Eradication of Helicobacter pylori for prevention of aspirin-associated peptic ulcer bleeding in adults over 65 years: the HEAT RCT.

BACKGROUND: Peptic ulcers in patients on aspirin are associated with Helicobacter pylori infection. We investigated whether H. pylori eradication would protect against aspirin-associated ulcer bleeding. METHODS: The Helicobacter Eradication Aspirin Trial was a randomised placebo-controlled trial (European Union Drug Regulating Authorities Clinical Trials 2011-003425-96), conducted in United Kingdom primary care using routinely collected clinical data. Consenting participants aged ≥ 60 years prescribed aspirin ≤ 325 mg but not ulcerogenic or gastroprotective medication underwent C13 urea breath testing for H. pylori. Those with a positive test were randomised to receive either a combination of clarithromycin 500 mg, metronidazole 400 mg and lansoprazole 30 mg, or placebos twice daily for 7 days. The primary outcome, time to death or hospitalisation due to peptic ulcer bleeding, was analysed using a Cox proportional hazards model. FINDINGS: Between 14 September 2012 and 22 November 2017, 30,166 participants underwent H. pylori breath testing, 5367 had a positive result, 5352 were randomised to an intention-to-treat population of 2677 (eradication) and 2675 (placebo) and followed up for a median of 5.0 years (interquartile range 3.9-6.4). Statistical analysis of the primary outcome showed an overall hazard ratio of 0.69 [95% confidence interval 0.38 to 1.25; p = 0.22], but there was a significant departure from the proportional hazards assumption (p = 0.0068), requiring analysis split at the median time to event: 2.5 years. There was a significant reduction in the primary outcome in the eradication treatment group in the first 2.5 years (hazard ratio 0.35, 95% confidence interval 0.14 to 0.89; p = 0.028) but not the second period (hazard ratio 1.31, 95% confidence interval 0.55 to 3.11). The number needed to treat (first period) was 238 (95% confidence interval 184 to 1661). Results in the first 2.5 years remained significant when accounting for the competing risk of death (p = 0.028). During the study period, 657 participants died (306 in the eradication group and 351 in the controls group; hazard ratio 0.86, 95% confidence interval 0.74 to 1.01; p = 0.058). Malignancy was the most common cause of death and largely accounted for the numerical difference between the treatment groups. A health economic analysis found proactive screening not cost-effective, since the monetised benefits of the intervention in preventing a peptic ulcer bleed failed to outweigh the costs. INTERPRETATION: Helicobacter pylori eradication protects against aspirin-associated peptic ulcer bleeding, but this may not be sustained or cost-effective when applied non-selectively to our study population. The possibility that H. pylori eradication, on a background of aspirin use, might affect death from malignancies warrants further evaluation. LIMITATIONS AND FUTURE WORK: Studying subjects already established on aspirin probably contributed to the low event rate. A future study should investigate subjects starting on aspirin when the event rate is higher. TRIAL REGISTRATION: This trial is registered as ISRCTN10134725; ClinicalTrials.gov number NCT01506986. FUNDING: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/55/52) and is published in full in Health Technology Assessment; Vol. 29, No. 42. See the NIHR Funding and Awards website for further award information.