Heart Failure, OSA - Obstructive Sleep Apnea
Conditions
Keywords
heart failure, OSA, clinical trial, biomarker, quality of life
Brief summary
Heart failure with reduced ejection fraction (HFrEF) is a serious condition that limits daily activities and often leads to hospital stays and early death. Many patients with HFrEF also have obstructive sleep apnea (OSA), a common but often undiagnosed condition where breathing repeatedly stops during sleep. This causes drops in oxygen, poor sleep, and stress on the heart, which can make heart failure worse. The investigators are studying whether a device called a mandibular advancement device (MAD)-a mouthpiece worn during sleep that keeps the airway open-can help people with both HFrEF and moderate-to-severe OSA. This device is already approved to treat OSA and is often more comfortable and easier to use than a CPAP machine. In our study, 328 patients in Singapore will be randomly assigned to use either the MAD or a sham device that looks the same but doesn't move the jaw. They will wear the device for 12 months. We will measure changes in a blood marker linked to heart failure severity, as well as exercise ability, blood pressure, sleep quality, and hospital visits. The investigators hope this study will show that MAD is a simple and patient-friendly way to improve outcomes in people with heart failure.
Detailed description
Heart failure profoundly impacts health, quality-of-life, and survival. Patients with heart failure (HF) experience fatigue, breathlessness, and exercise intolerance. Recurrent hospitalizations due to disease exacerbations further burden patients and healthcare systems. Despite advances in therapies, long-term outcomes remain poor with only 50% survival at 5 years post-diagnosis. Based on the left ventricular ejection fraction, HF is classified into three categories: reduced, mildly reduced, and preserved ejection fraction. This proposal focuses specifically on HF with reduced ejection fraction, which carries the worst prognosis. The term "HF" in this proposal refers exclusively to this subtype. A growing body of evidence highlights the critical role of non-traditional and modifiable risk factors in heart failure progression, with obstructive sleep apnea (OSA) emerging as a particularly important contributor. OSA is highly prevalent in patients with HF, with estimates ranging from 40% to 70%. However, it remains substantially underdiagnosed and undertreated. OSA is characterized by repeated collapse of the upper airway during sleep, resulting in intermittent hypoxia, hypercapnia, serial arousals, and surges in sympathetic activity and blood pressure. These stressors contribute to elevated cardiac afterload, myocardial oxygen demand, and neurohormonal activation-all of which exacerbate ventricular dysfunction and HF progression. The relationship between OSA and HF is bidirectional. OSA not only contributes to the worsening of HF, but HF itself can increase the likelihood of OSA due to pulmonary congestion and fluid redistribution during sleep. Among patients with established HF, the presence of OSA has been linked to worse outcomes, including more frequent hospitalizations and higher mortality. Despite this compelling evidence, the therapeutic potential of treating OSA in HF remains underexplored. While small studies suggest that short-term (3-6 months) treatment with continuous positive airway pressure (CPAP) in HF may improve cardiac function, adherence is suboptimal, with many patients unable to tolerate nightly use of CPAP. Given the rising prevalence of obesity, OSA and HF, there is an urgent need for well-tolerated, effective alternatives to CPAP. The mandibular advancement device (MAD) is an oral appliance approved for the treatment of OSA. Compared with CPAP, more patients accept MAD and use it for long-term with better adherence. Our team previously demonstrated in a randomized trial that MAD was associated with better adherence and improved nighttime blood pressure control compared to CPAP. In a pilot study of HF patients, the investigators found that treatment of OSA with MAD led to a reduction in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP)-a robust prognostic biomarker for HF
Interventions
DEVICEMandibular advancement device
Mandibular advancement devices (MAD) and continuous positive airway pressure (CPAP) are non-surgical treatments for obstructive sleep apnea (OSA) that maintain upper airway patency during sleep. CPAP delivers pressurized air via a mask to splint the airway and is the gold-standard therapy, providing the greatest reduction in apnea-hypopnea index across all OSA severities. MADs are custom-made oral appliances that advance the mandible forward, enlarging the upper airway and reducing collapsibility, and are most effective in mild to moderate OSA. Both therapies improve snoring, daytime sleepiness, and sleep quality, but differ in efficacy and tolerability. CPAP is more physiologically effective, while MADs are often better tolerated, more portable, and associated with higher real-world adherence. As a result, MADs are an accepted alternative for patients who cannot tolerate CPAP, with overall effectiveness influenced by both efficacy and adherence.
DEVICEMandibular advancement device (Sham)
Arm Description: The patients randomized to the sham MAD arm, the same MAD device as described above for the MAD arm will be used. Unlike an active MAD which advances the mandible to maintain airway patency, the sham-MAD is designed to resemble the real device while minimizing therapeutic effects. Its titration process ensures participant comfort while maintaining study blinding. The sham MAD is custom-fitted using standard dental impressions but is adjusted to allow only minimal mandibular protrusion (0-2 mm). During follow-up visits, minor, non-therapeutic adjustments are made to simulate an active titration process. These may involve small, inconsequential changes that do not significantly alter mandibular position.
Sponsors
National University Hospital, Singapore
Alexandra Hospital
Ng Teng Fong General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Intervention model description
We designed a randomized, single-blind, placebo-controlled, outcome-assessor-blinded, superiority clinical trial (MARVEL-HF trial) to evaluate the efficacy of treating OSA (defined as AHI ≥15 events/hour) with MAD in reducing NT-proBNP levels in patients with HF. A sham MAD (same device, without mandibular advancement) will be used as the placebo control (standard practice, as in other clinical trials comparing MAD vs sham MAD). Due to the nature of the intervention, double blinding is not feasible. However, all outcome-assessors will be blinded to treatment allocation. The primary endpoint (plasma NT-proBNP level) is an objective measure.
Eligibility
Sex/Gender
ALL
Age
40 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Age of at least 40 years old with the capacity to provide signed, written informed consent * Ischemic or non-ischemic cardiomyopathy with a left ventricular ejection fraction of 20% to 40% in the previous 6 months * Stable chronic HF with NYHA functional class I-III symptoms on maximally tolerated background therapy for at least 4 weeks * NT-proBNP \>600 pg/mL (for participants in sinus rhythm) or \>900 pg/mL (for participants in atrial fibrillation) in the previous 6 months (same as leading HF trials) * Agree to follow the study protocol * Able and willing to undergo a hospital-based overnight polysomnography
Exclusion criteria
* Known OSA and already on regular treatment * Moderate or severe valvular stenosis or regurgitation * Severe hypoxemia on polysomnography ODI \>60 or min SpO2 \<60% * Specific HF etiologies, including hypertrophic cardiomyopathy with left ventricular outflow tract obstruction; pericardial disease; infiltrative or inflammatory myocardial disease; valvular heart disease with severe aortic or primary mitral regurgitation, moderate or severe aortic stenosis, any mitral stenosis requiring surgical repair, or active endocarditis * Contraindications to MAD: less than six teeth in each arch; inability to advance the mandible and open the jaw widely. * Pre-existing temporomandibular joint problems, severe bruxism, and advanced periodontal disease (with mobility affecting MAD stability). * Patients who are planning to have restorations, dental prostheses or implants done in the next 12 months * Limited life expectancy (\< one year) * Cardiac or cerebrovascular events in the past 6 months, including myocardial infarction, unstable angina leading to hospitalization, uncontrolled cardiac arrhythmia, carotid surgery or stenting, stroke, transient ischemic attack, carotid revascularization, endovascular procedure, or surgical intervention for peripheral vascular disease * Current or planned mechanical circulatory support or heart transplantation Current or planned (within the next 6 months) hemodialysis or peritoneal dialysis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| N-terminal pro-B-type natriuretic peptide (NT-pro BNP) | Baseline and 6 months (primary outcome) | NT-proBNP (Primary endpoint) is a circulating biomarker released from the cardiac ventricles in response to myocardial wall stress and volume overload. It is commonly used to assess the presence and severity of heart failure. NT-proBNP levels are measured in picograms per milliliter (pg/mL). Higher values indicate greater cardiac wall stress and worse heart failure severity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Left ventricular ejection fraction (LVEF), expressed as percentage (%). | Baseline and 6 months | Transthoracic echocardiography determined parameters |
| Kansas City Cardiomyopathy Questionnaire (KCCQ). | Baseline, 6 months, and 12 months | Quality of life assessment tool for heart failure. The Overall Summary Score ranges from 0 to 100, with higher scores indicating better health status and quality of life. |
| Epworth Sleepiness Scale (ESS) | Baseline, 6 months, and 12 months | The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire used to evaluate daytime sleepiness. The total score ranges from 0 to 24, with higher scores indicating greater daytime sleepiness. |
| Sleep Apnea Quality of Life Index (SAQLI) | Baseline, 6 months, and 12 months | The Sleep Apnea Quality of Life Index (SAQLI) is a disease-specific questionnaire assessing the impact of obstructive sleep apnea on daily functioning, social interactions, emotional functioning, and symptoms. The total score ranges from 1 to 7, with higher scores indicating better quality of life. |
| EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) | Baseline, 6 months, and 12 months | The EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L) is a standardized instrument used to measure general health status across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The index score typically ranges from less than 0 (worse than death) to 1.0 (perfect health), with higher scores indicating better health status. |
| Montreal Cognitive Assessment (MoCA) | Baseline, 6 months, and 12 months | The Montreal Cognitive Assessment (MoCA) is a widely used screening tool for the assessment of global cognitive function, including domains such as attention, executive function, memory, language, visuospatial ability, abstraction, and orientation. The total score ranges from 0 to 30, with higher scores indicating better cognitive function. A score of 26 or above is considered normal cognitive function. |
| Adverse cardiovascular events | 6 months, 12 months, and 36 months | Adverse events. Although this trial is not powered to detect differences in hard clinical outcomes, we will collect them for exploratory analysis: hierarchical composite of death within 12 months after randomization and HF hospitalizations within 12 months after randomization. |
| Ambulatory BP monitoring | Baseline and 6 months | Ambulatory BP will be performed over a 24-hour period at baseline and 12 months. Key parameters will include 24-hour mean systolic and diastolic BP, daytime and nighttime averages, and nocturnal BP dipping patterns. |
| Peak oxygen uptake (VO₂peak) | Baseline and 6 months | Peak oxygen uptake (VO₂peak) is measured (one third of the participants) during cardiopulmonary exercise testing and reflects the maximum capacity of the body to transport and utilize oxygen during exercise, representing overall cardiorespiratory fitness. VO₂peak is expressed in mL/kg/min. Higher values indicate better cardiorespiratory fitness and exercise capacity. |
Countries
Singapore
Contacts
CONTACTChi-Hang Ronald Lee, MBBS, MD
Outcome results
None listed