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Published ahead of print on March 9, 2006, doi:10.1164/rccm.200511-1745PP
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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 1300-1308, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200511-1745PP

Pulmonary Perspective

Treatment of Sleep Apnea in Heart Failure

Michael Arzt and T. Douglas Bradley

Sleep Research Laboratories of the Toronto Rehabilitation Institute; Toronto General Hospital–University Health Network; and the Centre for Sleep Medicine and Circadian Biology, University of Toronto, Toronto, Ontario, Canada

Correspondence and requests for reprints should be addressed to T. Douglas Bradley, M.D., Toronto General Hospital/University Health Network, 9N-943, 200 Elizabeth Street, Toronto, ON, M5G 2C4 Canada. E-mail: douglas.bradley{at}utoronto.ca

ABSTRACT

Obstructive and central sleep apnea are common in heart failure, and may participate in its progression by exposing the heart to intermittent hypoxia, increased preload and afterload, sympathetic activation, and vascular endothelial dysfunction. Treatment of sleep apnea in patients with heart failure may reverse these detrimental effects, in addition to alleviating symptoms of sleep apnea. In patients with heart failure and obstructive sleep apnea, short-term randomized trials have demonstrated that continuous positive airway pressure (CPAP) improves cardiac function, and lowers sympathetic activity and blood pressure. However, there are no data on whether treating obstructive sleep apnea in patients with heart failure improves morbidity and mortality. Various treatments have been tested in heart failure patients with central sleep apnea, particularly oxygen and CPAP. Both reduce the frequency of central respiratory events, and lower sympathetic activity. In addition, CPAP improves cardiac function. However, the largest randomized trial did not demonstrate any beneficial effect of CPAP on the rate of mortality and cardiac transplantation (32 vs. 32 events in the control and treatment groups, respectively; p = 0.54), but ultimately lacked power to conclude with certainty whether CPAP has an effect on morbidity and mortality in such patients. Thus, although there are data to indicate that treating both obstructive and central sleep apnea in patients with heart failure improves cardiovascular function, larger randomized trials involving interventions such as oxygen, CPAP, or other forms of positive airway pressure will be required to determine whether treating these sleep-related breathing disorders reduces clinically important outcomes such as morbidity and mortality.

Key Words: oxygen • positive airway pressure • randomized trial • sleep apnea

Obstructive and central sleep apnea (OSA and CSA, respectively) are common in heart failure (HF) (1–3) and may participate in its progression by exposing the heart to intermittent hypoxia, increased preload and afterload (4–7), sympathetic nervous system activation (8–10), and vascular endothelial dysfunction (11). Treatment of sleep apnea may attenuate these detrimental effects. Our objective in writing this article is to provide a critical review of clinical trials in which the effects of various forms of therapy for OSA and CSA have been examined in patients with HF, and to provide our perspective on a rational approach to the assessment and therapy of these sleep-related breathing disorders.

PREVALENCE OF SLEEP APNEA IN PATIENTS WITH HF

Sleep apnea and HF are common diseases affecting approximately 10 (12) and 2% (13) of the population, respectively. Although there are no reports of the prevalence of sleep apnea in representative samples of patients with HF on contemporary medication, the literature to date suggests that sleep apnea is more common in patients with HF than in subjects with normal cardiac function (1–3, 12, 14). Whether the addition of these newer anti-HF agents has influenced the prevalence of sleep apnea in patients with HF remains to be determined. Studies enrolling either consecutive patients with HF (1, 3) or patients with HF referred to a sleep clinic (2) reported that 11 to 38% of participants had predominantly OSA and 33 to 42% had predominantly CSA. In one study of patients with HF, the main risk factors for OSA were male sex, obesity (for men), and age of 60 yr or older (for women), whereas the presence of CSA was associated with male sex, age of 60 yr or older, atrial fibrillation, and an awake PaCO2 of 38 mm Hg or less (2). In addition, data from the Sleep Heart Health Study revealed that the presence of OSA increased odds of having HF by 2.2-fold compared with those without OSA (14).

OSA IN HF

Pathophysiology
Increased inspiratory efforts against the occluded pharynx during obstructive apneas and hypopneas generate exaggerated negative intrathoracic pressure (5) that increases left ventricular (LV) transmural pressure, and hence, afterload. Negative pressure also increases venous return causing distension of the right ventricle and leftward displacement of the interventricular septum during diastole. This impairs LV filling and reduces stroke volume (7). Intermittent hypoxia during OSA may impair cardiac contractility directly or reduce cardiac output indirectly by increasing pulmonary artery pressure. In patients with ischemic heart disease, it may also precipitate myocardial ischemia. Intermittent apnea, hypoxia, CO2 retention, and arousal from sleep trigger increases in sympathetic neural outflow that are accompanied by surges in systemic blood pressure acutely (6, 8), and by cardiac myocyte necrosis, beta-adrenoceptor desensitization, and cardiac arrhythmias chronically (15). These nocturnal cardiovascular stresses have after-effects, including elevated sympathetic activity (8), reduced parasympathetic modulation of heart rate (16), and hypertension, which are sustained into the daytime (17).

OSA may also contribute to the development of vascular endothelial dysfunction and atherosclerosis. For example, patients with OSA have signs of increased oxidative stress (18), vascular endothelial dysfunction with impaired endothelially mediated vasodilatation (11), and early signs of atherosclerosis involving the carotid arteries, independently of known risk factors (19–21).

Impact on Clinical Outcomes
There is growing evidence that OSA contributes to the risk for fatal and nonfatal cardiovascular events (14, 22–26). For example, Marin and colleagues (25) recently reported data from a nonrandomized prospective observational study involving a sleep clinic population, and a community sample of healthy subjects without OSA followed up for a mean of 10 yr. They found that, compared with the healthy subjects, those with untreated severe OSA (i.e., apnea–hypopnea index [AHI] of >= 30/h of sleep) had a 2.9-fold higher rate of fatal cardiovascular events, and a 3.2-fold higher rate of nonfatal cardiovascular events, including ischemic heart disease and stroke, after controlling for confounding variables (25). In contrast, the risk of cardiovascular events among patients whose severe OSA was treated with continuous positive airway pressure (CPAP) did not differ from healthy subjects. Although these findings support the notion that OSA increases, and its treatment decreases, the risk of cardiovascular events, they are not definitive because of the nonrandomized nature of the study. For example, subjects who adhere to either active treatment or to placebo in randomized trials have better cardiovascular outcomes than those who do not (27). No studies have evaluated long-term impact of untreated OSA on cardiovascular outcomes in patients with HF.

Treatment of OSA in HF
The only treatment for OSA subjected to clinical trials in patients with HF is nasal CPAP. In such patients, CPAP abolishes acute OSA and related hypoxia, reduces nocturnal heart rate, blood pressure, and LV afterload, and improves the neural control of blood pressure and heart rate by increasing baroreflex sensitivity (6, 28). Chronic application of CPAP to such patients also causes long-term improvements in cardiovascular function.

Malone and colleagues (5) reported, in a before and after trial of CPAP in patients with HF and OSA, that 1 mo of CPAP increased mean LV ejection fraction (LVEF) from 37 to 49% and improved New York Heart Association functional class. Subsequently, Kaneko and colleagues (29) randomized 24 patients with HF and OSA to either a control group, who received optimal medical therapy for HF, or a treatment group, who in addition received CPAP at night. Over 1 mo, those randomized to CPAP used a mean pressure of 8.9 cm H2O for 6.2 h/night. CPAP alleviated OSA in association with a 9% increase in LVEF (from 25 ± 3 to 34 ± 2%, p < 0.001) and reductions in daytime systolic blood pressure (from 126 ± 6 to 116 ± 5 mm Hg, p = 0.02) that were more pronounced than in the control group. Interestingly, despite the presence of moderate to severe OSA, the average Epworth Sleepiness Scale scores of 6 to 7 did not indicate daytime sleepiness (29). In a subsequent study, Usui and coworkers (30) demonstrated that CPAP reduced daytime blood pressure in association with a reduction in muscle sympathetic vasoconstrictor nerve traffic. These data indicate that one mechanism whereby CPAP reduces blood pressure in such patients is by reducing sympathetically mediated vasoconstriction. Ryan and coworkers (31) also demonstrated that treatment of OSA in patients with HF by CPAP significantly reduced the frequency of premature nocturnal ventricular beats.

In the largest randomized trial to date, Mansfield and coworkers (32) tested the effects of CPAP in 40 patients with HF and OSA over 3 mo. Subjects had to complain of daytime sleepiness to be enrolled (mean Epworth Sleepiness Scale scores of 9 to 11), and had milder LV dysfunction and OSA (mean LVEF of 38% and AHI of 25/h) than in Kaneko and colleagues (29). In CPAP-treated patients (mean usage of 5.6 ± 0.4 h/night), LVEF increased (from 38 ± 3 to 43 ± 0%, p = 0.04), and nocturnal urinary norepinephrine levels decreased (p = 0.036). This was accompanied by significant improvement in quality of life assessed by the Short Form-36 and a significant reduction in self-reported sleepiness, but no change in blood pressure. The smaller improvement in LVEF in this study than in that by Kaneko and colleagues (29), without a reduction in blood pressure, was probably due to milder LV dysfunction and OSA. The long-term impact of treating OSA on cardiovascular events in patients with HF has not been assessed.

CSA AND HF

Pathophysiology
In HF, CSA is associated with chronic hypocapnia, which is related to elevated LV filling pressures and end-diastolic volumes, pulmonary congestion that may provoke hyperventilation through stimulation of pulmonary vagal irritant receptors, and increases in central and peripheral chemosensitivity (3, 33, 34). Central apneas are usually triggered by hyperventilation and reductions in PaCO2 below the apneic threshold, often provoked by arousals (35). In the presence of augmented chemosensitivity, the ventilatory response to the fall in SaO2 and increase in PaCO2 at apnea termination is exaggerated, causing ventilatory overshoot, a fall in PCO2 below threshold, then cyclic alternation of hyperventilation and apneas. Like OSA, CSA causes intermittent nocturnal hypoxia and surges in sympathetic nervous system activity and blood pressure (4). In contrast to OSA, however, CSA does not cause generation of negative intrathoracic pressure (35). Consequently, the impact of CSA on LV preload and afterload is less than in OSA. Sympathetic activity is also higher during sleep and wakefulness in HF patients with CSA than in those without sleep apnea (9, 10).

Impact on Clinical Outcome
There are reports that CSA in patients with HF confers an increased risk of death and cardiac transplantation independently of known risk factors (36, 37). However, in those studies, beta-blockers were used in only 0 (36) and 22% (37) of patients. Increased use of beta-blockers for HF in more recent times may have modified this risk.

One mechanism through which CSA could reduce survival is through increased sympathetic nervous system activity (10, 36, 38). beta-Blockers inhibit excess sympathetic activity and improve survival in patients with HF, but with unknown CSA status (27, 39). Indeed, during the course of the Canadian Continuous Positive Airway Pressure for Treatment of Central Sleep Apnea in Heart Failure (CANPAP) trial (40), there was a significant fall in the combined rate of mortality and heart transplantation in patients with HF and CSA (from 20 to 4 per 100 person-years between 1998 and 2004, p = 0.003). This falling event rate was associated with increasing use of beta-blockers at the time of enrollment. Accordingly, observations on the impact of CSA on morbidity and mortality from studies conducted before widespread use of beta-blockers and spironolactone (36, 37) may not be applicable to patients with HF treated with optimal contemporary medical therapy.

Effects of HF Treatment on CSA
Because CSA is largely a consequence of HF, first-line therapy should be optimization of HF treatment. Case series suggest that intensification of pharmacologic therapy for HF can attenuate CSA (41, 42). Similarly, in nonrandomized trials, cardiac resynchronization pacemaker therapy was accompanied by alleviation of CSA in association with an improvement of cardiac function (43, 44). Heart transplantation can also alleviate CSA in patients with HF (45). Thus, optimizing HF therapy can stabilize ventilatory control and attenuate CSA in some patients.

Specific Treatment of CSA in Patients with HF
Respiratory stimulants.
Theophylline stimulates central respiratory drive, and augments cardiac contractility by antagonism of adenosine. In a randomized trial involving 15 patients with stable HF and CSA, theophylline administered for 5 d reduced the AHI, but did not improve LVEF (46). However, theophylline, once widely used for therapy for acute HF, is no longer used for this purpose because it increased the incidence of cardiac arrhythmias (47) and sudden death (48). The carbonic anhydrase inhibitor acetazolamide stimulates respiration by causing metabolic acidosis. In a short-term randomized trial (49) in 12 patients with HF and CSA, acetazolamide reduced the AHI (by 38%), daytime sleepiness, and fatigue. However, it cannot be recommended for therapy for CSA in HF at present, because its long-term safety and effectiveness in such patients remain to be demonstrated.

Atrial overdrive pacing.
Garrigue and colleagues (50) generated considerable excitement when they observed, in a randomized trial involving patients with bradyarrhythmias but without HF, that pacing the heart at 15 beats/min above its intrinsic rate during sleep by atrial overdrive pacing caused a 50% reduction in both central and obstructive apneas and hypopneas. The most likely mechanism for alleviation of CSA was by augmentation of cardiac output and relief of pulmonary congestion. However, it is not clear how it alleviated obstructive events. Indeed, in three subsequent randomized trials, atrial overdrive pacing had no significant effect on AHI in patients with OSA but without HF (51–53). Moreover, long-term overdrive pacing in patients with HF who have no established indication for a pacemaker may cause harm by promoting pacing-induced arrhythmias (54). Consequently, neither CSA nor OSA constitutes an indication for this type of cardiac pacing.

Oxygen.
Small randomized trials with durations from 1 night to 1 mo have demonstrated that nocturnal oxygen reduces the AHI by approximately 50% in patients with HF and CSA (55–57). Staniforth and colleagues (58) found, in addition, that supplemental oxygen for 1 mo reduced overnight urinary norepinephrine excretion, but had no effect on daytime plasma norepinephrine, brain natriuretic peptide, neurocognitive function, sleepiness, or quality of life. In another randomized trial, Andreas and coworkers (55) reported that administration of nocturnal oxygen for 7 d to 22 patients with HF improved peak oxygen consumption and ventilatory efficiency, but had no effect on quality of life. Arzt and colleagues (59) allocated 10 consecutive patients to nocturnal oxygen and the next 16 consecutive patients to CPAP at 8 to 10 cm H2O for 3 mo. Both CPAP and oxygen reduced the AHI by 67%, but only CPAP improved ventilatory efficiency and LVEF. Neither intervention had any effect on peak exercise oxygen consumption.

Although oxygen attenuates CSA in patients with HF and can reduce nocturnal sympathetic activity, there is no consistent evidence that it improves cardiovascular function or clinical outcomes in such patients. Consequently, the evidence does not support its use for therapy for CSA in patients with HF. Moreover, administration of supplemental oxygen to patients with HF could cause hyperoxia, and by doing so, increase the generation of oxygen free radicals and, hence, oxidative stress. This can exert adverse hemodynamic effects, such as raising vascular resistance, blood pressure, and LV filling pressure, and lowering cardiac output (60, 61). These effects are at least partially reversible by intravascular administration of the antioxidant vitamin C (60–62). Therefore, larger trials are required to determine whether oxygen improves clinical outcomes in HF patients with CSA.

Carbon dioxide.
Raising PCO2 above the apneic threshold either via inhaled CO2 or addition of dead space abolishes CSA instantaneously in patients with HF (63, 64). However, there is no evidence that raising PCO2 improves cardiovascular outcomes in such patients. Moreover, raising PCO2 may cause adverse effects by activating the sympathetic nervous system (65). Therefore, raising PCO2 either by inhalation of CO2 or by using a face mask with increased dead space cannot be recommended for therapy for CSA in patients with HF at this time.

CPAP.
CPAP reduces LV transmural pressure and afterload in patients with HF by increasing intrathoracic pressure (66). It also reduces LV preload by reducing end-diastolic volume and pressure (3, 67). The acute response of cardiac output to CPAP therapy in awake patients with HF is dependent on cardiac preload and rhythm. In patients with HF and with high LV filling pressure (i.e., >= 12 mm Hg), CPAP of 5 to 10 cm H2O generally augments cardiac output, but in patients with HF and with low LV filling pressure (i.e., < 12 mm Hg) (68, 69) or atrial fibrillation (70), it generally reduces cardiac output. However, it is not known whether CPAP has long-term adverse hemodynamic effects when applied nightly to patients with HF and CSA and low filling pressures or atrial fibrillation. Because CSA in patients with HF is associated with increased LV filling pressures (2, 3), CPAP has been applied to these patients to improve hemodynamics.

The effects of CPAP on CSA in patients with HF have been inconsistent, probably because of differences in how it is applied. In randomized trials in which nocturnal CPAP was applied for 1 night to 2 wk at low pressure (5–7.5 cm H2O), CSA was not alleviated (71, 72). In contrast, where patients were acclimatized to CPAP during a gradual 2- to 7-d titration to higher pressures of 8 to 12.5 cm H2O, the frequency of central apneas and hypopneas fell by 50 to 67% after 2 to 12 wk (10, 40, 57, 59, 73–75).

In small single-center trials lasting 1 to 3 mo, where CPAP was titrated gradually, CSA was alleviated in association with an increase in PCO2 and improvements in cardiorespiratory function. These included increases in LVEF (37, 59, 74, 76) and inspiratory muscle strength (77) and reductions in functional mitral regurgitation (75), nocturnal and daytime norepinephrine levels (10), and daytime plasma atrial natriuretic peptide concentrations (75). These physiologic improvements were associated with significant improvements in symptoms of HF (10). In one trial of CPAP in HF (37) involving 29 patients with and 37 without CSA (AHI >= 15 and < 15, respectively), CPAP had no effect on LVEF or the combined rate of mortality and cardiac transplantation among those without sleep apnea. In contrast, among patients with CSA, CPAP improved LVEF after 3 mo in association with a trend toward a reduced combined rate of mortality plus cardiac transplantation during the median 2.2-yr follow-up period (p = 0.059). Among patients who were compliant with CPAP, the reduction in the combined rate of death and cardiac transplantation was significant (p = 0.017).

Taken together, these studies demonstrate that CPAP improves cardiovascular function in patients with HF and CSA, but only when it is titrated slowly to pressures of 8 to 12.5 cm H2O, and is accompanied by reductions in the AHI (37, 59, 74, 76). These findings imply that CPAP improves cardiovascular function over time in HF patients with CSA by attenuating the adverse cardiovascular effects of CSA. However, because of the small number of participants in those studies, and because beta-blockers had not yet come into widespread use for the therapy for HF, their results may not be applicable to patients receiving optimal contemporary pharmacologic HF therapy. For these reasons, the multicenter CANPAP trial sought to determine whether CPAP would improve CSA, morbidity, mortality, and cardiovascular function in HF patients with CSA receiving contemporary medical therapy for HF (40).

The CANPAP trial included 258 patients with HF (LVEF < 40%) and CSA (AHI >= 15/h of sleep of which > 50% were central). One hundred thirty were randomized to a control group and 128 to a CPAP-treated group. The intention-to-treat analyses confirmed previous findings that CPAP attenuates CSA, improves nocturnal oxygenation and LVEF, and lowers plasma norepinephrine concentrations (Figure 1). Importantly, those effects were sustained with long-term therapy (at least 2 yr). In addition, CPAP caused a significant increase in 6-min walking distance. However, some effects were less pronounced compared with previous trials. For example, the 2.2% rise in LVEF (40) was less than the 7.7% increase observed in a single-center randomized trial (74). This difference may be attributable to lower CPAP (8–9 vs. 10 cm H2O), and daily CPAP usage (4.3 vs. 5.9 h/d), a higher initial LVEF (24.5 vs. 20.0%), or possibly, the greater proportion of patients who were receiving beta-blockers than in previous studies (77 vs. < 20%). Because one mechanism by which CPAP appears to exert its therapeutic effect is by lowering sympathetic activity, it is possible that beta-blockade rendered some of CPAP's effects redundant. Although the CANPAP trial demonstrated that CPAP attenuates CSA and improves LVEF to a modest extent (40), this increase is similar to that induced by angiotensin-converting enzyme inhibitors, such as enalapril, which have been shown to reduce mortality in HF (78–80).


Figure 1
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  		Figure 1. Continuous positive airway pressure (CPAP) caused significant sustained effects on the number of apneas and hypopneas per hour of sleep (A), mean and minimum nocturnal oxygen saturation (B and D), and left ventricular ejection fraction (LVEF; C). p values represent time–treatment interactions over the entire trial. Data are mean and 95% confidence intervals. Reprinted by permission from Reference 40.

 
Although CPAP attenuated CSA and improved cardiovascular function, there were no significant differences in transplant-free survival (32 vs. 32 events, p = 0.54; Figure 2), rate of hospitalizations, or quality of life between the two groups (40). Survival analysis revealed a divergence of event rates in the first 18 mo favoring the control group (p = 0.02), which reversed after 18 mo to favor CPAP (p = 0.06). This suggests that CPAP had an early adverse effect in some subjects, but a late beneficial effect in others (40, 68–70). Because of the early divergence of the transplant-free survival curves favoring the control group, lower than anticipated enrollment, and a falling primary event rate, the trial was terminated early (40). A much larger trial would have been required to determine whether the physiologic improvements observed predict improved clinical outcomes (81). Although CANPAP lacked power to conclude with certainty that CPAP does not improve survival in this patient population, the data do not support its routine use in patients with CSA and HF to prolong survival. Further analyses of the CANPAP database may provide insights into who might or might not benefit from CPAP.


Figure 2
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  		Figure 2. There was no difference in transplant-free survival rates between the control and CPAP-treated groups. Reprinted by permission from Reference 40.

 
Other forms of positive airway pressure.
Two other types of noninvasive positive airway pressure have been evaluated in patients with HF: bilevel pressure support in the spontaneous-timed mode with a back-up rate, and adaptive servo-ventilation. The latter provides 4 to 5 cm H2O expiratory and 8 cm H2O end-inspiratory pressure support during regular breathing. When a central apnea is detected, inspiratory pressure support increases up to 15 cm H2O to maintain minute ventilation at 90% of the long-term average ventilation. In both cases, central apneas are overridden when inspiratory pressure support is triggered by cessation of outflow. However, because both devices provide minimal positive pressure during normal breathing and lower expiratory pressures (4–5 cm H2O) during apneas, the average pressure would be lower than CPAP of 8 to 12.5 cm H2O (82).

Teschler and colleagues (82) compared the effects of a single night each of supplemental oxygen (2 L/min), CPAP (mean, 9.3 cm H2O), bilevel pressure support (mean, 13.5/5.2 cm H2O), and adaptive servo-ventilation (mean, 7–9 cm H2O) on CSA and sleep quality on 5 consecutive nights in random order in 14 patients with HF. The AHI declined significantly from 45 (control) to 28 (oxygen), to 27 (CPAP), to 16 (bilevel pressure support), and to 15 (adaptive servo pressure support). Improvements in sleep structure characterized by increases in slow-wave and REM sleep time occurred only with adaptive servo pressure support. However, effects on cardiovascular function were not assessed.

Only two studies have compared two forms of pressure support for therapy for CSA in HF of more than 1 night's duration. In the first trial, Köhnlein and colleagues (73) found that bilevel pressure support (mean, 8.5/3 cm H2O) and CPAP (mean 8.5, cm H2O) caused similar significant improvements of CSA, sleep quality, and daytime fatigue in 16 patients with HF and CSA over 2 wk, but did not assess cardiac function. Philippe and coworkers (83) found that both adaptive servo-ventilation and CPAP (mean, 8.0 cm H2O) alleviated CSA in 25 patients with HF, but only adaptive servo-ventilation completely corrected CSA at 6 mo, with an AHI below 10/h. Measurement of LVEF was available in a subset of 13 patients with HF. Within the adaptive servo-ventilation group, LVEF increased significantly, but within the CPAP group it did not. However, because CPAP was lower than the effective pressures previously used (74–77), and no time–treatment interaction analysis was performed, it cannot be concluded that adaptive servo-ventilation improves LVEF more than CPAP.

Pepperell and colleagues (84) performed a randomized trial of therapeutic versus subtherapeutic adaptive servo-ventilation over 1 mo in 30 patients with stable HF and CSA. The therapeutic and subtherapeutic adaptive servo-ventilation delivered 8.0 to 15.0 and 2.5 to 4.5 cm H2O inspiratory pressure support, respectively. Nocturnal urinary metadrenaline and daytime brain natriuretic peptide concentrations as well as daytime sleepiness were reduced significantly more by therapeutic than subtherapeutic adaptive servo-ventilation. However, because follow-up polysomnography was not performed, effects of these interventions on AHI and sleep quality were not determined. Furthermore, contrary to Philippe and colleagues (83), adaptive servo-ventilation did not cause any significant change in LVEF (online supplement of Reference 84). This lack of effect on LVEF contrasts with CPAP (37, 40, 59, 74, 76), possibly because adaptive servo-ventilation applies a lower mean pressure than CPAP with insufficient unloading of the left ventricle to induce improvements in systolic function.

It is premature to recommend forms of variable positive-pressure support for therapy for CSA in patients with HF because these have not been shown consistently to improve cardiac function and have not been subjected to large-scale, long-term randomized trials. However, among patients with HF and CSA, CPAP has only been shown to improve cardiovascular function when CSA has been alleviated (37). Because other forms of positive airway pressure, such as adaptive servo-ventilation, might cause greater suppression of CSA than CPAP (82, 83), it may be worthwhile subjecting these forms of positive airway pressure to large-scale trials to assess whether they have a beneficial effect on cardiovascular endpoints.

CONCLUSIONS

There is growing evidence that both OSA and CSA can contribute to the progression of HF (9, 10, 85, 86). However, because medical and device therapies for HF have progressed over the last few years, and will continue to evolve, it may be necessary from time to time to reassess the prevalences and pathophysiologic and therapeutic significance of OSA and CSA in patients with HF.

Because of the generation of negative intrathoracic pressure during obstructive apnea, OSA may expose the failing heart to greater stresses than CSA. Consequently, reversal of these greater stresses through treatment of OSA should have greater potential to reduce fatal and nonfatal cardiovascular events in patients with HF than treatment of CSA. However, no large-scale randomized trials have tested the long-term effects of treating OSA in patients with and without HF on cardiovascular function, morbidity, or mortality. In patients with HF and OSA who complain of daytime sleepiness, CPAP can reduce sleepiness and improve quality of life (32). Therefore, in patients with HF and OSA, a complaint of excessive daytime sleepiness would be an indication for CPAP therapy. However, most patients with HF and OSA do not complain of excessive daytime sleepiness (1, 29). Barbe and coworkers (87) demonstrated, in a randomized clinical trial with a placebo control (sham CPAP), that treatment of severe OSA (AHI > 30) by CPAP in nonsleepy patients without HF did not improve symptoms or neuropsychologic or cardiovascular function. Therefore, it has not been demonstrated that treating nonsleepy patients with OSA, even those with a very high AHI, improves clinical outcomes. Because it has not been shown that quality of life improves in such patients with CPAP therapy (87), it remains uncertain whether treating OSA in such patients will provide clinically important benefits.


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  		TABLE 1. EFFECTS OF CONTINUOUS POSITIVE AIRWAY PRESSURE IN PATIENTS WITH HEART FAILURE AND OBSTRUCTIVE SLEEP APNEA

 
Although several single-center randomized trials have established that treating OSA in patients with HF without subjective excessive daytime sleepiness lowers blood pressure, sympathetic nervous system activity, and the frequency of nocturnal ventricular ectopy, and improves LVEF (29–31), these studies were only 1 mo in duration and did not establish that these cardiovascular benefits were long-lasting or that they were associated with symptomatic improvement. Moreover, even though treatment of OSA in patients with HF improves cardiac function, this does not constitute a solid indication for treatment, since several drugs that improve cardiovascular function do not reduce, and may even increase, morbidity and mortality in HF (88, 89). We therefore believe that larger randomized trials should be conducted in patients with HF and with OSA, but without excessive daytime sleepiness, to determine whether the beneficial cardiovascular effects of treating OSA are long-lasting and associated with improvement in quality of life. A large-enough trial may even determine whether treating OSA reduces morbidity and mortality in patients with HF and OSA.


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  		TABLE 2. EFFECTS OF DIFFERENT TREATMENTS IN PATIENTS WITH HEART FAILURE AND CENTRAL SLEEP APNEA

 
In patients with HF, CSA is also seldom accompanied by a complaint of hypersomnolence (1, 90), and there is no consistent evidence that treating CSA with oxygen or various forms of positive airway pressure relieves this symptom (55, 58, 84). Although the CANPAP trial demonstrated that CPAP attenuates CSA and improves cardiovascular function in patients with HF (40), it did not demonstrate any beneficial effects of CPAP on morbidity and mortality. Therefore, the data do not support its routine use in patients with CSA and HF to prolong life.

Although CANPAP did not demonstrate a beneficial effect of CPAP on survival in HF patients with CSA, the sample of 258 subjects was probably too small to demonstrate such an effect if it exists. Pharmacologic trials required thousands of patients to demonstrate beneficial effects on morbidity and mortality in patients with HF. Therefore, it remains possible that given a large-enough sample size, trials of interventions, such as oxygen, CPAP or other forms of positive airway pressure, may provide clinically important benefits. CPAP only improves cardiovascular function chronically in patients with HF and CSA when it relieves CSA (37, 72). These observations suggest that alleviation of CSA may be a key factor in improving cardiac function in patients with HF and CSA. Therefore, interventions that markedly reduce AHI, such as variable positive airway pressure support, may provide greater benefits in the long term than CPAP. Until such trials are conducted, however, the evidence does not support widespread screening for sleep-related breathing disorders in patients with HF without symptoms of sleep apnea.

FOOTNOTES

Supported by grants from the Canadian Institutes of Health Research (MOP-11607 and UI-14909). M.A. was supported by a Research Fellowship from the Heart and Stroke Foundation of Ontario.

Originally Published in Press as DOI: 10.1164/rccm.200511-1745PP on March 9, 2006

Conflict of Interest Statement: M.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.D.B. was the principal investigator on the Canadian Institutes of Health Research university/industry clinical trial of CPAP for patients with heart failure and CSA, with Respironics, ResMed and Tyco as industrial partners, from 1998–2004, and approximately $1,500,000 was contributed by these three partners. He also consulted for Medtronic.

Received in original form November 14, 2005; accepted in final form March 8, 2006

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