Long-term Noninvasive Ventilation in Obesity Hypoventilation Syndrome Without Severe OSA

Abstract

BackgroundNoninvasive ventilation (NIV) is an effective form of treatment in obesity hypoventilation syndrome (OHS) with severe OSA. However, there is paucity of evidence in patients with OHS without severe OSA phenotype.Research QuestionIs NIV effective in OHS without severe OSA phenotype?Study Design and MethodsIn this multicenter, open-label parallel group clinical trial performed at 16 sites in Spain, we randomly assigned 98 stable ambulatory patients with untreated OHS and apnea-hypopnea index < 30 events/h (ie, no severe OSA) to NIV or lifestyle modification (control group) using simple randomization through an electronic database. The primary end point was hospitalization days per year. Secondary end points included other hospital resource utilization, incident cardiovascular events, mortality, respiratory functional tests, BP, quality of life, sleepiness, and other clinical symptoms. Both investigators and patients were aware of the treatment allocation; however, treating physicians from the routine care team were not aware of patients’ enrollment in the clinical trial. The study was stopped early in its eighth year because of difficulty identifying patients with OHS without severe OSA. The analysis was performed according to intention-to-treat and per-protocol principles and by adherence subgroups.ResultsForty-nine patients in the NIV group and 49 in the control group were randomized, and 48 patients in each group were analyzed. During a median follow-up of 4.98 years (interquartile range, 2.98-6.62), the mean hospitalization days per year ± SD was 2.60 ± 5.31 in the control group and 2.71 ± 4.52 in the NIV group (adjusted rate ratio, 1.07; 95% CI, 0.44-2.59; P = .882). NIV therapy, in contrast with the control group, produced significant longitudinal improvement in Paco2, pH, bicarbonate, quality of life (Medical Outcome Survey Short Form 36 physical component), and daytime sleepiness. Moreover, per-protocol analysis showed a statistically significant difference for the time until the first ED visit favoring NIV. In the subgroup with high NIV adherence, the time until the first event of hospital admission, ED visit, and mortality was longer than in the low adherence subgroup. Adverse events were similar between arms.InterpretationIn stable ambulatory patients with OHS without severe OSA, NIV and lifestyle modification had similar long-term hospitalization days per year. A more intensive program aimed at improving NIV adherence may lead to better outcomes. Larger studies are necessary to better determine the long-term benefit of NIV in this subgroup of OHS.Trial RegistryClinicalTrials.gov; No.: NCT01405976; URL: www.clinicaltrials.gov ; Noninvasive ventilation (NIV) is an effective form of treatment in obesity hypoventilation syndrome (OHS) with severe OSA. However, there is paucity of evidence in patients with OHS without severe OSA phenotype. Is NIV effective in OHS without severe OSA phenotype? In this multicenter, open-label parallel group clinical trial performed at 16 sites in Spain, we randomly assigned 98 stable ambulatory patients with untreated OHS and apnea-hypopnea index < 30 events/h (ie, no severe OSA) to NIV or lifestyle modification (control group) using simple randomization through an electronic database. The primary end point was hospitalization days per year. Secondary end points included other hospital resource utilization, incident cardiovascular events, mortality, respiratory functional tests, BP, quality of life, sleepiness, and other clinical symptoms. Both investigators and patients were aware of the treatment allocation; however, treating physicians from the routine care team were not aware of patients’ enrollment in the clinical trial. The study was stopped early in its eighth year because of difficulty identifying patients with OHS without severe OSA. The analysis was performed according to intention-to-treat and per-protocol principles and by adherence subgroups. Forty-nine patients in the NIV group and 49 in the control group were randomized, and 48 patients in each group were analyzed. During a median follow-up of 4.98 years (interquartile range, 2.98-6.62), the mean hospitalization days per year ± SD was 2.60 ± 5.31 in the control group and 2.71 ± 4.52 in the NIV group (adjusted rate ratio, 1.07; 95% CI, 0.44-2.59; P = .882). NIV therapy, in contrast with the control group, produced significant longitudinal improvement in Paco2, pH, bicarbonate, quality of life (Medical Outcome Survey Short Form 36 physical component), and daytime sleepiness. Moreover, per-protocol analysis showed a statistically significant difference for the time until the first ED visit favoring NIV. In the subgroup with high NIV adherence, the time until the first event of hospital admission, ED visit, and mortality was longer than in the low adherence subgroup. Adverse events were similar between arms. In stable ambulatory patients with OHS without severe OSA, NIV and lifestyle modification had similar long-term hospitalization days per year. A more intensive program aimed at improving NIV adherence may lead to better outcomes. Larger studies are necessary to better determine the long-term benefit of NIV in this subgroup of OHS. ClinicalTrials.gov; No.: NCT01405976; URL: www.clinicaltrials.gov ; Obesity hypoventilation syndrome (OHS) is defined by the presence of obesity, sleep-disordered breathing, and chronic hypercapnic respiratory failure in the absence of other diseases causing daytime hypoventilation.1Mokhlesi B. Kryger M.H. Grunstein R.R. Assessment and management of patients with obesity hypoventilation syndrome.Proc Am Thorac Soc. 2008; 5: 218-225Crossref PubMed Scopus (167) Google Scholar Most patients with OHS have severe OSA, but nocturnal hypoventilation may be the only respiratory sleep disorder present.2Kessler R. Chaouat A. Schinkewitch P. et al.The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive cases.Chest. 2001; 120: 369-376Abstract Full Text Full Text PDF PubMed Scopus (330) Google Scholar Approximately 27% of patients with OHS do not have severe OSA.3Masa J.F. Corral J. Alonso M.L. et al.Efficacy of different treatment alternatives for obesity hypoventilation syndrome. Pickwick Study.Am J Respir Crit Care Med. 2015; 192: 86-95Crossref PubMed Scopus (165) Google Scholar Patients with untreated OHS are at increased risk of cardiovascular and respiratory morbidity, mortality, and health-care resource utilization compared with patients with eucapnic OSA4Castro-Añón O. Pérez de Llano L.A. De la Fuente Sánchez S. et al.Obesity-hypoventilation syndrome: increased risk of death over sleep apnea syndrome.PLoS One. 2015; 10e0117808Crossref PubMed Scopus (111) Google Scholar,5Basoglu O.K. Tasbakan M.S. Comparison of clinical characteristics in patients with obesity hypoventilation syndrome and obese obstructive sleep apnea syndrome: a case-control study.Clin Respir J. 2014; 8: 167-174Crossref PubMed Scopus (41) Google Scholar and patients with eucapnic obesity.4Castro-Añón O. Pérez de Llano L.A. 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Health, social and economical consequences of sleep-disordered breathing: a controlled national study.Thorax. 2011; 66: 560-566Crossref PubMed Scopus (160) Google Scholar, 9Pérez de Llano L.A. Golpe R. Ortiz Piquer M. et al.Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome.Chest. 2005; 128: 587-594Abstract Full Text Full Text PDF PubMed Scopus (238) Google Scholar, 10Ojeda Castillejo E. de Lucas Ramos P. López Martin S. et al.Noninvasive mechanical ventilation in patients with obesity hypoventilation syndrome. Long-term outcome and prognostic factors.Arch Bronconeumol. 2015; 51: 61-68Crossref PubMed Scopus (21) Google Scholar, 11Nowbar S. Burkart K.M. Gonzales R. et al.Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome.Am J Med. 2004; 116: 1-7Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 12Borel J.C. Burel B. Tamisier R. et al.Comorbidities and mortality in hypercapnic obese under domiciliary noninvasive ventilation.PLoS One. 2013; 8e52006Crossref PubMed Scopus (68) Google Scholar Patients with OHS with predominant and nonpredominant OSA have different phenotypes. Those with OHS and coexistent severe OSA tend to be younger, are mostly men, are more obese, have higher levels of sleepiness, have worse gas exchange, have a lower prevalence of cardiovascular comorbidities, have better exercise tolerance, and have fewer days hospitalized than patients with OHS without severe OSA.13Masa J.F. Corral J. Romero A. et al.Protective cardiovascular effect of sleep apnea severity in obesity hypoventilation syndrome.Chest. 2016; 150: 68-79Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar OHS is typically treated with positive airway pressure (PAP) (CPAP or noninvasive ventilation [NIV]).14Soghier I. Brożek J.L. Afshar M. et al.Noninvasive ventilation versus CPAP as initial treatment of obesity hypoventilation syndrome: a systematic review.Ann Am Thorac Soc. 2019; 16: 1295-1303Crossref PubMed Scopus (25) Google Scholar,15Mokhlesi B. J.F. J.L. et and management of obesity hypoventilation syndrome. clinical J Respir Crit Care Med. 2019; PubMed Scopus Google Scholar CPAP may not be an effective treatment for patients with OHS without significant I. B. et hypoventilation syndrome as a of respiratory 2001; 120: Full Text Full Text PDF PubMed Scopus Google Scholar in the form of and nocturnal CPAP and NIV have to have similar J.F. Corral J. Alonso M.L. et al.Efficacy of different treatment alternatives for obesity hypoventilation syndrome. Pickwick Study.Am J Respir Crit Care Med. 2015; 192: 86-95Crossref PubMed Scopus (165) Google Grunstein R.R. trial of CPAP in the treatment of obesity hypoventilation syndrome without severe nocturnal 2008; PubMed Scopus Google B. et controlled trial of CPAP versus ventilation for initial treatment of obesity hypoventilation PubMed Scopus Google Scholar and J.F. B. I. et al.Long-term clinical of positive airway pressure versus ventilation in patients with obesity hypoventilation syndrome: a controlled 2019; Full Text Full Text PDF PubMed Scopus Google Scholar in controlled of patients with OHS with severe OSA. In there only controlled trial NIV with lifestyle in patients with OHS but without severe J.F. Corral J. C. et ventilation in obesity hypoventilation syndrome without severe obstructive sleep 2016; PubMed Scopus Google Scholar In this NIV to significant improvement in Paco2, sleepiness, and compared with the control group at are no long-term controlled in this OHS phenotype. performed a trial to determine the long-term of NIV and lifestyle modification with at years of follow-up using hospitalization days per year as the primary outcome study is the long-term from the parallel controlled trial of the Pickwick from the of J.F. Corral J. Alonso M.L. et al.Efficacy of different treatment alternatives for obesity hypoventilation syndrome. Pickwick Study.Am J Respir Crit Care Med. 2015; 192: 86-95Crossref PubMed Scopus (165) Google J.F. Corral J. Romero A. et al.Protective cardiovascular effect of sleep apnea severity in obesity hypoventilation syndrome.Chest. 2016; 150: 68-79Abstract Full Text Full Text PDF PubMed Scopus (53) Google J.F. B. I. et al.Long-term clinical of positive airway pressure versus ventilation in patients with obesity hypoventilation syndrome: a controlled 2019; Full Text Full Text PDF PubMed Scopus Google Scholar, J.F. Corral J. C. et ventilation in obesity hypoventilation syndrome without severe obstructive sleep 2016; PubMed Scopus Google Scholar, J.F. Corral J. et and long-term of ventilation in obesity hypoventilation syndrome: the Bronconeumol. 2016; PubMed Scopus Google Scholar, J. et with ventilation and CPAP in obesity hypoventilation PubMed Scopus Google Scholar a multicenter, open-label controlled trial with parallel The study was stopped years of follow-up to with the of the 16 clinical because of the of absence of enrollment in the year. to we patients between and years of were for because of OHS or OSA at 16 care in OHS was defined as obesity 30 stable hypercapnic respiratory failure and no clinical the no significant evidence of had to be in was < and no clinical evidence of or were the OSA index < 30 an absence of or and a NIV treatment The were the a to severe chronic severe chronic nasal and a of J.F. B. I. et al.Long-term clinical of positive airway pressure versus ventilation in patients with obesity hypoventilation syndrome: a controlled 2019; Full Text Full Text PDF PubMed Scopus Google Scholar The Pickwick was by the of 16 and was from patients patients with OHS without severe OSA were by an in each a electronic randomization without to NIV or the control group and for a of Patients to NIV were lifestyle was daytime or nocturnal was (control group) or J.F. Corral J. Romero A. et al.The effect of in obesity hypoventilation Med. 2016; PubMed Scopus Google Scholar The lifestyle modification of a and the of sleep and The NIV was pressure The study was and investigators and patients were aware of the treatment at each was in of and follow-up to treatment adherence and to or NIV and The investigators were not in other of clinical care or clinical Patients were at over at first and until and until years was only performed at and The were J.F. Corral J. C. et ventilation in obesity hypoventilation syndrome without severe obstructive sleep 2016; PubMed Scopus Google Scholar days for were at visit the outcome was from the electronic and with patients in of visit the visit, we mortality and its and other hospital resource utilization as hospitalization days ED and hospital in the as hospitalization In the and we the of cardiovascular events in the as hospitalization the visit, we to Paco2, and pH, and each visit the visit, we with a et of the and of PubMed Scopus Google Scholar and M. of and Bronconeumol. 2013; PubMed Scopus Google Scholar for for the J Respir Crit Care Med. 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The intention-to-treat analysis showed similar long-term between the in hospitalization other hospital resource utilization, BP, cardiovascular events, mortality, and However, gas and quality of life of the and daytime were better with NIV. In the per-protocol NIV lead to lower ED analysis of adherence showed high of adherence to NIV was with ED and Most and in untreated patients with OHS to be by respiratory as respiratory failure and S. Burkart K.M. Gonzales R. et al.Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome.Am J Med. 2004; 116: 1-7Abstract Full Text Full Text PDF PubMed Scopus (395) Google M. in clinical and death in the J. Google C. The clinical characteristics and hospital and of patients with the obesity hypoventilation syndrome: analysis of a 2016; PubMed Scopus (41) Google Scholar However, in of patients with OHS long-term NIV O. Pérez de Llano L.A. De la Fuente Sánchez S. et al.Obesity-hypoventilation syndrome: increased risk of death over sleep apnea syndrome.PLoS One. 2015; 10e0117808Crossref PubMed Scopus (111) Google I. C. S. et al.The between adherence to positive airway pressure and long-term in patients with obesity hypoventilation syndrome: a prospective Med. PubMed Scopus Google Scholar and in long-term for patients with severe OSA, of the were of cardiovascular J.F. B. I. et al.Long-term clinical of positive airway pressure versus ventilation in patients with obesity hypoventilation syndrome: a controlled 2019; Full Text Full Text PDF PubMed Scopus Google Scholar may and mortality because of respiratory but cardiovascular outcomes. In the the mortality similar between the predominant of mortality in the NIV was cardiovascular events and respiratory failure in the control group In the high NIV adherence there were no to respiratory in the OHS without severe OSA with higher cardiovascular morbidity, NIV may respiratory but this improvement may not be to health-care resource utilization and mortality because NIV cardiovascular for a of difference in the and control may be low NIV an improvement in hospital resource utilization and mortality in the subgroup of patients with high NIV adherence compared with the low adherence subgroup of NIV and the control The median adherence to NIV in the treatment in the study was lower than in patients with OHS with severe OSA J.F. B. I. et al.Long-term clinical of positive airway pressure versus ventilation in patients with obesity hypoventilation syndrome: a controlled 2019; Full Text Full Text PDF PubMed Scopus Google Scholar low adherence was by the higher of patients with NIV treatment follow-up in the study in the severe OSA may lower Paco2, and with and the of improvement in was similar to the improvement with in the parallel trial of the Pickwick study with severe OSA J.F. B. I. et al.Long-term clinical of positive airway pressure versus ventilation in patients with obesity hypoventilation syndrome: a controlled 2019; Full Text Full Text PDF PubMed Scopus Google Scholar of improvement in is similar to we in the patients in this study of J.F. Corral J. C. et ventilation in obesity hypoventilation syndrome without severe obstructive sleep 2016; PubMed Scopus Google Scholar and is in with clinical of patients with OHS without severe OSA treated with J.F. M. Sánchez De J. C. The obesity hypoventilation syndrome be treated with noninvasive mechanical 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, P. de J. A. J.L. at year of nocturnal intermittent positive pressure ventilation in patients with obesity-hypoventilation Med. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, S. G. S. P. C. Long-term ventilation and in obesity-hypoventilation Med. Full Text Full Text PDF PubMed Scopus Google Scholar However, the of improvement in was lower than was in patients with OHS with severe OSA treated with J.F. B. I. et al.Long-term clinical of positive airway pressure versus ventilation in patients with obesity hypoventilation syndrome: a controlled 2019; Full Text Full Text PDF PubMed Scopus Google Scholar In the longitudinal improvement in was lower than in patients with OHS with severe OSA. Patients with OHS with severe OSA were more obese, and is NIV was more effective in to improvement in and Moreover, is a higher of adherence is necessary to of and the lower mean adherence to NIV may have to improvement in in of the improvement in the of improvement in with NIV was lower in patients with OHS without severe OSA than in patients with OHS with severe OSA. may be because of the (ie, lower more more or lower NIV adherence to NIV may be an to the patients were to long-term treatment NIV better outcomes. is a paucity of the of to NIV adherence in patients with OHS. However, is to CPAP adherence in I. and to of positive airway pressure in with obstructive sleep 2014; Google Scholar may be effective to adherence to NIV in patients with OHS. (ie, or by or for use of NIV or to and adherence be in patients with OHS low levels of adherence to long-term NIV was a subgroup of a disorder low prevalence of OHS 27% of the OHS 16 clinical and years of the study was stopped early because of difficulty identifying patients with OHS with no severe OSA in the year of the the study lower than for the outcome the in the this study in a subgroup of OHS in a longitudinal in a controlled trial. patients in NIV and control over to the other group, we to this effect by a per-protocol and subgroup analysis adherence to NIV. is NIV may have because we not NIV levels sleep In in the OHS without severe OSA, NIV was similar to lifestyle modification in as hospital resource utilization, incident cardiovascular events, and However, NIV was more effective in improving daytime Paco2, of quality of life, and sleepiness. A more intensive program aimed at improving NIV adherence may lead to better outcomes. Larger studies are necessary to better determine the long-term benefit of NIV in this subgroup of however, the lower prevalence of this of be to long-term clinical with J. M. had to the in the study and had the for the to for J. M. J. I. J. M. A. M. A. C. M. M. S. J. M. O. E. C. B. J. J. A. J. E. M. M. E. S. J. B. M. S. M. A. E. J. C. J. B. E. J. M. J. R. M. A. S. and M. B. to study and of or analysis and of J. B. I. J. M. A. C. M. E. M. S. J. M. S. E. C. J. J. M. A. M. and J. C. the or the for J. B. I. J. M. A. and J. C. performed the to be of The and of the study had no or in study in the and of in the and in the to the for A. de de de de de de A. J. de de de A. de de de de de B. de de de de M. de la de la A. de de de and for in the of the and for The and be in the of the as study analysis and be from the Pickwick be by for use in and be and of the analysis and of a with the Pickwick be from to years the of this trial. be to the with

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