Title: A randomised controlled trial to investigate clinical and cost effectiveness of Amiodarone vs Beta Blockade for new onset atrial fibRillation in icU - a Pragmatic sTudy (ABBRUPT)
Funder: Department of Health and Social Care

Abstract: AIM To discover the best way to treat people in intensive care who develop the irregular heart rhythm, Atrial Fibrillation. We will do this by allocating people to one of two groups; one to receive beta blockers, the other, amiodarone. We will work out which treatment is most effective by comparing how many sustain complications such as stroke or heart attack but, most importantly, how many are alive at 90 days. BACKGROUND TO THE RESEARCH Atrial Fibrillation (AF) is the most common irregular heart rhythm (arrhythmia); it is more common in older patients (5.9% of the over 65’s have AF (8)). When patients in the Intensive Care Unit (ICU) are very sick, they can develop new onset AF (NOAF) but it can happen even in the very young. To ICU doctors, AF is easily treatable, often resolves and does not seem to harm patients. However, studies show that patients who develop AF in ICU are much more likely to have life-changing complications such as stroke, heart attack or die in the three months after their ICU stay. An analysis of real world data (1) involving over 1000 patients suggested that beta blockers reduced complications and death at 90-days and that amiodarone was associated with a worse mortality rate. On the other hand, a scoping analysis on behalf of the HTA used additional databases and did not find that one treatment was any better than another (6). These analyses are not enough to change ICU practice as there may be unmeasured factors (such as sicker patients not tolerating beta blockers) which would make beta blocker-treated (but less sick) patients more likely to survive. ICU doctors use either amiodarone or beta blockers but more often choose amiodarone. This might not be the correct prescribing habit and so there is an urgent need to study NOAF in a randomised trial. It is only comparing these treatments side-by-side that we will understand the best treatment to use. Outside ICU, beta blockers are the treatment of choice for AF as they reduce stroke, heart attacks and improve mortality. The causes of AF in ICU are different and so we do not know whether treating very sick ICU patients in the same way is correct. In addition to mortality at 3 months, we will also monitor patients to report complications of AF such as stroke or heart attacks. An economic study will also be carried out to measure whether the one of the treatments improves the quality of life. This will help understand the impact of treating AF. DESIGN AND METHODS USED Patients in ICU wear an ECG constantly and are monitored for AF. When AF is detected and the patient is not known to have had AF before ICU, we will randomise patients either to receive amiodarone or beta blocker. Patients will be followed up by clinical and research teams and data collected about important outcomes and safety. PATIENT AND PUBLIC INVOLVEMENT Patients and public have helped us design this proposal and will be involved throughout its delivery and reporting. We have received input from those with lived experience, a charity helping patients and carers (the Arrhythmia Alliance) and an expert PPI advisory group Clinical Research Ambassador Group. DISSEMINATION The findings will be submitted to high-impact peer reviewed journals and presented at national and international meetings. We will work with our PPI team to create materials in accessible formats and disseminate these through print and social media.

Lay abstract: RESEARCH QUESTION: In adult intensive care (ICU) patients with new onset atrial fibrillation (NOAF), what is the clinical and cost effectiveness of amiodarone versus beta blockade? BACKGROUND: NOAF in ICU is common, generally short-lived, tends to occur when the patient is at their sickest but at the time, relatively easily treated. However NOAF is associated with increased in-hospital and 90-day mortality (1, 2), ICU and hospital stay (3, 4) and life-changing complications such as stroke, thromboembolic events or myocardial infarction (MI) even once the patient has left the ICU (5). A retrospective analysis of NOAF from the large MIMIC dataset (1) reported that beta blocker treatment was associated with a reduction in 90-day mortality whereas amiodarone was associated with increased mortality. However, a combined analysis of MIMIC and PICRAM databases (6) found no difference in hospital mortality but did not report longer term outcomes. The majority of intensivists worldwide (7) prefer amiodarone but there is a paucity of evidence on which is the most effective AF management. The finding of increased mortality associated with amiodarone and the lack of evidence means that there is an urgent need to understand how best to manage this common condition. AIMS AND OBJECTIVES: To conduct a multi-centre, randomised trial to compare two commonly used treatments for NOAF in ICU. To perform clinical and full economic evaluation to compare treatment with beta blockers and amiodarone. METHODS: Multicentre, pragmatic, open label, parallel group allocation concealed randomised controlled with economic evaluation. Patients with NOAF (defined as AF lasting 30 minutes in patients not previously known to have AF) randomised to receive either beta blocker (bisoprolol, metoprolol or esmolol) or amiodarone. The primary outcome will be survival at 90 days with secondary outcomes of cost-effectiveness of the interventions, ICU / hospital mortalities, ICU / hospital length of stay, rates of stroke and MI, rate of established AF by the end of ICU stay / death. TIMELINES FOR DELIVERY: Months 1-6: set-up; 7-42: recruitment (with embedded 9-month pilot); 42-45: 90-day follow-up; 45-51: data cleaning, analysis, close out and publication ANTICIPATED IMPACT AND DISSEMINATION: Of ICU doctors, amiodarone treatment is used by 45% and beta blockers 23% for AF worldwide (7). Should ABBRUPT demonstrate superiority for one treatment over the other, it will curtail inferior management of a significant number of ICU patients. Late death and adverse cardiovascular events such as stroke and MI are an important but often overlooked legacy of surviving ICU. These are much more common when the patient has had NOAF during their critical illness. This trial will provide evidence about the most effective way to prevent long term sequalae and death following NOAF in ICU. We will disseminate our findings through live presentation of the results at an international meeting (such as criticalcarereviews.com) and social media, simultaneously with publication in a leading medical journal. We will work with our PPI and the Intensive Care Society to develop clinical guidelines to accelerate implementation of the findings in clinical practice. Our PPI will also disseminate the trial findings to interested partners. AF in ICU is so common and both beta blockers and amiodarone relatively inexpensive drugs, that many healthcare systems worldwide will implement the findings of ABBRUPT.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR