Relationship Between CPAP Termination and All-Cause Mortality
2022; Elsevier BV; Volume: 161; Issue: 6 Linguagem: Inglês
10.1016/j.chest.2022.02.013
ISSN1931-3543
AutoresJean‐Louis Pépin, Sébastien Bailly, Pierre Rinder, Dan Adler, Adam Benjafield, Florent Lavergne, Anne Josseran, Paul Sinel-Boucher, Renaud Tamisier, Peter A. Cistulli, Atul Malhotra, Pierre Hornus,
Tópico(s)Neonatal and fetal brain pathology
ResumoBackgroundRandomized controlled trials have failed to demonstrate an effect of CPAP therapy on mortality. However, these studies have a number of important limitations, including low CPAP adherence, patient selection, and a small number of mortality events.Research QuestionWhat are the effects of CPAP therapy termination in the first year on all-cause mortality in patients with OSA from the Nationwide Claims Data Lake for Sleep Apnea study?Study Design and MethodsData from the Système National des Données de Santé (SNDS) database, the French national health insurance reimbursement system, for all new CPAP users ≥ 18 years of age were analyzed. The SNDS contains comprehensive, individualized, and anonymized data on health spending reimbursements for > 99% of all individuals living in France. OSA diagnosis was based on specific disease codes, whereas CPAP prescription was identified using specific treatment method codes. CPAP therapy termination was defined as the cessation of CPAP reimbursements triggered by the respiratory physician or sleep specialist in charge of follow-up. Patients who terminated therapy in the first year were propensity score matched with those who continued to use CPAP. The primary outcome was all-cause mortality. Three-year survival was visualized using Kaplan-Meier curves. Contributors to mortality also were determined.ResultsData from two matched groups each including 88,007 patients were included (mean age, 60 years; 64% men). Continuation of CPAP therapy was associated with a significantly lower risk of all-cause death compared with CPAP therapy termination (hazard ratio [HR], 0.61; 95% CI, 0.57-0.65; P < .01, log-rank test). Incident heart failure also was less common in patients who continued vs terminated CPAP therapy (HR, 0.77; 95% CI, 0.71-0.82; P < .01).InterpretationThese real-world data from a comprehensive, unbiased database highlight the potential for ongoing use of CPAP treatment to reduce all-cause mortality in patients with OSA. Randomized controlled trials have failed to demonstrate an effect of CPAP therapy on mortality. However, these studies have a number of important limitations, including low CPAP adherence, patient selection, and a small number of mortality events. What are the effects of CPAP therapy termination in the first year on all-cause mortality in patients with OSA from the Nationwide Claims Data Lake for Sleep Apnea study? Data from the Système National des Données de Santé (SNDS) database, the French national health insurance reimbursement system, for all new CPAP users ≥ 18 years of age were analyzed. The SNDS contains comprehensive, individualized, and anonymized data on health spending reimbursements for > 99% of all individuals living in France. OSA diagnosis was based on specific disease codes, whereas CPAP prescription was identified using specific treatment method codes. CPAP therapy termination was defined as the cessation of CPAP reimbursements triggered by the respiratory physician or sleep specialist in charge of follow-up. Patients who terminated therapy in the first year were propensity score matched with those who continued to use CPAP. The primary outcome was all-cause mortality. Three-year survival was visualized using Kaplan-Meier curves. Contributors to mortality also were determined. Data from two matched groups each including 88,007 patients were included (mean age, 60 years; 64% men). Continuation of CPAP therapy was associated with a significantly lower risk of all-cause death compared with CPAP therapy termination (hazard ratio [HR], 0.61; 95% CI, 0.57-0.65; P < .01, log-rank test). Incident heart failure also was less common in patients who continued vs terminated CPAP therapy (HR, 0.77; 95% CI, 0.71-0.82; P < .01). These real-world data from a comprehensive, unbiased database highlight the potential for ongoing use of CPAP treatment to reduce all-cause mortality in patients with OSA. FOR EDITORIAL COMMENT, SEE PAGE 1444Take-home PointsStudy Question: What are the effects of CPAP therapy termination in the first year on all-cause mortality in patients with OSA from the Nationwide Claims Data Lake for Sleep Apnea study?Results: In matched patient groups, continuation of CPAP therapy was associated with a significantly lower risk of all-cause death compared with CPAP therapy termination. In addition, incidence heart failure was significantly less common in patients who continued vs terminated CPAP therapy in the first year.Interpretation: These data highlight the potential for ongoing use of CPAP to reduce all-cause mortality in patients with OSA. OSA is characterized by repeated upper airway collapse during sleep. These episodes are associated with several important consequences, including sympathetic activation, marked negative intrathoracic pressure swings, intermittent oxygen desaturation, hypercapnia, and arousal from sleep. In turn, these effects are thought to contribute to common comorbidities in patients with OSA, including hypertension, cardiovascular and cerebrovascular disease, and metabolic abnormalities.1Bonsignore M.R. Suarez Giron M.C. Marrone O. Castrogiovanni A. Montserrat J.M. Personalised medicine in sleep respiratory disorders: focus on obstructive sleep apnoea diagnosis and treatment.Eur Respir Rev. 2017; 26: 170069Crossref PubMed Scopus (44) Google Scholar, 2Knauert M. Naik S. Gillespie M.B. Kryger M. Clinical consequences and economic costs of untreated obstructive sleep apnea syndrome.World J Otorhinolaryngol Head Neck Surg. 2015; 1: 17-27Crossref PubMed Google Scholar, 3Lévy P. Kohler M. McNicholas W.T. et al.Obstructive sleep apnoea syndrome.Nat Rev Dis Primers. 2015; 1: 15015Crossref PubMed Scopus (478) Google Scholar, 4Pepin J.L. Borel A.L. Tamisier R. Baguet J.P. Levy P. Dauvilliers Y. Hypertension and sleep: overview of a tight relationship.Sleep Med Rev. 2014; 18: 509-519Crossref PubMed Scopus (144) Google Scholar These comorbidities could be responsible for the increased all-cause mortality risk that has been reported in patients with OSA.5Lavie P. Lavie L. Herer P. All-cause mortality in males with sleep apnoea syndrome: declining mortality rates with age.Eur Respir J. 2005; 25: 514-520Crossref PubMed Scopus (243) Google Scholar, 6Yaggi H.K. Concato J. Kernan W.N. Lichtman J.H. Brass L.M. Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death.N Engl J Med. 2005; 353: 2034-2041Crossref PubMed Scopus (2354) Google Scholar, 7Marin J.M. Carrizo S.J. Vicente E. Agusti A.G. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study.Lancet. 2005; 365: 1046-1053Abstract Full Text Full Text PDF PubMed Scopus (2688) Google Scholar, 8Young T. Finn L. Peppard P.E. et al.Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort.Sleep. 2008; 31: 1071-1078PubMed Google Scholar, 9Marshall N.S. Wong K.K. Cullen S.R. Knuiman M.W. Grunstein R.R. 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: 355-362Crossref PubMed Scopus (313) Google Scholar, 10Punjabi N.M. Caffo B.S. Goodwin J.L. et al.Sleep-disordered breathing and mortality: a prospective cohort study.PLoS Med. 2009; 6e1000132Crossref PubMed Scopus (977) Google Scholar Despite the reported association between OSA and mortality, randomized clinical trials evaluating the effects of treating OSA on cardiovascular events and all-cause death have not demonstrated any beneficial effect of CPAP therapy, the gold standard treatment for moderate to severe OSA.11McEvoy R.D. Antic N.A. Heeley E. et al.CPAP for prevention of cardiovascular events in obstructive sleep apnea.N Engl J Med. 2016; 375: 919-931Crossref PubMed Scopus (1150) Google Scholar, 12Peker Y. Glantz H. Eulenburg C. Wegscheider K. Herlitz J. Thunström E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (358) Google Scholar, 13Sánchez-de-la-Torre M. Sánchez-de-la-Torre A. Bertran S. et al.Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial.Lancet Respir Med. 2020; 8: 359-367Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar However, the ability of CPAP to influence hard mortality end points may have been limited by several factors, including low adherence to CPAP and patient selection. In addition, the total number of mortality events was low in all randomized trials, limiting statistical power to detect between-group differences and perhaps not representative of what happens in the real world. Thus, although randomized controlled trials provide a high level of evidence, real-world data may be able to provide a more accurate and generalizable picture of the effects of routine clinical use of CPAP on mortality. The Nationwide Claims Data Lake for Sleep Apnea study uses data from the Système National des Données de Santé (SNDS) database, the French national health insurance reimbursement system. This analysis investigated all-cause mortality in new users of CPAP who terminated therapy during the first year or continued with long-term CPAP therapy. This analysis included data from the French SNDS database, which contains comprehensive, individualized and anonymized data on health spending reimbursements for > 99% of all individuals living in France. The Nationwide Claims Data Lake for Sleep Apnea project was approved by the Commission Nationale Informatique et Liberté, the French information technology and personal data protection authority. Specific approval was obtained from the Commission Nationale Informatique et Liberté to perform this study (Identifier: DR-2019-78, no. 919194). Eligible patients were adults ≥ 18 years of age who had not previously used CPAP and had initiated CPAP therapy between January 2015 and December 2016. OSA diagnosis was based on specific disease codes, whereas CPAP prescription was identified using specific treatment method codes.14Pépin J.L. Bailly S. Rinder P. et al.on behalf of the medXcloud GroupCPAP therapy rates by OSA phenotype: a French nationwide database analysis.J Clin Med. 2021; 10: 936Crossref PubMed Scopus (20) Google Scholar Patients who terminated CPAP during the first year of therapy were matched with those who continued CPAP therapy for 1 year using propensity score matching to eliminate the influence of biases and confounding factors affecting both therapy termination and mortality rates in the therapy termination and therapy continuation groups. Propensity score matching was based on the following factors: patient demographics (age and sex), insurance coverage, socioeconomic status, and comorbidities (stroke, heart failure, peripheral arterial occlusive disease, hypertension, diabetes mellitus, other cardiovascular diseases, COPD, bariatric surgery, neurotic disorders, use of psychotropic medication, and kidney diseases). To account for possible selection bias, a sensitivity analysis was performed in the untruncated cohort with CPAP initiation being the starting date in a survival Cox model with CPAP continuation as a time-dependent covariate. Variables for adjustments were the same variables used for the propensity score analysis. One year after CPAP initiation, the propensity score was applied to select a matched population of CPAP users and nonusers; patients then were followed up for an additional 3 years (e-Fig 1). CPAP therapy termination was defined as the cessation of CPAP reimbursements triggered by the respiratory physician or sleep specialist in charge of follow-up. French national recommendations for reimbursement are CPAP device use of > 4 h/night. Reimbursement rates progressively decrease when very low adherence to CPAP occurs, although delivery and reimbursement of therapy can continue when CPAP use is 2 to 4 h/night, with a requirement for additional patient education and coaching. A mandatory follow-up visit occurs at 4 months after CPAP initiation, then every year thereafter to determine treatment reimbursement renewal. For this analysis, it was assumed that CPAP termination was linked with nonadherence. Individuals with a valid and documented reason for stopping CPAP therapy (ie, sleep apnea cure after bariatric surgery, otorhinolaryngology surgery, switch to oral appliances, death) were censored in the Kaplan-Meier analysis. In the SNDS database, mortality is defined by the registered date of death, but the cause of death is not available. Data are expressed as median (interquartile range) for quantitative data and as number (percentage) for qualitative data. Comparisons between groups (CPAP termination vs CPAP continuation) were performed using the Student t test for quantitative data and the χ 2 test for qualitative data. Mortality and the cumulative incidence rate for heart failure were compared using Kaplan-Meier curves, and between-group comparisons were performed by using the log-rank test. These analyses also were performed separately for men and women. The primary objective was assessed using a propensity score analysis. First, a propensity score model was performed to compute the factors associated significantly with the probability of CPAP termination during the first year. A nonparsimonious multivariate regression model was created including all major factors (list of variables and results in e-Table 1). A 1:1 greedy matching was performed with a caliper of 0.1%. Standardized differences were used to ensure the quality of the propensity score matching. The standardized difference was reduced for all variables after matching (e-Fig 2). Finally, a semiparametric Cox model was used to assess the impact of CPAP termination or continuation on outcomes (mortality, incident heart failure, incident coronary artery disease (CAD), new hospitalization for diabetes, incident arrhythmias, and incident hypertension); cancer was not evaluated because of the comparatively short follow-up time for this analysis. To account for mortality as a competing event for all outcomes, sensitivity analyses were performed considering only patients who were alive. Hazard proportionality assumption was not checked, and hazard ratio (HR) values must be interpreted as an average HR, rather than instantaneous HR.15Stensrud M.J. Hernán M.A. Why test for proportional hazards?.JAMA. 2020; 323: 1401-1402Crossref PubMed Scopus (93) Google Scholar Analyses were performed using Python version 3.6.7 software with the libraries Numpy version 1.18.1 and Pandas version 0.24.2 for data management and analysis, Statsmodel version 0.12.1 for logistic regression, and Lifelines version 0.14.1 for Kaplan-Meier curves and Cox models. A P value of .05 was considered statistically significant. The Nationwide Claims Data Lake for Sleep Apnea cohort includes 480,000 patients, of whom 365,301 had undergone at least 1 year of follow-up and did not have a valid reason for CPAP therapy termination (4,882 patients had a valid reason for CPAP termination during the first year) (e-Table 2). Of these 365,301 patients, 76% (n = 277,242) continued CPAP therapy and 24% (n = 88,059) terminated CPAP therapy. After propensity score matching, the study population for this analysis included 88,007 patients in each group (total of 176,014 patients) (Fig 1). As expected, propensity score matching generated two patient groups that were well matched for baseline characteristics (Table 1).Table 1Baseline Characteristics of the Matched Study PopulationVariableCPAP Continuation (n = 88,007)CPAP Termination (n = 88,007)Age, y60.0 (70.0-50.0)59.0 (69.0-49.0)Female sex32,227 (36.6)31,666 (36.0)Comorbidity Chronic psychiatric disorders4,621 (5.2)4,606 (5.2) Stroke2,735 (3.1)2,684 (3.1) Heart failure2,306 (2.6)2,046 (2.3) Coronary heart disease8,023 (9.1)8,037 (9.1) Hypertension42,568 (48.4)43,231 (49.1) Diabetes mellitus18,610 (21.1)18,304 (20.8) COPD7,156 (8.1)7,387 (8.4)Data are presented as No. (%) or median (interquartile range). Open table in a new tab Data are presented as No. (%) or median (interquartile range). Over a 3-year observation period, death occurred in 3,204 of 88,007 patients (3.6%) in the CPAP therapy termination group compared with 2,053 of 88,007 patients (2.3%) in the therapy continuation group (e-Table 3). Continuation of CPAP therapy was associated with a significantly lower risk of all-cause death compared with CPAP therapy termination (HR, 0.61; 95% CI, 0.57-0.65; P < .01, log-rank test) (Fig 2). The results were similar in men and women (HR, 0.63 [95% CI, 0.57-0.68] and 0.54 [95% CI, 0.47-0.62]; P < .01 for both) (e-Fig 3). The sensitivity analysis also showed a significant reduction in all-cause mortality associated with CPAP continuation, with an HR of 0.73 (95% CI, 0.70-0.76; P < .01 [10,795 events in 336,415 patients, or an event rate of 3.2%]). The cumulative incidence of heart failure (based on disease codes entered in the SNDS database) was significantly lower in patients who continued vs terminated CPAP therapy (HR, 0.77; 95% CI, 0.71-0.82; P < .01, log-rank test) (e-Table 3, Fig 3). During follow-up, incident hypertension and heart failure occurred significantly less frequently in patients with OSA who continued vs terminated CPAP therapy (e-Table 3, Fig 4). In addition, a trend toward a lower risk of new hospitalizations for diabetes in the therapy continuation vs therapy termination group was found (P = .06) (e-Table 3, Fig 4). Sensitivity analysis that excluded patients censored for death during the analysis period yielded similar results to the primary analysis (e-Fig 4).Figure 4Forest plot showing risk of all-cause mortality and factors potentially contributing to death. HR of < 1 indicates a lower risk with CPAP continuation. HR = hazard ratio.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The results of this analysis of a comprehensive, unbiased national dataset showed a significant association between continuation of CPAP during the first year of therapy and lower all-cause mortality. One potential mechanism underlying this association may be the lower rate of incident heart failure seen in the group who continued CPAP compared with those who terminated CPAP therapy. In our main analysis, only patients who survived long-enough to discontinue the use of CPAP were included. As such, patients who either had died, had < 1 year of follow-up, or who discontinued CPAP during the first year were used for propensity score matching, but were not included in the main all-cause mortality analysis. To avoid potential selection bias resulting from arbitrarily splitting the dataset into two groups that were not created at baseline, we performed a sensitivity analysis using CPAP termination as a time-dependent covariate and evaluated its association with overall survival. The results of this sensitivity analysis confirmed and strengthened the study findings by showing that there was a 27% reduction in all-cause mortality in patients who continued CPAP. Our findings contrast with those of randomized controlled trials evaluating the effects of CPAP on mortality. The Sleep Apnea Cardiovascular Endpoints (SAVE) study, the Impact of Sleep Apnea Syndrome in the Evolution of Acute Coronary Syndrome—Effect of Intervention With CPAP study, and the Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA study investigated the effects of CPAP on a composite end point that included cardiovascular death and nonfatal cardiovascular events.11McEvoy R.D. Antic N.A. Heeley E. et al.CPAP for prevention of cardiovascular events in obstructive sleep apnea.N Engl J Med. 2016; 375: 919-931Crossref PubMed Scopus (1150) Google Scholar, 12Peker Y. Glantz H. Eulenburg C. Wegscheider K. Herlitz J. Thunström E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (358) Google Scholar, 13Sánchez-de-la-Torre M. Sánchez-de-la-Torre A. Bertran S. et al.Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial.Lancet Respir Med. 2020; 8: 359-367Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar All found no significant difference between the CPAP and usual care groups with respect to the primary end point or for cardiovascular death alone as a secondary end point.11McEvoy R.D. Antic N.A. Heeley E. et al.CPAP for prevention of cardiovascular events in obstructive sleep apnea.N Engl J Med. 2016; 375: 919-931Crossref PubMed Scopus (1150) Google Scholar, 12Peker Y. Glantz H. Eulenburg C. Wegscheider K. Herlitz J. Thunström E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (358) Google Scholar, 13Sánchez-de-la-Torre M. Sánchez-de-la-Torre A. Bertran S. et al.Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial.Lancet Respir Med. 2020; 8: 359-367Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar However, several factors may have limited the ability of these studies to detect any statistically significant effect of CPAP on mortality. First, adherence to treatment was low (3.3 ± 2.3 h/night in SAVE and 2.78 ± 2.73 h/night in the Impact of Sleep Apnea Syndrome in the Evolution of Acute Coronary Syndrome—Effect of Intervention With CPAP study),11McEvoy R.D. Antic N.A. Heeley E. et al.CPAP for prevention of cardiovascular events in obstructive sleep apnea.N Engl J Med. 2016; 375: 919-931Crossref PubMed Scopus (1150) Google Scholar,13Sánchez-de-la-Torre M. Sánchez-de-la-Torre A. Bertran S. et al.Effect of obstructive sleep apnoea and its treatment with continuous positive airway pressure on the prevalence of cardiovascular events in patients with acute coronary syndrome (ISAACC study): a randomised controlled trial.Lancet Respir Med. 2020; 8: 359-367Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar and these levels of adherence do not seem to reflect what is seen with CPAP use in broader clinical settings.16Cistulli P.A. Armitstead J. Pepin J.L. et al.Short-term CPAP adherence in obstructive sleep apnea: a big data analysis using real world data.Sleep Med. 2019; 59: 114-116Crossref PubMed Scopus (80) Google Scholar,17Pack A.I. Magalang U.J. Singh B. Kuna S.T. Keenan B.T. Maislin G. To RCT or not to RCT? Depends on the question. A response to McEvoy et al.Sleep. 2021; 44: zsab042Crossref PubMed Scopus (3) Google Scholar Device use of ≥ 4 h/night may be needed for the benefits of therapy to be realized.12Peker Y. Glantz H. Eulenburg C. Wegscheider K. Herlitz J. Thunström E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (358) Google Scholar,18Barbé F. Durán-Cantolla J. Sánchez-de-la-Torre M. et al.Effect of continuous positive airway pressure on the incidence of hypertension and cardiovascular events in nonsleepy patients with obstructive sleep apnea: a randomized controlled trial.JAMA. 2012; 307: 2161-2168Crossref PubMed Scopus (583) Google Scholar For example, in the Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA study, a preplanned analysis in patient subgroups using CPAP for ≥ 4 h/night vs < 4 h/night showed that those using CPAP for ≥ 4 h/night had a significantly lower rate of composite end point events, including mortality (adjusted HR, 0.29; 95% CI, 0.10-0.86; P = .026).12Peker Y. Glantz H. Eulenburg C. Wegscheider K. Herlitz J. Thunström E. Effect of positive airway pressure on cardiovascular outcomes in coronary artery disease patients with nonsleepy obstructive sleep apnea. The RICCADSA randomized controlled trial.Am J Respir Crit Care Med. 2016; 194: 613-620Crossref PubMed Scopus (358) Google Scholar Furthermore, in the SAVE study, patients with OSA who were adherent to CPAP therapy showed a lower risk of stroke and the composite end point of cerebral events than those in the usual care group.11McEvoy R.D. Antic N.A. Heeley E. et al.CPAP for prevention of cardiovascular events in obstructive sleep apnea.N Engl J Med. 2016; 375: 919-931Crossref PubMed Scopus (1150) Google Scholar Second, the trials included highly selected patient populations, namely nonsleepy patients with OSA with existing cardiovascular disease. In particular, the noninclusion of patients with excessive daytime sleepiness from randomized controlled trials for ethical reasons might exclude a group likely to adhere and respond well to CPAP therapy.19Mazzotti D.R. Keenan B.T. Lim D.C. Gottlieb D.J. Kim J. Pack A.I. Symptom subtypes of obstructive sleep apnea predict incidence of cardiovascular outcomes.Am J Respir Crit Care Med. 2019; 200: 493-506Crossref PubMed Scopus (181) Google Scholar Recently, a comparison was made between consecutive sleep clinic patients (n = 3,965) and participants in the prominent recent randomized controlled trials examining the effect of CPAP on adverse cardiovascular outcomes in OSA.20Reynor A. McArdle N. Shenoy B. et al.Continuous positive airway pressure and adverse cardiovascular events in obstructive sleep apnea: are participants of randomized trials representative of sleep clinic patients?.Sleep. 2022; 45: zsab264Crossref PubMed Scopus (7) Google Scholar Less than 20% of real-world patients with OSA presented with all eligibility criteria of randomized controlled trials, and routine clinic patients with OSA were younger, sleepier, and more likely to be women.20Reynor A. McArdle N. Shenoy B. et al.Continuous positive airway pressure and adverse cardiovascular events in obstructive sleep apnea: are participants of randomized trials representative of sleep clinic patients?.Sleep. 2022; 45: zsab264Crossref PubMed Scopus (7) Google Scholar Finally, the total number of mortality events in each study was very small (25 in the CPAP group and 20 in the usual care group in the SAVE study, and 12 in the CPAP group and 14 in the usual care group in the Impact of Sleep Apnea Syndrome in the Evolution of Acute Coronary Syndrome—Effect of Intervention With CPAP study), limiting statistical power for this end point. In contrast, the current analysis included all patients with OSA in France with an indication for CPAP therapy, making it applicable to general populations, and the large number of deaths provides adequate power for mortality analyses. Furthermore, differentiating between patients who continued using CPAP and those who did not provides a clearer picture of the benefits of CPAP use. Thus, although randomized controlled trials provide the highest level of evidence, real-world data may provide a better indication of overall effectiveness in patient populations likely to be encountered in routine clinical practice. Others also recently suggested that design features and enrolled populations in randomized controlled trials of CPAP therapy in patients with OSA limit the ability of these trials to identify the benefits of treatment.21Labarca G. Dreyse J. Drake L. Jorquera J. Barbe F. Efficacy of continuous positive airway pressure (CPAP) in the prevention of cardiovascular events in patients with obstructive sleep apnea: systematic review and meta-analysis.Sleep Med Rev. 2020; 52: 101312Crossref PubMed Scopus (48) Google Scholar Contrary to classical observational studies with exposed and unexposed patients, the discontinuation design provides a more homogeneous initial study population on which the applied propensity score matching further limits unmeasured bias. Specifically, it recently was suggested that observational studies using propensity scores can overcome the ethical limitations around inclusion of patients with sleep apnea who experience excessive daytime sleepiness into randomized controlled trials.22Pack A.I. Magalang U.J. Singh B. Kuna S.T. Keenan B.T. Maislin G. Randomized clinical trials of cardiovascular disease in obstructive sleep apnea: understanding and overcoming bias.Sleep. 2021; 44: zsaa229Crossref PubMed Scopus (35) Google Scholar The US Food and Drug Administration also has indicated that studies using propensity score methods are appropriate to support approval of medical devices such as CPAP.23Food and Drug Administration Center for Devices and Radiological HealthDesign considerations for pivotal clinical investigations for medical devices: guidance for industry, clinical investigators, institutional review boards and Food and Drug Administration staff. 2013.https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-considerations-pivotal-clinical-investigations-medical-devicesDate accessed: March 23, 2021Google Scholar Two other recent real-world studi
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