Monitoring of hemodynamics in heart failure patients by intracardiac impedance measurement

Heart failure (HF) is a syndrome with a broad spectrum of heterogeneous
symptoms and signs caused by a cardiac dysfunction and resulting in a wide
range of clinical expression. The overall mortality for the population is 50%
in the first 4 years. 40% of the patients with HF-related hospitalizations have
to be readmitted to hospital or die within one year. Cardiac Resynchronization
Therapy (CRT) is used in order to synchronize interventricular and
intraventricular contraction pattern of the heart in patients with HF in whom
there is evidence of electrical dyssynchrony (QRS width >120 ms). The clinical
benefits of long-term CRT have been evaluated in a large number of randomized
multi-center trials. The results showed a significant alleviation of symptoms
and an increase in exercise capacity for patients with CRT as well as a lowered
risk for all-cause mortality and HF-related hospitalizations. A consistent
finding from the randomized trials has been an up to 15% absolute reduction in
LV end-diastolic diameter and an up to 6% absolute increase in LVEF following
initiation of CRT. These observations provide consistent evidence of a
significant, progressive, and sustained reverse remodeling effect conferred by
CRT. The management of patients with Heart Failure represents a substantial
economic burden, and cost for inpatient treatment of the patients is
responsible for >50% of this expense. The need for inpatient treatment arises
from acute deterioration of cardiac function, called decompensation. By
diagnosing an imminent cardiac decompensation in due time, acute decompensation
and hospitalization might be prevented by an early and adequate adaptation of
medical therapy. Improved diagnostic methods for assessment of the clinical
status of HF patients are therefore warranted.

New diagnostic tools and a wide range of sensor technology are nowadays
available for patients being implanted with a pacemaker, ICD or CRT-D device
for therapeutic reasons. As a commonly used approach, accumulation of thoracic
fluid can be detected by implants using thoracic impedance (TI) measurement.
Its efficacy to predict cardiac decompensation was not yet satisfactory due to
an insufficient sensitivity and specificity profile in clinical trials.
Therefore, for detection of imminent cardiac decompensation a continuous
monitoring of the hemodynamic status of the heart may be a more adequate
approach. At present, the assessment of the pump function of the heart can only
be realized using time-consuming and sophisticated methods like e.g.
echocardiography (which is the current standard) or invasive methods like
catheterization. It is hypothesized that intracardiac impedance measurement
(ICI) by Biotronik implemented in a new generation of CRT-D devices can be used
for providing information of the hemodynamic status of the heart. The
underlying working principle of the ICI is based on the different electrical
conductance of blood and the surrounding cardiac tissue. A current is injected
via the RV-lead coil and tip which is conducted by the blood and myocardial
tissue between and around the injecting electrodes. Voltage is sampled via tip
and ring of the LV-lead which is positioned in an epicardial vein on the left
ventricle of the patient. As the current passes through the left ventricle of
the patient, the measured intracardiac impedance is affected by the blood
filling state and the diameter of the ventricle, the latter determines the
distance of the RV- and LV-lead. The larger the left ventricle, and the more
filled with blood, the smaller is the intracardiac impedance value. Constant
current injections are performed at intervals of 8 ms so that impedance data
for the whole heart cycle may be collected. Intracardiac impedance measurements
do not provide absolute, but relative measurands of hemodynamic parameters.
Therefore, serial measures recorded over a period of time or data collected
prior to and after a change of conditions (like e.g. overdrive-pacing at higher
heart rate for provoking immediate hemodynamic changes) are required for
meaningful comparisons.

In animal and acute human studies, the impedance measurement proved to provide
reliable data for detection of LV-volume changes (especially stroke volume
changes) in acute settings. This study was designed to non-invasively
investigate the relationship of hemodynamic measurands and intracardiac
impedance data in a larger patient collective. Echocardiography is the common
non-invasive clinical standard for diagnosis of HF and allows the determination
of SV. It is widely available, non-invasive, and safe. Therefore,
echocardiography as the current non-invasive gold standard was chosen as the
primary reference method. Additionally, the Finapres-method will be used in a
subset of patients. This method records blood-pressure tracings from a finger
cuff and allows the determination of SV in a non-invasive manner. The
Finapres-method allows the continuous beat-to-beat evaluation of SV and may be
valuable to understand SV variability due to external influences.

Primary objective:
The primary objective is aimed at determining the comparability of intracardiac
impedance (ICI) measurements to echocardiographic reference parameters in
assessment of changes in stroke volume (SV) in an acute setting. It is expected
that the mean intra-individual correlation coefficient between SZ and SV
exceeds 0.65 (r>0.65):

h1-hypothesis: r(SV,SZ) > 0,65
h0-hypothesis: r(SV,SZ) < 0.65

Secondary objectives:
1. Determination of comparability of intracardiac impedance measurements to
echocardiographic reference parameters in assessment of
changes in left-ventricular end-systolic volume (LVESV) in an acute setting.
2. Determination of comparability of intracardiac impedance measurements to the
Finapres®- method in assessment of changes in stroke volume (SV) in an acute
setting.
3. Assessment of the ability of the ICI to detect mid-term hemodynamic changes
during cardiac reverse remodeling.
4. Collection of additional clinical data for analysis in the context of their
meaning to the ICI-trend curve. Identification of additional suitable
parameters for hemodynamic monitoring of the heart.
5. Safety assessments: Incidence and severity of Adverse Events, Incidence and
severity of Adverse Device Effects.

Multi-center, international, non-randomized, noncontrolled, open-label,
interventional study.

The diagnostic ICI sensor will be activated in study context after CRD-D device
implantation in all patients by special release code for measurment of chonic
hemodynamic changes (the ICI data is sent daily to the Home Monitoring Serive
Center via the Home Monitoring system). For provocation of acute hemodynamic
changes of the heart an overdrive-pacing protocol using the implanted CRT-D
system is performed. Patients enrolled to BIO.Detect HF II will be subjected to
the protocol 2 months after CRT-D implantation. In total, measurement at five
different heart rates will be performed: at intrinsic heart rate, intrinsic
heart rate plus 30 bpm, intrinsic heart rate plus 10 bpm, intrinsic heart rate
plus 20 bpm, and intrinsic heart rate plus 40 bpm. Between the different heart
rates the patient will be given time to recover (~1 min) at intrinsic heart
rates. For every scheduled pacing rate 6 Ao-VTI, CW Doppler / stroke impedance
(SZ) pairs will be collected. Additional echocardiographic parameters will be
assessed for every frequency after the SV-values have been collected: LVESV
index, LVEDV index, LVEF, Biplane stroke volume (calculated), MR dP/dtmax,
calculated MR volume, visual classification of mitral regurgitation (color
Doppler) and PW SV (measured via PW-Doppler). The overdrive-pacing will be
terminated as soon as measurements at five different pacing rates have been
collected if not terminated before due to other reasons (patients clinical
condition, negative threshold test).

The associated risk with an ICD implanation in study context are not study
specific and not different from risks associated during routine CRT-D device
implantation. The risks associated with over-drive pacing as described in
protocol section 6.2 are minimized due to the fact that the physician will
evaluate the clinical condition of each participation patient prior to the
over-drive pacing. The patient will not undergo the over-drive pacing protocol
if his/her condition does not allow for further testing. In addition the
intracadiac impedance measurement is code-protected and can only be release in
study context. Prior to over-drive pacing an automatic threshold test will be
performed. If succesful the protocol will be released. If the study
demonstrates that the new hemodynamic sensor (intracardia impedance measurment)
works effectivly and safly, the feature will be released in routine clincal
practice. The patients may benefit from it by better diagnostic methods towards
better managment of their heart failure status.