WITHDRAWal of heart failure directed therapies in recovered Atrial Fibrillation mediated cardiomyopathy- the WITHDRAW-AF study

This is a randomised controlled study comparing staged withdrawal versus continuation of heart failure pharmacotherapy in patients with rhythm controlled atrial fibrillation (AF) and recovered cardiomyopathy. Patients undergoing staged withdrawal will first withdraw from a heart failure (HF) specific beta blocker with the option to replace with an antiarrhythmic agent (such as sotalol, amiodarone or flecainide) at the time of enrolment at Cardiologist discretion with an ECG performed at baseline and during initiation of antiarrhythmic therapy to monitor QTc intervals. Antiarrhythmic dose will be decided at the physician’s discretion. At subsequent visits, mineralocorticoid receptor antagonists (MRAs) will be weaned, followed by angiotension receptor antagonists (ACE) inhibitors, angiotensin receptor blockers (ARBs) or angiotensin receptor blocker/neprilysin inhibitor (Eg. Entresto) combinations. Diuretics can be ceased if the patient is taking the equivalent or less than frusemide 40mg daily or spironolactone 25mg daily. Participants taking 25% or less of the maximum recommended dose of ACE inhibitor or ARB can be discontinued; higher doses will be weaned by 50% every 2 weeks. The withdrawal stage involves weaning neurohormonal agents at fortnightly intervals over an 8 week period. There will be no 'wash out' period between treatment intervals. Initial withdrawal will occur at enrolment, with reduction or cessation of diuretics (depending on dose) and changing beta blocker to anti-arrhythmic agent as appropriate. Participants will then be followed up at 3, 6, 9 and 12 months. Additional clinical reviews can be arranged based on clinical need. This phased withdrawal method is adapted from the recent TRED-HF study. Patients in the control group (continued medical therapy) will undergo regular clinical review at 3, 6, 9 and 12 months with interval visits as clinically indicated. The total study duration is 12 months. Participants will spend 6 months in each treatment group. Those in the initial withdrawal arm will crossover to the medical treatment arm at 6 months with a cardiac MRI prior to ensure stable left ventricular systolic function, with reinitiation of baseline or maximal tolerated neurohormonal therapy as clinically appropriate. This reinitiation will take place over the first 8 weeks after the 6 month withdrawal phase. Conversely, participants initially allocated to the continued medical therapy group will continue their baseline neurohormonal therapy until 6 months, have a repeat cardiac magnetic resonance imaging (MRI or CMR) to ensure left ventricular (LV) function remains stable, then commence staged withdrawal over 8 weeks, with a subsequent final CMR at 12 months for cardiomyopathy surveillance. Repeat CMR at 6 and 12 months is designed as a safety mechanism for the early detection of LV dysfunction in patients during the withdrawal treatment phase. Patients with a reduction in left ventricular ejection fraction (LVEF) <45% at 6 months from weaning, in the absence of AF recurrence will be able to re-initiate anti-heart failure therapy. For the purpose of analysis of the primary end-point, the LVEF value from the 6 months scan prior to the re-introduction of neuro-hormonal blockade will be utilised. Double crossover study design: The participants initially allocated to continuing medical therapy will continue standard care for 6 months and then crossover into the staged withdrawal group. The participants initially allocated to staged withdrawal will undergo supervised withdrawal of heart failure therapy and remain in this allocation for 6 months and then crossover into the standard care/continued medical therapy arm after 6 months, where their usual medical therapy will be reintroduced over a 6 week period. An additional transthoracic echocardiogram (TTE) will be arranged within 1 month of medication cessation to ensure stable cardiac function off heart failure therapy. Participants will monitor blood pressure at least twice weekly while weaning therapies and if blood pressure is consistently elevated, blood pressure lowering therapy may be considered based on clinical need.