity is a very broad concept, usually poorly defined in individual studies, and therefore difficult to investigate. In fact, different evidenced-based guidelines concerning NSAIDs provide slightly different definitions of comorbidity as risk factor. The guidelines of the American college of Rheumatology do identify serious co-morbidity as a risk factor for NSAID-related UGI complications, but they do not specify this concept further [43]. The obsolete guideline of the American College of Gastroenterology, originating from 1998, did not identify co-morbidity as a risk factor among NSAID users [44]. However, in 2009, Lanza et al. updated these guidelines of the American College of Gastroenterology [22]. In this more recent version of the guidelines, they identified ‘chronic debilitating disorders’ as a risk factor, and specified cardiovascular disease. Also the National Health Service (NHS) Clinical Knowledge Summaries and NHS National Institute for Clinical Excellence (NICE) state that serious co-morbidity is a risk factor for developing UGI ulcer/complication during NSAID therapy [45,46]. The NICE guidance specifies serious co-morbidity as follows: cardiovascular disease, hepatic or renal impairment (including dehydration), diabetes, or hypertension. A Dutch guideline on NSAID-gastropathy specified co-morbidity as heart failure or diabetes mellitus [47]. This is true for NSAIDs, but there are even fewer aspirin studies concerning this issue. No reviews or guidelines specifically for aspirin users are available which define co-morbidity as risk factor [23,25]. Few studies have been conducted concerning co-morbidities as risk factor for aspirin-associated UGIB among low dose aspirin users, other than a medical history of ulcer disease of upper gastrointestinal complication itself. A study by Lanas et al. in 2002 found that patients with an UGIB had a more frequent history of chronic pulmonary obstructive disease, albeit non-significant [28]. In a crude analysis, 14.4% of the

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cases and 6.6% of controls matched for age, sex and aspirin regimen had such a pulmonary disease (crude OR, 2.4; 95% CI, 0.95–5.94). Other clinical findings referring to the concept of co-morbidity such as a history of rheumatic disease or liver disease showed no difference between cases and controls in this unadjusted analysis. In a prospective Chinese cohort study of 991 patients with coronary artery disease on low-dose aspirin, hypertension was an independent risk factor for UGIB in a multivariate analysis. Patients with hypertension had a 4.6-fold higher probability of UGIB while taking low-dose aspirin as compared to aspirin users without hypertension (95% CI, 1.5–14.7) [29]. In a univariate analysis the presence of renal impairment, impaired left ventricle function, or New York Heart Association (NYHA) functional class III–IV were predictors of UGIB among aspirin users. Diabetes mellitus was studied additionally, but there was no evidence to support this condition as risk factor for aspirin-related UGIB. This was in line with the result of Okada et al. in which neither diabetes mellitus itself nor the use of insulin therapy was associated with UGIB [30]. Many patient characteristics, such as hypertension, diabetes mellitus, atrial fibrillation, and rheumatic disease, were considered in a cohort study of 903 patients taking low-dose aspirin for the prevention of cardiovascular disease. None of them was associated with an altered risk of UGIB among patients taking low-dose aspirin, except for the presence of a history of peptic ulcer disease or UGIB [31], which we discussed previously as separate risk factor. (P-6) Gender Gender is not clearly associated with a change in risk among aspirin users. This was illustrated by a systematic review in which four studies published until 2001 were aggregated showing that both women and men had a three-fold increased risk as compared to non-aspirin users (women, OR, 3.0; 95% CI, 2.6–3.6; men, OR, 3.0; 95% CI, 2.7–3.4) [20]. One of the included studies was a Danish cohort study, of which 49.9% was male [34]. In the total cohort, the standardized incidence rate ratio (SIR) was 2.6 (95% CI, 2.2–2.9). When stratified by sex, the UGIB risk among aspirin users was lower for women (SIR, 2.3; 95% CI, 1.8–2.9) than for men (SIR, 2.8; 95% CI, 2.3–3.3). Although not statistically significant, this showed that the risk estimates tended to be higher among male low-dose aspirin users than among female low-dose aspirin users. From 2001 onwards, four studies confirmed that male gender is not statistically significantly associated with aspirin-related UGIB risk [28–31]. Again, some non-significant evidence is available showing higher rates for male aspirin users than for female aspirin users. Lanas et al. reported a crude OR for men of 1.22 (95% CI, 0.69–2.15) in Spanish patients (71% male sex) taking low-dose aspirin [28]. Okada et al. reported a very similar, but non-significant, adjusted risk estimate (SIR, 1.28; 95% CI, 0.71–2.32) [30]. (P-7) Life style; alcohol use, smoking and body mass Alcohol use. Two studies clearly reported a positive association between alcohol use and UGIB among patients taking aspirin [27,28]. In a population of 245 aspirin users, 15.1% used alcohol, defined as any alcoholic beverage consumed regardless of the amount, and alcohol use was identified as risk factor for ulcer bleeding after adjusting for confounding variables (OR, 4.3; 95% CI, 1.7–10.4) [28]. Another publication studied the dose–response of alcoholic units among aspirin users. Patients using excessive alcohol (>24 alcoholic units per week) had a higher risk to develop complications compared to abstainers (0 alcoholic units per week) with an OR of 3.0 (95% CI, 1.4–6.2). Moderate to severe alcohol drinkers (1–24 alcoholic units/week) did not have an elevated risk to develop aspirin-associated UGIB as compared to aspirin users free of alcohol use [27]. In contrast with the previous studies, one study with a high prevalence of daily alcohol use (30.2% of cohort) showed no association [31], whereas the study of Okada et al. shows a trend to a protective effect of alcohol use, albeit non-significant (OR, 0.52; 95% CI, 0.25–1.09) [30]. Nicotine use/smoking. Smoking is not associated with the risk of UGIB attributable to aspirin use [27,30,31]. Body mass. In one study it was reported that patients with a high lean body mass had a higher probability of UGIB, while on low-dose aspirin (P ¼ 0.016) [29]. Most studies did not report on this variable.

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(P-8) Concurrent use of other drugs One study reported on the concomitant use of aspirin and corticosteroids stating that no relevant interaction was observed between aspirin and steroids beyond the sum of the independent effects [32]. In contrast, one study significantly associated the risk of UGIB in users of low-dose aspirin with concomitant calcium channel blocker use (OR, 2.53; 95% CI, 1.25–5.14) [28]. (P-9) History of dyspepsia In a British case–control study, the impact of a history of dyspepsia was studied in relation to the risk of UGIB among aspirin users. Of the 169 UGIB cases during aspirin use, 29% reported a history of dyspepsia versus only 22.5% of 2000 age- and sex-matched controls. Patients with dyspepsia thus had a higher risk to develop UGIB compared to patients without dyspepsia, while adjusting for many potential confounders (OR, 1.77; 95% CI: 1.20–2.61) [27]. (P-10) H. pylori infection The role of H. pylori infection in the pathway of aspirin-induced gastropathy will be discussed in Chapter 7. In short, one study with the specific aim to evaluate the role of H. pylori infection in the risk of UGIB in patients on aspirin showed that H. pylori-positive patients had a 4.7-fold increased risk to develop upper gastrointestinal complications compared to aspirin users without H. pylori infection (95% CI, 2.0– 10.9) [28]. In concordance with this study, another study found that the risk of peptic ulcer bleeding was higher in the subgroup of low-dose ASA users (50–250 mg/day) who tested positive for H. pylori (OR, 17.7; 95% CI, 2.3–136.7) than in low-dose ASA users as a whole (OR, 4.1; 95% CI, 1.1–16.3) [48]. However, the significant association observed between low-dose ASA and gastric ulcer bleeding by Santolaria et al. (OR, 3.1; 95% CI, 1.4–6.6) became non-significant when restricted to individuals taking low-dose ASA who tested positive for H. pylori (OR, 0.6; 95% CI, 0.1–3.6) [49]. This may have been due to the smaller sample size in the sub-analysis. As H. pylori infection is important for gastroduodenal damage among patients on aspirin, eradication of H. pylori in aspirin users with a previous upper gastrointestinal partially prevents recurrent bleeding and is equivalent to treatment with omeprazole (20 mg/day) [50]. Aspirin-related risk factors (A-1) Aspirin dose A study on the dose–response relationship between aspirin and UGIB showed that patients using regular aspirin in a dose exceeding 325 mg/day have a higher risk to develop complications compared with daily use of lower dosages (325 mg) with an OR of 2.6 going to 5.8, respectively [51]. This was confirmed by a case–control study conducted in Spain [33]. Similarly, this result was emphasized by a meta-analysis of 31 clinical trials reporting that ASA doses of <200 mg caused fewer major bleeding events, particularly gastrointestinal bleeding, compared with doses of >200 mg [17]. However, a metaregression study to test for a linear relation between daily dose of aspirin (ASA doses between 50 and 1500 mg/day) and risk of gastrointestinal haemorrhage was not significant [13]. Some observational studies examined the influence of different aspirin doses up to 325 mg daily on the risk of upper GI bleeding. The results of these studies were inconsistent. No evidence for a dose– response relation was reported by three studies [32,34,52], in contrast with four other observational studies clearly reporting an increased UGIB risk at higher aspirin doses [27,31,33,35]. In one study, increasing aspirin dosages of 100 mg/day, 200 mg/day, and 300 mg/day were associated with an increased UGIB risk of respectively 2.7 (95% CI, 2.0–3.6), 3.8 (95% CI, 2.7–5.2), 6.1 (95% CI, 4.3–8.7) compared to no aspirin use [33]. However, another study failed to show a clear relation between daily aspirin dose within the range 75–300 mg and the risk of UGIB. As compared to non-use of aspirin, aspirin dosages of 75 mg/day, 150 mg/day, and 300 mg/day were associated with an increased UGIB risk of respectively 1.9 (95% CI, 1.5–2.4), 2.1 (95% CI, 1.6–2.8), 1.9 (95% CI, 1.3–2.7) [32]. In a meta-analysis of randomized controlled trials by McQuaid et al. ‘low’ low-dose aspirin (75– 162.5 mg/day) was not associated with a protective effect compared with ‘high’ low-dose aspirin (>162.5–325 mg/day) [15]. Although these data are conflicting, the general recommendation is to prescribe the lowest, but effective, aspirin dose for primary or secondary prevention of cardiovascular events [23].

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(A-2) Aspirin duration The risk of UGIB associated with low-dose aspirin use is also likely to be maintained over time. One study assessed the risk of UGIB over time in users of all doses of aspirin (from 100 mg to >1 g per day) [33]. They found that the risk of UGIB was highest in patients who had been using aspirin for 31–90 days (OR, 15.8; 95% CI, 6.8–36.8) but that the risk of UGIB was still increased three-fold in patients who had been taking aspirin for more than one year (OR, 3.1; 95% CI, 2.5–3.8). The observation of a higher risk for upper gastrointestinal bleeding occurring in the first month after start of aspirin therapy has been confirmed by others [26,32,35]. Weil et al. found the risk almost five-fold increased in the first week of aspirin therapy (OR, 4.8; 95% CI, 2.9–7.9), and only three-fold after more than three months of aspirin use (OR, 3.2; 95% CI, 2.3–4.5) [35]. With longer therapy durations, the risk reduces and reaches a plateau at around six months to a year. This on one hand suggests that gastric adaptation to low-dose aspirin exposure does occur [32,53], but that there is still a risk of UGIB regardless of the duration of aspirin treatment. On the other hand, this phenomenon may be due to the so-called ‘depletion of susceptibles’, meaning that patients remaining on aspirin are those who tolerate it, while those who are susceptible for UGI bleeding discontinue aspirin treatment and thereby select themselves out of the population at risk. (A-3) Aspirin preparation A few observational case–control studies reported on the risk of UGIB associated with different preparations of low-dose aspirin [32,34,35,51]. Kelly et al. found the risk of UGIB as a whole to be similar in users of plain (OR, 2.6; 95% CI, 1.7–4.0), enteric-coated (OR, 2.7; 95% CI, 1.4–5.3) and buffered (OR, 3.1; 95% CI, 1.3–7.6) low-dose aspirin [51]. The risk of gastric bleeding was also similar across the three preparations. The risk of duodenal bleeding was significantly increased in users of plain low-dose aspirin (OR, 2.4; 95% CI, 1.2–4.6), but not in the smaller number of patients taking buffered (OR, 2.6; 95% CI, 0.7–9.9) or enteric-coated (OR, 2.6; 95% CI, 1.0–7.0) low-dose aspirin. Another study also found that UGIB rates were similar in individuals taking enteric-coated low-dose aspirin (standardized incidence rate [SIR], 2.6; 95% CI, 1.8–3.5) and in those taking uncoated low-dose aspirin (SIR, 2.6; 95% CI, 2.2–3.0) [34]. A study with the specific aim to understand whether the coating of aspirin modified the risk, reported, irrespective of aspirin dose, similar UGIB risk estimates for plain and coated aspirin preparations, respectively OR, 2.0; 95% CI, 1.6–2.4 and OR, 2.2; 95% CI, 1.5–3.2 [32]. This was supported by results of a meta-analysis of four studies [20]. Hence, no clear benefit of buffered or enteric-coated aspirin preparations is expected over plain aspirin preparations. (A-4) Aspirin regimen One study suggested that taking plain aspirin occasionally, defined as one–three days of use during the week, reduced the risk of upper gastrointestinal bleeding as compared to regular use (at least every alternate day) [51]. Summary of risk factors for UGIB among aspirin users After discussing all the separate risk factors which could play a role in the development of upper GI complications attributable to aspirin use, we categorized the risk factors as: definite, probable, controversial, or no risk factor. We summarized the evidence as follows (Table 1):

Definite risk factors There are consistent data to include the following factors as definite risk factors: (P-1) History of peptic ulcer disease or history of gastrointestinal bleeding; (P-3) Concomitant use with NSAIDs, including coxibs; (P-10) H. pylori infection; (A-2) Short aspirin duration.

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Probable risk factors There are no consistent data to include the following factors as definite risk factors, but some studies do suggest that they play a role in aspirin-induced gastropathy. Therefore, these variables are classified as probable risk factors: (P-4) (P-7) (P-7) (P-8) (P-8) (P-9) (A-1) (A-4)

Concomitant use of anticoagulants and other platelet aggregation inhibitors; Excessive alcohol use; High body mass; Concurrent use of corticosteroids; Concurrent use of calcium channel blockers; History of dyspepsia; High aspirin dose; Regular aspirin use.

Controversial risk factors The current belief is that the following risk factors are of importance for aspirin-related upper gastrointestinal bleeding, but they lack convincing evidence and are therefore classified as controversial risk factor: (P-2) Older age; (P-5) The presence of severe co morbidities.

No risk factors There are consistent data to exclude the following factors and are therefore classified as no risk factor: (P-6) Male gender; (P-7) Current smoking; (A-3) Plain aspirin preparation. In general, it should be acknowledged that the above mentioned risk factors only have an impact on the incidence of UGIB due to aspirin use when either the risk factor is very common amongst aspirin users and/or when the risk estimate for that risk factor is very substantial.

Practice points  Aspirin-related UGI risk factors include: a history of peptic ulcer disease or gastrointestinal bleeding, concomitant use with NSAIDs, including coxibs, H. pylori infection, and a short aspirin duration  Probable aspirin-related UGI risk factors include: concomitant use of anticoagulants and other platelet aggregation inhibitors, as well as corticosteroids and calcium channel blockers, excessive alcohol use, high body mass, a history of dyspepsia, high aspirin dose, and daily aspirin use  Male gender, current smoking and plain aspirin preparation do not influence the UGI risk of aspirin.

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Strategies to reduce aspirin-related UGI bleeding Some key strategies have been proposed to minimize the upper gastrointestinal adverse effects of low-dose aspirin. These strategies include reducing the modifiable risk factors, reduce aspirin dose, the use of co-therapy with a gastroprotective agent, and eradication of H. pylori infection. Reducing modifiable risk factors Some guidelines suggest to avoid aspirin use at all in high-risk users and to substitute aspirin with clopidogrel monotherapy as it is believed that the risk of GI bleeding with clopidogrel is lower than that with aspirin [54,55]. However, in the guideline on prevention of GI risks the use of an alternative platelet inhibitor (such as clopidogrel) is not a recommended strategy to reduce the risk of recurrent ulcer bleeding in high-risk patients as it is inferior as an UGIB prevention strategy to the combination of aspirin plus proton pump inhibitor (PPI) [23]. This is a similar advice as in the consensus recommendations on management of upper GI bleeding [56]. Guidelines do strongly suggest to avoid the combination of aspirin and NSAIDs and thereby decrease the risk of aspirin-related GI harm [23,57]. A similar strategy to avoid other concurrent medication is not specifically mentioned in the guidelines, but does of course apply for other medications such as corticosteroids or calcium channel blockers, with which aspirin may have an increased risk of developing UGI bleedings. The guidelines recommend against treatment with enteric-coated or buffered aspirin rather than plain aspirin as a preventive strategy [23]. Reduce aspirin dose Guidelines agree that the lowest possible doses of aspirin should be prescribed to reduce the potentially increased risk of UGIB associated with dose escalation. Maintenance treatment of ASA 75– 100 mg/day is recommended for patients with non-ST-segment elevation acute coronary syndromes [55,57]. The US guideline on reducing the GI risks of antiplatelet therapy also recommend that doses greater than 81 mg/day of ASA should not be used routinely [23]. Only the ACCF/AHA guideline by Anderson et al. concerning the treatment of patients with unstable angina or non-ST-segment elevation myocardial infarction, recommend prescription of aspirin up to dosages to 162 mg per day indefinitely [54]. Co-therapy with a gastroprotective agent Several guidelines advice concomitant gastroprotection to prevent gastrointestinal complications due to low-dose aspirin [23]. In the US guideline, patients at risk for upper gastrointestinal events during aspirin use are defined as those with a history of peptic ulcer disease, elderly patients, and patients using NSAIDS or antithrombotic agents. In addition, a very recent European guideline on the management of patients with acute coronary syndrome without ST-segment elevation recommends the use of a proton pump inhibitor in combination with dual (oral) antiplatelet therapy in patients with a history of gastrointestinal haemorrhage or peptic ulcer, and also as appropriate for use in patients with multiple other risk factors (H. pylori infection, age 65 years, concurrent use of anticoagulants or steroids) [57]. This new European guideline did not address gastroprotective strategies in patients on aspirin alone, but only for those on dual antiplatelet therapy, and only if they have additional risk factors as mentioned before. There is a rather large gap between these two guidelines in their recommendations towards patients on dual oral antiplatelet therapy. According to the US guideline, every patient on dual oral antiplatelet therapy should receive gastroprotection (preferably a proton-pump inhibitor) irrespective of additional risk factors, as the second antiplatelet agent is already considered as a sufficient risk factor to justify PPI use [23]. In contrast, according to the European guideline, only patients on dual antiplatelet therapy with additional risk factors should receive a PPI [57].

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In case of uncertainty whether to co-prescribe a gastroprotective agent to a potential at-risk aspirin user, the physician should co-prescribe a proton pump inhibitor to reduce UGI harm. However, the potential adverse events associated with PPI therapy should not outweigh the benefits for the individual person in terms of (the generally small) risks for hypomagnesaemia, osteoporosis, pneumonia, or infection with Clostridium difficile. In spite of these clear recommendations, appropriate adherence to guidelines-supported advice remains low in daily clinical practice for NSAID users [58]. Although extensive data are available on the use of preventive strategies in NSAID users, little is known concerning the likelihood of adequate adherence to gastroprotective agents in at-risk low-dose aspirin users. However, similar as for NSAID use, adherence to the guideline is perceived to be low in aspirin users. The importance of adequate adherence to gastroprotective agents should be underlined, as a recent study showed that the risk of UGI events was significantly higher in NSAID users with non-adherence to gastroprotection compared to patients fully adherent to gastroprotective agents [59]. Eradication of H. pylori infection If a patient has had a previous history of ulcer disease (bleeding or non-bleeding) this patient should be tested for H. pylori infection and treated before aspirin therapy is initiated [23]. Despite successful eradication of H. pylori, gastroprotection with PPI is still strongly recommended together with aspirin use.

Practice points To prevent upper gastrointestinal harm related to aspirin use:  Physicians should not prescribe aspirin dosages of more than 100 mg/day for prevention of cardiovascular disease.  Avoid the combination of aspirin and NSAID use.  Co-prescribe proton pump inhibitors to at-risk aspirin users (e.g. patients with history of peptic ulcer disease or history of gastrointestinal bleeding, concomitant use with NSAIDs, including coxibs).  Test and treat for H. pylori infection in a patient with a previous history of ulcer disease.

Summary Aspirin use is the cornerstone of antiplatelet therapy for preventing and treating vascular events. In spite of the harms associated with aspirin use, especially in the gastrointestinal tract, the benefitto-risk ratio is favourable for considerable categories of patients. Patients on low dose aspirin are at increased for gastrointestinal complications, in particular gastroduodenal ulcer disease and its complications, such as upper gastrointestinal bleeding. Physicians need to co-prescribe gastroprotective agents, with proton pump inhibitors being the preferred agents, especially to those with the following underlying gastrointestinal risk factors: (1) a history of peptic ulcer disease or gastrointestinal bleeding, (2) concomitant use with NSAIDs, including coxibs, or (3) patients with H. pylori infection. In addition, a test for H. pylori and subsequent eradication must be considered in patients with a history of peptic ulcer disease. This review focused on the evidence for upper gastrointestinal risk factors in aspirin users and found that male gender, current smoking and plain aspirin preparation are no aspirin-related UGI risk factors. Although the current belief is that older age and the presence of severe co morbidities are of importance for aspirin-related upper gastrointestinal bleeding, convincing evidence is lacking and are therefore classified as controversial risk factors.

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Research agenda  Detailed studies are necessary to clarify what are the most important risk factors in aspirin users.  Studies should focus on co-morbidity in aspirin users and carefully define this concept.  Further studies should not neglect the fact that lower gastrointestinal bleedings are important to report as well, but should clearly specify the location of the bleed and thus separate upper versus lower GI bleeding.  Due to the analogy with NSAID risk factors, concomitant use of selective serotonin re-uptake inhibitors (SSRIs) and spironolactone should be studied in low-dose aspirin users as potential UGI risk factors.

Role of the funding source No sources of funding. Conflict of interest Vera Valkhoff, as employee of the Erasmus MC, has conducted research for AstraZeneca. Miriam Sturkenboom is head of a unit that conducts research for pharmaceutical companies: Pfizer, Lilly, AstraZeneca and Altana. She has also acted as a consultant for Pfizer and Lundbeck. Ernst Kuipers has served as a consultant and advisory board member for AstraZeneca. Acknowledgements None. References [1] Sprigg ER, Fleming KM, Logan RFA. Is low dose aspirin use associated with iron deficiency anaemia? An analysis of data from the Health Survey for England 2006. Gut 2009;58(Suppl II). A91. [2] McKenna MT, Michaud CM, Murray CJ, Marks JS. Assessing the burden of disease in the United States using disabilityadjusted life years. Am J Prev Med 2005;28:415–23. [3] Baigent C, Sudlow C, Collins R, Peto R. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86. [4] Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research Group. N Engl J Med 1989;321:129–35. [5] Swedish Aspirin Low-Dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events. The SALT Collaborative Group. Lancet 1991;338:1345–9. [6] Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey Jr DE, et al. American College of Cardiology (ACC)/ American Heart Association (AHA) 2007 guidelines for the management of patients with unstable angina/non STelevation myocardial infarction: a report of the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation 2007;116: e148–304. [7] Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373: 1849–60. [8] Gao R, Li X. Risk assessment and aspirin use in Asian and Western populations. Vasc Health Risk Manag 2010;6:943–56. [9] Smecuol E, Pinto Sanchez MI, Suarez A, Argonz JE, Sugai E, Vazquez H, et al. Low-dose aspirin affects the small bowel mucosa: results of a pilot study with a multidimensional assessment. Clin Gastroenterol Hepatol 2009;7:524–9. [10] Fortun PJ, Hawkey CJ. Nonsteroidal antiinflammatory drugs and the small intestine. Curr Opin Gastroenterol 2005;21: 169–75. [11] Rockall TA, Logan RF, Devlin HB, Northfield TC. Incidence of and mortality from acute upper gastrointestinal haemorrhage in the United Kingdom. Steering Committee and members of the National Audit of Acute Upper Gastrointestinal Haemorrhage. BMJ 1995;311:222–6.

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