In Barrett esophagus, high- vs low-dose esomeprazole improved clinical outcomes; aspirin vs no aspirin did not

The safety of high-dose proton-pump inhibitor therapy is probably acceptable, but the addition of aspirin carries more risk, has less evidence on efficacy, and needs an individualized approach, an ACP Journal Club commentary said.


The industry-supported Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial (AspECT) was conducted at 84 centers in the United Kingdom (U.K.) and one in Canada. Researchers randomized 2,557 patients with Barrett esophagus (BE) of 1 cm or more to receive high-dose (40 mg twice daily) or low-dose (20 mg once daily) esomeprazole proton-pump inhibitor (PPI) therapy, with or without aspirin (300 mg/d in the U.K., 325 mg/d in Canada), for at least eight years. The primary composite endpoint was time to all-cause mortality, esophageal adenocarcinoma, or high-grade dysplasia in the intention-to-treat population. High-dose PPI was superior to low-dose PPI, and aspirin was not significantly better than no aspirin unless patients using NSAIDs were censored at the time of first use. High-dose PPI and aspirin had the strongest effect compared with low-dose PPI without aspirin.

The study results were published by The Lancet on July 26 and were summarized in the August ACP Gastroenterology Monthly. The following commentary by John K. Marshall, MD, MSc, FRCPC, appeared in the ACP Journal Club section of the Nov. 20 Annals of Internal Medicine.

BE is a precursor to esophageal adenocarcinoma, and its incidence is increasing in developed countries. Although population prevalence of BE is low, about 1 in 300 affected patients develops cancer each year. Recent guidelines advocate once-daily PPI therapy as chemoprevention (unless higher doses are needed for symptom relief) and recommend against routine use of aspirin or NSAIDs. However, supporting evidence was mainly derived from retrospective analyses of observational data, which can be criticized for the usual reasons.

AspECT has been eagerly awaited as a unique and definitive intervention trial. Its investigators are to be congratulated on executing a broad and rigorous study with long follow-up. Results support high-dose PPI therapy, based on a composite endpoint driven primarily by reduced mortality. The benefit of aspirin is less clear because it emerged only when patients were censored at first NSAID exposure in a prespecified secondary analysis.

Safety is a major concern for any long-term therapy given to healthy patients. The safety of PPI exposure has been controversial, with some alarming associations noted in observational datasets. However, few of these are believed to be causal—scrutiny of the data suggests that few purported adverse effects can be directly attributed to PPI exposure. Aspirin has well-characterized toxicity, including gastrointestinal bleeding. Although such events were rare in AspECT (all patients received concomitant gastroprotection with esomeprazole), they cannot be ignored, and incidence increases with age.

Should this chemopreventive strategy be widely adopted? The safety of high-dose PPI therapy is probably acceptable, and its benefit seems clear. However, the addition of aspirin carries more risk, has less robust evidence for efficacy, and needs an individualized approach. Moreover, absolute risk for progression from BE to esophageal adenocarcinoma itself varies by segment length, sex, and age, among other factors. Chemoprevention may not be a “one-size-fits-all” solution, and such resources might still be best invested where their reward is greatest.