Aspirin and NSAIDs; benefits and harms for the gut

Aspirin and NSAIDs; benefits and harms for the gut

Best Practice & Research Clinical Gastroenterology 26 (2012) 197–206 Contents lists available at SciVerse ScienceDirect Best Practice & Research Cli...

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Best Practice & Research Clinical Gastroenterology 26 (2012) 197–206

Contents lists available at SciVerse ScienceDirect

Best Practice & Research Clinical Gastroenterology

9

Aspirin and NSAIDs; benefits and harms for the gut Prarthana Thiagarajan, MBBS (Lond), BSc (Lond) a, **, Janusz A. Jankowski, MSc (Oxon), MD (Dund), PhD (Lond), FRCP (Lond), Professor b, c, d, * a

Department of Emergency Medicine, Balmoral Building, Leicester Royal Infirmary, London LE1 5WW, UK Digestive Disease Centre, Level 4, Windsor Building, Leicester Royal Infirmary, London LE1 5WW, UK Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK d Centre for Digestive Diseases, Queen Mary University of London, London E1 7AT, UK b c

Keywords: Oesophageal cancer Colorectal cancer Chemoprevention

Despite modern advances in cancer research, screening and treatment options, gastrointestinal tumours remain a leading cause of death worldwide. Both oesophageal and colorectal malignancies carry high rates of morbidity and mortality, presenting a challenge to clinicians in search of effective management strategies. In recent years, the increasing burden of disease has led to a paradigm shift in our approach from treatment to prevention. Among several agents postulated as having a chemopreventive effect on the gastrointestinal tract, aspirin has been most widely studied and has gained universal acknowledgement. There is an expanding evidence base for aspirin as a key mediator in the prevention of dysplastic change in Barrett’s oesophagus and colorectal adenomas. Its cardioprotective effects also impact positively on the patient population in question, many of whom have ischaemic vascular disease. The major side effects of aspirin have been well-characterised and may cause significant morbidity and mortality in their own right. Complications such as peptic ulceration, upper gastrointestinal bleeding and haemorrhagic stroke pose serious threats to the routine administration of aspirin and hence a balance between the risks and benefits must be struck if chemoprevention is to be effective on a large scale. In this review, we address the current

* Corresponding author. Digestive Disease Centre, Level 4, Windsor Building, Leicester Royal Infirmary, London LE1 5WW, UK. ** Corresponding author. E-mail addresses: [email protected] (P. Thiagarajan), [email protected] (J.A. Jankowski). 1521-6918/$ – see front matter Ó 2012 Published by Elsevier Ltd. doi:10.1016/j.bpg.2012.01.007

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evidence base for aspirin use in gastrointestinal oncology, as well as several key questions surrounding its safety, cost effectiveness and optimal dose. Ó 2012 Published by Elsevier Ltd.

Introduction Tumours of the gastrointestinal (GI) tract dominate cancer demographics worldwide. Colorectal cancer (CRC) is the third most common malignancy, with approximately 1 million new cases diagnosed in 2008 [1]. The majority of disease burden occurs in Western nations (60% of cases diagnosed in 2008), where CRC is associated with substantial morbidity, impacting on quality of life though treatment and progression of the disease [2]. Oesophageal cancer currently ranks as the 8th most common malignancy worldwide. Its two histological subtypes, squamous cell carcinoma and adenocarcinoma, have different aetiological mechanisms and demographics. Alarmingly, the incidence of oesophageal adenocarcinoma is rising exponentially in Western nations, with the United Kingdom having the highest reported incidence of adenocarcinoma worldwide [3,4]. This is likely to be secondary to lifestyle factors such as diet and obesity, leading to an increased incidence of symptomatic acid reflux and ultimately, the premalignant condition Barrett’s oesophagus. Diagnosis usually occurs late, with either locally advanced disease or distant metastases. Prognosis for oesophageal adenocarcinoma remains worryingly bleak and has changed little over the last four decades; it is an aggressive malignancy with a 5-year survival rate of 10–15% [5]. Whilst rapid advances in the fields of molecular biology, cancer genetics and medical technology have improved our understanding of carcinogenesis, and provided valuable tools with which to detect malignant change through endoscopic surveillance, the rising burden of GI malignancies warrants consideration of alternative strategies to tackle the problem. In recent years, the concept of chemoprevention has gained increasing popularity. The ability to perform regular endoscopic surveillance on high-risk populations affords a window of opportunity in which to implement preventative strategies prior to dysplastic change. Several agents have been suggested as having potentially chemopreventive effects on the gastrointestinal mucosa. Amongst these, non-steroidal anti-inflammatory drugs (NSAIDs) and in particular aspirin, have been studied most extensively. The ability of aspirin to decrease the development of, and mortality from, GI malignancies is gradually becoming clear from clinical trials and observational studies. This review focuses on the current evidence for use of aspirin as a chemopreventive agent in GI cancers. Amongst all NSAIDs, it is the most widely used and its side effect profile is therefore well established, whereas those of other NSAIDs are likely to be more heterogeneous. It is widely available, cheap and acceptable to patients; all features which could support its routine administration on a global scale. We examine the available evidence for benefit of regular aspirin use in colorectal and oesophageal malignancies, and aim to shed light on important questions such as optimal dose, costeffectiveness and the side effects of long-term aspirin therapy. Aspirin – overview and scope in chemoprevention Aspirin, the archetypal non-steroidal anti-inflammatory drug (NSAID), is the most widely consumed drug in the world [6]. Its diverse pharmacological actions arise mainly as a result of irreversible inhibition of the cyclo-oxygenase (COX) enzyme, thus preventing the biosynthesis of prostaglandins and thromboxanes from arachidonic acid. The cardioprotective properties of aspirin are well established; indeed it forms the cornerstone of primary and secondary prevention in ischaemic vascular disease though inhibition of platelet aggregation. In gastroenterology, a wealth of emerging research suggests a potential key role for aspirin and selective COX-2 inhibitors in prevention of oesophageal and colorectal malignancies. Results from recent meta-analyses have fuelled further enthusiasm for this paradigm, estimating that long-term aspirin use may reduce the incidence of gastrointestinal cancers by up to 30% [7].

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Barrett’s oesophagus Several clinical trials and population-based observational studies have focused on the effect of longterm aspirin use on malignant transformation in Barrett’s oesophagus, demonstrating statistically significant reductions in progression to both squamous carcinoma and adenocarcinoma [8–10]. So far, best evidence is derived from meta-analyses of cohort and case–control studies and high-quality data from large scale, multicentre randomised controlled trials is lacking. Colorectal cancer In colorectal cancer, there is little doubt as to the chemoprotective effect of long-term aspirin use. Observational studies and pooled analyses of RCTs have consistently demonstrated a reduction in recurrence of adenomatous polyps, as well as effectiveness of aspirin in primary prevention of colonic neoplasia in both high-risk and general populations [11–13]. Side effects, safety and economic considerations Whilst there is good evidence to support long-term aspirin use in chemoprevention of gastrointestinal tumours, the well-recognised side effect profile of NSAIDs presents a major drawback to their routine administration. In particular, the risks of upper gastrointestinal bleeding, peptic ulceration and haemorrhagic stroke must be addressed if the paradigm of primary prevention is to become regular and safe clinical practice [14]. Many approaches to reduce harmful side effects of regular aspirin are under investigation, including co-administration with proton pump inhibitors (PPIs), histamine-2 receptor antagonists, prostaglandin analogues and Helicobacter pylori eradiation [15]. Other factors such as economic feasibility, patient acceptance, optimal dosage and the potential for aspirin resistance also warrant further consideration and analysis. Targeting higher-risk individuals (e.g. those with highgrade dysplasia in Barrett’s oesophagus) may provide a means of minimising harmful side effects whilst maximising cost-effectiveness. AspECT trial The on-going Aspirin Esomeprazole Chemoprevention Trial (AspECT) is a large, multicentre phase III randomised controlled trial (RCT) which aims to answer many of the questions and uncertainties remaining with regards to aspirin use in chemoprevention in Barrett’s oesophagus. It is hoped that results from this trial will provide the quantitative data needed to advance decision-making in clinical practice, and clarify the role of aspirin and PPIs in gastrointestinal chemoprevention. Side effects of long-term aspirin use Upper gastrointestinal haemorrhage Gastrointestinal (GI) bleeding is perhaps the most notorious complication of long-term aspirin use. This is thought to occur via inhibition of the COX-1 enzyme, thereby reducing synthesis of prostaglandins, which protect the gastric mucosa from acid-induced damage. A recent meta-analysis of 35 randomised controlled trials demonstrated an increased risk of major GI haemorrhage in subjects using low-dose aspirin alone (75–325 mg/day) compared with placebo (odds ratio (OR) 1.55). This decreased significantly in patients taking regular PPI therapy in combination with lowdose aspirin (OR 0.34) [16]. Whilst some studies have shown no dose-dependent between aspirin and risk of gastrointestinal side effects, recent work by Huang and colleagues followed up approximately 87,700 patients, demonstrating that the multivariate relative risk (RR) of GI bleeding was directly related to frequency of aspirin use (RR 1.30 in patients using 1  325 mg tablet/week, compared with RR 2.24 for patients using 14 tablets/week, p < 0.01) [17]. The risk of GI haemorrhage increases with age in the general population; so too does the risk of Barrett’s oesophagus and colonic neoplasia [15].

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COX-2 inhibitors The advent of selective COX-2 inhibitors, such as celecoxib, was heralded as a potential solution to prevent the deleterious gastric effects of aspirin and other non-selective NSAIDs. Unfortunately these agents have been associated with serious cardiovascular consequences (myocardial infarction and ischaemic stroke) compared with standard NSAIDs, and their popularity has declined dramatically [18,19]. Intracranial haemorrhage Haemorrhagic stroke is another feared consequence of long-term NSAID use, with studies reporting an increased incidence in populations taking aspirin for primary or secondary prevention of occlusive vascular events [20]. There is also evidence that preceding regular aspirin use increases overall mortality from intracranial haemorrhage due to rapid haematoma enlargement [21]. A meta-analysis of 50 trials analysing 338,191 patients sought to assess the risk of bleeding complications associated with use of antiplatelet agents in patients with acute coronary syndromes [22]. Results demonstrated that whilst low-dose aspirin (75–325 mg/day) was associated with lower bleeding risks compared with other NSAIDs, there was nevertheless a dose-dependent relationship in the incidence of haemorrhagic stroke (0.3% in patients taking low-dose aspirin, compared with 1.1% in patients taking >325 mg/day). Macular degeneration There have been reports of an association between regular aspirin use and development of agerelated macular degeneration (AMD). A recent European population-based cross-sectional study of approximately 4700 patients showed a dose-dependent increase in the development and severity of early and late wet AMD amongst patients taking regular aspirin (OR 2.22 for daily users) [23]. However, a double-blind RCT including over 39,000 female health professionals who were randomly allocated to receive low-dose (100 mg/day) aspirin or placebo demonstrated no significant difference in the risk of AMD after 10 years of treatment [24]. Aspirin-exacerbated asthma Aspirin is known to precipitate bronchospasm in patients with asthma. Aspirin-exacerbated asthma (AEA) is a well-recognised phenotype, whose prevalence in asthmatic populations has been reported to be as high as 21% [25]. Aspirin is thought to induce bronchospasm through COX-1 inhibition and its effects in asthma may be severely debilitating. Treatment involves avoidance of aspirin-containing compounds, inhaled corticosteroids and leukotriene antagonists. Methods to suppress the hypersensitivity response include aspirin desensitisation, a concept which has gained increasing popularity in recent years. Patients are given incremental doses of aspirin on a daily basis in an attempt to desensitise mediators of hypersensitivity. This has been reported to be an effective technique, with a success rate of 89% in one recent retrospective analysis [26]. Aspirin desensitisation may merit consideration in patients with poorly controlled symptoms despite optimal treatment, who require aspirin due to concomitant cardiovascular disease or arthritis [27]. Aspirin-induced urticaria and angioedema Aspirin and other non-selective NSAIDs may provoke a range of hypersensitivity reactions in susceptible individuals. Again, the proposed mechanism is COX-1 inhibition leading to excess production of leukotrienes. Clinical manifestations include cutaneous urticaria, rhinosinusitis and angioedema. The prevalence of aspirin-associated urticaria in the general population has been reported to be 0.3% [28]. In contrast, up to one-third of individuals with pre-existing chronic urticaria experience exacerbations with aspirin or other NSAIDs [29,30]. Management consists of avoiding aspirin and other NSAIDs, along with antihistamine therapy in some instances. Again, aspirin

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desensitisation may be of benefit in and is worth considering particularly in subjects with cardiovascular disease for whom aspirin is extremely protective against thrombosis. In a recent retrospective study of 76 patients with NSAID-induced urticaria and angioedema, the authors reported that the selective COX-2 inhibitors meloxicam and celecoxib were well tolerated and did not reproduce symptoms [31]. Cautions in extremes of age Aspirin is generally contraindicated in children and adolescents under the age of 16 due to reports of a causal association with Reye’s syndrome. This is an acquired acute metabolic encephalopathy, with hepatic dysfunction and long-term neurological sequelae. It was originally reported in children taking aspirin following viral illness, but has since been linked to inborn errors of metabolism including defective mitochondrial oxidation of long-chain fatty acids. Nevertheless, the incidence of Reye’s syndrome has fallen significantly since cessation of aspirin use in children [32]. As a group, NSAIDs have fallen out of favour for use in elderly patients due to their potential to cause acute renal failure and interstitial nephritis. One recent cohort study of 106 elderly inpatients reported a significant deterioration in renal function after 2 weeks of low-dose (100 mg/day) aspirin therapy (4% increase in creatinine concentration, p < 0.05) [33]. Renal function improved after aspirin withdrawal, suggesting a causative effect. The risk of other aspirin-related side effects, such as GI haemorrhage, also increases with advancing age. For these reasons, regular aspirin use in elderly populations is avoided. If required for cardioprotection or arthritis, extreme caution and regular monitoring of renal function is advised. Hepatic dysfunction Hepatotoxicity is a rare complication of NSAID use, and reportedly occurs within 12 weeks of commencing therapy [34]. Although more strongly associated with diclofenac and sulindac, aspirin may nevertheless induce hepatocellular dysfunction and is an important complication to consider, especially in patients with pre-existing liver disease. Reported incidence of NSAID-induced liver damage ranges from 3 to 23 per 100,000 patient years [35]. This may present acutely with fulminant hepatic failure, or may pursue an insidious course in which patients are asymptomatic but have biochemical and histological features of chronic active hepatitis [34]. It is thought that NSAIDs exert this effect through uncoupling of mitochondrial oxidative phosphorylation, ultimately leading to acute hepatocyte injury [36]. Whilst management would generally consist of discontinuing NSAID treatment, O’Connor and colleagues suggest that aspirin may be safely used in patients with documented hepatotoxicity from other NSAIDs, as it is structurally different and less likely to cause damage at antiplatelet doses (75–300 mg/day) [35]. Drug interactions Principal drug interactions are outlined in Table 1. Patients with Barrett’s metaplasia or colonic neoplasms, who would be targeted for GI chemoprevention, often have comorbidities. In particular, many cardioprotective and anticoagulant drugs interact with aspirin. It is important for clinicians dealing with these patients to be aware of the major drug classes which interact with aspirin and monitor patients regularly for any adverse effects. Minimising NSAID-induced GI toxicity Several methods have been postulated to minimise the side effects of long-term aspirin therapy, including concomitant PPI use, H. pylori eradication and use of prostaglandin analogues. Yeomans and colleagues (2008) conducted a multicentre RCT in which patients taking standard dose aspirin (75– 325 mg/day) were randomised to receive either esomeprazole 20 mg/day or placebo [37]. The incidence of gastric or duodenal ulceration at 26 weeks was 5.4% in the placebo group versus 1.6% in the

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Table 1 Aspirin drug interactions. Drug ACE inhibitors/angiotensin-2 receptor antagonists NSAID analgesics Anticoagulants Antidepressants Antiepileptics Clopidogrel Corticosteroids Cytotoxics Diuretics

Interaction with aspirin            

Risk of renal impairment Hypotensive effect antagonised Increased side effects Increased bleeding risk with warfarin Enhances anticoagulant effect of heparins Increased bleeding risk with SSRIs or venlafaxine Enhanced effect of phenytoin and sodium valproate Increased bleeding risk Increased risk of peptic ulceration and GI haemorrhage Corticosteroids decrease plasma salicylate levels Reduced excretion of methotrexate Effect of spironolactone antagonised by aspirin

Source: British Medical Association and the Royal Pharmaceutical Society of Great Britain. British National Formulary. 58th ed. UK: BMJ Publishing Group. 2009.

esomeprazole group (p ¼ 0.0007). In addition, patients taking esomeprazole reported significantly fewer symptoms such as dyspepsia and epigastric pain (p < 0.05). H. pylori eradication has been reported to reduce the incidence of gastroduodenal ulceration and symptoms in patient populations taking long-term NSAIDs. A meta-analysis of 5 studies including 939 patients reported a 5.9% reduction in ulcer development in patients randomised to receive H. pylori eradication versus placebo (or 0.43) [38]. The analysis also demonstrated that maintenance PPI therapy was superior to eradication therapy alone (OR 7.43). Conversely, de Leest and colleagues (2007) reported no significant difference in the development of gastroduodenal erosion, dyspepsia or quality of life in H. pylori positive subjects taking long-term NSAIDs who were randomised to receive eradication therapy or placebo (p ¼ 0.65) [39]. These conflicting reports indicate that further high-quality clinical trials are needed to clarify the role of eradication therapy in patients requiring long-term treatment with aspirin and other NSAIDs. Misoprostol, an analogue of prostaglandin E, has been shown to be effective in reducing the risk of gastropathy in patients taking long-term NSAIDs for osteoarthritis [40]. However, compliance with misoprostol is problematic due to the relatively frequent occurrence of side effects such as nausea, abdominal pain and diarrhoea. Recent work by Lee and colleagues compared the gastroprotective effect of a novel antioxidant (DA-9601) with misoprostol, demonstrating similar efficacy in prevention of gastroduodenal toxicity, but superiority in side effect profile and therefore patient acceptability [41]. The authors recommend treatment with DA-9601 in patients taking long-term NSAIDs for prevention of GI toxicity. What is the optimal dose of aspirin for GI chemoprevention? Speculation remains as to the risk–benefit ratio of long-term aspirin use, and the optimal dose required for effective chemoprevention whilst minimising side effects is unknown. Until recently, results from various studies have indicated that high-dose aspirin (>500 mg/day) may confer stronger protection than standard dose regimens. However, recent work by Rothwell and colleagues (2010) challenged this notion, providing evidence for the use of low-dose aspirin in preventing colorectal cancer [42]. The group followed up four RCTs evaluating aspirin versus placebo in the primary and secondary prevention of occlusive vascular events, and focused on the effect of aspirin at varying doses on the incidence of colorectal cancer over a 20-year follow-up period. Meta-analysis of approximately 14,000 participants revealed that allocation to aspirin reduced the 20-year risk of colonic malignancy (Hazard ratio (HR) 0.76, p ¼ 0.02). This effect was most pronounced for proximal colonic neoplasms, with a 70% risk reduction observed after 5 years of treatment. Reduction in mortality from colorectal cancer was also greater than the reduction in incidence. Interestingly, aspirin doses of 75 mg/day were shown to be as effective as higher doses and no increased benefit was observed in patients taking doses of aspirin >75 mg/day. However, very low doses of aspirin (e.g. 30 mg/day) were associated with

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Table 2 Summary of aspirin chemoprevention in GI cancers. Advantages

Major side effects

Chemoprevention efficacy (20–30%) Economically feasible (£4/year) Cardioprotective of MIs (20%) Acceptable to patients (>80%)

Severe dyspepsia or heartburn (0.5–2%/year) Gastrointestinal bleeding (0.1–2%/year) Allergy or intolerance (2–5% on initiation) Haemorrhagic stroke (0.2%/year)

a higher risk of fatal colorectal cancer than higher doses. In conclusion, the group observed an absolute risk reduction in colorectal malignancy of approximately 1.5% after a 5-year period of treatment with at least 75 mg aspirin. Burn and colleagues recently published results from the Cancer Prevention Programme 2(CAPP2) study, a double-blind RCT in which 861 carriers of Lynch syndrome were randomly allocated to receive 600 mg aspirin/day or aspirin placebo [43]. The group demonstrated a statistically significant reduction in cancer incidence after 55.7 months mean follow-up in the group allocated to receive aspirin (HR 0.65, p ¼ 0.05). This trial did not establish the optimal dose or duration of aspirin therapy for chemoprevention, which will be assessed in the forthcoming CAPP3 study. Is aspirin chemoprevention economically justified? Cost-effectiveness of aspirin, either alone or in combination with endoscopic surveillance, is of vital importance if it is to have a global impact on chemoprevention of GI malignancies. Although not proven to be cost effective in the general population, aspirin chemoprevention has been shown increase years of life saved in populations with prior colonic adenomas, both alone and in combination with colonoscopy surveillance [44]. Squires et al (2011) estimated an incremental cost of £23,000 per quality adjusted – life year (QALY) gained with aspirin chemoprevention when combined with screening in the general population aged 50–60 years. The authors suggest that this would constitute an acceptable cost-effectiveness profile for intermediate and high-risk populations, but less so for the general population [45]. Aspirin chemoprevention has also been studied in the context of Barrett’s oesophagus, and appears to be cost-effective with an increase of 0.19 QALYs with aspirin alone, and 0.27 QALYS when combined with endoscopic surveillance [46].

Fig. 1. Four estimates of aspirin safety. (A) Serious adverse events (SAEs) reported prior to 2010 (red). (B) Serious adverse events (SAEs) reported 2010 onwards (yellow). (C) Serious adverse events (SAEs) unreported from AspECT trial (green). (D) Serious adverse events (SAEs) reported from all trials in patients >70 years of age (light blue). (E) The chemoprevention benefits of aspirin in the will take at least 10 years (hatched blue line). Therefore arguably the risk benefit of aspirin may not be apparent until at least 6 years after initiation.

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AspECT trial The AspECT trial is the largest RCT investigating the effect of aspirin, alone or in combination with PPI therapy, in chemoprevention of malignant transformation in Barrett’s metaplasia. Patients with confirmed Barrett’s oesophagus were randomised in 2  2 design to receive high-dose (80 mg/day) or low dose (20 mg/day) esomprazole, plus either low-dose aspirin (300 mg/day), or no aspirin. The primary end points studied include all-cause mortality, as well as any reduction in development of high-grade dysplasia or oesophageal adenocarcinoma [15]. The trial finished recruiting in February 2009, with a total of 2513 patients. It is expected to end in 2019, with interim results to be reported in 2013. Preliminary analysis by Das and colleagues (2009) indicated that over 85% of patients initially recruited remained stable on their randomised medications, with an overall dropout rate of 7% [47]. Results from the AspECT trial are keenly awaited, and may provide robust, quantitative data with which to direct clinical practice and establish the role of chemoprevention in oesophageal malignancies.

Practice points  The incidence of gastrointestinal cancers continues to rise worldwide, carrying significant morbidity and mortality despite novel therapeutic advances.  The aggressive nature and bleak prognosis of oesophageal adenocarcinoma has led to a paradigm shift in clinical focus from treatment towards prevention.  There is increasing evidence to suggest a beneficial role for aspirin and other NSAIDs in chemoprevention of GI malignancies. This is a desirable option especially in those patients with concomitant cardiovascular disease.  The putative benefits of aspirin and other NSAIDs must be weighed against their side effects, some of which are potentially life threatening.  Daily use of aspirin in GI chemoprevention appears to be economically justifiable in high-risk populations  Results from the AspECT trial will help to direct future clinical practice by establishing the role of chemoprevention in oesophageal cancers.

Research agenda  Establish the optimal dose of aspirin required for effective chemoprevention (CAPP3 study)  Establish the effect of aspirin plus PPI therapy in prevention of dysplastic change in patients with Barrett’s metaplasia (AspECT trial)  Identify an appropriate target population for chemoprevention, in order to maximise clinical and economic benefits from this intervention and minimise side effects.

Conclusion The emergence of aspirin and other non-steroidal agents as key mediators in gastrointestinal chemoprevention is exciting. That the incidence of colorectal cancer and oesophageal cancer continues to rise worldwide, despite advances in medical and surgical interventions, is alarming and mandates a shift in focus of clinical practice from treatment to prevention. A wealth of evidence is building to suggest that aspirin has clinically significant effects in reducing both the incidence of, and mortality from, gastrointestinal malignancies. Many of the patient groups targeted in GI chemoprevention also suffer cardiovascular disease and may merit regular aspirin therapy in this context. However, the putative benefits must be weighed

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against the risk of potentially life-threatening complications such as gastrointestinal bleeding, peptic ulceration and haemorrhagic stroke (Table 2). Crucial to this risk–benefit analysis is an accurate understanding of optimal aspirin dose as well as target populations. Recent advances in our understanding of these parameters will help to guide clinical application of chemoprevention, and tailor therapy towards those individuals who are at high risk (Fig. 1). The demographics of GI malignancies suggest a window of benefit from ages 55 to 75 years. Before 55 years of age, the incidence of Barrett’s oesophagus and colonic neoplasia is low. Above 75 years of age, the risks of aspirin side effects are likely to outweigh potential benefits of chemoprevention, as a minimum of 5–10 years is required for aspirin to exert an anti-tumour effect. However, further large, high-quality trials are needed before chemoprevention can become licensed for routine practice in gastroenterology. Funding Cancer Research UK and Wellcome Trust. Conflict of interest Professor Janusz Jankowski is the chief investigator for the Aspirin Esomeprazole Chemoprevention (AspECT) trial. Author contribution The contributions of the authors to the manuscript are as follows: JJ: idea, PT and JJ: writing, PT and JJ: proof reading. Acknowledgements The authors would like to thank Dr Nicola Burch, consultant gastroenterologist, Walsgrave Hospital, Coventry, United Kingdom, for providing specialist advice and support in the production of this review article. We also thank Sharon Love of the AspECT data monitoring committee. References [1] http://info.cancerresearchuk.org/cancerstats/world/colorectal-cancer-world/ [accessed 30.11.11]. [2] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008 v1.2, cancer incidence and mortality worldwide. Available from:. IARC CancerBase No. 10 Internet Lyon, France: International Agency for Research on Cancer http://globocan.iarc.fr; 2010 www.cancerresearchuk.org; 2010 [accessed 30.11.11]. [3] Holmes RS, Vaughan TL. Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol 2007;17:2–9. [4] Bollschweiler E, Wolfgarten E, Gutschow C, Hölscher AH. Demographic variations in the rising incidence of esophageal adenocarcinoma in white males. Cancer 2001;92(3):549–55. [5] Crane SJ, Locke 3rd GR, Harmsen WS, Zinsmeister AR, Romero Y, Talley NJ. Survival trends in patients with gastric and esophageal adenocarcinomas: a population-based study. Mayo Clin Proc 2008 Oct;83(10):1087–94. [6] Fuster V, Sweeny J. Contemporary reviews in cardiovascular medicine. Circulation 2011 Feb 22;123(7):768–78. [7] Jankowska H, Hooper P, Jankowski JA. Aspirin chemoprevention of gastrointestinal cancer in the next decade. A review of the evidence. Pol Arch Med Wewn 2010 Oct;120(10):407–12. [8] Gonzalez-Perez A, Garcia Rodriguez LA, Lopez-Ridaura R. Effects of nonsteroidal anti-inflammatory drugs on cancer sites other than the colon and rectum: a meta-analysis. BMC Cancer 2003;3:28. [9] Vaughan TL, Dong LM, Blount PL, et al. Non-steroidal anti-inflammatory drugs and risk of neoplastic progression in Barrett’s oesophagus: a prospective study. Lancet Oncol 2005;6:945–52. [10] Farrow DC, Vaughan TL, Hansten PD, et al. Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev 1998;7:97–102. [11] Asano TK, McLeod RS. Non steroidal anti-inflammatory drugs (NSAID) and aspirin for preventing colorectal adenomas and carcinomas. Cochrane Database Syst Rev 2004;2:CD004079. [12] Grau MV, Sandler RS, McKeown-Eyssen G, Bresalier RS, Haile RW, Barry EL, et al. Nonsteroidal anti-inflammatory drug use after 3 years of aspirin use and colorectal adenoma risk: observational follow-up of a randomized study. J Natl Cancer Inst 2009 Feb 18;101(4):267–76. [13] Flossmann E, Rothwell PM. British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007 May 12;369(9573):1603– 13.

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