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Pressure Reduction During Exhalation in Sleep Apnea Patients Treated by Continuous Positive Airway Pressure
CHEST
Original Research SLEEP MEDICINE
Pressure Reduction During Exhalation in Sleep Apnea Patients Treated by Continuous Positive Airway Pressure Jean-Louis Pe´pin, MD, PhD; Jean-Franc¸ois Muir, MD, PhD; Thibaut Gentina, MD; Yves Dauvilliers, MD, PhD; Renaud Tamisier, MD, PhD; Marc Sapene, MD; Pierre Escourrou, MD, PhD; Bernard Fleury, MD; Franc¸ois Philip-Joet, MD; Pierre Philip, MD, PhD; and Marie-Pia d’Ortho, MD, PhD
Introduction: This French, multicenter, randomized double-blind controlled trial tested the hypothesis that pressure reduction during exhalation (C-Flex; Respironics; Murrysville, PA) would improve continuous positive airway pressure (CPAP) compliance, comfort, and quality of life. Methods: Two hundred eighteen newly diagnosed sleep apnea patients (seven centers; mean [ⴞ SD] age, 55 ⴞ 11 years; mean body mass index, 31 ⴞ 6 kg/m2; mean apnea-hypopnea index, 44 ⴞ 21 events/h) were randomly assigned to receive 3 months of treatment with CPAP (108 patients) or C-Flex (110 patients). Objective compliance, generic quality-of-life questionnaire (SF-36) scores, disease-specific quality-of-life questionnaire (Grenoble Sleep Apnea Quality of Life [GrenobleSAQOL]) scores, and visual analog scales for CPAP comfort and side effects were determined at baseline and after 3 months. After 3 months, patients in the CPAP arm were moved to the C-Flex arm for 3 additional months (open study). Results: An intention-to-treat analysis demonstrated that there were no differences at 3 months between C-Flex and CPAP use in terms of compliance, the rate of side effects, and comfort. Low compliers receiving CPAP therapy (< 4 h of use) significantly improved this outcome during the open study (p ⴝ 0.04). There was a significant improvement in six of eight of the SF-36 domain scores and in all of the domains of the GrenobleSAQOL scores in both groups using either CPAP or C-Flex. Conclusion: In unselected sleep apnea patients, C-Flex was associated with similar outcomes to standard CPAP. Low compliers receiving CPAP therapy improved their adherence when moving to C-Flex. Trial registration: ISRCTN Register Identifier: 08065291 (CHEST 2009; 136:490 – 497) Abbreviations: AHI ⫽ apnea-hypopnea index; CPAP ⫽ continuous positive airway pressure; ESS ⫽ Epworth sleepiness scale; GrenobleSAQOL ⫽ Grenoble Sleep Apnea Quality of Life; OSA ⫽ obstructive sleep apnea syndrome; PAP ⫽ positive airway pressure; Sao2 ⫽ arterial oxygen saturation; SF-36 ⫽ Medical Outcomes Study 36-item short form
sleep apnea syndrome (OSA) reO bstructive duces cognitive function, mood, and quality of life,1 and increases sleepiness-related accidents2,3 and cardiovascular morbimortality.4 Continuous positive airway pressure (CPAP) is the “gold standard” treatment for OSA and is effective in reducing sleep fragmentation, resolving nocturnal desaturation, and reducing daytime sleepiness. Additionally, it has been shown to be a cost effective use of health-care resources by reducing the risk of motor vehicle accidents and cardiovascular morbidity.4,5
Although CPAP is a highly effective treatment, its success relies on regular use.6,7 Compliance remains a problem, with 8 to 15% of patients refusing treatment after a single night of use8,9 and a further 20% failing to use the treatment long term.10,11 A variety of measures have been shown to improve CPAP compliance, including group education, intensive follow-up, heated humidification, and adjustments to the mask.12,13 During CPAP use, patients frequently experience side effects, the most common being nasal discomfort and pressure intolerance. Accordingly, more
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comfortable modes of positive airway pressure (PAP) therapy, such as auto-adjusting PAP, were developed in an attempt to improve compliance. Auto-adjusting PAP devices provide lower mean therapeutic pressures compared with fixed CPAP by altering the delivered pressure in response to abnormal respiratory events; however, a metaanalysis14 showed that despite applying a significantly lower mean pressure, compliance is not improved. A further technological advance in patient comfort was C-Flex (Respironics; Murrysville, PA). C-Flex was designed to give pressure relief during early exhalation while maintaining optimal pneumatic splinting. Previous studies15,16 have reported an efficacy for C-Flex similar to that of conventional CPAP, and one nonrandomized study17 has suggested a dramatic increase in overall compliance over a 3-month period. Our study is the first to evaluate efficacy and compliance over a long period of time (6 months). The study design consisted of a 3-month randomized, double-blind study comparing conventional CPAP therapy to C-Flex, followed by a 3-month open study during which patients initially allocated to receive CPAP were moved to C-Flex. The primary outcome of the study was to compare objective compliance with CPAP and C-Flex therapy over an initial 3-month period. We also compared quality of life, daytime sleepiness, symptoms evolution, tolerance, comfort, and side effects, and Manuscript received November 7, 2009; revision accepted April 22, 2009. Affiliations: From the HP2 Laboratory (Drs. Pe´pin and Tamisier), Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), Equipe Re´gion INSERM 17, Grenoble University Hospital, Grenoble, France; Clinique de La Louvie`re (Dr. Gentina), Lille, France; University Hospital of Montpellier (Dr. Dauvilliers), Montpellier, France; Polyclinique de Bordeaux (Dr. Sapene), Bordeaux, France; Groupe Henri-Mondor Albert Chennevier (Dr. d’Ortho), Service de Physiologie–Explorations Fonctionnelles, Assistance Publique–Hoˆpitaux de Paris, Cre´teil, France; Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) [Dr. d’Ortho], Unite´ 841, Cre´teil, F-94010 France; Universite´ Paris-7-Denis Diderot (Dr. d’Ortho), Faculte´ de Me´decine Xavier Bichat, Paris, France; Service de Physiologie– Explorations Fonctionnelles (Dr. Escourrou), Hoˆpital A. Be´cle`re, Assistance Publique–Hoˆpitaux de Paris, Clamart, France; Service de Pneumologie (Dr. Fleury), Hoˆpital St Antoine, Assistance Publique–Hoˆpitaux de Paris, Paris, France; Service de Pneumologie (Dr. Philip-Joet), Hoˆpital St Joseph, Assistance Publique– Hoˆpitaux de Marseille, Marseille, France; Service de Physiologie–Explorations Fonctionnelles (Dr. Philip), Hoˆpital Pellegrin, Bordeaux, France; and Service de Pneumologie (Dr. Muir), Hoˆpital Boisguillaume, Rouen, France. Funding/Support: This work was supported by grants from “Comite´ National des Maladies Respiratoires” and Respironics. © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). Correspondence to: Jean-Louis Pe´pin, MD, PhD, Sleep Laboratory and EFCR, Grenoble University Hospital, BP 217, 38043 Grenoble Cedex 09, France; e-mail: [email protected] DOI: 10.1378/chest.08-2646 www.chestjournal.org
whether patients transitioning from CPAP to CFlex after 3 months of therapy displayed improved compliance. Materials and Methods Study Design This 3-month, French, multicenter, randomized, double-blind, controlled trial was conducted comparing compliance and clinical benefits of CPAP therapy vs C-Flex therapy with an additional 3-month open-label follow-up period in which patients initially allocated to receive CPAP therapy were moved to the group receiving C-Flex therapy (Fig 1). Study Group Newly diagnosed sleep apnea patients were enrolled in the study if they were ⬎ 18 years of age and were referred for CPAP treatment by the consulting physician. Patients were excluded if they were pregnant, medically unstable, or had predominantly central sleep apnea. The study was approved by the Grenoble ethics committee, and all patients gave written informed consent. Baseline Assessment OSA was diagnosed by in-laboratory polysomnography or cardiorespiratory polygraphy. Cardiorespiratory polygraphy included at least the following signals: nasal pressure; thoracic and abdominal movements; arterial oxygen saturation (Sao2); and body position. Sleep stages, arousals, episodes of apnea and hypopnea, and the mean and lowest arterial oxygen saturation levels were assessed according to a standard method at all centers.18,19 Respiratory efforts were assessed by inductance plethysmography, and airflow was assessed by nasal pressure. Apneas were defined as a cessation of airflow lasting at least 10 s, and hypopneas were defined as a ⱖ 30% reduction of airflow followed by a 3% desaturation and/or a microarousal.20 Apneas and hypopneas were classified as obstructive if there were out-of-phase motions of the rib cage and abdomen or if airflow limitation was present. Sleep apnea syndrome was defined by ⱖ 15 episodes of apnea and hypopnea per hour of sleep. Sleepiness was evaluated using the Epworth sleepiness scale (ESS). Quality of life was assessed using a generic questionnaire (Medical Outcomes Study 36-item short form [SF-36]) and a questionnaire specific to OSA (Grenoble Sleep Apnea Quality of Life [GrenobleSAQOL]).21 The GrenobleSAQOL includes 40 questions rated according to a 5-point scale, with higher scores indicating worse conditions (13 related to sleep quality, 5 related to sleepiness, 6 related to every-day life, 7 related to emotions, and 9 related to “other functioning”). Effective-Pressure Assessment In all of the patients, effective pressure was determined using 2 nights with an autotitration device without C-Flex activated (REMstar Auto; Respironics). The pressure range used during the titration was left to the judgment of the physicians. Following the autotitration period, fixed CPAP was used at the pressure that was effective for ⬎ 90% of the night after visual editing of the device curves. Randomization Eligible patients were randomly assigned to receive therapy with conventional CPAP or C-Flex. Randomization was perCHEST / 136 / 2 / AUGUST, 2009
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Figure 1. Trial profile: study flow chart over 6 months. Following the first 3 months of double-blind randomized treatment with either CPAP or C-Flex, patients underwent an additional 3-month open-label study.
formed by a computer-generated schedule in random blocks of six and was stratified according to study centers. Treatment assignment was communicated to the study centers by the data management center after verification that the patient met all of the inclusion criteria. Patients were not aware of whether they were receiving CPAP with or without C-Flex activated, and the clinical research assistant who assigned patients to treatment groups did not take part in outcome assessments. The investigators who assessed outcome were unaware of the randomization status of the patients and did not set up or maintain the machines. The study was effectively double blinded. 3-Month Follow-up (End of Randomized Study) and 6-Month Evaluation (End of Open-Label Study) The same evaluations were conducted at 3 and 6 months. Objective compliance and residual apnea-hypopnea index (AHI) were downloaded and reported from the memory card (Encore Pro Smartcard; Respironics) located in the PAP device. The rate of PAP-related side effects was collected by questionnaires assessing both presence or absence and severity. Positive-pressure tolerance and comfort was assessed using visual analog scales, and ESS, SF-36, and GrenobleSAQOL questionnaires were completed. Statistical Analysis The data for all outcomes were analyzed on an intention-totreat basis. Data analysis was conducted with a statistical software
package (SPSS; SPSS; Chicago, IL). Normally, distributed data are presented as the mean ⫾ SD, skewed data are presented as the median (interquartile range), and categorical data are presented as percentages. Normality was assessed using tests of skewness and kurtosis. CPAP and C-Flex comparisons were made using unpaired t tests and Mann-Whitney U tests, depending on normality. For categorical variables, the 2 test was used. Baseline, 3-month, and 6-month comparisons were made using paired t tests and Wilcoxon signed-rank tests, depending on normality. A repeatedmeasures analysis of variance was used to analyze time and group effects on quality of life. Finally, all of the continuous variables potentially influencing CPAP compliance and tolerance were included in a logistic regression analysis to determine their respective roles.
Results Patients Two hundred eighteen newly diagnosed sleep apnea patients from seven centers met the eligibility criteria and were randomly assigned to receive 3 months of CPAP therapy (108 patients) or pressure reduction during exhalation using C-Flex (110 patients). Consistent with the usual clinical cohorts, the patients were predominantly male,
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Table 1—Baseline Characteristics of the Patients Completing the 3-Month Trial Characteristics Sex Male Female Age, yr BMI, kg/m² BMI ⱖ 30 kg/m², % Smoking consumption, % Alcohol consumption, % ESS score ESS score ⱖ 12, % Therapeutic pressure, cm H2O AHI, events/h AHI ⱖ 30 events/h, % Mean nocturnal Sao2, % Minimal nocturnal Sao2, %
CPAP
C-Flex
p Value
58 24 56 ⫾ 9 31 ⫾ 6.3 57.3 12.2 24.4 11.4 ⫾ 5.2 53.7 10.7 ⫾ 2
61 22 55 ⫾ 12 31 ⫾ 5.7 50 9.6 18.1 11.7 ⫾ 5.1 51.8 10.6 ⫾ 2.1
NS NS NS NS NS NS NS NS
44.9 ⫾ 21.8 80.2 92.6 ⫾ 3.6 77.5 ⫾ 11.1
42.7 ⫾ 20.8 68.7 93 ⫾ 2.9 78.3 ⫾ 10.7
NS NS NS NS
NS
Values are given as the mean ⫾ SD. There were no significant differences in the baseline values between the CPAP and the C-Flex groups. BMI ⫽ body mass index; NS ⫽ not significant.
middle-aged, and obese, and had moderate-tosevere OSA. There were no differences between the groups in these variables or their baseline characteristics (Table 1). Figure 1 shows the patient flow. During the first randomized study (first 3 months), 26 subjects withdrew from the CPAP group and 27 withdrew from the C-Flex group. The majority of these withdrawals were due to an initial refusal of PAP treatment. The mean AHI values reported by the device over the autotitration period were 2.89 ⫾ 4.87 and 3.48 ⫾ 3.09 events/h, respectively, for CPAP and C-Flex (p ⫽ 0.03). This difference was statistically, but not clinically, significant. The proportion of patients with an AHI below 5 and 10 events/h were similar in both groups (CPAP group, 87.8% and 96.3%, respectively; C-Flex group, 79.7 and 93.9%, respectively). Primary Outcome Analysis: 3-Month Compliance There was no difference in compliance between CPAP and C-Flex (CPAP group, 4.91 ⫾ 2.41 h of use; C-Flex, 4.98 ⫾ 1.96 h of use) [Fig 2]. Secondary Outcome Analyses Sleepiness: ESS scores were significantly improved using both treatments (CPAP, 11.4 ⫾ 5.2 to 8.0 ⫾ 5.5; C-Flex, 11.7 ⫾ 5.1 to 7.8 ⫾ 4.6). The differences between the treatment modes were not statistically significant. Symptoms, Comfort, and Side Effects: Symptoms, side effects, and comfort were significantly www.chestjournal.org
Figure 2. Primary outcome analysis: compliance with PAP therapy. Treatment efficacy at the 3-month evaluation. The results are shown as a box-whisker plot, with median and 25th quartile of AHI NS ⫽ not significant.
improved on both treatments. The differences between the treatment modes were not statistically significant. Quality of Life: Six of eight domains on the SF-36 questionnaire (Fig 3, A) and all domains of the GrenobleSAQOL questionnaire (Fig 3, B) were significantly improved with both treatments. The differences between the treatment modes were not statistically significant. Predictive Factors for Compliance In a logistic regression analysis, mean nocturnal Sao2 (percentage), plus the sleepiness and perceived treatment efficacy (treatment domain) domains of the GrenobleSAQOL were the only significant predictive factors (Table 2). Treatment mode was not a significant predictor of low compliance. Open-Label Study The group of patients moving from CPAP to C-Flex did not significantly change their PAP adherence (from 5.53 ⫾ 2.01 to 5.52 ⫾ 1.93 h of use). However, there was a significant increase in compliance in the CPAP patients who were classified as low compliers (⬍ 4 h per night of CPAP use) during the initial 3-month study when using C-Flex during the 3-month open-label study (from 2.81 ⫾ 0.97 to 3.40 ⫾ 1.64 nights of use; p ⫽ 0.04; n ⫽ 15) [Fig 4]. By contrast, the group of patients who continued receiving C-Flex therapy (from 5.80 ⫾ 1.57 to CHEST / 136 / 2 / AUGUST, 2009
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Figure 3. The evolution of the different domains of the generic quality-of-life questionnaire (SF-36) [A] and the specific quality-of-life questionnaire (GrenobleSAQOL) [B]. PF ⫽ physical functioning; RP ⫽ role limitation due to physical health; BP ⫽ bodily pain; GH ⫽ general health perception; VT ⫽ vitality; SF ⫽ social functioning; RE ⫽ role limitation due to emotional problems; MH ⫽ mental health; column A ⫽ sleep domain; column B ⫽ waking and falling asleep domain; column C ⫽ sleepiness domain; column D ⫽ domain of daily life; column E ⫽ emotional domain; column F ⫽ domain of personal relations.
5.93 ⫾ 1.58 nights of use) and the low compliers in this group (from 3.02 ⫾ 0.91 to 3.28 ⫾ 1.14 nights of use) did not significantly improve their compliance between 3 and 6 months when continuing to receive C-Flex therapy (Fig 4).
Discussion During the first 3 months of treatment, C-Flex users demonstrated compliance similar to that of conventional CPAP users. An increase in compliance
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Table 2—Predictive Factors for Compliance: Logistic Regression Analysis Variables

SE 
OR
95% CI
Age (increase of 10 yr) Mean nocturnal Sao2 (%) Noise (3 mo) Feel resistance to exhalation (3 mo) Sleepiness domain Treatment domain (3 mo)
⫺0.11 0.2 0.01 0.02 0.13 0.15
0.2 0.09 1 0.01 0.05 0.07
0.9 1.22 0.74 1.02 1.13 1.16
0.54–1.34 1.03–1.45 0.98–1.02 1–1.04 1.04–1.24 1.02–1.32
p Value 0.59 0.02 0.1 ⬍ 0.01 0.02
OR ⫽ odds ratio; CI ⫽ confidence interval.
was observed during the open study (3 to 6 months) in the subgroup of low compliers who were switching from CPAP to C-Flex therapy. C-Flex efficacy was equivalent to CPAP efficacy in terms of AHI correction, reduction of sleepiness, and quality-of-life benefits, comfort, and side effects. CPAP compliance is a key issue in sleep medicine as any reductions in daytime sleepiness, sleepiness-related accidents,22 and cardiovascular morbidity6 are expected to be proportional to use. Compliance is influenced by a number of different factors, independent of therapy comfort. Psychosocial factors, such as living alone,23 recent major life events,23 high levels of anxiety or depression,24 and unfavorable coping strategies25 have all been shown to reduce CPAP therapy compliance. By contrast, having a higher AHI score26 and greater daytime sleepiness10 have been shown to be associated with better CPAP compliance. Quality of sleep during the first night and the perceived benefit of treatment also predicts subsequent compliance.26 The logistic regression analysis we performed supports these studies by showing the major impact on compliance of sleepiness, perceived efficacy, and severity of desaturations rather than treatment mode. Other factors directly related to the CPAP device, such as a high CPAP pressure, have also been shown10
to negatively influence CPAP therapy compliance. Accordingly, various technological innovations have been developed to solve this problem such as autoadjusting devices that modify applied pressure in response to patient needs. This technology resulted in lower mean therapeutic pressures but failed to increase compliance.14 Difficulty exhaling against a fixed positive pressure is also a common complaint when using CPAP and has led to the development of a new algorithm that reduces pressure at the beginning of exhalation (C-Flex). Aloia et al17 reported a better compliance in patients receiving C-Flex therapy compared with patients receiving conventional CPAP therapy, which equated to 1.4 h of additional use per night after 3 months, but this study was not randomized as patients received the treatment that was available at the time they were enrolled. Interestingly, compliance decreased over the 12-week follow-up period in patients using CPAP, whereas it remained stable in patients using C-Flex. The finding of higher compliance with C-Flex therapy was not confirmed by Nilius et al,16 who performed the first randomized controlled trial comparing CPAP and C-Flex therapy in a 3-month study. However, it has to be noted that compliance was high in both groups (⬎ 5 h/night),
Figure 4. Evolution of compliance between 3 and 6 months (open study). Individual data are presented. The patients were separated into two subgroups exhibiting ⬍ 4 h or ⬎ 4 h of PAP therapy use after 3 months. See the legend of Figure 2 for abbreviation not used in the text. www.chestjournal.org
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making it unlikely that significant improvements could be obtained. This was also the case in the large randomized multisite trial of Dolan et al,27 in which patients who did not demonstrate sufficient adherence (defined as ⱖ 4 h of CPAP use per night) during a lead-in period of 1 week were excluded. In accordance with these studies, we did not find any significant compliance differences between CPAP and C-Flex therapy during the first 3 months of this randomized controlled trial. However, a significant improvement in compliance for patients switched to C-Flex therapy in the openlabel segment of the study occurred in initially low CPAP compliers. This was not the case in patients already using CPAP for ⬎ 4 h. This can be partly attributed to the effect of a change in therapy being perceived by the patients as a positive step in their management, thereby fostering greater adherence. However, these data provide a strong rationale for proposing such a shift in PAP therapy in the clinical management of low-CPAP compliance patients. These results also underline the need to target studies specifically dedicated to this subgroup of low-CPAP compliers.12 One criticism of systems that reduce pressure during exhalation is that they may increase the risk of upper airway collapse because of underpressurization and treatment inefficacy. Two studies16,27 have demonstrated that C-Flex is as effective as conventional CPAP therapy in correcting the AHI and daytime sleepiness. The significantly higher mean residual AHI seen with C-Flex (3.48 ⫾ 3.09 events/h) compared with CPAP (2.89 ⫾ 4.87 events/h) has no clinical relevance. In addition to previous works, our study also showed that C-Flex and CPAP therapy equivalently improve functional outcomes and quality of life, with no difference in side effects. Limitations and Strength of the Study We acknowledge some study limitations. First, the 25% rate of withdrawal during the study could be considered high. However, this percentage included a 10 to 15% initial CPAP refusal rate, which is in line with previous reports.8 –10 Dropouts related to other causes did not exceed 15%, which is also usual in similar studies in the field.28,29 A second potential limitation was the assessment of treatment efficacy by the internal device software and the possible heterogeneity in CPAP indications and initiation procedures among the different centers. This can explain differences in mean compliance from one center to another but, because of the randomized, controlled trial design of the study, should not significantly interfere with the comparison between CPAP and C-Flex therapy.
Because of logistical issues, a number of patients had a longer titration period than was originally prescribed in the protocol (range, 3 to 14 days). An analysis excluding these violators provided data and conclusions similar to those of the intention-to-treat analysis. On the other hand, our study is the largest in the field and benefited from a randomized, doubleblind, prospective, multicenter design. Moreover, as conducted over a 6-month period, it allows extrapolation to long-term treatment. Additionally, consecutive recruitment and the inclusion of patients coming from different centers with different educational programs and levels of CPAP compliance better reflect real-life situations and allow the generalization of these data to clinical populations. Conclusion C-Flex was no more effective than CPAP in the treatment of OSA, reducing daytime sleepiness and improving quality of life. Low compliers with CPAP therapy significantly improved their adherence when moving to C-Flex therapy. Further studies specifically targeting this subgroup of low-CPAP compliers are needed.
Acknowledgments Author contributions: Dr. Pépin contributed to the study concept and design, acquisition of data, drafting the manuscript, and study supervision. Dr. Tamisier contributed to the study concept and design and acquisition of data. Dr. d’Ortho contributed to the drafting of the manuscript and acquisition of data. All other authors contributed to the acquisition of data and critical revision of the manuscript. Role of sponsors: The sponsors had no role in the collection, analysis, or interpretation of the data. Other contributions: We thank Nathalie Arnol for statistical analysis and Florence Portier, Carlos Molano, Beatriz Abril, Maria Stoïca-Herman, and Xavier Drouot for including and evaluating patients in the different participating centers.
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Original Research SLEEP MEDICINE
Pressure Reduction During Exhalation in Sleep Apnea Patients Treated by Continuous Positive Airway Pressure Jean-Louis Pe´pin, MD, PhD; Jean-Franc¸ois Muir, MD, PhD; Thibaut Gentina, MD; Yves Dauvilliers, MD, PhD; Renaud Tamisier, MD, PhD; Marc Sapene, MD; Pierre Escourrou, MD, PhD; Bernard Fleury, MD; Franc¸ois Philip-Joet, MD; Pierre Philip, MD, PhD; and Marie-Pia d’Ortho, MD, PhD
Introduction: This French, multicenter, randomized double-blind controlled trial tested the hypothesis that pressure reduction during exhalation (C-Flex; Respironics; Murrysville, PA) would improve continuous positive airway pressure (CPAP) compliance, comfort, and quality of life. Methods: Two hundred eighteen newly diagnosed sleep apnea patients (seven centers; mean [ⴞ SD] age, 55 ⴞ 11 years; mean body mass index, 31 ⴞ 6 kg/m2; mean apnea-hypopnea index, 44 ⴞ 21 events/h) were randomly assigned to receive 3 months of treatment with CPAP (108 patients) or C-Flex (110 patients). Objective compliance, generic quality-of-life questionnaire (SF-36) scores, disease-specific quality-of-life questionnaire (Grenoble Sleep Apnea Quality of Life [GrenobleSAQOL]) scores, and visual analog scales for CPAP comfort and side effects were determined at baseline and after 3 months. After 3 months, patients in the CPAP arm were moved to the C-Flex arm for 3 additional months (open study). Results: An intention-to-treat analysis demonstrated that there were no differences at 3 months between C-Flex and CPAP use in terms of compliance, the rate of side effects, and comfort. Low compliers receiving CPAP therapy (< 4 h of use) significantly improved this outcome during the open study (p ⴝ 0.04). There was a significant improvement in six of eight of the SF-36 domain scores and in all of the domains of the GrenobleSAQOL scores in both groups using either CPAP or C-Flex. Conclusion: In unselected sleep apnea patients, C-Flex was associated with similar outcomes to standard CPAP. Low compliers receiving CPAP therapy improved their adherence when moving to C-Flex. Trial registration: ISRCTN Register Identifier: 08065291 (CHEST 2009; 136:490 – 497) Abbreviations: AHI ⫽ apnea-hypopnea index; CPAP ⫽ continuous positive airway pressure; ESS ⫽ Epworth sleepiness scale; GrenobleSAQOL ⫽ Grenoble Sleep Apnea Quality of Life; OSA ⫽ obstructive sleep apnea syndrome; PAP ⫽ positive airway pressure; Sao2 ⫽ arterial oxygen saturation; SF-36 ⫽ Medical Outcomes Study 36-item short form
sleep apnea syndrome (OSA) reO bstructive duces cognitive function, mood, and quality of life,1 and increases sleepiness-related accidents2,3 and cardiovascular morbimortality.4 Continuous positive airway pressure (CPAP) is the “gold standard” treatment for OSA and is effective in reducing sleep fragmentation, resolving nocturnal desaturation, and reducing daytime sleepiness. Additionally, it has been shown to be a cost effective use of health-care resources by reducing the risk of motor vehicle accidents and cardiovascular morbidity.4,5
Although CPAP is a highly effective treatment, its success relies on regular use.6,7 Compliance remains a problem, with 8 to 15% of patients refusing treatment after a single night of use8,9 and a further 20% failing to use the treatment long term.10,11 A variety of measures have been shown to improve CPAP compliance, including group education, intensive follow-up, heated humidification, and adjustments to the mask.12,13 During CPAP use, patients frequently experience side effects, the most common being nasal discomfort and pressure intolerance. Accordingly, more
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comfortable modes of positive airway pressure (PAP) therapy, such as auto-adjusting PAP, were developed in an attempt to improve compliance. Auto-adjusting PAP devices provide lower mean therapeutic pressures compared with fixed CPAP by altering the delivered pressure in response to abnormal respiratory events; however, a metaanalysis14 showed that despite applying a significantly lower mean pressure, compliance is not improved. A further technological advance in patient comfort was C-Flex (Respironics; Murrysville, PA). C-Flex was designed to give pressure relief during early exhalation while maintaining optimal pneumatic splinting. Previous studies15,16 have reported an efficacy for C-Flex similar to that of conventional CPAP, and one nonrandomized study17 has suggested a dramatic increase in overall compliance over a 3-month period. Our study is the first to evaluate efficacy and compliance over a long period of time (6 months). The study design consisted of a 3-month randomized, double-blind study comparing conventional CPAP therapy to C-Flex, followed by a 3-month open study during which patients initially allocated to receive CPAP were moved to C-Flex. The primary outcome of the study was to compare objective compliance with CPAP and C-Flex therapy over an initial 3-month period. We also compared quality of life, daytime sleepiness, symptoms evolution, tolerance, comfort, and side effects, and Manuscript received November 7, 2009; revision accepted April 22, 2009. Affiliations: From the HP2 Laboratory (Drs. Pe´pin and Tamisier), Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), Equipe Re´gion INSERM 17, Grenoble University Hospital, Grenoble, France; Clinique de La Louvie`re (Dr. Gentina), Lille, France; University Hospital of Montpellier (Dr. Dauvilliers), Montpellier, France; Polyclinique de Bordeaux (Dr. Sapene), Bordeaux, France; Groupe Henri-Mondor Albert Chennevier (Dr. d’Ortho), Service de Physiologie–Explorations Fonctionnelles, Assistance Publique–Hoˆpitaux de Paris, Cre´teil, France; Institut National de la Sante´ et de la Recherche Me´dicale (INSERM) [Dr. d’Ortho], Unite´ 841, Cre´teil, F-94010 France; Universite´ Paris-7-Denis Diderot (Dr. d’Ortho), Faculte´ de Me´decine Xavier Bichat, Paris, France; Service de Physiologie– Explorations Fonctionnelles (Dr. Escourrou), Hoˆpital A. Be´cle`re, Assistance Publique–Hoˆpitaux de Paris, Clamart, France; Service de Pneumologie (Dr. Fleury), Hoˆpital St Antoine, Assistance Publique–Hoˆpitaux de Paris, Paris, France; Service de Pneumologie (Dr. Philip-Joet), Hoˆpital St Joseph, Assistance Publique– Hoˆpitaux de Marseille, Marseille, France; Service de Physiologie–Explorations Fonctionnelles (Dr. Philip), Hoˆpital Pellegrin, Bordeaux, France; and Service de Pneumologie (Dr. Muir), Hoˆpital Boisguillaume, Rouen, France. Funding/Support: This work was supported by grants from “Comite´ National des Maladies Respiratoires” and Respironics. © 2009 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/ misc/reprints.xhtml). Correspondence to: Jean-Louis Pe´pin, MD, PhD, Sleep Laboratory and EFCR, Grenoble University Hospital, BP 217, 38043 Grenoble Cedex 09, France; e-mail: [email protected] DOI: 10.1378/chest.08-2646 www.chestjournal.org
whether patients transitioning from CPAP to CFlex after 3 months of therapy displayed improved compliance. Materials and Methods Study Design This 3-month, French, multicenter, randomized, double-blind, controlled trial was conducted comparing compliance and clinical benefits of CPAP therapy vs C-Flex therapy with an additional 3-month open-label follow-up period in which patients initially allocated to receive CPAP therapy were moved to the group receiving C-Flex therapy (Fig 1). Study Group Newly diagnosed sleep apnea patients were enrolled in the study if they were ⬎ 18 years of age and were referred for CPAP treatment by the consulting physician. Patients were excluded if they were pregnant, medically unstable, or had predominantly central sleep apnea. The study was approved by the Grenoble ethics committee, and all patients gave written informed consent. Baseline Assessment OSA was diagnosed by in-laboratory polysomnography or cardiorespiratory polygraphy. Cardiorespiratory polygraphy included at least the following signals: nasal pressure; thoracic and abdominal movements; arterial oxygen saturation (Sao2); and body position. Sleep stages, arousals, episodes of apnea and hypopnea, and the mean and lowest arterial oxygen saturation levels were assessed according to a standard method at all centers.18,19 Respiratory efforts were assessed by inductance plethysmography, and airflow was assessed by nasal pressure. Apneas were defined as a cessation of airflow lasting at least 10 s, and hypopneas were defined as a ⱖ 30% reduction of airflow followed by a 3% desaturation and/or a microarousal.20 Apneas and hypopneas were classified as obstructive if there were out-of-phase motions of the rib cage and abdomen or if airflow limitation was present. Sleep apnea syndrome was defined by ⱖ 15 episodes of apnea and hypopnea per hour of sleep. Sleepiness was evaluated using the Epworth sleepiness scale (ESS). Quality of life was assessed using a generic questionnaire (Medical Outcomes Study 36-item short form [SF-36]) and a questionnaire specific to OSA (Grenoble Sleep Apnea Quality of Life [GrenobleSAQOL]).21 The GrenobleSAQOL includes 40 questions rated according to a 5-point scale, with higher scores indicating worse conditions (13 related to sleep quality, 5 related to sleepiness, 6 related to every-day life, 7 related to emotions, and 9 related to “other functioning”). Effective-Pressure Assessment In all of the patients, effective pressure was determined using 2 nights with an autotitration device without C-Flex activated (REMstar Auto; Respironics). The pressure range used during the titration was left to the judgment of the physicians. Following the autotitration period, fixed CPAP was used at the pressure that was effective for ⬎ 90% of the night after visual editing of the device curves. Randomization Eligible patients were randomly assigned to receive therapy with conventional CPAP or C-Flex. Randomization was perCHEST / 136 / 2 / AUGUST, 2009
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Figure 1. Trial profile: study flow chart over 6 months. Following the first 3 months of double-blind randomized treatment with either CPAP or C-Flex, patients underwent an additional 3-month open-label study.
formed by a computer-generated schedule in random blocks of six and was stratified according to study centers. Treatment assignment was communicated to the study centers by the data management center after verification that the patient met all of the inclusion criteria. Patients were not aware of whether they were receiving CPAP with or without C-Flex activated, and the clinical research assistant who assigned patients to treatment groups did not take part in outcome assessments. The investigators who assessed outcome were unaware of the randomization status of the patients and did not set up or maintain the machines. The study was effectively double blinded. 3-Month Follow-up (End of Randomized Study) and 6-Month Evaluation (End of Open-Label Study) The same evaluations were conducted at 3 and 6 months. Objective compliance and residual apnea-hypopnea index (AHI) were downloaded and reported from the memory card (Encore Pro Smartcard; Respironics) located in the PAP device. The rate of PAP-related side effects was collected by questionnaires assessing both presence or absence and severity. Positive-pressure tolerance and comfort was assessed using visual analog scales, and ESS, SF-36, and GrenobleSAQOL questionnaires were completed. Statistical Analysis The data for all outcomes were analyzed on an intention-totreat basis. Data analysis was conducted with a statistical software
package (SPSS; SPSS; Chicago, IL). Normally, distributed data are presented as the mean ⫾ SD, skewed data are presented as the median (interquartile range), and categorical data are presented as percentages. Normality was assessed using tests of skewness and kurtosis. CPAP and C-Flex comparisons were made using unpaired t tests and Mann-Whitney U tests, depending on normality. For categorical variables, the 2 test was used. Baseline, 3-month, and 6-month comparisons were made using paired t tests and Wilcoxon signed-rank tests, depending on normality. A repeatedmeasures analysis of variance was used to analyze time and group effects on quality of life. Finally, all of the continuous variables potentially influencing CPAP compliance and tolerance were included in a logistic regression analysis to determine their respective roles.
Results Patients Two hundred eighteen newly diagnosed sleep apnea patients from seven centers met the eligibility criteria and were randomly assigned to receive 3 months of CPAP therapy (108 patients) or pressure reduction during exhalation using C-Flex (110 patients). Consistent with the usual clinical cohorts, the patients were predominantly male,
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Table 1—Baseline Characteristics of the Patients Completing the 3-Month Trial Characteristics Sex Male Female Age, yr BMI, kg/m² BMI ⱖ 30 kg/m², % Smoking consumption, % Alcohol consumption, % ESS score ESS score ⱖ 12, % Therapeutic pressure, cm H2O AHI, events/h AHI ⱖ 30 events/h, % Mean nocturnal Sao2, % Minimal nocturnal Sao2, %
CPAP
C-Flex
p Value
58 24 56 ⫾ 9 31 ⫾ 6.3 57.3 12.2 24.4 11.4 ⫾ 5.2 53.7 10.7 ⫾ 2
61 22 55 ⫾ 12 31 ⫾ 5.7 50 9.6 18.1 11.7 ⫾ 5.1 51.8 10.6 ⫾ 2.1
NS NS NS NS NS NS NS NS
44.9 ⫾ 21.8 80.2 92.6 ⫾ 3.6 77.5 ⫾ 11.1
42.7 ⫾ 20.8 68.7 93 ⫾ 2.9 78.3 ⫾ 10.7
NS NS NS NS
NS
Values are given as the mean ⫾ SD. There were no significant differences in the baseline values between the CPAP and the C-Flex groups. BMI ⫽ body mass index; NS ⫽ not significant.
middle-aged, and obese, and had moderate-tosevere OSA. There were no differences between the groups in these variables or their baseline characteristics (Table 1). Figure 1 shows the patient flow. During the first randomized study (first 3 months), 26 subjects withdrew from the CPAP group and 27 withdrew from the C-Flex group. The majority of these withdrawals were due to an initial refusal of PAP treatment. The mean AHI values reported by the device over the autotitration period were 2.89 ⫾ 4.87 and 3.48 ⫾ 3.09 events/h, respectively, for CPAP and C-Flex (p ⫽ 0.03). This difference was statistically, but not clinically, significant. The proportion of patients with an AHI below 5 and 10 events/h were similar in both groups (CPAP group, 87.8% and 96.3%, respectively; C-Flex group, 79.7 and 93.9%, respectively). Primary Outcome Analysis: 3-Month Compliance There was no difference in compliance between CPAP and C-Flex (CPAP group, 4.91 ⫾ 2.41 h of use; C-Flex, 4.98 ⫾ 1.96 h of use) [Fig 2]. Secondary Outcome Analyses Sleepiness: ESS scores were significantly improved using both treatments (CPAP, 11.4 ⫾ 5.2 to 8.0 ⫾ 5.5; C-Flex, 11.7 ⫾ 5.1 to 7.8 ⫾ 4.6). The differences between the treatment modes were not statistically significant. Symptoms, Comfort, and Side Effects: Symptoms, side effects, and comfort were significantly www.chestjournal.org
Figure 2. Primary outcome analysis: compliance with PAP therapy. Treatment efficacy at the 3-month evaluation. The results are shown as a box-whisker plot, with median and 25th quartile of AHI NS ⫽ not significant.
improved on both treatments. The differences between the treatment modes were not statistically significant. Quality of Life: Six of eight domains on the SF-36 questionnaire (Fig 3, A) and all domains of the GrenobleSAQOL questionnaire (Fig 3, B) were significantly improved with both treatments. The differences between the treatment modes were not statistically significant. Predictive Factors for Compliance In a logistic regression analysis, mean nocturnal Sao2 (percentage), plus the sleepiness and perceived treatment efficacy (treatment domain) domains of the GrenobleSAQOL were the only significant predictive factors (Table 2). Treatment mode was not a significant predictor of low compliance. Open-Label Study The group of patients moving from CPAP to C-Flex did not significantly change their PAP adherence (from 5.53 ⫾ 2.01 to 5.52 ⫾ 1.93 h of use). However, there was a significant increase in compliance in the CPAP patients who were classified as low compliers (⬍ 4 h per night of CPAP use) during the initial 3-month study when using C-Flex during the 3-month open-label study (from 2.81 ⫾ 0.97 to 3.40 ⫾ 1.64 nights of use; p ⫽ 0.04; n ⫽ 15) [Fig 4]. By contrast, the group of patients who continued receiving C-Flex therapy (from 5.80 ⫾ 1.57 to CHEST / 136 / 2 / AUGUST, 2009
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Figure 3. The evolution of the different domains of the generic quality-of-life questionnaire (SF-36) [A] and the specific quality-of-life questionnaire (GrenobleSAQOL) [B]. PF ⫽ physical functioning; RP ⫽ role limitation due to physical health; BP ⫽ bodily pain; GH ⫽ general health perception; VT ⫽ vitality; SF ⫽ social functioning; RE ⫽ role limitation due to emotional problems; MH ⫽ mental health; column A ⫽ sleep domain; column B ⫽ waking and falling asleep domain; column C ⫽ sleepiness domain; column D ⫽ domain of daily life; column E ⫽ emotional domain; column F ⫽ domain of personal relations.
5.93 ⫾ 1.58 nights of use) and the low compliers in this group (from 3.02 ⫾ 0.91 to 3.28 ⫾ 1.14 nights of use) did not significantly improve their compliance between 3 and 6 months when continuing to receive C-Flex therapy (Fig 4).
Discussion During the first 3 months of treatment, C-Flex users demonstrated compliance similar to that of conventional CPAP users. An increase in compliance
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Table 2—Predictive Factors for Compliance: Logistic Regression Analysis Variables

SE 
OR
95% CI
Age (increase of 10 yr) Mean nocturnal Sao2 (%) Noise (3 mo) Feel resistance to exhalation (3 mo) Sleepiness domain Treatment domain (3 mo)
⫺0.11 0.2 0.01 0.02 0.13 0.15
0.2 0.09 1 0.01 0.05 0.07
0.9 1.22 0.74 1.02 1.13 1.16
0.54–1.34 1.03–1.45 0.98–1.02 1–1.04 1.04–1.24 1.02–1.32
p Value 0.59 0.02 0.1 ⬍ 0.01 0.02
OR ⫽ odds ratio; CI ⫽ confidence interval.
was observed during the open study (3 to 6 months) in the subgroup of low compliers who were switching from CPAP to C-Flex therapy. C-Flex efficacy was equivalent to CPAP efficacy in terms of AHI correction, reduction of sleepiness, and quality-of-life benefits, comfort, and side effects. CPAP compliance is a key issue in sleep medicine as any reductions in daytime sleepiness, sleepiness-related accidents,22 and cardiovascular morbidity6 are expected to be proportional to use. Compliance is influenced by a number of different factors, independent of therapy comfort. Psychosocial factors, such as living alone,23 recent major life events,23 high levels of anxiety or depression,24 and unfavorable coping strategies25 have all been shown to reduce CPAP therapy compliance. By contrast, having a higher AHI score26 and greater daytime sleepiness10 have been shown to be associated with better CPAP compliance. Quality of sleep during the first night and the perceived benefit of treatment also predicts subsequent compliance.26 The logistic regression analysis we performed supports these studies by showing the major impact on compliance of sleepiness, perceived efficacy, and severity of desaturations rather than treatment mode. Other factors directly related to the CPAP device, such as a high CPAP pressure, have also been shown10
to negatively influence CPAP therapy compliance. Accordingly, various technological innovations have been developed to solve this problem such as autoadjusting devices that modify applied pressure in response to patient needs. This technology resulted in lower mean therapeutic pressures but failed to increase compliance.14 Difficulty exhaling against a fixed positive pressure is also a common complaint when using CPAP and has led to the development of a new algorithm that reduces pressure at the beginning of exhalation (C-Flex). Aloia et al17 reported a better compliance in patients receiving C-Flex therapy compared with patients receiving conventional CPAP therapy, which equated to 1.4 h of additional use per night after 3 months, but this study was not randomized as patients received the treatment that was available at the time they were enrolled. Interestingly, compliance decreased over the 12-week follow-up period in patients using CPAP, whereas it remained stable in patients using C-Flex. The finding of higher compliance with C-Flex therapy was not confirmed by Nilius et al,16 who performed the first randomized controlled trial comparing CPAP and C-Flex therapy in a 3-month study. However, it has to be noted that compliance was high in both groups (⬎ 5 h/night),
Figure 4. Evolution of compliance between 3 and 6 months (open study). Individual data are presented. The patients were separated into two subgroups exhibiting ⬍ 4 h or ⬎ 4 h of PAP therapy use after 3 months. See the legend of Figure 2 for abbreviation not used in the text. www.chestjournal.org
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making it unlikely that significant improvements could be obtained. This was also the case in the large randomized multisite trial of Dolan et al,27 in which patients who did not demonstrate sufficient adherence (defined as ⱖ 4 h of CPAP use per night) during a lead-in period of 1 week were excluded. In accordance with these studies, we did not find any significant compliance differences between CPAP and C-Flex therapy during the first 3 months of this randomized controlled trial. However, a significant improvement in compliance for patients switched to C-Flex therapy in the openlabel segment of the study occurred in initially low CPAP compliers. This was not the case in patients already using CPAP for ⬎ 4 h. This can be partly attributed to the effect of a change in therapy being perceived by the patients as a positive step in their management, thereby fostering greater adherence. However, these data provide a strong rationale for proposing such a shift in PAP therapy in the clinical management of low-CPAP compliance patients. These results also underline the need to target studies specifically dedicated to this subgroup of low-CPAP compliers.12 One criticism of systems that reduce pressure during exhalation is that they may increase the risk of upper airway collapse because of underpressurization and treatment inefficacy. Two studies16,27 have demonstrated that C-Flex is as effective as conventional CPAP therapy in correcting the AHI and daytime sleepiness. The significantly higher mean residual AHI seen with C-Flex (3.48 ⫾ 3.09 events/h) compared with CPAP (2.89 ⫾ 4.87 events/h) has no clinical relevance. In addition to previous works, our study also showed that C-Flex and CPAP therapy equivalently improve functional outcomes and quality of life, with no difference in side effects. Limitations and Strength of the Study We acknowledge some study limitations. First, the 25% rate of withdrawal during the study could be considered high. However, this percentage included a 10 to 15% initial CPAP refusal rate, which is in line with previous reports.8 –10 Dropouts related to other causes did not exceed 15%, which is also usual in similar studies in the field.28,29 A second potential limitation was the assessment of treatment efficacy by the internal device software and the possible heterogeneity in CPAP indications and initiation procedures among the different centers. This can explain differences in mean compliance from one center to another but, because of the randomized, controlled trial design of the study, should not significantly interfere with the comparison between CPAP and C-Flex therapy.
Because of logistical issues, a number of patients had a longer titration period than was originally prescribed in the protocol (range, 3 to 14 days). An analysis excluding these violators provided data and conclusions similar to those of the intention-to-treat analysis. On the other hand, our study is the largest in the field and benefited from a randomized, doubleblind, prospective, multicenter design. Moreover, as conducted over a 6-month period, it allows extrapolation to long-term treatment. Additionally, consecutive recruitment and the inclusion of patients coming from different centers with different educational programs and levels of CPAP compliance better reflect real-life situations and allow the generalization of these data to clinical populations. Conclusion C-Flex was no more effective than CPAP in the treatment of OSA, reducing daytime sleepiness and improving quality of life. Low compliers with CPAP therapy significantly improved their adherence when moving to C-Flex therapy. Further studies specifically targeting this subgroup of low-CPAP compliers are needed.
Acknowledgments Author contributions: Dr. Pépin contributed to the study concept and design, acquisition of data, drafting the manuscript, and study supervision. Dr. Tamisier contributed to the study concept and design and acquisition of data. Dr. d’Ortho contributed to the drafting of the manuscript and acquisition of data. All other authors contributed to the acquisition of data and critical revision of the manuscript. Role of sponsors: The sponsors had no role in the collection, analysis, or interpretation of the data. Other contributions: We thank Nathalie Arnol for statistical analysis and Florence Portier, Carlos Molano, Beatriz Abril, Maria Stoïca-Herman, and Xavier Drouot for including and evaluating patients in the different participating centers.
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