BEYOND THE BLUE: What Fellows Are Reading in Other Journals Continuous Positive Airway Pressure plus Weight Loss for Obstructive Sleep Apnea (OSA), Association of Cancer with OSA, and Hypoglossal Nerve Stimulation for OSA Treatment Imran H. Iftikhar, Meredith A. Donley, Mohammed Al-Jaghbeer, and Angel Monserrate Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of South Carolina School of Medicine, Columbia, South Carolina Recommended Reading from the University of South Carolina School of Medicine Pulmonary Medicine Fellowship Program; Imran H. Iftikhar, Senior Program Faculty Member
Chirinos JA, et al. CPAP, Weight Loss, or Both for Obstructive Sleep Apnea. N Engl J Med (1) Reviewed by Meredith A. Donley and Imran H. Iftikhar
In a randomized, parallel-group, 24-week trial (1), Chirinos and colleagues compared the effects of continuous positive airway pressure (CPAP), weight loss (WL), or a combined intervention (CPAP plus a weight loss intervention, CI) in obese adults with moderate to severe obstructive sleep apnea (OSA) (apnea–hypopnea index [AHI], >15), and a serum C-reactive protein (CRP) concentration greater than 1.0 mg/L. CPAP intervention included nightly CPAP therapy, and WL intervention was composed of dietary modification and an exercise training program. By structuring the trial with three intervention groups, the authors sought to investigate the presence of independent causal relationships between OSA and obesity on inflammation, insulin resistance, dyslipidemia, and hypertension. The primary end point was the effect of the interventions on CRP level. Both WL and CI were associated with significant reductions in CRP at 24 weeks. However, no significant incremental effect on CRP levels was found for the CI compared with either singular intervention alone. In contrast, by showing additional reductions in blood pressure (BP) with the CI group (14.1 mm Hg) compared with either the WL group (6.8 mm Hg) or the CPAP group (3.0 mm Hg), the authors report that both OSA and obesity have an independent causal relationship to hypertension. The study population was not defined by excessive daytime sleepiness (mean Epworth Sleepiness Scale [ESS] score , 11 in the CPAP group), suggesting that most were minimally symptomatic. The BP response to CPAP in those with ESS scores less than 11 is known to be smaller as compared with those with ESS scores greater than
11 (2). Finally, the CI group, compared with the CPAP group, had an effect on insulin resistance and serum triglyceride levels. However, there were no significant differences when the former was compared with the WL group. The effect size of BP reduction with CI and WL as compared with CPAP only, and the long-term increase in insulin sensitivity seen only in the CI and WL groups, have important bearings on clinical practice. In light of emerging data (3) on expected weight gain in CPAPcompliant patients, findings of this study are timely and reaffirm the beneficial effects of WL and exercise that extend past AHI reduction, especially because converging evidence (4) indicates that exercise alone, independent of weight changes, decreases OSA severity. Perhaps, in addition to CPAP, counseling on dietary modifications and exercise training ought to be formally incorporated as the standard of care for OSA treatment and as a core clinical competency in sleep medicine training programs. Last, the insignificant effect of CPAP on CRP suggests that modification of systemic inflammation may not be the mechanistic link underpinning the beneficial effect of CPAP on improving cardiovascular outcomes. n References 1. Chirinos JA, Gurubhagavatula I, Teff K, Rader DJ, Wadden TA, Townsend R, Foster GD, Maislin G, Saif H, Broderick P, et al. CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med 2014; 370:2265–2275. 2. Bratton DJ, Stradling JR, Barbe´ F, Kohler M. Effect of CPAP on blood pressure in patients with minimally symptomatic obstructive sleep apnoea: a meta-analysis using individual patient data from four randomised controlled trials. Thorax 2014;69:1128–1135. 3. Quan SF, Budhiraja R, Clarke DP, Goodwin JL, Gottlieb DJ, Nichols DA, Simon RD, Smith TW, Walsh JK, Kushida CA. Impact of treatment with continuous positive airway pressure (CPAP) on weight in obstructive sleep apnea. J Clin Sleep Med 2013;9:989–993.
( Received in original form December 22, 2014; accepted in final form January 15, 2015 ) Author Contributions: Conception and design: I.H.I., M.A.D., M.A.-J., and A.M.; interpretation: I.H.I., M.A.D., M.A.-J., and A.M.; drafting the manuscript for important intellectual content: I.H.I., M.A.D., M.A.-J., and A.M. Correspondence and requests for reprints should be addressed to Imran H. Iftikhar, M.D., One Medical Park, Suite 300, Columbia, SC 29203. E-mail: imran. [email protected] Am J Respir Crit Care Med Vol 191, Iss 7, pp 845–847, Apr 1, 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1164/rccm.201412-2287RR Internet address: www.atsjournals.org
Beyond the Blue: What Fellows Are Reading in Other Journals
845
BEYOND THE BLUE 4. Iftikhar IH, Kline CE, Youngstedt SD. Effects of exercise training on sleep apnea: a meta-analysis. Lung 2014;192:175–184.
Kendzerska T, et al. Obstructive Sleep Apnea and the Prevalence and Incidence of Cancer. CMAJ (5) Reviewed by Mohammed Al-Jaghbeer and Imran H. Iftikhar
Previous studies have suggested a link between obstructive sleep apnea (OSA) and the development of cancer. Kendzerska and colleagues (5) performed an observational, historical cohort study, analyzing the prevalence and incidence of cancer among 10,419 patients with an apnea–hypopnea index (AHI) greater than 5. AHI and sleep time spent below 90% oxygen saturation were tested as predictors for association with cancer development. The prevalence of cancer at baseline was 5.1%, comprising mostly older patients with a greater number of comorbidities, who were likely to be former smokers. Incident cancer was diagnosed in 6.5% of 9,629 patients who were free of cancer at baseline, over a median follow-up period of 7.8 years. Although there was a significant association between AHI severity and cancer on univariate analysis, no association was seen between both the prevalence and incidence of cancer and AHI after controlling for age, sex, body mass index (BMI), and smoking status. When data were analyzed by applying the same categories of OSA severity, as in previous positive studies (6), and restricting the analysis to patients who did not claim OSA treatment, the association remained nonsignificant. In a subgroup analysis, a significant association was observed between oxygen desaturation and smokingrelated cancers. Except for this finding, which partly agrees with those of Campos-Rodriguez and colleagues (6), the rest of the findings stand in stark contrast, despite the fact that Kendzerska and colleagues had a longer duration of follow-up (median, 7.8 vs. 4.5 yr) and a higher number of incident cancers (627 vs. 261). Although the authors compare their results with the study by CamposRodriguez and colleagues (6) in different ways, it is important to bear in mind that the comparator study (6) was composed of relatively older patients, with higher BMI and more severe OSA. However, neither of the two studies (5, 6) used the oxygen desaturation index, a surrogate for intermittent hypoxia, postulated as one of the likely mechanisms for carcinogenesis associated with OSA. Nevertheless, several strengths of this study deserve credit as the authors carefully avoided length-time bias by separately performing sensitivity analyses to account for the possibility of 1 or 2 years of lag time that may have existed between the diagnosis of OSA and cancer. Furthermore, the authors overcame measurement bias by using AHI obtained from polysomnograms, contrary to some earlier studies (6, 7), and misclassification bias by specifying cancer incidence and not mortality as their outcomes, unlike earlier studies (7, 8) where this bias may have been introduced in studying an association with cancer mortality. Additional longitudinal studies are warranted before we dismiss the previously reported associations between cancer and OSA. n References 5. Kendzerska T, Leung RS, Hawker G, Tomlinson G, Gershon AS. Obstructive sleep apnea and the prevalence and incidence of cancer. CMAJ 2014;186:985–992.
846
6. Campos-Rodriguez F, Martinez-Garcia MA, Martinez M, Duran-Cantolla J, Peña MdeL, Masdeu MJ, Gonzalez M, Campo Fd, Gallego I, Marin JM, et al.; Spanish Sleep Network. Association between obstructive sleep apnea and cancer incidence in a large multicenter Spanish cohort. Am J Respir Crit Care Med 2013;187:99–105. 7. Marshall NS, Wong KK, Cullen SR, Knuiman MW, Grunstein RR. Sleep apnea and 20-year follow-up for all-cause mortality, stroke, and cancer incidence and mortality in the Busselton Health Study cohort. J Clin Sleep Med 2014;10:355–362. 8. Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farre´ R. Sleepdisordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2012;186:190–194.
Strollo PJ Jr, et al. Upper-Airway Stimulation for Obstructive Sleep Apnea. N Engl J Med (9) Reviewed by Angel Monserrate and Imran H. Iftikhar
The Stimulation Therapy for Apnea Reduction (STAR) trial (9) is the largest industry-sponsored, multicenter, prospective trial to date on hypoglossal nerve stimulation (HGNS) for the treatment of obstructive sleep apnea (OSA). The procedure involves surgically implanting a stimulation electrode on the hypoglossal nerve, a ventilatory effort–sensing lead between the intercostal muscles, and the neurostimulator below the clavicle. Stimulation of the hypoglossal nerve in turn leads to stimulation of the genioglossus muscle, which results in anterior tongue displacement. Strollo and colleagues studied HGNS in 126 participants with body mass index (BMI) less than 32 and moderate-to-severe OSA (apnea–hypopnea index [AHI], 20–50/hr), who were either resistant or nonadherent to continuous positive airway pressure (CPAP) treatment. The study was conducted as a multicenter, prospective, single-group trial with participants serving as their own controls. Before device implantation, screened participants underwent an endoscopy during drug-induced sleep to determine a favorable oropharyngeal anatomy amenable to HGNS, in specific absence of complete concentric retropalatal airway collapse. After the device was implanted, participants were monitored for 1 year with assessments at 2, 3, 6, and 12 months. At 12 months, HGNS led to a 68% reduction in the median AHI and a 70% reduction in the median oxygen desaturation index (ODI). In addition, in 66% of the participants AHI dropped by 50% to less than 20/hour, and in 75% the ODI was reduced by 25%. There were significant improvements in daytime sleepiness and quality of life as well. Although minor side effects were common, the rate of serious adverse effects was less than 2%. At the end of 12 months, the first 46 consecutive responders were randomized to either a therapy-maintenance or therapy-withdrawal group. Whereas the former continued therapy, the device was turned off for 7 days in the latter, and at the end of 1 week this group showed a significant resurgence of their sleep apnea (AHI, 25.8 vs. 7.6/hr; P , 0.001). Even though several alternative treatment options to CPAP exist, frequent use of these has been hampered by a lack of highquality evidence for their efficacy and effectiveness and proper selection of patients. This study indicates that HGNS may be a useful intervention in selected patients who are refractory to conventional CPAP therapy. In particular, the 86% adherence rate shown in this trial holds promise, because CPAP adherence rates from two recent
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 7 | April 1 2015
BEYOND THE BLUE trials, APPLES (10) and HomePAP (11), have been of the order of only 39–50%. In addition, compared with surgical options, HGNS offers several unique advantages, such as the ability to achieve real-time titration in overnight polysomnography, obtaining multilevel airway improvement in one procedure, and allowing the patient self-control. However, factors such as high upfront costs, the need for drug-induced endoscopy, surgical implantation, incompatibility with magnetic resonance imaging, and proper screening of eligible patients may limit its widespread use. In addition, even though permanent hypoglossal nerve weakness was not shown in this study, longitudinal studies lasting well over 12 months are warranted to alleviate such concerns. n Author disclosures are available with the text of this article at www.atsjournals.org.
Beyond the Blue: What Fellows Are Reading in Other Journals
References 9. Strollo PJ Jr, Soose RJ, Maurer JT, de Vries N, Cornelius J, Froymovich O, Hanson RD, Padhya TA, Steward DL, Gillespie MB, et al.; STAR Trial Group. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med 2014;370:139–149. 10. Kushida CA, Nichols DA, Holmes TH, Quan SF, Walsh JK, Gottlieb DJ, Simon RD Jr, Guilleminault C, White DP, Goodwin JL, et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2012;35:1593–1602. 11. Rosen CL, Auckley D, Benca R, Foldvary-Schaefer N, Iber C, Kapur V, Rueschman M, Zee P, Redline S. A multisite randomized trial of portable sleep studies and positive airway pressure autotitration versus laboratory-based polysomnography for the diagnosis and treatment of obstructive sleep apnea: the HomePAP study. Sleep 2012;35:757–767.
847
Chirinos JA, et al. CPAP, Weight Loss, or Both for Obstructive Sleep Apnea. N Engl J Med (1) Reviewed by Meredith A. Donley and Imran H. Iftikhar
In a randomized, parallel-group, 24-week trial (1), Chirinos and colleagues compared the effects of continuous positive airway pressure (CPAP), weight loss (WL), or a combined intervention (CPAP plus a weight loss intervention, CI) in obese adults with moderate to severe obstructive sleep apnea (OSA) (apnea–hypopnea index [AHI], >15), and a serum C-reactive protein (CRP) concentration greater than 1.0 mg/L. CPAP intervention included nightly CPAP therapy, and WL intervention was composed of dietary modification and an exercise training program. By structuring the trial with three intervention groups, the authors sought to investigate the presence of independent causal relationships between OSA and obesity on inflammation, insulin resistance, dyslipidemia, and hypertension. The primary end point was the effect of the interventions on CRP level. Both WL and CI were associated with significant reductions in CRP at 24 weeks. However, no significant incremental effect on CRP levels was found for the CI compared with either singular intervention alone. In contrast, by showing additional reductions in blood pressure (BP) with the CI group (14.1 mm Hg) compared with either the WL group (6.8 mm Hg) or the CPAP group (3.0 mm Hg), the authors report that both OSA and obesity have an independent causal relationship to hypertension. The study population was not defined by excessive daytime sleepiness (mean Epworth Sleepiness Scale [ESS] score , 11 in the CPAP group), suggesting that most were minimally symptomatic. The BP response to CPAP in those with ESS scores less than 11 is known to be smaller as compared with those with ESS scores greater than
11 (2). Finally, the CI group, compared with the CPAP group, had an effect on insulin resistance and serum triglyceride levels. However, there were no significant differences when the former was compared with the WL group. The effect size of BP reduction with CI and WL as compared with CPAP only, and the long-term increase in insulin sensitivity seen only in the CI and WL groups, have important bearings on clinical practice. In light of emerging data (3) on expected weight gain in CPAPcompliant patients, findings of this study are timely and reaffirm the beneficial effects of WL and exercise that extend past AHI reduction, especially because converging evidence (4) indicates that exercise alone, independent of weight changes, decreases OSA severity. Perhaps, in addition to CPAP, counseling on dietary modifications and exercise training ought to be formally incorporated as the standard of care for OSA treatment and as a core clinical competency in sleep medicine training programs. Last, the insignificant effect of CPAP on CRP suggests that modification of systemic inflammation may not be the mechanistic link underpinning the beneficial effect of CPAP on improving cardiovascular outcomes. n References 1. Chirinos JA, Gurubhagavatula I, Teff K, Rader DJ, Wadden TA, Townsend R, Foster GD, Maislin G, Saif H, Broderick P, et al. CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med 2014; 370:2265–2275. 2. Bratton DJ, Stradling JR, Barbe´ F, Kohler M. Effect of CPAP on blood pressure in patients with minimally symptomatic obstructive sleep apnoea: a meta-analysis using individual patient data from four randomised controlled trials. Thorax 2014;69:1128–1135. 3. Quan SF, Budhiraja R, Clarke DP, Goodwin JL, Gottlieb DJ, Nichols DA, Simon RD, Smith TW, Walsh JK, Kushida CA. Impact of treatment with continuous positive airway pressure (CPAP) on weight in obstructive sleep apnea. J Clin Sleep Med 2013;9:989–993.
( Received in original form December 22, 2014; accepted in final form January 15, 2015 ) Author Contributions: Conception and design: I.H.I., M.A.D., M.A.-J., and A.M.; interpretation: I.H.I., M.A.D., M.A.-J., and A.M.; drafting the manuscript for important intellectual content: I.H.I., M.A.D., M.A.-J., and A.M. Correspondence and requests for reprints should be addressed to Imran H. Iftikhar, M.D., One Medical Park, Suite 300, Columbia, SC 29203. E-mail: imran. [email protected] Am J Respir Crit Care Med Vol 191, Iss 7, pp 845–847, Apr 1, 2015 Copyright © 2015 by the American Thoracic Society DOI: 10.1164/rccm.201412-2287RR Internet address: www.atsjournals.org
Beyond the Blue: What Fellows Are Reading in Other Journals
845
BEYOND THE BLUE 4. Iftikhar IH, Kline CE, Youngstedt SD. Effects of exercise training on sleep apnea: a meta-analysis. Lung 2014;192:175–184.
Kendzerska T, et al. Obstructive Sleep Apnea and the Prevalence and Incidence of Cancer. CMAJ (5) Reviewed by Mohammed Al-Jaghbeer and Imran H. Iftikhar
Previous studies have suggested a link between obstructive sleep apnea (OSA) and the development of cancer. Kendzerska and colleagues (5) performed an observational, historical cohort study, analyzing the prevalence and incidence of cancer among 10,419 patients with an apnea–hypopnea index (AHI) greater than 5. AHI and sleep time spent below 90% oxygen saturation were tested as predictors for association with cancer development. The prevalence of cancer at baseline was 5.1%, comprising mostly older patients with a greater number of comorbidities, who were likely to be former smokers. Incident cancer was diagnosed in 6.5% of 9,629 patients who were free of cancer at baseline, over a median follow-up period of 7.8 years. Although there was a significant association between AHI severity and cancer on univariate analysis, no association was seen between both the prevalence and incidence of cancer and AHI after controlling for age, sex, body mass index (BMI), and smoking status. When data were analyzed by applying the same categories of OSA severity, as in previous positive studies (6), and restricting the analysis to patients who did not claim OSA treatment, the association remained nonsignificant. In a subgroup analysis, a significant association was observed between oxygen desaturation and smokingrelated cancers. Except for this finding, which partly agrees with those of Campos-Rodriguez and colleagues (6), the rest of the findings stand in stark contrast, despite the fact that Kendzerska and colleagues had a longer duration of follow-up (median, 7.8 vs. 4.5 yr) and a higher number of incident cancers (627 vs. 261). Although the authors compare their results with the study by CamposRodriguez and colleagues (6) in different ways, it is important to bear in mind that the comparator study (6) was composed of relatively older patients, with higher BMI and more severe OSA. However, neither of the two studies (5, 6) used the oxygen desaturation index, a surrogate for intermittent hypoxia, postulated as one of the likely mechanisms for carcinogenesis associated with OSA. Nevertheless, several strengths of this study deserve credit as the authors carefully avoided length-time bias by separately performing sensitivity analyses to account for the possibility of 1 or 2 years of lag time that may have existed between the diagnosis of OSA and cancer. Furthermore, the authors overcame measurement bias by using AHI obtained from polysomnograms, contrary to some earlier studies (6, 7), and misclassification bias by specifying cancer incidence and not mortality as their outcomes, unlike earlier studies (7, 8) where this bias may have been introduced in studying an association with cancer mortality. Additional longitudinal studies are warranted before we dismiss the previously reported associations between cancer and OSA. n References 5. Kendzerska T, Leung RS, Hawker G, Tomlinson G, Gershon AS. Obstructive sleep apnea and the prevalence and incidence of cancer. CMAJ 2014;186:985–992.
846
6. Campos-Rodriguez F, Martinez-Garcia MA, Martinez M, Duran-Cantolla J, Peña MdeL, Masdeu MJ, Gonzalez M, Campo Fd, Gallego I, Marin JM, et al.; Spanish Sleep Network. Association between obstructive sleep apnea and cancer incidence in a large multicenter Spanish cohort. Am J Respir Crit Care Med 2013;187:99–105. 7. Marshall NS, Wong KK, Cullen SR, Knuiman MW, Grunstein RR. Sleep apnea and 20-year follow-up for all-cause mortality, stroke, and cancer incidence and mortality in the Busselton Health Study cohort. J Clin Sleep Med 2014;10:355–362. 8. Nieto FJ, Peppard PE, Young T, Finn L, Hla KM, Farre´ R. Sleepdisordered breathing and cancer mortality: results from the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2012;186:190–194.
Strollo PJ Jr, et al. Upper-Airway Stimulation for Obstructive Sleep Apnea. N Engl J Med (9) Reviewed by Angel Monserrate and Imran H. Iftikhar
The Stimulation Therapy for Apnea Reduction (STAR) trial (9) is the largest industry-sponsored, multicenter, prospective trial to date on hypoglossal nerve stimulation (HGNS) for the treatment of obstructive sleep apnea (OSA). The procedure involves surgically implanting a stimulation electrode on the hypoglossal nerve, a ventilatory effort–sensing lead between the intercostal muscles, and the neurostimulator below the clavicle. Stimulation of the hypoglossal nerve in turn leads to stimulation of the genioglossus muscle, which results in anterior tongue displacement. Strollo and colleagues studied HGNS in 126 participants with body mass index (BMI) less than 32 and moderate-to-severe OSA (apnea–hypopnea index [AHI], 20–50/hr), who were either resistant or nonadherent to continuous positive airway pressure (CPAP) treatment. The study was conducted as a multicenter, prospective, single-group trial with participants serving as their own controls. Before device implantation, screened participants underwent an endoscopy during drug-induced sleep to determine a favorable oropharyngeal anatomy amenable to HGNS, in specific absence of complete concentric retropalatal airway collapse. After the device was implanted, participants were monitored for 1 year with assessments at 2, 3, 6, and 12 months. At 12 months, HGNS led to a 68% reduction in the median AHI and a 70% reduction in the median oxygen desaturation index (ODI). In addition, in 66% of the participants AHI dropped by 50% to less than 20/hour, and in 75% the ODI was reduced by 25%. There were significant improvements in daytime sleepiness and quality of life as well. Although minor side effects were common, the rate of serious adverse effects was less than 2%. At the end of 12 months, the first 46 consecutive responders were randomized to either a therapy-maintenance or therapy-withdrawal group. Whereas the former continued therapy, the device was turned off for 7 days in the latter, and at the end of 1 week this group showed a significant resurgence of their sleep apnea (AHI, 25.8 vs. 7.6/hr; P , 0.001). Even though several alternative treatment options to CPAP exist, frequent use of these has been hampered by a lack of highquality evidence for their efficacy and effectiveness and proper selection of patients. This study indicates that HGNS may be a useful intervention in selected patients who are refractory to conventional CPAP therapy. In particular, the 86% adherence rate shown in this trial holds promise, because CPAP adherence rates from two recent
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 7 | April 1 2015
BEYOND THE BLUE trials, APPLES (10) and HomePAP (11), have been of the order of only 39–50%. In addition, compared with surgical options, HGNS offers several unique advantages, such as the ability to achieve real-time titration in overnight polysomnography, obtaining multilevel airway improvement in one procedure, and allowing the patient self-control. However, factors such as high upfront costs, the need for drug-induced endoscopy, surgical implantation, incompatibility with magnetic resonance imaging, and proper screening of eligible patients may limit its widespread use. In addition, even though permanent hypoglossal nerve weakness was not shown in this study, longitudinal studies lasting well over 12 months are warranted to alleviate such concerns. n Author disclosures are available with the text of this article at www.atsjournals.org.
Beyond the Blue: What Fellows Are Reading in Other Journals
References 9. Strollo PJ Jr, Soose RJ, Maurer JT, de Vries N, Cornelius J, Froymovich O, Hanson RD, Padhya TA, Steward DL, Gillespie MB, et al.; STAR Trial Group. Upper-airway stimulation for obstructive sleep apnea. N Engl J Med 2014;370:139–149. 10. Kushida CA, Nichols DA, Holmes TH, Quan SF, Walsh JK, Gottlieb DJ, Simon RD Jr, Guilleminault C, White DP, Goodwin JL, et al. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep 2012;35:1593–1602. 11. Rosen CL, Auckley D, Benca R, Foldvary-Schaefer N, Iber C, Kapur V, Rueschman M, Zee P, Redline S. A multisite randomized trial of portable sleep studies and positive airway pressure autotitration versus laboratory-based polysomnography for the diagnosis and treatment of obstructive sleep apnea: the HomePAP study. Sleep 2012;35:757–767.
847
