Introduction

Heart failure (HF) is defined as a structural or functional cardiac disorder that causes the heart not to provide enough oxygen to meet the metabolic needs of the tissues despite the normal filling pressures. Approximately 1-2% of the adult population in developed countries has HF. The prevalence of HF is reported to be 10% or more in individuals aged 70 years and older (1).

Sleep disorder is one of the most important problems of HF patients. Hypoxia, hypercapnia and over-excitation of the sympathetic system are present in HF patients with obstructive and central sleep apnea (CSA). As a result, negative intrathoracic pressure and left ventricular afterload increase. Determination of the degree of sleep disturbance by polysomnography (PSG) and administration of oxygen therapy, continuous positive airway pressure (CPAP), bi-level (BI) PAP for the treatment of obstructive sleep apnea (OSA) and adaptive servo-ventilation methods (ASV) for the treatment of nocturnal hypoxemia during the night are recommended in patients with HF (1).

The degree of SRD is determined by PSG and OSA and/or CSA classification is done. The hourly apnea-hypopnea index (AHI) between 5-15 is classified as mild OSA, between 15-30 as moderate OSA, and >30 as severe OSA. In the literature, it has been shown that patients with OSA with an AHI value of >20 have increased risk of morbidity and mortality if not treated (2). The diagnostic criteria of primary CSA syndrome are as follows: a) At least one of the following from frequent arousals and awakenings during sleep, excessive daytime sleepiness and awakening short of breath; b) PSG shows ≥5 central apneas per hour of sleep, representing >50% of total respiratory events in the AHI; and c) the disorder is not better explained by another current sleep disorder, a medical or neurologic disorder, medication use, or a substance use disorder. The diagnostic criteria of Cheyne-Stokes respiration (CSR) include ≥5 central apneas-hypopneas during sleep and monitoring crescendo-decrescendo cycle over a period of at least 10 minutes (3).

The gold standard treatment of OSA is PAP. The aim of the treatment of SRD is to ensure that the upper airway remains open during sleep and to regulate quality of breathing and sleep. However, the patient benefits from this treatment during the time she/he uses the device. For this reason, it is recommended that the patient should use the device over 70% and more than 4 hours during the night (2,3).

As reviewed in the literature, the treatment of sleep disturbance in chronic (C) HF patients is important for the prognosis of the disease. Therefore, the aim of this systematic review was to evaluate the efficacy of interventions for the treatment of SRD in CHF patients.

Methods

This systematic review was planned and carried out as a descriptive study to evaluate the efficacy of interventions used for the treatment of SRD in CHF patients. The following steps were used in systematic review. The framework of the study was based on (population, intervention, comparator, outcome and study design) (4). These steps are described in detail in Table 1.

Inclusion criteria were RCTs published between 2007-2017, including patients with CHF and RSD (OSA, CSA) (left ventricular ejection fraction (LVEF) ≤45%, AHI >10/hour) followed for at least 3 months (Table 1).

All of the RCTs included in the study were evaluated by two researchers using an appropriate quality assessment checklist (5). The results of the evaluation were discussed and the publications prepared according to the RCT criteria were included in the study.

In data extraxtion analysis, one of the researchers first examined the researches included and collected data on the findings and characteristics of the research. The second researcher then checked the accuracy of this data. Data extraction steps were carried out by the authors. The data extraction steps and the findings are explained in detail in Table 2.

In this study, the answer to the question “Which interventions are effective in the treatment of SRD in patients with CHF?” was investigated.

No funding was received during the research. Researchers used their own means throughout the study. The researchers took part in each phase of the study according to the timetable. The timetable of the study was carried out as follows:

1. Preparation of the research protocol: 07/06/2017

2. Scanning period: June-September 2017

3. Analysis: October 2017-March 2018

4. Article writing: April-August 2018

In the study, keywords were selected in accordance with the research topic (Figure 1) and electronic scanning was performed. In the selection of keywords, attention was paid to the scanning of the full text of RCTs, in which the effectiveness of interventions used in the treatment of CHF patients diagnosed with SRD.

Cochrane Library, Scopus, Springer Link, Science Direct, Clinical Key, PubMed, EBSCO and Turkey Citation Index electronic databases were used for scanning. Medline, EMBASE, Ovid and CINAHL databases were not used because they could not be accessed. When all the studies recorded according to inclusion criteria were examined, 16 publications from total scanned 2.691.006 data were included in our study (Figure 1) (6).

In the studies, CPAP, BIPAP, ASV, overdrive pacemaker, home oxygen therapy (HOT), slow breathing exercise device (RESPERATE) and structured physical exercise interventions were applied as treatment interventions for the group with SRD (Table 2, 3). In addition, in the studies evaluated, it was found that symptom evaluation scales such as Epworth Sleepiness Scale (ESS), Pittsburg Sleep Quality Index (PSQI), Fatigue Severity Scale, and disease-specific quality of life scales such as Minnesota Living with HF Questionnaire (MLHFQ) and Chronic HF Questionnaire (Q), and SF-36 general quality of life scale, mental status and motor function assessment tools were used (Table 2).

Results

The randomized controlled trials included in the study were mostly conducted with male CHF patients who were 60 years of age and over and who had a diagnosis of OSA and CSA (AHI >10/hr., LVEF ≤45%) (Table 2).

In a study evaluating the effect of CPAP therapy on cardiac functions in CHF patients with OSA, it was reported that CPAP treatment improved LVEF compared to those treated with fake-CPAP (placebo) treatment. However, no significant difference was found in the cardiological variables and quality of life of patients in both the intervention and placebo groups. The authors stated that the improvement in LVEF would not necessarily improve cardiological symptoms (7). However, Khayat et al. (8) stated that, contrary to this study, BIPAP treatment was more effective on improvement in LVEF than CPAP. Bradley et al. (9) reported that CPAP treatment, in addition to medical treatment, improved the CSA and nocturnal oxygenation compared to medical treatment only, and that the CPAP group had more improvement in their functional capacity (six minutes walking distance-6MWD) (p=0.016) (Table 2).

In the study of O’Connor et al. (10), in which the effectiveness of ASV therapy was evaluated, it was found that ASV treatment added to the optimal medical therapy in patients with moderate-to-severe sleep apnea did not improve cardiovascular (CV) outcomes over 6 months, and that functional capacity in both control and intervention group did not differ. However, Arzt et al. (11) reported that ASV treatment added to medical therapy was an effective treatment for CSA and OSA, and that it improved cardiac function compared to medical therapy only in patients with sleep apnea. Similarly, in another study conducted in 2012, it was found that ASV significantly reduced central, periodical various respiratory disorders (12). In another study, it was found that ASV treatment at home caused a mild improvement in sleep fragmentation and improved sleep efficiency in CHF patients with CSA or OSA (13). However, Cowie et al. (14) stated that ASV treatment in addition to medical therapy did not improve outcomes, increased risk of CV death, and had no beneficial effect on quality of life and HF symptoms
(Table 2).

Kasai et al. (15) found a significant increase in functional capacity (6MWD) in the ASV-mode group compared to the CPAP-mode group. Priefert et al. (16) found that ASV therapy for patients with EF <40% lower ejection fraction (HFrEF) and SRD provided significant improvement in AHI at 12 weeks compared to the group treated with medical therapy only. In the same study, it was found that ASV treatment had an effect on nocturnal ventricular and supraventricular arrhythmias and the number of ventricular beats was less in the ASV treated group compared to the control group (Table 2).

Kawecha-Jaszcz et al. (17) found that the use of slow breathing device at home in patients with stable chronic systolic HF tended to reduce sleep disturbance and predominantly narrow central apnea, improve functional capacity and systolic left ventricular function. In one study, the authors stated that CPAP treatment titrated automatically at night in patients with OSA and CHF improved the daytime sleepiness, but did not improve other quality of life measures or severe CHF markers (Table 2) (18).

In another study, daytime sleepiness was found to be better in the CPAP group than the BIPAP group. In the same study, quality of life, functional capacity and blood pressure (BP) changes were found to be better in the BIPAP group than in CPAP (8). Similarly, Egea et al. (7) reported that CPAP therapy did not show a significant improvement in cardiological changes and quality of life except daytime sleepiness (Table 2).

Nakao et al. (19) reported that nocturnal oxygen therapy for 12 weeks at home improved SRD and had a positive effect on functional capacity in chronic HF patients with CSA (Table 2).

Suna et al. (20) found that exercise training administered to the intervention group significantly improved poor sleep quality in patients with HF followed by a disease management program for 12 weeks
(Table 2).

As a result of the studies, only one RCT evaluated the effect of atrial overdrive pacemaker treatment on SRD in systolic HF patients with OSA and the intervention was found to reduce AHI safely (Table 2) (21).

Effect of Adaptive Servo-ventilation Methods and Continuous Positive Airway Pressure on Mortality

Two studies published in 2015 showed that there was no significant difference between the ASV treatment group and the medical treatment group in terms of quality of life or changes in HF symptoms (14), and that ASV treatment increased the risk of death due to all reasons and CV death (p<0.05) (14). In contrast to these studies, the ADVENT-HF study showed that treatment with ASV in HFrEF patients improved health-related quality of life and reduced morbidity and mortality (22) (Table 2, 3).

Discussion

One newly defined factor that is considered to contribute to morbidity and mortality in CHF is SRD. Sleep respiratory disorder is usually defined as OSA and CSA (23).

As a result of the polysomnographic examination, the presence of more than 5 AHIs indicates the presence of OSA. For the diagnosis of OSA with AHI, excessive daytime sleepiness and cardiac disorders are expected. It has been shown that the risk of morbidity and mortality increases especially when AHI is more than 20 (2).

Non-invasive mechanical ventilator devices used in the treatment of PAP include CPAP, Auto CPAP (APAP), BIPAP, Auto BIPAP, BIPAP-ST (/Auto), volume cycle ventilator (AVAPS/IVAPS), and Servo-Ventilator (/Auto). The first treatment option for the treatment of SRD is CPAP. The aim of the treatment of SRD is to ensure that the upper airway remains open during sleep and to regulate ventilation and sleep quality (2). This method has been shown to significantly improve symptoms such as snoring, morning headaches and daytime sleepiness in many studies. It is stated that BIPAP treatment should be considered for the treatment of CSA in CHF patients to normalize AHI when it does not respond to adequate CPAP, ASV and oxygen treatments. However, it is also emphasized that ASV treatment is indicated for the treatment of CSA (23).

As a result of the evaluations made in this study, treatment interventions for CHF patients with OSA and CSA included mostly CPAP (7-9,12,18) and ASV (10-16,22), as well as BIPAP (8), overdrive pacing (21), oxygen therapy with nasal cannula (6,19), slow breathing training (17) and exercise training (20).

In these studies, the CPAP treatment for the treatment of CHF patients with OSA was found to improve LVEF (7) and daytime sleepiness (7,8,18), and ASV treatment was also found to improve AHI (10,11,16), reduce obstructive events, improve respiratory distress (12) and quality of life (22), increase oxygen saturation (11,16) and sleep time, reduce ventricular premature stroke and mean heart rate (16) (Table 2,3).

The American College of Cardiology/American Heart Association 2013 guide states that CPAP may be useful for improving functional status and increasing LVEF in HF patients with sleep apnea (Evidence B) (24). Similarly, HF Society of America (2010) guideline also recommends the use of CPAP therapy in HF patients with a diagnosis of PSG-documented OSA to improve daily functional capacity and quality of life (25). The treatment of OSA with CPAP showed decrease in sympathetic flow and BP during sleep. The results of studies describing the effect of long-term CPAP treatment on BP in patients with OSA are not very impressive. Most studies have reported a reduction in systolic or diastolic pressure between 2-10 mmHg after several weeks of CPAP treatment. These studies have shown that the effect of CPAP treatment on BP in patients with OSA is modest and variable (26).

In patients with HF, CSA appears as CSR, a periodic respiration resulting in a long apnea or hypopnea. CSA, which is quite common in HF, is seen in 30-50% of patients. CPAP treatment aimed at normalizing AHI is shown as the first treatment to be considered for CHF patients (23). CPAP treatment intervention for the treatment of HF patients with CSA has been found to improve nocturnal oxygenation, LVEF, sympathetic nerve activity and functional capacity (9), however, in the same patient group, ASV treatment has been found to decrease plasma proBNP (12,15), the amount of norepinephrine in 24-hour urine (UNE), left ventricular end systolic diameter (15), in central AHI and to increase functional capacity (16). Improvement in LVEF is associated with improvement in plasma BNP levels (Table 2,3) (27). For this reason, BNP levels were also examined in the studies in which ASV and CPAP treatments were used. In contrast, Hastings et al. (27) found no change in BNP levels in ASV-treated patients compared to the control group.

Adaptive servo-ventilators work primarily with the BIPAP principle. ASV is indicated in the presence of CSR on PSG in patients with predominant congestive HF (EF <40%) (2). However, it has been reported that ASV treatment is indicated for normalizing AHI and for the treatment of CSA syndrome associated with CHF (23). In a non-randomized study, 11 patients were treated with ASV in addition to medical treatment for 6 months, and only medical treatment was applied to the comparison group. At the end of 6 months, AHI hourly event decreased significantly compared to the baseline (p=0.001) and there was also a significant improvement in sleep efficiency (p=0.01), LVEF (p=0.04), daytime sleepiness (p=0.001) and quality of life (p=0.005) in the ASV group (28).

BIPAP is not the first treatment option in patients with OSA, but it is stated that it can be the first choice in non-invasive methods in patients with hypoxemia-hypoventilation syndromes who can not tolerate CPAP treatment and who are not able to exhale against high pressure (2). As a result of the evaluations, only one study has applied BIPAP therapy in CHF patients with OSA and improvement was observed in LVEF, quality of life and functional capacity (8).

American Academy of Sleep Medicine (2011) states that administered oxygen therapy at night is indicated for the treatment of CSA in patients with CHF (29). In patients with HF, additional nocturnal oxygen therapy is administered through nasal cannula for the treatment of CSA. Data from some small-sample, short-term studies suggest that oxygen therapy with nasal cannula improves AHI, exercise capacity and LVEF, and decreases BNP level and sympathetic nervous system activity (23). In a small sample study with CHF patients with CSA (LVEF <45%, mean age 65 years, AHI >5/hour), oxygen therapy at night was shown to improve exercise capacity, cardiac function, and cardiac sympathetic nerve activity (30). In the light of the findings of our study, two studies in the literature (6,19) reported that oxygen therapy for the treatment of CHF patients with CSA improved SRD (6,19), LVEF (19) and had a positive effect on ventricular arrhythmias (19). One of the studies showed that oxygen therapy improved quality of life and functional capacity (17), but the other study (6) did not achieve the same effect (Table 2). When the literature is examined, it has been shown that night oxygen therapy through nasal cannula have no positive effect on daytime sleepiness, sleep quality, quality of life or cognitive functions. Unlike CPAP and ASV, nighttime oxygen therapy was found not effective in eliminating upper airway obstruction, which may be accompanied by central apneas. In the light of these findings, it is stated that oxygen therapy can be used only if pressure-assisted treatments are ineffective or patients cannot tolerate these treatments (23,31-33).

In the literature, it has been hypothesized that atrial overdrive pacemaker therapy can increase cardiac filling and decrease pulmonary obstruction by increasing the heart rate, thus reduce or prevent CSA formation. In some small sample studies, atrial overdrive pacemaker therapy has been shown to reduce the number of CSA attacks, improve oxygen saturation, and reduce stimulation in HF patients (23,34,35). In another study, it was reported that atrial overdrive pacemaker treatment in CSA did not provide any improvement (36). In this study, it was determined that atrial overdrive pacemaker treatment in CHF patients with OSA provided significant reduction in AHI in a single RCT (Table 2) (21).

Conclusion

Sleep disorder is a common problem in HF patients. In the studies performed within the systematic review, the effectiveness of medical treatments and interventions for sleep disturbance in HF patients were evaluated. When the efficacy of the interventions was examined, it was observed that the addition of CPAP to medical therapy improved CSA and nocturnal oxygenation and increased 6MWD. The use of CPAP improved daytime sleepiness and LVEF with regular use in HF patients with OSA, but no effect on quality of life was observed. ASV treatment added to medical therapy also improved CSA and OSA with regular use. ASV alone was effective in reducing respiratory distress and sleep apnea, and it reduced AHI, improved LVEF, and reduced ventricular pulse. The use of ASV increased 6MWD compared to CPAP. When CPAP and BIPAP were evaluated, CPAP was effective in improving sleep quality and quality of life, while BIPAP was more effective in improving quality of life, functional capacity and BP. In addition to these interventions, the physical exercise program has been shown to be effective in improving sleep quality.

Ethics

Peer-review: External and internal peer-reviewed.

Author Contributions: Concept - H.U., H.B.O.; Design - H.U., H.B.O.; Supervision - H.U.; Resources - H.U., H.B.O.; Materials - H.U., H.B.O.; Data Collection and/or Processing - H.U., H.B.O.; Analysis and/or Interpretation - H.U., H.B.O.; Literature Search - H.U., H.B.O.; Writing Manuscript - H.U., H.B.O.; Critical Review - H.U.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.