Stepwise Add-On and Endotype-informed Targeted Combination Therapy to Treat Obstructive Sleep Apnea: A Proof-of-Concept Study.

Rationale: Oral appliance therapy (OAT) is an effective treatment for many people with obstructive sleep apnea (OSA). However, OSA pathogenesis is heterogeneous, and, in ∼50% of cases, OAT does not fully control OSA. Objectives: This study aimed to control OSA in individuals with an incomplete response to OAT alone by using additional targeted therapies informed by OSA endotype characterization. Methods: Twenty-three people with OSA (apnea-hypopnea index [AHI], 41 ± 19 events/h) not fully resolved (AHI, >10 events/h) with OAT alone were prospectively recruited. OSA endotypes were characterized pretherapy during a detailed physiology study night. Initially, an expiratory positive airway pressure (EPAP) valve and supine avoidance device therapy were added to target the impaired anatomical endotype. Those with residual OSA (AHI, >10 events/h) then received one or more nonanatomical interventions based on endotype characterization. This included O2 (4 L/min) to reduce high loop gain (unstable respiratory control) and 80/5 mg atomoxetine-oxybutynin to increase pharyngeal muscle activity. Finally, if required, OAT was combined with EPAP and continuous positive airway pressure (CPAP) therapy. Results: Twenty participants completed the study. OSA was successfully controlled (AHI, <10 events/h) with combination therapy in all but one participant (17 of 20 without CPAP). OAT plus EPAP and supine avoidance therapy treated OSA in 10 (50%) participants. OSA was controlled in five (25%) participants with the addition of O2 therapy, one with atomoxetine-oxybutynin, and one required O2 plus atomoxetine-oxybutynin. Two participants required CPAP for their OSA, and another was CPAP intolerant. Conclusions: These novel prospective findings highlight the potential of precision medicine to inform targeted combination therapy to treat OSA. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN12618001995268).

CPAP combined with oral appliance therapy reduces CPAP requirements and pharyngeal pressure swings in obstructive sleep apnea.

Oral appliance (OA) therapy is the leading alternative to continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA). It is well tolerated compared with CPAP. However, ≥50% of patients using OA therapy have incomplete resolution of their OSA. Combination therapy with CPAP and oral appliance (CPAP + OA) is a potential alternative for incomplete responders to OA therapy. This study aimed to determine the extent to which combination therapy reduces therapeutic CPAP requirements using gold-standard physiological methodology in those who have an incomplete response to OA therapy alone. Sixteen incomplete responders [residual apnea/hypopnea index (AHI) > 10 events/h] to a novel OA with a built-in oral airway were recruited (3 women:13 men, aged 31-65 yr, body mass index: 22-38 kg/m2, residual AHI range: 13-63 events/h). Participants were fitted with a nasal mask, pneumotachograph, epiglottic pressure catheter, and standard polysomnography equipment. CPAP titrations were performed during non-rapid eye movement (NREM) supine sleep in each participant during three conditions (order randomized): CPAP only, CPAP + OA (oral airway open), and CPAP + OA (oral airway closed). OSA was resolved at pressures of 4 ± 2 and 5 ± 2 cmH2O during CPAP + OA (oral airway open) and CPAP + OA (oral airway closed) conditions versus 8 ± 2 cmH2O during CPAP only (P < 0.01). Negative epiglottic pressure swings in oral airway open and closed conditions were normalized to CPAP only levels [-2.5(-3.7, -2.6) vs. -2.3(-3.2, -2.4) vs. -2.1(-2.7, -2.3) cmH2O]. Combined CPAP and OA therapy reduces therapeutic CPAP requirements by 35%-45% and minimizes epiglottic pressure swings. This combination may be a therapeutic alternative for patients with incomplete responses to OA therapy alone and those who cannot tolerate high CPAP levels.NEW & NOTEWORTHY Combined CPAP and oral appliance therapy has been suggested as an alternative for incomplete responders to oral appliance therapy. We used a novel oral appliance incorporating an oral airway together with CPAP to show that pharyngeal pressure swings were normalized at reduced CPAP levels. Our findings demonstrate that using CPAP and oral appliance together may be a beneficial alternative for incomplete responders to oral appliance therapy and intolerant CPAP users due to high-pressure requirements.

Efficacy of a novel oral appliance and the role of posture on nasal resistance in obstructive sleep apnea.

STUDY OBJECTIVES: High nasal resistance is associated with oral appliance treatment failure in obstructive sleep apnea (OSA). A novel oral appliance with a built-in oral airway has been shown to reduce pharyngeal pressure swings during sleep and may be efficacious in those with high nasal resistance. The role of posture and mandibular advancement on nasal resistance in OSA remains unclear. This study aimed to determine (1) the effects of posture and mandibular advancement on nasal resistance in OSA and (2) the efficacy of a new oral appliance device including in patients with high nasal resistance. METHODS: A total of 39 people with OSA (7 females, apnea-hypopnea index (AHI) (mean ± standard deviation) = 29 ± 21 events/h) completed split-night polysomnography with and without oral appliance (order randomized). Prior to sleep, participants were instrumented with a nasal mask, pneumotachograph, and a choanal pressure catheter for gold standard nasal resistance quantification seated, supine and lateral (with and without oral appliance, order randomized). RESULTS: Awake nasal resistance increased from seated, to supine, to lateral posture (median [interquartile range] = 1.8 [1.4, 2.7], 2.7 [1.7, 3.5], 3.4 [1.9, 4.6] cm H2O/L/s, P < .001). Corresponding measures of nasal resistance did not change with mandibular advancement (2.3 [1.4, 3.5], 2.5 [1.8, 3.6], 3.5 [1.9, 4.8] cm H2O/L/s, P = .388). The median AHI reduced by 47% with oral appliance therapy (29 ± 21 versus 18 ± 15 events/h, P = .002). Participants with high nasal resistance (> 3 cm H2O/L/s) had similar reductions in AHI versus those with normal nasal resistance (61 [-8, 82] versus 40 [-5, 62] %, P = .244). CONCLUSIONS: Nasal resistance changes with posture in people with OSA. A novel oral appliance with a built-in oral airway reduces OSA severity in people with OSA, including in those with high nasal resistance. CLINICAL TRIAL REGISTRATION: Registry: ANZCTR; Title: Combination therapy for obstructive sleep apnoea; Identifier: ACTRN12617000492358; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372279.

Combination therapy with mandibular advancement and expiratory positive airway pressure valves reduces obstructive sleep apnea severity.

STUDY OBJECTIVES: Mandibular advancement splint (MAS) therapy is a well-tolerated alternative to continuous positive airway pressure for obstructive sleep apnea (OSA). Other therapies, including nasal expiratory positive airway pressure (EPAP) valves, can also reduce OSA severity. However, >50% of patients have an incomplete or no therapeutic response with either therapy alone and thus remain at risk of adverse health outcomes. Combining these therapies may yield greater efficacy to provide a therapeutic solution for many incomplete/nonresponders to MAS therapy. Thus, this study evaluated the efficacy of combination therapy with MAS plus EPAP in incomplete/nonresponders to MAS alone. METHODS: Twenty-two people with OSA (apnea-hypopnea index [AHI] = 22 [13, 42] events/hr), who were incomplete/nonresponders (residual AHI > 5 events/hr) on an initial split-night polysomnography with a novel MAS device containing an oral airway, completed an additional split-night polysomnography with MAS + oral EPAP valve and MAS + oral and nasal EPAP valves (order randomized). RESULTS: Compared with MAS alone, MAS + oral EPAP significantly reduced the median total AHI, with further reductions with the MAS + oral/nasal EPAP combination (15 [10, 34] vs. 10 [7, 21] vs. 7 [3, 13] events/hr, p < 0.01). Larger reductions occurred in supine nonrapid eye movement AHI with MAS + oral/nasal EPAP combination therapy (ΔAHI = 23 events/hr, p < 0.01). OSA resolved (AHI < 5 events/hr) with MAS + oral/nasal EPAP in nine individuals and 13 had ≥50% reduction in AHI from no MAS. However, sleep efficiency was lower with MAS + oral/nasal EPAP versus MAS alone or MAS + oral EPAP (78 ± 19 vs. 87 ± 10 and 88 ± 10% respectively, p < 0.05). CONCLUSIONS: Combination therapy with a novel MAS device and simple oral or oro-nasal EPAP valves reduces OSA severity to therapeutic levels for a substantial proportion of incomplete/nonresponders to MAS therapy alone. CLINICAL TRIALS: Name: Targeted combination therapy: Physiological mechanistic studies to inform treatment for obstructive sleep apnea (OSA)URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372279 Registration: ACTRN12617000492358 (Part C).