The helicobacter eradication aspirin trial (HEAT): demographic data for randomised (H.pylori positive) patients

Introduction The Helicobacter Eradication Aspirin Trial (HEAT) is a multicentre, double blind, randomised controlled trial investigating whether Helicobacter pylori eradication reduces the incidence of hospitalisation for peptic ulcer bleeding [1]. Participants are subjects aged over 60, taking low dose aspirin for at least four months at the time of recruitment; all participants were recruited from primary care. H. pylori positive participants were randomised to receive one week active trial treatment (lansoprazole 30mg, clarithromycin 500mg and metronidazole 400mg twice daily) or placebo. Recruitment to the trial started in 2012 and completed in 2017; follow-up is endpoint driven and is ongoing. Methods Participants are followed up using a bespoke web-based trial management system that communicates directly with HEAT Toolkit software downloaded at participating GP practices, which issues MIQUEST [2] queries searching follow-up criteria. The primary endpoint of the study is the rate of hospitalisation due to definite or probable peptic ulcer bleeding. The study will end when 87 adjudicated events have occurred. Events are tracked by accumulating information from MIQUEST searches of GP databases via the HEAT toolkit, patient contact, review of national secondary care admission and mortality data. Results HEAT is being conducted in practices across the whole of the UK with 188,428 invitation letters sent from 1,208 GP practices. A total of 37,247 positive responses were received, representing a 20% response rate. Of those, 30,025 patients were consented to the study of whom 5,356 H. pylori positive patients were randomised. The percent of H. pylori positive patients varied from 13% to 39% throughout the country. Multiple deprivation scores applied to the data indicated an increase in response with less deprivation, but a decrease in the number of randomised patients. The mean age at randomisation for all participants was 73.6 ± 7.0 (SD) years, and 73.8% of participants are male. Only 7.2% of participants are smokers although 52.9% are ex-smokers. A total of 15% of the randomised patients have withdrawn from the trial, and 100 patients have died so far. Discussion The trial methodology has shown that recruitment of large numbers of patients from primary care is attainable, with the assistance of the NIHR Clinical Research Network, and could be applied to other outcomes studies at relatively low cost. Last year, there were almost 17,000 hospital admissions for gastric ulcers [3] and more than 1,850 recorded deaths [4] for gastric and duodenal ulcers. If successful, the study will help to reduce NHS costs and improve health outcomes by reducing hospital admissions, increasing patient safety and preventing premature deaths

Recruitment to a large scale randomised controlled clinical trial in primary care: the Helicobacter Eradication Aspirin Trial (HEAT)

Background The Helicobacter Eradication Aspirin Trial (HEAT) is a multicentre, double blind, randomised controlled trial investigating whether Helicobacter (H.) pylori eradication reduces hospitalisation for peptic ulcer bleeding. Recruited participants were aged 60 and over and taking aspirin (≤325 mg daily) for at least four months prior to consent. Based on results of a pilot study, a sample size calculation predicted 6600 H. pylori-positive randomised participants would be required, from 33,000 volunteers, recruited from 170,000 invited patients. Methodology was therefore designed for recruitment of large numbers of patients from primary care using a novel electronic search tool, automated mail-out and electronic follow-up. Recruitment started in 2012 and completed in 2017. Methods All participants were recruited from GP practices, with assistance from the UK Clinical Research Network (UKCRN). H. pylori-positive participants were randomised to one week of eradication treatment or placebo. Recruitment was managed using a bespoke web-based database that communicated directly with a programmed search tool downloaded at participating practices. The primary endpoint is hospitalisation due to peptic ulcer bleeding. The trial will end when 87 adjudicated events have occurred, identified from searches of GP databases, review of secondary care admission data and mortality data, and reported events from randomised participants and GPs. Results HEAT has recruited participants from 1208 GP practices across the UK. Of the 188,875 invitation letters sent, 38,771 returned expressions of interest. Of these, 30,166 patients were consented to the trial, of whom 5355 H. pylori-positive participants (17.8% of those consented) were randomised. Mean age at consent was 73.1 ± 6.9 (SD) years and 72.2% of participants were male. Of the randomised (H. pylori-positive) participants, 531 have died (as of 17 Sep 2020); none of the deaths was due to trial treatment. Conclusion The HEAT trial methodology has demonstrated that recruitment of large numbers of patients from primary care is attainable, with the assistance of the UKCRN, and could be applied to other clinical outcomes studies. Trial registration ClinicalTrials.gov; registration number NCT01506986. Registered on 10 Jan 2012

Allopurinol versus usual care in UK patients with ischaemic heart disease (ALL-HEART): a multicentre, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease. METHODS: ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426. FINDINGS: Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77). INTERPRETATION: In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care. FUNDING: UK National Institute for Health and Care Research