Continuous Positive Airway Pressure Versus Noninvasive Ventilation in Patients With Overlap Syndrome

Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death
worldwide. Acute exacerbations of COPD (AECOPD), in particular, serve as marker of an
accelerated disease course and thus herald an increased risk of not only repetitive AECOPD
episodes but also deteriorating pulmonary function and death (2). Obstructive sleep apnea
(OSA), when it occurs in combination with COPD, is an increasingly recognized contributor to
AECOPD episodes. OSA consists of repetitive sleep-related partial loss of airway caliber
arising from increased transmural pressures which favor luminal collapse. OSA is estimated
to afflict 4 to 9% of the populations, a prevalence which is anticipated to climb
hand-in-hand with the rising incidence of obesity.

The combination of the two disorders, which has been arbitrarily labeled as Overlap Syndrome
(OS), has been linked with greater elevations in arterial carbon dioxide tensions and
pulmonary vascular resistance and lower arterial oxygen tensions than is seen with either of
its component disorders in isolation. Elevated pulmonary artery pressures may progress to
cause cor pulmonale, a process whereby compensatory right ventricle remodeling, hypertrophy,
and eventually, florid heart failure. In the setting of OSA, the therapeutic gold standard
is nightly continuous positive airway pressure (CPAP). Essentially, CPAP machines function
by administering a single continuous positive pressure airflow to the person's airway via an
appropriately fitted nasal mask. The applied pressure stents open partially occluded airway
segments during sleep. Though effective in OSA and OS, it is increasingly realized that for
OS patients there may exist a reduction not only in airway patency but also in ventilatory
drive when sleeping such that means to augment per breath volumes may attain incremental
benefits to the use of CPAP alone. Although CPAP is ineffective in COPD, Bipap has shown
benefit suggesting that patient with OSA and COPD may derive an improvement in
health-related outcomes by using a ventilation modality which addresses both of the
underlying conditions.

Bipap functions by combining the single flow in CPAP with a second inspiratory pressure
assist which not only overcomes sleep-related airway resistance but also increases the
magnitude of each breath resulting in lower diurnal carbon dioxide tensions and pulmonary
artery pressures. Bipap may harbor a mortality benefit in COPD; but the study results are
conflicting. It is unclear if Bipap is more effective at treating OSA than usual CPAP.
However, it is in the setting of OS that Bipap may assume a prominent role through its
ability to address both disorders; CPAP for the OSA portion and an inspiratory pressure
assist to ameliorate the COPD piece. Thus far no study has been conducted to address whether
OS may derive a particular benefit from Bipap or, more specifically, examine whether Bipap
may diminish the risk of AECOPD, or heart failure-related hospitalizations.

Inclusion Criteria:

- Patients aged > 35 years, the diagnosis of both OSA and COPD. OSA must have been
diagnosed using an American Academy of Sleep Medicine (AASM)-protocol overnight Type
I polysomnogram assessment with a resultant RDI of >5 events/hour in association with
OSA-attributable diurnal symptoms.

- COPD must be diagnosed using American Thoracic Society (ATS)-protocol pulmonary
function testing.

- Patients must have Global Obstructive Lung Disease (GOLD) stage II COPD FEV1/FVC <
70% predicted in conjunction with an FEV1 <80% predicted.

- The patient must have a > 10 pack years smoking history and a documented history of
at least one exacerbation leading to treatment with systemic glucocorticoids or
antibiotics or hospitalization within the previous year.

Exclusion Criteria:

- Significant diseases other than COPD, i.e. disease or condition which, in the opinion
of the investigator, may have put the patient at risk because of participation in the
study or may have influenced either the results of the study or the patients' ability
to participate in the study

- Patients with a diagnosis of asthma

- Patients with a life-threatening pulmonary obstruction, or a history of cystic
fibrosis

- Patients with known active tuberculosis

- Patients with brittle/unstable diabetes mellitus

- Patients with a history of and/or active significant alcohol or drug abuse. See
exclusion criterion 1

- Patients with a history of myocardial infarction within the year prior to Visit 1

- Patients with cardiac arrhythmia that required medical or surgical treatment in the 3
months prior to enrollment

- Patients who had taken an investigational drug within 30 days or 6 half-lives
(whichever is greater) prior to Visit 1

- Use of systemic corticosteroid medication at unstable doses (i.e., less than 6 weeks
on stable dose) or at doses in excess of the equivalent of 10 mg prednisolone per day
or 20 mg every other day

- Pregnant or nursing women or women of childbearing potential not using a medically
approved means of contraception (i.e., oral contraceptives).

- Patients with any respiratory infection or COPD exacerbation in the 4 weeks prior to
Visit 1 or during the run-in period should have been postponed. In the case of a
respiratory infection or COPD exacerbation during the run-in period, the run-in
period could have been extended up to 4 weeks

- Patients who, during their CPAP titration study are found to require such excessive
CPAP pressures as to mandate a Bipap titration

- Patients with either Cheyne-stokes respiration noted on PSG assessment or a central
sleep apnea with an associated central event index > 5 events/hour (using AASM
central apnea/hypopnea scoring criteria)