Esomeprazole and aspirin in Barrett's oesophagus (AspECT): a randomised factorial trial

TY - JOUR

T1 - Esomeprazole and aspirin in Barrett's oesophagus (AspECT)

T2 - a randomised factorial trial

AU - Jankowski, Janusz A. Z.

AU - de Caestecker, John

AU - Love, Sharon B.

AU - Reilly, Gavin

AU - Watson, Peter

AU - Sanders, Scott

AU - Ang, Yeng

AU - Morris, Danielle

AU - Bhandari, Pradeep

AU - Attwood, Stephen

AU - Ragunath, Krish

AU - Rameh, Bashir

AU - Fullarton, Grant

AU - Tucker, Art

AU - Penman, Ian

AU - Rodgers, Colin

AU - Neale, James

AU - Brooks, Claire

AU - Wise, Adelyn

AU - Jones, Stephen

AU - Church, Nicholas

AU - Gibbons, Michael

AU - Johnston, David

AU - Vaidya, Kishor

AU - Anderson, Mark

AU - Balata, Sherzad

AU - Davies, Gareth

AU - Dickey, William

AU - Goddard, Andrew

AU - Edwards, Cathryn

AU - Gore, Stephen

AU - Haigh, Chris

AU - Harding, Timothy

AU - Isaacs, Peter

AU - Jackson, Lucina

AU - Lee, Thomas

AU - Lim, Peik Loon

AU - Macdonald, Christopher

AU - Mairs, Philip

AU - McLoughlin, James

AU - Monk, David

AU - Murdock, Andrew

AU - Murray, Iain

AU - Preston, Sean

AU - Pugh, Stirling

AU - Smart, Howard

AU - Soliman, Ashraf

AU - Todd, John

AU - Turner, Graham

AU - Worthingon, Joy

AU - Harrison, Rebecca

AU - Barr, Hugh

AU - Moayyedi, Paul

N1 - Funding: Cancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.

PY - 2018/8/4

Y1 - 2018/8/4

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Anti-Inflammatory Agents, Non-Steroidal/administration & dosage

KW - Aspirin/administration & dosage

KW - Barrett Esophagus/drug therapy

KW - Drug Administration Schedule

KW - Drug Therapy, Combination

KW - Esomeprazole/administration & dosage

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Proton Pump Inhibitors/administration & dosage

KW - Young Adult

UR - https://www.scopus.com/pages/publications/85053605255

U2 - 10.1016/S0140-6736(18)31388-6

DO - 10.1016/S0140-6736(18)31388-6

M3 - Article

C2 - 30057104

SN - 0140-6736

VL - 392

SP - 400

EP - 408

JO - Lancet

JF - Lancet

IS - 10145

M1 - 10145

ER -