pErsonalised Nocebo Assessment of Beta-blockEr Symptoms in Heart Failure

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Method: ENABLE-HF is a prospective, N-of-1 randomised study of symptoms in participants with HFrEF. The study population will be patients who have an indication for oral beta-blockade due to HFrEF, and are currently not taking any beta-blockers licenced for HFrEF, having previously tried and stopped taking them due to perceived symptoms that they and/or their clinician(s) attributed to the beta-blocker(s). Participants' suitability will be assessed by a detailed clinical history, clinical examination and review of their medical history to confirm the diagnosis of HFrEF, indication for beta-blocker therapy and that they are currently not taking it. The inclusion and exclusion criteria will be applied. At enrolment, a researcher will generate and allocate an unused randomisation code to the participant. This will also determine the contents of their 9 study bottles to be taken in Phase 2. The participant will then be provided with packs containing all phases' medications, and a smartphone if required. The study protocol has three main phases: (i) Phase 1 - a two week, open-label period of 2.5mg bisoprolol daily (ii) Phase 2 - a nine week double blinded n-of-1 phase consisting of three separate weeks of daily bisoprolol 2.5mg, three separate weeks of daily matched placebo, and three separate weeks of no study tablet. The order of the nine weeks will be randomised at the outset. (iii) Phase 3 - another two week, open-label period of 2.5mg bisoprolol daily. Patients will report the intensity of the main symptom that led to them stopping beta-blocker tablets using a smartphone app daily. They will answer a weekly quality-of-life questionnaire. In this way the investigators will discover, for an individual patient, the proportion of their symptom that is due to the beta-blocker tablet, and whether knowing their personalised results helps them to restart beta-blocker tablets. Each participant will receive a personalised report of their symptom scores from the n-of-1 Phase 2 period. At this point patients and researchers will be unblinded and patients will be counselled by a Cardiologist from research team about what these results mean and how much of their perceived side-effects are attributable to the beta-blocker. These findings will be delivered using pre-determined standardised language. This study will develop a novel method to provide patients with HFrEF who are currently missing out on the prognostic benefits of beta-blockers with personalised information about their symptom aetiology. It is expected that getting these personalised results will improve long-term beta-blocker adherence in heart failure.