Mortality risk factors in sleep apnoea: a matched case ...

J. Sleep Res. (2007) 16, 128–134

Mortality risk factors in sleep apnoea: a matched case–control
study

P E R E T Z L A V I E , P A U L A H E R E R and L E N A L A V I E

Lloyd Rigler Sleep Apnea Research Laboratory, Ruth and Bruce Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa,
Israel

Accepted in revised form 6 December 2006; received 20 July 2006

SUMMARY Sleep apnoea syndrome was reported to be associated with increased mortality but it is
not known if this association is independent of obesity and co-morbidities. The present
study investigated predictors of mortality in a large cohort of men with sleep apnoea
using a case–control design. The study population consisted of 10 981 men diagnosed
during 1991–2000 by whole-night polysomnography with sleep apnoea; 331 men died
prior to 1 September 2001, of whom 277 were matched by age, gender, site and time of
study to patients who were alive in September 2001. Multivariate analysis revealed that
all-cause mortality was associated with chronic obstructive pulmonary disease (COPD)
(odds ratio, OR: 7.07, 95% CI 2.75–18.16), chronic heart failure (CHF) (OR: 5.47, 95%
CI 1.06–28.31), diabetes mellitus (DM) (OR: 3.30, 95% CI 1.51–7.20) and body mass
index (BMI) (increase of 5 kg m)2, OR: 1.44, 95% CI: 1.04–1.99). Chronic upper
airway problems were associated with survival (OR: 0.45, 95% CI 0.23–0.90). There
were significant interactions between respiratory disturbance index and BMI and
COPD. Mortality of patients younger than the median age (62 years) was associated
with COPD, DM and an interaction between BMI and apnoea severity. Predictors of
mortality for the older patients were COPD, CHF and DM. We conclude that all-cause
mortality in sleep apnoea is associated with co-morbidities and obesity. Severity of sleep
apnoea affects mortality by interacting with obesity and lung disease.

k e y w o r d s all-cause mortality, body mass index, sleep apnoea, case–control

INTRODUCTION shown in people displaying nocturnal breathing events regard-
less of daytime symptoms (Hedner, 2001; Nieto et al., 2000;
Breathing disorder in sleep is a prevalent phenomenon. One in Shahar et al., 2001). There is less information on mortality
every four men and one in every ten women have at least five with regard to sleep apnoea. Recent studies have shown that
disordered breathing events in each hour of sleep in the form people with obstructive sleep apnoea have a peak in sudden
of apnoeas or hypopnoeas, and in at least 4% of men and 2% death from cardiac causes during the sleeping hours (Gami
of women the nocturnal respiratory events are accompanied by et al., 2005), that cardiovascular mortality in sleep apnoea
subjective complaints of excessive daytime sleepiness that patients is severity dependent (Marin et al., 2005; Yaggi et al.,
constitutes the sleep apnoea–hypopnoea syndrome (Young 2005) and that mortality in sleep apnoea is higher in patients
et al., 1993). There is a large body of evidence linking sleep younger than 50 years of age (Lavie et al., 1995; Lavie et al.,
apnoea syndrome with increased cardiovascular morbidity, 2005; Marti et al., 2002; Veale et al., 2000). There are
and in particular with hypertension (Basseti et al., 1996; Bixler conflicting results if coexistence of sleep apnoea and cardio-
et al., 2000; Dyken et al., 1996; Lavie et al., 2000; Mooe et al., vascular disease results in higher mortality than cardiovascular
2001; Peker et al., 1999; Peppard et al., 2000). This link was disease alone. While Peker et al. (2000) reported that sleep
apnoea was an independent predictor of mortality in patients
Correspondence: Peretz Lavie, PhD, Lloyd Rigler Sleep Apnea with coronary artery disease, Marin et al. (1998) reported that
Research Laboratory, Rappaport Building, Efron St Bat-Galim, Haifa there was no difference in the clinical course after MI as a
31096, Israel. Tel.: +972-4-8120881; fax: +972-4-8343934; e-mail: function of sleep apnoea. Also, it is not clear if elderly patients
[email protected]

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Mortality risk factors in sleep apnoea 129

with coexisting chronic heart failure (CHF) and obstructive clinical interviews carried out by the clinician of the sleep
sleep apnoea have higher mortality rates than patients with laboratory. Hypertension was defined as having a history of
CHF alone (Roebuck et al., 2004). using anti-hypertensive medications or blood pressure higher
than 140/90 mmHg. The study was approved by the local
Thus, even though sleep apnoea may play a role in initiating human ethics committee.
the disease process resulting in cardiovascular morbidity, it is
not known what is the risk involved with the coexistence of Analytical methods
sleep apnoea and other co-morbidities. The present paper
addresses this question by investigating all-cause mortality of The association of three factors – RDI, BMI and medical
laboratory diagnosed sleep apnoea patients using a case– condition at the time when the sleep measurements were
control design. recorded – with mortality risk was investigated through logistic
regression using matched data of the case–control pairs. First,
METHODS descriptive statistics were used to compare the two groups and
then univariable logistic regression was performed to select
Study population variables for the multivariate analysis. A model using all the
variables that had a value of P £ 0.15 was set up. Then
Our study population consisted of men (20–100 years of age) insignificant variables (determined by Wald and likelihood
living in Israel, who were diagnosed with sleep apnoea during ratio tests) were removed one at a time to reduce the number of
1991–2000. The sleep study, using whole-night polysomnog- variables in the model. After arriving at a satisfactory main
raphy (PSG), was conducted in one of the four Technion Sleep effects model, BMI and RDI were checked for linearity in the
Laboratories, located in Haifa, Tel Aviv, Hulon, and Jerusa- logit using design variables based on the quintiles of the
lem. Details about the diagnostic procedures in our laborat- combined case–control population. A model using the appro-
ories were provided previously (Lavie et al., 2005). priate scale for BMI and RDI was fit and then interactions
between BMI and RDI and all the variables were determined
Cases and controls using likelihood ratio tests with P < 0.10 as the inclusion
criterion. Alternative models using BMI and RDI as catego-
The vital status of the study population was determined by rical variables (ÔmildÕ, ÔmoderateÕ, ÔsevereÕ for sleep apnoea and
searching via identification number in the Israel National Ônormal weightÕ, ÔoverweightÕ, and ÔobeseÕ for BMI) were also
Population Registry, which maintains a registry of all Israeli calculated, but as the results were not substantially different
citizens, for all patients who underwent whole-night PSG they are not presented. The PROC LOGISTIC program from
between 1 January 1991 and 1 October 2000 and were the SAS package was used for this analysis.
diagnosed with sleep apnoea. A diagnosis of sleep apnoea
was based on a laboratory finding of RDI > 10 and charac- A number of subjects had missing information for some
teristic symptoms, such as chronic fatigue, excessive daytime variables. Such data were excluded, so there is some variation
sleepiness or non-restorative sleep. Cases were defined as in the number of cases included in the analyses. As neither
patients older than 19 years of age studied during that period drug treatment nor subjective complaints emerged as signifi-
who died prior to 1 September 2001. In addition to the vital cant predictors of mortality risk they were dropped from the
status, the Registry includes the following information: gender, analysis and are not further discussed in this paper.
date of birth, date, place and cause of death. However, this
paper presents predictors of death from all causes. In total, RESULTS
10 981 men were diagnosed with sleep apnoea syndrome
during the study period; 331 of whom died prior to 1 Two hundred and seventy-seven of the 331 (83.7%) cases were
September 2001 and met the case criteria definition. successfully matched with controls. Comparison of cases
successfully matched and cases who could not be matched
For each case, a living control matched by year of birth revealed that all were similar in age, year at death, year at
(5 year bands), time (95.9% within ±1 year) and place of sleep examination, weight, BMI and RDI.
examination (96.8% at the same site), similarly diagnosed with
sleep apnoea was selected from the study population. Data Comparison of the 277 cases and their matched controls
collection for cases and controls included: socio-demographic revealed that cases had higher BMI (29.9 ± 5.9 versus 28.5 ±
data, self-reported medical history and use of medications, 4.7 kg m)2; P < 0.001), were heavier (87.8 ± 18.3 versus
sleep questionnaire, respiratory disturbance index (RDI) and 85.3 ± 15.0 kg; P < 0.02), had higher RDI (39.7 ± 24.3
minimum arterial oxygen saturation during sleep, which were versus 35.1 ± 21.2 events per hour; P < 0.004) and lower
obtained from the results of the whole-night PSG study, and minimum oxygen saturation (80.2 ± 11.9% versus 82.9 ±
body mass index (BMI) in kg m)2. Apnoea was defined as a 9.7%; P < 0.005) (Table 1). Cases were more likely to have a
cessation of airflow for at least 10 s, while hypopnoea was prior history of ischaemic heart disease (IHD) (31.6% versus
defined as a decrease in airflow of at least 50% associated with 19.2%, P < 0.01), CHF (10.9% versus 1.6%; P < 0.0003),
either a decrease of 3% in oxygen saturation or signs of chronic obstructive pulmonary disease (COPD) (27.5% versus
physiological arousal. Medical history was based on the 6.7%; P < 0.0001), diabetes mellitus (DM) (20.7% versus

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130 P. Lavie et al.

Table 1 Demographics and results of sleep study of cases and controls

Cases Controls

Variable n Mean SD Min Max Mean SD Min Max t-value P-value

Age at examination 277 61.2 11.1 19 89 60.9 10.9 19 88 –*
–*
Examination date 277 1994.7 2.2 1991 2000 1994.6 2.3 1991 2001 –
0.001
Death age 277 64.8 11.2 22 90 –– – –– 0.02
0.004
BMI 272 29.9 5.9 19.0 64.4 28.5 4.7 16.0 54.0 3.27 0.005

Weight 272 87.8 18.3 36 160 85.3 15.0 53 155 2.43

RDI 272 39.7 24.3 11 152 35.1 21.2 11 106 2.88

Min Oxygen Saturation 215 80.2 11.9 38 100 82.9 9.7 40 99 )2.81

RDI, respiratory disturbance index; Min oxygen, minimum nocturnal oxygen saturation.
*Matching variable. Comparisons between cases and controls were made by paired t-tests. Two-tailed P-values are reported.

Table 2 Medical history of cases and controls at the time of diagnosis increased risk of mortality. On the other hand, upper airway
(n ¼ 221) problems decreased the risk of mortality (OR: 0.34, 95% CI
0.19–0.61) (Table 3).
Variable Cases Controls v2 P-value
Main effects model
Hypertension 44.0 38.3 1.15 NS
MI 18.6 9.3 5.78 0.02 The best-fitting multivariate main effects model using stepwise
IHD 31.6 19.2 6.15 0.01 selection and forcing RDI and BMI on the model showed that
Cardiac arrythmia 8.3 5.2 1.04 NS increased risk of mortality was associated with COPD (OR:
CHF 10.9 1.6 13.14 0.0003 7.07, 95% CI 2.75–18.16), CHF (OR: 5.47, 95% CI 1.06–
Vulvolar heart disease 3.6 2.6 <1.00 NS 28.31), DM (OR: 3.3, 95% CI 1.51–7.20) and BMI. An
CVA 5.7 3.1 <1.00 NS increase of five BMI units increased the risk of mortality by
Hyperlipidemia 8.3 7.8 <1.00 NS 44% (OR: 1.44, 95% CI: 1.04–1.99). In contrast, upper airway
Heavy smoking 13.5 10.4 <1.00 NS problems were associated with survival (OR: 0.45; 95% CI
Upper airway problems 7.8 21.8 12.75 0.0003 0.43–0.90). Neither MI nor IHD entered the model, but when
Treated upper airways 0.0 2.6 2.25 NS IHD was removed from the model, MI bordered on statistical
COPD 27.5 6.7 29.25 0.0001 significance (P < 0.08). Likewise, when MI was removed,
Asthma 6.2 5.7 <1.00 NS IHD bordered on statistical significance (P < 0.10). No
Diabetes 20.7 8.8 9.49 0.002 significant mortality risk was associated with RDI (OR: 1.02,
Hyperthyroidism 3.6 2.7 <1.00 NS 95% CI 0.90–1.15), and replacing RDI with minimum oxygen
Psychiatric 3.6 4.2 <1.00 NS saturation did not change the model (Table 4).
Others 50.3 46.1 <1.00 NS
Model with interactions
Comparisons between the cases and controls were made by McNe-
mar’s tests. Two-tailed P-values are reported. MI, myocardial infarc- When interactions between RDI and BMI and the medical
tion; IHD, ischaemic heart disease; CHF, chronic heart failure; CVA, history variables were added the best-fitting model showed
cerebrovascular accident; COPD, chronic obstructive pulmonary significant two-way interactions between RDI and BMI
disease; heavy smoking, at least two packages per day. (P < 0.0002) and between RDI and COPD (P < 0.02);
CHF (OR: 8.78 95% CI 1.45–53.10), DM (OR: 3.83, 95%
8.8%; P < 0.002) and myocardial infarction (MI) (18.6% CI 1.68–8.72) and MI (OR: 2.41, 95% CI 1.12–5.18) remained
versus 9.3%; P < 0.02). Controls had more upper airways independent predictors. The shape of the interaction between
problems, such as deviated septum, vasomotor rhinitis and RDI and BMI is provided in Fig. 1 that presents the RDI
chronic sinusitis (21.8% versus 7.8%; P < 0.0004) (Table 2). distributions in deceased and alive patients for three BMI
categories of normal weight, overweight and obese. The most
Univariable analysis notable difference was evident for the category of obese
patients (BMI > 30 kg m)2) with the most severe sleep
The results of the univariable logistic regression showed that apnoea (RDI > 60), in which there were 2.4-fold more cases
before adjusting for any other variable, a history of CHF than controls, and in the categories with Ônormal weightÕ and
(Odds ratio, OR: 10.0, 95% confidence interval, CI 2.34– ÔoverweightÕ (BMI 18–25 and 26–30 kg m)2) with RDI 11–20,
42.78), COPD (OR: 7.67, 95% CI 3.27–17.95), DM (OR: 2.64, in which there were 50% and 40% more controls than cases.
95% CI 1.43–4.89), MI (OR: 2.12, 95% CI 1.17–3.85) and Otherwise, the number of cases and controls did not show any
IHD (OR: 1.92, 95% CI 1.20–3.09) significantly increased the systematic trend. Thus, interaction analysis revealed that when
risk of mortality. Likewise, an increase in five BMI units (OR:
1.33, 95% CI 1.11–1.58), and an increase in 10 respiratory
events per hour (OR: 1.11, 95% CI 1.03–1.19), or a decrease of
10% in minimum arterial oxygen saturation during sleep (OR:
0.78, 95% CI 0.65–0.93) were individually associated with

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Mortality risk factors in sleep apnoea 131

Table 3 Mortality risk factors as determined by univariable logistic regression model: odds ratio (OR) and 95% Wald confidence interval (Wald
95% CI)

Variable Coefficient SE P-value OR Wald 95% CI Discordant pairs

BMI 0.0566 0.0181 0.002 1.33* 1.11–1.58 NR
RDI 0.0104 0.0037 0.005 1.11  1.03–1.19 NR
Minimum oxygen saturation )0.0252 0.0093 0.007 0.78à 0.65–0.93 NR
Hypertension 0.2542 0.2162 0.24 1.29 0.84–1.97 49, 38
Diabetes 0.9719 0.3138 0.002 2.64 1.43–4.89 37, 14
IHD 0.6538 0.2418 0.007 1.92 1.20–3.09 50, 26
MI 0.7536 0.3032 0.01 2.12 1.17–3.85 34, 16
CHF 2.3026 0.7416 0.002 10.00 2.34–42.78 20, 2
CVA 0.6061 0.5075 0.23 1.83 0.68–4.96 11, 6
COPD 2.0369 0.4341 0.0001 7.67 3.27–17.95 46, 6
Heavy smoking 0.3365 0.3381 0.32 1.40 0.72–2.72 21, 15
Hypercholesterol 0.0870 0.4174 0.84 1.09 0.48–2.47 12, 11
Upper airway problems )1.0761 0.2990 0.0003 0.34 0.19–0.61 13, 40
Upper airways interventions§ – – – – 0, 5
–

BMI, body mass index; RDI, respiratory disturbance index; IHD, ischaemic heart disease; MI, myocardial infarction; CHF, chronic heart failure;

CVA, cerebrovascular accident; COPD, chronic obstructive pulmonary disease; heavy smoking, at least two packages per day.
*Odds ratio for a 5 kg m)2 increase in BMI.
 Odds ratio for 10 respiratory events per hour increase.
àOdds ratio for a 10% decrease in arterial oxygen saturation.
§Model could not be fit because of zero discordant cell. NR, not relevant.

Table 4 Main effects model, odds ratio (OR) and 95% Wald hour; P < 0.02) and lower minimum oxygen saturation
confidence interval (CI), for mortality risk factors (79.1 ± 13.4% versus 82.8 ± 10.1%; P < 0.01). Cases were
more likely to have a prior history of IHD (29.0% versus
Variable OR 95% Wald CI P-value 12.9%, P < 0.009), CHF (7.5% versus 1.1%; P < 0.08),
COPD (22.6% versus 3.2%; P < 0.0003), DM (21.5% versus
RDI 1.02* 0.90–1.15 0.77 7.5%; P < 0.02) and MI (18.3% versus 6.5%; P < 0.03).
BMI 1.44** 1.04–1.99 0.03 Controls had more upper airway problems, such as deviated
CHF 5.47 1.06–28.31 0.04 septum, vasomotor rhinitis and chronic sinusitis (19.4% versus
COPD 7.07 2.75–18.16 0.0001 6.5%; P < 0.003) and tended to have more treated upper
Diabetes 3.30 1.51–7.20 0.003 airway problems (3.2% versus 0.0%; P < 0.07).
upper airway problems 0.45 0.43–0.90 0.02
Cases who were above the median age had higher BMI
RDI, respiratory disturbance index; BMI, body mass index; CHF, (29.1 ± 5.0 versus 28.0 ± 3.7 kg m)2; P < 0.05) and were
more likely to have a prior history of CHF (14.0% versus 2.0%;
chronic heart failure; COPD, chronic obstructive pulmonary disease. P < 0.003) and COPD (32.0% versus 10.0%; P < 0.0001).
There was no difference in RDI or oxygen saturation.
*Odds ratio for 10 respiratory events per hour increase.
**Odds ratio for a 5kg ⁄ m-2 increase in BMI. For the cases at or below the median age the best-fitting
multivariate main effects model using stepwise selection and
RDI increased from 10 to 40 events per hour, the risk forcing RDI and BMI on the model showed that increased risk
associated with five BMI units increased from 1.88 (95% CI of mortality was associated with COPD (OR: 8.60, 95% CI
1.22–2.89) to 3.14 (95%CI 1.71–5.77). Similarly, when BMI 1.76–42.06) and DM (OR: 3.15, 95% CI 1.02–9.70). Also, an
increased from 23 to 30 kg m)2, the risk associated with 10 increase of five BMI units increased the risk of mortality by
respiratory events per hour increased from 2.37 to 3.10. 75% (OR: 1.75, 95% CI: 1.04–2.92). On the other hand, in
cases above the median age increased risk of mortality was
The interaction between COPD and RDI revealed that in associated with CHF (OR: 9.88, 95% CI 1.05–92.63), COPD
the presence of COPD, a change in RDI from 10 to 40 events (OR: 8.94, 95% CI 2.46–32.50) and DM (OR: 3.76, 95% CI
per hour was associated with a threefold increase in the risk of 1.24–11.38).
mortality, from 9.98 to 33.65. There were no significant three-
way interactions. When interactions between RDI and BMI and the medical
history variables were added the best-fitting model for cases
Men above and below the median age below the median age showed significant two-way interactions
between RDI and BMI (P < 0.002) and included DM (OR:
The median age of the male cases was 62 years. Comparison of 3.88, 95% CI 1.11–13.62) and COPD (OR: 8.83, 95% CI 1.72–
the cases who were of the median age or below with their 45.36) as significant predictors. Analysis of the interaction
matched controls revealed that cases had higher BMI between BMI and RDI revealed that when RDI increased
(30.7 ± 6.6 versus 29.0 ± 5.6 kg m)2; P < 0.01), were from 10 to 40 events per hour, the risk associated with five
heavier (92.6 ± 20.0 versus 89.4 ± 16.4 kg; P < 0.04),
had higher RDI (40.9 ± 24.8 versus 36.3 ± 24.8 events per

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132 P. Lavie et al.

50 BMI 18–25 adjustment to co-morbidities severity of sleep apnoea was no
40 longer independently associated with risk of mortality, but
30 Case Control significantly increased the risk of death by interacting with
20 BMI and with COPD. An analysis of the data of patients
NN N 10 21–30 31–40 41–50 51–60 >60 younger and older than the median age revealed that the
impact of obesity and the interaction between obesity and
0 RDI sleep apnoea severity were most profound in patients younger
11–20 than the median age. In contrast to the younger patients, the
interaction between BMI and RDI in the older group was only
BMI 26–30 of borderline statistical significance and BMI was not a
significant predictor.
50 21–30 31–40 41–50 Case Control
40 51–60 >60 The present findings are in general agreement with the
30 RDI literature regarding predictors of mortality in sleep apnoea
20 patients as well as in other populations (Hoes et al., 1993;
10 Lavie et al., 1995; Marti et al., 2002; Sto¨ rk et al., 2006; Veale
et al., 2000). Thus, our observation that COPD and CHF were
0 the most important independent predictors of mortality is
11–20 congruent with findings on mortality of untreated (Lavie et al.,
1995) as well as treated sleep apnoea patients (Marti et al.,
50 BMI >30 2002; Veale et al., 2000). In these earlier studies, similar to our
40 present findings, after adjustment to co-morbidities the sever-
30 Case Control ity of the syndrome was unrelated to mortality. Because of lack
20 of statistical power, none of the previous studies examined
10 21–30 31–40 41–50 51–60 >60 interactions between sleep apnoea and other variables. Of
note, the observation that the relative risk associated with
0 RDI greater body weight was higher among younger subjects was
11–20 reported previously as well (Stevens et al., 1998).

Figure 1. Respiratory disturbance indices (RDI) in three body Our findings indicate that the risk of mortality associated
mass categories (BMI) of 18–25, 26–30 and >30 kg m)2 in cases and with CVA, CHF diabetes and IHD was not affected by the
coexistence of sleep apnoea as there were no interactions
controls. between the presence of these diseases and the severity of the
syndrome. Previous report that patients with coexisting CHF
BMI units increased from 2.08 (95% CI 1.02–4.25) to 11.85 and obstructive sleep apnoea did not have higher mortality
(95% CI 1.21–115.67); a further increase in RDI to 60 rates than patients with CHF alone is in agreement with the
increased the risk to 28.28 (95% CI: 1.02–784.67). In cases present observation (Roebuck et al., 2004). There are conflict-
above the median age the interaction between RDI and BMI ing results, however, if the combined effect of IHD and sleep
was only of borderline statistical significance (P < 0.06); CHF apnoea on mortality is greater than the effect of either of them
(OR: 11.62, 95% CI 1.23–109.41), DM (OR: 4.15, 95% CI individually (Marin et al., 1998; Peker et al., 2000). A recent
1.28–13.44) and COPD (OR: 9.72, 95% CI 2.54–37.10) were report on an association between sleep disordered breathing
identified as significant predictors. and cerebrovascular mortality (Parra et al., 2004) is also
problematic, as the deceased patients in that study had shown
DISCUSSION a high rate of Cheyne–Stokes breathing which could indicate
that the disordered breathing occurred as a result of the stroke
We report here on the predictors of all-cause mortality in men disease but did not cause it. Moreover, overall mortality in
with sleep apnoea syndrome based on a very large case–control that study was lower than expected. Thus, even though sleep
study. Multivariate analysis revealed that the following co- apnoea may play a role in initiating the disease process
morbidities: COPD, CHF, DM and obesity, significantly resulting in cardiovascular morbidity, the combined risk of
increased the risk of mortality in men with sleep apnoea. In coexisting sleep apnoea and cardiovascular morbidity does not
contrast, the existence of upper airway problems conferred a appear to be significantly greater than that of the cardio-
protective effect and was significantly associated with survival. vascular morbidity alone.
Before adjustment to co-morbidities, the severity of sleep
apnoea, expressed by the number of respiratory events per As is evident from the shape of the figure depicting the
hour of sleep or by a 10% decrease in arterial oxygen relationship between RDI and BMI in cases and controls, the
saturation, was associated with only a moderate risk of interaction between BMI and RDI predominantly stems from
mortality of 11% and 22% respectively. However, after the disparate number of cases and controls at the high end of
the RDI distribution in the obesity category and at the lower
end of the RDI distributions in the normal weight and

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Mortality risk factors in sleep apnoea 133

overweight categories. For RDI values within the range of 21– included recommendation for treatment, we know that nasal
60 events per hour, the numbers of cases and controls in all continuous positive airway pressure (nCPAP) treatment and
three BMI categories are remarkably similar. Thus, our data upper airway interventions were recommended to approxi-
suggest that obese patients, particularly younger than 62 years, mately the same number of cases and controls. We do not
having the most severe sleep apnoea syndrome have the know, however, how many cases and controls actually
highest risk of dying. The fact that COPD has been consis- complied with treatment and to what extent. The question if
tently associated with mortality in sleep apnoea (Lavie et al., treatment of sleep apnoea patients decreases mortality is still
1995; Marin et al., 2005; Yaggi et al., 2005) and the significant unanswered. While a recent study demonstrated that comply-
interaction between COPD and apnoea severity observed in ing with nCPAP treatment decreases cardiovascular mortality
the present study suggest that their coexistence confers in severe sleep apnoea patients (Marin et al., 2005), in another
mortality risk which is higher than the risk presented by either study, all-cause mortality of a large cohort of sleep apnoea
of them independently. This could be related to the fact that patients was reported to be unaffected by treatment (Yaggi
for patients manifesting the combination of COPD and sleep et al., 2005). The facts that upper airway problems emerged as
apnoea, termed the Ôoverlap syndromeÕ, higher pulmonary a significant predictor of survival and that controls had more
artery mean pressure, both resting and exercising, was interventions in the upper airway than cases, raise the
displayed. Therefore, these patients are at risk of developing possibility that a variety of treatments in the upper airways
respiratory insufficiency and corpulmonale (see a review in may indeed decrease mortality in sleep apnoea patients. Others
Mohsenin, 2005). Likewise, it was shown that they have more also reported on beneficial effects of such treatments on sleep
severe nocturnal arterial oxygen desaturation and a greater apnoea mortality (Keenan et al., 1994; Weaver et al., 2004).
degree of sleep disturbance than patients with either COPD or This observation makes an interesting research agenda for
sleep apnoea only (Weitzenblum and Chaouat, 2004). future studies. We should also note that measurement of
visceral fat could be more relevant to the long-term outcomes
Previously, we reported that the hazards of mortality in the of sleep apnoea than BMI, as there is evidence that sleep
parent cohort of the cases and controls investigated in the apnoea patients have a significantly greater amount of visceral
present study significantly increased with both RDI and BMI, fat compared with obese controls and that apnoea severity is
but there was no interaction between them (Lavie et al., 2005). more closely related to visceral fat than to BMI (Vgontzas
The reasons for the difference between the results of the two et al., 2000). Another limitation of the study is that because of
studies are possibly related to the different reference groups the small number of women in comparison with men, only men
employed and the variables included in the analysis. In our were included in the present study and therefore the present
previous study, the population included men studied by whole- findings cannot be generalized to women.
night PSG because of suspected sleep apnoea regardless of
their final diagnosis. Thus, the hazards of mortality were We believe, however, that the strengths of our study that
estimated in reference to the group of men who did not meet rely on a large cohort all diagnosed by whole-night PSG and
the sleep apnoea diagnosis criteria of having RDI > 10. In the on a careful matching between cases and controls, outweigh
present study, however, we included in the analysis only men the limitations. The observations that co-morbidities and
with a polysomnographically confirmed diagnosis of sleep obesity are significant mortality risk factors and that the risk of
apnoea. Thus, both cases and controls comprised overweight mortality is particularly high in young obese patients with
and obese patients having moderate-to-severe sleep apnoea severe sleep apnoea, together with our previous finding that
syndrome. Even though there was a significant difference in sleep apnoea patients younger than 50 years of age have the
apnoea–hypopnoea index and in oxygen desaturation between highest risk of mortality in comparison with the general
cases and controls, these were rather small and of doubtful population (Lavie et al., 2005), foresee important clinical
clinical significance. implications regarding the diagnosis and treatment of the
syndrome. As the combination of obesity and severe sleep
Our present study has several limitations that should be apnoea confers the highest risk of death, diagnosis and
acknowledged. First, only 83.7% of the cases could be treatment of obese patients are of particular importance.
matched with controls, which could introduce some selection Likewise, in view of the increased mortality risk associated
bias into the results. Cases without controls, however, had the with the combination of COPD and sleep apnoea, when one of
same characteristics as cases with controls. Also, a complete these disorders is diagnosed, clinicians should consider the
medical record was available for only 221 of the 315 cases, and independent existence of the other. Such a practice should
this could also introduce some bias into the results. We should prove valuable for preventing mortality in patients with
point out, however, that a separate analysis of patients below COPD.
and above the median age, and of cases and controls
accumulated until the median time of the study period and In summary, using a case–control design based on a large
after the median time of the study period, resulted in similar cohort of sleep apnoea patients, we found that medical
profiles of risk factors (data not presented). Thirdly, we did not history of COPD, CHF, DM and obesity constitute
have reliable information to allow the examination of treat- significant risk factors for mortality. The severity of the
ment effects on mortality. Based on the summary letter sent to syndrome significantly interacted with COPD and obesity to
the referring physician after the sleep examination which increase mortality. Based on these observations, there is a

Ó 2007 European Sleep Research Society, J. Sleep Res., 16, 128–134

134 P. Lavie et al.

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