Should all sleep apnoea patients be treated?

Sleep Medicine Reviews, Vol. 6, No. 1, pp 7–14, 2002 doi:10.1053/smrv.2001.0178, available online at http://www.idealibrary.com on

SLEEP MEDICINE reviews

CLINICAL REVIEW

Should all sleep apnoea patients be treated? Jose´ M. Montserrat1, Ferran Barbe2 and Daniel O. Rodenstein3 1

Hospital Clı´nic, Universitat de Barcelona, Spain, 2Hospital Son Dureta, Palma de Mallorca and 3Cliniques Universitaires Saint-Luc, Universite´ Catholique de Louvain, Brussels, Belgium KEYWORDS sleep apnoea hypopnoea syndrome, CPAP treatment indications, apnoea hypopnoea index

Summary Sleep apnoea is a condition in which people stop breathing during sleep. A number of studies in general and worker populations have shown that the prevalence of an apnoea–hypopnoea index (AHI) >10 is in the range of 20%. Subjects with an AHI >10 that complain of excessive daytime somnolence, tiredness, asphyxic episodes during the night or non-refreshing sleep, among other symptoms, suffer from the sleep apnoea hypopnoea syndrome (SAHS). The prevalence of SAHS is around 4%. Owing to its high prevalence, clinical symptoms, probable secondary cardiovascular consequences and associated social problems, SAHS has a considerable impact on health, management of which is worth considering. Despite the fact that SAHS treatment has been challenged recent studies conclude that nasal continuous positive airway pressure (nCPAP) is undoubtedly effective in clearly symptomatic patients. Its use in clinical practice is adequately supported in the treatment of moderate to severe SAHS. Further studies are needed in order to define the lower range of symptoms to be treated. One of the most important problems encountered in this area results from the combination of two situations. On the one hand, different epidemiological studies have demonstrated that an AHI >10 without symptoms is present in around 15% of the general population. On the other hand, several studies suggest that having a high AHI, even without secondary symptoms, gives rise to some undesirable effects such as traffic accidents and cardiovascular consequences. In this context, comprehensive epidemiological studies are therefore warranted to define the role of nCPAP treatment especially in those subjects with a high AHI but with few or no symptoms.  2002 Published by Elsevier Science Ltd

INTRODUCTION Sleep apnoea is a condition in which people stop breathing during sleep [1]. The most common type, obstructive sleep apnoea or hypopnoea, is the result of a complete or partial pharyngeal occlusion during sleep [2]. The frequency of occurrence is generally

Correspondence should be addressed to: Dr J.M. Montserrat, Institut Clı´nic de Peumologia i Cirugia Tora´cica, Hospital Clı´nic, Villarroel 170, 08036 Barcelona, Spain. E-mail: [email protected]

expressed as the number of events per hour of sleep, the apnoea–hypopnoea index (AHI). Different prevalence studies in general [3] and worker [4] populations have shown that the prevalence of an AHI >10 is in the range of 20%. Sleep apnoea hypopnoea syndrome (SAHS) is diagnosed when subjects with apnoeas or hypopnoeas during sleep complain of secondary symptoms such as excessive daytime somnolence, tiredness, asphyxic episodes during the night or non-refreshing sleep. The prevalence of SAHS is around 4% [3, 4] and it occurs more frequently in middle-aged obese men. SAHS is an independent risk factor for cardiovascular

1087–0792/02/$-See front matter  2002 Published by Elsevier Science Ltd

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disease [5–7] and systemic arterial hypertension [8, 9]. Moreover, patients with SAHS suffer from a decrease in the quality of life and from intellectual and social functioning deterioration. Excessive daytime sleepiness is the most common and relevant symptom [10]. Impairment of alertness could make these patients susceptible to occupational or automobile accidents and/or to poor work and social functioning [11–13]. Given its high prevalence, clinical symptoms, probable secondary cardiovascular consequences and associated social problems, SAHS has a considerable impact on health [14]. The treatment of SAHS should relieve both the physiological abnormalities and the complaints of the patients. The main (but by no means the only) therapy used for patients with SAHS is nasal continuous positive airway pressure (nCPAP). Thus, there are in the general adult population around 15% of subjects without symptoms but with an AHI >10 and about 4% of the population with different degrees of symptoms and an AHI >10. In the present review we would like to support the following position: the presence of apnoeas and/or hypopnoeas during sleep unaccompanied by associated nocturnal and daytime symptoms does not justify the institution of treatment. Only those patients with nocturnal and daytime symptoms due to the presence of apnoeas and/or hypopnoeas during sleep should be treated. This review will be mainly focused on CPAP treatment.

IS nCPAP AN EFFICIENT TREATMENT? Treatment of SAHS with nCPAP has been challenged recently by Wright et al. in a review article [15] and in a very recent Pro/Con editorial in the American Journal of Respiratory and Critical Care Medicine [16, 17]. In the British Medical Journal review, Wright et al. suggested that the role of nCPAP treatment was unclear because there were not enough data to prove the effectiveness of CPAP on SAHS. In the American Journal of Respiratory and Critical Care Medicine Pro/Con paper, the conclusion was more moderate: “although trials show that CPAP relieves symptoms in patients with fairly severe sleep apnoea, definition problems and the lack of good evaluation of less severely affected patients leave much uncertainty”. Despite being in agreement with this sentence we think that the author places undue emphasis on the incomplete aspect of the current

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knowledge. In keeping with other physicians who have dealt with SAHS patients for many years we have observed that a large number of patients can benefit substantially from nCPAP treatment. Most of the national guidelines for nCPAP treatment specify that only symptomatic patients with moderate to severe SAHS should be treated. In this regard, even Wright et al. agree with us when they state in the British Medical Journal that “There is enough evidence suggesting benefit in reducing daytime sleepiness with CPAP”. As has been mentioned previously, our position in the present review is that only those patients with nocturnal and daytime symptoms due to the presence of apnoeas and/or hypopnoeas during sleep should be treated. This position is based on a number of comprehensive studies that have been carried out recently. Nevertheless, the amount and degree of severity of the associated symptoms required still need further discussion. It should be stressed, however, that in asymptomatic or pauci-symptomatic subjects caution is desirable given that recent data suggest that the AHI alone, even without associated symptoms, may be linked to untoward effects such as traffic accidents or some cardiovascular consequences. Therefore, we should like to focus our attention on two main considerations: (1) the studies demonstrating that CPAP is very useful in symptomatic patients and (2) the studies suggesting that the AHI alone, even without symptoms, is responsible for some undesirable effects. What must be stressed is that we should treat patients and not subjects who have a given AHI; this means the group (or at least a subgroup) of the 4% of individuals that have an SAHS (apnoeas, hypopnoeas and clinical complaints). On the other hand, the group of people with an AHI >10 without symptoms, accounting for approximately 15% of the adult population, should not be treated at the present time. This approach differs from the one taken, for instance, for cholesterol, where an abnormal value in blood is treated in completely asymptomatic subjects since the longterm consequences of this abnormal value are well characterized.

NCPAP effects in patients with moderate to severe SAHS The efficacy of CPAP in moderate–severe SAHS is supported by a strong body of evidence coming from some randomized, placebo-controlled studies

SHOULD ALL SLEEP APNOEA PATIENTS BE TREATED?

published recently. In some cases, the placebo was a pill or a suboptimal or a true sham CPAP. To illustrate this, we shall review the two most recent studies in this area confirming the pioneering work performed by the Edinburgh group and others [18– 20]. The Oxford group in a paper in The Lancet compared, in 101 SAHS patients, the efficacy of optimal CPAP versus suboptimal CPAP [21]. Fortynine patients received subtherapeutic CPAP and 52 therapeutic levels of CPAP for a period of 4 weeks. Patients with optimal CPAP improved significantly more in almost all outcomes compared with patients on suboptimal CPAP. The outcomes measured were the Epworth sleepiness scale, a test of maintenance of wakefulness, SF-36 measures of energy and vitality and SF-36 mental summary score. A similar study was recently carried out in Barcelona [22]. Fifty patients entered a randomized placebo-controlled (sham CPAP) trial in order to evaluate the effectiveness of CPAP in improving SAHS-related symptoms, Epworth sleepiness scale, daytime function (FOSQ) and quality of life (SF-36) in patients with moderate to severe SAHS. In both studies, the relief of sleepiness and other SAHS-related clinical symptoms and FOSQ vigilance scales was much greater in the group receiving optimal CPAP compared with the group with sham CPAP. When the sham CPAP group was shifted to optimal CPAP a marked improvement was observed. As in the Oxford paper, both groups used the optimal and the sham or suboptimal CPAP for a similar number of hours. Therefore, it seems clear that CPAP is effective in the treatment of moderate to severe SAHS and its use in clinical practice is adequately supported. It is worth mentioning that a placebo effect was observed in both studies. It should be pointed out that all patients in the placebo group of both studies used their useless machines for more than 4 hours per night, a really remarkable achievement.

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controlled trial, assessed the results of CPAP treatment versus conservative measures in a group of 97 patients with mild SAHS [25]. Mild SAHS was defined as an AHI between 5 and 30 without pathological sleepiness. The response was assessed by questionnaires after 8 weeks of treatment. The authors measured changes between pre- and posttreatment in mood, energy/fatigue, functional status and general health. From the 51 subjects assigned to CPAP, 25 (49%) experienced an improved outcome compared with 26% of the 46 patients assigned to conservative measures. The odds of experiencing an improvement in the CPAP group compared with the conservative group was 2.72 (odds ratio (OR): 1.18–6.58, 95% confidence interval (CI)). Vidal et al. have recently completed a large multicentre randomized controlled study where 125 patients with mild SAHS were also allocated to CPAP or conservative treatment [26]. Mild SAHS was defined as an AHI between 10 and 30 but with an apnoea index lower than 20 with an absence of severe sleepiness defined by ATS criteria. As outcomes, the following parameters were studied: SAHS-related symptoms, Epworth sleepiness scale, daytime functional status (FOSQ), Nottingham health profile, cognitive function, multiple sleep latency test and spot systemic blood pressure measurement. A full polysomnography (PSG) was obtained at the end of the 6 month trial. The main results were as follows: SAHS-related symptoms improved significantly and the Epworth sleepiness scale also showed a greater improvement with CPAP. The remaining outcomes showed no difference. However, most of the latter had a ceiling effect. The full PSG at 6 months showed a normalization of the AHI in the CPAP group while on CPAP. A small decrease in the AHI was observed in the conservatively treated group. The evidence from these studies, although less robust, also supports the role of the CPAP treatment in such patients, bearing in mind that our main goal is to improve SAHS-related symptoms and well-being.

NCPAP in patients with mild SAHS The picture is less clear in SAHS patients with mild–moderate AHI or in those that are paucisymptomatic. As far as patients with mild SAHS are concerned, two recent studies on a large number of patients merit some comments that again confirm the pioneering work performed by the Edinburgh group [23, 24]. Redline et al., in a randomized

NCPAP in asymptomatic subjects who stop breathing during sleep Finally, the role of CPAP in subjects with a high AHI, but without daytime sleepiness, has recently been addressed in a randomized placebo-controlled multicentre study performed by Barbe´ et al. [27]. The authors studied 55 patients from six teaching

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hospitals. Twenty-nine patients received optimal CPAP whereas 25 were given sham CPAP. Inclusion criteria were an AHI greater than 30, Epworth sleepiness scale less than 10 and a total absence of daytime sleepiness or a mild daytime sleepiness defined by ATS and ASDA criteria. As outcomes, the following parameters were studied: Epworth sleepiness scale, multiple sleep latency test, daytime functional status (FOSQ), SF-36 general health profile, cognitive function and 24 h systemic blood pressure measurement. None of the outcome measurements showed improvement with optimal CPAP when compared with sham CPAP. Therefore, the authors concluded that their results do not support the use of CPAP in non-sleepy subjects with a high AHI. In summary, we can conclude that CPAP is without doubt effective in the treatment of moderate to severe SAHS and its use in clinical practice is adequately supported. Until now only symptomatic patients have benefited. However, it is necessary to define the lower range of symptoms that can be improved with CPAP beyond the improvement seen with a placebo treatment. The fact that, in some studies carried out in mild to moderate SAHS patients, a ceiling effect was found in some of the classic questionnaires employed highlights the need for further work in this group of patients. New and different outcomes such as cardiovascular parameters and perhaps more refined tests that identify symptoms related to sleep-disordered breathing will improve our understanding on the efficacy of CPAP at different levels of SAHS severity.

HEALTH CONSEQUENCES OF SLEEP-RELATED DISORDERED BREATHING Different epidemiological studies have demonstrated that the prevalence of an AHI >10 with or without symptoms is extremely high, in the range 15–20% [3, 4] More disturbing is the fact that some comprehensive studies have demonstrated an association between some undesirable health events, such as traffic accidents [11, 12] or cardiovascular events [5, 7–9], and the AHI itself regardless of the presence or absence of symptoms.

Cardiovascular consequences Data from the two large ongoing epidemiological studies, the Wisconsin Sleep Cohort study and

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the Sleep Heart Health Study, have been recently published. Peppard et al. performed a prospective, population-based study on the association between sleep-disordered breathing and systemic hypertension [9]. Data on sleep-disordered breathing, blood pressure and health history at baseline and after 4 years of follow-up in more than 700 subjects were analysed. Furthermore, data from 184 subjects after 8 years of follow-up were also analysed. The ORs for the presence of systemic hypertension (defined as a laboratory measure of at least 140/90 or by the use of antihypertensive medication) after a 4 year follow-up were studied. Adjustment was performed for some confounding factors such as body mass index (BMI), neck and waist circumference, age, sex and weekly use of tobacco and alcohol. With respect to a reference category of subjects with an AHI of 0 events per hour at baseline, the ORs for the presence of hypertension at follow-up were 1.42. (1.13–1.78, 95% CI) for subjects with an AHI of 0.1–4.9 events/h at baseline, 2.03 (1.29–3.17, 95% CI) for subjects with an AHI of 5–14.9 events/h at baseline and, 2.89 (1.46–5.64, 95% CI) for participants with an AHI of 15 or more events per hour at baseline. Therefore, the authors concluded that there is a dose–response association between sleep-disordered breathing at baseline and the presence of hypertension 4 years later which was independent of known confounding factors. Nieto et al., who recently published the initial results of the Sleep Heart Health Study [8], have assessed the association between sleep-disordered breathing and hypertension in a large cohort of middle-aged and older persons (aged >39 years, 53% female). Cross-sectional analyses of 6132 participants in the study were performed also taking into account the most common confounding factors. The authors found that the mean systolic and diastolic blood pressures as well as the prevalence of hypertension rose significantly with increasing sleep disorders of breathing. Although part of this association was attibuted to the BMI, alcohol and tobacco consumption, the OR for hypertension, comparing the highest category of AHI (up to 29) with the lowest category (AHI < 1.5), was 1.37 (1.03–1.83, 95% CI). Furthermore, in a stratified analysis, the association of hypertension with sleep-disordered breathing was observed in both sexes, older and younger people, all ethnic groups and among normal weight and overweight subjects. Therefore, in agreement with Peppard et al., Nieto et al. concluded that sleepdisordered breathing is associated with systemic

SHOULD ALL SLEEP APNOEA PATIENTS BE TREATED?

hypertension regardless of the most common confounding factors. Lavie et al. [28] recently established that sleep apnoea syndrome was an independent risk factor for hypertension. The authors studied 2677 adults, aged 20–85 years, who had been referred to the sleep clinic with suspected sleep apnoea syndrome. The following data were analysed: medical history, demographic data, morning and evening blood pressure, and full-night polysomnography. The main results were the following. Blood pressure and number of patients with hypertension increased linearly with the severity of sleep apnoea, as shown by the AHI. Multiple regression analysis of blood pressure levels of all patients not taking antihypertensives showed that apnoea was a significant predictor of both systolic and diastolic blood pressure after adjustment for age, BMI and sex. Multiple logistic regression showed that each additional apnoeic event per hour of sleep increased the odds of hypertension by about 1%, whereas each 10% decrease in nocturnal oxygen saturation raised the odds by 13%. Therefore, the authors conclude that sleep apnoea syndrome is closely associated with hypertension regardless of all relevant risk factors. These data from the USA and Israel have also been confirmed in Europe. Dura´n et al. carried out a large epidemiological study in Vitoria, Spain [3]. In this study the prevalence of obstructive sleep apnoea-hypopnoea during sleep and the associated clinical features in the general population were estimated in a two-phase cross-sectional study. The first phase, completed by 2148 subjects, included a home survey, blood pressure and a portable respiratory recording, whereas, in the second, subjects with an abnormal number of respiratory events (n=442) and a subgroup of those with normal results (n=305) were invited to undergo polysomnography. Habitual snoring was found in 35% of the population and breathing pauses in 6%. Both features occurred more frequently in men, showing a trend to increase with age, and were significantly associated with the presence of apnoeas and hypopnoeas during sleep. Daytime hypersomnolence occurred in 18% of the subjects and was not associated with obstructive sleep apnoea–hypopnoea. An AHI [10 was found in 19% of men and 15% of women. The prevalence of sleep-disordered breathing (AHI [5) increased with age in both sexes, with an OR of 2.2 (1.7–3.0, 95% CI) for each 10 year increase. AHI was associated with hypertension after adjusting for age, gender, BMI, neck circumference,

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alcohol use and smoking habits. Accordingly, these studies support the link between sleep-disordered breathing and hypertension, regardless of the presence or absence of associated symptoms or comorbidity factors. One important point remains to be clarified: does the link between sleep-related apnoeas and/or hypopnoeas and systemic arterial hypertension imply that subjects with apnoeas– hypopnoeas during sleep need to be treated with nCPAP (or other SAHS-specific treatments) to prevent the appearance of hypertension in the future, even if they are asymptomatic? Given the pharmacological “offer” existing nowadays for the treatment of hypertension, no clear answer can be given today.

Traffic accidents Traffic accidents represent other undesirable events that have been linked to SAHS, particularly in those patients with a severe disease. Findley et al. were pioneers in this field [29, 30]. The initial studies included a small number of subjects, were based on self-reported questionnaires and lacked a control group. It is worth commenting on the most recent papers on this topic. Barbe et al. investigated the association between SAHS and automobile accidents, and evaluated the possible mechanisms [12]. These authors recruited 60 consecutive SAHS patients and 60 healthy controls, matched for sex and age. The number of traffic accidents for the previous 3 years was obtained from the participants and insurance companies. The group of SAHS patients had more accidents than the controls and was more likely to have had more than one accident with an OR 5.2 (1.07–25.29, 95% CI). These differences persisted after stratification for km/year, age and alcohol intake. However, the authors did not find any correlation between the different clinical (somnolence, anxiety, cognitive function) or physiological (AHI, nocturnal desaturations) markers commonly used to define SAHS severity and the number of accidents. In other words, apnoeas or hypopnoeas during sleep increase the risk of traffic accidents but without a dose–response relationship. Teran-Santos et al. also studied the relationship between traffic accidents and AHI [11]. These authors performed a case control study where 102 drivers who received emergency treatment at a hospital for traffic accidents on a highway were compared with 152 controls. The subjects with an

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AHI up to 10 had an OR of 6.3 (2.4–16.2, 95% CI) for having a traffic accident with respect to controls. This increased risk remained significant after adjustment for potential confounders, such as alcohol intake, age, medications, or sleep schedule. However, as in the paper of Barbe´ et al., there was no correlation between the number of respiratory events during sleep and the number of traffic accidents. To summarize the earlier data, it seems that an abnormal AHI may give rise to undesirable effects even in subjects who do not experience any symptoms. These data underline the impact of sleep apnoea on vigilance while driving, but do not indicate that CPAP treatment should be undertaken in asymptomatic patients. It is worth mentioning that nCPAP treatment reduces the number of domestic, vehicle and workplace accidents in patients with SAHS [31–33], i.e. patients with symptoms. No data are available for subjects with apnoeas and hypopnoeas during sleep but without symptoms. Consequently, the problem is incompletely understood. Comprehensive epidemiological studies are, therefore, warranted especially in asymptomatic subjects with a high AHI. Masa et al., in a very recent paper [34], confirmed the previous finding. They interviewed 4002 randomly selected drivers to define the prevalence of sleepy drivers. They found 145 habitually sleepy drivers (3.6%). This group had a higher prevalence of car crashes than controls (OR 13.3; 4.1–43, 95% CI) as well as a higher prevalence of respiratory events during sleep. For an AHI >15 the adjusted OR was 6.0, 95% CI 1.1–32. In summary, current evidence suggests that sleep-disordered breathing (with and without clinical impairment) is associated with an increase in the risk of traffic accident. In patients with SAHS, uncontrolled studies showed that CPAP treatment is effective in reducing traffic accidents; however, the preventive approach for asymptomatic patients deserves future studies.

WHO SHOULD BE TREATED It appears that subjects who have apnoeas or hypopnoeas during sleep, and do complain of daytime somnolence, tiredness, fatigue, morning headaches, nycturia, unrefreshing sleep and other common symptoms of sleep apnoea syndrome, should have specific sleep apnoea syndrome, treatment (nCPAP or other treatments that might prove efficient, such as oral devices or surgery). As far as nCPAP is

concerned, patients with these symptoms, and an AHI >10, should be offered a trial of nCPAP especially if the dietetic and sleep hygiene measures have failed. Whether this treatment should be maintained in the long term will depend on the symptomatic improvement experienced by the patient during the initial trial period, provided of course that nCPAP is proven to correct the physiological abnormalities during sleep. At present, subjects with AHI >10 and systemic hypertension but without symptoms need antihypertensive treatment but not nCPAP. Patients with AHI >10, but without symptoms, should not be treated for these sleep-related physiological abnormalities, at least until further studies prove or disprove that a specific treatment to suppress apnoeas and hypopnoeas leads to a reduction in the risk for traffic, workplace and domestic accidents.

CONCLUSIONS In our opinion the available evidence shows that nCPAP is suitable in symptomatic patients and in this group of patients CPAP treatment is adequately and robustly supported. There is a pressing need for further studies to define the lower range of symptoms to be treated, to improve outcomes and to understand better the situation of the 15% of the general population with an abnormal AHI but without clinical impairment. We also need to improve our understanding of why there are subjects that can lead a normal life without daytime symptoms while ceasing to breathe 30 or 40 times every hour of their sleep. Practice Points 1. SAHS is a highly prevalent disease. 2. Treatment with nCPAP in symptomatic patients has been robustly demonstrated. No further studies are needed in this group of patients to establish treatment efficacy.

Research Agenda 1. To define the lower range of symptoms that can be improved with a CPAP treatment beyond the improvement seen with a placebo treatment.

SHOULD ALL SLEEP APNOEA PATIENTS BE TREATED?

2. To obtain new information on the long-term evolution of patients with a high AHI and no symptoms. 3. To define the role of nCPAP treatment in subjects without symptoms to avoid cardiovascular consequences and traffic accidents.

ACKNOWLEDGEMENTS This work was supported by grants from the FIS 00/0575, 99/0032 and SEPAR/2000.

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∗ The most important references are denoted by an asterisk.

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