Rationale: Continuous positive airway pressure (CPAP) is the current treatment for patients with symptomatic obstructive sleep apnea (OSA). Its use for all subjects with sleep-disordered breathing, regardless of daytime symptoms, is unclear.
Objectives: This multicenter controlled trial assesses the effects of 1 year of CPAP treatment on blood pressure (BP) in nonsymptomatic, hypertensive patients with OSA.
Methods: We evaluated 359 patients with OSA. Inclusion criteria consisted of an apnea–hypopnea index (AHI) greater than 19 hour−1, an Epworth Sleepiness Scale score less than 11, and one of the following: under antihypertensive treatment or systolic blood pressure greater than 140 or diastolic blood pressure greater than 90 mm Hg. Patients were randomized to CPAP (n = 178) or to conservative treatment (n = 181). BP was evaluated at baseline and at 3, 6, and 12 months of follow-up.
Measurements and Main Results: Mean (SD) values were as follows: age, 56 ± 10 years; body mass index (BMI), 32 ± 5 kg · m−2; AHI, 45 ± 20 hour−1; and Epworth Sleepiness Scale score, 7 ± 3. After adjusting for follow-up time, baseline blood pressure values, AHI, time with arterial oxygen saturation less than 90%, and BMI, together with the change in BMI at follow-up, CPAP treatment decreased systolic blood pressure by 1.89 mm Hg (95% confidence interval: −3.90, 0.11 mm Hg; P = 0.0654), and diastolic blood pressure by 2.19 mm Hg (95% confidence interval: −3.46, −0.93 mm Hg; P = 0.0008). The most significant reduction in BP was in patients who used CPAP for more than 5.6 hours per night. CPAP compliance was related to AHI and the decrease in Epworth Sleepiness Scale score.
Conclusions: In nonsleepy hypertensive patients with OSA, CPAP treatment for 1 year is associated with a small decrease in BP. This effect is evident only in patients who use CPAP for more than 5.6 hours per night.
Continuous positive airway pressure (CPAP) is the current treatment for patients with symptomatic obstructive sleep apnea (OSA). The effects of CPAP on blood pressure are moderate and variable. Short-term studies performed in subjects with severe OSA but without daytime sleepiness failed to show any effect of CPAP on 24-hour ambulatory blood pressure. These studies infer that CPAP in not useful in nonsleepy patients.
This study shows that, in hypertensive patients with severe obstructive sleep apnea but without daytime hypersomnolence, 1 year of CPAP treatment slightly reduces blood pressure.
Continuous positive airway pressure (CPAP) acts as a pneumatic splint to the upper airway during sleep and corrects the obstruction. CPAP improves daytime sleepiness and quality of life in patients with OSA (10). Several randomized, controlled trials have shown that CPAP treatment of OSA reduces 24-hour blood pressure (11–19). However, the positive effects of CPAP on blood pressure are not observed across the entire range of patients with OSA. Three meta-analyses of the effects of treating patients with OSA with CPAP suggest that there are moderate and variable effects of CPAP on blood pressure (20–22). Blood pressure reduction is either modest or absent in normotensive subjects (23, 24) and a randomized placebo-controlled study showed no significant changes in ambulatory blood pressure in severely hypertensive patients (25). Short-term studies performed in subjects with severe sleep-disordered breathing but without daytime sleepiness failed to show any effect of CPAP on 24-hour ambulatory blood pressure (26, 27). These studies infer that CPAP in not useful in nonsleepy patients. Nonetheless, related to the high incidence of cardiovascular complications in patients with OSA, some authors advocate long-term use of CPAP treatment for all subjects with sleep-disordered breathing (28), regardless of daytime symptoms. The extension of this treatment to all subjects with sleep-disordered breathing regardless of symptoms would have a huge economic impact, principally because 50% of patients with OSA are hypertensive (29) and 20% of the adult general population show an abnormal number of respiratory events while asleep (apnea–hypopnea index greater than 10 h−1) (2), even though they do not complain of sleepiness.
The goal of this study was to assess whether CPAP treatment produces a clinically significant reduction in blood pressure in nonsleepy hypertensive patients with OSA. To this end, we have analyzed the long-term effects of CPAP treatment on a large group of hypertensive patients with OSA included in the Spanish cohort of nonsleepy patients with OSA. This would establish whether there is likely to be a cardiovascular benefit to treating hypertensive patients with OSA, even when they do not report significant daytime hypersomnolence. Some of the results of these studies have been previously reported in the form of an abstract (30).
The Spanish cohort of nonsleepy patients with OSA constituted a randomized controlled trial whose main objective was to evaluate the effect of CPAP treatment on the incidence of cardiovascular events during 3 years of follow-up. Patient inclusion started in May 2004 and was completed in May 2006. Patients were eligible for the trial if they were between 18 and 70 years of age, had proven obstructive sleep apnea, greater than 19 apneas plus hypopneas per hour (apnea–hypopnea index [AHI]) in an overnight sleep study, had no daytime hypersomnolence, and an Epworth Sleepiness Scale (ESS) score less than 11. This cohort enrolled a group of 725 patients, of whom 358 received CPAP treatment and 367 received no active treatment. We report the effects of CPAP treatment on blood pressure in the subgroup of 374 patients who were hypertensive at enrollment. Hypertension was defined as taking antihypertensive medication, or blood pressure greater than 140/90 mm Hg, following the international recommendations for blood pressure measurements (31).
The exclusion criteria were as follows: psychophysical incapacity; any previous cardiovascular event; chronic disease such as cancer, chronic pain, renal failure, chronic obstructive pulmonary disease, liver dysfunction, neurological disease; drug or alcohol addiction; chronic intake of hypnotics; or refusal to participate in the study. The study was approved by the ethics committee of each participating center. All participants provided informed consent in writing.
The centers that participated in the study had to be teaching hospitals, with expertise in treating patients with sleep breathing disorders, and be members of the Spanish Sleep and Breathing Group, under the auspices of the Spanish Respiratory Society.
The diagnosis of OSA was reached on the basis of conventional polysomnography or a cardiorespiratory sleep study. All sleep studies were analyzed manually at each participating center, using standard criteria (32). The polysomnographies included the continuous recording of neurological variables: electroencephalogram (C3/A2 and C4/A1), electrooculogram, and electromyogram. Breathing variables were scored on the basis of the flow tracing provided by a nasal cannula and thermistor. Thoracoabdominal motion was measured with thoracic and abdominal bands. Oxygen saturation was recorded with a finger-pulse oximeter. The cardiorespiratory sleep study included, at minimum, continuous recording from nasal cannula, thoracoabdominal motion, oxygen saturation, and body position. An apnea was defined as an absence of airflow for at least 10 seconds and a hypopnea as a clear (>50%) airflow reduction for at least 10 seconds with a drop in oxygen saturation of at least 4% or an arousal. Obstructive sleep apneas were defined as the absence of airflow in the presence of chest or abdominal wall motion. The AHI was calculated according to the average number of episodes of apnea plus hypopnea per hour of sleep or recording time.
After baseline assessments, patients were randomized to the CPAP treatment group or the conservative group. Randomization was performed with a computer-generated list of random numbers in the coordinating center (F.B.). The results were posted to each participating center in a series of numbered opaque envelopes. The coordinating center saved a sealed copy of the randomization list sent to each center.
Conservative treatment included dietary counseling and sleep hygiene advice. This treatment was offered to all participants and did not include restricted sodium intake. CPAP titration was performed by conventional polysomnography or with an autoCPAP device in accordance with a validated protocol (33). Briefly, patients slept with the autoCPAP device at home or in the hospital (unattended) for one night. Pressure was set to start automatically, after 20 minutes for adaptation (from 4 cm H2O up to a maximum of 16 cm H2O). On the following morning the patient answered a simple questionnaire with the questions: (1) At what time did you fall asleep? (2) At what time did you wake up? The automatic pressure profile was reviewed in the sleep laboratory. Recording was considered to be acceptable if all the following criteria were met: (1) total sleep time, as subjectively appreciated by the patient, was at least 5 hours; (2) the recording period in the autoCPAP device was at least 6 hours; (3) the mean leak was lower than 0.4 L per second in the statistics obtained from the autoCPAP machine or the leak was lower than 0.4 L per second for at least 5 hours as determined by visual examination of the raw data. Recording was repeated for two additional nights when the original was unacceptable. Optimal pressure was determined visually from the raw data of the autoCPAP device by analyzing the pressure curve that included the periods with a leak lower than 0.4 L per second (90th percentile). A titration failure was defined when none of the three recordings obtained were acceptable. These patients were titrated by in-hospital polysomnography. Once the optimal pressure was achieved, treatment was initiated with a fixed level of CPAP at home. CPAP compliance was measured from the machines' internal clocks.
Subjects were evaluated at 3, 6, and 12 months. At each visit ESS score, weight, CPAP compliance and blood pressure determined by sphygmomanometer, drug intake, alcohol and tobacco consumption, and any clinical relevant events were all recorded. Blood pressure measurements were taken by certified nurses in each study center according to international guidelines (31). Briefly, pressure was measured with a sphygmomanometer while the patient was seated at least for 5 minutes in a quiet environment, with his or her right arm resting on a standard support. An appropriately sized cuff was placed on the arm with the lower edge of the cuff 2 cm above the antecubital fossa. Initially, the cuff was inflated to 30 mm Hg above the palpated systolic pressure. Blood pressure was then measured three times, with a pause of at least 30 seconds between measurements. The first and last Korotkoff sounds were used to determine systolic and diastolic blood pressure, respectively. The average of the second and third measurements was recorded for study.
Data were stored in a specific web application (www.redrespira.net). Each center had access to their own data and only the principal investigator (F.B.) had access to the entire database.
After correction of data inconsistencies, missing values from follow-up visits for the variables tobacco use, body mass index (BMI), and antihypertensive drug treatment were imputed by the method of carrying the last observation forward, under the assumption that the physician did not report this information because it had not changed. BMI was ascribed only once for 4 (1.1%) patients and tobacco use for 16 (4.5%) patients, 3 of them in two separate follow-up visits. Antihypertensive drug treatment was imputed for 30 (8.4%) patients, for 7 of them in two separate follow-up visits. Overall, for 45 (12.5%) patients, missing follow-up values for either tobacco use, BMI, or antihypertensive treatment were ascribed from valid values from previous visit. Only five of them were assigned for two of these variables.
The mean treatment compliance for the first year of follow-up was computed as the area under the curve obtained from compliance reported in follow-up visits, taking into account the time between visits and the last available compliance information. Initially, we performed a graphical descriptive analysis of blood pressure over time and a comparative analysis (t test and Pearson's chi-squared test with Yates' continuity correction for continuous and categorical variables, respectively) for patient characteristics between the two groups (control and CPAP) at baseline. The effect of the intervention with CPAP was assessed using mixed-effects linear models with data from all the follow-up visits. In these models, hospitals and their patients were taken into account as random effects. Study groups (CPAP and control) and follow-up time were included in the models as fixed effects, together with baseline blood pressure and only those baseline variables that showed statistically significant differences between the groups of intervention. Because both study groups included dietary counseling, the covariates BMI at baseline and change in BMI at follow-up were added to a second model as fixed effects to estimate the CPAP effect. This second model assumes that CPAP intervention does not influence BMI but that changes in BMI can explain part of the variability of blood pressure at follow-up. While building the model, all fixed effects were estimated as additive effects, without assessing interactions. No assessment was done of the possible differential effect of the covariates on blood pressure between men and women because of the low number of women in this study (60 in total, 27 in the CPAP group). Finally, to assess a possible dose–response relationship, the variable indicating the study group was recoded into four categories (control and three compliance categories). Patients in the intervention group were assigned to one of the three compliance tertiles based on their CPAP compliance during the first year of follow-up. In addition, the evolution of ESS was adjusted by the same methodology to assess the effect of CPAP treatment.
Those variables associated with compliance were analyzed using the Kruskal-Wallis nonparametric test for continuous variables (age, BMI, AHI, ESS score, time with arterial oxygen saturation [SaO2] below 90%, and blood pressure) and the Fisher's exact test for categorical variables (tobacco consumption, antihypertensive drug use, and sex). In the case of significant differences shown by the Kruskal-Wallis test, multiple comparisons were performed with a Mann-Whitney test.
All multiple comparisons (including confidence intervals of variables with more than two categories) were corrected according to the Bonferroni method (type I error divided by the number of comparisons).
R software, version 2.7.0, was used to perform the analyses. Data are presented according to current recommendations for trials assessing nonpharmacological treatments (CONSORT) (34). This study is registered with ClinicalTrials.gov, number NCT00127348.
The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit this study for publication.
Of 374 randomized patients, a total of 359 (96.0%) with initially registered blood pressure had recorded blood pressure measurements from at least one follow-up visit. Therefore, 15 patients were excluded from the analysis (13 from the CPAP group and 2 from the control group). Details of these patients are available in Figure 1. Out of the 359 patients finally analyzed, 20 (5.6%) had only one follow-up visit, whereas 296 completed all follow-up visits (82.5%). The number of patients with blood pressure measurements in each visit was 350, 335, and 309 at 3, 6, and 12 months of follow-up.
Finally, 181 patients assigned to conservative intervention (control) and 178 allocated to the CPAP group were included in the analysis. Figure 1 presents a flowchart of the study. Table 1 shows the patient characteristics at baseline. Both groups were comparable in their baseline characteristics except for apnea–hypoapnea index and time with SaO2 below 90%, values of which were significantly higher in the group with CPAP intervention.
Comparison P Value
|Age (yr), mean (SD)||176||55 (10)||176||56 (10)||0.44|
|Body mass index (kg·m−2), mean (SD)||181||32 (5)||178||33 (5)||0.32|
|Any antihypertensive drugs, %||181||44||178||49||0.43|
|ACE inhibitors, %||181||25||178||25||0.90|
|Angiotensin receptor blockers II, %||181||4||178||6||0.64|
|Calcium channel blockers, %||181||6||178||11||0.13|
|More than one antihypertensive drug treatment, %||181||14||178||15||1|
|Epworth Sleepiness Scale score, mean (SD)||181||6.4 (2.4)||177||6.4 (2.3)||0.97|
|Apnea–hypopnea index (h−1), mean (SD)||180||43 (19)||178||49 (21)||0.001|
|Time with SaO2 below 90% (%), mean (SD)||180||14 (20)||171||20 (25)||0.014|
|Diagnosis by polysomnography, %||179||47.5%||178||57.3%||0.071|
|Systolic blood pressure (mm Hg), mean (SD)||181||141 (15)||178||141 (15)||0.94|
|Diastolic blood pressure (mm Hg), mean (SD)||181||86 (10)||178||85 (11)||0.79|
Patient blood pressures did not show a linear or quadratic trend during follow-up. Figure 2 shows the systolic blood pressure (SBP) and diastolic blood pressure (DBP) at baseline and follow-up as well as changes from the baseline values by study group and time. At the 3-month visit, changes in SBP were markedly less variable in the CPAP group, but median changes in the two study groups were similar. In the CPAP group, DBP decreased from baseline in all follow-up visits, compared with the control group, which had a median change equal to zero.
Table 2 describes the observed mean changes from baseline in SBP, DBP, BMI, and ESS score, as well as percentages of smoking and antihypertensive drug use at every follow-up visit. The mean SBP, DBP, BMI, and ESS score decreased. The percentage of smokers decreased slightly, whereas the percentage of antihypertensive drug users increased.
|Variable||Group||3 mo||6 mo||12 mo||P Value|
|Change in systolic blood pressure (mm Hg),* mean (SD)||Control||−5.69 (14.82)||−6.29 (16.71)||−4.20 (16.93)||0.42|
|CPAP||−6.87 (13.76)||−6.56 (15.83)||−6.34 (15.31)|
|Change in diastolic blood pressure (mm Hg),* mean (SD)||Control||−3.06 (9.72)||−2.68 (11.86)||−2.22 (11.64)||0.01|
|CPAP||−3.76 (10.31)||−4.32 (11.46)||−4.12 (11.28)|
|Change in body mass index, kg·m−2,* mean (SD)||Control||−0.29 (1.19)||−0.35 (1.70)||−0.48 (1.78)||0.13|
|CPAP||−0.16 (1.32)||−0.14 (1.61)||−0.13 (2.10)|
|Change in Epworth Sleepiness Scale score,* mean (SD)||Control||−0.41 (2.68)||−0.26 (3.26)||−0.27 (3.38)||<0.0001|
|CPAP||−1.19 (2.91)||−1.47 (3.13)||−1.53 (2.98)|
|New smokers at follow-up,† n; %||Control||0; 0.0||4; 2.4||1; 0.7||0.78|
|CPAP||5; 2.9||6; 3.5||7; 4.3|
|Ex-smokers at follow-up,† n; %||Control||9; 5.1||9; 5.5||10; 6.7||0.43|
|CPAP||7; 4.0||7; 4.1||8; 4.9|
|Antihypertensive treatment, %||Control||46.89||45.78||48.00||0.57|
|Initiating antihypertensive drug treatment at follow-up,† n; %||Control||5; 2.8||7; 4.2||12; 8.0||0.16|
|CPAP||5; 2.9||8; 4.7||11; 6.7|
|Stopping antihypertensive drug treatment at follow-up,† n; %||Control||2; 1.1||4; 2.4||5; 3.3||0.44|
|CPAP||0; 0.0||1; 0.6||2; 1.2|
|Initiating ACE inhibitor treatment at follow-up,† n; %||Control||4; 2.3||7; 4.2||7; 4.7||0.88|
|CPAP||4; 2.3||5; 2.9||9; 5.5|
|Stopping ACE inhibitor treatment at follow-up,† n; %||Control||2; 1.1||2; 1.2||4; 2.7||1|
|CPAP||3; 1.7||4; 2.3||4; 2.5|
|Initiating angiotensin receptor blocker II treatment at follow-up,† n; %||Control||0; 0.0||2; 1.2||4; 2.7||0.17|
|CPAP||1; 0.6||2; 1.2||1; 1.1|
|Stopping angiotensin receptor blocker II treatment at follow-up,† n; %||Control||0; 0.0||1; 0.6||1; 0.7||0.01|
|CPAP||2; 1.1||3; 1.8||3; 1.8|
|Initiating calcium channel blocker treatment at follow-up,† n; %||Control||4; 2.3||4; 2.4||5; 3.3||0.69|
|CPAP||3; 1.7||3; 1.8||3; 1.8|
|Stopping calcium channel blocker treatment at follow-up,† n; %||Control||1; 0.6||1; 0.6||1; 0.7||0.99|
|CPAP||1; 0.6||1; 0.6||1; 0.6|
|Initiating β-blocker treatment at follow-up,† n; %||Control||0; 0.0||0; 0.0||3; 2.0||<0.001|
|CPAP||4; 2.3||6; 3.5||5; 3.1|
|Stopping β-blocker treatment at follow-up,† n; %||Control||4; 2.3||5; 3.0||3; 2.0||0.15|
|CPAP||2; 1.1||2; 1.2||2; 1.2|
|Initiating diuretic treatment at follow-up,† n; %||Control||2; 1.1||3; 1.8||3; 2.0||<0.001|
|CPAP||4; 2.3||7; 4.1||9; 5.5|
|Stopping diuretic treatment at follow-up,† n; %||Control||2; 1.1||5; 3.0||7; 4.7||0.89|
|CPAP||3; 1.7||2; 1.2||4; 2.5|
|Initiating multiantihypertensive treatment, n; %||Control||2; 1.1||3; 1.8||4; 2.7||0.13|
|CPAP||5; 2.9||9; 5.3||9; 5.5|
|Reducing antihypertensive treatment to one or no medications, n; %||Control||3; 1.7||4; 2.4||4; 2.7||1|
|CPAP||3; 1.7||4; 2.3||5; 3.1|
Previous studies have shown a lack of effectiveness of CPAP treatment administered during a short period of time (26, 27). We analyzed whether there were differences after 3 months of follow-up, adjusted by the characteristics that showed significant differences between treatment groups at baseline (AHI and time with SaO2 < 90%). At 3 months, adjusted mean differences for the CPAP group, compared with the control group, were not significant either for SBP (−1.39 mm Hg; 95% confidence interval [CI], −3.91, 1.14 mm Hg; P = 0.2852) or DBP (−1.01 mm Hg; 95% CI, −2.64, 0.61 mm Hg; P = 0.2008). At 12 months, however, adjusted mean differences were −2.21 mm Hg (95% CI, −5.04, 0.61 mm Hg; P = 0.1275) and –2.89 mm Hg (95% CI, −4.70, −1.07 mm Hg; P = 0.0021), respectively.
Table 3 shows the estimates obtained from mixed-effects models with baseline blood pressure, follow-up time, variables that differed at baseline (AHI and time with SaO2 <90%), and study group as fixed effects, and hospitals and patients within hospitals as random effects. SBP and DBP were both significantly associated with their baseline values, but only DBP showed a significant positive association with time below 90% SaO2, and a negative association with CPAP intervention. Thus, although CPAP did not significantly decrease SBP values in follow-up (−1.61 mm Hg; 95% CI, −3.63, 0.41 mm Hg; P = 0.1184), it did significantly decrease the DBP values in follow-up (−2.01 mm Hg; 95% CI, −3.29, −0.73 mm Hg; P = 0.0022). Blood pressures at follow-up showed no significant association with either AHI or follow-up time.
Systolic Blood Pressure
Diastolic Blood Pressure
|Fixed Effect||Coefficient (SE)||P Value||Coefficient (SE)||P Value|
|Intercept||133.71 (1.200)||<0.0001||83.68 (0.919)||<0.0001|
|Value at baseline||0.41 (0.034)||<0.0001||0.29 (0.032)||<0.0001|
|Time of follow-up, yr||0.35 (1.064)||0.74||−0.16 (0.743)||0.83|
|Apnea–hypopnea index||0.02 (0.027)||0.54||−0.01 (0.017)||0.59|
|Time with SaO2 <90%||0.04 (0.024)||0.14||0.04 (0.015)||0.005|
|CPAP intervention||−1.61 (1.029)||0.12||−2.01 (0.653)||0.002|
|Variance in hospital||6.10||5.53|
|Variance in patients within hospital||50.49||16.93|
The effect of adding BMI at baseline and change in BMI in the follow-up period to the previous model is shown in Table 4. Adjusting by these two covariates, both with statistically significant effects on SBP and DBP (likelihood ratio test, P < 0.0001), the intervention with CPAP showed a nearly statistically significant effect on SBP (mean change, −1.89 mm Hg; 95% CI, −3.90, 0.11 mm Hg; P value = 0.065), and a clearly significant effect on DBP (mean change, −2.19 mm Hg; 95% CI, −3.46, −0.93 mm Hg; P = 0.0008). The associations with the rest of the covariates were similar in significance to the previous model.
Systolic Blood Pressure
Diastolic Blood Pressure
|Coefficient (SE)||P Value||Coefficient (SE)||P Value|
|Intercept||132.19 (1.269)||<0.0001||82.89 (0.964)||<0.0001|
|Value at baseline||0.42 (0.034)||<0.0001||0.29 (0.032)||<0.0001|
|Time of follow-up, yr||0.43 (1.057)||0.69||−0.09 (0.739)||0.90|
|Apnea–hypopnea index||0.01 (0.027)||0.83||−0.01 (0.017)||0.45|
|Time with SaO2 <90%||0.02 (0.024)||0.41||0.04 (0.016)||0.02|
|CPAP intervention||−1.89 (1.023)||0.0654||−2.19 (0.647)||0.0008|
|Body mass index at baseline||0.33 (0.105)||0.0015||0.17 (0.067)||0.01|
|Change in body mass index||0.95 (0.275)||0.0006||0.68 (0.182)||0.0002|
|Variance in hospital||4.70||5.11|
|Variance in patient and hospital||49.46||16.29|
The intercept in the SBP model can be interpreted as the estimated SBP at the first follow-up visit (3 mo) of a patient assigned to the control group with a baseline SBP of 140 mm Hg, a minimal observed AHI of 20, no time with SaO2 less than 90%, and a BMI of 25 kg · m−2 at baseline and follow-up (without changes in BMI). Similarly, the intercept in the DBP model can be interpreted as the estimated DBP at the first follow-up visit of a patient assigned to the control group with a baseline DBP of 90 mm Hg and the same values as before for the rest of covariates.
The mean compliance with CPAP treatment was 4.7 ± 2 hours per night. Table 5 is derived from the same mixed-effects models as Table 4, but with CPAP compliance instead of the CPAP/control variable. Values in Table 5 show a significant decrease in SBP and DBP for the group of patients with the highest CPAP treatment compliance.
Systolic Blood Pressure
Diastolic Blood Pressure
Epworth Sleepiness Scale Score
|Hours||Coeff (SE)||95% CI (P Value)||Coeff (SE)||95% CI (P Value)||Coeff (SE)||95% CI (P Value)|
|≤3.60||0.07 (1.692)||−3.98, 4.12 (P = 0.9688)||−1.38 (1.060)||−3.92, 1.15 (P = 0.1926)||−0.208 (0.3693)||−1.09, 0.68 (P = 0.5745)|
|3.61 to 5.65||−1.43 (1.461)||−4.93, 2.06 (P = 0.3273)||−1.18 (0.912)||−3.37, 1.00 (P = 0.1964)||−1.225 (0.3235)||−2.00, −0.45 (P = 0.0002)|
|>5.65||−3.73 (1.372)||−7.02, −0.45 (P = 0.0069)||−3.51 (0.857)||−5.57, −1.46 (P = 0.0001)||−1.357 (0.3013)||−2.08, −0.64 (P < 0.0001)|
When assessing the association between the characteristics of the patients and compliance, only the AHI variable was statistically significant (P = 0.002). Differences were observed only between the highest and lowest compliance groups, with a median difference of about 9 hour−1 (95% CI, 1–18 hour−1).
Although the study cohort was not sleepy according to the ESS values at baseline, compliance with CPAP treatment was related to a decrease in the ESS values at follow-up (Table 5).
This study shows that, in hypertensive patients with severe obstructive sleep apnea but without daytime hypersomnolence, CPAP significantly reduces diastolic blood pressure (P = 0.0008) and nearly significantly reduces systolic blood pressure (P = 0.0654). We have observed a dose–response effect in systolic blood pressure, reinforcing the positive effect of CPAP treatment on blood pressure. These data are in concordance with the results observed in hypersomnolent patients with OSA treated with CPAP, and results suggest that CPAP may play a role not only by treating symptoms (daytime sleepiness) but also may provide cardiovascular benefits, as suggested by others (28, 35). This new therapeutic approach could have an important economic impact for health care systems because of the large number of patients with both a cardiovascular disorder and obstructive events without somnolence.
The effect of CPAP on blood pressure in nonsleepy patients is probably not as evident as in sleepy patients. In nonsleepy patients with OSA, CPAP treatment must be used for a longer period of time to reduce blood pressure. Previous studies performed in sleepy patients show a clear decrease after a few weeks of CPAP treatment (11–18). By contrast, short-term studies in nonsleepy patients do not show any significant effect of CPAP treatment on blood pressure (26, 27). According to the data from the present study, CPAP had no effect on blood pressure after 3 months of treatment. However, we have shown a decrease in blood pressure in nonsleepy patients after 1 year of treatment. These data could suggest that, in nonsleepy patients, CPAP needs more time to be effective. Also, the magnitude of the effect of CPAP on blood pressure is less than in the sleepy patients. The largest randomized study in the field compared the effect of 4 weeks of CPAP treatment versus treatment at nontherapeutic pressure in 118 patients with OSA and daytime sleepiness (mean ESS score, 16). CPAP decreased SBP by 5.7 mm Hg and DBP by 3.2 mm Hg (14). The magnitude of this decrease is clearly higher than that seen in our study. The patients included in both of these studies were obese, with similar ages (51 vs. 56 yr), and they had similar AHI scores (37 vs. 45 h−1). The clearest difference was in the ESS score (16 vs. 7). Other randomized controlled trials performed in patients with severe OSA have shown even greater decreases in blood pressure (15, 18). However, the reduction of 2 mm Hg in blood pressure observed in our study is clinically relevant and has been associated with a reduction in the incidence of cardiovascular disease (36). Also, there is a dose–effect relationship, mainly for SBP, and the effect of CPAP on blood pressure is evident only in patients who use CPAP more than 5.6 hours per night, a high level of CPAP use. In nonsleepy patients with OSAS, CPAP compliance is related to the AHI and to the decrease in ESS score during follow-up. Previous studies associated AHI with a significant mortality risk irrespective of sleepiness symptoms (37). The role of CPAP treatment in this population should be defined in future studies.
The mechanisms of hypertension in patients with OSA are not clear but are likely to be secondary to chemoreceptor stimulation (38) and to primarily increase sympathetic muscle tone (9). CPAP decreases sympathetic tone, improves nocturnal hypoxemia, and prevents pleural pressure fluctuations (7, 39). These effects of CPAP on the pathogenic mechanisms of hypertension in patients with OSA favor the correction of high blood pressure in patients with OSA.
The pathogenesis of daytime sleepiness in OSA is not clear. Daytime sleepiness could be a marker of sleep fragmentation and hypoxemia (40). However, there must be an individual susceptibility to the consequences of sleep fragmentation and/or hypoxemia. In fact, Rees and colleagues have shown considerable interindividual variation in the degree to which patients with OSA experience cortical electroencephalographic arousal with each apnea (41), suggesting that there are patients more susceptible to the cortical effects of apneas. Data indicate that sleepiness is related to cardiovascular function in patients with OSA. Choi and colleagues showed that a higher ESS score was significantly related to lower stroke and cardiac indexes even after controlling for age, sex, ethnicity, respiratory disturbance index, and mean sleep oxygen saturation (42). Other studies have also shown that daytime sleepiness is associated with an increased risk of cardiovascular morbidity and mortality (43). The mechanism for the increased incidence of cardiovascular disease in patients with OSA is uncertain but it is likely to be related to increased sympathetic tone and to nocturnal autonomic cardiac modulation (7, 44). Therefore, increased sympathetic tone associated with sleep fragmentation could provide a link between daytime sleepiness and impaired cardiac function in OSA.
As expected, the evolution of blood pressure was related to inclusion values. The biggest changes were related to the highest values at baseline. This tendency could be a “regression to the mean” effect. It was more evident for SBP, which had a higher mean value. In accordance with other data (44), blood pressure was also related to baseline BMI and its evolution over time. In accordance with some experimental studies (8), the evolution in blood pressure was related to the baseline hypoxemia level. In contrast, and in concordance with other studies (45), there was no relationship between baseline AHI and blood pressure decrease, probably because of the narrow AHI range in our patients.
The strengths of our study included a large sample size, 1 year of follow-up, and the generalizability of the trial findings. Nonetheless, this study had several potential limitations. First, research medical personnel were not blinded to patient allocation. In theory, knowledge of group allocation can bias study results. However, the assessment of blood pressure (main outcome) was an objective measurement done by personnel (nurses) not involved in the study. Second, the CPAP group showed slightly more severe OSA at baseline, as assessed by AHI and time with SaO2 below 90%. These differences, although statistically significant, were of little clinical importance because both groups consisted of patients with severe OSA, and all the other characteristics (including blood pressure) were similar between the two groups at baseline. Third, at the collection stage, blood pressure values were usually rounded to the closest value that is a multiple of five, reflecting normal practice but affecting the accuracy of the results. Fourth, blood pressure values were measured at clinic visits, an approach known to be affected by major problems such as the white coat effect, observer bias, limited reproducibility, and the intrinsic inaccuracy of the auscultatory technique. However, the measurements were done by experienced nurses in accordance with international guidelines.
In conclusion, this study shows that CPAP treatment is associated with a small decrease in systolic and diastolic blood pressure in nonsleepy hypertensive patients with OSA. This effect is evident only in patients who use CPAP more than 5.6 hours per night.
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