762

CHEST Original Research

SLEEP DISORDERS
Original Research
gest the OSA syndrome.
1
With the increasing preva-
lence of obesity, the primary risk factor for OSA, this
syndrome is becoming an emerging health problem
and has been recognized as a risk factor for cardio-
vascular diseases, especially hypertension, and death.
1

Hypoxia leads to hyperactivity of the sympathetic ner-
vous system; increased oxidative stress and endothe-
lial dysfunction; and metabolic and hormonal changes,
O
SA is characterized by periodic reductions or ces-
sations of respiration during sleep. When frequent
apneic episodes are accompanied by symptoms of
daytime somnolence or unrefreshing sleep, they sug-
Background: CPAP is considered the therapy of choice for OSA, but the extent to which it can
reduce BP is still under debate. We undertook a systematic review and meta-analysis of random-
ized controlled trials (RCTs) to quantify the effect size of the reduction of BP by CPAP therapy
compared with other passive (sham CPAP, tablets of placebo drug, conservative measures) or
active (oral appliance, antihypertensive drugs) treatments.
Methods: We searched four different databases (MEDLINE, EMBASE, Web of Science, and the
Cochrane Library) with specic search terms and selection criteria.
Results: From 1,599 articles, we included 31 RCTs that compared CPAP with either passive or
active treatment. In a random-effects meta-analysis vs passive treatment (29 RCTs, 1,820 subjects),
we observed a mean SEM net difference in systolic BP of 2.6 0.6 mm Hg and in diastolic
BP of 2.0 0.4 mm Hg, favoring treatment with CPAP ( P , .001). Among studies using 24-h
ambulatory BP monitoring that presented data on daytime and nighttime periods, the mean dif-
ference in systolic and diastolic BP was, respectively, 2.2 0.7 and 1.9 0.6 mm Hg during day-
time and 3.8 0.8 and 1.8 0.6 mm Hg during nighttime. In meta-regression analysis, a higher
baseline apnea/hypopnea index was associated with a greater mean net decrease in systolic
BP ( b SE, 0.08 0.04). There was no evidence of publication bias, and heterogeneity was mild
( I
2
, 34%-36%).
Conclusions: Therapy with CPAP signicantly reduces BP in patients with OSA but with a low
effect size. Patients with frequent apneic episodes may benet the most from CPAP.
CHEST 2014; 145(4):762771
Abbreviations: ABPM 5 ambulatory BP monitoring; AHI 5 apnea/hypopnea index; GRADE 5 Grading of Recommen-
dations Assessment, Development and Evaluation; RCT 5 randomized controlled trial
Effect of CPAP on Blood Pressure in
Patients With OSA/Hypopnea
A Systematic Review and Meta-analysis
Cristiano Fava , MD , PhD ; Stefania Dorigoni , MD ; Francesco Dalle Vedove , MD ;
Elisa Danese , PharmD ; Martina Montagnana , MD ; Gian Cesare Guidi , MD ;
Krzysztof Narkiewicz , MD, PhD ; and Pietro Minuz , MD
Manuscript received May 15, 2013; revision accepted August 20,
2013.
Afliations : From the Department of Medicine (Drs Fava,
Dorigoni, Dalle Vedove, Danese, and Minuz), Division of Inter-
nal Medicine C, and Department of Life and Reproduction Sci-
ences (Drs Danese, Montagnana, and Guidi), Clinical Biochemistry
Section, University Hospital of Verona, Verona, Italy; and Depart-
ment of Hypertension and Diabetology (Dr Narkiewicz), Medical
University of Gdask, Gdask, Poland.
Drs Dorigoni and Dalle Vedove contributed equally to this work.
Funding/Support: The authors have reported to CHEST that no
funding was received for this study .
Correspondence to: Cristiano Fava, MD, PhD, Department of
Medicine, Division of Internal Medicine C, Piazzale LA Scuro 10,
37134 Verona, Italy; e-mail: cristiano.fava@med.lu.se
2014 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.13-1115
Downloaded From: http://journal.publications.chestnet.org/ by M Darwich on 10/15/2014
journal.publications.chestnet.org CHEST / 145 / 4 / APRIL 2014 763
tion to May 23, 2012) to identify all RCTs that assessed the effect
of CPAP therapy on BP in patients with OSA with or without
accompanying daytime somnolence or symptoms of unrefreshing
sleep. The search algorithm combined the categories for OSAS,
CPAP therapy, and randomized controlled trials by the Boolean
operator AND.
Clinical Eligibility Criteria and Outcome
Studies were eligible for inclusion if they met the following
criteria:
1. The study populations were limited to adults aged . 18 years
with a signicant number of OSA episodes ( . 5 apneas/hypo-
pneas per hour of sleep).
2. The diagnosis of OSA was obtained by polysomnography.
3. BP measurements were available both before and after CPAP
or other treatment, and treatments lasted at least 2 weeks.
4. The studies were RCTs with a reasonable control group.
The following comparator groups were considered:
a. Passive control group treatment: either sham CPAP (when
CPAP is used at a lower pressure than is needed to main-
tain airway patency), oral tablets, or nonstructured con-
servative measures such as weight reduction and counseling
or usual care.
b. Active control group treatment: (1) oral devices or (2) anti-
hypertensive drugs.
When more than one passive control group was available in
the same RCT, the primary analysis was conducted vs the
one we considered the most appropriate control group accord-
ing to this rank: (1) sham CPAP, (2) tablets, (3) conservative
measures/usual care. It should be noted that in two studies,
both active (oral devices) and passive (either conservative
measures or oral tablets) were used vs CPAP in separate arms;
thus, they were inserted in the analyses vs both passive and
active treatment.
16,17

5. Patients with an ongoing illness other than OSA (eg, heart
failure) were included. However, patients with central apnea
syndromes (dened as nonobstructive apneas . 50% of total
apneic episodes) were excluded.
Data Collection Process and Extracted Items
Two investigators independently retrieved and extracted data
from the included studies (F. D. V., S. D.). Inconsistencies were
resolved by discussion with C. F., and a nal consensus was reached.
For details about the extracted data, see e-Appendix 1.
Assessment of Quality
We assessed the methodological quality of the included studies
with the scale by Jadad et al
18
and the Grading of Recommenda-
tions Assessment, Development and Evaluation (GRADE) system.
19

See e-Appendix 1 for more details.
Summary Effect Measures
We calculated mean net change in either systolic or diastolic
BP from intervention with CPAP for each study. For both par-
allel and crossover trials, mean net change in BP was calculated
as the difference (CPAP group 2 control group) of the change
(baseline 2 follow-up) in mean values. Anticipating heterogeneity
between the studies, we calculated the difference in means accord-
ing to the DerSimonian and Laird
20
random-effects model. The
results are presented as mean SE. A two-sided P , .05 indicates
including activation of the renin-angiotensin-aldosterone
system, which accompanies the elevation of BP in
these patients.
2

Counteracting apneic episodes and consequent hyp-
oxia, CPAP is considered the gold standard therapy for
OSA and has been associated, in observational studies,
with a reduced mortality and morbidity in patients
with moderate to severe OSA.
1,2
Indeed, several stud-
ies and international guidelines have emphasized OSA
as a potentially curable secondary form of hyperten-
sion.
3,4
However, the magnitude of the effect of OSA
on BP was modest in four meta-analyses published in
2006 and 2007.
5-8
Another meta-analysis found sim-
ilar results but did not pool studies that used 24-h
ambulatory BP monitoring (ABPM) and conventional
ofce BP measurements,
9
whereas a more recent meta-
analysis by Montesi et al
10
referred especially to diur-
nal BP values from pooled estimates and subgroup
analyses . Since the rst meta-analyses were published,
additional sound randomized controlled trials (RCTs)
have been published with large sample sizes that at
least double the number of subjects who can be pooled
in a meta-analysis.
11-13
These studies attempted to
respond to several unanswered issues regarding the
efcacy of CPAP in subjects with metabolic syndrome
or with masked or resistant forms of hypertension and
to assess the efcacy of CPAP in decreasing the inci-
dence of hypertension in normotensive people with
OSA. Moreover, because of the lower number of
included studies, the rst meta-analyses of CPAP could
not have had the power to perform a meaningful sub-
group analysis to reveal which patients would most
benet from CPAP therapy. Furthermore, none of
previous meta-analyses tried to grade the level of
evidence by the quality of included trials.
Thus, the aim of the present study was to summa-
rize in a systematic review and, where meaningful, in
a meta-analysis old and new information about the
efcacy of CPAP in decreasing BP in people with
OSA with or without symptoms. In addition, we aimed
to elucidate the elements linked to the severity of
OSA and hypertension that could signicantly inu-
ence the results.
Materials and Methods
An extended version of the Materials and Methods section is
presented in e-Appendix 1. The systematic review and meta-analysis
adhere to the PRISMA (Preferred Reporting Items for Systematic
Reviews and Meta-Analyses) statement for reporting on system-
atic reviews.
14
We conducted the meta-analysis in accordance with
the general guidelines of the Cochrane Handbook for Systematic
Reviews of Interventions .
14,15

Literature Search
We performed a systematic computerized search of MEDLINE,
EMBASE, Web of Science, and the Cochrane Library (from incep-
Downloaded From: http://journal.publications.chestnet.org/ by M Darwich on 10/15/2014
764 Original Research
study evaluated the effect of CPAP vs usual care on
the incidence of hypertension (e-Appendix 2).
11
Two
RCTs examined CPAP vs an oral device,
16,17
and one
RCT compared CPAP to an antihypertensive agent.
41

These last three studies, because of their distinc-
tive features, were not included in the main analysis
(CPAP vs passive treatment) but were analyzed sepa-
rately (CPAP vs active treatment).
Impact of CPAP vs Passive Treatment in Mean
Net BP Change
As illustrated in the forest plots ( Figs 2, 3 ), the mean
net decrease in systolic and diastolic BP was highly
signicant compared with a low to moderate effect
size (systolic BP, 2.6 0.6 mm Hg; diastolic BP, 2.0
0.4 mm Hg), favoring treatment with CPAP ( P , .001
for both). Among studies using ABPM and in which
a separate analysis of daytime and nighttime values
was available (n 5 14), the mean difference in systolic
a nominally signicant overall association. For subgroup analyses,
P , .01 was set for signicance.
Details about methods used to assess heterogeneity
21
; bias across
studies
22,23
; and how sensitivity analyses, meta-regression, and sub-
group analyses were conducted are reported in e-Appendix 1. All
statistical analyses were performed with Comprehensive Meta
Analysis, version 2.2.064 (Biostat, Inc) software.
Results
Study Selection
From a total of 1,599 reports in the initial search,
we identied 31 studies
11-13,16,17,24-49
that met the inclu-
sion criteria and included these in the systematic review,
with 29 being included in the main meta-analysis
(n 5 1,820) ( Fig 1 ).
12,13,16,17,24-40,42-49
The k statistic
indicated a strong agreement between the extracting
investigators (0.89 0.04). Characteristics of the indi-
vidual studies are summarized in Table 1 , and a detailed
description is presented in e-Appendix 2. Only one
Figure 1. Flow diagram illustrating the number of citations identied, retrieved, extracted, and included
in the nal analysis. RCT 5 randomized controlled trial .
Downloaded From: http://journal.publications.chestnet.org/ by M Darwich on 10/15/2014
journal.publications.chestnet.org CHEST / 145 / 4 / APRIL 2014 765
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Downloaded From: http://journal.publications.chestnet.org/ by M Darwich on 10/15/2014
766 Original Research
and diastolic BP was, respectively, 2.2 0.7 and 1.9
0.6 mm Hg during daytime and 3.8 0.8 and 1.8
0.6 mm Hg during nighttime ( P , .001) (e-Figs 1, 2);
Q was 2.31 (1 degree of freedom, P 5 .13) for the
difference between daytime and nighttime systolic
BP and 0.019 (1 degree of freedom, P not signicant)
for the difference between daytime and nighttime
diastolic BP. A single study evaluated the impact of
CPAP in a population of normotensive subjects on
future incidence of hypertension and observed a non-
signicant association with respect to usual care (not
pooled in the main meta-analysis).
11

Impact of CPAP vs Active Treatment in Mean
Net BP Change
When directly compared with an antihyperten-
sive treatment (in a single study of valsartan 160 mg
per day) in subjects with an apnea/hypopnea index
(AHI) . 15/h and hypertension but naive of any treat-
ment, CPAP was inferior to the drug in decreasing
BP values ( 2 7.00 mm Hg; 95% CI, 10.9-3.1 mm Hg;
P . .001 between the groups in mean arterial pres-
sure).
41
In two trials, CPAP was also tested against an
oral appliance and a passive control group arm with
conicting results (e-Appendix 2).
16,17

Figure 2. Effect of CPAP with respect to passive treatment on mean net change in systolic BP in 29 ran-
domized controlled trials.
Figure 3. Effect of CPAP with respect to passive treatment on mean net change in diastolic BP in 29 ran-
domized controlled trials.
Downloaded From: http://journal.publications.chestnet.org/ by M Darwich on 10/15/2014
journal.publications.chestnet.org CHEST / 145 / 4 / APRIL 2014 767
Metaregression
In a metaregression, studies showed that a greater
AHI is associated with a greater mean net decrease
in systolic BP ( b SE, 0.08 0.04, P , .01) (e-Fig 5).
This suggests that for each increase in AHI of 10/h
from baseline, a systolic BP decrease of approximately
1 mm Hg could be expected in subjects treated by
CPAP compared with passive treatment.
Publication Bias
A funnel plot of the studies included in the main
meta-analysis is shown in e-Figure 6, with no sig-
nicant asymmetry detectable. See e-Appendix 2 for
details.
Discussion
The results of the present meta-analysis indicate
that CPAP is associated with a signicant reduction
in both systolic and diastolic BP with respect to pas-
sive treatment with a low to moderate effect size.
Sensitivity Analysis
In a cumulative meta-analysis according to the time
of publication (e-Fig 3), statistical signicance was
reached and maintained after nine to 10 studies were
published with a slightly increasing effect size over
time. In the cumulative meta-analysis according to sam-
ple size, no clear trend was apparent (e-Fig 4).
Meta-analysis in Subgroups and According to
Quality Score
Results from meta-analyses in subgroups and accord-
ing to the quality score are shown in Tables 2 and 3 .
In Table 3 , only studies graded 3 to 4 on the basis
of the GRADE system (ie, intermediate- to high-
quality studies as indicated in Table 1 ) were analyzed.
e-Appendix 1 provides a complete description on which
elements of the single RCTs were evaluated for the
grading. The main nding is that in studies of subjects
with an average AHI , 30/h and an average Epworth
Sleepiness Scale score , 10, the difference in both
systolic and diastolic BP was not statistically signicant.
Table 2 WMD in Systolic and Diastolic BP in Subjects Treated With CPAP vs Passive Therapy in Specic Subgroups
Systolic BP Diastolic BP
Variable/Subgroup
WMD SE, mm Hg
( P Value)
Metaregression
b SE ( P Value)
WMD SE, mm Hg
( P Value)
Metaregression
b SE ( P Value)
BP as the primary outcome (n 5 15) 2.7 0.7 ( , .001) BP at baseline 2.3 0.5 ( , .001) BP at baseline
BP not the primary outcome (n 5 14) 2.3 1.1 ( , .05) 0.07 0.09 (ns) 1.1 0.8 (ns) 0.05 0.10 (ns)
HT in the inclusion criteria (n 5 5)
a
1.9 0.7 ( , .01) % subjects with HT
b
1.6 0.4 ( , .001) % subjects with HT
b

HT not in the inclusion/exclusion criteria
(n 5 20)
3.8 1.0 ( , .001) 0.01 0.01 (ns) 2.4 0.7 ( , .001) 0.004 0.01 (ns)
HT in the exclusion criteria (n 5 4) 1.0 0.9 (ns) 1.3 0.6 ( , .05)
Concomitant AHT drugs (n 5 14) 2.5 1.0 ( , .05) % receiving AHT
drugs
2.0 0.7 ( , .01) % receiving AHT
drugs
No concomitant AHT drugs (n 5 9) 3.3 1.0 (.001) 2 0.01 0.02 (ns) 2.5 0.8 (.001) 2 0.01 0.01 (ns)
Average ESS 10 (n 5 18) 2.4 0.6 ( , .001) 0.19 0.17 (ns) 1.9 0.5 ( , .001) 0.06 0.14 (ns)
Average ESS , 10 (n 5 7) 1.3 1.2 (ns) 1.6 0.9 (ns)
Average AHI at baseline . 30/h (n 5 20) 2.6 0.6 (.001) 0.08 0.04 ( , .05) 2.1 0.5 ( , .001) 0.04 0.03 (ns)
Average AHI at baseline 30/h (n 5 7) 0.5 1.0 (ns)
c
0.4 0.9 (ns)
Jadad quality score 4 (n 5 9) 2.6 1.0 (.01) 0.21 0.55 (ns) 1.9 0.7 (.01) 2 0.07 0.41 (ns)
Jadad quality score , 4 (n 5 20) 2.5 0.7 (.001) 2.1 0.6 (.001)
GRADE quality score medium-high (n 5 8) 3.6 0.9 ( , .001) 0.46 0.69 (ns) 2.7 0.7 ( , .001) 0.28 0.54 (ns)
GRADE quality score low-very low (n 5 21) 1.9 0.7 ( , .01) 1.5 0.5 ( , .01)
Sham CPAP as comparator (n 5 14) 3.0 0.8 ( , .001) na 2.1 0.6 ( , .001) na
UC/placebo as comparator (n 5 15) 2.2 0.8 ( , .01) 1.9 0.6 ( , .01)
Average age 50 y (n 5 10) 3.6 1.0 ( , .001) 2 0.12 0.13 (ns) 2.7 0.8 ( , .001) 2 0.14 0.1 (ns)
Average age , 50 y (n 5 19) 2.0 0.7 ( , .01) 1.7 0.5 ( , .001)
Duration of trial . 9 wk (n 5 14) 2.3 0.9 ( , .01) 2 0.02 0.05 (ns) 1.6 0.6 ( , .01) 0.00 0.03 (ns)
Duration of trial 9 wk (n 5 15) 2.9 0.8 ( , .001) 2.5 0.6 (.001)
Parallel design (n 5 19) 3.1 0.8 ( , .001) na 2.3 0.5 ( , .001) na
Crossover design (n 5 10) 2.0 0.8 ( , .05) 1.6 0.7 ( , .05)
Compliance with CPAP 4 h/night (n 5 21) 2.8 0.7 ( , .001) 0.59 0.7 (ns) 2.0 0.5 ( , .001) 2 0.01 0.52 (ns)
Compliance with CPAP , 4 h/night (n 5 6) 2.0 1.0 (ns) 1.9 0.7 ( , .05)
AHT 5 antihypertensive; na 5 not applicable; ns 5 not signicant; UC 5 usual care; WMD 5 weighted mean difference. See Table 1 legend for
expansion of other abbreviations.

a
Having a diagnosis of HT was a necessary criterion to be included in the trial.

b
Either systolic BP 140 mm Hg or diastolic BP 90 mm Hg or use of AHT drug.

c
P , .01 for the comparison between studies with low to moderate vs severe OSA.
Downloaded From: http://journal.publications.chestnet.org/ by M Darwich on 10/15/2014
768 Original Research
where OSA episodes are more frequent and somno-
lence more marked, suggesting that the severity of the
OSA syndrome per se is associated with a better BP
response to CPAP. Additionally, the effect of adherence
to CPAP could be important (not conrmed when only
intermediate- to high-quality studies where analyzed).
International guidelines emphasize the role of the
OSA syndrome as a secondary and potentially cur-
able form of hypertension
3,4
; however, according to
the present data, the treatment of OSA by CPAP can
rarely normalize BP by itself. A single study that spe-
cically evaluated the effect of CPAP in subjects with
resistant hypertension found that the CPAP in com-
bination with existing antihypertensive therapy was
superior to conventional treatment only in subjects
with ABPM-conrmed resistant hypertension and not
in the entire cohort.
36
Moreover, the only head-to-head
study comparing CPAP with an antihypertensive
agent (valsartan) revealed a marked difference in BP
decrease, favoring the drug.
42
Thus, more studies are
needed to understand which kind of patient with hyper-
tension may benet more from CPAP therapy in addi-
tion or as an alternative to common antihypertensive
medications.
52

To our knowledge, six meta-analyses (four published
between 2006 and 2007 and two more recently)
5-9

Because most of the included primary studies showed
either a low or very-low quality, these results should
be regarded with caution. However, when analyz-
ing only the intermediate- to high-quality studies,
the results are strengthened, and there is a tendency
toward a more marked BP lowering effect of CPAP.
In any case, the effect size of CPAP on BP is at
least one-half the magnitude of most of the com-
monly used antihypertensive drugs when examined
by meta-analytic methods.
51
Thus, even the less-than-
overwhelming difference of 2.6/2.0 mm Hg for sys-
tolic/diastolic BP could be clinically meaningful, as
was also demonstrated by observational data on stroke
and mortality in subjects treated with CPAP.
1,2
How-
ever, most of the CPAP trials included in the present
review lasted only a few weeks, and the results about
the maintenance of BP in the long run are difcult to
extrapolate.
1,2

The effect size appears to be greater at night than
during the day when measured by ABPM. Moreover,
this result was always signicant when subjects with
hypertension were not excluded from the primary
studies, especially when they were not receiving anti-
hypertensive therapy.
The present meta-regression and subgroup analyses
reveal that the decrease in BP is signicant in trials
Table 3 WMD in Systolic and Diastolic BP in Subjects Treated With CPAP vs Passive Therapy When Only RCTs
With Intermediate and High Quality (GRADE) Are Included
Systolic BP Diastolic BP
Variable/Subgroups
WMD SE, mm Hg
( P Value) b SE ( P Value)
WMD SE, mm Hg
( P Value) b SE ( P Value)
BP as the primary outcome (n 5 8) na Systolic BP at
baseline
na Diastolic BP at
baseline
BP not the primary outcome (n 5 0) 2 0.34 0.19 (ns) 2 0.07 0.22 (ns)
HT in the inclusion criteria (n 5 3)
a
2.0 1.1 (ns) % subjects with HT
b
2.3 1.3 (ns) % subjects with HT
b

HT not in the inclusion/exclusion criteria
(n 5 5)
5.0 1.1 ( , .001) 2 0.03 0.03 (ns) 3.1 1.0 ( , .001) 2 0.03 0.02 (ns)
Concomitant AHT drugs (n 5 4) 2.3 1.8 (ns) % receiving AHT
drugs
2.9 1.1 ( , .01) % receiving AHT
drugs
No concomitant AHT drugs (n 5 3) 5.2 1.7 (.001) 2 0.03 0.03 (ns) 3.0 1.2 (.05) 2 0.02 0.02 (ns)
Average ESS 10 (n 5 6) 3.9 1.1 ( , .001) 0.22 0.33 (ns) 2.9 0.8 ( , .001) 0.16 0.23 (ns)
Average ESS , 10 (n 5 2) 2.0 2.6 (ns) 1.8 1.8 (ns)
Average AHI at baseline . 30/h(n 5 6) na 0.11 0.18 (ns) na 2 0.02 0.09 (ns)
Average AHI at baseline 30/h (n 5 0)
Sham CPAP as comparator (n 5 6) 3.0 1.0 ( , .001) na 2.3 0.6 (.01) na
UC/placebo as comparator (n 5 2) 6.6 2.2 ( , .01) 4.7 1.6 ( , .001)
Average age 50 y (n 5 6)
c
2.3 0.7 (.001) 2 0.58 0.20 (ns) 1.8 0.5 (.001)
c
2 0.39 0.16 (ns)
Average age , 50 y (n 5 2) 7.4 1.4 ( , .001) 5.6 1.3 ( , .001)
Duration of the trial . 9 wk (n 5 4) 3.8 1.7 ( , .01) 0.12 0.30 (ns) 3.0 1.1 ( , .001) 0.09 0.2 (ns)
Duration of the trial 9 wk (n 5 4) 3.5 1.5 ( , .05) 2.6 1.0 ( , .01)
Parallel design (n 5 7) 2.9 0.9 ( , .001) na 2.4 0.7 (.001) na
Crossover design (n 5 1) 6.7 2.0 ( , .001) 4.9 1.9 ( , .01)
Compliance with CPAP 4 h/night (n 5 6) 3.1 1.0 ( , .01) 2 0.43 1.64 (ns) 2.2 0.6 ( , .01) 2 0.26 1.2 (ns)
Compliance with CPAP , 4 h/night (n 5 2) 5.8 1.9 ( , .01) 4.2 1.2 ( , .01)
See Table 1 and 2 legends for expansion of abbreviations.

a
Having a diagnosis of HT was a necessary criterion to be included in the trial.

b
Either systolic BP 140 mm Hg or diastolic BP 90 mm Hg or use of AHT drug.

c
P , .01 for the comparison between studies with average age 50 y vs studies with average age , 50 y.
Downloaded From: http://journal.publications.chestnet.org/ by M Darwich on 10/15/2014
journal.publications.chestnet.org CHEST / 145 / 4 / APRIL 2014 769
which we consider the ideal comparator in these types
of studies. The Jadad and GRADE scores indicate
that most of the included trials are not considered high
quality, thus inuencing the overall quality of the
results. However, the subgroup analyses performed
specically in the intermediate- and high-quality stud-
ies are substantially similar in effect size and signi-
cance to the main meta-analysis.
In conclusion, this meta-analysis conrms that CPAP
can signicantly lower BP in patients with OSA but
with a low effect size. CPAP has proven to be efca-
cious in treating symptoms, such as daytime somno-
lence, especially in patients with frequent apneic
episodes. Observational studies have suggested that
CPAP might also decrease cardiovascular outcomes
in patients with OSA.
1,2
Because of its benecial effect
on BP, even if low, CPAP might be prescribed as an
adjunct to antihypertensive drugs to all patients with
hypertension and OSA, especially when apneic/hypo-
pneic episodes are frequent and somnolence severe,
with the aim also of improving BP. The small effect
size, inferior to that of a common antihypertensive drug,
should alert physicians to the fact that in most patients,
CPAP is not the only treatment that should be pre-
scribed to normalize BP. Furthermore, even if no
important side effects are associated with the use of
CPAP, compliance with the device is problematic.
58

Additional high-quality studies are needed to assess
the capacity of CPAP to prevent hypertension inci-
dence or its worsening over time, to normalize BP in
patients with resistant or refractory forms of hyper-
tension, and to quantify its effect compared with oral
devices or antihypertensive drugs.
Note added in proof: An earlier Online First version
of this article cited and used data from Sharma SK,
Agrawal S, Damodaran D, et al. CPAP for the meta-
bolic syndrome in patients with obstructive sleep apnea.
N Engl J Med. 2011;365(24):2277-2286. Because that
article was retracted October 31, 2013 (Retraction:
CPAP for the metabolic syndrome in patients with
obstructive sleep apnea. N Engl J Med. 2011;365:
2277-2286. N Engl J Med. 2013;369:1770), the authors
reworked their analysis of the data in this version of
the article, eliminating material from the retracted arti-
cle. Because the results and conclusions did not change
after elimination of the Sharma article, the revised
manuscript was accepted for publication.
Acknowledgments
Author contributions: Dr Fava had full access to all of the data
in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis .
Dr Fava: contributed to the study design, literature search, data
extraction, statistical analysis, and drafting of the manuscript.
Dr Dorigoni: contributed to the study design, retrieval of studies,
data extraction from the original articles, statistical analysis, and
drafting of the manuscript.
analyzed the BP response to CPAP; the present results
go in the same direction as suggested by the cumula-
tive analysis according to time. We included addi-
tional articles in the present study that at least double
the number of subjects who could be pooled in the
meta-analysis and were careful to exclude studies
where an overlap of subjects existed, as conrmed by
the corresponding authors.
50,53-55
Another strength of
the present meta-analysis is the in-depth sensitivity
analysis, including subgroup analyses and metaregres-
sions. In contrast with other meta-analyses, we decided
to exclude studies with a follow-up time of , 2 weeks
8,56

because, in our opinion, this length is the minimum
amount of time required to achieve a stable effect in
BP by CPAP. We also decided not to include trials
where BP information could not be retrieved from
the published studies (ie, provided directly from the
authors but not included in the published material)
or where not the initiation of the CPAP but its sus-
pension was tested. In particular, at variance with
Montesi et al,
10
we chose to take 24-h BP when avail-
able and not just the daytime BP in the analysis. This
choice was motivated by the fact that CPAP effects
on BP could be relevant mostly during the night when
OSA occurs and CPAP is used, and 24-h BP is more
reproducible with respect to partitioned daytime and
nighttime measures
57
; moreover, different denitions
of the daytime and nighttime periods were used in
different studies included in the meta-analysis, poten-
tially increasing heterogeneity. All these differences
could explain some discrepancies in the subgroup anal-
yses. Furthermore, a specic distinctive trait of the
present meta-analysis is its attention to the quality of
the analyzed studies.
The present results appear robust, and no single study
seems to be primarily responsible for the observed
differences between the treatment arms. It is impor-
tant to note that 23 of the 29 studies indicated a pos-
itive trend (either systolic or diastolic) in BP response to
CPAP, and for nine studies, the effect was statistically
signicant when analyzed as the d difference with
respect to baseline. The funnel plot is fairly symmet-
rical, and no publication or small study bias seems plau-
sible. Sensitivity analyses found no signicant changes
and reversal results; thus, we consider the results of
the present meta-analysis to be stable and reliable.
Only two studies evaluated the effect of oral devices
compared with CPAP. No rm conclusion can be
drawn from these data.
This systematic review and meta-analysis have sev-
eral limitations. First, although we applied a highly
sensitive search strategy for the retrieval of potentially
eligible studies, we cannot rule out that some studies
might have been overlooked. Second, we excluded
results from RCTs existing only as abstracts. Only 14
of the total 29 studies used sham CPAP as a placebo,
Downloaded From: http://journal.publications.chestnet.org/ by M Darwich on 10/15/2014
770 Original Research
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Dr Dalle Vedove: contributed to the study design, retrieval of
studies, data extraction from the original articles, statistical anal-
ysis, and drafting of the manuscript.
Dr Danese: contributed to the study coordination and drafting of
the manuscript.
Dr Montagnana: contributed to the study coordination and draft-
ing of the manuscript.
Dr Guidi: contributed to the study coordination and drafting of
the manuscript.
Dr Narkiewicz: contributed to the study coordination and draft-
ing of the manuscript.
Dr Minuz: contributed to the study coordination and drafting of
the manuscript.
Financial/nonnancial disclosures: The authors have reported
to CHEST that no potential conicts of interest exist with any
companies/organizations whose products or services may be dis-
cussed in this article .
Other contributions: The authors thank all the authors of the
primary studies who promptly answered questions.
Additional information: The e-Appendixes and e-Figures can
be found in the Supplemental Materials area of the online article.
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