Evaluating Diuretics in Normal Care (EVIDENCE): a feasibility report of a pilot cluster randomised trial of prescribing policy in primary care to compare the effectiveness of thiazide-type diuretics in hypertension

BackgroundObtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exemplar of a more general framework for efficient generation of such evidence.In 2011, the UK NICE hypertension guideline included a recommendation that thiazide-like diuretics (such as indapamide) be used in preference to thiazide diuretics (such as bendroflumethiazide) for hypertension. There is sparse evidence backing this recommendation, and bendroflumethiazide remains widely used in the UK.MethodsPatients prescribed indapamide or bendroflumethiazide regularly for hypertension were identified in participating General Practices. Allocation of a prescribing policy favouring one of these drugs was then randomly applied to the Practice and, where required to comply with the policy, repeat prescriptions switched by pharmacy staff. Patients were informed of the potential switch by letter and given the opportunity to opt-out. Practice adherence to the randomised policy was assessed by measuring the amount of policy drug prescribed as a proportion of total combined indapamide and bendroflumethiazide. Routinely collected hospitalization and death data in the NHS will be used to compare cardiovascular event rates between the two policies.ResultsThis pilot recruited 30 primary care practices in five Scottish National Health Service (NHS) Boards. Fifteen practices were randomised to indapamide (2682 patients), and 15 to bendroflumethiazide (3437 patients); a study population of 6119 patients. Prior to randomisation, bendroflumethiazide was prescribed to 78% of patients prescribed either of these drugs. Only 1.6% of patients opted out of the proposed medication switch.ConclusionThe pilot and subsequent recruitment confirms the methodology is scalable within NHS Scotland for a fully powered larger study, currently 102 GP practices (>12,700 patients) are participating in this study. It has the potential to efficiently produce externally valid comparative effectiveness data with minimal disruption to practice staff or patients. Streamlining this pragmatic trial approach, has demonstrated the feasibility of a random prescribing policy design framework that can be adapted to other therapeutic areas.Trial registration numberISRCTN 46635087; registered pre-results, 11/08/2017.SummaryWe report on a Chief Scientist Office for Scotland-funded pilot of the feasibility of the (Evaluating Diuretics in Usual Care) EVIDENCE study. This report will describe:Recruitment and policy randomisation of 30 GP practices across 5 NHS health board regions in Scotland.Acceptability of study implementation information provided to primary healthcare practitioners and patients.Recruitment rates, staffing, training, and funding requirement estimations to inform the full-sized project.How knowledge and practical experience gained has informed scaling of activities to realise a fully powered EVIDENCE study, including 250 practices.Key messages regarding feasibilityWhat uncertainties existed regarding the feasibility?For widely prescribed medicines with similar mode of action and similar indications differences in effectiveness are likely to be quite small indicating the need for very large study sizes. Previous work has demonstrated that practices would be reluctant to take part in this kind of study if it involved any extra work within already limited practice capacity. Would NHS Primary Care leads be willing to endorse the study taking place in their region? In addition, the large size and geographically distributed nature of this study meant devising solutions for work to take place remotely or using pre-existing regional staff needed to be devised. There was also uncertainty about the overall acceptability for patients in having their medication changed for research purposes.What are the key feasibility findings?The experience from the pilot and subsequent successful expanded recruitment shows that the solutions we developed seemed to be acceptable and achievable both for general practice staff and the patients they care for. Obtaining endorsement from key stakeholders in NHS health boards improved recruitment success with the practices and sustained support for the study. Negotiations with pharmacy regional leads around workforce implications enabled us to approach practices with a range of solutions for study implementation. It was found that offering training for the EVIDENCE study along with general clinical trials training for regional Pharmacists was key to recruitment of pharmacy delegates on a large scale. We were able to develop the IT infrastructure around the study to allow remote delivery of both training and implementation providing a framework that could be delivered during the covid-19 pandemic. We found that concerns from patients constituted a very small minority indeed indicating overwhelming tacit support for the objectives of the studyWhat are the implications of the feasibility findings for the design of the main study?The initial engagement with a range of healthcare providers offered support for the study in areas that may otherwise have become a potential barrier to success. We will use this approach in the main study. Many of the practical skills required to undertake the EVIDENCE study were also useful skills for pharmacy teams in their everyday practice so acceptance of the study training and implementation was higher. We will continue to progress the study using this methodology as this provided beneficial professional development for pharmacy staff and a platform for a future research ready workforce. Demonstrating the success of this approach we have currently recruited over 100 practices and have 29 pharmacy delegates across Scotland outside the core study team. This indicates that recruiting the target of 250 practices (approximately 50,000 individuals is entirely feasible.