Benefit of dual-chamber pacing with Closed Loop Stimulation (CLS) in tilt-induced cardio-inhibitory reflex syncope. A randomized double-blind parallel trial.

The latest update of the European Society of Cardiology (ESC) guidelines for
cardiac pacing has set a Class IIb (evidence B) indication for permanent
cardiac pacing in patients with tilt induced cardio-inhibitory response with
recurrent, frequent, unpredictable syncope and age >40 years after alternative
therapy has failed. The reason behind the indication is that randomized
clinical trials (RCTs) did not lead to a conclusive evidence due to some
limitations in study design and controversial results.

Consequently, the status quo is that pacing may be considered (Class IIb
indication) in patients with a cardio-inhibitory response to Tilt-Test (TT),
after any cardiac dysfunction likely leading to loss of consciousness and other
non-syncopal causes (including epilepsy, psychiatric, metabolic, drop-attack,
etc.) have been excluded.

On the other hand, the 2009 ESC guidelines for diagnosis and management of
syncope established that cardiac pacing showed higher evidence of benefit and
should be considered (Class IIa indication) in patients with frequently
recurrent reflex syncope, age >40 years and spontaneous cardio-inhibitory
episodes during long-term monitoring.

Recently, a sub-analysis of the ISSUE-3 showed that an asystolic response to TT
predicts similar clinical forms of asystolic syncopal events during follow-up
with an 86% probability, thus tracing back to a Class IIa indication for
cardiac pacing. This is the main reason why pacing is currently preferred in
structured Syncope Units and, more generally, in normal medical practice.

In most of the trials, a dual-chamber pacing mode was used with an automatic
feature (rate-response: R) promptly responding to heart rate drops by rapid DDD
pacing for a programmed interval (atrio-ventricular stimulation in DDD mode
with R function: DDDR). However, few small studies have reported that the
DDD-CLS mode may be effective as well. During the CLS mode intracardiac
impedance curves are collected during systolic phases by injecting subthreshold
high frequency current pulses. The waveforms of such rheometric signals are
influenced by contractility, and this principle is exploited to adjust the
pacing rate in normal rate responsive operation.

It has been hypothesized that the detection of an increase in contractility in
the early stage of a vasovagal syncope could allow the system to activate
atrio-ventricular pacing that may anticipate withdrawal of sympathetic tone and
counterbalance vagal tone reaction. Therefore
CLS would react early during a first sympathetic phase of the reflex, while
rate-drop response functions (R-function) would intervene after the vagal
reaction (bradycardia) has been already triggered for a while.

In conclusion, further research is extremely important as it is very likely to
have an important impact on recommendations.

Primary objective:
The study has the primary objective of comparing the time to the first syncopal
recurrence between
· active group (CLS): CLS in addition to DDD pacing mode.
· control group (CTL): sensing only, "ODO" mode (PM stimualtion
function "OFF")

It is suspected that the 2-year survival rate of syncopal recurrence in the
treatment arm is different from the 2-year survival rate of the control arm.

H0: SCLS(t=2 years) = SCTL(t=2 years)
H1: SCLS(t=2 years) * SCTL(t=2 years)


Secondary objective:
The Secondary endpoint will be the time to the first recurrence of pre-syncope
or syncope, whichever comes first, compared between the study groups during
follow-up.

It is suspected that the 2-year survival rate to the combined event of
pre-syncope or syncope is different in the two study groups.

H0: SCLS(t=2 years) = SCTL(t=2 years)
H1: SCLS(t=2 years) * S CTL(t=2 years)

Multicenter, international, randomized, placebo controlled, double blind,
interventional study.

Patients will be randomized to the active or to the placebo group immediately
after their enrolment and before any subsequent study-related procedure.
Both patient groups will implanted with a Biotronik pacemaker with the
capability of the CLS function.

- Active group: before post-implant hospital discharge, the pacemaker will be
programmed in a dual-chamber DDD pacing mode with the CLS function ON.

- Control group: before post-implant hospital discharge, the pacemaker will be
programmed in the "ODO" mode (sensing mode). During the "ODO" mode the
pacemaker does not deliver any pacing therapy, while it maintains all the
sensing and related diagnostic functions to monitor cardiac rhythm. The "ODO"
mode is outside the intended use of the pacemaker. The investigators of the
participating centers are able to program the pacemaker into the "ODO" mode via
a special code. The only difference compared to standard therapy is the
programming of the "ODO" mode in the control group (PM stimulation fucntion to
"OFF").

The implantation of the investigational device systems and the follow-up
procedures do not differ from the procedures in routine care with comparable
systems. Only CE market medical devices will be used according to their IFU,
only study sites and investigators with proven long-term experience in
pacemaker implantation will be included, only study sites and investigators for
whom the pacemaker therapy is routinely practiced in the patient population
enrolled in the BIOSync CLS study will be selected.

Nevertheless, patients will undergo a randomization procedure which will assign
each of them either to the treatment (pacing ON with CLS) or to the placebo.
Placebo will consist of the implantation of the investigational device and
subsequent programming with only sensing and diagnostic functions activated
("ODO" mode). The potential risks linked to the use of the "ODO" mode are
described in the CIP (section 6.2), the Investigator Brochure and the Risk
Analysis Document. Additional protective measures will be adopted within the
study setting in order to minimize the risks: programming of the "ODO" mode is
only possible with a special release code, the "ODO" mode will be de-activated
upon reaching the primary endpoint, there is an independent DSMB and 3 interim
analysis will be performed.

Previous studies (e.g., the ISSUE 3 trial) have shown that "ODO" mode is safe
in the study population: syncopal recurrences associated with trauma were rare
and as frequent as in the active arm; no deaths were reported. However, in
order to limit the risk of syncopal recurrences, a sequential study design will
be adopted (see sections 11.6 and 11.7 of the protocol).

Based on this methodology, the study will be stopped immediately when the
calculated number of events will be reached thus avoiding an unnecessary number
of extra events.

Participating patients may optionally undergo a tilt-test (TT) examination one
month after IPG implantation. TT is a safe procedure and often considered as
part of normal clinical practice in the study population, even after pacemaker
implant, to predict response to the therapy. There have been no reported deaths
nor severe complications during the tests.