Should aspirin and PPIs be recommended for patients with Barrett's oesophagus?
Authors: Frederik Hvid-Jensen, Asbjørn Mohr Drewes
Journal: The Lancet (2018)

During the past two decades, beneficial effects from aspirin, statins, and non-steroidal anti-inflammatory drugs (NSAIDS) have been observed in epidemiological studies, initially as preventive medicine for cardiovascular disease. Protective effects have also been seen against several cancer types, including malignancies of the gastrointestinal tract. This protection was first described for colorectal cancer and later also for oesophageal adenocarcinoma.1Rothwell PM Wilson M Elwin CE et al.Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials.Lancet. 2010; 376: 1741-1750Summary Full Text Full Text PDF PubMed Scopus (1056) Google Scholar The incidence of oesophageal adenocarcinoma has increased by ten times during the past 40 years. Despite strenuous endoscopic surveillance and local treatment regimens, its incidence is still increasing and 5 year survival is less than 25%.2Njei B McCarty TR Birk JW Trends in esophageal cancer survival in United States adults from 1973 to 2009: a SEER database analysis.J Gastroenterol Hepatol. 2016; 31: 1141-1146Crossref PubMed Scopus (181) Google Scholar Prevention—if possible—is therefore extremely relevant in patients with Barrett's oesophagus, a premalignant condition that often precedes oesophageal adenocarcinoma. Several case-control studies have explored chemoprophylaxis with proton pump inhibitors (PPIs), aspirin, NSAIDs, or statins to prevent progression of dysplasia and oesophageal adenocarcinoma in patients with Barrett's oesophagus.3Rothwell PM Fowkes FG Belch JF Ogawa H Warlow CP Meade TW Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.Lancet. 2011; 377: 31-41Summary Full Text Full Text PDF PubMed Scopus (1204) Google Scholar, 4Masclee GM Coloma PM Spaander MC Kuipers EJ Sturkenboom MC NSAIDs, statins, low-dose aspirin and PPIs, and the risk of oesophageal adenocarcinoma among patients with Barrett's oesophagus: a population-based case-control study.BMJ Open. 2015; 5: e006640Crossref PubMed Scopus (37) Google Scholar, 5Schneider JL Zhao WK Corley DA Aspirin and nonsteroidal anti-inflammatory drug use and the risk of Barrett's esophagus.Dig Dis Sci. 2015; 60: 436-443Crossref PubMed Scopus (24) Google Scholar, 6Tsibouris P Vlachou E Isaacs PE Role of chemoprophylaxis with either NSAIDs or statins in patients with Barrett's esophagus.World J Gastrointest Pharmacol Ther. 2014; 5: 27-39Crossref PubMed Google Scholar, 7Choi SE Perzan KE Tramontano AC Kong CY Hur C Statins and aspirin for chemoprevention in Barrett's esophagus: results of a cost-effectiveness analysis.Cancer Prev Res (Phila). 2014; 7: 341-350Crossref PubMed Scopus (26) Google Scholar, 8Beales IL Vardi I Dearman L Regular statin and aspirin use in patients with Barrett's oesophagus is associated with a reduced incidence of oesophageal adenocarcinoma.Eur J Gastroenterol Hepatol. 2012; 24: 917-923Crossref PubMed Scopus (38) Google Scholar, 9Omer ZB Ananthakrishnan AN Nattinger KJ et al.Aspirin protects against Barrett's esophagus in a multivariate logistic regression analysis.Clin Gastroenterol Hepatol. 2012; 10: 722-727Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 10Beales IL Dearman L Vardi I Loke Y Reduced risk of barrett's esophagus in statin users: case-control study and meta-analysis.Dig Dis Sci. 2016; 61: 238-246Crossref PubMed Scopus (23) Google Scholar, 11Huo X Zhang X Yu C et al.Aspirin prevents NF-κB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus.Gut. 2018; 67: 606-615PubMed Google Scholar, 12Ogunwobi OO Beales IL Statins inhibit proliferation and induce apoptosis in Barrett's esophageal adenocarcinoma cells.Am J Gastroenterol. 2008; 103: 825-837Crossref PubMed Scopus (121) Google Scholar, 13Nguyen T Khan A Liu Y El-Serag HB Thrift AP The association between statin use after diagnosis and mortality risk in patients with esophageal cancer: a retrospective cohort study of united states veterans.Am J Gastroenterol. 2018; (published online June 27.)DOI:10.1038/s41395-018-0169-6Crossref Scopus (22) Google Scholar The results have been mixed, varying from protective effects to no positive associations. Apart from the beneficial acid-lowering effect of PPIs, the role of chemoprophylaxis in the pathway from normal mucosa through Barrett's epithelium to oesophageal adenocarcinoma is not entirely clear. For aspirin and NSAIDs, the inhibitory effects of cyclo-oxygenase might be protective, whereas statins have several anticancer effects on cellular pathways.3Rothwell PM Fowkes FG Belch JF Ogawa H Warlow CP Meade TW Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.Lancet. 2011; 377: 31-41Summary Full Text Full Text PDF PubMed Scopus (1204) Google Scholar Daily aspirin given for cardiovascular diseases has, in some studies, been associated with a marked decrease in cancer-related deaths at doses ranging from 75 mg per day to 300 mg per day.9Omer ZB Ananthakrishnan AN Nattinger KJ et al.Aspirin protects against Barrett's esophagus in a multivariate logistic regression analysis.Clin Gastroenterol Hepatol. 2012; 10: 722-727Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar Among oesophageal cancers, this protective effect of aspirin has only been seen in oesophageal adenocarcinoma. Findings from some studies suggest that, together with PPIs (and potentially statins), long-term use of aspirin is not only associated with a potential decrease in risk of cancer but also with lower incidence of Barrett's oesophagus among patients with gastro-oesophageal reflux disease.4Masclee GM Coloma PM Spaander MC Kuipers EJ Sturkenboom MC NSAIDs, statins, low-dose aspirin and PPIs, and the risk of oesophageal adenocarcinoma among patients with Barrett's oesophagus: a population-based case-control study.BMJ Open. 2015; 5: e006640Crossref PubMed Scopus (37) Google Scholar, 5Schneider JL Zhao WK Corley DA Aspirin and nonsteroidal anti-inflammatory drug use and the risk of Barrett's esophagus.Dig Dis Sci. 2015; 60: 436-443Crossref PubMed Scopus (24) Google Scholar, 12Ogunwobi OO Beales IL Statins inhibit proliferation and induce apoptosis in Barrett's esophageal adenocarcinoma cells.Am J Gastroenterol. 2008; 103: 825-837Crossref PubMed Scopus (121) Google Scholar These studies, although retrospective, have provided some new insight into potential future chemoprophylactic regimens. However, the results have been conflicting, and our group did not find a prophylactic effect from PPIs in 9883 patients with Barrett's oesophagus.14Hvid-Jensen F Pedersen L Funch-Jensen P Drewes AM Proton pump inhibitor use may not prevent high-grade dysplasia and oesophageal adenocarcinoma in Barrett's oesophagus: a nationwide study of 9883 patients.Aliment Pharmacol Ther. 2014; 39: 984-991Crossref PubMed Scopus (72) Google Scholar Instead, our data suggested that, in the long term, high doses of and adherence to PPIs were related to increased risk of oesophageal adenocarcinoma.14Hvid-Jensen F Pedersen L Funch-Jensen P Drewes AM Proton pump inhibitor use may not prevent high-grade dysplasia and oesophageal adenocarcinoma in Barrett's oesophagus: a nationwide study of 9883 patients.Aliment Pharmacol Ther. 2014; 39: 984-991Crossref PubMed Scopus (72) Google Scholar These conflicting results between studies could be due to various biases related to retrospective and epidemiological studies, such as study designs, differences in disease extent and duration, selection bias, concomitant diseases, and medications. The long-awaited prospective AspECT trial,15Jankowski JAZ de Caestecker J Love SB et al.Esomeprazole and aspirin in Barrett's oesophagus (AspECT): a randomised factorial trial.Lancet. 2018; (published online July 26.)http://dx.doi.org/10.1016/S0140-6736(18)31388-6Summary Full Text Full Text PDF PubMed Scopus (152) Google Scholar reported by Janusz Jankowski and colleagues in The Lancet, could help to tie off some of the loose ends from the previous population-based studies. AspECT enrolled 2557 consecutive patients with Barrett's oesophagus who were then randomly assigned to receive different open-label regimens of PPIs and aspirin (high-dose or low-dose esomeprazole, with or without aspirin). The study included patients with newly confirmed Barrett's oesophagus (>1 cm) from 84 centres (2022 men, 513 women, median age 59 years [IQR 56–65]) throughout the UK and one in Canada and had a median follow-up of 8·9 years, for a total of 20 095 follow-up years of data. High-dose PPI (40 mg twice daily) was superior to low-dose PPI (20 mg once daily) in delaying oesophageal adenocarcinoma and high-grade dysplasia (time ratio 1·27, 95% CI 1·01–1·58, p=0·0375) The addition of aspirin increased the effect, whereas aspirin alone was not associated with improved outcomes. Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (1·59, 1·14–2·23, p=0·0068). For high-dose PPI plus aspirin versus high-dose PPI without aspirin, the time ratio was 1·38 (0·98–1·94, p=0·068). The dose of aspirin used in this study (300 mg per day for UK participants, 325 mg per day for Canadian participants) is higher than the 75 mg per day used for standard low-dose preventive therapy, potentially increasing the risk of gastrointestinal bleeding. The observed 1% prevalence of serious adverse events might therefore have been lower if a lower dose had been used. A lower dose could still be associated with a protective effect against cancer, as seen in other studies.4Masclee GM Coloma PM Spaander MC Kuipers EJ Sturkenboom MC NSAIDs, statins, low-dose aspirin and PPIs, and the risk of oesophageal adenocarcinoma among patients with Barrett's oesophagus: a population-based case-control study.BMJ Open. 2015; 5: e006640Crossref PubMed Scopus (37) Google Scholar, 5Schneider JL Zhao WK Corley DA Aspirin and nonsteroidal anti-inflammatory drug use and the risk of Barrett's esophagus.Dig Dis Sci. 2015; 60: 436-443Crossref PubMed Scopus (24) Google Scholar Additionally, aspirin can potentially result in ulcerations and strictures in the small and large intestines, and prophylactic PPI will not have any effect on these complications. Unfortunately, the AspECT study does not present data for other medications or for adherence to the prescribed PPI and aspirin, which would be of great importance when analysing the results. Further data are therefore needed to confirm the reported positive combined effects from aspirin and PPI use before this approach should be recommended as an additional chemopreventive measure. Whether combination therapy should be offered for patients with Barrett's oesophagus, or even whether prophylactic treatment should be provided for patients with gastro-oesophageal reflux disease to prevent Barrett's oesophagus and reduce the risk of oesophageal adenocarcinoma, is still open for debate. Treatment with PPIs is related to increased gastrin levels, which have been shown to potentially increase the long-term risk of gastric cancers.16Brusselaers N Wahlin K Engstrand L Lagergren J Maintenance therapy with proton pump inhibitors and risk of gastric cancer: a nationwide population-based cohort study in Sweden.BMJ Open. 2017; 7: e017739Crossref PubMed Scopus (117) Google Scholar However, the risk reduction and dose-response relationship for PPI in the AspECT trial are rather convincing and probably outweigh these considerations. Future guidelines should consider whether the notion of the lowest possible dose to control symptoms still applies and whether high-dose PPIs should be used as prophylaxis in Barrett's oesophagus. We declare no competing interests. Esomeprazole and aspirin in Barrett's oesophagus (AspECT): a randomised factorial trialHigh-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus. Full-Text PDF Open Access