Resynchronization/Defibrillation for Ambulatory Heart Failure Trial in Patients With Permanent Atrial Fibrillation

Study Overview
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Brief Summary
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Atrial fibrillation (AF) and heart failure (HF) are two common heart conditions that are encountered with an increase in death and suffering. When both these two conditions occur in a patient, the patient's prognosis is poor with a reduced quality of life and impaired heart function. These patients have enlarged hearts, specifically the left ventricle (major pumping chamber), which impairs the heart's pumping capacity, leading to symptoms such as fatigue, shortness of breath from any type of exertion, and swelling, usually of the feet and ankles. In these HF patients who are in AF all of the time, who would otherwise be a suitable candidate for an implantable defibrillator to prevent sudden cardiac death, we would like to determine whether adding pacing of both ventricles will reduce heart size (left ventricular end systolic volume index LVESVi) as measured by ultrasound, which can improve its function and help the heart pump more efficiently. Other studies have shown that adding pacing to both ventricles is of benefit in HF patients with mild to moderate symptoms and have a regular heart rhythm. The Investigators now want to explore if this therapy will benefit those patients with a permanent irregular heart rhythm (AF).

Detailed Description
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Heart failure (HF) is increasing in prevalence and incidence and is the most common reason for hospital admissions of patients over the age of 65. Therapy for HF has evolved over the last two decades. Cardiac resynchronization therapy (CRT) is a therapy that attempts to resynchronize the sequence of ventricular contraction in heart failure (HF) patients with left ventricular (LV) systolic dysfunction and ventricular dyssynchrony. CRT is achieved by stimulating both RV and LV together, synchronized to right atrial excitation to achieve atrio-ventricular synchrony. Clinical trials have demonstrated that CRT reduced heart size, improved survival and reduced HF hospitalization in mild to advanced HF patients. This knowledge translated to a change in practice guidelines and the adoption of CRT into clinical practice benefitting many HF patients CRT is now an important state-of-the-art therapy for HF patients with LV systolic dysfunction, low LVEF, and prolonged QRS duration in sinus rhythm, since the vast majority of the CRT clinical research was performed in patients in sinus rhythm. However, in the  25% of HF patients with permanent atrial fibrillation (AF), the effectiveness of CRT is not clear. It is therefore timely to address the question of whether the addition of CRT to optimal HF treatment, rate control and an ICD improves cardiac outcomes in individuals with heart failure (HF) and permanent atrial fibrillation (AF). The outcomes will be measured by a hierarchy of all-cause mortality, HF events, Left Ventricular Ejection Fraction (LVEF) and improvement in Quality of Life (QoL) in patients with permanent AF, mild to moderate HF, left ventricular (LV) systolic dysfunction, and prolonged QRS duration, when compared to implantable cardioverter defibrillator (ICD) therapy alone. Objectives: To determine whether cardiac resynchronization therapy will improve cardiac outcomes for heart failure patients with permanent atrial fibrillation, mild to moderate heart failure, left ventricular systolic dysfunction, and prolonged QRS duration, when compared to implantable cardioverter defibrillator (ICD) therapy alone. Methods: This is a multi-centre randomized controlled trial of two treatment groups. The patients, primary physicians and the heart failure caregivers will be blinded to the treatment allocation. The device follow-up caregivers will not be blinded. Patients with NYHA Class II and III HF symptoms, LVEF HF ≤ 35%, permanent AF, on optimal medical therapy and QRS durations ≥ 130 ms when the QRS morphology is LBBB, or QRS durations ≥ 150 ms when the QRS morphology is non-LBBB, or Paced QRS will be included in the trial. Patients should be suitable candidates for either of the 2 treatment strategies. There will be 200 patients randomized in 1:1 ratio to two groups: 1) ICD-CRT, 2) ICD only. All patients will undergo baseline clinical evaluation, echocardiogram measurements, quality of life assessment, medication assessment, and 6-minute walk distance.. The patients will be followed at 1 month, 3 months, 6 months and then every 6 months.

Official Title
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Resynchronization/Defibrillation for Ambulatory Heart Failure Trial in Patients With Permanent Atrial Fibrillation

Conditions
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Heart Disease, Congestive Heart Failure, Atrial Fibrillation

Intervention / Treatment
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* Device: Optimal Medical therapy plus ICD
* Device: Optimal Medical therapy plus CRT/ICD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with NYHA Class II or III HF symptoms (assessment in the last 3 months) Permanent AF Optimal Medical Therapy for HF of at least 3 months (according to 2009 ACCF/AHA and ESC 2012 recommendations,) LVEF ≤ 35% (assessment in the last 6 months) Candidacy for an ICD for primary or secondary prevention of sudden cardiac death QRS durations ≥ 130 ms when the QRS morphology is LBBB, or QRS durations ≥ 150 ms when the QRS morphology is non-LBBB or Paced QRS Exclusion Criteria: In-hospital patients who have acute cardiac or non-cardiac illness that requires intensive care Intra-venous inotropic agent in the last 4 days Patients with a life expectancy of less than one year from non-cardiac cause. Expected to undergo cardiac transplantation within one year (status I) Acute coronary syndrome (including MI) < 4 weeks Unable or unwilling to provide informed consent Uncorrected or uncorrectable primary valvular disease Restrictive, hypertrophic or reversible form of cardiomyopathy Severe primary pulmonary disease such as cor pulmonale Tricuspid prosthetic valve Patients included in other clinical trial that will affect the objectives of this study Coronary revascularization (CABG or PCI) < 3 months Patients with an existing ICD or CRT pacemaker

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Optimal Medical therapy plus ICD<br>Patients randomized to the (ICD) Implantable-Defibrillator-Cardioverter only group will receive an ICD + optimal medical therapy | Device: Optimal Medical therapy plus ICD<br> <br> |
| Active Comparator: Optimal Medical therapy plus CRT/ICD<br>Patients randomized to the (ICD) Implantable-Defibrillator-Cardioverter plus cardiac resynchronisation therapy (CRT) group will receive an ICD + CRT and optimal medical therapy | Device: Optimal Medical therapy plus CRT/ICD<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome is a hierarchy (winratio) of 1) all-cause mortality | Mortality data will be collected for the duration of the study | 12 months | 
| The primary outcome is a hierarchy (winratio) of 2) Heart Failure Events (>24 Hours admission for Heart Failure or clinically worsening Heart Failure leading to IV diuretics administered | HF events (> 24 hour admit or < 24 hr with IV diuretics) will be collected for the duration of the study | 12 months | 
| The primary outcome is a hierarchy (winratio) of 3) Left ventricular ejection fraction | Change in echocardiogram parameters LVEF measure | baseline to 12 months | 
| The primary outcome is a hierarchy (winratio) of 4) QoL - Minnesota Living with Heart Failure Questionnaire | Change in QoL MLHFQ. The MLHFQ score is used to measure quality of life. The MLHFQ consists of 21 questions answered on a 0-5 likert scale, with higher scores indicating a stronger impact of heart failure on QoL. | baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | Death all cause | Baseline to a minimum of 12 months | 
| Heart Failure Events | Admission to Hospital > 24 hrs for Heart Failure or <24 hrs with clinical worsending of HF leading to intervention | Baseline to a minimum of 12 months | 
| Changes in LVEF | Left Ventricular ejection fraction | Baseline to 12 months | 
| Quality of Life Questionnaire | Minnesota Living with Heart Failure | Baseline to a minimum of 12 months | 
| Composite of all-cause mortality and heart failure | All cause death and admission to to Hospital > 24 hours for Heart Failure | Baseline to a minimum of 12 months | 
| 6 Minute walk distance | Hall walk distance over 6 minute timeframe | Baseline to a minimum of 12 months | 
| Cardiovascular mortality | Cardiovascular Death | Baseline to a minimum of 12 months | 
| Cost-effectiveness | Readmission for Heart Failure | Baseline to a minimum of 12 months | 
| Cardiovascular hospitalizations | Cardiovascular Admission to Hospital > 24 hours | Baseline to a minimum of 12 months | 
| Quality of Life Questionnaire | EQ5D-5L | Baseline to a minimum of 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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defibrillator, cardiac resynchronization