In the last decade, large epidemiological and prospective studies have shown an independent association between obstructive sleep apnea (OSA) and hypertension [1–4]. Also based on experimental animal models [5,6], complex interactions among OSA, sympathetic activation, increase in plasma aldosterone levels, and blood pressure (BP) changes have been proposed as possible mediators for this association [7–9]. In particular, a few small epidemiological studies have shown a strong association between drug-resistant hypertension and OSA [7,10–12]. Based on such evidence, the seventh report of the Joint National Committee in United States (JNC VII recommendations ) and the 2007 European Society of Cardiology-European Society of Hypertension guidelines , first acknowledged OSA as an important identifiable cause of hypertension and, more specifically, as one of the factors responsible for resistant hypertension.
Resistant hypertension is a worrisome clinical condition, favoring target-organ damage and being associated with a higher long-term cardiovascular risk than controlled hypertension . Despite the multiple therapeutic options available, about 34% of the hypertensive population remains uncontrolled . Given the demonstration that OSA plays a role in poor responsiveness to antihypertensive therapy of patients in whom OSA and hypertension coexist, it has been consequently hypothesized that OSA treatment might reduce BP levels. However, studies on the effects on BP of OSA treatment by continuous positive airway pressure (CPAP) application have shown highly variable results [17–37]. Meta-analyses, on the contrary, have demonstrated an average small lowering effect of CPAP on BP [38–40]. The small magnitude of this effect is probably the result, in addition to some methodological problem with BP measurement, of a highly different susceptibility of each patient to BP reduction in response to CPAP treatment. Baseline BP values, severity of OSA both in terms of apnea/hypopnea index (AHI) and of nocturnal hypoxemia, excessive daytime sleepiness, obesity, duration of and compliance to treatment, administration of different antihypertensive drugs, as well as resistance of hypertension to pharmacological treatment are all factors that could interfere with the effects of CPAP.
So far, studies focusing on OSA patients with resistant hypertension have shown beneficial effects of CPAP on BP. However these studies were either uncontrolled [41,42] or retrospective in nature .
On such a background of multiple and methodologically different studies, the work of Lozano et al. published in this issue of the Journal of Hypertension offers an additional contribution by focusing on the BP effects of CPAP treatment in patients with OSA and resistant hypertension making use of a randomized, controlled design.
In their investigation Lozano et al. prospectively studied patients with resistant hypertension in whom a polysomnography had demonstrated OSA with an AHI of at least 15. Patients were randomly subdivided into one group assigned to pharmacological antihypertensive treatment together with CPAP, and another group with pharmacological antihypertensive treatment without concomitant CPAP. Patients were followed up for a 3-month period. On average, BP response to CPAP, evaluated by intermittent 24 h ambulatory BP monitoring (ABPM), was very small and not significant. In order to eliminate the possible confounding effect of the occurrence of a false resistant hypertension condition (possibly owing to a persisting emotional reaction to the BP measurement in the doctors' office, i.e. of a persisting white-coat effect), both groups were then subdivided into subgroups with resistant hypertension confirmed or not confirmed by ABPM. Among the patients with ABPM-confirmed resistant hypertension, significant differences in BP changes during follow-up were found between individuals treated and not treated with CPAP. Furthermore, patients with ABPM-confirmed resistant hypertension and assigned to CPAP treatment were further subdivided into one subsubgroup with high, and one with low compliance to CPAP: despite the small number of individuals available for this additional stratification, the former subsubgroup showed significantly larger BP changes than the other patients with ABPM-confirmed resistant hypertension, but either poorly compliant to CPAP or not treated with CPAP.
Thus, the study by Lozano et al. upholds the usefulness of OSA treatment with CPAP to decrease BP in patients with resistant hypertension.
A relevant question, facing these results, is whether the conclusions of the study by Lozano et al. have practical implications for the daily management of ‘difficult’ hypertensive patients, such as those with BP elevation resistant to treatment. At present, patients poorly symptomatic for sleep-disordered breathing, as it may be the case for individuals with resistant hypertension, are rarely addressed to instrumental diagnosis of OSA and, if such a diagnosis is made, they are often considered difficult to treat with CPAP. This paper supports a change in these common attitudes, emphasizing the importance of considering a diagnosis of OSA and the possibility of its treatment with CPAP when facing individuals with resistant hypertension.
The results of this study are in agreement with those of a previous paper  in showing that individuals being evaluated because of resistant hypertension rarely exhibit the most typical features of OSA. Although no information was provided about snoring in the recruited individuals, most of them did not report excessive daytime sleepiness, and did not suffer from severe obesity, although the average AHI in the sample was representative of severe OSA. Therefore, OSA may be difficult to suspect in patients with resistant hypertension based on their clinical presentation. The use of the Berlin questionnaire has been proposed for screening of OSA in these patients, but it may have a low specificity . However, in spite of these methodological difficulties, if the very high prevalence of OSA in resistant hypertensive patients reported so far [10,11], affecting the great majority of these patients, will be confirmed by future studies, it would be advisable to search for OSA in every patient with resistant hypertension, regardless of the presence of any other element of suspect.
Another practical implication of the study by Lozano et al. is related to the common skepticism about the feasibility of CPAP treatment in nonsleepy individuals. In fact, excessive daytime sleepiness may be one of the factors enhancing compliance to treatment , but a high AHI has also been pointed out as an important correlate of compliance with nocturnal CPAP [46,47], whereas psychological factors , high motivation to be treated, and support from personnel in charge of the patients  may be even more important. A large proportion of individuals of this study showed a good compliance to treatment. Follow-up was 3 months, which may not be long enough to accurately assess long-term compliance, but other studies have shown that initial compliance to CPAP may predict successive CPAP use [46,50]. Moreover, average use of CPAP in initially good compliers tends to increase progressively over time . Therefore, CPAP could become a routine part of cardiovascular treatment in patients with OSA and hypertension, regardless of coexistent excessive daytime somnolence. It has to be emphasized that compliance with CPAP treatment is the most important determinant of BP lowering in these patients, the best results being obtained in the study by Lozano et al. by patients who used CPAP more than 5.8 h per night.
These data enlighten the importance of a correct initial titration of CPAP, which also may favor compliance, and of a very meticulous care by specialized personnel in the early stages of CPAP therapy application.
Lack of excessive daytime sleepiness in the patients of the study by Lozano et al. stimulates further interest in the background of the controversies on the actual effectiveness of CPAP in decreasing BP in nonsleepy OSA hypertensive patients. A meta-analysis published a few years ago showed no relationship between subjective sleepiness, evaluated with the Epworth sleepiness scale, before CPAP initiation, and successive decrease in BP values . By contrast, recently in nonsleepy individuals no effect on BP , or only a very small reduction in its values  after CPAP treatment have been reported, so that the actual benefits of OSA treatment in such cases have been questioned. An important result of one of these very recent studies  has to be emphasized. Barbé et al. have demonstrated that asymptomatic OSA patients with hypertension may need regular and prolonged CPAP treatment for its benefits to become manifest, because BP reduction may not be apparent over a short follow-up. This implies that apparent lack of BP effects in asymptomatic OSA patients after a few months of treatment should not lead to CPAP discontinuation. On the contrary, long-term therapy has to be reinforced .
These last studies did not deal specifically with individuals with resistant hypertension, however. It may thus be hypothesized that excessive daytime sleepiness and severity of hypertension are two independent conditions both related to the magnitude of the hypotensive effect of CPAP. Probably, individuals with both resistant hypertension and severe sleepiness are those from whom we may expect the most marked effects of CPAP treatment.
Although demonstrating that excessive daytime sleepiness is not a prerequisite for the BP lowering effect of CPAP to become apparent, the study by Lozano et al. was able to show CPAP effectiveness only in those individuals with resistant hypertension confirmed by ABPM, but not in patients with false resistant hypertension, in whom the difficulty in reducing office BP was due to a persisting white-coat effect. These data should be considered together with those of a previous paper , which came to the conclusion that only resistant hypertension, but not less severe forms of hypertension, might benefit from OSA treatment. Indeed, it has been suggested that the effect of CPAP may be more marked in individuals with higher baseline BP values . OSA patients with resistant hypertension could, thus, represent the edge of the population that is most responsive to CPAP. Is this enough to conclude that hypertension may be a target for CPAP treatment only in OSA patients with truly resistant hypertension? At present a firm conclusion cannot be drawn, because other studies have shown BP reductions by CPAP treatment also in patients not selected for resistant hypertension or, to some extent, even in normotensive individuals [19,24].
The study by Lozano et al. has a number of merits, which strengthen its conclusions. These include the randomized design, the objective control of compliance to both pharmacological and CPAP treatment, the maintenance of a constant pharmacological treatment during the whole 3-month period, and the use of ABPM to ensure accurate assessment of the possible BP effect of CPAP treatment all over the 24 h, an approach not commonly employed in previous studies.
However, some weaknesses of this paper should also be recognized. The most important limitation is the small sample size, which is particularly evident after subgroup identification as explained before. The lack of use of a sham CPAP in the control group is another recognized limitation of the study, as acknowledged by the authors. Probably, this was done because the authors were concerned about the possible loss of patients during the treatment period if using a sham CPAP in addition to pharmacological treatment, which was the reason for choosing drug treatment as the only intervention in the control group. Moreover, changes in BP during the treatment period showed very wide standard deviations, particularly in their nocturnal values, which probably was responsible for the lack of any significant change in nocturnal BP after CPAP. This problem could have partly resulted from the 30 min-sampling rate of BP during the night, a measurement frequency that might have been insufficient in the context of the very high short-term BP variability that characterizes severe OSA at night . Finally, no data are reported about the severity of nocturnal hypoxemia, which is another limitation on the background of the results of previous studies supporting a role of intermittent hypoxia in the pathogenesis of hypertension among individuals with sleep-related disorders [56,57].
In conclusion, notwithstanding the above limitations, the study by Lozano et al. provides a strong support to the use of CPAP for the treatment of resistant hypertension in OSA individuals. It also emphasizes the need of a systematic search for an OSA condition in resistant hypertension, because OSA treatment in these patients appears not only theoretically effective, but also feasible in clinical practice. While diagnosis and treatment of OSA in resistant hypertensive patients appear to be mandatory, also based on the work by Lozano et al. , other studies are needed to better clarify the possible role of CPAP to improve BP control in individuals with OSA when hypertension is less severe.
There are no conflicts of interest.
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