Download CPAP Should Be Used for Central Sleep Apnea in Congestive Heart

PRO/CON DEBATE
CPAP Should Be Used for Central Sleep Apnea
in Congestive Heart Failure Patients
T. Douglas Bradley, M.D.
Sleep Research Laboratories of the Toronto Rehabilitation Institute, and Toronto General Hospital of the University Health Network, and the Centre
for Sleep Medicine and Circadian Biology of the University of Toronto, Toronto, ON, Canada
monary vagal irritant receptors, and to increases in central and
peripheral chemosensitivity.7,8,10 Hence, treating CSA might improve cardiovascular outcomes either by alleviating CSA per se
or by alleviating underlying cardiovascular dysfunction that is associated with CSA.
The prevalence of CSA in patients with stable CHF is approximately 25% to 40%,1,6,11 compared with less than 1% in the
general population.12 This high prevalence in the setting of CHF
is probably attributable to derangements in cardiovascular physiology that influence the respiratory system, as described above.
Accordingly, because CSA is largely a consequence of CHF, one
could anticipate that treatments for CHF that relieved pulmonary
edema and/or lowered LV filling pressures might also relieve
CSA.
Case series suggest that intensification of pharmacologic therapy for CHF can attenuate CSA.13,14 Similarly, in nonrandomized
trials, cardiac resynchronization pacemaker therapy was accompanied by alleviation of CSA in association with an improvement
of cardiac function.15,16 Heart transplantation can also alleviate
CSA in patients with CHF.17 Thus, optimizing CHF therapy can
stabilize ventilatory control and attenuate CSA in some patients.
These observations suggest that, in addition to optimal contemporary CHF therapy, specific interventions for CSA in patients
with CHF would be most effective if the therapy also had direct
beneficial effects on cardiovascular function.
RATIONALE FOR TREATING CENTRAL SLEEP APNEA IN PATIENTS WITH HEART FAILURE
T
here are 2 possible rationales for treating Cheyne-Stokes respiration or central sleep apnea (CSA) in patients with congestive heart failure (CHF). First, alleviation of CSA might alleviate
symptoms directly related to CSA, such as sleep disruption and
excessive daytime sleepiness. Second, treating CSA might improve cardiovascular outcomes, such as cardiovascular function,
as well as morbidity and mortality due to CHF.
Regarding the first rationale, there is little evidence that CSA
itself gives rise to symptoms of a sleep apnea syndrome. For example, most CHF patients with CSA do not snore and do not complain of excessive daytime sleepiness.1,2 Thus, relief of symptoms
of CSA is not a strong rationale to treat CSA in patients with CHF.
Regarding the second rationale, this is largely based on observations from some,3,4 but not all, reports5,6 that, in patients with
CHF, CSA increases the risk of death and cardiac transplantation
independently of known risk factors. This observation suggests
the possibility that, in patients with CHF, treating and alleviating
coexisting CSA might reduce some of the excess morbidity and
mortality attributable to this condition.
Closely linked to this notion is evidence that CSA arises secondary to CHF itself and is, to some extent, a sign of the severity
of CHF. For example, although cardiac output does not appear
to differ between CHF patients with and without CSA, patients
with CSA have higher left ventricular (LV) filling pressures, LV
end-diastolic volumes, and sympathetic nervous system activity,
as compared with CHF patients without CSA.7,8 These are signs
of worse cardiovascular function in patients with CSA that should
have adverse prognostic implications. In CHF, CSA is associated
with chronic hypocapnia.9 This is related to elevated LV filling
pressures and end-diastolic volumes, and pulmonary congestion
that may provoke hyperventilation through stimulation of pul-
RATIONALE FOR USING CONTINUOUS POSITIVE AIRWAY
PRESSURE TO TREAT CSA IN CHF
Continuous positive airway pressure (CPAP) has a number of
beneficial acute respiratory and cardiovascular effects in patients
with CHF. When applied to awake patients with CHF, it increases intrathoracic pressure. This unloads the inspiratory muscles,
thereby reducing the work of breathing. It also reduces LV transmural pressure, thereby reducing LV afterload, and reduces LV
end-diastolic volume and pressure, thereby reducing preload.7,18,19
This, combined with a reduction in heart rate,18 reduces overall
cardiac workload and increases cardiac pumping efficiency. Randomized trials have shown that when CPAP of 10 cm H2O is applied to patients with acute cardiogenic pulmonary edema, it lowers elevated PCO2, reduces the alveolar-arterial PO2 difference,
lowers heart rate, and reduces the rate of intubation, as compared
with standard medical therapy.20,21 Although not demonstrated di-
Disclosure Statement
Dr. Bradley has received research support from Respironics, ResMed, and
Tyco.
Address correspondence to: T. Douglas Bradley, MD, Toronto General Hospital/University Health Network, 9N-943, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada; Tel: (416) 340-4719; Fax: (416) 340-4197; E-mail:
[email protected]
Journal of Clinical Sleep Medicine, Vol. 2, No. 4, 2006
394
CPAP for Central Apnea in Heart Failure
rectly, these results suggest that improved gas exchange results, in
part, from more rapid clearing of pulmonary edema and improvement in ventilation/perfusion matching.
The acute cardiac output response to CPAP therapy in awake
patients with CHF is dependent on cardiac preload and rhythm.
In CHF patients with high LV filling pressure (i.e., ≥ 12 mm Hg),
CPAP of 5 to 10 cm H2O generally augments cardiac output, but in
CHF patients with low LV filling pressure (i.e., < 12 mm Hg)22,23
or atrial fibrillation,24 CPAP generally reduces cardiac output.
However, it is not known whether CPAP has long-term adverse
hemodynamic effects when applied nightly to CHF patients with
CSA and low filling pressures or atrial fibrillation. As it happens,
CHF patients with CSA generally have increased LV filling pressures, as compared with CHF patients without CSA.7,11 One might
anticipate that CPAP applied to such patients would improve hemodynamics. Indeed, this is one of the reasons why CPAP has
been used to treat CSA in patients with CHF.
The effects of CPAP on CSA in patients with CHF have been
inconsistent in the smaller trials, probably as the result of differences in how the CPAP is applied. In randomized trials in which
nocturnal CPAP was applied for 1 night to 2 weeks at low pressure
(5 - 7.5 cm H2O), CSA was not alleviated.25,26 In contrast, in trials
in which patients were acclimatized to CPAP during a gradual
2- to 7-day titration to higher pressures of 8 to 12.5 cm H2O, the
frequency of central apneas and hypopneas fell by 53% to 67%
after 2 to 12 weeks.27-34
In small single-center trials lasting 1 to 3 months, CPAP, titrated
gradually, alleviated CSA in association with an increase in PCO2
and improvements in cardiorespiratory function. These included
increases in LVEF4,29,33,35 and inspiratory muscle strength36 and
reductions in functional mitral regurgitation34 and nocturnal and
daytime norepinephrine levels,32 as well as daytime plasma atrial
natriuretic peptide concentrations.34 These physiologic improvements were associated with significant improvements in symptoms of CHF.32 In 1 trial of CPAP in CHF4 involving 29 patients
with and 37 without CSA (apnea-hypopnea index [AHI] ≥ 15 and
< 15, respectively), CPAP had no effect on LV ejection fraction
(LVEF) or the combined rate of mortality and cardiac transplantation among those without sleep apnea. In contrast, in an intention-to-treat analysis, among patients with CSA, CPAP improved
LVEF after 3 months in association with a trend toward a reduced
combined rate of mortality plus cardiac transplantation during the
median 2.2-year follow-up period (p = .059). Among patients who
were compliant with CPAP, the reduction in the combined rate of
death and cardiac transplantation was significant (p = .017).
Taken together, these studies demonstrated that CPAP improves
cardiovascular function in CHF patients with 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.4,29,33,35 These findings imply
that CPAP improves cardiovascular function over time in CHF
patients with CSA by attenuating the adverse cardiovascular effects of CSA. However, because of the small number of participants in those studies, and because β-blockers had not yet come
into widespread use for the therapy of CHF, the results of those
studies may not be applicable to patients on optimal contemporary
pharmacologic CHF therapy. For these reasons, the multicenter
Canadian Continuous Positive Airway Pressure for Patients with
Central Sleep Apnea and Heart Failure (CANPAP) Trial sought to
determine whether CPAP would improve CSA, morbidity, mortality, and cardiovascular function in CHF patients with CSA on
contemporary medical therapy for CHF.27
Journal of Clinical Sleep Medicine, Vol. 2, No. 4, 2006
The CANPAP Trial
The CANPAP trial was a multicenter randomized controlled
clinical trial carried out in 10 centers in Canada and 1 in Germany.27 It included 258 patients with CHF (LVEF < 40%) and
CSA (AHI ≥ 15/h of sleep, of which > 50% were central), 130
of whom were randomly assigned to a control group and 128 to
a CPAP-treated group. These patients were followed for a mean
and maximum of 2.2 and 5.3 years, respectively. The first important finding was that compliance with CPAP therapy was very
good; 85% of patients assigned to CPAP used it throughout the
trial. This is as good or better than adherence to drug therapies in
long-term CHF trials.37,38
The intention-to-treat analyses confirmed previous findings
that CPAP attenuates CSA (it reduced the AHI by 53%, from 40
to 19 per hour of sleep) but does not affect total sleep time. It also
improves nocturnal oxygenation and LVEF and lowers plasma
norepinephrine concentrations. Importantly, those effects were
sustained with long-term therapy (at least 2 years). In addition,
CPAP caused a significant 20-meter increase in 6-minute walking
distance, a degree of improvement that is considered clinically
significant.39 However, some effects were less pronounced, compared with previous trials. For example, plasma atrial natriuretic
peptide concentration did not fall, compared with a significant fall
in a previous study.34 The 2.2% rise in LVEF27 was less than the
7.7% increase observed in a single-center randomized trial.33 This
difference may be attributable to lower CPAP (8-9 vs 10 cm H2O)
and daily CPAP usage (4.3 vs 5.9 hours per day), a higher initial
LVEF (24.5% vs 20.0%), or, possibly, the greater proportion of
patients who were on β-blockers than in previous studies (77%
versus <20%). Because 1 mechanism by which CPAP appears
to exert its therapeutic effect is by lowering sympathetic activity, it is possible that β-blockade rendered redundant some of the
effects of CPAP. Although the CANPAP trial demonstrated that
CPAP attenuates CSA and improves LVEF to a modest extent,27
this increase is similar to that induced by angiotensin converting
enzyme inhibitors, such as enalapril, which have been shown to
reduce mortality in CHF.40-42
Although CPAP attenuated CSA and improved cardiovascular
function, there were no significant differences in transplant-free
survival (32 vs 32 events, p = .54), rate of hospitalizations, or
quality of life, measured by the Chronic Heart Failure questionnaire, between the 2groups.27 Survival analysis revealed a divergence of event rates in the first 18 months favoring the control
group (p = .02) that reversed after 18 months to favor CPAP (p
= .06). This suggests that CPAP had an early adverse effect in
some subjects but a late beneficial effect in others. 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 indicating that the original sample-size calculation was insufficient to detect a difference in transplant-free
survival between the 2 groups,43 the trial was terminated early.27
Consequently, CANPAP lacked power to conclude with certainty that CPAP does not improve survival in this patient population. A much larger trial would have been required to determine
whether the physiologic improvements observed are surrogates
for improved survival.44 Nevertheless, the physiologic benefits
are probably clinically important, since they are similar to those
described for β-blockers for therapy of CHF.
To date, β-adrenergic receptor blockers have proven to be the
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TD Bradley
most potent pharmacologic agents for improving survival in CHF
yet tested. They work mainly by blocking adrenergic activity at
peripheral receptors, thereby slowing heart rate and reducing
myocardial energy consumption. To put the results of trials of
CPAP for CHF patients with CSA into perspective, a brief overview of β-blocker therapy for CHF may be helpful.
The first moderate-sized randomized trial of the selective β1receptor blocker, metoprolol,45 for treating CHF involved 383 patients. In this trial, metoprolol increased LVEF but did not affect
survival, most likely because it was underpowered to do so. Nevertheless, 6 years later, in a much larger trial involving 3991 patients with CHF,46 metoprolol did improve survival. Similarly, in
an early randomized trial involving 301 CHF patients,39 those assigned to treatment with carvedilol, a nonselective β1-/β2-receptor
blocker with α1-receptor blocking and antioxidant properties, experienced an improvement in LVEF and a marginal improvement
in 6-minute walking distance but no change in quality of life or
mortality rate. Subsequently, in a much larger trial involving 2289
patients with CHF,37 carvedilol caused a significant reduction in
mortality. In another trial, involving 3029 patients with CHF,47 it
was shown that carvedilol caused a greater reduction in mortality
than did metoprolol, suggesting that nonselective β-blockade may
be more effective than β-1 selective blockade in reducing mortality in CHF. It has also been shown in numerous trials of various
β-blockers that an early improvement in LVEF is a good predictor
of improved survival.48 These examples illustrate that small trials
demonstrating beneficial effects of interventions on cardiovascular function, but without improving mortality, do not preclude the
possibility that much larger trials involving the same or similar
interventions may demonstrate mortality benefits.
Table 1 displays the physiologic and clinical effects of CPAP
in patients with CHF. It shows that CPAP reduces sympathetic
activity, during both sleep and wakefulness, in CHF patients with
CSA,32,49 but, unlike with the use of β-blockers, this is due to a
reduction in central sympathetic outflow rather than to peripheral
receptor blockade. Thus, the effects of CPAP are more akin to
those of the nonselective β-blocking agent, carvedilol, than to the
selective β1 blocking agent, metoprolol. CPAP also slows heart
rate, reduces LV wall tension and myocardial O2 consumption,18
and increases nocturnal oxygenation in CHF patients with CSA.
In such patients, CPAP also improves LVEF and exercise capacity.27 Interventions for CHF that improve LVEF and exercise capacity in conjunction with lowering of LV afterload, heart rate,
and inhibition of sympathetic nervous system activity, but that do
not have inotropic properties, have generally improved survival
when a large enough sample size has been studied. In particular,
an early improvement in LVEF in response to β-blockers is a good
predictor of improved survival.37,39,48
Table 1—Cardiovascular Effects of CPAP in Patients with CHF
A. Acute Physiologic Effects
• Increases intrathoracic pressure
• Unloads inspiratory muscles and reduces work of breathing
• Reduces preload by impeding venous return and compressing the
ventricles
• Reduces LV afterload by reducing LV transmural pressure
• Augments stroke volume and cardiac output in patients with high
LV filling pressure, but reduces stroke volume and cardiac output in
those with low or normal LV filling pressure
• Reduces cardiac SNA
• Improves ventilation/perfusion matching
B. Effects in acute cardiogenic pulmonary edema
• In those with CO2 retention, reduces PCO2
• Increases PO2
• Reduces heart rate
• Reduces rate of intubation and mechanical ventilation
C. Effects in heart-failure patients with CSA
• Attenuates CSA in association with a reduction in minute ventilation (and thus work of breathing) and increases PCO2 and nocturnal
oxygen saturation when titrated slowly to at least 8-12.5 cm H2O
• Suppresses ventricular ectopy in those in whom it attenuates CSA
acutely
• Increases inspiratory muscle strength
• Increases daytime LVEF
• Reduces daytime SNA
• Increases submaximal exercise capacity
• Has no significant effect on hospitalization rate
• Has no significant effect on mortality rate
• Has no reported significant adverse effects
CPAP refers to continuous positive airway pressure; CHF, congestive
heart failure; LV, left ventricular; SNA, sympathetic nervous system activity; LVEF, left ventricular ejection fraction.
would justify a trial of CPAP.27,39 CPAP is also well tolerated in
CHF patients with CSA. For these reasons, a trial of CPAP should
be provided as adjunctive therapy for patients with CHF who
continue to have CSA despite being on optimal contemporary
medical therapy. However, one must keep in mind that CPAP has
only been shown to improve cardiovascular function chronically
in CHF patients with CSA when it relieves CSA.4,29,33,35 These observations suggest that alleviation of CSA may be a key factor in
improving cardiac function in CHF patients with CSA.
However, if one uses CPAP for this purpose, it must be titrated
slowly over several days to weeks to a target pressure of 8 to 12.5
cm H2O.27,33 A follow-up sleep study from 1 to 3 months after initiating CPAP to assess its effect on CSA is therefore an important
aspect of clinical management. If at this time the AHI decreases
substantially, then the patient could be told to continue the use of
CPAP. If, on the other hand, the AHI has decreased only marginally or not at all, then one should probably recommend discontinuing the use of CPAP, since it is unlikely that it will provide
any long-term clinical benefits. It is also important to maintain
close follow-up once CPAP has been started to maintain good
compliance, just as one would when initiating β-blocker therapy
for CHF.
CONCLUSION
Given the generally beneficial effects of CPAP on CSA and cardiovascular function (especially improved LVEF) in patients with
CHF, the lack of documented inotropic or adverse effects with the
use of CPAP, and the similarities of the effects of CPAP to those
of β-receptor blockers, it is quite likely that a much larger trial of
CPAP for CHF patients with CSA would demonstrate a mortality
benefit. Even if CPAP does not improve survival, however, these
improvements in cardiovascular function do translate into a clinically important improvement in walking distance, which alone
Journal of Clinical Sleep Medicine, Vol. 2, No. 4, 2006
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