Abstract
Rationale: Patients with chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) (overlap syndrome) are more likely to develop pulmonary hypertension than patients with either condition alone.
Objectives: To assess the relation of overlap syndrome to mortality and first-time hospitalization because of COPD exacerbation and the effect of continuous positive airway pressure (CPAP) on these major outcomes.
Methods: We included 228 patients with overlap syndrome treated with CPAP, 213 patients with overlap syndrome not treated with CPAP, and 210 patients with COPD without OSA. All were free of heart failure, myocardial infarction, or stroke. Median follow-up was 9.4 years (range, 3.3–12.7). End points were all-cause mortality and first-time COPD exacerbation leading to hospitalization.
Measurements and Main Results: After adjustment for age, sex, body mass index, smoking status, alcohol consumption, comorbidities, severity of COPD, apnea-hypopnea index, and daytime sleepiness, patients with overlap syndrome not treated with CPAP had a higher mortality (relative risk, 1.79; 95% confidence interval, 1.16–2.77) and were more likely to suffer a severe COPD exacerbation leading to hospitalization (relative risk, 1.70; 95% confidence interval, 1.21–2.38) versus the COPD-only group. Patients with overlap syndrome treated with CPAP had no increased risk for either outcome compared with patients with COPD-only.
Conclusions: The overlap syndrome is associated with an increased risk of death and hospitalization because of COPD exacerbation. CPAP treatment was associated with improved survival and decreased hospitalizations in patients with overlap syndrome.
The coexistence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) is denominated “overlap syndrome.” Long-term outcomes in patients with overlap syndrome remain unknown.
In patients with COPD, the coexistence of OSA is associated with an increased risk of death from any cause, and hospitalization because of COPD exacerbation. Effective treatment with continuous positive airway positive was associated with improved survival and decreased hospitalizations.
Patients with the overlap syndrome may have a worse prognosis compared with patients with only one of those diseases for several reasons. During sleep, patients with both COPD and OSA suffer from more frequent episodes of oxygen desaturation and more total sleep time with hypoxemia and hypercapnia than OSA patients without COPD (5). The apneic events are also associated with more profound hypoxemia and more cardiac dysrythmias (6). Finally, patients with simultaneous COPD and OSA are more likely to develop daytime pulmonary hypertension (7) and right heart failure (8) than patients with either condition alone.
Chaouat and coworkers (9) have shown that patients with the overlap syndrome have a lower 5-year survival rate than patients who only suffer from OSA. However, in that study no adjustment was made for potential confounding factors and, more importantly, all patients were treated with nasal continuous positive airway pressure (CPAP), so the potential effect of untreated OSA on COPD survival was not determined. In a nonrandomized observational study of patients with OSA, we reported higher rates of fatal and nonfatal cardiovascular events in patients with untreated severe OSA compared with treated severe OSA or non-OSA subjects (10). In that study, all patients had spirometry recorded at baseline.
We expanded the database of this prospective cohort and selected patients with COPD defined according to standard criteria (11) to test the following hypotheses: first, untreated OSA in patients with COPD (overlap syndrome) is associated with a higher mortality than COPD without OSA; and second, CPAP favorably impacts on major outcomes among patients with the overlap syndrome. Some of the results of theses studies have been previously reported in the form of an abstract (12).
This study was initiated in January 1996 and includes those patients referred to the Sleep Clinic (Hospital Universitario Miguel Servet in Zaragoza, Spain [HUMS]) for suspected sleep-disordered breathing up to December 2001. The cohort was divided into three groups: (1) patients with COPD without OSA (apnea-hypopnea index [AHI] <5 events/hour sleep); (2) patients with COPD and OSA (overlap syndrome) not treated with CPAP; and (3) patients with overlap syndrome treated with CPAP. Patients were excluded if they had a history of heart failure, myocardial infarction, or stroke. OSA patients were treated according to national guidelines (13) (see online supplement). The study was approved by the institutional review board and all participants gave their informed consent.
Clinical data were recorded using a standardized protocol described previously (10). The Epworth Sleepiness Scale was used to assess daytime sleepiness (14). The degree of comorbidity was quantified using the Charlson index (15). Forced spirometry was performed according to the guidelines of the American Thoracic Society (16). COPD was diagnosed by staff pulmonologist according to standards criteria (11). All participants underwent an attended overnight polysomnography as previously described (10) (see online supplement for detailed description of the variables and sleep study and noninvasive ventilation [NIV] titration).
After the baseline evaluation, all patients were seen at the clinic at least once a year or until death. The primary outcome of the study was time to death from any cause. Specific causes of death were determined by independent physicians from the Department of Medical Records of the HUMS after reviewing the medical information, death certificates, and National Death Registries. The secondary outcome of interest was the time to a first severe COPD exacerbation, defined as a change in the respiratory condition that required hospital admission. Hospitalization events were tracked from the Regional Health Resources Utilization Register. To accurately capture patients who were admitted with exacerbations, only those with discharge codes ICD-9-CM of 491, 492, 493, and 496 were ultimately included for analysis.
The differences among the groups were compared using chi-square test for categorical variables and analysis of variance for continuous variables. To describe the frequency of outcomes for the three study groups by time, we constructed Kaplan-Meier cumulative-event curves for all-cause mortality and first severe COPD exacerbation. Data were censored at the time of the last medical assessment or when new NIV started (or a change from CPAP to noninvasive positive pressure ventilation in the overlap group treated from baseline with CPAP [group 3]). The log-rank test was used to compare differences among the three groups. Multivariate Cox proportional hazard regression model was used to determine whether OSA increases the risk of all-cause mortality and first severe COPD exacerbation among patients with COPD not treated with CPAP at enrollment. Relative risks (RR) and 95% confidence intervals (CI) were calculated for the association between end points and baseline characteristics. Confounding variables with a statistical significance with end points at P < 0.05 in the bivariate analysis were entered in a forward stepwise analysis sequentially. All analyses were performed using SPSS 15.0 software (SPSS, Chicago, IL).
The flow of patients in the study is described in Figure 1. From the 4,241 patients eligible to participate in the study, a total of 3,102 had OSA and 1,139 had simple snoring. COPD was diagnosed at the time of the first assessment in 589 (19%) patients with OSA and in 210 (18%) simple snorers. In the overlap group, NIV was recommended to 468 patients but was declined by 213 patients. After NIV titration, CPAP was initiated in 228 and noninvasive positive pressure ventilation in 27 patients. Characteristics and outcomes of the noninvasive positive pressure ventilation subgroup are reported separately (see Table E1 in the online supplement). In the CPAP group, 23 were noncompliant and the machine was withdrawn but they were included in the analysis in an intention-to-treat approach. The rest of the 121 patients with overlap syndrome did not meet the criteria for treatment with CPAP and received alternative treatment: upper airway surgery (n = 35); obesity surgery (n = 8); and no specific therapy (n = 78). Baseline characteristics of the patients grouped according to the treatment of OSA that was indicated after the sleep study can be found in the online supplement (Table E2). Table 1 shows the baseline characteristics of the three final groups. As expected, the two groups of patients with overlap syndrome had a higher body mass index (BMI), AHI, and Epworth sleepiness score than the group with COPD only (P < 0.05). The Charlson comorbidity index was lowest in COPD, intermediate in overlap treated with CPAP, and highest in untreated overlap syndrome (all P < 0.05).
Figure 1. Cohort profile. AHI = apnea-hypopnea index; COPD = chronic obstructive pulmonary disease; CPAP = continuous positive airway pressure; NIV = noninvasive ventilation; OSA = obstructive sleep apnea.
[More] [Minimize]Characteristic | COPD Only (n = 210) | Overlap Untreated (n = 213) | Overlap Treated with CPAP (n = 228) | P Value† | ||||
|---|---|---|---|---|---|---|---|---|
| Age, yr | 57 ± 8 | 58 ± 7 | 57 ± 8 | 0.44 | ||||
| Male sex, % | 90 | 93 | 94 | 0.25 | ||||
| Body mass index, Kg/m2 | 27.6 ± 3.2 | 30.5 ± 5.11 | 30.7 ± 7.12 | <0.001 | ||||
| Smoking history | ||||||||
| Pack-years | 40 ± 15 | 45 ± 171 | 42 ± 16 | 0.012 | ||||
| Current smoker, % | 40 | 42 | 42 | 0.72 | ||||
| Alcohol use, % | 33 | 35 | 41 | 0.21 | ||||
| Charlson index | 0.82 ± 0.95 | 1.18 ± 1.201 | 1.07 ± 1.26 | 0.004 | ||||
| Medications | ||||||||
| Antihypertensives, % | 29 | 401 | 442 | 0.002 | ||||
| Statins, % | 10 | 11 | 11 | 0.90 | ||||
| Inhaled LABD, % | 46 | 46 | 48 | 0.87 | ||||
| Inhaled CS, % | 28 | 30 | 30 | 0.69 | ||||
| COPD exacerbation, %‡ | 8 | 15 | 15 | 0.04 | ||||
| FEV1, L | 1.5 ± 0.5 | 1.5 ± 0.5 | 1.5 ± 0.4 | 0.72 | ||||
| FEV1, % predicted | 56 ± 17 | 57 ± 16 | 56 ± 16 | 0.91 | ||||
| Severity of COPD, No., % | ||||||||
| Stage I (FEV1 80% predicted) | 14 | 14 | 12 | 0.97 | ||||
| Stage II (FEV1, 50–79% predicted) | 43 | 46 | 45 | |||||
| Stage III (FEV1, 30–49% predicted) | 34 | 31 | 33 | |||||
| Stage IV (FEV1, <30% predicted) | 9 | 9 | 10 | |||||
| Apnea-hypopnea index | 2 ± 3 | 34 ± 121 | 35 ± 132 | <0.001 | ||||
| Resting O2 saturation, % | 94 ± 3 | 93 ± 41 | 93 ± 32 | <0.001 | ||||
| Mean O2 saturation during sleep, % | 92 ± 2 | 90 ± 4 | 91 ± 6 | <0.001 | ||||
| Epworth Sleepiness Scale | 6 ± 3 | 12 ± 41 | 12 ± 42 | <0.001 | ||||
Death from any cause occurred in 213 patients (32.7%) over a median follow-up of 9.4 years (range, 3.3–12.7). Patients died of cardiovascular (28.1%), cancer (26%), and pulmonary (25.8%) causes. Death from any cause and from cardiovascular causes were higher in the overlap group not treated with CPAP (5.07 events and 1.75 events per 100 person-years, respectively) compared with the overlap group treated with CPAP (3.37 events and 0.79 events per 100 person-years, respectively) and with COPD without OSA (2.60 and 0.61 events per 100 person-years, respectively). The group with overlap syndrome treated with CPAP did not show differences in these outcomes compared with the COPD-only patients (Table 2). The Kaplan-Meier analysis shows that patients with untreated overlap syndrome had increased mortality compared with the group with overlap syndrome treated with CPAP and with the group of patients without OSA (Figure 2).
Figure 2. Kaplan-Meier survival curves for outcomes among chronic obstructive pulmonary disease (COPD) patients without obstructive sleep apnea (OSA) (COPD group), patients with COPD and coexisting OSA (overlap group), and patients with overlap syndrome treated with continuous positive airway pressure (CPAP) since enrollment (overlap with CPAP group). Percentage survival (top), percentage of severe COPD exacerbation-free survival curves among the three study groups (bottom). The differences among curves from COPD only and COPD with OSA treated with CPAP are statistically significant from the curve of patients with COPD and untreated OSA (P < 0.001).
[More] [Minimize]Cause | All Patients (n = 651) | COPD Only (n = 210) | Overlap Untreated (n = 213) | Overlap Treated with CPAP (n = 228) | P Value* |
|---|---|---|---|---|---|
| Cancer, No. (%) | 56 (8.6) | 16 (7.6) | 20 (9.4) | 20 (8.8) | 0.43 |
| CVS, No. (%) | 60 (9.2) | 12 (5.7) | 31 (14.6)1 | 17 (7.5)2 | 0.004 |
| Pulmonary, No. (%) | 55 (8.4) | 11 (5.2) | 25 (11.7) | 19 (8.3) | 0.06 |
| Other, No. (%) | 42 (6.5) | 12 (5.7) | 14 (6.5) | 16 (7) | 0.85 |
| All causes, No. (%) | 213 (32.7) | 51 (24.2) | 90 (42.2)1 | 72 (31.6)2 | <0.001 |
Table 3 shows the crude and adjusted Cox regression models regarding all-cause mortality. Compared with the COPD-only group, the untreated overlap group had a higher mortality (RR, 2.23; 95% CI, 1.59–3.14), whereas mortality was not different in the overlap group treated with CPAP (RR, 1.32; 95% CI, 0.89–1.88). Explanatory variables associated in the bivariate analysis were age, BMI, Charlson index, smoking status, severity of COPD, AHI, and daytime sleepiness (all P < 0.05). These results were similar in the Cox-adjusted multivariate model, which showed a higher mortality risk in those with untreated overlap syndrome (RR, 1.76; 95% CI, 1.24–2.53). The patients with overlap syndrome treated with CPAP had a similar risk for death than patients with COPD even when adjusted by age, sex, BMI, Charlson index, current smoking, and COPD severity.
Variable | Crude Relative Risk (95% confidence interval) | P Value | Adjusted Relative Risk (95% confidence interval) | P Value | ||||
|---|---|---|---|---|---|---|---|---|
| Age, yr | 1.10 (1.09–1.13) | <0.001 | 1.08 (1.06–1.11) | <0.001 | ||||
| Body mass index, kg/m2 | 0.95 (0.92–0.97) | 0.012 | 0.97 (0.94–0.99) | 0.04 | ||||
| Current smoker | 1.44 (1.14–1.95) | 0.004 | 1.45 (1.11–2.00) | 0.008 | ||||
| Alcohol use | ||||||||
| No | Reference | 0.88 | ||||||
| Yes | 0.87 (0.66–1.17) | |||||||
| Charlson index | 1.62 (1.47–1.78) | <0.001 | 1.42 (1.28–1.59) | <0.001 | ||||
| Severity of COPD | ||||||||
| Stage I (FEV1 80% predicted) | Reference | 0.60 | 1.37 (1.14–1.65) | 0.001 | ||||
| Stage II (FEV1, 50–79% predicted) | 1.10 (0.68–1.77) | 0.03 | ||||||
| Stage III (FEV1, 30–49% predicted) | 1.62 (1.01–2.59) | <0.001 | ||||||
| Stage IV (FEV1, <30 predicted) | 4.03 (2.36–6.91) | |||||||
| COPD exacerbation | 1.76 (1.22–2.55) | 0.003 | 1.08 (0.68–1.95) | 0.81 | ||||
| COPD group | ||||||||
| COPD only | Reference | <0.001 | 1.79 (1.16–2.77) | 0.009 | ||||
| COPD with untreated OSA | 2.26 (1.60–3.19) | 0.16 | ||||||
| COPD treated with CPAP | 1.29 (0.90–1.85) | |||||||
| Epworth Sleepiness Scale | ||||||||
| <10 | Reference | 0.011 | 1.02 (0.97–1.07) | 0.41 | ||||
| 10–14 | 1.66 (1.12–2.49) | <0.001 | ||||||
| ≥15 | 2.87 (1.82–4.51) | |||||||
At least one hospitalization because of COPD exacerbation occurred in 39.5%, 61.4%, and 46.9% in the study groups (COPD only, overlap untreated, and overlap treated with CPAP, respectively). Figure 1B shows the Kaplan-Meier curves of the time to a first severe exacerbation requiring hospitalization. The probability of event-free survival was lower for patients with untreated overlap than for patients with overlap treated with CPAP or only COPD (P < 0.001 by the log-rank test). No difference among the curves was apparent between the last two groups. Among patients with COPD not treated with CPAP, those patients with coexisting OSA (overlap) had a higher risk of first-time hospitalization because of COPD exacerbation (RR, 2.13; 95% CI, 1.61–2.80) versus the COPD-only group. Age, Charlson index, severity of COPD, previous COPD exacerbation, and Epworth scale also had a significant association with the risk of first-time severe exacerbation of COPD. After the model was fully adjusted, OSA retained a significant association (RR, 1.70; 95 CI, 1.21–2.38) with time to first exacerbation (Table 4). Other variables that also remained in the model were age, severity of COPD, and having a COPD exacerbation in the year before recruitment. Further adjustment with sex, current use of medications, baseline O2 saturation, and mean O2 saturation during sleep did not change the results.
Variable | Crude Relative Risk (95% confidence interval) | P Value | Adjusted Relative Risk (95% confidence interval) | P Value | ||||
|---|---|---|---|---|---|---|---|---|
| Age, yr | 1.05 (1.03–1.06) | <0.001 | 1.04 (1.02–1.06) | <0.001 | ||||
| Body mass index, Kg/m2 | 0.97 (0.94–1.00 | 0.10 | ||||||
| Current smoker | 1.17 (0.89–1.53) | 0.26 | ||||||
| Alcohol use | ||||||||
| No | Reference | 0.09 | ||||||
| Yes | 1.27 (0.96–1.67) | |||||||
| Charlson index | 1.23 (1.10–1.37) | <0.001 | 1.06 (0.93–1.19) | 0.37 | ||||
| Severity of COPD | ||||||||
| Stage I (FEV1 80% predicted) | Reference | 0.24 | 1.87 (1.30–2.70) | <0.001 | ||||
| Stage II (FEV1, 50–79% predicted) | 1.42 (0.84–2.34) | <0.001 | ||||||
| Stage III (FEV1, 30–49% predicted) | 3.37 (2.04–5.56) | <0.001 | ||||||
| Stage IV (FEV1, <30 predicted) | 6.67 (3.77–10.2) | |||||||
| COPD exacerbation | 3.33 (2.35–4.71) | <0.001 | 1.91 (1.33–2.70) | 0.001 | ||||
| COPD group | ||||||||
| COPD only | Reference | <0.001 | 1.70 (1.21–2.38) | 0.002 | ||||
| COPD with untreated OSA | 2.13 (1.61–2.80) | |||||||
| Epworth Sleepiness Scale | ||||||||
| <10 | Reference | 0.02 | 1.02 (0.99–1.04) | 0.41 | ||||
| 10–15 | 1.52 (1.09–2.01) | <0.001 | ||||||
| ≥15 | 2.22 (1.52–3.20) | |||||||
There were three novel findings in this study. First, the coexistence of COPD and OSA is associated with increased mortality compared with COPD alone. Second, effective treatment of OSA reduced mortality in patients with the overlap syndrome. Third, at baseline, patients with the overlap syndrome reported a higher incidence of COPD exacerbations even though the three groups of patients had similar markers of COPD severity and received similar respiratory medications and medical care. However, during the study period, patients with the overlap syndrome treated with CPAP had similar event-free survival time to first COPD hospitalization than patients with COPD alone.
Several potential mechanisms to account for the observed higher mortality in overlap patients are recently reviewed (17). It has been shown that in patients with OSA with similar AHI, the presence of COPD is associated with more important nocturnal hypoxemia (5, 18). In addition, daytime hypoxemia is rare in OSA patients but is quite common in patients with the overlap syndrome. Chaouat and coworkers (5) reported a Pao2 less than or equal to 65 mm Hg in 54 (23%) of 235 patients with COPD without OSA compared with 17 (57%) out of 30 of patients with the overlap syndrome. In the same report, right-heart catheterization identified pulmonary hypertension in 7% of patients with COPD and 36% in those with the overlap syndrome. These findings are supported by other studies. In patients with COPD alone, pulmonary hypertension is primarily observed in patients with severe disease, when the FEV1 is lower than 50% predicted and diurnal Pao2 is less than 60 mm Hg (19). In contrast, several authors studying overlap patients with mild to moderate COPD found marked daytime hypoxemia and more frequent pulmonary hypertension in those patients (8, 20). In agreement with this, in our cohort, pulmonary function was similar at baseline between COPD alone and overlap but resting O2 saturation and mean level of O2 saturation during sleep were lower in the patients with overlap syndrome. It has been shown that both COPD and OSA are associated with vascular endothelial dysfunction (21, 22), elevated inflammatory mediators (23, 24), and accelerated atherosclerosis (25, 26), all of them factors associated with reduced survival. In addition, OSA is considered to lead to insulin resistance, hypertension, and cardiovascular diseases through increased sympathetic activity, inflammation, and oxidative stress (27, 28). Indeed, in our cohort there were significantly more patients treated with antihypertensives at baseline in patients with the overlap syndrome than in those suffering only from COPD (Table E2). In clinical cohorts and epidemiologic studies, OSA has been associated with an increased risk of death mainly because of cardiovascular causes (10, 29, 30), and the observed causes of death in our study confirms this association. Indeed, in our cohort there were similar number of cancer deaths and death from “other” causes in all three groups of patients, but there was a significantly higher number of cardiovascular deaths in patients with untreated overlap syndrome compared with treated overlap patients, and also higher than those with COPD only (Table 2).
The second important finding of our study was that effective treatment of OSA reduced mortality in patients with the overlap syndrome. At baseline, CPAP-treated and untreated overlap patients were comparable in terms of anthropometric variables, medical conditions, pulmonary impairment, and severity of OSA, but these two groups compared with the group of COPD alone had higher BMI, comorbid conditions, more COPD exacerbations in the previous year, lower basal O2 saturation, and a higher AHI. Thus, if OSA is a nonreversible risk factor for mortality in patients with COPD, those in the CPAP-treated overlap group should have had higher mortality, rather than the lower mortality that we observed. Our findings indicate that in patients with COPD and OSA, effective treatment of OSA with CPAP improves survival. The beneficial effect of the treatment seems related to a significant reduction in cardiovascular mortality in overlap patients treated with CPAP compared with the untreated overlap group (7.5% versus 14.5% mortality, respectively).
Third, this is the first study to report a beneficial effect of CPAP in reducing COPD exacerbations in patients with COPD and associated OSA. At baseline, patients with the overlap syndrome reported a higher incidence of COPD exacerbations even though the three groups of patients had similar markers of COPD severity and received similar respiratory medications and medical care. Nevertheless, during follow-up there was also a delay in the time to a first severe COPD exacerbation in CPAP-treated compared with untreated overlap patients. In a previous controlled trial of NIV in patients with COPD, 90 patients were randomized to receive NIV plus long-term oxygen therapy compared with oxygen therapy alone. After 2 years of follow-up, patients treated with NIV had fewer hospital days per patient per year (31). However, it was not possible to know if any patients had the overlap syndrome because no sleep studies were recorded. The mechanism by which CPAP may decrease COPD exacerbations has not been determined. It is possible that NIV relieves the increased mechanical load imposed by hyperinflation on poorly functioning respiratory muscles. In addition, NIV normalizes nocturnal hypoxemia, enhances the quality of sleep, and may even restore the hyporesponsiveness to CO2 that has been shown to occur in these patients (32).
This study had several limitations. First, CPAP was not allocated randomly, but rather was indicated according to the national guidelines for the treatment of OSA syndrome. The ideal experimental design of our study (a randomized placebo-controlled trial) was not feasible because of ethical constrains and our design was, therefore, the second best alternative. As in any nonrandomized trial, refusing a proposed therapy (CPAP in this case) could be a marker of nonadherent behavior to other drugs capable of preventing cardiovascular events. We do not think this is the case because we observed no differences between groups according to the therapy offered to treat the sleep-breathing disorder. Indeed, all of the characteristics and medication use were similar between those who accepted or refused CPAP. Moreover, medication adherence and persistence is known not to be related with CPAP adherence (33). Also, patients with heart failure and previous cerebrovascular or myocardial infarction events were excluded from our cohort, so the influence of previously present cardiovascular disease on outcomes in patients with overlap syndrome remains unlikely. Finally, because we do not have a nonsnoring COPD control group, we cannot generalize our results to patients with COPD who do not snore.
In patients with COPD, the coexistence of OSA is associated with an increased risk of death from any cause, cardiovascular deaths, and hospitalization because of COPD exacerbation. However, effective treatment with CPAP was associated with improved survival and decreased hospitalizations. Patients with COPD should be screened for OSA because, if present, its treatment is associated with improved outcomes.
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