Treatment of sleep-disordered breathing with predominant central sleep apnoea by adaptive servo ventilation in patients with heart failure

Despite recent advances in pharmacological treatment, chronic heart failure
(chronic HF) continues to cause debilitating symptoms, frequent hospital
admissions, and a high mortality. Although therapy with beta-blockers and
ACE-inhibitors as well as other drugs or cardiac resynchronisation therapy
(CRT) has become guideline therapy, many patients have persistent symptoms and
most will eventually die of cardiovascular causes, often from progressive heart
failure. New interventions that reduce symptoms, increase quality of life,
reduce hospital admissions and mortality are warranted.
It is likely that new interventions will be targeted at specific subgroups of
chronic HF patients rather than the entire population. Treatment of Sleep
Disordered Breathing (SDB) is potentially such an intervention. SDB is very
common in heart failure populations with reported prevalence rates of 50-75%.
Two types of abnormal breathing predominate, Obstructive Sleep Apnoea (OSA) and
Central Sleep Apnoea/Cheyne-Stokes-Respiration (CSA/CSR). OSA is seen in 20-45%
of chronic HF patients, a rate which is considerably higher than the general
population. CSA/CSR is also common and reported in 25-40% of chronic HF
patients.
There are several mechanisms by which SDB may be detrimental to cardiac
function. These include tissue hypoxia and repetitive arousal from sleep with
increased sympathetic nervous system activity. Treatment of OSA with CPAP
(Continuous Positive Airway Pressure) rapidly reduces tissue hypoxia and
arousals, and over a period of months reduces elevated sympathetic activity to
normal. CPAP is also known to reduce blood pressure. Two studies have
demonstrated marked improvements in cardiac function over periods of 1 and 3
months, but no large outcome study has been performed. With the known effects
of CPAP on sleepiness, quality of life and hypertension in patients with OSA,
this study is now difficult to perform in patients with OSA and symptoms.
CSR induces chemical, neural and hemodynamic changes similar to those seen in
OSA, and is most commonly seen in the chronic HF population. It is an
independent risk factor for death in chronic HF. CSR can be treated with
oxygen, CPAP or ventilation in increasing order of effectiveness, but there are
few trials with clinical endpoints or even outcome data.
The only trial to date that has investigated the impact of Continuous Positive
Airway Pressure treatment for central sleep apnea and heart failure on heart
transplant-free survival was the CANPAP-Study. The trial was stopped after 200
patients were followed up for at least six months. After a prespecified interim
analysis the DSMB recommended the termination of the study because of an early
divergence of the transplantation-free survival curves favouring the control
group, an enrolment at only 50 percent of predicted rate
(0,03patients/center/month) and a falling rate of death and heart
transplantation.
Although CPAP attenuated central sleep apnea (AHI was lowered from 40
events/hour to 19 events/hour), improved nocturnal oxygenation, increased the
ejection fraction, lowered norepinephrine levels, and increased the distance
walked in six minutes, it did not affect survival or rehospitalization. The
authors concluded that their data do not support the use of CPAP to extend life
in patients who have central sleep apnea and heart failure.
A recently published further analysis of the CANPAP-data tested the hypothesis
that suppression of CSA below 15 events per hour by CPAP would improve left
ventricular ejection fraction and heart transplant-free survival. Of the 258
heart failure patients with CSA in CANPAP, 110 of the 130 randomized to the
control group and 100 of the 128 randomized to CPAP had sleep studies 3 months
later. CPAP patients were divided post hoc into two groups, whose
apnea-hypopnea index was or was not reduced below 15 at this time. In 57
patients CSA was suppressed effectively under CPAP, while in 43 patients CPAP
did not suppress CSA. Their changes in left ventricular ejection fraction and
heart transplant-free survival were compared with those in the control group.
Despite similar CPAP pressure and hours of use in the 2 groups, patients with
CPAP whose CSA was suppressed experienced a greater increase in left
ventricular ejection fraction at 3 months and significantly better
transplant-free survival than control subjects, whereas the patients with
unsuppressed CSA under CPAP did not improve left ventricular ejection fraction
or transplant-free survival. The authors conclude that in heart failure
patients, PAP might improve both left ventricular ejection fraction and heart
transplant-free survival if sleep-disordered breathing is suppressed early
after initiation of therapy.

The purpose of this trial is to evaluate the long-term effects and
cost-effectiveness of adaptive servo-ventilation (ASV) on the mortality and
morbidity of patients with stable heart failure due to left ventricular
systolic dysfunction, already receiving optimal medical therapy, who have sleep
disordered breathing (SDB) that is predominantly central sleep apnoea.

Randomised, multi-centre, international trial with parallel group design, with
patients randomised to either control (optimal medical management) or active
treatment (optimal medical treatment plus use of adaptive servoventilation) in
a 1:1 ratio. There will be no sham-positive airway pressure treatment in the
control arm. Assumptions: the intervention reduces the hazard rate by 20%. The
event rate in the control group is 35% in the first year. It is assumed that
the hazard rate is constant over time.
The trial is based on an event-driven design: the final analysis will be
performed when 651 events have been observed or the study was terminated at one
of the interim analyses.
The primary analysis is in the intention-to-treat population that consists of
all patients randomized.

A non-invasive device, providing adaptive-servo ventilation algorithms to
provide ventilatory support for central sleep apnea, or periodic breathing. It
comprises a microprocessor-controlled flow generator, air delivery hose mask
and headgear.
The device provides a ventilatory pressure support between 3-16 cm H2O
superimposed on an end expiratory pressure (EPAP) between 4-15 cm H2O. The
default EPAP is 5 cm H2O. The device is limited to a maximum peak inspiratory
pressure of 25 cm H2O.
The device measures the patient*s instantaneous ventilation, and calculates an
adapting target ventilation equal to 90% of the patient*s recent average
ventilation (time constant 100 seconds). It then adjusts the degree of pressure
support to servo-control the subject*s ventilation to at least equal the target
ventilation. If the subject resumes normal spontaneous effort, support will
fall back to the minimum of 3 cm H2O over a similar time period. Smaller or
slower changes in patient*s effort will result in proportionally smaller,
slower changes in the degree of support. In the steady state, ventilation
exceeds the 90% target, so support stays at the minimum of 3 cm H2O.

The AutoSet CS offers Climate Control, a state-of-the-art humidification system
that intelligently adapts to environmental conditions to deliver optimal
pressure and temperature in order to promote long-term compliance. Complemented
by the ClimateLine heated tube it protects patients from rainout without
compromising humidity or temperature levels.

There are no major known side effects of taking part in this research project.
The AutoSet CS device has been used for over 10 years and has a CE mark meaning
it has been approved for use in countries of the European Union.
When blood samples are taken some patients may experience bruising on the site
where the blood is taken from. Sometimes the mask used with the AutoSet CS is
uncomfortable. If so, we will swap to a more comfortable mask.

When put into group one (ASV+standard medical therapy) we hope that by using
the device it will reduce the sleep disordered breathing and perhaps the
progression of the heart failure. When in group two it is unlikely that the
study will help but the information we get might help improve the treatment of
people with a similar condition in the future.