AV-Node Stimulation to influence heart failure markers in Acutely Decompensated Heart Failure patients

The overall prognosis of heart failure (HF) patients remains poor despite
advances made in the treatment of heart failure with drugs, implantable
cardioverter defibrillators and cardiac resynchronization devices. Increased
sympathetic tone and reduced parasympathetic tone contribute to the progression
of heart failure by affecting arrhythmia occurrence and remodeling. An
increased parasympathetic tone by vagal stimulation might limit cardiac
remodeling by affecting the release of anti-inflammatory compounds and
maintaining connexin-43 activity. Also, an increased parasympathetic tone might
limit arrhythmia occurrence as found in various animal models, by inducing
bradycardia, increasing the refractory period, bringing the restitution slope
lower than 1, affecting nitric oxide release and acetylcholine release.
Importantly, an increased parasympathetic output affects sympathetic output via
remodeling of the stellate ganglia neurons and might affect sympathetic output
of the cardiac plexus, since both systems are connected at this location.
Sympathetic activation in return increases the vasoconstrictor tone,
accompanied by activation of the renin-angiotensin-aldosteron-system (RAAS) and
the endothelin 1 and vasopressin system, which may be responsible for
peripheral organ dysfunction and damage in the setting of congestive HF.

The autonomic disbalance is more profound in acute decompensated than in
chronic heart failure. Furthermore, vagal withdrawal has been shown to precede
acute decompensation. Thus, it is expected that affecting autonomic balance
might be more beneficial in acutely decompensated than in chronic heart failure
for example by preventing peripheral organ dysfunction. In addition to the
mechanisms mentioned above for heart failure in general, it was recently
hypothesized that in acute decompensated heart failure an endogenous fluid
shift from the splanchnic bed is triggered by an increase in sympathetic tone
causing vasoconstriction in the splanchnic bed, a mechanism that can
translocate blood rapidly into the effective circulating volume, generating the
raised venous pressure and congestion seen in ADHF. Episodes of autonomic
disbalance for example due to hypoxia or increased chemosensitivity might
affect the endogenous fluid shift. Potentially, by increasing parasympathetic
output of the heart, the endogenous fluid shift can be prevented via decreasing
sympathetic output of the heart via the stellate ganglion and cardiac plexus.

An approach to influence the autonomic balance has been studied in various
animal models and recently in chronic heart failure patients by promoting
parasympathetic activity using a vagal cuff (VNS). Recently a multicenter
open-label phase II safety and feasibility study was reported using the system
of Biocontrol (Cardiofit). Results with respect to left ventricular ejection
fraction (LVEF), NYHA class, Quality of Life and 6 minute walk distance were
favorable in 32 patients after 6 months. However, beneficial effects were
accompanied by serious adverse events. In the ANTHEM-HF study 25 patients were
implanted at the left or right vagal nerve. After 12 months, LVEF, NYHA class,
non-sustained VT, heart rate variability and T-wave alternans were
significantly reduced. Although some outcome measures exhibited a trend toward
higher efficacy with right-sided stimulation, implant side did not appear to be
a statistically significant factor. Note that in the ANTHEM-HF study a
frequency of 10Hz was used and in the Biocontrol study a frequency of only 1-2
pulses. Based on previous experience with AVNS the value of 50Hz is considered
optimal. In addition, the NECTAR-HF study of Boston Scientific evaluated VNS
using a cuff approach with a much lower voltage than in the Biocontrol study
and reported no effect on LVEF, although an effect was found on Quality of Life
measures.The disadvantage of the vagal cuff approach is that it is invasive and
might result in adverse events such as infection leading to nerve damage. In
addition it requires the implantation of a separate system in cardiac patients.

The action of vagal stimulation is not necessarily directly on the heart, i.e.
via the efferent system but could also be via the afferent system. This was
postulated by Dr. Rossi et al. who found an effect of epicardial ganglionated
plexus stimulation on the post-operative inflammatory response in coronary
artery bypass grafting (CABG) patients. Furthermore, an effect of low-level
transcutaneous electrical vagal tragus stimulation on atrial fibrillation and
cytokines was found in dogs. This means that it may not be necessarily the
trunk that needs to be stimulated but that it might be sufficient to stimulate
a vagal cardiac branch/plexus to obtain an effect on systemic parameters like
autonomic balance reflected in cathecholamines and inflammation markers. Both
could potentially influence remodeling. A vagal branch could be reached by
stimulating the parasympathetic nerves affecting the AV-node intra-cardially
using a standard atrial lead. Besides affecting heart failure via an effect on
autonomic balance and inflammation, this could also affect the VR during AT/AF.
Patients with acutely decompensated heart failure often have AT/AF, which
worsens the heart failure.

The advantage of such an intra-cardiac therapy would be that it could be
combined with a pacemaker/ICD device and no extra risk or costs are introduced.
The ultimate aim would be to prevent acutely decompensated heart failure
periods by stimulating an intra-cardiac vagal branch. Such a study will require
long term follow-up of heart failure patients and dedicated software. As a
first step, an acute study will be performed in acutely decompensated heart
failure patients, in which such a therapy might be a last resort. In this
population the effect on surrogate end-points like heart failure markers,
catecholamines, inflammation markers, kidney parameters, heart rate
variability, arrhythmias and ventricular rate will be assessed. Since no good
therapies are available for acutely decompensated heart failure, it is expected
that AV-node stimulation (AVNS) might also appear to be a valuable temporary
therapy for patients who enter the hospital with acutely decompensated heart
failure. The acute therapy might help to prevent organ damage. In this way
potentially hospitalizations and mortality can be decreased.

AVNS will be performed for 24 hours, since after 24 hours an effect was found
with medication on our primary objective NT-proBNP (see sample size
calculation). In addition, a statistically significant effect was found after 3
hours of AVNS on inflammation markers. Additional literature review,
pre-clinical testing and previous clinical experience will be reported in the
Investigator*s Brochure (IB).

The purpose of the research trial is to assess if heart failure markers and
clinical end-points are influenced by 24 hours of AV-node stimulation (AVNS) in
acutely decompensated heart failure (ADHF) patients.

Primary Objective(s)
The primary objective is to demonstrate that the AVNS treatment together with
the standard drug therapy for acutely decompensated heart failure (ADHF)
patients is able to maintain the level of amino-terminal fragment of the B-type
natriuretic peptide prohormone (NT-proBNP) plasma concentration significantly
lower than the standard drug therapy alone 24 hours after time 0. Time 0 is
set for both groups around 9:00 ± 1 hour in the morning the day after the
patient has been hospitalized to eliminate the effect of circadian variation in
blood markers on the difference between groups. For AVNS patients AVNS will
start at time 0.

Secondary Objectives

Local norepinephrine
To evaluate the performance of AVNS in affecting autonomic balance as assessed
by coronary sinus sampled norepinephrine and epinephrine measurements within
the patient during intra-operative stimulation testing.

Inflammatory status
To evaluate the performance of AVNS in affecting inflammatory status as
assessed by measurements of Interleukin (IL)-6, tumor necrosis factor
(TNF)-alfa in the treatment group compared to the control group over 24 hours.

Preventing heart failure deterioration
To evaluate the performance of AVNS in preventing heart failure deterioration
as assessed by measurements of Troponin T and amino-terminal fragment of the
B-type natriuretic peptide prohormone (NT-proBNP) level in the treatment group
compared to the control group over 24 hours.

Kidney function
To evaluate the performance of AVNS in affecting kidney function as assessed by
measurements of aldosterone and renin concentration as well as by diuretic
response in the treatment group compared to the control group over 24 hours.

Safety of the AVNS procedure
To evaluate the safety of the investigational procedure by assessing:
a. Adverse events and serious adverse events related to AVNS and Adverse events
related to selective atrial lead placement at implant and in the follow-up
period in both study phases, training and AVNS;
b. Burden of arrhythmias for 24 hours after time 0 in the AVNS phase;
c. ADHF symptoms in the AVNS phase for 24 hours after time 0.

Data gathering for further possible applications of AVNS
To gather data for further possible applications of AVNS:
a. The performance of AVNS in decreasing mean ventricular rate VR and its
standard deviation over
during first 24 hours after time 0;
b. The effect of AVNS on cardiac output (CO) change derived from arterial
finger pressure over 24 hours after time 0 compared to the control group
c. The effect of AVNS on heart rate variability (HRV) during the during first
24 hours after time 0 compared to the control group;
d. Medication therapy of the treatment group compared to the control group
during during first 24 hours after time 0;
e. The effect of the 24 hour AVNS therapy on heart failure hospitalizations and
mortality after 6 months follow-up.

The study is designed in two phases called training and AVNS phase
respectively. Patients will take part in the training or AVNS phase but not in
both. Patients of both phases, training and AVNS, satisfying all inclusion
criteria and none of the exclusion criteria for the respective phase are
eligible for this study. This will be a multi-center trial.
The training phase will allow investigators without a documented experience in
positioning the atrial lead at the specific AVNS septal position to be trained
on atrial lead placement. All patients that are candidates for a dual chamber
cardiac device implantation (IPG, ICD, CRT cardiac devices) in accordance with
the current guideline are eligible to be enrolled in the training phase. The
expected length of time that a patient will be in the training phase is in
total about 2-6 weeks, consisting of the acute procedure phase of 1 hour
(training) and a follow-up 4 weeks (± 2 weeks) after implantation.
The second phase, the so-called AVNS phase, will consider exclusively patients
in ADHF. Only patients of AVNS phase will be randomized.
The expected length of time a patient will be in the study is in total about 6
months, consisting of the acute procedure phase of 24 hours, a first follow-up
1 month (± 2 weeks) after hospital discharge and a final follow-up at 6 months
(± 2 weeks) after hospital discharge. The expected time of participation in the
clinical study for the clinical center is 30 months.

Training phase procedure
In the training phase the procedure will coincide with a cardiac device
implantation. Subjects will undergo a standard implant procedure with the
exception of atrial lead placement, which will be placed at the AVNS position.
The atrial lead implant time will be limited to an hour. If not successful
within an hour the lead will be placed at a standard position.

AVNS phase procedure
The procedure visit will start as close as practical to 9:00 AM ± 1 hour in the
morning (before time 0, see definition in Appendix L.4). Before the procedure
visit, patients will be randomly assigned to either AVNS or to the control
group. Both groups will continue receiving the standard treatment as
recommended in the current guideline to manage heart failure patient. In
addition to the standard treatment, AVNS patients will receive the AVNS
treatment for 24 hours. To do so, an atrial lead will be implanted. The maximum
lead implant time will be limited to one hour.

Potential Risks

It is anticipated that subjects enrolled in this study in the training group or
AVNS treatment group will be exposed to the same risks associated to being
implanted with an atrial lead during pacemaker implantation. Only those
potential adjunctive risks associated to the participation to this study are
listed in this section and include, but are not limited to the following
procedures:

Training group.
The atrial lead is placed at a non-conventional position. In a previous study
lead dislodgement during the follow-up period of half a year occurred in 2/32
cases, i.e. 6%. This was not significantly different from the amount of
dislodgements at a standard position. One dislodgement occurred within the
first 24 hours;
Mitigation: after implant, within 24 hours after implant, and before hospital
discharge and at the 1 month follow-up visit a pacing tests will be performed
to test atrial lead dislodgement, which is common clinical practice.

AVNS and training group
- Delivery of AVNS in the absence of AT or AF may result in atrial arrhythmia.
Mitigation: It was found in animal studies that low voltage stimulation of the
vagal nerve is anti-arrhythmic in the atrium [32], [33], [9]. However, these
studies concern one aspect of our stimulation which is vagal nerve stimulation.
It can not be excluded that simultaneous stimulation of the atrial myocard at
low voltages during sinus rhythm is enhancing AT/AF inducibility. Therefore,
during sinus rhythm the bursts will be synchronized on the P-wave and will not
induce atrial arrhythmias. In case the sinus rhythm converts to AT/AF the
physician will manually reset the burst trigger so that it will be triggered on
the QRS and burst stimulation is still given once per cardiac cycle. Another
scenario could be that the atrial arrhythmia stops and triggering is still on
the QRS. In that case an alarm (hospital equipment intensive care unit) will
notify the physician or nurse to reset the triggering on the P-wave. Even if
during sinus rhythm, the triggering is for a short period on the QRS the
re-induction of AT/AF is not expected, with a negative capture test at 10.5 V,
but cannot be excluded.

- There is a remote possibility that the AVNS burst pacing induces a
ventricular arrhythmia.
Mitigation: During AT/AF the AVNS burst pacing is triggered on the QRS and
there is little chance to induce ventricular arrythmias. During sinus rhythm, a
high output during the AVNS bursting synchronized on the P-wave, imposes a risk
for the occurrence of ventricular arrhythmia. The tests deliveCONSENTred at
baseline with high output (10.5V) ensure that ventricular capture does not
occur during atrial burst pacing equal or below 4V. In addition, defibrillation
patches will be placed on the patient to potentially defibrillate in the
unlikely event (0.1-1%) a ventricular arrhythmia occurs.

- In the presence of AT/AF, AVNS is programmed to be triggered on the QRS and
ventricular oversensing may result in inappropriate deployment of AVNS therapy
outside the ventricular refractory period and may induce a ventricular
arrhythmia.
Mitigation: First appropriate ventricular sensing will be checked. The
Cardiotek device uses filters (see Cardiotek manuals) to correct for strong
movements of the patient and artifacts on the ECG. In case of ECG dislodgement
there will be no signal and no triggering. As a safety measure a refractory
period to prevent a too high frequency of activation will be programmed.

- The AVNS burst pacing could cause the VR to slow to an inappropriate rate.
Mitigation: During the implant the voltage will be titrated so that the VR will
not drop below 50 bpm due to AVNS. In case of changing during 24 hoursaddition,
the monitoring system of the ICU will alarm if rates below 50 bpm occur. In
that case the voltage will be adapted.

- AVNS at 4Volt may give symptoms to the patient.
Mitigation: In case of symptoms the voltage will be lowered to a level which is
not causing symptoms for the patient. Note that in a previous AVNS study, in
some patients symptoms were noted like muscular and chest pain at 8V, but none
at 6V [24]. In this study an amplitude of 4V or lower will be used.

- Placing the lead will subject the patient in the AVNS and training group to
X-ray radiation.
Mitigation: In the AVNS group the X-ray exposure and time is not expected to
exceed the rontgen exposure and time during a conventional CRT implant and is
therefore considered acceptable.
In the training group additional X-ray radiation is expected since the atrial
lead positioning might take longer. To prevent too much radiation the atrial
lead placement procedure is limited to one hour.
- Standard adverse events associated with leads of CRT, ICD devices and their
implantation.
Mitigation: Risks normally associated with leads of CRT, ICD devices and their
implantation will be minimized by selecting investigators who are experienced
in the diagnosis and treatment of patients with HF patients as well as with
tachy and brady arrhythmia management and in the implantation of the cardiac
devices.


AVNS and control group
- During the AVNS study blood samples from the venous system are taken and
might lead to bruising.
Mitigation: experienced hospital staff will take the venous samples. The venous
line will be standard of care, but may cause bruising in 1-10% of the cases.

AVNS group
- During the AVNS study, the atrial lead may become dislodged and may induce
arrhythmia.
Mitigation: Electrical characteristics (impedance, threshold, sensing, FFRW))
of the atrial lead will be assessed directly after implant before stimulation
and at 1, 6, and 24 hours after the start of stimulation to confirm adequate
lead positioning. In case lead positioning is not adequate after the implant
procedure the lead will be removed. In a previous study in which 32 patients
obtained a chronic AVNS lead it was found that in one patient an atrial lead
dislodgement occurred in the first 48 hours. Thus, in the 2 days after lead
implantation there is a small risk (3%) that the lead becomes dislodged.

In the case of dislodgement of atrial lead into ventricle:
During AF/AT:
If the burst triggering signal is still set to atrial events: since the lead
senses in case of dislodgement not the atrial senses, but possibly the
ventricular events, it might stimulate the ventricle (during its refractory
period). If the burst triggering signal is already set to ventricular events
(via ECG): the burst train is short enough to be completed within the
ventricular refractory period and will not cause ventricular arrhythmias. Our
animal study provided no evidence of ventricular pro-arrhythmia due to delivery
of AVNS burst pulses in the ventricles, as long as the pulse train was within
200ms after the QRS. In patients, the lowest 95% CI of ventricular refractory
period over 24 hours was found to be between 269 and 283 ms. Since it will be
delivered in burst trains within 170 ms it is assumed that the risk to induce a
ventricular arrhythmia in this case is small. In our previous chronic AVNS
study with 32 patients no ventricular arrhythmias were found to be induced
shortly after the start of AVNS, synchronized on the QRS if stimulating with
8V, 1.5 ms.

During Sinus Rhythm:
In the event that during sinus rhythm the lead would dislodge into the
ventricle, AVNS therapy would be synchronized on the signal sensed by the lead,
this means on the QRS instead of the P-wave. The burst train is short enough to
be completed within the ventricular refractory period and will not cause
ventricular arrhythmias., which was the intention of the programming.
However, in the unlikely event that the dislodgement occurs during a burst it
is possible that the stimulation is triggered on P-wave and stimulates the
ventricle. The first stimulus will then stimulate the ventricle and make it for
the rest of the stimuli refractory. This may also happen in the unlikely case
the lead is dislodged in the atrium and is close to tricuspid valve. The
patient will be continuously monitored on the intensive care. In the unlikely
event (0.1-1%) of the occurrence of a VT/VF the patient can be defibrillated
with the equipment available at the bed of the patient.
In summary, even if not anticipated, risks related to the above described
procedures may include the induction or prolongation of atrial tachycardia or
AFfibrillation, and the induction of ventricular tachycardia or fibrillation.
This study has been designed to minimize these risks.
Subjects will be compensated in the event of injury arising from participation
in the clinical investigations. Arrangements for additional health care for
subjects required as a result of an adverse device effect shall be made and
documented in the investigator site file.
Potential Benefits

The potential clinical benefit for patients in the AVNS therapy arm could be
that there is a decrease in heart failure deterioration as indicated by
ejection fraction and blood markers. Furthermore, the effect of fast conducted
atrial fibrillation on ventricular rateVR will might be eliminated. Patients in
the control group will be monitored more closely during the study procedure/
visits than standard medical care. The potential benefit for subjects in the
training phase could be that their lead is located in the AVNS position,
allowing the use of a potential future download to reduce the ventricular rate
during fastly conducted AT/AF to prevent inappropriate shocks or preventing
heart failure worsening. Moreover, results of two prospective randomized
studies indicate that septal pacing, when compared to the traditional right
atrial appendage pacing, significantly reduces : (1) paroxysmal AF recurrences
and burden; and (2) progression to chronic AF. However, this benefit was not
seen in another study.