Rate Adaptive Atrial Pacing in Heart Failure Patients with Chronotropic Incompetence

Patients with congestive heart failure caused by systolic left ventricular (LV)
dysfunction often suffer from chronotropic incompetence (CI). Prevalence rates
vary from 24% up to 72% dependent on the degree of heart failure and the
definition of CI, and seem independent of beta-blocker usage. While the normal
heart increases both heart rate and stroke volume in response to increased
demand, contractility reserve is largely lost in the failing heart thus
rendering increases in cardiac output (CO) primarily dependent on
cardio-acceleration. Insufficient cardio-acceleration due to CI is therefore
considered to be a significant limiting factor in the exercise capacity of
heart failure patients.
A substantial part of this patient population will be eligible for implantation
of an ICD/CRT-D device, thus offering an unique opportunity to study heart rate
by routinely recorded variables. Moreover, these devices offer the possibility
of treatment of CI by rate adaptive (atrial) stimulation based on the
incorporated activity sensor. Most ICD/CRT-D manufacturers include
accelerometer sensors in their devices, which have known drawbacks since these
sensors are insensitive for activity not related to body movements (e.g.,
isometric exercise, mental stress, or metabolic inadequacy consequent to
pathologic conditions). Recently, however, Boston Scientific has incorporated a
minute ventilation (MV) sensor in their ICD/CRT-D's. This sensor provides a
superior index for metabolic demand, and has successfully been utilized in
pacemakers. Although studies mentioned above suggest that CI in congestive
heart failure affects a substantial portion of the heart failure population,
literature on the subject as well as on its treatment by rate adaptive
stimulation is scarce, and has drawn limited attention. Small scale studies
have shown rate responsive pacing to be associated with improvement in walking
distance and exercise tolerance especially in patients with severe CI. To date,
the MV sensor has not been systematically evaluated in CI patients with
congestive heart failure.

Please refer to chapter 1 of the protocol (introduction and rationale)

Primary Objective
The primary objective of this pilot study is to assess the ability of MV sensor
driven rate adaptive atrial stimulation to restore the quality of life in CI
heart failure patients.

Secondary Objective(s)
The secondary objectives of this study are:
- Improvement of functional capacity in CI heart failure patients. 6MWT with
and without rate adaptive atrial pacing using the MV sensor will be compared;
- Assessment of the reversibility of CI by rate adaptive atrial pacing using a
MV sensor;
- Assessment of the effect of rate adaptive atrial pacing on clinical status
and daily activity level.

Please refer to chapter 2 of the protocol (objectives)

This is a prospective randomized, double-blind, crossover trial in a
multi-center setting. Prior to initiating a full scale study, this pilot study
will be performed in the Vrije Universiteit Medical Center (VUMC), Noordwest
Ziekenhuisgroep location Alkmaar (NWZ) and University Medical Center Utrecht
(UMCU). All HF patients who received a Boston Scientific dual chamber ICD/CRT-D
equipped with MV sensor for metabolic-demand driven rate adaptive pacing can be
evaluated for the study. At least one month after implantation, CI patients
will be identified using the modified heart rate score (mHRS) or the Age
Predicted Maximal Heart Rate (APMHR). The mHRS can be calculated from the rate
histogram provided by the ICD/CRT-D; the APMHR cal be calculated based on an
exercise test(see chapter 6.2.1). Patients diagnosed with CI will be included
in the study after receiving written informed consent. Study subjects will
undergo a set of evaluations at baseline: New York Heart Association (NYHA)
functional class assessment, quality-of-life evaluation (QoL) using the
Minnesota Living with Heart Failure Questionaire, six-minute walking test
(6MWT) and interrogation of the ICD/CRT-D (heart rate histograms and activity
level). Subsequently, all patients enter the double blind randomized cross-over
study. In the cross-over study, patients will be randomized in a 1:1 fashion to
either rate responsive (MV only) function ON (AAIR-50) or OFF (DDI-50). MV
sensor optimization will be performed with the Sensor replay in Rightrate
technology using the intrinsic heart rate (HR) curve obtained during the latest
6MWT (same day). The MV sensor activity will be used to aim at achieving an
maximum heart rate (upper rate) based on the derived equation [119 +
0.5(resting HR) * 0.5(age)] for heart failure patients during exercise. The
pacing mode set by the pacemaker technician will not be disclosed to either
patients or the study physician. After one week the patient will send a
homemonitoring rapport, so the pacemaker technician can evaluate MV sensor
optimalization. After 3-4 months all CI patients will again undergo the test
set including NYHA assessment, QoL scoring, 6MWT and interrogation of the
ICD/CRT-D. Subsequently, the pacing mode will be switched to the opposite mode
(AAIR-50 to DDI-50 and vice versa). After one week, the patient will send a new
home monitoring rapport for the pacemaker technician. After another 3-4 months
all CI patients will undergo their final test set.

Please refer to chapter 3 of the protocol (study design)

In this study, the intervention is MV sensor driven rate adaptive atrial
stimulation as previously described.

Presently, the MV sensor driven rate adaptive atrial pacing function is widely
used in patients implanted with a pacemaker. More recently, Boston Scientific
also incorporated this function in their latest generation ICD/CRT-D*s. Since
this function aims to adapt heart rate to exercise, patients who are unable to
tolerate increased pacing rates will be excluded (for example patients with
severe ischemic heart disease). Furthermore rate adaptive pacing might have a
pro-arrhythmic effect. In case potentially dangerous ventricular arrhythmias
are initiated the ICD will act appropriately by anti-tachycardia pacing or
defibrillation. Risk for these severe cardiac arrhythmias, however, is very
small since rate adaptive pacing is performed by the atrial lead only. MV
driven rate adaptive pacing might be hazardous in patients with respiratory
rate abnormalities (hyperventilation) or use of a mechanical ventilator as this
may lead to inappropriate atrial overdrive pacing, therefore these patients are
excluded from the present study.
Subjects may have a direct benefit from the study as participation will result
in treatment of their CI. Small studies suggest that this leads to improvement
in functional capacity but large scale studies are lacking, therefore the
benefit of participation is described as *potential*.

Please refer to chapter 9.3 of the protocol (risk and benefit for the study
subject)