Esomeprazole and aspirin in Barrett's oesophagus (AspECT): a randomised factorial trial
Janusz A Z Jankowski, John de Caestecker, Sharon B Love, Gavin Reilly, Peter Watson, Scott Sanders, Yeng Ang, Danielle Morris, Pradeep Bhandari, Stephen Attwood, Krish Ragunath, Bashir Rameh, Grant Fullarton, Art Tucker, Ian Penman, Colin Rodgers, James Neale, Claire Brooks, Adelyn Wise, Stephen Jones, Nicholas Church, Michael Gibbons, David Johnston, Kishor Vaidya, Mark Anderson, Sherzad Balata, Gareth Davies, William Dickey, Andrew Goddard, Cathryn Edwards, Stephen Gore, Chris Haigh, Timothy Harding, Peter Isaacs, Lucina Jackson, Thomas Lee, Peik Loon Lim, Christopher Macdonald, Philip Mairs, James McLoughlin, David Monk, Andrew Murdock, Iain Murray, Sean Preston, Stirling Pugh, Howard Smart, Ashraf Soliman, John Todd, Graham Turner, Joy Worthingon, Rebecca Harrison, Hugh Barr, Paul Moayyedi
Summary
Background
Oesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus.
Methods
The Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial had a 2?×?2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barrett's oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barrett's oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77.
Findings
Between March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2–9·8), and we collected 20?095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01–1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98–1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01–1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14–2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events.
Interpretation
High-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus.
Funding
Cancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.