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PAPER
Study Selection
Clinical trials based on the following predefined inclusion criteria were retrieved: (1) those enrolling adult
participants with OSA and hypertension; (2) those
comparing therapeutic CPAP treatment and control
(no CPAP, sham-CPAP, oral placebo tablet, or mere
standard conservative care); (3) those reporting
METHODS
Study Search Strategy
We searched the database of Medline, Embase, the
Cochrane Central Register of Controlled Trials, and
relevant Web sites (www.acc.org, www.tctmd.com,
www.theheart.org, www.clinicaltrialresults.org) for target studies before July 2014 by using the following
keywords: sleep apnea syndrome or obstructive sleep
apnea or OSA, hypertension or hypertensive,
and continuous positive airway pressure or CPAP.
215
MEDLINE: 456
(50 trials )
EMBASE: 67
(2 trials)
(87 trials)
RESULTS
Literature Search and Quality Assessment
Figure 1 shows the detailed flow chart of the selection
process of the studies. By using our predefined searching
strategy, seven RCTs were consequently selected for
data extraction and meta-analysis.13,14,1620 Table I
summarizes the outcomes of quality assessment and
Jadad scores of included studies (j=0.910.06).
Characteristics of the Studies and Patients Included
The main characteristics of included trials are presented
in Table II. Seven studies of 794 patients were analyzed.
216
11 excluded:
Three studies recruited patients with OSA and hypertension,13,14,16 and the other four trials selectively
enrolled patients with OSA and resistant hypertension.1720 Untreated hypertensive patients at baseline
were enrolled in one study.16 Of the seven RCTs, six
studies were parallel14,1620 and one study was a
crossover design.13 Four RCTs examined CPAP vs no
CPAP1720 and three compared CPAP with shamCPAP.13,14,16 The treatment duration ranged from 1 to
6 months. All studies reported the changes in 24-hour
ambulatory BP, and the outcomes of diurnal and
nocturnal ambulatory BP were available in five studies.1620
The diagnoses of OSA in the included trials were all
made by polysomnography monitoring. The majority of
enrolled patients were documented as moderate to
severe OSA (apnea hypopnea index 15). The mean
age of participants in individual trials varied from 53.2
to 59.2 years. All included trials predominantly
recruited males patients (mean percentage 74%). The
mean BMIs were all beyond 30 kg/m2. The mean
Epworth Sleepiness Scale ranged from 5 to 15 (total
score 24), while the mean CPAP adherence ranged from
4.5 hours to 6.0 hours per night. There were no
significant differences in the patients main baseline
characteristics between CPAP and control group.
Trial
20
Journal, Year
Study
Age
AHI, Events
of Publication
Duration, mo
Range, y
per h
>18
Intervention/
Jadad
Trial Type
Control
Scale
15
Parallel RCT
CPAP+drugs/drugs
Barcelona,
Spain
Site
Lloberes et al
J Hypertens,
2014
Martinez-Garcia et al19
JAMA, 2013
1875
15
Parallel RCT
CPAP+drugs/drugs
Valencia,
Spain
Pedrosa et al18
CHEST, 2013
3065
15
Parallel RCT
CPAP+drugs/drugs
Sao Paulo,
Brazil
Lozano et al17
J Hypertens,
2010
1880
15
Parallel RCT
CPAP+drugs/drugs
Barcelona,
Spain
Duran-Cantolla et al16
BMJ, 2010
1875
15
Parallel RCT
CPAP/sham
Vitoria,
Spain
Campos-Rodriguez et al14
CHEST, 2006
3070
10
Parallel RCT
CPAP/sham
Sevilla,
Spain
Robinson et al13
Eur Respir J,
2006
Crossover RCT
CPAP/sham
Oxford,
UK
>18
>5
Abbreviations: AHI, apnea hypopnea index; CPAP, continuous positive airway pressure; RCT, randomized controlled trial.
Pooled Analysis
Pooled outcome was displayed as forest plot. As
illustrated in the forest plot in Figure 2, the net change
in 24-hour ambulatory systolic blood pressure (SBP) and
diastolic blood pressure (DBP) was significantly
decreased in patients receiving CPAP therapy compared
with those in the control group (change in SBP, 2.32
mm Hg, 95% confidence interval [CI], 3.65 to 1.00,
P=.001; change in DBP, 1.98 mm Hg, 95% CI, 2.82
to 1.14, P<.001, respectively), without significant
heterogeneity (I2=0% for SBP, I2=21% for DBP,
respectively).
Five studies with 691 patients were pooled for the
subset analysis of diurnal and nocturnal BP change.
Nocturnal BP was significantly decreased by CPAP
treatment compared with control (pooled SBP change
2.74 mm Hg, 95% CI, 4.26 to 1.23, P<.001;
pooled DBP change 1.75 mm Hg, 95% CI, 2.79 to
0.71, P=.001, respectively) (Table III) without significant heterogeneity across trials (I2=0%, I2=0%, respectively).
Although the pooled mean difference of diurnal DBP
was found significantly to be 2.85 mm Hg (95% CI,
5.58 to 0.12, P=.041), the pooled diurnal SBP
change was 3.58 mm Hg (95% CI, 8.04 to 0.89,
P=.117) without statistical significance. A significant
heterogeneity for diurnal SBP and DBP was found to be
89% and 88%, respectively.
Additionally, subgroup analysis for 24-hour BP was
performed to identify the magnitude of the effect of
CPAP in different subgroups. The pooled results from
trials of resistant hypertension1720 showed that OSA
patients with resistant hypertension had a significantly
greater reduction in 24-hour SBP change ( 3.88 mm
Hg; 95% CI, 6.55 to 1.22, P=.004), as well as 24hour DBP change ( 3.65 mm Hg; 95% CI, 5.19 to
2.10, P<.001) after CPAP intervention, as compared
with controls.
DISCUSSION
Mechanism Related to BP-Lowering Effect With
CPAP
As a result of pharyngeal collapse, OSA induces intermittent hypoxemia and CO2 retention, with oxygen
saturation dropping to as much as <60% in severe cases
This leads to disordered autonomic and hemodynamic
responses during sleep, particularly featured by
The Journal of Clinical Hypertension
217
218
Representing the mean baseline body mass index (BMI) and 95% confidence interval. cRepresenting the mean baseline apnea hypopnea index (AHI) and 95% confidence interval. dRepresenting
the mean baseline Epworth Sleepiness Scale (ESS) and 95% confidence interval.
b
(3.07.0)d
(18.038.0)
Abbreviations: CPAP, continuous positive airway pressure; NR, not reported; SD, standard deviation. aRepresenting the mean number of antihypertensive drugs and 95% confidence interval.
15.03.9
5.3
58.324.6
28.1
35.75.6
33.25.3
1
1
Campos-Rodriguez et al14
Robinson et al13
68
35
34
18
Yes
Yes
2.00.9
NR
9.51.9
10.41.5
5.01.4
5.22.1
55.39.6
548
55.8
88.6
10.34.2
6.143.30
3
3
Duran-Cantolla et al16
Lozano et al17
340
64
169
29
No
Yes
0
3.410.57
8.81.6
9.621.54
4.51.7
5.61.52
53.210.2
59.29.9
44.524.6
52.6721.5
31.95.7
30.85
9.13.7
101
79.0
75.9
7.34
50.020.3
34.15.4
32 (2839)b
68.6
77.0
40.4 18.9
29 (2448)c
32.04.9
72.4
56.09.5
561
51.9
6.020.33
5.71.5
9.61.5
8.52.1
11.50.5
3.70.9
4 (45)a
NR
Yes
Yes
Yes
98
19
29
58
3
6
Martinez-Garcia et al19
Pedrosa et al18
194
35
3
Lloberes et al20
Trial
58.79.5
(MeanSD),
No./night
(MeanSD),
kg/m2
(MeanSD),
No.
AHI
BMI
Age,
y
(MeanSD),
h/Night
(MeanSD),
cm/H2O
drugs (MeanSD),
No.
Drugs at
Baseline
Patients,
No.
Size,
No.
Duration,
mo
CPAP
Compliance
CPAP Pressure
Antihypertensive
Antihypertensive
CPAP
Sample
Stduy
Mean
Male,
%
ESS
chemoreflex-mediated sympathetic activity and peripheral blood vessel constriction effect, consequently resulting in a high level of blood pressure through the
night.22,23 In addition, induced by recurrent hypoxemia,
vasoactive substance such as endothelin and angiotensin,
or other pathological effects such as oxidative stress,
systemic inflammation and insulin resistance may all
contribute to the upregulation of blood pressure.2427 To
treat the obstructive apneas, CPAP can hold the collapsed airway open, improve the patients ventilation
situation by which CPAP can attenuate subsequent
overactivity of sympathetic nervous axis and relevant
disorders, and thus decrease BP during sleep.28
Previous Studies and Findings of the Present MetaAnalysis
Which patient group benefits the most by BP improvement from CPAP therapy remains a subject of interest.
Existing evidence suggested that there were viable
effects of CPAP on BP in patients with OSA. Previous
meta-analyses1012 enrolling a considerable number of
normotensive patients showed a near 2-mm Hg BP
reduction after CPAP treatment. By including OSA
patients complicated with hypertension, the pooled
results of the present meta-analysis demonstrated a
weighted mean reduction in 24-hour ambulatory SBP of
2.32 mm Hg and DBP of 1.98 mm Hg, suggesting a
greater magnitude in BP reduction among hypertensive
and OSA patients.
Furthermore, subgroup analysis including trials of
resistant hypertension1720 showed that OSA patients
with resistant hypertension had a more substantial
reduction in 24-hour SBP and 24-hour DBP change after
CPAP intervention as compared with overall patients.
This result was also echoed by early studies.29 It was
extrapolated that CPAP may be a first-choice adjunctive
treatment strategy for OSA patients with refractory
hypertension.
Effective CPAP therapy and antihypertensive pharmacotherapy are both considered to be of importance in
the improvement of BP control.30 In the systematic
review of included trials, six studies13,14,1720 in which
the patients received antihypertensive medication
appeared to achieve a greater BP reduction than those
without antihypertensive drugs enrolled in one study.16
This synergic efficacy was also shown by our subgroup
meta-analysis, indicating that the combination therapy
of CPAP and antihypertensive drug therapy should be
recommended as a standard treatment for OSA and
hypertension.
The present meta-analysis revealed that CPAP had
significant BP-lowering effects mainly on nocturnal SBP;
however, its impact on diurnal SBP seemed modest.
Mechanism research has showed that CPAP continuously
supports the collapsed airway and prevents hypoxia
events, thus balancing autonomic nervous activity and
regulating BP during the night.7,31 Immediate nocturnal
BP improvement can be achieved by the direct effect of
CPAP in minutes,29 whereas the regulation of daytime BP
FIGURE 2. Forest plot for 24-hour ambulatory systolic blood pressure (A) and diastolic blood pressure (B). CI indicates confidence interval; CPAP,
continuous positive airway pressure.
TABLE III. Results of Subgroup Analysis of 24-h Ambulatory Blood Pressure Change
Pooled Effects
Trials, No.
Mode
Difference in Means
Standard Error
P Value
Random
3.58
2.28
( 8.04, 0.89)
5
5
Random
Fixed
2.85
2.74
1.39
0.77
( 5.58,
( 4.26,
0.12)
1.23)
.117
.041
<.001
5
1
Fixed
Fixed
1.75
2.10
0.53
0.84
( 2.79,
( 3.74,
0.71)
0.46)
.001
.012
6
3
Fixed
Fixed
2.73
1.81
1.14
0.78
( 9.83, 3.83)
( 3.34, 0.29)
.016
.020
4
1
Fixed
Fixed
3.88
1.30
1.36
0.54
( 6.55,
( 2.35,
1.22)
0.25)
.004
.015
6
3
Fixed
Fixed
3.19
1.28
0.72
0.51
( 4.59,
( 2.28,
1.79)
0.27)
<.001
.013
Fixed
3.65
0.79
( 5.19,
2.10)
<.001
219
TABLE IV. Results of Meta-Regression of the 24-h Ambulatory and Diurnal BP Change
Trials,
Patients,
24-h Ambulatory
24-h Ambulatory
No.
No.
SBP (P Value)
DBP (P Value)
Diurnal SBP
Diurnal DBP
(P Value)
(P Value)
7
7
794
794
.730
.328
.214
.016
<.001
<.001
<.001
<.001
Mean age, y
Male (decimal)
7
7
794
794
.328
.681
.024
.324
.004
.460
.003
.792
7
7
794
794
.673
.941
.707
.649
.082
<.001
.547
<.001
7
7
794
794
.840
.097
.122
.206
.621
<.001
.880
<.001
5
7
701
794
.405
.201
.053
.036
<.001
<.001
<.001
<.001
794
.368
.842
NA
NA
Explanatory Variable
Abbreviations: AHI, apnea hypopnea index; BMI, body mass index; BP, blood pressure; CPAP, continuous positive airway pressure; DBP, diastolic
blood pressure; ESS, Epworth Sleepiness Scale; NA, not available; SBP, systolic blood pressure.
FIGURE 3. Funnel plot for 24-hour ambulatory systolic blood pressure (A), 24-hour ambulatory diastolic blood pressure (B), nocturnal systolic
blood pressure (C), nocturnal diastolic blood pressure (D), diurnal systolic blood pressure (E), and diurnal diastolic blood pressure (F).
CONCLUSIONS
For OSA and hypertensive patients, CPAP treatment
results in a significant reduction in 24-hour ambulatory BP, which is characterized by nocturnal BP.
Those with resistant hypertension or taking antihypertensive pharmacotherapy are shown to have more
substantial BP reduction. CPAP adherence, age, and
baseline SBP are positively correlated with the
decrease of 24-hour DBP. In addition to aforementioned factors, effective CPAP pressure, OSA severity,
and treatment duration may also predict improvement
in diurnal BP control. None are associated with the
reduction in 24-hour SBP.
Disclosures: This work was partly supported by Sunshine Cardiovascular
Research Foundation of Chinese Medical Doctor Association.
Conflicts of Interest: None.
References
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disease: part II: overview of cardiovascular diseases associated with
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2. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep
apnea: a population health perspective. Am J Respir Crit Care Med.
2002;165:12171239.
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28.
222