Comments
Abstract
Rationale: Obstructive sleep apnea (OSA) is common in patients with coronary artery disease (CAD), many of whom do not report daytime sleepiness. First-line treatment for symptomatic OSA is continuous positive airway pressure (CPAP), but its value in patients without daytime sleepiness is uncertain.
Objectives: To determine the effects of CPAP on long-term adverse cardiovascular outcome risk in patients with CAD with nonsleepy OSA.
Methods: This single-center, prospective, randomized, controlled, open-label, blinded evaluation trial was conducted between December 2005 and November 2010. Consecutive patients with newly revascularized CAD and OSA (apnea–hypopnea index ≥15/h) without daytime sleepiness (Epworth Sleepiness Scale score <10) were randomized to auto-titrating CPAP (n = 122) or no positive airway pressure (n = 122).
Measurements and Main Results: The primary endpoint was the first event of repeat revascularization, myocardial infarction, stroke, or cardiovascular mortality. Median follow-up was 57 months. The incidence of the primary endpoint did not differ significantly in patients who did versus did not receive CPAP (18.1% vs. 22.1%; hazard ratio, 0.80; 95% confidence interval, 0.46–1.41; P = 0.449). Adjusted on-treatment analysis showed a significant cardiovascular risk reduction in those who used CPAP for ≥4 versus <4 hours per night or did not receive treatment (hazard ratio, 0.29; 95% confidence interval, 0.10–0.86; P = 0.026).
Conclusions: Routine prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse cardiovascular outcomes in the intention-to-treat population. There was a significant reduction after adjustment for baseline comorbidities and compliance with the treatment.
Clinical trial registered with www.clinicaltrials.gov (NCT 00519597).
Obstructive sleep apnea is common in patients with coronary artery disease, many of whom do not report daytime sleepiness. Continuous positive airway pressure is the first-line treatment for symptomatic obstructive sleep apnea, but its value in patients without daytime sleepiness is uncertain.
This is the first randomized controlled study to address impact of continuous positive airway pressure on adverse cardiovascular outcomes in revascularized patients with coronary artery disease with obstructive sleep apnea but no daytime sleepiness. Routine prescription of the device did not reduce the adverse outcomes in this high-risk population in intention-to-treat analysis. There was a significant reduction after adjustment for baseline comorbidities and compliance with treatment.
Coronary artery disease (CAD) is one of the most common health problems in Western countries, having a poor prognosis and a high risk of mortality (1). Moreover, an increasing number of patients with CAD undergo percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) with a considerable risk of relapse of CAD in the years following the intervention, despite advances in medical treatment and revascularization techniques (2, 3).
Many of the traditional risk factors contributing to adverse outcomes in these patients are managed. However, obstructive sleep apnea (OSA), a common condition in patients with CAD (4), has largely been neglected. The paucity of data on the contribution of OSA to adverse outcomes in cardiac patients has been highlighted by the American Heart Association/American College of Cardiology (5), and probably contributes to a lack of recognition of OSA in the CAD setting.
Elimination of obstructive apneas and hypopneas with nasal continuous positive airway pressure (CPAP) is first-line treatment for OSA, reducing daytime sleepiness and improving quality of life (6). However, most patients with CAD with OSA do not experience daytime sleepiness (i.e., asymptomatic), and there is currently no clearly established rationale for treatment of such patients, notwithstanding clinical practice guidelines from the American Academy of Sleep Medicine that generally recommend CPAP treatment for OSA (7). Observational studies have demonstrated that CPAP is beneficial in patients with CAD and OSA who are adherent to treatment (8–10). There are many published short-term randomized controlled trials (RCTs) with CPAP, especially in patients with OSA with systemic hypertension, and CPAP has been shown to effectively lower blood pressure (BP) in these patients (11, 12). However, other trials suggest no benefit of CPAP in those without daytime sleepiness (13, 14), except one, suggesting a significant BP reduction in patients with newly diagnosed hypertension (15). Overall, there is good evidence to suggest that symptomatic patients with OSA should be treated with CPAP to reduce daytime sleepiness (6) and the risk of traffic accidents (16), and also perhaps to lower BP in hypertensive patients with OSA (11, 12, 15). Nevertheless, evidence from long-term prospective RCTs to determine whether cardiac patients with nonsleepy OSA should be offered CPAP treatment to reduce cardiovascular morbidity and mortality is lacking.
The RICCADSA (Randomized Intervention with Continuous Positive Airway Pressure in CAD and OSA) trial investigated the effects of CPAP on the risk of cardiovascular events in patients with CAD and concomitant OSA without daytime sleepiness. Some of the results have been previously reported in the form of an abstract (17).
Methodologic details have been published previously (18, 19), and are fully detailed in the online supplement. The target population comprised adult patients with angiography-verified CAD who had undergone PCI or CABG in Skaraborg County, West Sweden, in the previous 6 months, and had an apnea–hypopnea index (AHI) of less than 5 or greater than or equal to 15 per hour during a sleep study (see online supplement). Patients with existing OSA, an AHI of 5.0–14.9 per hour, and predominantly central apneas with Cheyne-Stokes respiration were excluded (Figure 1). Patients were recruited between December 2005 and November 2010, and follow-up was completed in May 2013. The study was a single-center (two sites), prospective, open, randomized, parallel, interventional, superiority trial of CPAP in patients with CAD with nonsleepy OSA (AHI ≥15/h; Epworth Sleepiness Scale [ESS] score <10) (Figure 1). Patients with CAD and sleepy OSA phenotype (AHI ≥15/h; ESS score ≥10) receiving CPAP and patients with CAD without OSA were followed as additional control subjects in observational arm for further post hoc comparisons (to be reported separately).
Figure 1. Flow of patients through the study. AHI = apnea–hypopnea index; CAD = coronary artery disease; CPAP = continuous positive airway pressure; CSA-CSR = central sleep apnea–Cheyne-Stokes respiration; ESS = Epworth Sleepiness Scale; OSA = obstructive sleep apnea.
[More] [Minimize]The study protocol was approved by the Ethics Committee of the Medical Faculty of the University of Gothenburg (approval No. 207-05; 09.13.2005; amendment T744-10; 11.26.2010; amendment T512-11; 06.16.2011), and all patients provided written informed consent. A blinded interim analysis was conducted in February 2010, and the protocol was amended with a new power calculation for the primary endpoints (see later). An independent clinical event committee reviewed all data obtained from hospital records and death certificates by the end of May 2013, unaware of patient identities and group allocation. A data monitoring board reviewed the protocol and monitored a random 10% selection of the database for baseline clinical data and follow-up procedures, including CPAP adherence and primary endpoints. All authors prepared the manuscript for publication, and made the decision to submit the manuscript without input from or review by ResMed Foundation and ResMed Ltd., who partly funded the trial by institutional grants. All authors guarantee the accuracy and completeness of the data. The trial was registered with the national researchweb.org (FoU i Sverige – Research and development in Sweden; No. VGSKAS-4731; 04.29.2005) and with ClinicalTrials.gov (NCT 00519597).
Details of home sleep recordings (cardiorespiratory polygraphy [PG]) and in-hospital polysomnography (PSG) and randomization procedures are provided in the online supplement. The 1:1 random assignment of patients with CAD and nonsleepy OSA was scheduled with a block size of eight patients (four CPAP, four control subjects) stratified by sex and revascularization type (PCI/CABG).
Nonsleepy patients with OSA who were randomized to treatment were fitted with an automatic CPAP device (S8 or S9; ResMed, San Diego, CA) by trained staff. Additional follow-up details, including adherence to CPAP treatment, are provided in the online supplement.
The primary endpoint was a composite of repeat revascularization, myocardial infarction (MI), stroke, and cardiovascular mortality. Information was obtained from patients’ medical records and, when necessary, from the Swedish Hospital Discharge Register and the Swedish National Cause of Death Registry. Each event was evaluated separately and as part of the combined endpoint. For patients who experienced more than one event during the follow-up period, only the first event was included in the combined endpoint. All-cause mortality and acute hospital admission for cardiovascular reasons were among the secondary endpoints. Criteria for the cardiovascular diagnosis defined by the independent clinical event committee are available in the online supplement.
Descriptive statistics are given as mean ± SD and as numbers (percentages). For baseline differences between the groups, the chi-square test and Fisher exact test were applied. Total sleep time, time spent on supine position and AHI values on the repeated sleep recordings (PG vs. PSG) at the individual level were compared with paired Student t test. Pearson correlation analysis was performed to test the linear relationship between the AHI values on PG versus PSG. All statistical tests were two-sided, and a P value less than 0.05 was considered significant. Statistical analysis was performed using SPSS 22.0 for Windows (SPSS Inc., Chicago, IL) and Stata version 14 (StataCorp LP, College Station, TX).
Kaplan-Meier analyses and Cox proportional hazards models were performed in the intention-to-treat (ITT) population to estimate the impact of CPAP on the primary endpoint. For the on-treatment (OT) analysis, a time-dependent Cox model (20, 21) was used to estimate the impact of CPAP usage on the primary endpoint. This approach accounts for the time-varying character of the intervention because subject follow-up is split into multiple intervals according to the visit dates of the CPAP usage evaluation. Originally, visits were planned after 1, 3, 6, and 12 months and then annually until the end of the study. Incomplete usage data caused by missed visits were replaced as follows. One missing episode was replaced by the last observation, if the missing episode was followed by a visit. Two or more subsequent missing visits were replaced by 0. If the data from the first visit after 1 month were missing, they were replaced by the usage data of the 3-month visit. Multivariate adjustment was made for CPAP nights per period and baseline left ventricular ejection fraction, age, sex, AHI, body mass index, current smoking, revascularization type, former revascularization, acute MI, hypertension, diabetes mellitus, and lung disease.
At the time of the study start in 2005, available literature suggested that the incidence rate for a combination of cardiovascular mortality, acute MI, and the need for a new revascularization within a year of PCI was 27% (22). Moreover, in a systemic review of the comparative effectiveness of PCI and CABG, the 5-year repeat revascularization rate was reported to be 40.1% in PCI with stents and 9.8% in patients with CABG (23). There were no studies in revascularized patients with CAD and concomitant OSA before 2005 to accurately inform estimates of study power for the primary outcome assessments; therefore, a composite endpoint rate of 25% in nonsleepy patients with untreated OSA over a 3-year follow-up period was hypothesized. The RCT arm was designed to initially comprise a consecutive sample of 200 patients with (100 nonsleepy OSA randomized to CPAP; 100 to no CPAP). It was assumed that approximately 25% of the OSA subjects would be noncompliant with CPAP during the follow-up period. The trial was expected to have an 80% power to detect a risk reduction in the rate of the composite endpoint from 25% to 10% on an ITT basis (P < 0.05 level, two-sided test). An interim analysis blinded to randomization group performed in February 2010 revealed an incident rate of 21%, and a CPAP adherence rate of 60% at 1 year, resulting in a protocol amendment. As a result, using an enlarged sample size of 242 patients (121 in each of the randomization arm) and an extended follow-up period of 2 or more years and 7 or fewer years, a significant risk reduction for the primary endpoint from 25% to 12% was hypothesized.
A total of 1,259 patients met the inclusion criteria for screening, of whom 662 (52.7%) agreed to participate in the sleep study (Figure 1). Diagnostic PG was performed at home after an average of 63 days following mechanical revascularization (median, 59 d; interquartile range, 42–78), and patients fulfilling the inclusion criteria for the RCT or the observational arm underwent baseline investigations on average 35 days (median, 30; interquartile range, 20–45) after home sleep recordings.
A total of 244 patients with CAD and OSA fulfilled the inclusion criteria for the RCT arm. Nonsleepy patients with OSA allocated to CPAP did not differ significantly from nonsleepy patients with OSA allocated to no CPAP with regard to demographic and clinical characteristics (Table 1).
| CPAP (n = 122) | No CPAP (n = 122) | P Value | |
|---|---|---|---|
| Age, yr | 65.5 (8.5) | 66.5 (8.2) | 0.382 |
| AHI, events/h | 28.3 (12.7) | 29.3 (14.0) | 0.545 |
| ODI, events/h | 16.7 (11.4) | 16.3 (11.8) | 0.804 |
| ESS score | 5.5 (2.4) | 5.5 (2.2) | 0.991 |
| BMI, kg/m2 | 28.4 (3.8) | 28.5 (3.5) | 0.840 |
| LVEF, % | 56.9 (9.0) | 56.1 (9.9) | 0.479 |
| Obesity, % | 27.9 | 27.9 | 1 |
| Female, % | 18.0 | 13.9 | 0.382 |
| Current smoker, % | 18.0 | 13.9 | 0.382 |
| Pulmonary disease, % | 3.3 | 9.8 | 0.067 |
| Hypertension, % | 68.9 | 59.0 | 0.110 |
| Acute MI at baseline, % | 53.3 | 45.9 | 0.249 |
| CABG at baseline, % | 27.0 | 27.0 | 1 |
| Previous PCI or CABG, % | 22.1 | 18.9 | 0.526 |
| Diabetes mellitus, % | 27.9 | 20.5 | 0.178 |
| β-Blocker use, % | 91.5 | 86.7 | 0.230 |
| Diuretic use, % | 20.3 | 22.7 | 0.660 |
| CCB use, % | 22.9 | 16.7 | 0.229 |
| ACE inhibitor use, % | 47.5 | 47.5 | 0.995 |
| ARB use, % | 12.7 | 16.7 | 0.389 |
| Anticoagulant use, %* | 100 | 97.5 | 0.083 |
| Lipid-lowering agent use, % | 96.6 | 93.3 | 0.248 |
Median follow-up time until mortality, loss to follow-up, or the end of the study was 56.9 months (range, 6.5–90.2). All patients were included in the ITT analysis for primary outcomes; 16 patients died, and one was lost to follow-up (Figure 1). Of 244 patients with AHI greater than or equal to 15 per hour on PG, four had AHI less than 5 per hour on in-hospital PSG the day before the RCT started, 19–54 days after initial at-home PG. Follow-up data for these four patients are provided in Table E1 in the online supplement, and correlations between AHI values on PG versus PSG for the OSA group are shown in Figure E1. Of patients with OSA allocated to CPAP at baseline, 49 returned the device within 2 years. Of the nonsleepy patients with OSA randomized to no CPAP, three wanted to start CPAP at baseline, and 22 during the amended follow-up period because of reaching the nonfatal endpoints and/or completing the initial 3-year follow-up, or developing daytime sleepiness. CPAP compliance data from CPAP devices are shown in Table E2.
Overall, 49 patients reached the combined endpoint during follow-up, 22 (18.1%) in the CPAP group and 27 (22.1%) in the no-CPAP group (not significant). The incidence of the composite endpoint was 4.65 (95% confidence interval [CI], 4.56–4.73) per 100 person-years; 4.18 (95% CI, 2.75–6.35) per 100 person-years in the CPAP group versus 5.21 (95% CI, 3.57–7.60) per 100 person-years in the no-CPAP group, respectively (P = 0.449). Cumulative incidences of the primary endpoint are illustrated in Figure 2. There were no significant differences in the individual incidences of the endpoints in the PCI and CABG subgroups (see Table E3). Univariate predictors of adverse outcomes were diabetes mellitus and former revascularization, whereas CABG at baseline was protective (Table 2). On multivariate analysis, diabetes mellitus (hazard ratio [HR], 2.05; 95% CI, 1.06–3.98; P = 0.034) and former revascularization (HR, 3.29; 95% CI, 1.77–6.10; P < 0.001) were significantly associated with increased risk for the composite endpoint, whereas CABG at baseline (HR, 0.30; 95% CI, 0.12–0.75; P < 0.001) was associated with reduced risk (Table 2).
Figure 2. Cumulative incidences of the composite endpoint in the intention-to-treat population. CPAP = continuous positive airway pressure.
[More] [Minimize]| Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|
| Hazard Ratio | 95% CI | P Value | Hazard Ratio | 95% CI | P Value | |
| CPAP assignment vs. no CPAP | 0.80 | 0.46–1.41 | 0.449 | 0.62 | 0.34–1.13 | 0.120 |
| Age | 1.02 | 0.98–1.05 | 0.372 | 1.01 | 0.98–1.05 | 0.474 |
| Females vs. males | 0.48 | 0.17–1.33 | 0.155 | 0.43 | 0.15–1.23 | 0.114 |
| Apnea–hypopnea index | 1.00 | 0.98–1.02 | 0.783 | 0.99 | 0.97–1.01 | 0.363 |
| Body mass index | 1.01 | 0.94–1.09 | 0.753 | 0.99 | 0.91–1.08 | 0.802 |
| CABG vs. PCI | 0.38 | 0.17–0.84 | 0.017 | 0.30 | 0.12–0.75 | 0.010 |
| Current smoking | 1.29 | 0.63–2.67 | 0.485 | 1.78 | 0.80–3.96 | 0.156 |
| Hypertension | 1.09 | 0.60–1.96 | 0.776 | 1.59 | 0.81–3.12 | 0.176 |
| Diabetes mellitus | 1.92 | 1.06–3.47 | 0.030 | 2.05 | 1.06–3.98 | 0.034 |
| Acute myocardial infarction | 1.02 | 0.58–1.79 | 0.947 | 1.03 | 0.54–1.94 | 0.937 |
| Previous PCI or CABG | 3.36 | 1.91–5.93 | <0.001 | 3.29 | 1.77–6.10 | <0.001 |
| Pulmonary disease | 1.39 | 0.50–3.85 | 0.532 | 0.95 | 0.33–2.74 | 0.925 |
| Left ventricular ejection fraction | 0.99 | 0.96–1.02 | 0.594 | 0.99 | 0.96–1.02 | 0.513 |
There was no significant difference in incidence rates between the groups when applying a cut-off level of 3 hours of CPAP usage per night, but there was a significant between-group difference based on CPAP usage for 4 or more hours per night (six events) versus less than 4 hours per night or no CPAP (43 events) with an HR 0.29 and 95% CI of 0.10–0.86 with covariable adjustments (Table 3). The incidence of the composite endpoint was 2.31 (95% CI, 0.96–5.54) per 100 person-years for CPAP usage for 4 or more hours per night, and 5.32 (95% CI, 3.96–7.15) per 100 person-years for CPAP usage less than 4 hours per night or no CPAP.
| Univariate | Multivariate* | |||||
|---|---|---|---|---|---|---|
| Hazard Ratio | 95% CI | P Value | Hazard Ratio | 95% CI | P Value | |
| CPAP usage ≥3 h/night | 0.64 | 0.31–1.33 | 0.234 | 0.91 | 0.16–5.13 | 0.911 |
| CPAP usage ≥4 h/night | 0.43 | 0.18–1.02 | 0.057 | 0.29 | 0.10–0.86 | 0.026 |
| CPAP usage ≥5 h/night | 0.43 | 0.17–1.09 | 0.075 | 0.34 | 0.10–1.12 | 0.075 |
One patient (age 81 yr) with CAD and mechanical aortic valve prosthesis, who was on combination therapy with warfarin and clopidogrel after PCI, could not use the CPAP device because of frequent nasal bleeding on treatment. This patient restarted CPAP therapy without any nasal bleeding when clopidogrel was discontinued 3 years after PCI. Other patient-reported side effects during CPAP fitted with the known tolerability profile of CPAP, and included dry mouth, nasal symptoms, claustrophobia, insomnia, noise problems, and mask fit.
This study showed that routine prescription of CPAP to patients with CAD and nonsleepy OSA did not significantly reduce the long-term cardiovascular event rate. A significant beneficial effect of CPAP was seen first after adjusting for baseline comorbidities and CPAP adherence.
To our knowledge, this is the first RCT investigating the effect of CPAP on long-term cardiovascular outcomes in patients with CAD and concomitant OSA without daytime sleepiness. Two RCTs are currently underway investigating the impact of CPAP on long-term outcomes in larger cohorts with established cardiovascular disease (24, 25). Many previous studies that showed beneficial effects of CPAP in patients with CAD and OSA had an observational design. A review of 371 patients with OSA and CAD who underwent PCI reported a significantly lower 5-year cardiac death rate (3%) among 175 patients treated with CPAP compared with 196 untreated patients (10%) (10). Data from a sleep clinic cohort demonstrated that CPAP treatment significantly reduced cardiovascular risk in men with severe OSA (26). Similarly, adequate CPAP treatment has been shown to reduce the risk of a composite endpoint of incident CAD or stroke in women with OSA (27). Moreover, after adjustment for confounding factors, post-MI patients with OSA who were compliant with CPAP had a lower risk of recurrent MI and repeat revascularization than untreated patients, and similar to patients without OSA (28).
In this RCT, CPAP treatment of CAD and nonsleepy patients with OSA did not significantly reduce the rate of adverse cardiovascular outcomes. These results may reflect the fact that getting nonsleepy patients to comply with CPAP is challenging. Between-group differences at baseline may also have influenced the findings. Randomization was not stratified by comorbidities, and there was a higher proportion of patients with acute MI, diabetes mellitus, and hypertension in the CPAP arm. OT analysis showed that CPAP was effective in nonsleepy patients who used the device for 4 or more hours per night, with an adjusted HR that was of similar magnitude to that reported in a previous observational study (27).
Many patients with CAD with OSA do not experience daytime sleepiness, and it has been suggested that nonsleepy patients with OSA might have poor CPAP adherence because they do not experience subjective benefits from therapy (29). This may be the case, although overall adherence in the current CAD population did not differ markedly from long-term adherence rates in sleep clinic cohorts (30). Indeed, an observational study of a sleep clinic cohort with CAD suggested comparable adherence to CPAP in sleepy and nonsleepy patients (31), and a larger RCT addressing the impact of CPAP treatment on incident hypertension or cardiovascular events in nonsleepy patients with OSA from sleep clinics reported that 64% of patients were using CPAP for 4 or more hours per night after a median 4-year follow-up (32).
The results of the current study suggest that CPAP treatment is feasible in CAD populations with nonsleepy OSA, given the additional assumption that such high-risk patients might expect greater cardiovascular benefits, and may be more motivated to comply with treatment despite the lack of daytime sleepiness. However, initial data from the SAVE trial suggest a lower CPAP compliance rate than in this study, despite an initial 1-week run-in phase with sham-CPAP to exclude noncompliant patients before randomization (15% of all eligible patients were excluded) (33). Thus, adherence remains a challenging issue when evaluating the cardiovascular benefits of CPAP treatment in patients with CAD and concomitant OSA without daytime sleepiness. Also, the finding that CPAP use for 4 or more hours per night is required to achieve cardiovascular benefits in nonsleepy patients with OSA is similar to the results of a previous post hoc analysis (32).
CPAP is not the only treatment option for OSA. In a recent RCT, adherence to a weight loss regimen and CPAP resulted in incremental BP reductions compared with either intervention alone (34). There is also accumulating evidence for a beneficial impact of mandibular advancement devices on BP in patients with OSA (35, 36). Moreover, given the emergence of new mechanical and pharmacologic interventions in sleep medicine (37), improved “personalization” of OSA therapy may be possible through better characterization of individual patient pathophysiology.
Despite the lack of conclusive evidence for a beneficial effect of CPAP in the current trial, the high prevalence of OSA in the entire study population (19) indicates that OSA should be considered when assessing the impact of different treatments (e.g., lipid-lowering agents, bare-metal vs. drug-eluting stents) in revascularized CAD cohorts. Effective treatment of OSA with CPAP, or other approaches, is challenging in patients with CAD with nonsleepy OSA, but needs to be evaluated in secondary prevention models.
The strengths of this study include its randomized controlled design for patients with CAD and nonsleepy OSA with only one lost to follow-up. Although the inclusion rate for eligible patients for sleep screening was only 53%, the inclusion design was consecutive, and there were no significant differences in baseline characteristics of patients undergoing versus not undergoing sleep study (19).
This study also had a number of limitations. First, it was a single-center trial with two sites, which limits generalizability of results across geographic regions. Second, “nonsleepy” OSA relied on an ESS threshold, which may not reflect an objective sleepiness. However, this is a generally accepted tool for subjective daytime sleepiness, and other methods, such as Multiple Sleep Latency Test (38), which is used as an objective tool, is time consuming and not feasible to run for the large-scale cardiac populations. Third, the study was underpowered for the ITT arm for several reasons. CPAP adherence in patients with CAD and nonsleepy OSA was lower than initially expected, which possibly resulted in an inadequately powered sample size estimation. Although CPAP adherence rates were slightly higher than those reported in the SAVE trial (33), those data had not been published when the current study started or when the interim analysis was performed. Furthermore, revascularized patients with CAD were a heterogeneous group, including both PCI and CABG, and both acute/subacute and elective PCI, and the apparent treatment effect was far smaller than anticipated because of an optimistic first assumption.
Fourth, the trial was open-label, and had no placebo control arm. As previously discussed (39), there is no true sham CPAP or other appropriate placebo for CPAP in a long-term trial in patients with cardiovascular disease. It is also possible that sham CPAP consisting of a mask attached to tubing, but without pressure application, would worsen sleep disturbance and act as a “negative placebo” (40). Finally, results of the OT analysis must be interpreted with care because device usage is patient-driven and self-selection bias cannot be excluded.
In conclusion, routine CPAP prescription of CPAP to patients with CAD with nonsleepy OSA did not significantly reduce long-term adverse outcomes. However, the study may have had limited power to detect a significant difference in the ITT population. The risk reduction was observed first after adjustment for baseline comorbidities and CPAP adherence. These findings need to be further explored in larger clinical cohorts with more homogenous CAD populations.
The authors thank the independent clinical event committee, Lennart Welin (M.D., Ph.D., Associate Professor of Medicine), the data monitoring board, Marina Modin (R.N., M.Sc.), sleep technologist Paul Murphy (RPSGT, EST) for scoring of the in-hospital PSG recordings, Andras Trezl (MD, Department of Medical Biometry and Epidemiology, University Medical Center, Hamburg-Eppendorf, Germany) for his contribution to the statistical analysis plan, and research secretary Eija Magnusson for her professional assistance in data entry and coordinating quality control of patient records and data follow-up during the whole trial period. Editing assistance was provided by Nicola Ryan, independent medical writer, funded by ResMed.
| 1. | Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, Naghavi M, Mensah GA, Murray CJ. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med 2015;372:1333–1341. |
| 2. | Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR, Mack MJ, Ståhle E, Feldman TE, van den Brand M, Bass EJ, et al.; SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med 2009;360:961–972. |
| 3. | Kappetein AP, Feldman TE, Mack MJ, Morice MC, Holmes DR, Ståhle E, Dawkins KD, Mohr FW, Serruys PW, Colombo A. Comparison of coronary bypass surgery with drug-eluting stenting for the treatment of left main and/or three-vessel disease: 3-year follow-up of the SYNTAX trial. Eur Heart J 2011;32:2125–2134. |
| 4. | Hedner J, Franklin K, Peker Y. Coronary artery disease and sleep apnea. In: Kryger MH, Roth TT, Dement WT, editors. Principals and practice of sleep medicine. 5th ed. Philadelphia: Elsevier; 2011. pp. 1393–1399. |
| 5. | Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, et al.; American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology; American Heart Association Stroke Council; American Heart Association Council on Cardiovascular Nursing; American College of Cardiology Foundation. Sleep apnea and cardiovascular disease: an American Heart Association/American College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 2008;118:1080–1111. |
| 6. | Engleman HM, Martin SE, Kingshott RN, Mackay TW, Deary IJ, Douglas NJ. Randomised placebo controlled trial of daytime function after continuous positive airway pressure (CPAP) therapy for the sleep apnoea/hypopnoea syndrome. Thorax 1998;53:341–345. |
| 7. | Epstein LJ, Kristo D, Strollo PJ Jr, Friedman N, Malhotra A, Patil SP, Ramar K, Rogers R, Schwab RJ, Weaver EM, et al.; Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med 2009;5:263–276. |
| 8. | Milleron O, Pillière R, Foucher A, de Roquefeuil F, Aegerter P, Jondeau G, Raffestin BG, Dubourg O. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J 2004;25:728–734. |
| 9. | Doherty LS, Kiely JL, Swan V, McNicholas WT. Long-term effects of nasal continuous positive airway pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest 2005;127:2076–2084. |
| 10. | Cassar A, Morgenthaler TI, Lennon RJ, Rihal CS, Lerman A. Treatment of obstructive sleep apnea is associated with decreased cardiac death after percutaneous coronary intervention. J Am Coll Cardiol 2007;50:1310–1314. |
| 11. | Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, Mullins R, Jenkinson C, Stradling JR, Davies RJ. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002;359:204–210. |
| 12. | Becker HF, Jerrentrup A, Ploch T, Grote L, Penzel T, Sullivan CE, Peter JH. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003;107:68–73. |
| 13. | Barbé F, Mayoralas LR, Duran J, Masa JF, Maimó A, Montserrat JM, Monasterio C, Bosch M, Ladaria A, Rubio M, et al. Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. a randomized, controlled trial. Ann Intern Med 2001;134:1015–1023. |
| 14. | Robinson GV, Smith DM, Langford BA, Davies RJ, Stradling JR. Continuous positive airway pressure does not reduce blood pressure in nonsleepy hypertensive OSA patients. Eur Respir J 2006;27:1229–1235. |
| 15. | Durán-Cantolla J, Aizpuru F, Montserrat JM, Ballester E, Terán-Santos J, Aguirregomoscorta JI, Gonzalez M, Lloberes P, Masa JF, De La Peña M, et al.; Spanish Sleep and Breathing Group. Continuous positive airway pressure as treatment for systemic hypertension in people with obstructive sleep apnoea: randomised controlled trial. BMJ 2010;341:c5991. |
| 16. | Mazza S, Pépin JL, Naëgelé B, Rauch E, Deschaux C, Ficheux P, Lévy P. Driving ability in sleep apnoea patients before and after CPAP treatment: evaluation on a road safety platform. Eur Respir J 2006;28:1020–1028. |
| 17. | Peker Y, Glantz H, Eulenburg C, Wegscheider K, Herlitz J, Thunström E. Impact of continuous positive airway pressure treatment on cardiovascular outcomes in coronary artery disease and obstructive sleep apnea: the RICCADSA trial. Am J Respir Crit Care Med 2015;191:A6317. |
| 18. | Peker Y, Glantz H, Thunström E, Kallryd A, Herlitz J, Ejdebäck J. Rationale and design of the Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnoea--RICCADSA trial. Scand Cardiovasc J 2009;43:24–31. |
| 19. | Glantz H, Thunström E, Herlitz J, Cederin B, Nasic S, Ejdebäck J, Peker Y. Occurrence and predictors of obstructive sleep apnea in a revascularized coronary artery disease cohort. Ann Am Thorac Soc 2013;10:350–356. |
| 20. | Cox DR. Regression models and life tables (with discussion). J R Stat Soc, B 1972;34:187–220. |
| 21. | Fisher LD, Lin DY. Time-dependent covariates in the Cox proportional-hazards regression model. Annu Rev Public Health 1999;20:145–157. |
| 22. | Odell A, Gudnason T, Andersson T, Jidbratt H, Grip L. One-year outcome after percutaneous coronary intervention for stable and unstable angina pectoris with or without application of general usage of stents in unselected European patient groups. Am J Cardiol 2002;90:112–118. |
| 23. | Bravata DM, Gienger AL, McDonald KM, Sundaram V, Perez MV, Varghese R, Kapoor JR, Ardehali R, Owens DK, Hlatky MA. Systematic review: the comparative effectiveness of percutaneous coronary interventions and coronary artery bypass graft surgery. Ann Intern Med 2007;147:703–716. |
| 24. | McEvoy RD, Anderson CS, Antic NA, Chen B, He Q, Heeley E, Huang S, Huang Y, Wang J, Zhong N. The sleep apnea cardiovascular endpoints (SAVE) trial: rationale and start-up phase. J Thorac Dis 2010;2:138–143. |
| 25. | Esquinas C, Sánchez-de-la Torre M, Aldomá A, Florés M, Martínez M, Barceló A, Barbé F; Spanish Sleep Network. Rationale and methodology of the impact of continuous positive airway pressure on patients with ACS and nonsleepy OSA: the ISAACC Trial. Clin Cardiol 2013;36:495–501. |
| 26. | Marin JM, Carrizo SJ, Vicente E, Agusti AG. 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;365:1046–1053. |
| 27. | Campos-Rodriguez F, Martinez-Garcia MA, Reyes-Nuñez N, Caballero-Martinez I, Catalan-Serra P, Almeida-Gonzalez CV. Role of sleep apnea and continuous positive airway pressure therapy in the incidence of stroke or coronary heart disease in women. Am J Respir Crit Care Med 2014;189:1544–1550. |
| 28. | Garcia-Rio F, Alonso-Fernández A, Armada E, Mediano O, Lores V, Rojo B, Fernández-Lahera J, Fernández-Navarro I, Carpio C, Ramírez T. CPAP effect on recurrent episodes in patients with sleep apnea and myocardial infarction. Int J Cardiol 2013;168:1328–1335. |
| 29. | Pack AI, Gislason T. Obstructive sleep apnea and cardiovascular disease: a perspective and future directions. Prog Cardiovasc Dis 2009;51:434–451. |
| 30. | Weaver TE, Grunstein RR. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc 2008;5:173–178. |
| 31. | Sampol G, Rodés G, Romero O, Jurado MJ, Lloberes P. Adherence to nCPAP in patients with coronary disease and sleep apnea without sleepiness. Respir Med 2007;101:461–466. |
| 32. | Barbé F, Durán-Cantolla J, Sánchez-de-la-Torre M, Martínez-Alonso M, Carmona C, Barceló A, Chiner E, Masa JF, Gonzalez M, Marín JM, et al.; Spanish Sleep and Breathing Network. 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;307:2161–2168. |
| 33. | Chai-Coetzer CL, Luo YM, Antic NA, Zhang XL, Chen BY, He QY, Heeley E, Huang SG, Anderson C, Zhong NS, et al. Predictors of long-term adherence to continuous positive airway pressure therapy in patients with obstructive sleep apnea and cardiovascular disease in the SAVE study. Sleep 2013;36:1929–1937. |
| 34. | Chirinos JA, Gurubhagavatula I, Teff K, Rader DJ, Wadden TA, Townsend R, Foster GD, Maislin G, Saif H, Broderick P, et al. CPAP, weight loss, or both for obstructive sleep apnea. N Engl J Med 2014;370:2265–2275. |
| 35. | Gotsopoulos H, Kelly JJ, Cistulli PA. Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial. Sleep 2004;27:934–941. |
| 36. | Phillips CL, Grunstein RR, Darendeliler MA, Mihailidou AS, Srinivasan VK, Yee BJ, Marks GB, Cistulli PA. Health outcomes of continuous positive airway pressure versus oral appliance treatment for obstructive sleep apnea: a randomized controlled trial. Am J Respir Crit Care Med 2013;187:879–887. |
| 37. | Peker Y, Redline S. Update in sleep medicine 2013. Am J Respir Crit Care Med 2014;189:1345–1350. |
| 38. | Wise MS. Objective measures of sleepiness and wakefulness: application to the real world? J Clin Neurophysiol 2006;23:39–49. |
| 39. | Bradley TD, Logan AG, Floras JS; CANPAP Investigators. Rationale and design of the Canadian Continuous Positive Airway Pressure Trial for Congestive Heart Failure patients with Central Sleep Apnea--CANPAP. Can J Cardiol 2001;17:677–684. |
| 40. | Leung RS, Tkacova R, Bradley TD. Obstructive sleep apnoea. Lancet 1999;354:1212–1213. |
Supported by the Swedish Research Council (521-2011-537 and 521-2013-3439); Swedish Heart-Lung Foundation (20080592, 20090708, and 20100664); the “Agreement concerning research and education of doctors” of Västra Götalandsregionen (ALFGBG-11538 and ALFGBG-150801); Research Fund at Skaraborg Hospital (VGSKAS-4731, VGSKAS-5908, VGSKAS-9134, VGSKAS-14781, VGSKAS-40271, and VGSKAS-116431); Skaraborg Research and Development Council (VGFOUSKB-46371); Heart Foundation of Kärnsjukhuset; ResMed Foundation; and ResMed Ltd. ResMed Sweden provided some of the sleep recording devices and technical support. None of the funders had any direct influence on the design of the study, the analysis of the data, the data collection, drafting of the manuscript, or the decision to publish.
Author Contributions: Y.P., H.G., and J.H. designed the study in 2005. C.E. and K.W. amended the statistical analysis plan after interim analysis in 2010. Y.P., H.G., and E.T. performed the patient recruitment and clinical follow-ups. Y.P., C.E., and K.W. performed the statistical analysis. All authors interpreted the data, prepared the manuscript, and drafted the article. Y.P. obtained study funding and takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript. All authors approved this manuscript in its final form.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201601-0088OC on February 25, 2016
Author disclosures are available with the text of this article at www.atsjournals.org.
