Obstructive sleep apnea therapy for cardiovascular risk reduction—Time for a rethink?

Abstract Obstructive sleep apnea (OSA) is a highly prevalent and underdiagnosed medical condition, which is associated with various cardiovascular and metabolic diseases. The current mainstay of therapy is continuous positive airway pressure (CPAP); however, CPAP is known to be poorly accepted and tolerated by patients. In randomized controlled trials evaluating CPAP in cardiovascular outcomes, the average usage was less than 3.5 hours, which is below the 4 hours per night recommended to achieve a clinical benefit. This low adherence may have resulted in poor effectiveness and failure to show cardiovascular risk reduction. The mandibular advancement device (MAD) is an intraoral device designed to advance the mandible during sleep. It functions primarily through alteration of the jaw and/or tongue position, which results in improved upper airway patency and reduced upper airway collapsibility. The MAD is an approved alternative therapy that has been consistently shown to be the preferred option by patients who are affected by OSA. Although the MAD is less efficacious than CPAP in abolishing apnea and hypopnea events in some patients, its greater usage results in comparable improvements in quality‐of‐life and cardiovascular measures, including blood pressure reduction. This review summarizes the impact of OSA on cardiovascular health, the limitations of CPAP, and the potential of OSA treatment using MADs in cardiovascular risk reduction.

OSA (apnea-hypopnea index ≥15 events/h). 1,2 OSA is an important public health challenge due to its association with excessive daytime sleepiness, motor vehicle accidents, and various manifestations of metabolic, cardiovascular, and cerebrovascular diseases. 3,4 Continuous positive airway pressure (CPAP), with positive airway pressure applied through a nasal or oronasal interface to splint the upper airway open, is the mainstay of therapy for OSA. CPAP is effective in ameliorating OSA-associated sleepiness. Moreover, epidemiological data have demonstrated that patients with OSA who use CPAP have a lower risk of fatal and nonfatal cardiovascular events than nonusers. 5 Similarly, randomized trials have shown the benefits of CPAP in improving surrogate markers such as blood pressure (BP), inflammation, and endothelial function. 6 However, randomized controlled trials have failed to verify the benefits of CPAP in reducing cardiovascular events. [7][8][9] Various explanations for these conflicting findings have been proposed. 10 These include poor CPAP adherence among trial participants who did not experience excessive daytime sleepiness, limited ability of the apnea-hypopnea index (the conventional measure of OSA severity) to risk-stratify patients with OSA, and the trials being underpowered. Consequently, a panel discussion on long-term outcome research in OSA was held during the SLEEP 2021 meeting, in which many suggestions were proposed; these included (i) adopting different study designs, (ii) replacing the apnea-hypopnea index with novel indexes to better identify at-risk individuals, and (iii) exploring alternative therapies, such as a mandibular advancement device (MAD) (Figure 1). In this review article, we summarize the impact of OSA on cardiovascular disease and the potential of MADs in improving cardiovascular outcomes. Our narrative review complements recent systematic reviews and meta-analyses and provides a comprehensive overview on MADs for cardiologists who do not have practical experience with the device.

| OSA AND CARDIOVASCULAR STRESS
OSA is a complex and heterogeneous disease characterized by multiple underlying mechanisms (endotypes). The immediate effects of attempting to inspire against an obstructed upper airway include a drop in intrathoracic pressure, cortical arousal from sleep, hypoxia, and sympathetic activation.
Reduced intrathoracic pressure results in decreased left ventricular filling and increased afterload, ultimately reducing stroke volume.
Furthermore, OSA causes marked, repeated BP elevation and tachycardia secondary to sympathetic nerve hyperactivity. 11 The sympa-

| CLINICAL TRIALS OF CPAP AND CARDIOVASCULAR OUTCOMES
Interest in the cardiovascular benefits of treating OSA was ignited by studies showing that OSA was an independent predictor of adverse cardiovascular events, 3,13 and that CPAP improved cardiovascular surrogate markers. 6,14 In the past decade, three randomized controlled trials have been conducted to explore the potential benefits of CPAP in cardiovascular risk reduction (Table 1). In the randomized intervention with CPAP in CAD and OSA (RICCADSA) trial, 8  in the first 90 days was only 72.6%. 16 Although these patients presented with symptomatic OSA, a visible decrease in use over time was observed. 16 To rectify this problem, interventions such as mask optimization, heated humidification, topical nasal therapy, education programs, and patient engagement apps have been introduced. 17 However, these interventions have had limited success, and this treatment modality continues to be plagued by problems with adherence.
Indeed, the overall nonadherence remains consistent at 30%-40%, especially in health systems where the cost of CPAP is not reimbursable. [18][19][20] Given the above, it is not surprising that many research participants with cardiovascular disease, who tend to be less sleepy, were unable to tolerate the CPAP over the duration of the trials to achieve clinically significant benefits. In the RICCADSA trial, 38% of the participants in the CPAP group stopped using the device within the first year. The adjusted on-treatment analysis showed a cardiovascular risk  When a MAD is prescribed for a patient with OSA, it is recommended that a qualified dentist uses a custom-made, titratable device rather than non-custom oral devices. It is imperative to note that even though MADs are primarily administered by dentists, OSA should be treated as a chronic disease entity requiring long-term, multidisciplinary management, and follow-up.

| Design
There is currently no conclusive evidence to indicate that a specific MAD design is most effective in improving polysomnographic indices.
The efficacy of a MAD depends on many factors, including the severity of OSA, materials, and methods of fabrication, type of MAD (monobloc/twin block), and the degree of protrusion (sagittal or vertical).
F I G U R E 2 A MAD functions primarily through protrusion of the lower jaw (blue arrows). The amount of protrusion is titratable based on patient's tolerance. MAD, mandibular advancement device Nevertheless, customized devices are preferred over thermoplastic devices as they are associated with a higher rate of treatment success (60% customized vs. 31% non-customized). Lower adherence of thermoplastic devices has also been shown, which is attributable to insufficient retention of the device during sleep.

| Adherence
Using temperature microsensors to collect objective adherence data is a

| Therapeutic efficacy
In  MAD, mandibular advancement device 9-31 teeth are missing, and 61% greater in the completely edentulous. Of even greater significance, edentulism is associated with cardiovascular health and is an independent risk factor for cardiovascular events, with each missing tooth associated with a 1% increase in myocardial infarction, a 1.5% increase in heart failure and stroke, and a 2% increase in mortality. 28 Whenever a MAD is prescribed, the success of the device often depends on the oral health of patients. Edentulism considerably reduces the suitability of MAD as sufficient dentition is necessary to support and retain the device. Besides edentulism, other dental contraindications that preclude the use of MAD may include periodontal problems such as tooth mobility, active temporomandibular joint disorder, and limited maximum protrusive distance (<6 mm).

| Side effects of MADs
A recent meta-analysis found a significant change in overbite and overjet with MAD use. However, their extent and importance remain unclear and need to be considered against the benefits of treating OSA. Another limiting factor in MAD therapy is patient preference.
Some patients cannot tolerate wearing a MAD. Commonly reported problems include the device falling out overnight, oral dryness, excessive saliva production, and masticatory muscle discomfort. Furthermore, it is known that poor dental health is associated with cardiovascular disease and poor dental health may be a contraindication for the use of MAD. This could potential limit the role of MAD in some patients with cardiovascular disease. 29

| Tongue retaining devices
Although this review focuses on MADs, studies involving tongue retaining devices have also shown efficacy in the management of OSA. A systematic review demonstrated tongue retaining devices having a substantial effect (a relative reduction of apnea-hypopnea index by 53% and oxygen desaturation index by 56%) from baseline, and may provide an effective alternative treatment option for OSA. It is important to note that these are results garnered from supervised studies as opposed to over-the-counter tongue devices that were not selected and delivered by dentists. 30

| MADs AND CARDIOVASCULAR RISK
Although CPAP is more effective than MADs in reducing the apneahypopnea index, 35 there is a growing body of evidence demonstrating comparable benefits between MADs and CPAP in ameliorating OSAassociated quality of health and adverse health consequences. 36

| MADs and BP reduction
The relationship between OSA and hypertension is best evidenced by the treatment of OSA using CPAP, which works by lowering incident hypertension 37 and BP in patients with pre-existing hypertension. 38 Many clinical trials have shown similar effectiveness between MADs and CPAP in terms of BP reduction. 39,40 As the sample sizes of all these trials were less than 150 participants, systematic review and meta-analysis play an important role in providing insight into the effects of MAD on BP reduction. It is worthwhile to note that these data comprised a wide range of OSA severity, some included patients with mild to moderate OSA, and some had severe OSA patients.
In the largest meta-analysis so far, Pengo

DATA AVAILABILITY STATEMENT
Data sharing not applicable -no new data generated. This is a review article.