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Preliminary work with the use of implantable hemodynamic
monitoring devices in PAH is very exciting. Because there
is not yet enough evidenced-based work in the form of
large clinical trials with these devices, there was no
discussion about them in the ACCP recommendations. Dr.
Benza, you have been very involved with research in this
area. What has your experience been thus far? Do you think
they have a future for the PAH patient? If so, what kind
of patient would you consider?
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 Raymond
L. Benza, MD
Associate Professor
Division of Cardiovascular Disease
University of Alabama School of Medicine
Birmingham, Alabama
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The impaired vascular compliance caused by PAH leads
to a progressive increase in pulmonary vascular resistance.
As a result, right ventricular pressure and afterload
dramatically increase, leading to eventual right heart
failure. It is this decline in right ventricular performance
that closely ties to mortality in patients with PAH and
that is best predicted by serial assessments of hemodynamics.
Unfortunately, these serial assessments require frequent
invasive procedures that affect patient comfort and are
costly. The ability to reliably measure these hemodynamic
parameters on line without repeated procedures would,
therefore, be a significant advancement in the field.
Let me offer some background about this technology and
how it can be used. I will include a few selected references
also.
The Chronicle® (Medtronic, Inc., Minneapolis, Minnesota)
consists of an implantable hemodynamic monitor (IHM) with
a memory for continuous storage of data from a pressure
sensor lead (Medtronic, Inc.) positioned in the right
ventricle.
Continuous hemodynamic variables such as right ventricular
systolic, diastolic, and estimated pulmonary artery diastolic
pressure, pre-ejection and systolic time intervals, as
well as heart rate are derived by the IHM from each cardiac
cycle. The estimated pulmonary artery diastolic pressure
is derived from the right ventricular pressure waveform
at maximum dP/dt, the time of pulmonary valve opening.
Mean artery pulmonary pressure is calculated based on
the collected variables. Measured values are stored continuously
as the median or median and range (6th and 94th percentiles)
over each storage interval. The storage interval can be
programmed to high-resolution data (2-second storage interval)
or low-resolution data (1-hour storage interval), with
several programmable steps in between. Activity counts
allow for an estimate of the patient’s daily activities.
The absolute pressure, measured by the pressure sensor
in the right ventricle, requires correction for atmospheric
pressures by an external pressure reference device (Medtronic,
Inc.).
Patients with an IHM routinely send long-term, continuous,
hemodynamic information from home via an Interactive Remote
Monitor to the Internet-based Chronicle Information Network.
Healthcare staff log on to the Network using a personal
user identification and password. Trend plots and summary
tables of all hemodynamic variables, as well as triggered
events, sample pressure waveforms, and user-entered notes
are available in the application.1
A series of patient studies have been performed to verify
the feasibility of continuous hemodynamic monitoring in
congestive heart failure patients and devices for remote
transfer and use of these data. Several acute studies
support the ability to reliably estimate pulmonary artery
diastolic pressures from the right ventricular pressure
signal. The results of several separate studies in heart
failure patients who received systems for long-term hemodynamic
monitoring support the technical feasibility and the long-term
accuracy and stability of these systems. These findings
set the stage to determine the potential clinical value
of implantable hemodynamic monitoring and its impact on
the care of patients with heart failure. An early research
study designed to optimize diuretics showed that the Chronicle
IHM was a sensitive tool for volume changes.2
Findings in 32 patients implanted with a Chronicle
IHM described hemodynamic changes that preceded patient
symptoms in the case of a mild decompensation (not hospitalized)
by at least 24 hours and preceding a severe decompensation
(hospitalized) by 4 ± 2 days.3
The authors concluded that if the changes had been detected
at an early stage and medication regimens changed, periods
of decompensation and subsequent hospitalization
might have been avoided.
Hemodynamic response to submaximal walk and bike tests
were compared to symptom-limited exercise tests in patients
previously receiving an IHM. Changes in pressures ranged
from 72% to 79% and in SvO2 from 80% to 91 % of the maximal
tests.4 Observations from
monitoring of daily activity can, when compared to data
from submaximal exercise tests, give a good estimate on
how heavy daily activity is for a patient. Comparisons
over time can then serve as an indicator of deterioration
or improvement. Case studies describing hemodynamic changes
under such circumstances as beta-blocker titration, anesthesia,
and pacemaker optimization have also been published or
are in press.
In the setting of PAH, a study using the IHM to guide
therapy in 5 patients with pulmonary hypertension on inhaled
iloprost has now been published5
and several other small studies in which therapy has been
guided by the IHM are in press. PAH is becoming an increasingly
recognizable entity as emerging therapies and screening
of at-risk populations have evolved over the last several
years. PAH therapies are targeted directly to reduction
of pulmonary pressure and resistance. Frequent monitoring
of clinical status and hemodynamics is essential particularly
in the first year of therapy to achieve and maintain optimal
therapy that improves functional class and prognosis.
Today, this monitoring of hemodynamics still requires
repeated catheterizations. Use of the Chronicle IHM system
in this patient population has the potential to allow
more precise and individualized titration of drugs by
providing data during rest and exercise in the hospital
and during normal activities during
daily living.
Can you tell us about the ongoing pilot study?
A PAH pilot study is in progress and is designed as a
prospective, multicenter, nonrandomized study to assess
the feasibility and safety of implanting and using an
IHM in patients diagnosed with PAH. A maximum of 24 patients
will be included in the study. The aim is to show that
continuous pressure monitoring by the IHM provides accurate
hemodynamic data in patients with PAH and can be used
to optimize treatment with approved therapies.
To be included in the study, patients must be 18 years
old or older and newly diagnosed with PAH; if diagnosed
earlier, the patient should be on stable PAH therapy for
at least 3 months. The patient must also be in functional
class II-IV, have a PA systolic pressure >50 mm Hg
(echo), low probability of pulmonary embolism, total lung
capacity >70%, and be willing to comply with the study
protocol. Patients will be excluded if the PAH is related
to left-to-right shunt, sickle cell anemia, HIV infection,
schistosomiasis, or parenchymal pulmonary disease. Other
exclusion criteria are left ventricular dysfunction, 6-minute
walk <50 or >450 meters, pulmonary occlusive disease,
presence of other implantable device (pacemaker or ICD),
septal defect, mechanical right heart valve, and stenotic
mitral, tricuspid, or pulmonary valve. Before the start
of treatment it is typical to test the patient’s
pulmonary vasodilator response to prostacyclin, adenosine,
or nitric oxide during invasive monitoring in order to
predict prognosis and guide therapy choices.
Let me offer a bit of background information on the pilot
study patients so far. Sixteen PAH patients have been
enrolled and have had a monitor implanted to date. The
mean age is 48 ± 15 years (range, 19 to 74), 14
are women, and the majority of patients are in WHO class
III (14 in III, 2 in IV). Baseline pulmonary artery pressure
(PAP) measured at rest was 89 ± 38 mm Hg (range,
28 to 137) and 38 ± 15 mm Hg (range, 14 to 65)
for systolic and diastolic pressures, respectively, and
the mean PAP was 62 ± 25 mm Hg (range, 21 to 99).
Before the start of treatment the patients performed a
6-minute hall walk test. The average walked distance was
328 ± 100 meters (range, 79 to 476) resulting in
an increase in systolic (37%), diastolic (40%), and mean
(45%) pulmonary artery pressures.6-9
Treatment with oral bosentan was started in 7 patients,
with subcutaneous treprostinil in 6 patients, and with
intravenous epoprostenol in 1 patient. One patient, already
treated with calcium channel blockers was not considered
in need of any additional treatment and another patient
died before treatment could be initiated.
All patients are asked to send data from their IHMs to
the Chronicle Information Network once a week to allow
easy and quick access to data review for the clinical
staff in charge of the patient’s treatment. Compliance
with the protocol has been high and most patients have
sent data on a weekly basis or more often.
Results from individual patients or the total study population
are not available yet; analysis will be completed when
24 patients have been included in the study and followed
for a minimum of 3 months of PAH treatment. Case-by-case
observations
of the hemodynamic trends displayed on the IHM Chronicle
Information Network have led to adjustments and medication
changes.
Dr. Benza, what is the future of implantable hemodynamic
monitoring?
There is the potential for future technological
improvement in these devices. Implementation of an oxygen
sensor in the IHM system would offer new diagnostic possibilities.
Cardiac output measurements using a modified Fick method
would be an option, and measurements of oxygen consumption
and demand could be useful, especially in the PAH population.
The possibility of estimating flow using measurements
from the IHM is undergoing investigation. Despite improvements
in medical care, mortality remains high in PAH and no
cure for the disease is available. As new treatments are
evaluated, we are continuously reminded about the close
link between the efficacy of these drugs, including improvement
in symptoms, improvement in quality of life, and prolonged
survival. This performance is best as gauged by improvement
in related hemodynamics. The IHM, which reads pressures
in the right ventricle as well as estimating the pulmonary
artery pressure, should be able to adequately reflect
the impact of the disease on heart function and
help guide the need for earlier intensification in medical
therapies in order to prevent the insidious development
of right heart failure. Continuous ambulatory monitoring
with the Chronicle IHM might be helpful to assure efficacy
as well as safety in
guiding these therapies. I am including a few selected
references about this technology.
References
1.Kjellström B, Igel D, Abraham J,
Bennett T, Bourge R. Trans-telephonic monitoring of continuous
hemodynamic measurements in heart failure patients. JTT.
Submitted October 20, 2004.
2. Braunschweig F, Linde C, Eriksson MJ,
Hofman-Bang C, Rydén L. Continuous hemodynamic
monitoring during withdrawal of diuretics in patients
with congestive heart failure. Eur Heart J. 2002;23:59-69.
3. Adamson PB, Reynolds D, Luby A, Magalski
A, Steinhaus D, Linde C, Braunschweig F, Rydén
L, Böhm M, Stäblein A, Takle T, Bennett T. Ongoing
right ventricular hemodynamics in heart failure: clinical
value of measurements derived from an implantable monitoring
system. J Am Coll Cardiol. 2003;41:565-71.
4. Ohlsson A, Steinhaus D, Kjellstrom
B, Ryden L, Bennett T. Serial exercise testing in heart
failure patients with central hemodynamic recording using
implantable hemodynamic monitors. Eur J Heart Failure.
2003;5:253-9.
5. Fruhwald F, Kjellström B, Perthold
W, Watzinger N, Maier R, Grandjean P, Klein W. Continuous
haemodynamic monitoring in pulmonary hypertensive patients
treated with inhaled iloprost. Chest.2003;124:351-9.
6. McGoon M, Frantz R, Benza R, Bourge
R, Severson C, Roettger A, Kjellstrom B, Bennett T. Continuous
monitoring of pulmonary hemodynamics with an implantable
device: initial experience in patients with pulmonary
arterial hypertension. Abstract, PHA 6th International
Conference, 2004.
7. Benza R, McGoon M, Frantz R, Bourge
R, Severson C, Kjellstrom B, Roettger A, Bennett T. Monitoring
pulmonary hemodynamic responses to epoprostenol infusions
with an implantable hemodynamic monitoring device. Abstract,
PHA 6th International Conference, 2004.
8. Frantz R, McGoon M, Benza R, Bourge
R, Severson C, Kjellstrom B, Roettger A, Bennett T. Monitoring
pulmonary artery and right ventricular hemodynamic responses
to six-minute walk tests with an implantable monitoring
device in PAH patients. Abstract, PHA 6th International
Conference, 2004.
9. McGoon M, Frantz R, Benza R, Bourge
R, Severson C, Kjellstrom B, Roettger A, Bennett T. Range
of pulmonary artery-right heart pressures in ambulatory
patients with pulmonary arterial hypertension: preliminary
results from an implanted monitoring system. Abstract,
PHA 6th International Conference, 2004.
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