Sandrine H. Launois

Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea.

RATIONALE Randomized controlled trials (RCTs) have shown that continuous positive airway pressure (CPAP) treatment of obstructive sleep apnea (OSA) reduces blood pressure (BP). CPAP treatment has never been compared with antihypertensive medications in an RCT. OBJECTIVES To assess the respective efficacy of CPAP and valsartan in reducing BP in hypertensive patients with OSA never treated for either condition. METHODS In this 8-week randomized controlled crossover trial, 23 hypertensive patients (office systolic BP/diastolic BP: 155 ± 14/102 ± 11 mm Hg) with OSA (age, 57 ± 8 yr; body mass index, 28 ± 5 kg/m(2); apnea-hypopnea index, 29 ± 18/h) were randomized first to either CPAP or valsartan (160 mg). The second 8-week period consisted of the alternative treatment (crossover) after a 4-week washout period. MEASUREMENTS AND MAIN RESULTS Office BP and 24-hour BP were measured before and at the end of the two active treatment periods. Twenty-four-hour mean BP was the primary outcome variable. There was an overall significant difference in 24-hour mean BP between treatments: the change in 24-hour mean BP was -2.1 ± 4.9 mm Hg (P < 0.01) with CPAP, and -9.1 ± 7.2 mm Hg with valsartan (P < 0.001), with a difference of -7.0 mm Hg (95% confidence interval, -10.9 to -3.1 mm Hg; P < 0.001). The difference was significant not only during daytime but also during nighttime: the change in nighttime mean BP with CPAP was -1.3 ± 4.6 mm Hg (not significant), and -7.4 ± 8.4 mm Hg with valsartan (P < 0.001), with a difference of -6.1 mm Hg (P < 0.05) (95% confidence interval, -10.8 to -1.4 mm Hg). CONCLUSIONS In an RCT, although the BP decrease was significant with CPAP treatment, valsartan induced a fourfold higher decrease in mean 24-hour BP than CPAP in untreated hypertensive patients with OSA. Clinical trial registered with www.clinicaltrials.gov (NCT00409487).

Impact of Mandibular Advancement Therapy on Endothelial Function in Severe Obstructive Sleep Apnea

Rationale: Endothelial dysfunction, a major predictor of late cardiovascular events, is linked to the severity of obstructive sleep apnea (OSA). Objectives: To determine whether treatment with mandibular advancement device, the main alternative to continuous positive airway pressure, improves endothelial function in patients with severe OSA. Methods: In this trial, we randomized patients with severe OSA and no overt cardiovascular disease to receive 2 months of treatment with either effective mandibular advancement device or a sham device. The primary outcome, change in reactive hyperemia index, a validated measurement of endothelial function, was assessed on an intention‐to‐treat basis. An embedded microsensor objectively measured treatment compliance. Measurements and Main Results: A total of 150 patients (86% males; mean [SD] age, 54 [10] yr; median [interquartile range] apnea‐hypopnea index, 41 [35‐53]; mean [SD] Epworth sleepiness scale, 9.3 [4.2]) were randomized to effective mandibular advancement device (n = 75) or sham device (n = 75). On intention‐to‐treat analysis, effective mandibular advancement device therapy was not associated with improvement of endothelial function compared with the sham device. Office and ambulatory blood pressure outcomes did not differ between the two groups. Effective mandibular advancement device therapy was associated with significant improvements in apnea‐hypopnea index (P < 0.001); microarousal index (P = 0.008); and symptoms of snoring, fatigue, and sleepiness (P < 0.001). Mean (SD) objective compliance was 6.6 (1.4) h/night with the effective mandibular advancement device versus 5.6 (2.3) h/night with the sham device (P = 0.006). Conclusions: In moderately sleepy patients with severe OSA, mandibular advancement therapy reduced OSA severity and related symptoms but had no effect on endothelial function and blood pressure despite high treatment compliance. Clinical trial registered with www.clinicaltrials.gov (NCT 01426607).

On treatment but still sleepy: cause and management of residual sleepiness in obstructive sleep apnea.

Purpose of review Although continuous positive airway pressure (CPAP) treatment effectively reduces sleepiness in obstructive sleep apnea (OSA) patients, some patients remain sleepy in spite of proper treatment. After exclusion or treatment of known causes of sleepiness, residual sleepiness may be diagnosed. Recent changes in approval for currently available wakefulness stimulants in Europe, development of new stimulants and questions about the reality of residual sleepiness prompted this review. Recent findings Prevalence of residual sleepiness is approximately 10% and clearly decreases with increased nightly use of CPAP. Before treatment, patients with residual sleepiness are younger, suffer from less severe OSA and have worse health perception and mood than patients who respond to CPAP. Residual sleepiness is accompanied by other residual symptoms (e.g. fatigue, poor quality of life), suggesting the existence of a ‘CPAP resistant syndrome’. Pathophysiological mechanisms remain unclear. Stimulant medication may be beneficial in some patients and is well tolerated. Summary In spite of a substantial prevalence, residual sleepiness remains still poorly understood and may be difficult to treat. There remains a need for large prospective studies to better define predictive baseline characteristics and further research on causal mechanisms and pharmacological treatments, including large, long-term clinical trials of wakefulness stimulants, is needed.

Response to Statin Therapy in Obstructive Sleep Apnea Syndrome: A Multicenter Randomized Controlled Trial

Rationale. Accumulated evidence implicates sympathetic activation as inducing oxidative stress and systemic inflammation, which in turn lead to hypertension, endothelial dysfunction, and atherosclerosis in obstructive sleep apnea (OSA). Statins through their pleiotropic properties may modify inflammation, lipid profile, and cardiovascular outcomes in OSA. Methods. This multicenter, randomized, double-blind study compared the effects of atorvastatin 40 mg/day versus placebo over 12 weeks on endothelial function (the primary endpoint) measured by peripheral arterial tone (PAT). Secondary endpoints included office blood pressure (BP), early carotid atherosclerosis, arterial stiffness measured by pulse wave velocity (PWV), and metabolic parameters. Results. 51 severe OSA patients were randomized. Key demographics for the study population were age 54 ± 11 years, 21.6% female, and BMI 28.5 ± 4.5 kg/m2. In intention to treat analysis, mean PAT difference between atorvastatin and placebo groups was 0.008 (−0.29; 0.28), P = 0.979. Total and LDL cholesterol significantly improved with atorvastatin. Systolic BP significantly decreased with atorvastatin (mean difference: −6.34 mmHg (−12.68; −0.01), P = 0.050) whereas carotid atherosclerosis and PWV were unchanged compared to the placebo group. Conclusion. In OSA patients, 3 months of atorvastatin neither improved endothelial function nor reduced early signs of atherosclerosis although it lowered blood pressure and improved lipid profile. This trial is registered with NCT00669695.

Severe excessive daytime sleepiness induced by hydroxyurea.

Excessive daytime sleepiness (EDS) has been reported with many drugs, either as an extension of a hypnotic effect (e.g. central nervous system depressants) or as an idiosyncratic response of the patient. Here, we report unexpected and severe subjective and objective EDS induced by hydroxyurea therapy, with a favorable outcome after withdrawal. Clinical history, sleep log, polysomnography, and multiple sleep latency tests confirming the absence of other EDS causes are presented.

Late Breaking Abstract - Effect of custom made vs thermoplastic heat-molded mandibular advancement devices (MADs) for Obstructive Sleep Apnea (OSA): A randomized non-inferiority trial

Background: Custom-made MADs are reported as providing higher efficacy rates compared to thermoplastic heat-molded MADs but at the price of higher costs and treatment delays. Objective: To determine if a thermoplastic heat-molded adjustable MAD (ONIRISTM) is noninferior to a custom made acrylic MAD (TALITM) in OSA. Methods: We conducted a multicenter, single-blind, randomized controlled trial in OSA patients refusing or not tolerating CPAP. Participants were randomly assigned to a thermoplastic heat-molded adjustable MAD or a custom made acrylic MAD for 2 months with a stratification by center and OSA severity. The non-inferiority primary effectiveness outcome was a composite rate of success defined by a 50% reduction in apnea-hypopnea index (AHI) or an AHI Results: Of 198 patients (mean age 51 [SD, 12] years; 138 [72.6%] men; mean BMI 26 [SD, 2.7]kg/m2; mean AHI 26.6/hour [SD, 10.4]), 100 received TALITM and 98 ONIRISTM. Fifty two percent (51.7%) in the TALITM group vs 53.6% in the ONIRISTM groups were successfully treated for OSA (absolute difference, 2; 90%CI, -11 to 15 within the noninferiority margin). ONIRISTM group patients reported more frequently excessive salivation (P Conclusion: In OSA patients refusing or not tolerating CPAP, a thermoplastic heat-molded adjustable MAD (ONIRISTM) was noninferior to a custom made acrylic MAD.

Impact of mandibular advancement therapy on endothelial function in severe obstructive sleep apnoea

This study aimed to determine whether treatment with mandibular advancement device, the main alternative to continuous positive airway pressure, improves endothelial function in patients with severe OSA. We randomized patients with severe OSA and no medical history of cardiovascular disease to receive 2 months of treatment with either effective mandibular advancement device or a sham device. The primary outcome, change in reactive hyperemia index, a validated measurement of endothelial function, was assessed on intention-to-treat bases. An embedded micro sensor objectively measured treatment compliance. 150 patients [86% males; mean (SD) age, 54 (10); median [IQR] apnea-hypopnoea index, 41 [35-53]; mean Epworth sleepiness scale, 9.3 (4.2)] were randomized to effective mandibular advancement device (n=75) or sham device (n=75). In the intention-to-treat analysis, effective mandibular advancement device therapy was not associated with an improvement in endothelial function when compared to sham device. Office and ambulatory blood pressure outcomes did not differ between the 2 groups. Effective mandibular advancement device therapy was associated with significant improvements in apnea-hypopnea index (p vs 5.6 (2.3) h/night with sham device (p=0.006). Conclusion In moderately sleepy patients with severe OSA, mandibular advancement therapy reduced OSA severity and related symptoms with no effect on endothelial function and blood pressure despite high treatment compliance.