Chronotropic Incompetence, Heart Failure, Diastolic, Heart Failure With a Preserved Ejection Fraction
Conditions
Keywords
HFpEF, Heart failure, Heart failure with preserved ejection fraction, Chronotropic incompetence
Brief summary
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).
Interventions
DEVICEPacemaker system will be implanted but set to Pacing Off.
The identical pacing system will be implanted, but will be set to Pacing Off.
DEVICERate adaptive atrial pacing using a dual-chamber pacemaker
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.
Sponsors
Medtronic
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age \>18 years and able to provide informed consent to enroll in the trial, or consent through a legal guardian or power of attorney. 2. Previous clinical diagnosis of HF with current NYHA Class II-III symptoms 3. 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 ) 4. Left ventricular EF ≥40% within 12 months with clinical stability 5. Stable cardiac medical therapy for ≥30 days 6. Sinus rhythm 7. 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 8. Meet both screening criteria on clinically-performed cardiopulmonary exercise testing within 12 months.
Exclusion criteria
1. Inability to exercise, or non-cardiac condition that precludes exercise testing 2. Any contraindication to a pacemaker system 3. Non-cardiac condition limiting life expectancy to less than one year 4. Significant left sided structural valve disease (\>mild stenosis, \>moderate regurgitation) 5. Hypertrophic cardiomyopathy 6. Infiltrative or inflammatory myocardial disease (amyloid, sarcoid) 7. Pericardial disease 8. Non-group 2 pulmonary arterial hypertension 9. Chronic stable exertional angina 10. Acute coronary syndrome or revascularization within 60 days 11. Other clinically important causes of dyspnea 12. Atrial fibrillation 13. PR interval \>210 msec 14. Resting heart rate (HR) \> 100 bpm 15. A history of reduced ejection fraction (EF\<40%) 16. Advanced chronic kidney disease (GFR \< 20 ml/min/1.73m2 by modified MDRD equation) 17. Women of child bearing potential without negative pregnancy test and effective contraception 18. Severe anemia (Hemoglobin \<10 g/dL) 19. Severe hepatic disease 20. Complex congenital heart disease 21. Listed for cardiac transplantation 22. Other class I indications for pacing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxygen Consumption (VO2) at Ventilatory Anaerobic Threshold (VAT) | baseline, after 4 weeks of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Aerobic Capacity (Peak VO2) | 4 weeks after pacemaker activation | 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. |
| Ventilatory Efficiency (VE/VCO2) | 4 weeks | 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). |
| Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | baseline, after 4 weeks of treatment | 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. |
| Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score | baseline, after 4 weeks of treatment | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Mean Peak Heart Rate (HR) | 4 weeks | Determined as the maximum heart rate . Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions of the heart per minute (beats per minute, or bpm). |
Countries
United States
Participant flow
Pre-assignment details
Three subjects did not return for baseline testing following pacemaker implantation, leaving a total of 29 patients who were randomized into the study.
Participants by arm
| Arm | Count |
|---|---|
| Pacing Off First, Then Pacing on Subjects who received pacing off in either the first or last 4 weeks of the study
Pacing off for the first for 4 weeks, followed by 4 week washout period, and then cross-over to pacing on for an additional 4 weeks.
Rate adaptive atrial pacing using a dual-chamber pacemaker: 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.
Pacemaker system implanted but set to Pacing Off.: The identical pacing system will be implanted, but will be set to Pacing Off. | 15 |
| Pacing on First, Then Pacing Off Subjects who received pacing on either the first or last 4 weeks of the study
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
Rate adaptive atrial pacing using a dual-chamber pacemaker: 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.
Pacemaker system implanted but set to Pacing Off.: The identical pacing system will be implanted, but will be set to Pacing Off. | 14 |
| Total | 29 |
Baseline characteristics
| Characteristic | Pacing Off First, Then Pacing on | Total | Pacing on First, Then Pacing Off |
|---|---|---|---|
| Age, Continuous | 66.5 years STANDARD_DEVIATION 12.2 | 66.0 years STANDARD_DEVIATION 9.7 | 65.4 years STANDARD_DEVIATION 6.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 29 Participants | 14 Participants |
| Region of Enrollment United States | 15 participants | 29 participants | 14 participants |
| Sex: Female, Male Female | 8 Participants | 13 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 16 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 29 | 0 / 29 | 0 / 32 | 0 / 29 |
| other Total, other adverse events | 8 / 29 | 7 / 29 | 5 / 32 | 0 / 29 |
| serious Total, serious adverse events | 0 / 29 | 0 / 29 | 1 / 32 | 0 / 29 |
Outcome results
Primary
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.
Time frame: baseline, after 4 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pacing Off | Change in Oxygen Consumption (VO2) at Ventilatory Anaerobic Threshold (VAT) | 10.4 ml/kg/min | Standard Deviation 2.9 |
| Pacing on | Change in Oxygen Consumption (VO2) at Ventilatory Anaerobic Threshold (VAT) | 10.7 ml/kg/min | Standard Deviation 2.6 |
Secondary
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.
Time frame: baseline, after 4 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pacing Off | Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score | 4.7 score on a scale | Standard Deviation 16.4 |
| Pacing on | Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score | 3.8 score on a scale | Standard Deviation 20.2 |
Secondary
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.
Time frame: baseline, after 4 weeks of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pacing Off | Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | -88.0 pg/mL | Standard Deviation 390 |
| Pacing on | Change in Plasma N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | -36.0 pg/mL | Standard Deviation 255 |
Secondary
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.
Time frame: 4 weeks after pacemaker activation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pacing Off | Peak Aerobic Capacity (Peak VO2) | 16.5 ml/kg/min | Standard Deviation 4.3 |
| Pacing on | Peak Aerobic Capacity (Peak VO2) | 16.8 ml/kg/min | Standard Deviation 4.1 |
Secondary
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).
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pacing Off | Ventilatory Efficiency (VE/VCO2) | 34.2 ratio | Standard Deviation 6.6 |
| Pacing on | Ventilatory Efficiency (VE/VCO2) | 34.9 ratio | Standard Deviation 6.3 |
Other Pre-specified
Mean Peak Heart Rate (HR)
Determined as the maximum heart rate . Heart rate (or pulse rate) is the frequency of the heartbeat measured by the number of contractions of the heart per minute (beats per minute, or bpm).
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pacing Off | Mean Peak Heart Rate (HR) | 109 bpm | Standard Deviation 21 |
| Pacing on | Mean Peak Heart Rate (HR) | 123 bpm | Standard Deviation 15 |