Heart FailureNCT03425422
ANTHEM-HFrEF Pivotal Study
A study testing VITARIA System in people with Heart Failure and Heart Failure, Congestive, run by LivaNova at 22 sites in United States.
Trial summary
A multi-center randomized controlled clinical trial to evaluate Autonomic Regulation Therapy with the VITARIA system in patients with symptomatic heart failure and reduced ejection fraction. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure, Heart Failure, Congestive, Heart Failure, Systolic
- What is being tested?
- VITARIA System
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 533 participants
- Where
- 22 sitesUnited States
- Study dates
- 1 May 2018to 31 May 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age 18 or above
- Willing and capable of providing informed consent
- Capable of participating in all testing associated with this clinical investigation
- Stable, guideline-directed medical therapy for at least 4 weeks before subject screening. Unrestricted changes in diuretics are allowed during the 4 weeks, as long as the subject remains on a diuretic. If the use of an ARNI is being contemplated for a study subject, ARNI should be administered, and GDMT optimized, before the subject is randomized. No more than a 100% increase or 50% decrease of the dosage of any medication other than a diuretic is permitted. For these medications, medication changes within a class are allowed, as long as the equivalent dosage is within these specified limits
- Stable symptomatic heart failure NYHA class III; or NYHA class II with a heart failure hospitalization in the previous 12 months. HF hospitalization may include an overnight hospital or hospital-based observation unit stay with a primary diagnosis of HF, or an emergency department visit with a primary diagnosis of HF, and will in either case include documentation of intravenous HF therapy administration or other intervention for HF
- Left ventricular ejection fraction (EF) ≤ 35% and left ventricular end-diastolic diameter (LVEDD) < 8.0 cm, as confirmed by the core echocardiography laboratory during screening
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- N-terminal pro-BNP (NT-proBNP) level of at least 800 pg/mL, as determined by the core laboratory; or NT-proBNP level of at least 1200 pg/mL, as determined by the core laboratory, for patients with permanent atrial fibrillation or reporting signs or symptoms of atrial fibrillation at the time that the NT-proBNP sample is drawn
- Received a standard cardiac assessment, including history, physical exam, and electrocardiogram, and determined by a heart failure cardiologist and study surgeon to be an appropriate candidate for the study's surgical procedure
- Physically capable and willing to perform repeated 6-minute walk tests associated with the study, and having a baseline distance of between 150 and 450 meters. Symptoms limiting the duration of the 6 minute walk test must be due primarily to heart failure
Who cannot join
- Refractory symptomatic hypotension (systolic blood pressure below 80 mmHg)
- Complete AV block treated with unipolar pacemaker therapy
- Currently implanted vagus nerve stimulation (VNS) device, baroreceptor activation therapy (BAT) device, other nerve stimulator, artificial or donor heart, or ventricular assist device (VAD)
- Heart failure of non-ischemic origin for less than 6 months, or due to congenital heart disease, hypertrophic obstructive cardiomyopathy, or infiltrative cardiomyopathy (e.g. amyloidosis, sarcoidosis)
- Moderate (3+) or severe (4+) aortic valve or mitral valve stenosis; moderate (3+) or severe (4+) aortic valve insufficiency; or severe (4+) mitral valve insufficiency
- Symptomatic uncontrolled bradycardia
- On renal dialysis
- Involvement in any concurrent clinical study with an investigational therapy
Trial locations and contacts
22 sites in 1 country.
22 sites in 1 country
United States22 sites
University of Alabama
Birmingham, Alabama, 35294
Tufts Medical Center
Boston, Massachusetts, 02111
Lahey Medical Center
Burlington, Massachusetts, 01805
MetroHealth System
Cleveland, Ohio, 44109
Hartford Hospital
Hartford, Connecticut, 06102
Penn State Health Milton Hershey Medical Center
Hershey, Pennsylvania, 17033
Baylor St. Luke's Medical Center
Houston, Texas, 77030
University of Mississippi Medical Center
Jackson, Mississippi, 39216
First Coast Cardiovascular Institute
Jacksonville, Florida, 32256
Central Arkansas Veterans Healthcare System
Little Rock, Arkansas, 72205
Long Beach Memorial Hospital
Long Beach, California, 90806
Greater Los Angeles VA Medical Center
Los Angeles, California, 90073
University of Wisconsin
Madison, Wisconsin, 53792
Indiana University Health Ball Memorial Hospital
Muncie, Indiana, 47303
Mount Sinai School St. Luke's
New York, New York, 10025
UnityPoint Health - Methodist Hospital
Peoria, Illinois, 61606
Providence Sacred Heart Medical Center
Spokane, Washington, 99204
ProMedica Northwest Ohio Cardiology Consultants
Toledo, Ohio, 43606
University of Arizona
Tucson, Arizona, 85724
Tyler Cardiovascular Consultants
Tyler, Texas, 75701
Pinnacle Health
Wormleysburg, Pennsylvania, 17043
Michigan Heart, PC
Ypsilanti, Michigan, 48197
About this study
Official title: Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure With Reduced Ejection Fraction
A multi-center randomized controlled clinical trial to evaluate Autonomic Regulation Therapy with the VITARIA system in patients with symptomatic heart failure and reduced ejection fraction.
Read the detailed description
ANTHEM-HFrEF is a multi-center, open-label, randomized controlled clinical trial with an adaptive design. Patients with symptomatic heart failure and reduced LVEF will be enrolled and randomized 2:1 to receive VITARIA system implantation on the right cervical vagus nerve in addition to stable guideline-directed medical therapy (therapy), or to continue receiving stable guideline-directed medical therapy alone (control arm).
Subjects in the therapy arm will receive continuous, periodic VNS stimulation after surgery is completed, and will undergo visits for VNS up titration over a period of 3 months. Subjects in the control arm will also undergo scheduled visits at a similar frequency as the titration visits that are scheduled for subjects in the therapy arm. Data for safety and efficacy assessments will be collected for both study arms at 4 weeks post-randomization, every 3 months for the first 12 months, and every 4 months thereafter.
- Being tested
- VITARIA System
- Keywords
- Vagus nerve stimulation
- Medical subject headings
- Heart Failure, Heart Failure, Systolic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VITARIA SystemDevice
Chronic stimulation of the right cervical vagus nerve
| Study group | Role | What they receive |
|---|---|---|
| Therapy | Experimental | VITARIA system implantation on the right cervical vagus nerve in addition to stable guideline-directed medical therapy Receives: Device: VITARIA System |
| Control | No intervention | Stable guideline-directed medical therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Event-free rate
The event-free rate, through 90 days after VITARIA implantation, from all VITARIA system-related and VITARIA implantation-related serious adverse events, as adjudicated by the Clinical Events Committee
Measured: 90 days
Cardiovascular mortality and HF hospitalization
A composite of cardiovascular mortality or heart failure hospitalization, as adjudicated by the Clinical Events Committee, based on time to first event after randomization
Measured: Through study completion, an average of 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Feb 2018
- Study start1 May 2018
- Primary completion31 May 2023
- Study completion31 May 2023
Why it stopped: Company decision to stop enrolling not associated with any safety concerns.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Heart FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 533 participants (actual)
Sponsor and investigators
- Lead sponsor
- LivaNova
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03425422
- Sponsor's protocol ID
- C-07
- Status last verified
- Oct 2023
- First submitted
- 26 Jan 2018
- Last updated
- 10 Oct 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- No
Publications
Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, DiCarlo LA, Ardell JL, Rector TS, Amurthur B, KenKnight BH, Anand IS. Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial. J Card Fail. 2014 Nov;20(11):808-16. doi: 10.1016/j.cardfail.2014.08.009. Epub 2014 Sep 1.
PubMed 25187002Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, DiCarlo LA, Ardell JL, Rector TS, Amurthur B, KenKnight BH, Anand IS. Extended Follow-Up of Patients With Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study. J Card Fail. 2016 Aug;22(8):639-42. doi: 10.1016/j.cardfail.2015.11.002. Epub 2015 Nov 11.
PubMed 26576716Konstam MA, Udelson JE, Mann DL, DiCarlo L, Butler J, Ardell J, De Ferrari GM, Klein HU, Filippatos G, Metra M, Anand I, Close N, Saville BR, Detry MA, Paulon G, Khandwala F, Bosse A, KenKnight B, Mindrebo S, Rice P, Trifunovic N, Popescu MI, Apostolovic S, Adler A, Parker JD, Teerlink JR; ANTHEM-HFrEF Investigators. Vagal Nerve Stimulation in Patients With Heart Failure and Reduced Ejection Fraction: The ANTHEM-HFrEF Trial. J Am Coll Cardiol. 2026 Jun 30;87(25):3490-3502. doi: 10.1016/j.jacc.2026.03.040. Epub 2026 May 20.
PubMed 42159539Konstam MA, Udelson JE, Butler J, Klein HU, Parker JD, Teerlink JR, Wedge PM, Saville BR, Ardell JL, Libbus I, DiCarlo LA. Impact of Autonomic Regulation Therapy in Patients with Heart Failure: ANTHEM-HFrEF Pivotal Study Design. Circ Heart Fail. 2019 Nov;12(11):e005879. doi: 10.1161/CIRCHEARTFAILURE.119.005879. Epub 2019 Nov 14.
PubMed 31722536
Study at a glance
From the registry record, last updated by the sponsor on 10 Oct 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure With Reduced Ejection Fraction
- ClinicalTrials.gov ID
- NCT03425422
- Acronym / sponsor ID
- C-07
- Keywords
- Vagus nerve stimulation
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Company decision to stop enrolling not associated with any safety concerns.
- Enrolment
- 533 participants (actual)
- Lead sponsor
- LivaNovaIndustry (pharma, biotech, devices)
- Study start
- 1 May 2018 (actual)
- Primary completion
- 31 May 2023 (actual)
- Study completion
- 31 May 2023 (actual)
- First posted
- 7 Feb 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A multi-center randomized controlled clinical trial to evaluate Autonomic Regulation Therapy with the VITARIA system in patients with symptomatic heart failure and reduced ejection fraction.
Detailed description
ANTHEM-HFrEF is a multi-center, open-label, randomized controlled clinical trial with an adaptive design. Patients with symptomatic heart failure and reduced LVEF will be enrolled and randomized 2:1 to receive VITARIA system implantation on the right cervical vagus nerve in addition to stable guideline-directed medical therapy (therapy), or to continue receiving stable guideline-directed medical therapy alone (control arm).
Subjects in the therapy arm will receive continuous, periodic VNS stimulation after surgery is completed, and will undergo visits for VNS up titration over a period of 3 months. Subjects in the control arm will also undergo scheduled visits at a similar frequency as the titration visits that are scheduled for subjects in the therapy arm. Data for safety and efficacy assessments will be collected for both study arms at 4 weeks post-randomization, every 3 months for the first 12 months, and every 4 months thereafter.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Therapy | Experimental | Device: VITARIA SystemVITARIA system implantation on the right cervical vagus nerve in addition to stable guideline-directed medical therapy |
| Control | No intervention | –Stable guideline-directed medical therapy |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Age 18 or above
- Willing and capable of providing informed consent
- Capable of participating in all testing associated with this clinical investigation
- Stable, guideline-directed medical therapy for at least 4 weeks before subject screening. Unrestricted changes in diuretics are allowed during the 4 weeks, as long as the subject remains on a diuretic. If the use of an ARNI is being contemplated for a study subject, ARNI should be administered, and GDMT optimized, before the subject is randomized. No more than a 100% increase or 50% decrease of the dosage of any medication other than a diuretic is permitted. For these medications, medication changes within a class are allowed, as long as the equivalent dosage is within these specified limits
- Stable symptomatic heart failure NYHA class III; or NYHA class II with a heart failure hospitalization in the previous 12 months. HF hospitalization may include an overnight hospital or hospital-based observation unit stay with a primary diagnosis of HF, or an emergency department visit with a primary diagnosis of HF, and will in either case include documentation of intravenous HF therapy administration or other intervention for HF
Key exclusion criteria (8 listed)
- Refractory symptomatic hypotension (systolic blood pressure below 80 mmHg)
- Complete AV block treated with unipolar pacemaker therapy
- Currently implanted vagus nerve stimulation (VNS) device, baroreceptor activation therapy (BAT) device, other nerve stimulator, artificial or donor heart, or ventricular assist device (VAD)
- Heart failure of non-ischemic origin for less than 6 months, or due to congenital heart disease, hypertrophic obstructive cardiomyopathy, or infiltrative cardiomyopathy (e.g. amyloidosis, sarcoidosis)
- Moderate (3+) or severe (4+) aortic valve or mitral valve stenosis; moderate (3+) or severe (4+) aortic valve insufficiency; or severe (4+) mitral valve insufficiency
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VITARIA SystemChronic stimulation of the right cervical vagus nerve | Device | Therapy |
Primary outcome
Event-free rate
Time frame: 90 days
The event-free rate, through 90 days after VITARIA implantation, from all VITARIA system-related and VITARIA implantation-related serious adverse events, as adjudicated by the Clinical Events Committee
Cardiovascular mortality and HF hospitalization
Time frame: Through study completion, an average of 2 years
A composite of cardiovascular mortality or heart failure hospitalization, as adjudicated by the Clinical Events Committee, based on time to first event after randomization
Results and safety
The study was stopped early (reason given: Company decision to stop enrolling not associated with any safety concerns.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Oct 2023.
- Background: PubMed 25187002Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, DiCarlo LA, Ardell JL, Rector TS, Amurthur B, KenKnight BH, Anand IS. Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial. J Card Fail. 2014 Nov;20(11):808-16. doi: 10.1016/j.cardfail.2014.08.009. Epub 2014 Sep 1.
- Background: PubMed 26576716Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, DiCarlo LA, Ardell JL, Rector TS, Amurthur B, KenKnight BH, Anand IS. Extended Follow-Up of Patients With Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study. J Card Fail. 2016 Aug;22(8):639-42. doi: 10.1016/j.cardfail.2015.11.002. Epub 2015 Nov 11.
- Derived from this study: PubMed 42159539Konstam MA, Udelson JE, Mann DL, DiCarlo L, Butler J, Ardell J, De Ferrari GM, Klein HU, Filippatos G, Metra M, Anand I, Close N, Saville BR, Detry MA, Paulon G, Khandwala F, Bosse A, KenKnight B, Mindrebo S, Rice P, Trifunovic N, Popescu MI, Apostolovic S, Adler A, Parker JD, Teerlink JR; ANTHEM-HFrEF Investigators. Vagal Nerve Stimulation in Patients With Heart Failure and Reduced Ejection Fraction: The ANTHEM-HFrEF Trial. J Am Coll Cardiol. 2026 Jun 30;87(25):3490-3502. doi: 10.1016/j.jacc.2026.03.040. Epub 2026 May 20.
- Derived from this study: PubMed 31722536Konstam MA, Udelson JE, Butler J, Klein HU, Parker JD, Teerlink JR, Wedge PM, Saville BR, Ardell JL, Libbus I, DiCarlo LA. Impact of Autonomic Regulation Therapy in Patients with Heart Failure: ANTHEM-HFrEF Pivotal Study Design. Circ Heart Fail. 2019 Nov;12(11):e005879. doi: 10.1161/CIRCHEARTFAILURE.119.005879. Epub 2019 Nov 14.
- ANTHEM-HFrEF Study SiteLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
22 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing VITARIA System in people with Heart Failure and Heart Failure, Congestive, run by LivaNova at 22 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 10 Oct 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 22 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: Company decision to stop enrolling not associated with any safety concerns.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Event-free rate (time frame: 90 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03425422, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Oct 2023; AzTrials last refreshed its copy on 28 Oct 2026.