Download The Relationship Between Congestive Heart Failure, Sleep Apnea

The Relationship Between Congestive
Heart Failure, Sleep Apnea, and
Mortality in Older Men*
Sonia Ancoli-Israel, PhD; Einat R. DuHamel, MD; Carl Stepnowsky, PhD;
Robert Engler, MD; Mairav Cohen-Zion, MA; and Matthew Marler, PhD
Study objectives: To examine the association of sleep apnea with heart disease.
Design: Prospective study.
Setting: Medical wards at the Veterans Affairs San Diego Healthcare System.
Patients: Three hundred fifty-three randomly selected inpatient men.
Measurements and results: Sleep was recorded for 2 nights in the hospital. Medical conditions
were obtained from hospital medical records. Cox proportional hazards analyses indicated that
patients with congestive heart failure (CHF) plus central sleep apnea (CSA) had shorter survival
than those with just CHF, just sleep apnea (obstructive or central), or neither. Survival for those
with obstructive sleep apnea (OSA) or CSA and no CHF was no different than for those with
neither disorder. Follow-up analysis showed that for those with no CHF, neither CSA nor OSA
shortened survival (p > 0.80). For those with CHF, having CSA shortened the life span with a
hazard ratio of 1.66 (p ⴝ 0.012), but having OSA had no effect. Patients with CHF had more
severe sleep apnea than those with no heart disease.
Conclusions: This study does not clarify the issues of cause and effect, but does reinforce the
strong associations between sleep apnea and heart disease in elderly men. These data suggest that
people with coronary disease should be regarded as a risk group for sleep apnea.
(CHEST 2003; 124:1400 –1405)
Key words: central sleep apnea; congestive heart failure; mortality
Abbreviations: AHI ⫽ apnea-hypopnea index; BMI ⫽ body mass index; CHF ⫽ congestive heart failure;
CPAP ⫽ continuous positive airway pressure; CSA ⫽ central sleep apnea; CSR ⫽ Cheyne-Stokes respiration;
ODI ⫽ oxygen desaturation index; OSA ⫽ obstructive sleep apnea; VASDHS ⫽ Veterans Affairs San Diego Healthcare
System
is a vulnerable time for death from
N ighttime
cardiovascular disease. Nighttime is also a vul1
nerable time for death from sleep apnea.2 Since
there is a high prevalence of sleep apnea in the
elderly,3 it has been suggested that sleep apnea may
*From the Departments of Psychiatry (Drs. Ancoli-Israel and
Marler, and Ms. Cohen-Zion), Reproductive Medicine (Dr.
DuHamel), and Medicine (Dr. Engler), University of California,
San Diego; and Veterans Affairs San Diego Healthcare System
(Dr. Stepnowsky), San Diego, CA.
All work was performed at University of California San Diego and
VASDHS.
Supported by NIA AG02711, NIA AG08415, NCI CA85264,
NHLBI HL44915, NHLBI HL36005; the Department of Veterans Affairs VISN-22 Mental Illness Research, Education, and
Clinical Center; and the Research Service of the VASDHS.
Manuscript received December 28, 2001; revision accepted May
27, 2003.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: Sonia Ancoli-Israel, PhD, Department of
Psychiatry 116A, VASDHS, 3350 La Jolla Village Dr, San Diego,
CA 92161; e-mail: [email protected]
increase the risk of both cardiovascular morbidity
and mortality in that age group.2,4
The cardiovascular consequences of sleep apnea
are of interest since these patients often have severe
hypoxemia, and the adverse effects of hypoxemia on
the heart are well documented.5,6 Sleep apnea has
been associated with cardiac arrhythmias, cyclic tachycardia, and hypertension in younger clinic patients.7,8
Schafer et al9 showed that patients with obstructive
sleep apnea (OSA) and coronary heart disease had
more apnea-associated ischemia, which in turn activated the CNS and fragmented sleep. Other studies10 –13 have also found a high prevalence of sleep
apnea in patients with heart failure. Work from the
Wisconsin cohort14 and from the Sleep Heart Health
Study15 has suggested sleep apnea may be a risk factor
for hypertension and consequent cardiovascular morbidity in the general population. If morbidity is increased, mortality may also be increased.
One approach to increasing survival in patients with
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Clinical Investigations
heart disease may be treating the sleep apnea. A series
of studies16 –21 and a recent study by Peker et al22
suggested that using continuous positive airway pressure (CPAP) to treat central sleep apnea (CSA) and
Cheyne-Stokes respiration (CSR) in patients with
chronic heart failure may also alleviate the heart
disease and possibly lengthen survival. Naughton and
Bradley23 treated congestive heart failure (CHF) and
CSR with continuous positive airway pressure (CPAP)
and found that nightly treatment attenuated the CSA
and CSR, improved cardiac function and alleviated
symptoms of heart failure. These data confirm that
some of the morbidity of heart disease, and therefore
perhaps mortality as well, may be worsened by the
presence of sleep apnea, particularly CSA.
Several investigators have postulated mechanisms
of action. The occurrence of frequent episodes of
oxygen desaturation and the many arousals caused by
apnea may contribute to both left and right ventricular
hypertrophy.24 Noda et al24 in fact showed that the
prevalence of left and right ventricular hypertrophy was
higher in patients with severe OSA syndrome than
those with mild OSA apnea. They suggested that sleep
apnea may influence structural changes in the heart,
hypoxia, and elevations in sympathetic activity.
It is clear that patients with CHF have shorter
survival.25 In many studies,26,27 CSA, and particularly
CSR, have also been associated with increased mortality. In our own laboratory, in a small study of
patients with left ventricular failure, we found that
all patients with left ventricular failure and CSR with
more than five apneas per hour of sleep died within
6 months, while only 30% of patients without recurrent apnea died within 6 months.27 Lanfranchi et al28
followed up 62 patients with chronic heart failure for
⬎ 2 years and found that those with higher respiratory disturbance indexes, but not higher percentage
of CSR, had shorter survival. In a third study,
Andreas et al29 found no association between mortality and CSA, but did find an association between
CSR during the day and increased mortality.
The studies discussed above focused on fairly small
samples followed up for approximately ⱕ 5 years. The
goal of this study was to examine whether having OSA
or CSA in addition to heart disease might have a
negative effect on survival in older adults. To answer
this question, a large sample of older men with and
without heart disease and with and without sleep apnea
were followed up for up to 17.5 years.
Materials and Methods
System (VASDHS) were randomly selected from all new daily
admissions to the medical wards. Exclusion criteria included
being ⬍ 60 years old; diagnosis of cancer, dementia, or infectious
disease; and being too sick to consent or being in the ICU. Initial
data gathering occurred over a 5-year period from 1985 to 1989.
The project was approved by the University of California, San
Diego Institutional Review Board in accordance with the recommendations found in the 1975 Helsinki Declaration.
Procedure
Sleep was recorded for 2 nights in the hospital using the
modified Respitrace/Medilog (Oxford Medical; Oxon, England)
portable recording system.30 At the time of the study, this system
was one of the only ambulatory systems available. The system
recorded thoracic and abdominal respiration, tibialis electromyogram, and wrist activity to distinguish sleep from wake state. This
system was previously validated against the “gold standard”
in-laboratory polysomnograph.30 Finger pulse oximetry was recorded on 1 of the 2 nights using a Biox finger-pulse oximeter
(model 3700; Ohmeda; Boulder, CO). All subjects were interviewed about their sleep. Medical conditions and diagnoses were
obtained from hospital medical records.
Recordings were scored for number of obstructive apneas
(defined as thoracic and abdominal respiration 180° out of phase,
and at least a 90% reduction in respiratory effort for a minimum
of 10 s), number of central apneas (defined as thoracic and
abdominal respiration in phase and at least a 90% reduction in
respiratory effort for a minimum of 10 s), number of hypopneas
(defined as a 50 to 90% reduction in effort), total sleep time, and
wake after sleep onset. The apnea-hypopnea index (AHI), the
number of apneas and hypopneas per hour of sleep, was computed for each night, and the mean of the two nights was used in
all analyses. Oximetry records were scored with the PROFOX
program (PROFOX Associates; Escondido, CA)31 for mean oxygen saturation, number of desaturations, and percentage of time
spent at an arterial oxygen saturation ⬍ 90%. An oxygen desaturation index (ODI), the number of desaturations per hour of
sleep, was computed. A desaturation was defined as a ⱖ 4%
decrease in the saturation level.
Follow-up
Follow-up was conducted yearly with the last follow-up occurring in the year 2002. A letter was sent to each participant asking
for current address; in cases where the person was no longer
living, information on where and when he died was requested.
Death certificate information was obtained either from the
hospital where the patient had died, from the San Diego County
records office or from the Benefits Information Records Locator
System (a Veterans Affairs automated system for identifying and
keeping track of veteran beneficiaries with a built-in linkage to
the veterans death certificates32).
Medical records at the Sleep Apnea Clinic at the VASDHS
were examined to determine if any of the patients had received
treatment for their sleep-disordered breathing. Although all
patients had been sent a letter reporting their condition after
their first sleep evaluation, no patients were treated at the
VASDHS for sleep apnea. It was not possible to determine if any
of the patients received treatment for sleep apnea at another
facility.
Subjects
Data Analysis
Three hundred fifty-three men who were inpatients on the
medical wards at the Veterans Affairs San Diego Healthcare
Logistic regression was run for the dependent variable CHF.
The continuous independent variables were age, education, body
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mass index (BMI), and years smoked ⫻ packs per year; dichotomous independent variables were race, income, alcohol intake,
history of hypertension, history of diabetes, and AHI. In addition,
smoking history, medical conditions (such as hypertension, pulmonary and bronchial disease, and diabetes), and other variables
that may confound the association between sleep apnea and CHF
were included in the analyses as dichotomous variables. ␹2
analyses were also run for presence/absence of CHF. The Cox
proportional hazards model was used for survival analysis. SPSS
(SPSS Version 10.0; SPSS; Chicago, IL) and SAS (SAS Version
9.0; SAS Institute; Cary, NC) were used for all analyses.
Results
Demographics
The mean age of the 353 men was 69 years (SD,
7.7 years; range, 60 to 99 years). Mean BMI was 25.4
(SD, 5.0; range, 14.2 to 47.6). Eighty-five percent of
the sample were white, 4% were African American,
and 11% were “other.” Table 1 shows the percentage
of the sample with different medical conditions, as
listed in medical records. Table 2 shows the medications received by these patients.
Prevalence
In this sample, at the initial visit, 53% of the men
(n ⫽ 186) had an AHI ⱖ 15. The mean AHI for the
entire sample was 23.2 (SD, 21.3; range, 0 to 112).
Thirty-two percent of the sample (n ⫽ 112) had CHF.
Sleep-Disordered Breathing
Those with a history of CHF had significantly
higher AHIs than those with no heart disease (mean
AHI, 27.6 [SD, 24.0] vs mean AHI, 20.0 [SD, 20.0];
p ⫽ 0.014) and significantly higher ODI (mean ODI,
42.5 [SD, 60.0] vs mean ODI, 27.5 [SD, 41.6];
Table 1—Percentage of Patients With Major Medical
Illnesses
Illnesses
%
Hypertension
Angina
Myocardial infarction
CHF
Peripheral vascular disease
COPD
Diabetes
Stroke
Bronchitis
Renal disease
Transient ischemic attack
History of cancer
Cirrhosis
Thyroid disease
Pancreatitis
50
50
37
32
27
25
24
16
14
12
7
3
3
4
1
Table 2—Percentage of Patients Receiving Medications
Medication Class
%
Cardiac drugs
Analgesics
Diuretics
Antihypertensives
Sedative-hypnotics
Bronchodilators
Steroids
Minor tranquilizers
Antidepressants
Antihistamines
Home oxygen
Narcotics
Anticonvulsants
Major tranquilizers
Vasodilators
Anti-Parkinsonian
Stimulants
70
54
42
36
25
21
16
9
6
6
5
3
2
2
2
1
0.6
p ⫽ 0.030). Forward selection logistic regression indicated that for CHF, age (in years), AHI, and years
smoked ⫻ packs per year, were all independently
significant (Table 3).
Mortality
A prospective study of mortality was performed.
Follow-up occurred up to 17.5 years (mean followup, 5.7 years; SD, 4.5 years; range, 0 to 17.5 years);
some subjects were studied in their last month of
life. As of 2002, of the original 353 men, 86% had
died (n ⫽ 303) and 14% were known to be alive
(n ⫽ 50). None were unavailable for follow-up.
The question was asked whether having OSA or
CSA in addition to heart disease might be associated
with shorter survival. Cox proportional hazards survival analyses were run for those with and without
sleep apnea and with and without CHF (Table 4).
As expected, those with CHF (with or without
OSA or CSA) had shorter survival than those without
CHF. However, those subjects with CHF comorbid
with either OSA or CSA (AHI ⱖ 15) [CHF plus
sleep apnea] had significantly shorter survival than
those with CHF and no OSA or CSA, OSA, or CSA
with no CHF, or neither (p ⬍ 0.001). Survival of
Table 3—Logistic Regression Analysis
Condition
CHF*
Risk Factors
Constant
Age, yr
AHI†
Pack-yr of smoking
Coefficient Odds Ratio p Value
⫺ 3.8362
0.0360
0.0127
0.0060
1.037
1.013
1.006
0.001
0.027
0.028
0.037
*Presence or absence.
†AHI ⱖ 15 vs AHI ⬍ 15.
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Clinical Investigations
Table 4 —Cox Proportional Hazards Model for CHF and Sleep Apnea
Variables
CHF plus CSA
CHF
Sleep apnea*
None
Percentage
Dead
Mean
Survival,
yr
95% Confidence
Interval, Mean
Median
Survival,
yr
Hazard
Ratio†
98.3
95.0
74.7
80.3
2.71
4.04
6.75
6.81
2.01–3.41
3.06–5.00
5.89–7.61
5.99–7.63
1.90
3.69
6.31
6.58
3.41
2.86
0.65
ref
*OSA or CSA.
†The hazard ratio takes into account the difference between those who have died and those who are still living at the time last contacted. The
mean survival includes the time in the study of everyone whether they have died or are still alive.
those with OSA or CSA but no CHF was no different
from survival for those with neither CHF nor sleep
apnea (Fig 1).
Since CHF is known to be associated with CSA,
and since close to half (48%) of the men with AHI
ⱖ 15 had CSA, analyses were done to determine if
mortality was related to having any type of apnea or
primarily to having CSA. The follow-up analysis
showed that for those with no CHF, neither CSA or
OSA shortened survival (p ⬎ 0.80). For those with
CHF, having CSA shortened the life span with a
hazard ratio of 1.66 (p ⫽ 0.012), but having OSA had
no effect.
Other variables added into the survival model as
controls that were significant included pulmonary
disease (p ⬍ 0.01), age (p ⬍ 0.01), BMI (p ⬍ 0.01),
use of home oxygen (p ⬍ 0.01), diabetes (p ⬍ 0.01),
dialysis (p ⬍ 0.05), and cancer (p ⬍ 0.01). Although
significant in the proportional hazards survival models, they did not account for the other significant
results, ie, these effects were additional to the effects
Figure 1. Survival curves for those with CHF, and/or sleepdisordered breathing, or neither. Those with CHF plus CSA had
significantly shorter survival (p ⬍ 0.001) than those with just
CHF or just OSA or CSA.
www.chestjournal.org
of CHF and sleep apnea. All other diseases (as listed
in Table 1) and saturation variables were not significant.
Discussion
Our study examined randomly selected Veteran
men ⬎ 60 years old who were inpatients on a
medical ward at the VASDHS, and who were followed up for 17.5 years. In this sample, there were
significantly greater mortality rates in patients who
had both CHF and CSA than in those with just CHF
or just CSA or just OSA. Patients with CSA or OSA
survived ⬎ 6.75 years, patients with CHF survived
just ⬎ 4 years, while patients with both CHF and
CSA survived just ⬎ 2.5 years. Survival of patients
with just CSA or OSA was no different than that of
those patients with neither heart disease nor sleep
apnea. The shorter survival for those with CSA and
CHF was not explained by any association with
pulmonary disease or other comorbidities.
The results of this study confirm previous findings
but in a larger sample with more years of follow-up
and with more covariates included in analyses than
some other studies. Findley et al,27 in a small sample
followed up for 6 months, was one of the first to
report that men with heart failure and CSA had a
greater rate of death than those with heart failure
and no sleep apnea. Hanly et al33 showed that the
risk of cardiac death in heart disease was increased in
those with CSA. Sin et al19 found that patients with
CSA who received CPAP had a reduction in the
combined rate of mortality and heart transplantation
compared to patients with CSA who did not receive
CPAP. However, among patients with no CSA, there
was no difference in mortality transplantation rate
between those who received and did not receive
CPAP. Those observations suggest that the CSA
initially was a risk factor in those patients. The results
of this study of larger samples with more years of
follow-up also suggest that CSA with CHF is a risk
factor.
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We have previously shown that in community
dwelling elderly, those with more severe sleep apnea, defined as an AHI ⬎ 30, had significantly
shorter survival (7.9 years) compared to those with
AHI ⬍ 15 (9.4 years). Multiple regression analysis
that included age, gender, BMI, and history of
pulmonary or cardiovascular disease, however, resulted in only age, pulmonary and cardiovascular
disease, but not AHI, being significant predictors of
mortality.2 In a review of sleep apnea and cardiovascular disease, Young and Peppard34 noted that this
should not be interpreted as a negative finding. They
presented a model of sleep apnea and cardiovascular
disease that suggested three components: nightly
exposure to sleep apnea as a direct cause of cardiovascular disease, nightly exposure to sleep apnea
causing hypertension and thus indirectly causing of
cardiovascular disease, or sleep apnea modifying the
effect of cardiovascular disease on mortality. Young
and Peppard34 suggested that the data of AncoliIsrael et al2 could be explained by their model, ie,
one would not expect AHI to be predictive when
cardiovascular disease was controlled for, since the
AHI would lead to the cardiovascular disease, which
would then lead to death. The same theory could be
applied to the data in this study. The fact that men
with both CSA and CHF had significantly shorter
survival, by several years, than men with just CHF,
may reflect the sleep apnea modifying effect of
cardiovascular disease on mortality or it may reflect
the severity of the heart disease; ie, it is possible that
sleep apnea is a marker for the severity of the heart
disease rather than a causal factor. Somers,35 in an
editorial, also suggested that the pathophysiology of
CHF and of sleep apnea may be linked and in fact
may potentiate each other. While additional research
is needed to more fully understand these relationships, the results of this study confirm previous
findings with a larger sample and longer follow-up.
Sleep apnea is found in approximately 60% of
patients with heart failure,23,36 and CSA and CSR
account for approximately 30 to 40% of those,13,37
with many of them having occult sleep apnea.12 In
this sample, patients with CHF had more severe
sleep apnea than those without CHF. Sin et al,38 in
a large study of 450 men and women referred to a
sleep laboratory, determined that the risk factors for
CSA were male gender, having atrial fibrillation and
hypocapnia, and being ⬎ 60 years old. Shahar et al39
reported that sleep apnea, even in the mild-tomoderate states, was strongly associated with selfreported heart failure and stroke in the ⬎ 6,000
participants of the Sleep Heart Health Study.
Two recent large epidemiologic studies, the Wisconsin cohort14 and the Sleep Heart Health Study,15
showed that sleep apnea may be a risk factor for
hypertension and consequent cardiovascular morbidity in general population. The authors suggested
that sleep apnea should be treated even at low levels
to avoid the development of these comorbidities.
Our data support this recommendation and suggest
extra caution when patients, particularly older patients with CHF, also have CSA. If the mortality rate
of those with CSA and CHF is higher than the rate
of those with just CHF, it is imperative that older
patients at risk for these disorders be treated.
This study does not clarify the issues of cause and
effect, but does reinforce the strong associations
between sleep apnea and heart disease, CHF, in
elderly hospitalized men. It is unknown whether the
same results would hold in nonhospitalized elderly
men. Nevertheless, these data suggest that older
men with coronary disease should be regarded as a
risk group for sleep apnea. Sleep apnea may adversely affect CHF and may induce a higher mortality rate among patients with CHF. Other investigators have shown that treating sleep apnea in patients
with chronic heart failure results in improved leftventricular ejection fraction and decreased daytime
plasma norepinephrine, atrial natriuretic peptide,
and heart rate.40,41 While controlled treatment trials
are still needed, given the shorter survival of patients
with CHF and CSA, there is an urgent need to
screen patients with CHF for sleep disorders and to
initiate treatment.
ACKNOWLEDGMENT: These data were originally collected in
collaboration with Daniel F. Kripke, MD, and Melville R.
Klauber, PhD.
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