IntroductionAtrial fibrillation (AF) is a common arrhythmia associated with 30% of strokes, as well as other cardiovascular disease, dementia and death. AF meets many criteria for screening, but there is limited evidence that AF screening reduces stroke. Consequently, no countries recommend national screening programmes for AF. The Screening for Atrial Fibrillation with ECG to Reduce stroke (SAFER) trial aims to determine whether screening for AF is effective at reducing risk of stroke. The aim of the pilot study is to assess feasibility of the main trial and inform implementation of screening and trial procedures.Methods and analysisSAFER is planned to be a pragmatic randomised controlled trial (RCT) of over 100 000 participants aged 70 years and over, not on long-term anticoagulation therapy at baseline, with an average follow-up of 5 years. Participants are asked to record four traces every day for 3 weeks on a hand-held single-lead ECG device. Cardiologists remotely confirm episodes of AF identified by the device algorithm, and general practitioners follow-up with anticoagulation as appropriate. The pilot study is a cluster RCT in 36 UK general practices, randomised 2:1 control to intervention, recruiting approximately 12 600 participants. Pilot study outcomes include AF detection rate, anticoagulation uptake and other parameters to incorporate into sample size calculations for the main trial. Questionnaires sent to a sample of participants will assess impact of screening on psychological health. Process evaluation and qualitative studies will underpin implementation of screening during the main trial. An economic evaluation using the pilot data will confirm whether it is plausible that screening might be cost-effective.Ethics and disseminationThe London—Central Research Ethics Committee (19/LO/1597) and Confidentiality Advisory Group (19/CAG/0226) provided ethical approval. Dissemination will be via publications, patient-friendly summaries, reports and engagement with the UK National Screening Committee.Trial registration numberISRCTN72104369.

Background The treatment of people with diabetes with metformin can reduce cardiovascular disease (CVD) and may reduce the risk of cancer. However, it is unknown whether or not metformin can reduce the risk of these outcomes in people with elevated blood glucose levels below the threshold for diabetes [i.e. non-diabetic hyperglycaemia (NDH)]. Objective To assess the feasibility of the Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT) and to estimate the key parameters to inform the design of the full trial. These parameters include the recruitment strategy, randomisation, electronic data capture, postal drug distribution, retention, study medication adherence, safety monitoring and remote collection of outcome data. Design A multicentre, individually randomised, double-blind, parallel-group, pragmatic, primary prevention trial. Participants were individually randomised on a 1 : 1 basis, blocked within each site. Setting General practices and clinical research facilities in Cambridgeshire, Norfolk and Leicestershire. Participants Males and females aged ≥ 40 years with NDH who had a high risk of CVD. Interventions Prolonged-release metformin (500 mg) (Glucophage® SR, Merck KGaA, Bedfont Cross, Middlesex, UK) or the matched placebo, up to three tablets per day, distributed by post. Main outcome measures Recruitment rates; adherence to study medication; laboratory results at baseline and 3 and 6 months; reliability and acceptability of study drug delivery; questionnaire return rates; and quality of life. Results We sent 5251 invitations, with 511 individuals consenting to participate. Of these, 249 were eligible and were randomised between March and November 2015 (125 to the metformin group and 124 to the placebo group). Participants were followed up for 0.99 years [standard deviation (SD) 0.30 years]. The use of electronic medical records to identify potentially eligible individuals in individual practices was resource intensive. Participants were generally elderly [mean age 70 years (SD 6.7 years)], overweight [mean body mass index 30.1 kg/m2 (SD 4.5 kg/m2)] and male (88%), and the mean modelled 10-year CVD risk was 28.8% (SD 8.5%). Randomisation, postal delivery of the study drug and outcome assessment using registers/medical records were feasible and acceptable to participants. Most participants were able to take three tablets per day, but premature discontinuation of the study drug was common (≈30% of participants by 6 months), although there were no differences between the groups. All randomised participants returned questionnaires at baseline and 67% of participants returned questionnaires by the end of the study. There was no between-group difference in Short Form questionnaire-8 items or EuroQol-5 Dimensions scores. Compared with placebo, metformin was associated with small improvements in the mean glycated haemoglobin level [–0.82 mmol/mol, 95% confidence interval (CI) –1.39 to –0.24 mmol/mol], mean estimated glomerular filtration rate (2.31 ml/minute/1.73 m2, 95% CI –0.2 to 4.81 ml/minute/1.73 m2) and mean low-density lipoprotein cholesterol level (–0.11 mmol/l, 95% CI –0.25 to 0.02 mmol/l) and a reduction in mean plasma vitamin B12 level (–16.4 ng/l, 95% CI –32.9 to –0.01 ng/l). There were 35 serious adverse events (13 in the placebo group, 22 in the metformin group), with none deemed to be treatment related. Limitations Changes to sponsorship reduced the study duration, the limited availability of information in medical records reduced recruitment efficiency and discontinuation of study medication exceeded forecasts. Conclusions A large, pragmatic trial comparing the effects of prolonged-release metformin and placebo on the risk of CVD events is potentially feasible. However, changes to the study design and conduct are recommended to enable an efficient scaling up of the trial. Recommendations include changing the inclusion criteria to recruit people with pre-existing CVD to increase the recruitment and event rates, using large primary/secondary care databases to increase recruitment rates, conducting follow-up remotely to improve efficiency and including a run-in period prior to randomisation to optimise trial adherence. Trial registration Current Controlled Trials ISRCTN34875079. Funding The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 18. See the NIHR Journals Library website for further project information. Merck KGaA provided metformin and matching placebo.

Atrial fibrillation (AF) is a common irregular heart rhythm associated with a five-fold increase in stroke risk. It is often not recognised as it can occur intermittently and without symptoms. A promising approach to detect AF is to use a handheld electrocardiogram (ECG) sensor for screening. However, the ECG recordings must be manually reviewed, which is time-consuming and costly. Our aims were to: (i) evaluate the manual review workload; and (ii) evaluate strategies to reduce the workload. In total, 2141 older adults were asked to record their ECG four times per day for 1–4 weeks in the SAFER (Screening for Atrial Fibrillation with ECG to Reduce stroke) Feasibility Study, producing 162,515 recordings. Patients with AF were identified by: (i) an algorithm classifying recordings based on signal quality (high or low) and heart rhythm; (ii) a nurse reviewing recordings to correct algorithm misclassifications; and (iii) two cardiologists independently reviewing recordings from patients with any evidence of rhythm abnormality. It was estimated that 30,165 reviews were required (20,155 by the nurse, and 5005 by each cardiologist). The total number of reviews could be reduced to 24,561 if low-quality recordings were excluded from review; 18,573 by only reviewing ECGs falling under certain pathological classifications; and 18,144 by only reviewing ECGs displaying an irregularly irregular rhythm for the entire recording. The number of AF patients identified would not fall considerably: from 54 to 54, 54 and 53, respectively. In conclusion, simple approaches may help feasibly reduce the manual workload by 38.4% whilst still identifying the same number of patients with undiagnosed, clinically relevant AF.

Qualitative research can enhance the design, conduct and interpretation of trials. Despite this, few trials incorporate qualitative methods, and those that do may not realise their full potential. In this commentary, we highlight how qualitative research can contribute to the design, conduct and day-to-day running of a trial, outlining the working arrangements and relationships that facilitate these contributions. In doing so, we draw on (i) existing frameworks on the role of qualitative research alongside trials and (ii) our experience of integrated qualitative research conducted as part of the feasibility study of the SAFER trial (Screening for Atrial Fibrillation with ECG to Reduce stroke), a cluster randomised controlled trial of screening people aged 70 and above for atrial fibrillation in primary care in England. The activities and presence of the qualitative team contributed to important changes in the design, conduct and day-to-day running of the SAFER feasibility study, and the subsequent main trial, informing diverse decisions concerning trial documentation, trial delivery, timing and content of measures and the information given to participating patients and practices. These included asking practices to give screening results to all participants and not just to ‘screen positive’ participants, and greater recognition of the contribution of practice reception staff to trial delivery. These changes were facilitated by a ‘one research team’ approach that underpinned all formal and informal working processes from the outset and maximised the value of both qualitative and trial coordination expertise. The challenging problems facing health services require a combination of research methods and data types. Our experience and the literature show that the benefits of embedding qualitative research in trials are more likely to be realised if attention is given to both structural factors and relationships from the outset. These include sustained and sufficient funding for qualitative research, embedding qualitative research fully within the trial programme, providing shared infrastructure and resources and committing to relationships based on mutual recognition of and respect for the value of different methods and perspectives. We outline key learning for the planning of future trials.Trial registration: Screening for atrial fibrillation with ECG to reduce stroke ISRCTN16939438 (feasibility study); Screening for atrial fibrillation with ECG to reduce stroke – a randomised controlled trial ISRCTN72104369.