Congestive Heart Failure, Heart Failure
Conditions
Keywords
Heart failure, Congestive heart failure, New York Heart Association Class II-III, Vagal therapy, Vagal nerve stimulation
Brief summary
The NECTAR-HF feasibility trial is designed to evaluate the application of right vagal nerve stimulation in heart failure patients with a New York Heart Association Class III, an ejection fraction equal to or less than 35 %, and a narrow QRS duration equal to or less than 130 ms.
Detailed description
The objectives of this study are to assess the impact of right vagal nerve stimulation on left ventricular remodeling, functional capacity, quality of life, and other measures in heart failure patients over a 6-month period. In addition, the study will assess the safety of the NECTAR-HF study system over an 18-month period.
Interventions
DEVICEImplant of investigational device system
Vagus nerve stimulation lead was wrapped around the right cervical vagus nerve and then connected to a stimulator permanently implanted in the right pectoral region.
PROCEDURETitration during the randomization phase
Amplitude of the chronically delivered vagus nerve stimulation in the experimental arm was adjusted to the highest tolerable by patient value. No chronically delivered vagus nerve stimulation in the control arm during the randomization phase.
PROCEDURETitration after the randomization phase
Amplitude of the chronically delivered vagus nerve stimulation was adjusted to the highest tolerable by patient value in all patients in both arms of the study.
DIAGNOSTIC_TESTBlood Draw
Blood draw before implant and 6 months after implant at the end of the randomization phase.
Sponsors
Boston Scientific Corporation
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
Patients were randomized in a 2:1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LVend systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 or above, and of legal age to give informed consent specific to national laws * Willing and capable of providing informed consent * Capable of participating in all testing associated with this clinical investigation * Stable symptomatic heart failure NYHA class II-III * Left ventricular (LV) ejection fraction equal or smaller than 35 % * Left ventricular end diastolic diameter (LVEDD) of 5.5 cm or greater * Prescribed to optimal pharmacologic therapy
Exclusion criteria
* QRS larger than 130 ms * Patients who have been hospitalized for heart failure and who required the use of HF IV therapy within 30 days before enrollment * Patients unable to tolerate anesthesia required for implant * Patients with unstable angina, myocardial infarction, PTCA, coronary artery bypass graft, cerebral vascular accident, or transient ischemic attack within previous 90 days before enrollment * Patients whose primary cause of heart failure is mitral or aortic valve disease, with a severe classification * Patients with persistent or permanent atrial fibrillation within 90 days prior to enrollment * Pacemaker indicated patients * Patients whose heart failure is due to congenital heart disease * Patients who have started treatment for sleep apnea or sleep disordered breathing with therapies to maintain airway patency (e.g., CPAP, Bi-PAP,APAP) with or without oxygen supplementation within the previous 6 months prior to enrollment * Patients with hypertrophic obstructive cardiomyopathy or infiltrative cardiomyopathy (e.g. amyloidosis, sarcoidosis) * Patients with documented chronic obstructive lung disease * Patients on or indicated for renal dialysis * Type 1 diabetic patients * Type 2 diabetic patients that have been treated with insulin for more than 5 years prior to enrollment * Patients with a life expectancy of less than 12 months per physician judgment * Patients involved in any concurrent clinical investigation * Women of childbearing potential who are or might be pregnant at the time of the study or breastfeeding * Patients with a prior cardiac transplant or expecting a heart transplant operation within the next 12 months * Patients with a prior vagotomy * Patients with prior or existing vagal nerve stimulation treatment * Patients implanted with any active implantable medical device other than a left sided single or dual chamber implantable cardioverter defibrillator (ICD) with bipolar sensing, or a left sided CRT device with each sensing channel programmed to either bipolar sensing or no sensing. All CRT patients must have had CRT for at least 1 year prior to enrollment. The total number of CRT patients will not exceed 30 * Patients with locally implanted semi-/permanent devices such as vascular catheters, etc. that would interfere with the NECTAR-HF study system * Patients with previously implanted devices on the right side that became infected before removal * Patients with previous neck surgery and resultant scar formation that interferes with the ability to implant the study system on the right side of the neck (Thyroid/parathyroid, carotid artery etc) * Patients with known recurrent nerve paralysis * Patients who have undergone radiotherapy for thyroid disease/cancer * Patients who have existing or prior tracheotomy * Patients with severe vertebral cervical disease and limited mobility in the neck; includes those that frequently wear a brace * Patients with carotid murmur/vascular bruit/carotid artery lesion * Patients with known/suspected vascular malformation in carotid/vertebral circulatory bed * Patients who are likely to need an MRI of the neck area because of previous medical conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Left Ventricular End-systolic Dimension (LVESD) | LVESD at Baseline and at 6-months post Baseline | Change in the Left ventricular end-systolic dimension (LVESD) between Baseline and the value at the end of the randomization phase (6 months after Baseline) i.e. 6 months after vagus nerve stimulation in the THERAPY Arm. No Vagus nerve stimulation during that time window in the CONTROL Arm. The sign (- ) indicates a reduction in the LVESD. Minus means a reduction in LVESD. The change was calculated from two time points as the value at the later time point minus the value at the earlier time point (e.g., value at 6 months minus value at baseline). |
| Percentage of Surviving Participants | 18-months | As pre-specified in the study protocol, the All-cause Survival endpoint combined both groups into one analysis population. Subjects contributed data according to the follow-up period during they received VNS therapy (Implant through 18 months for Therapy subjects, 6 through 18 months for Control subjects). Control patients who exited the study in the first 6 months, or who did not have a 6 month visit, were excluded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| LVEF, Left Ventricular Ejection Fraction | LVEF at Baseline and at 6-months after Baseline | LVEF, left ventricular ejection fraction. |
| Exercise Capacity, Peak VO2 | Measurements at Baseline and at 6-months after Baseline | Assessment of functional capacity (e.g., peak VO2) as measures related to patient heart failure status. |
| LVESV, Left Ventricular End Systolic Volume | At Baseline and at 6-months after Baseline | Measurements of LVESV, left ventricular end systolic volume at Baseline and 6 months after Baseline in the Control Arm and in the Therapy Arm |
Countries
Belgium, Czechia, France, Germany, Italy, Netherlands, Spain, United Kingdom
Contacts
PRINCIPAL_INVESTIGATORFaiez Zannad, M.D.
Centre d'Investigation Clinique (CIC), Batiment Louis Mathieu, CHU de Nancy
Participant flow
Recruitment details
Enrollment Start: 21-Sep-2011. First implant: 28-Sep-2011.Last Implant: 20-June-2013. 118 patients enrolled, 96 were found to be eligible and were implanted across 24 centres (7 sites with 5-10 implants, 1 site with 13 implants). 95 patients were randomized.
Pre-assignment details
22 patients were excluded after enrollment. 18 patients did not meet the inclusion criteria. 4 patients decided to withdraw their consent. 96 patients were finally implanted with the investigational device. One patient died after implant and before randomization. Randomization was done only after the investigational device implant had occurred.
Participants by arm
| Arm | Count |
|---|---|
| Therapy Therapy group was implanted with study system like the control arm, but did receive therapy soon after implant | 63 |
| Control Control group was implanted with study system like the experimental arm, but will receive no therapy until 6-month cross-over.
Vagal Nerve Stimulation System was implanted but inactive for the first 6 months: Patients randomized to therapy arm with receive right vagal nerve stimulation. Patients randomized to control arm will not receive right vagal nerve stimulation for the first 6-months post-implant, after which they will also receive therapy. | 32 |
| Total | 95 |
Baseline characteristics
| Characteristic | Control | Total | Therapy |
|---|---|---|---|
| Age, Continuous | 59.3 years STANDARD_DEVIATION 10.1 | 59.5 years STANDARD_DEVIATION 11.1 | 59.8 years STANDARD_DEVIATION 12.2 |
| Body mass index | 31.2 kg/m^2 STANDARD_DEVIATION 5.1 | 29.9 kg/m^2 STANDARD_DEVIATION 5.5 | 28.6 kg/m^2 STANDARD_DEVIATION 5.9 |
| Loop diuretics | 32 Participants | 86 Participants | 54 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Belgium | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Czech Republic | 4 participants | 10 participants | 6 participants |
| Region of Enrollment France | 3 participants | 7 participants | 4 participants |
| Region of Enrollment Germany | 4 participants | 16 participants | 12 participants |
| Region of Enrollment Italy | 5 participants | 10 participants | 5 participants |
| Region of Enrollment Netherlands | 6 participants | 19 participants | 13 participants |
| Region of Enrollment Spain | 5 participants | 15 participants | 10 participants |
| Region of Enrollment United Kingdom | 4 participants | 16 participants | 12 participants |
| Sex: Female, Male Female | 6 Participants | 13 Participants | 7 Participants |
| Sex: Female, Male Male | 26 Participants | 82 Participants | 56 Participants |
| Statin | 19 Participants | 69 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 63 | 2 / 32 | 3 / 92 |
| other Total, other adverse events | 32 / 63 | 15 / 32 | 66 / 92 |
| serious Total, serious adverse events | 21 / 63 | 18 / 32 | 44 / 92 |
Outcome results
Primary
Change in Left Ventricular End-systolic Dimension (LVESD)
Change in the Left ventricular end-systolic dimension (LVESD) between Baseline and the value at the end of the randomization phase (6 months after Baseline) i.e. 6 months after vagus nerve stimulation in the THERAPY Arm. No Vagus nerve stimulation during that time window in the CONTROL Arm. The sign (- ) indicates a reduction in the LVESD. Minus means a reduction in LVESD. The change was calculated from two time points as the value at the later time point minus the value at the earlier time point (e.g., value at 6 months minus value at baseline).
Time frame: LVESD at Baseline and at 6-months post Baseline
Population: The sign (- ) indicates a reduction in the LVESD. Participants without paired endpoint data did not contribute to the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Therapy | Change in Left Ventricular End-systolic Dimension (LVESD) | -0.04 cm | Standard Deviation 0.25 |
| Control | Change in Left Ventricular End-systolic Dimension (LVESD) | -0.08 cm | Standard Deviation 0.32 |
Primary
Percentage of Surviving Participants
As pre-specified in the study protocol, the All-cause Survival endpoint combined both groups into one analysis population. Subjects contributed data according to the follow-up period during they received VNS therapy (Implant through 18 months for Therapy subjects, 6 through 18 months for Control subjects). Control patients who exited the study in the first 6 months, or who did not have a 6 month visit, were excluded.
Time frame: 18-months
Population: Therapy group received VNS from implant to 18 months. Control group received VNS from 6 months to 18 months. These follow-up periods contributed to the endpoint analysis. Both groups were combined for mortality endpoint analysis. Control patients who exited the study in the first 6 months, or who did not have a 6 month visit, were excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Therapy | Percentage of Surviving Participants | 95 Percentage of participants surving |
Secondary
Exercise Capacity, Peak VO2
Assessment of functional capacity (e.g., peak VO2) as measures related to patient heart failure status.
Time frame: Measurements at Baseline and at 6-months after Baseline
Population: Participants without paired endpoint data did not contribute to the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Therapy | Exercise Capacity, Peak VO2 | Baseline | 15.6 ml/kg/min | Standard Deviation 3.9 |
| Therapy | Exercise Capacity, Peak VO2 | 6 months after Baseline | 15.8 ml/kg/min | Standard Deviation 4.4 |
| Control | Exercise Capacity, Peak VO2 | Baseline | 15.2 ml/kg/min | Standard Deviation 3.3 |
| Control | Exercise Capacity, Peak VO2 | 6 months after Baseline | 14.7 ml/kg/min | Standard Deviation 3.6 |
Secondary
LVEF, Left Ventricular Ejection Fraction
LVEF, left ventricular ejection fraction.
Time frame: LVEF at Baseline and at 6-months after Baseline
Population: LVEF echocardiographic measurements were made at Baseline and at 6 months after Baseline. Participants without paired endpoint data did not contribute to the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Therapy | LVEF, Left Ventricular Ejection Fraction | 6 months after Baseline | 32.7 % of blood ejected from ventricle | Standard Deviation 6.4 |
| Therapy | LVEF, Left Ventricular Ejection Fraction | Baseline | 30.5 % of blood ejected from ventricle | Standard Deviation 6 |
| Control | LVEF, Left Ventricular Ejection Fraction | 6 months after Baseline | 32.1 % of blood ejected from ventricle | Standard Deviation 5.6 |
| Control | LVEF, Left Ventricular Ejection Fraction | Baseline | 30.8 % of blood ejected from ventricle | Standard Deviation 4.2 |
Secondary
LVESV, Left Ventricular End Systolic Volume
Measurements of LVESV, left ventricular end systolic volume at Baseline and 6 months after Baseline in the Control Arm and in the Therapy Arm
Time frame: At Baseline and at 6-months after Baseline
Population: Measurements of LVESV, left ventricular end systolic volume at Baseline and at 6-months after Baseline. Participants without paired endpoint data did not contribute to the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Therapy | LVESV, Left Ventricular End Systolic Volume | Baseline | 154.7 ml | Standard Deviation 58.5 |
| Therapy | LVESV, Left Ventricular End Systolic Volume | 6 months after Baseline | 142.5 ml | Standard Deviation 57.1 |
| Control | LVESV, Left Ventricular End Systolic Volume | Baseline | 164.0 ml | Standard Deviation 39.2 |
| Control | LVESV, Left Ventricular End Systolic Volume | 6 months after Baseline | 152.1 ml | Standard Deviation 43.8 |