Clinical trial NCT02771561: PFO Closure for Obstructive Sleep Apnoea
Official title: PFO Closure for Obstructive Sleep Apnoea-1 Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Patent Foramen Ovale
Obstructive Sleep Apnea
Keywords: Patent Foramen Ovale
Obstructive Sleep Apnea
Apnea-Hypopnea Index
Oxygen Desaturation Index
Epworth Sleepiness Scale
Quality of life
Continuous Positive Airway Pressure
Obstructive Sleep Apnea-Hypopnea Syndrome
Gore™ septal occluder device
Lead sponsor: Papworth Hospital NHS Foundation Trust
Sponsor class: OTHER_GOV
First posted: 2016-05-13
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Obstructive sleep apnoea (OSA) is a condition which involves episodes of interrupted breathing during sleep due to repetitive narrowing or collapse of the throat. These episodes are usually associated with a drop in blood oxygen levels and brief awakenings, which disrupt the sleep of those affected and can lead to daytime sleepiness. OSA is associated with an increased risk of heart disease and stroke.

In some individuals, the low oxygen levels in the blood can be made worse by also having a small hole in the heart, called a patent foramen ovale (PFO). This hole is present at birth in everyone, but in some people (about 30% of the normal population) it fails to close. Usually a PFO does not cause any medical problems. However, it may be recommended to have a PFO closed by key-hole surgery if someone suffers a stroke, severe migraine or if they are professional divers. There is a higher incidence of PFO in patients with OSA (25-50%) compared to the wider population and this may account for some of the observed increased risk of heart disease and stroke in patients with OSA.

This study will assess the number of patients with OSA who also have a PFO, and whether closing the PFO can improve the symptoms of OSA (e.g. sleepiness, exercise capacity and general well-being), thereby enabling the patient to not be reliant on treatment for OSA. If the study shows that closing the PFO is beneficial then the investigators will assess in a larger study if this treatment can also reduce heart disease and strokes.

Detailed description: Under normal conditions an interatrial communication allows blood to shunt from left to right due to a higher pressure in the left atrium than the right atrium and a greater compliance of the right ventricle than the left ventricle. Right-to-left interatrial shunting (RLS) is usually associated with spontaneous or induced pulmonary hypertension. RLS may occur spontaneously during a release phase of a Valsalva manoeuvres that transiently generates a right to left pressure gradient across the interatrial septum or rarely due to a condition termed platypnea-orthodeoxia. The latter is characterized by dyspnoea and deoxygenation accompanying a change to a sitting or standing from a recumbent position. Platypnea-orthodeoxia is thought to be due to a combination of an interatrial communication and an anatomical variant e.g. a persistent Eustachian valve and/or stretching and distortion of atrial septum allowing more streaming of venous blood from inferior vena cava through the defect when in the upright position. The recommended treatment of platypnea-orthodeoxia is percutaneous closure of patent foramen ovale (PFO).

Obstructive Sleep Apnoea - Hypopnoea Syndrome (OSAHS) is characterised by repetitive upper airway obstruction during sleep causing apnoea (cessation of breathing) and oxygen desaturation. It is a significant health burden on the National Health Service (NHS) and society, affecting approximately 4% middle aged men and 2% middle-aged women. The risk of OSAHS rises with increasing body weight, active smoking and age. OSAHS is set to reach epidemic proportions as the Western population ages and the incidence of obesity rises. About 1% of men in the United Kingdom (UK) have severe OSAHS with an apnoea-hypopnoea index (AHI; the average number of episodes of apnoeas and hypopnoeas per hour of sleep) of \>20 and oxygen desaturation index (ODI; the number of desaturation episodes defined as ≥4% drop in oxygen saturations per hour during sleep) of \>20, measured by nocturnal oximetry and respiratory polygraphy (intermediate sleep study or Embletta™). Patients with untreated severe OSAHS have a higher incidence of fatal (OR 2.87) and non-fatal (OR 3.17) cardiovascular events compared to age and sex matched controls. The degree of oxygen desaturation inversely correlates with survival and the link is thought to be multifactorial; raised blood viscosity due to increased haematocrit, sympathetic activation leading to arrhythmias and systemic hypertension are thought to be important. In a Cox model a 1% decrease in average nocturnal oxygen saturation (SaO2) was associated with a 33% increase in the incident risk of fatal and nonfatal cardiovascular events. Treatment with continuous positive airways pressure (CPAP) ventilation at night reduces symptoms (snoring, mood, day time sleepiness and headache) and cardiovascular event rate, but it is poorly tolerated and refused by up to a fifth of patients. Improvement in ODI and sleepiness in OSAHS treated by CPAP is transient and when CPAP is discontinued, measurements return to baseline within 1 week.

PFO is found with a higher incidence in patients with OSAHS than controls (69% vs. 17%) and may exacerbate the oxygen desaturation in OSAHS during apnoeic/ hypopnoeic episodes observed in some patients. In OSAHS patients with greater ODI to AHI ratio (ODI/AHI\>0.67), the prevalence of large PFO was nine out of 15 (60%) versus two out of 15 (13%) in those with ODI/AHI \<0.33. OSAHS is believed to raise right heart pressures and increase RLS via the interatrial defect due to repeated nocturnal Valsalva and Muller manoeuvres. Prolonged oxygen desaturation may further exacerbate sleep apnoea by decreasing central respiratory drive. In selected populations of OSAHS patients, PFO closure may be beneficial. This has been reported in a number of case reports but has not been studied in a larger trial population.

Hypothesis:

RLS via a PFO in patients with severe OSAHS: ESS≥11 and ODI≥20 or ODI/AHI \>0.67, is deleterious and closing the PFO will improve oxygen saturation, exercise tolerance, symptoms, quality of life and will reduce CPAP requirement and, ultimately, will reduce the incidence of fatal/ non-fatal cardiovascular events.

This study will assess the improvement of symptoms of OSA (e.g. sleepiness, exercise capacity and general well-being) following PFO closure. Improving symptoms will enable patients to not be reliant on treatment for OSA. If PFO closure is beneficial the investigator aims to assess the efficacy of treatment to reduce heart disease and strokes in a larger study.

Eligibility criteria: Inclusion Criteria:

* Age 18 years and older
* Diagnosis of obstructive sleep apnoea-hypopnoea syndrome (OSAHS)
* Epworth Sleepiness Scale score of 11 or greater
* Oxygen Desaturation Index of 20 or greater (and/or oxygen desaturation index/apnoea-hypopnoea index greater than 0.67)
* Naive to Continuous Positive Airway Pressure (CPAP) treatment, or CPAP intolerant (defined at any review as: CPAP use less than 4 hours per night and unable to tolerate/receive no benefit, or at clinical discretion), or poor CPAP responders (defined at any review as: failure to improve Epworth Sleepiness Scale score by more than 4 points from Epworth Sleepiness Scale score at diagnostic visit plus persistent symptoms suggesting poorly controlled OSAHS and/or a prior failure to tolerate CPAP therapy)
* Moderate to large Patent Foramen Ovale (PFO) as seen on a transthoracic echocardiogram bubble study

CPAP naive patients with moderate-large PFO will start CPAP treatment during the study, but outcomes will be assessed at baseline (before starting CPAP treatment) and at six months post PFO closure (after one week of CPAP abstinence).

Exclusion Criteria:

* Coexistent significant respiratory disease (FEV1 \<50% predicted)
* Weight \>180kg (maximum weight allowance for echocardiogram table)
* Known or suspected pregnancy
* Other cardiac disease (valve disease, known cardiomyopathy, left ventricular failure, known congenital heart disease)
* Previous atrial septal closure device
* Inability to give informed consent or comply with the protocol
* Anatomically unsuitable for percutaneous PFO closure with Gore™ septal occluder device.

Primary outcomes:
measure: Change in Epworth Sleepiness Scale
timeFrame: Change from baseline Epworth Sleepiness Scale score at six months post Patent Foramen Ovale Closure
measure: Change in Apnoea-Hypopnoea Index
timeFrame: Change from baseline Apnoea-Hypopnoea Index at six months post Patent Foramen Ovale Closure
measure: Change in Oxygen Desaturation Index
timeFrame: Change from baseline Oxygen Desaturation Index at six months post Patent Foramen Ovale Closure
measure: Change in Six Minute Walk Test
timeFrame: Change from baseline six minute walk test at six months post Patent Foramen Ovale Closure
measure: Change in Sleep Apnea Quality of Life Index (SAQLI)
timeFrame: Change from baseline SAQLI at six months post Patent Foramen Ovale Closure
measure: Change in Functional Outcomes of Sleep Questionnaire (FOSQ)
timeFrame: Change from baseline FOSQ at six months post Patent Foramen Ovale Closure
measure: Change in Short Form (36) Health Survey (SF36)
timeFrame: Change from baseline SF36 at six months post Patent Foramen Ovale Closure
Secondary outcomes:
measure: Change in Continuous Positive Airway Pressure (CPAP)
timeFrame: Change from baseline CPAP use at six months post Patent Foramen Ovale Closure
measure: Cardiovascular events (CV)
timeFrame: Six months post Patent Foramen Ovale Closure
Other outcomes:
Locations:
city: Papworth Everard
country: United Kingdom
facility: Papworth Hospital NHS Foundation Trust
state: Cambridgeshire
Study officials:
affiliation: Papworth Hospital NHS Foundation Trust
name: Stephen Hoole, BM BCh
role: PRINCIPAL_INVESTIGATOR
affiliation: Papworth Hospital NHS Foundation Trust
name: Michael Davies, MB BS
role: PRINCIPAL_INVESTIGATOR
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