Efficacy Study of Pacemakers to Treat Slow Heart Rate in Patients With Heart Failure

Study Overview
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Brief Summary
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Determine the impact of restoring normal heart rate response during exercise and daily activity in patients with heart failure and a preserved ejection fraction (HFpEF) and chronotropic incompetence (CI).

Official Title
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Rate-Adaptive Atrial Pacing In Diastolic Heart Failure (RAPID-HF)

Conditions
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Heart Failure With a Preserved Ejection Fraction, Heart Failure, Diastolic, Chronotropic Incompetence

Intervention / Treatment
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* Device: Rate adaptive atrial pacing using a dual-chamber pacemaker
* Device: Pacemaker system will be implanted but set to Pacing Off.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age >18 years and able to provide informed consent to enroll in the trial, or consent through a legal guardian or power of attorney. Previous clinical diagnosis of HF with current NYHA Class II-III symptoms At least one of the following: Hospitalization for decompensated HF, Acute treatment for HF with intravenous loop diuretic or hemofiltration, Chronic treatment with a loop diuretic for control of HF symptoms + left atrial enlargement on echocardiography or E/e' ratio (≥14 average, ≥15 septal ) on echocardiography, Resting PCWP >15 mm Hg or LV end-diastolic pressure >18 mmHg at catheterization for dyspnea and/or exercise PCWP/LV end-diastolic pressure >25 mmHg, or Elevated NT-proBNP level (≥300 pg/ml ) Left ventricular EF ≥40% within 12 months with clinical stability Stable cardiac medical therapy for ≥30 days Sinus rhythm Chronotropic incompetence on recent (within 6 months) clinical or screening exercise test, defined as heart rate reserve (HRR) <0.80 or <0.62 if on beta blockers Meet both screening criteria on clinically-performed cardiopulmonary exercise testing within 12 months. Exclusion Criteria Inability to exercise, or non-cardiac condition that precludes exercise testing Any contraindication to a pacemaker system Non-cardiac condition limiting life expectancy to less than one year Significant left sided structural valve disease (>mild stenosis, >moderate regurgitation) Hypertrophic cardiomyopathy Infiltrative or inflammatory myocardial disease (amyloid, sarcoid) Pericardial disease Non-group 2 pulmonary arterial hypertension Chronic stable exertional angina Acute coronary syndrome or revascularization within 60 days Other clinically important causes of dyspnea Atrial fibrillation PR interval >210 msec Resting heart rate (HR) > 100 bpm A history of reduced ejection fraction (EF<40%) Advanced chronic kidney disease (GFR < 20 ml/min/1.73m2 by modified MDRD equation) Women of child bearing potential without negative pregnancy test and effective contraception Severe anemia (Hemoglobin <10 g/dL) Severe hepatic disease Complex congenital heart disease Listed for cardiac transplantation Other class I indications for pacing

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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pacing off first, then pacing on<br>No-pacing on for the first for 4 weeks, followed by 4 week washout period, and then cross-over to pacing on for an additional 4 weeks. | Device: Rate adaptive atrial pacing using a dual-chamber pacemaker<br>* The Azure XT DR is a permanent, dual-chamber cardiac pacemaker with the ability to continuously monitor and record patient activity, and respond to activity by pacing faster and increasing the heart rate (rate adaptive atrial pacing). It will be programmed in AAIR mode to pace the right atrium. The leads will be placed in the right atrium and right ventricle using CapSureFix model 5086.<br>* Other names: Medtronic CapSureFix MRI model 5086;Device: Pacemaker system will be implanted but set to Pacing Off.<br>* The identical pacing system will be implanted, but will be set to Pacing Off.<br>* Other names: Medtronic CapSureFix MRI model 5086;|
| Experimental: Pacing on first, then pacing off<br>Pacing on for the first for 4 weeks, followed by 4 week washout period, and then cross-over to pacing off for an additional 4 weeks | Device: Rate adaptive atrial pacing using a dual-chamber pacemaker<br>* The Azure XT DR is a permanent, dual-chamber cardiac pacemaker with the ability to continuously monitor and record patient activity, and respond to activity by pacing faster and increasing the heart rate (rate adaptive atrial pacing). It will be programmed in AAIR mode to pace the right atrium. The leads will be placed in the right atrium and right ventricle using CapSureFix model 5086.<br>* Other names: Medtronic CapSureFix MRI model 5086;Device: Pacemaker system will be implanted but set to Pacing Off.<br>* The identical pacing system will be implanted, but will be set to Pacing Off.<br>* Other names: Medtronic CapSureFix MRI model 5086;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Oxygen Consumption (VO2) at Ventilatory Anaerobic Threshold (VAT) | Maximal effort cardiopulmonary exercise testing was performed on a treadmill after 4 weeks of pacing-on and after 4 weeks of pacing-off to measure volumes of oxygen consumed (VO2). Change in VO2 at anaerobic threshold (VO2,AT) determined by the V-Slope method as the point of disproportionate rise in VCO2 relative to VO2 as measured in ml/kg/min. | baseline, after 4 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Aerobic Capacity (Peak VO2) | Determined as the mean of values obtained over the final 30 seconds of exercise. Maximal effort cardiopulmonary exercise testing was performed on a treadmill after 4 weeks of pacing-on and after 4 weeks of pacing-off to measure volumes of oxygen consumed (VO2). As measured in ml/kg/min. | 4 weeks after pacemaker activation | 
| Ventilatory Efficiency (VE/VCO2) | Determined as the nadir of VE/VCO2 ratio during exercise. Maximal effort cardiopulmonary exercise testing was performed on a treadmill after 4 weeks of pacing-on and after 4 weeks of pacing-off to measure volumes of oxygen consumed (VO2). | 4 weeks | 
| Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | Change in plasma NT-proBNP as measured in pg/mL. Natriuretic peptides are substances made by the heart. A main type of these substances is NT-proBNP. Elevated levels can mean the heart isn't pumping as much blood the body needs. | baseline, after 4 weeks of treatment | 
| Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score | Change from baseline in KCCQ-overall summary score was reported. KCCQ was a 23-item, self-administered questionnaire that measure the participant's perception of their health status, including their heart failure (HF) symptoms, impact on physical and social function and how their HF impacts the quality of life. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 to 100, with 0 denoting the worst and 100 the best possible status. KCCQ- overall summary score was average of domains- physical limitation, total symptoms (average of symptom frequency and symptom burden), quality of life, and social limitation, and transformed to a single score which ranged from 0 (worst) -100 (the best possible status), where the higher score reflected better health status. | baseline, after 4 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HFpEF, Heart failure, Heart failure with preserved ejection fraction, Chronotropic incompetence