Prognosis of Patients With Heart Failure and Obstructive Sleep Apnea Treated With Continuous Positive Airway Pressure*

Transcription

1 Original Research SLEEP MEDICINE Prognosis of With Heart Failure and Obstructive Sleep Apnea Treated With Continuous Positive Airway Pressure* Takatoshi Kasai, MD, PhD; Koji Narui, MD; Tomotaka Dohi, MD; Naotake Yanagisawa, MS; Sugao Ishiwata, MD; Minoru Ohno, MD; Tetsu Yamaguchi, MD; and Shin-ichi Momomura, MD Background: Therapy with continuous positive airway pressure (CPAP) provides several benefits for patients with heart failure (HF) complicated by obstructive sleep apnea (OSA). However, the effect on the prognosis of such patients remains unknown. Aims: To determine whether CPAP therapy and compliance affects the prognosis of HF patients with OSA. Methods: We classified 88 patients with HF and moderate-to-severe OSA into a CPAP-treated group (n 65) and an untreated group (n 23), and then those treated with CPAP were further subclassified according to CPAP therapy compliance. The frequency of death and hospitalization was analyzed using multivariate analysis. Results: During a mean ( SD) period of months, 44.3% of the patients died or were hospitalized. Multivariate analysis showed that the risk for death and hospitalization was increased in the untreated group (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.07 to 3.68; p 0.030) and in less compliant CPAP-treated patients (HR, 4.02; 95% CI, 1.33 to 12.2; p 0.014). Conclusion: Therapy with CPAP significantly reduced the risk of death and hospitalization among patients with HF and OSA. However, reduced compliance with CPAP therapy was significantly associated with an increased risk of death and hospitalization. (CHEST 2008; 133: ) Key words: compliance; continuous positive airway pressure; heart failure; obstructive sleep apnea; prognosis Abbreviations: AF atrial fibrillation; AHI apnea-hypopnea index; BMI body mass index; CI confidence interval; CPAP continuous positive airway pressure; ESS Epworth sleepiness scale; HF heart failure; HR hazard ratio; LVEF left ventricular ejection fraction; NYHA New York Heart Association; OSA obstructive sleep apnea; PNE plasma norepinephrine; REM rapid eye movement; So 2 oxyhemoglobin saturation; TST total sleep time The Sleep Heart Health Study 1 has identified an association between obstructive sleep apnea (OSA) and heart failure (HF). Other populationbased studies 2 4 have shown that 11 to 37% of HF patients have OSA. Among patients with HF and OSA, therapy with continuous positive airway pressure (CPAP) is regarded as effective therapy not only for OSA, but also for the underlying HF from the result of the short-term studies, as it reduces sympathetic overactivity, cardiac overload, the number of episodes of ventricular ectopy, and increases left ventricular ejection fraction (LVEF). 5 8 However, little is known about the prognosis of patients with HF and OSA. 9,10 One study 9 found no differences in mortality between patients with and without OSA. However, that study did not consider the influence of CPAP treatment on patients with OSA. Another study 10 has shown that OSA increases mortality rates. That study compared the mortality of CPAP-treated and untreated patients with OSA, and a trend toward reduced mortality in the treated OSA patients was identified, but it did not reach statistical significance. 690 Original Research

2 From this viewpoint, the prognosis of patients with HF and OSA treated with CPAP is of interest. Moreover, whether or not compliance with CPAP therapy affects the prognosis of patients with HF is important, since compliance with CPAP therapy is associated with prognosis among non-hf patients. 11 To know whether CPAP therapy compliance affects the prognosis, even in patients with HF, would be clinically very relevant. Thus, we investigated the prognosis of an observational cohort of patients with HF and OSA who were treated with CPAP and then determined whether compliance with CPAP therapy, as well as several pretreatment variables, affected the prognosis. Subjects Materials and Methods who were being followed up at the cardiovascular center in Toranomon Hospital (Tokyo, Japan) between January 1, 2001, and March 1, 2005, were enrolled into the study if they met the following inclusion criteria: (1) the presence of symptomatic HF, which was defined as an LVEF of 50% by echocardiography within 1 month before the diagnostic sleep study and New York Heart Association (NYHA) class II or above; (2) stable clinical status, which was defined as no hospital admissions 1 month before study enrollment and receiving optimal medical therapy for at least 1 month before study enrollment; and (3) having undergone a sleep study and received a diagnosis of moderate-to-severe sleep apnea, which was defined as 15 apnea or hypopnea events per hour of sleep (ie, apnea-hypopnea index [AHI]). The exclusion criteria were as follows: (1) age 20 or 80 years; (2) the presence of known untreated neoplasms; (3) a history of stroke with neurologic deficit; and (4) severe chronic pulmonary disease. Informed consent was obtained from all patients to participate in this study, which complied with the Declaration of Helsinki and proceeded according to the ethics policies of the involved institutions. Sleep Study and CPAP Sleep apnea was diagnosed in all patients based on the results of overnight polysomnography using a digital polygraph (SomnoStar Sleep System; SensorMedics Corp; Yorba Linda, CA) at *From the Sleep Center (Drs. Kasai and Narui) and the Cardiovascular Center (Drs. Dohi, Ishiwata, Ohno, and Yamaguchi), Toranomon Hospital, Tokyo, Japan; the Department of Cardiology (Dr. Yanagisawa), School of Medicine, Juntendo University, Tokyo, Japan; and the Cardiovascular Division (Dr. Momomura), Saitama Medical Center, Jichi Medical University, Saitama, Japan. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received July 31, 2007; revision accepted November 17, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Takatoshi Kasai, MD, PhD, Sleep Center, Toranomon Hospital., Toranomon, Minato-ku, Tokyo , Japan; kasai-t@mx6.nisiq.net DOI: /chest our sleep laboratory. We used the described definitions and scoring methods We defined patients with predominantly central sleep apnea as having an AHI of 15 events per hour of sleep, of which 50% were central events. These patients were excluded from further analysis. Residual patients in whom moderate-to-severe OSA was diagnosed were offered CPAP therapy. The CPAP was titrated manually during a second overnight sleep study to determine the appropriate pressure level for each patient. Thereafter, the patients started CPAP therapy at home. We classified eligible patients into CPAP-treated and untreated groups. The untreated group included patients who elected not to use CPAP therapy before or after titration, as well as those who dropped out of CPAP treatment within the first month. The patients treated with CPAP were subclassified into a more compliant subgroup (ie, average nightly usage during the study period of more than the median level) and less compliant subgroup (ie, average nightly usage of the median level or less) according to the average of nightly CPAP usage (downloaded monthly) over the entire follow-up period. Data Collection The following variables were recorded before starting CPAP therapy: body mass index (BMI); BP; heart rate; subjective sleepiness expressed according to the Epworth sleepiness scale (ESS); LVEF on echocardiograms; plasma norepinephrine (PNE) level; NYHA class; etiology of HF; the presence of atrial fibrillation (AF); and administered drugs. The etiology of HF was categorized as ischemic or nonischemic cardiomyopathy. fasted overnight and underwent diagnostic polysomnography, assuming that no nicotine or caffeine had been consumed on that morning. We then assessed PNE in venous blood samples obtained in the early morning after a 30-min rest period while the patient was in the supine position. The frequency of death and hospitalization was also assessed. The end point was a composite of death and hospitalization. Follow-up ended on March 31, 2006, and the prognosis was assessed by analyzing the medical records of patients who died and of those who continued to be followed up at our hospital. Information about the circumstances and the date of death was obtained from the families of patients who died at home. The reasons for hospitalization or the causes of death were determined from the institutions to which the patients had been admitted. Statistical Analysis All values are shown as the mean SD, and categoric variables are expressed as numbers and percentages. The baseline characteristics were compared using the Student t test or the Mann- Whitney U test for continuous variables; the 2 test or Fisher exact test was used for categoric variables. For the two subgroups of CPAP-treated patients, changes in polysomnographic variables were compared using the t test or the Wilcoxon signed-rank test. Event-free survival between the groups was compared using the Kaplan-Meier estimate with the log-rank test, and the hazard ratio (HR) was calculated using the Cox proportional hazards model. The assumption of proportional hazards was assessed using the log-minus-log survival graph. Univariate analysis was based on the proportional hazards model to determine the associations between prognosis and the following pretreatment variables between the groups: age; gender; BMI; LVEF; PNE; NYHA class; systolic/diastolic BP; heart rate; etiology of HF; AF; ESS; medications; total AHI; ratio of the time that oxyhemoglobin saturation (So 2 ) was 90%; lowest So 2 ; ratio of slow-wave sleep or rapid eye movement (REM) sleep to total sleep time (TST); and having been treated with CHEST / 133 / 3/ MARCH,

3 CPAP or not. regarded as significant (ie, p 0.10) were included in the multivariate analysis. The CPAP-treated groups were similarly analyzed except that CPAP therapy compliance status (more or less) was included instead of status as treated or not treated with CPAP, and CPAP level was included. Although the assumption was verified, a time-dependent Cox model including nightly CPAP usage per month instead of the CPAP therapy compliance status was also used, since compliance status changed during the study period. Multivariate analysis verified the interactions between each variable. A p value of 0.05 was considered to be statistically significant. All statistical analyses were performed using a statistical software package (SPSS, version 11.0 for Windows; SPSS Inc; Chicago, IL). Results We initially enrolled 149 patients in the study in whom moderate-to-severe sleep apnea had been diagnosed. Five patients who met the exclusion criteria and 56 patients (38%) with predominantly central sleep apnea were excluded. Thus, data from 88 patients were analyzed. The prognostic data were fully documented during the follow-up period (mean follow-up period months; follow-up range, 1.2 to 57.0 months). Comparison Between CPAP-Treated and Untreated Sixty-five patients were treated with CPAP, and 23 were untreated. Fourteen of the untreated patients personally elected not to use CPAP due to lack of sleepiness, and 9 patients dropped out of the program within the first month. Tables 1 3 show the baseline characteristics and polysomnographic findings. Table 1 Baseline Characteristics in 88 Treated or Untreated With CPAP* Treated (n 65) Untreated (n 23) p Value Age, yr Male gender 62 (95.4) 19 (82.6) BMI, kg/m Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, beats/min LVEF, % PNE, pg/ml NYHA class II 38 (58.5) 13 (56.5) III 27 (41.5) 10 (43.5) Ischemic 14 (21.5) 7 (30.4) cardiomyopathy AF 20 (30.8) 9 (39.1) ICD 2 (3.1) 0 (0.0) ESS score *Values are given as the mean SD or No. (%), unless otherwise indicated. ICD implantable cardioverter defibrillator. Table 2 Medication Use in 88 Treated or Untreated With CPAP* Overall, 21 events (32.3%), including 7 deaths, occurred among the CPAP-treated patients, and 18 events (78.3%), including 10 deaths, occurred in the untreated patients. The mean duration of follow-up was months in the treated patients, and months in the untreated patients (p 0.477). The event-free survival rate was significantly lower in the untreated patients than in the CPAP-treated patients (Fig 1). that were significantly associated with a poor prognosis according to the univariate analysis were as follows: BMI (HR, 0.95; 95% confidence interval [CI], 0.89 to 1.01; p 0.090); PNE (HR, 1.03; 95% CI, 1.01 to 1.05; p 0.007); NYHA class III (HR, 2.22; 95% CI, 1.17 to 4.20; p 0.015); ischemic cardiomyopathy (HR, 2.01; 95% CI, 1.03 to 3.93; p 0.040); AF (HR, 2.25; 95% CI, 1.20 to 4.23; p 0.012); and untreated OSA (HR, 2.63, 95% CI, 1.40 to 4.95; p 0.001). These were included in the multivariate analysis, and no interactions were identified between them. Thus, the risk for a poor prognosis was significantly higher among the untreated patients than among the treated patients (Table 4). Table 3 Baseline Polysomnographic Findings in 88 Treated or Untreated With CPAP* Treated (n 65) Treated (n 65) Untreated (n 23) p Value -blockers 38 (58.5) 14 (60.9) ACE inhibitors/arbs 54 (83.1) 21 (91.3) Diuretics 56 (86.2) 15 (65.2) Digoxin 21 (32.3) 5 (21.7) *Values are given as No. (%), unless otherwise indicated. ARB angiotensin II receptor blocker; ACE angiotensin-converting enzyme. Untreated (n 23) p Value TST, min Total AHI, events/h Obstructive AHI, events/h TST spent with So %, % Lowest So 2,% Arousal index, no./h Sleep stage, % TST Slow-wave sleep, % REM sleep, % *Values are given as the mean SD, unless otherwise indicated. 692 Original Research

4 Table 5 Baseline Characteristics of 65 CPAP-Treated * More (n 32) Less (n 33) p Value Figure 1. Cumulative event-free survival in CPAP-treated and untreated patients. The cumulative event-free survival was significantly lower in untreated patients than in CPAP-treated patients (p [log-rank test]). Analysis of CPAP-Treated The median value of nightly CPAP therapy usage among the 65 treated patients was 4.9 h (range, 1.7 to 7.3 h); 32 patients were classified as more compliant (average usage, 6.0 h), and 33 patients were classified as less compliant (average usage, 3.5 h). Tables 5 7 show the baseline characteristics of these groups, the polysomnographic findings obtained during the diagnostic study, and the CPAP titration. The parameters for CPAP titration were significantly improved in both subgroups. The prescribed mean pressure levels were and cm H 2 O(p 0.028), respectively, in the more and less compliant groups. Overall, 5 events (15.6%), including four deaths, occurred among the more compliant patients, and 16 events (48.5%), including six deaths, occurred among the less compliant patients. The mean follow-up periods were and (p 0.264), respectively, in the more and less compliant groups. The event-free survival rate was significantly lower in the less compliant patients than in the more compliant patients (Fig 2). that were significantly associated with a poor prognosis in the univariate Table 4 Results of Multivariate Analysis Among 88 Treated or Untreated With CPAP HR 95% CI p Value BMI (1 kg/m 2 increase) PNE (10 pg/ml increase) NYHA class III Ischemic cardiomyopathy-yes AF-yes Untreated-yes Age, yr Male gender 30 (93.8) 32 (97.0) BMI, kg/cm Systolic BP, mm Hg Diastolic BP, mm Hg Heart rate, beats/min LVEF, % PNE, pg/ml NYHA class II 19 (59.4) 19 (57.6) III 13 (39.4) 14 (42.4) Ischemic 7 (21.9) 7 (21.2) cardiomyopathy AF 7 (21.9) 13 (39.4) ICD 1 (3.1) 1 (3.0) ESS score *Values are given as the mean SD or No. (%), unless otherwise indicated. See Table 1 for abbreviation not used in the text. analysis were as follows: PNE (HR 1.03; 95% CI, 0.99 to 1.05; p 0.060); NYHA class III (HR, 4.43; 95% CI, 1.70 to 11.5; p 0.002); ischemic cardiomyopathy (HR, 2.33; 95% CI, 0.94 to 5.78; p 0.068); AF (HR, 3.34; 95% CI, 1.42 to 7.90; p 0.006); total AHI (HR, 1.03; 95% CI, 0.99 to 1.05; p 0.058); prescribed CPAP level (HR, 0.78; 95% CI, 0.61 to 1.01; p 0.058); and less compliant (HR, 3.69; 95% CI, 1.35 to 10.1; p 0.011). These values were then included in the multivariate analysis; no interactions were found among them. The risk of a poor prognosis was significantly increased among the less compliant patients according to the proportional hazard analysis (Table 8). Furthermore, the results of another analysis using the time-dependent model showed that shorter nightly usage per month was also a significant indicator of a poor prognosis (HR, 0.51; 95% CI, 0.34 to 0.78; p 0.002) [Table 8]. Table 6 Medication Use by 65 CPAP-Treated * More (n 32) Less (n 33) p Value -blockers 20 (62.5) 18 (54.5) ACE-inhibitors/ARBs 24 (75.0) 30 (90.9) Diuretics 26 (81.3) 30 (90.9) Digoxin 7 (21.9) 14 (42.4) *Values are given as the No. (%), unless otherwise indicated. See Table 2 for abbreviation not used in the text. CHEST / 133 / 3/ MARCH,

5 Table 7 Baseline and Changes in Polysomnographic Findings Among 65 CPAP-Treated * More (n 32) Less (n 33) p Value TST, min Diagnosis Receiving CPAP therapy Total AHI, events/h Diagnosis Receiving CPAP therapy Obstructive AHI, events/h Diagnosis Receiving CPAP therapy TST spent with So 2 90%, % Diagnosis Receiving CPAP therapy Lowest So 2,% Diagnosis Receiving CPAP therapy Arousal index, arousals/h Diagnosis Receiving CPAP therapy Sleep stage, % of TST Slow-wave sleep Diagnosis Receiving CPAP therapy REM sleep, % Diagnosis Receiving CPAP therapy *Values are given as the mean SD, unless otherwise indicated. p vs diagnosis. p 0.05 vs diagnosis. Discussion Based on observational data of HF patients with OSA, the present study showed that CPAP therapy improved prognosis, but the prognosis was poorer among less compliant patients who were treated with CPAP. The efficacy of CPAP treatment for patients with OSA and HF and their underlying cardiac dysfunction has been described. 5 8 Recent observational data 10 have shown a trend toward reduced mortality in CPAP-treated patients with OSA, but the difference did not reach statistical significance. However, the present study showed that CPAP therapy indeed improved the prognosis of patients with OSA. We also uncovered a significant association between CPAP therapy compliance and prognosis among OSA patients with HF. To our knowledge, this is the first report to show that CPAP therapy compliance affects prognosis even in patients with HF; hence, our findings are clinically important. A recent report 10 that did not show a statistically significant difference in prognosis between patients treated with CPAP and untreated patients includes Figure 2. Cumulative event-free survival determined by compliance status. Cumulative event-free survival was significantly lower in patients with poor compliance than in those with good compliance (p [log-rank test]). several limitations. One important limitation is that the number of hours of CPAP use was not monitored. If their treated group included many patients with poor CPAP therapy compliance, the prognoses of the treated and untreated patients would be quite similar and thus would explain their findings. We monitored the number of hours of CPAP use monthly and confirmed that patients with relatively better CPAP compliance predominated in one of two treated subgroups. This uncovered a statistically significant difference in prognoses between compliant and noncompliant patients, indicating that CPAP treatment could reduce the frequency of death and hospitalization for HF patients with OSA. We suggest that the prognostic benefit of CPAP therapy was caused by reducing the number of apnea-hypopnea episodes in association with the short-term efficacy of CPAP therapy for underlying HF. 5 8 A reduction in the number of myocardial ischemic episodes induced by decreased oxygen supply and/or increased oxygen demand and sympathetic overactivity might decrease cardiomyocyte damage as well as the likelihood of fatal arrhythmias that would lead to death or hospitalization Indeed, we found here that PNE and ischemic cardiomyopathy were significantly associated with a poor prognosis in addition to the absence of, or poor compliance with CPAP therapy, although using PNE as a test of sympathetic nervous activity has several limitations. 20 Campos-Rodriguez et al 11 have demonstrated that poor CPAP therapy compliance is a significant indicator of poor prognosis in patients with OSA who do not have HF. Our findings from patients with HF are compatible with their results. Several investigators 21,22 have examined the prevalence of poor CPAP therapy compliance. A European prospective study Original Research

6 Table 8 Result of Multivariate Analysis Among 65 CPAP-Treated Proportional Hazard Model Time-Dependent Model HR 95% CI p Value HR 95% CI p Value PNE (10 pg/ml increase) NYHA class III Ischemic cardiomyopathy-yes AF-yes Total AHI (1 event/h increase) Pressure level (1 cm H 2 O increase) Less compliant-yes Nightly usage (1-h increase) found that approximately 20% of patients have poor CPAP compliance, whereas Kribbs et al 22 and Campos- Rodriguez et al 11 found that 50% of OSA patients without HF had fair-to-poor CPAP therapy compliance. In general, few patients maintain good longterm compliance. In the present study, the median value of average nightly usage during the entire period was used as the cutoff point for CPAP therapy compliance, and this value is comparable with those of other studies that have evaluated patients without HF. Additionally, the results of the time-dependent model that account for fluctuations in CPAP usage during the follow-up period showed that CPAP usage continued to be related to poor prognosis. Therefore, an association between compliance status and a poor prognosis among patients with OSA and HF is plausible and robust. The present study has several limitations. One is the relatively small number of patients and thus, of events, which resulted in a limited statistical power for detecting differences in prognoses. Another is that we assessed only patients who underwent a sleep study, and the CPAP-treated or untreated groups were not randomly allocated. Therefore, the motivation to undergo the sleep study and to accept CPAP treatment might have biased the results. However, even though CPAP-treated patients had a higher AHI and more hypoxic events, indicating more severe OSA, the prognosis was significantly better in this group compared with the untreated patients. This emphasized the benefits of CPAP therapy if the presence of OSA is associated with a poor prognosis. The untreated group might have been more ill, because this group had a higher PNE level. This might have biased the poor prognosis of the untreated group, although PNE levels did not significantly differ between the treated and untreated groups. However, multivariate analysis showed that the risk associated with untreated status was independent of an increased PNE level. Moreover, since the present study was observational in nature, other unknown confounders might have affected the prognosis even after the multivariate analysis. Therefore, our findings should be interpreted with caution. Nevertheless, the present results highlighted the importance of initiating and maintaining CPAP therapy in patients with HF and OSA. In conclusion, the present study found that CPAP treatment for patients with OSA and HF reduced hospitalization as well as mortality rates, and that the risk of morbidity and mortality was increased with decreasing compliance. References 1 Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001; 163: Sin DD, Fitzgerald F, Parker JD, et al. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999; 160: Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure: types and their prevalences, consequences, and presentations. Circulation 1998; 97: Lanfranchi PA, Somers VK, Braghiroli A, et al. Central sleep apnea in left ventricular dysfunction: prevalence and implications for arrhythmic risk. Circulation 2003; 107: Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003; 348: Mansfield DR, Gollogly NC, Kaye DM, et al. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004; 169: Ryan CM, Usui K, Floras JS, et al. Effect of continuous positive airway pressure on ventricular ectopy in heart failure patients with obstructive sleep apnea. Thorax 2005; 60: Usui K, Bradley TD, Spaak J, et al. Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure. J Am Coll Cardiol 2005; 45: Roebuck T, Solin P, Kaye DM, et al. Increased long-term mortality in heart failure due to sleep apnoea is not yet proven. Eur Respir J 2004; 23: CHEST / 133 / 3/ MARCH,

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