RCT of Implantable Defibrillators in Patients With Non Ischemic Cardiomyopathy, Scar and Severe Systolic Heart Failure

Study Overview
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Brief Summary
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BRITISH is a UK multicentre trial of patients who have been diagnosed with heart failure due to Non-Ischemic Cardiomyopathy (NICM, or heart failure that is not caused by blocked heart arteries. Participants will be randomised into two groups. Half the participants will receive an Implantable Cardioverter-Defibrillator (ICD) and the other half will not. The aim of the study will be to compare all-cause mortality (death from any cause) between these two groups at 36 months, and longer-term to 10 years. The study has the potential to change international heart failure treatment guidelines and to improve how patients with this condition are managed.

Detailed Description
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Patients with Non-Ischemic Cardiomyopathy (NICM) have a higher risk of experiencing serious abnormal heart rhythms that might be life-threatening. Current guidelines recommend fitting a device that can correct these serious heart rhythms (Implantable Cardioverter-Defibrillator (ICD)). However, research studies have shown that 90% of patients who have an ICD will never use it because they won't experience any serious heart rhythms. A recent large trial (DANISH) of over one thousand patients with severe Non-Ischemic Cardiomyopathy has called the current guidelines into question. The trial concluded that for patients who received an ICD, there was no difference in the likelihood of dying when compared to patients that didn't have an ICD fitted. As a result, many doctors are choosing not to implant an ICD in patients with this type of heart failure, as they believe there is no overall survival benefit. However, there are clues that some patients with NICM may still benefit from an ICD, even though the headline results suggest they are not necessary. It's likely that it's the patients who are at increased risk of having a serious abnormal heart rhythm that stand to benefit from ICDs. But having an ICD fitted carries with it a significant risk of problems developing e.g. bleeding, infection, lead problems, and inappropriate shocks. These risks may not outweigh the benefits and it is this question which BRITISH will address. The study will randomly assign (like the toss of a coin), half the study participants to receive an ICD and the other half to no ICD. Both groups will be followed up to decide whether having an ICD fitted reduces the chances of dying.

Official Title
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Using Cardiovascular Magnetic Resonance Identified Scar as the Benchmark Risk Indication Tool for Implantable Cardioverter Defibrillators in Patients With Non-Ischemic Cardiomyopathy and Severe Systolic Heart Failure

Conditions
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Heart Failure

Intervention / Treatment
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* Device: Implantable Cardioverter-Defibrillator (ICD) or Cardiac Resynchronisation Therapy Defibrillator (CRTD)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A diagnosis of NICM on contrast-enhanced cardiovascular magnetic resonance imaging LV scar on routine CMR (patient without scar can enter the registry) New York Heart Association (NYHA) Heart Failure (HF) functional class I-III and severely impaired left ventricular function (LVEF ≤ 35% on any imaging modality) after a minimum of 3 months of treatment with optimal medical therapy (OMT) as recommended by National Institute for Health and Care Excellence (NICE) Able and willing to provide informed consent Exclusion Criteria: New York Heart Association (NYHA) HF functional class IV after 3 months of optimal medical therapy (OMT) Acute decompensated heart failure Previous implantable device in situ (PPM, Cardiac Resynchronisation Therapy (CRT) or ICD) Ischemic cardiomyopathy (ICM) is defined as segmental wall motion abnormalities or wall thinning in a particular coronary territory with subendocardial or transmural late gadolinium enhancement (LGE). Patients with an LVEF ≤35% and a small amount of ischemic LGE (i.e. an infarct out of keeping with the amount of LV dysfunction) will not be excluded (so-called dual pathology patients) Known diagnosis of amyloidosis, sarcoidosis, arrhythmogenic right ventricular cardiomyopathy, or hypertrophic cardiomyopathy (diseases in which there are specific guidelines regarding defibrillator therapy) Known Lamin gene mutation or a positive family history of a Lamin gene mutation Valve disease is considered likely to require surgery during the 3 years follow-up period Complex congenital heart disease Any secondary prevention ICD indication Heart transplant recipient or admitted for cardiac transplantation/ left ventricular assist device Clinically apparent myocardial ischemia which requires revascularization Intracardiac mass which requires surgery Active endocarditis Active Septicaemia Pregnancy Life expectancy <2 years secondary to any other cause (i.e. malignancy) Active treatment with chemotherapy Severe renal failure (GFR <30) Actively participating in another study without prior agreement between both Chief Investigators

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Eligible patients will be randomised in a controlled fashion into two arms (n=1252): Arm A: ICD implantation Arm B: No ICD implantation Patients with no scar on CMR will be followed up in a registry (n=1252)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>ICD or CRTD fitted | Device: Implantable Cardioverter-Defibrillator (ICD) or Cardiac Resynchronisation Therapy Defibrillator (CRTD)<br>* An ICD is a device that is implanted under the skin under a local anesthetic. It has a battery/generator component and leads which are fixed into the heart chambers. It has the ability to detect dangerous heart rhythms if they occur, and deliver a shock to treat this to help prevent sudden cardiac death. A CRTD is a pacemaker with a defibrillator function.<br>|
| No Intervention: Control<br>No ICD fitted (with Implantable Loop Recorder) or Cardiac Resynchronisation Therapy Pacemaker (CRTP) | |
| No Intervention: Registry<br>Usual medical care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients alive | All-cause mortality | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in health-related quality of life measured using KCCQ-12 | Short questionnaire including questions related to heart failure symptoms and how they affect daily activities | 3 years | 
| Change in health-related quality of life measured using EQ-5D-5L | Questionnaire consisting of 5 questions to evaluate a patients quality of life | 3 years | 
| Cardiovascular Death | Percentage of patients that have cardiovascular death | 3 years | 
| Sudden cardiac death | Percentage of patients that have sudden cardiac death | 3 years | 
| Aborted sudden cardiac death | Percentage of patients that have aborted sudden cardiac death | 3 years | 
| Appropriate ICD Therapy | Percentage of patients that have appropriate ICD therapy | 3 years | 
| Inappropriate ICD Therapy | Percentage of patients that have inappropriate ICD therapy | 3 years | 
| Significant ventricular arrhythmias | Percentage of patients that have significant ventricular arrhythmias | 3 years | 
| NYHA Status | Percentage of patients in each category | 3 years | 
| Heart failure hospitalisations | Number of events | 3 years | 
| Cardiac hospitalisations | Number of events | 3 years | 
| Procedures related to implanted device | Number of events | 3 years | 
| Percentage of patients alive | Mortality | At 5 and 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiac Magnetic Resonance Imaging (CMR), Implantable Cardioverter Device, Implantable Loop Recorder, Left ventricular ejection fraction (LVEF), Myocardial scar