INcrease Of VAgal TonE in chronic Heart Failure (INOVATE-HF) - A randomized study to establish the safety and efficacy of Cardiofit for the treatment of subjects with heart failure and left ventricular dysfunction.
A pivotal trial to establish the long-term safety and efficacy of the cardiofit system.

The clinical syndrome of congestive heart failure (CHF) is the result of a
number of conditions affecting the heart, preventing the heart to properly meet
the systemic demands for blood circulation. Common conditions leading to heart
failure are: hypertension, ischemic heart disease, valvular disease, familial
cardiomyopathy and infectious, toxic, metabolic or idiopathic causes. In some
cases these conditions co-exist and accelerate the progression of ventricular
dysfunction.
Heart failure is a chronic disease, beginning with early signs of ventricular
remodeling and progressing to severe symptoms and functional handicap. When
cardiac failure ensues, the affected person experiences a decrease in the
ability to carry out activities of daily living characterized by symptoms of
fatigue and shortness of breath at increasingly minimal efforts. There is
general fluid retention manifested in most subjects by weight gain and edema
particularly of the feet and ankles.
The prognosis for subjects with heart failure is poor. Thirty to forty percent
of subjects with advanced disease and 5-10% of subjects with mild disease die
within five to ten years.
Heart failure has reached the size of a pandemic. It is estimated that over 5.5
million people in the USA alone suffer from the condition, with more than half
a million new cases diagnosed each year. Approximately 1.2 to 2% of the general
adult population suffer from heart failure, and in the age group over 65 years
old, the prevalence is as high as 10%. The cost of hospitalizations for heart
failure is twice that for most forms of cancer.
Pharmacologic antagonism of the beta-adrenergic system, potentially shifting
autonomic balance by blunting sympathetic drive, is a well-proven treatment for
heart failure subjects, although there are subjects who cannot tolerate, or
only partially benefit from such a treatment.
Experimentally, direct parasympathetic stimulation (via the vagus nerve) has
been shown to induce equivalent biological effects potentially by restoring
parasympathetic tone and reducing the workload of the heart. Therefore, the
potential benefits of vagus nerve stimulation for the treatment of heart
failure may be substantial. It has been shown before that vagus nerve
stimulation might reduce the occurrence of sudden death associated with healed
myocardial infarction. Recently it was shown that chronic stimulation of the
vagus nerve improved survival in a rat model of heart failure. Preliminary
preclinical data in the canine HF model (ischemic) demonstrates favorable
effects on remodeling.
Implanted neurostimulators, which stimulate the cervical vagus nerve, have been
successfully used in humans for treatment of refractory seizures and depression
for more than 10 years. The therapy is safe, well tolerated and associated with
few side effects.

To determine the efficacy and safety of the CardioFit system for the treatment
of subjects with systolic heart failure who have failed to achieve symptom
relief through standard evidence-based management per applicable guidelines.

This study is designed as a prospective, randomized, open label, prospective,
event-driven interventional global study.
It is expected that 650 subjects will be recruited to the study overall to
provide up to 400 events. The independent Data Safety Monitoring Board (DSMB),
Clinical Event Committee (CEC) and the FDA will review safety data for the
CardioFit system in an ongoing manner.

The implantation of the CardioFit* system (in the implanted arm) is due 7-21
days post-randomization and takes place in three steps as follows, per the
device IFU.
a. Implantation of the Intracardiac Sensing Electrode (ISE).
b. Implantation of the CardioFit* Stimulation Lead (CSL).
c. Implantation of the CardioFit* Implantable Stimulator (CIS).
In order to prevent infection, and inflammation the following preventive steps
will be taken:
(1) Subject will be provided with antibiotics pre- and post-procedure,
according to the clinical site policy on prevention of infective diseases; and
(2) During the procedure, preventive anti-infection measures will be taken such
as use of sterile technique and irrigation of the implant sites with
antibiotics; and
(3) Subjects who present with signs of infection, such as body temperature
above normal (37oC or 98.6o F will not be included in the study until those
signs are cleared.

The treated group:
Echo grafic controls at baseline and during follow-up
Blood testing at baseline and during follow-up
Questionaires regarding Quality of life
6minute walk testing
X-rays of the chest
Pulmonary function testing
Holter-recording
Implantation of the cardiofit device. This is a risk in this population, but
this is described above already.

Controle group:
Normal care, with a little more frequency of controle moments. The questionaire
and 6min walking test will be an extra moment/intervention for the patiënts,
but we don't think this will be a risk/problem for the patiënts.