Copyright 2013 American Medical Association. All rights reserved.

Effect of CPAP on Blood Pressure in Patients

With Obstructive Sleep Apnea and Resistant Hypertension
The HIPARCORandomized Clinical Trial
Miguel-Angel Martnez-Garca, MD, PhD; Francisco Capote, MD, PhD; Francisco Campos-Rodrguez, MD, PhD; Patricia Lloberes, MD, PhD;
Mara Josefa Daz de Atauri, MD, PhD; Mara Somoza, MD, PhD; Juan F. Masa, MD, PhD; Mnica Gonzlez, MD, PhD; Lirios Sacristn, MD;
Ferrn Barb, MD, PhD; Joaqun Durn-Cantolla, MD, PhD; Felipe Aizpuru, PhD; Eva Maas, MD, PhD; Bienvenido Barreiro, MD, PhD;
Mar Mosteiro, MD, PhD; Juan J. Cebrin, MD, PhD; Mnica de la Pea, MD, PhD; Francisco Garca-Ro, MD, PhD; Andrs Maim, MD, PhD;
Jordi Zapater, MD; Concepcin Hernndez, MD, PhD; Nuria Grau SanMarti, MD, PhD; Josep Mara Montserrat, MD, PhD; for the Spanish Sleep Network
IMPORTANCE More than 70%of patients with resistant hypertension have obstructive sleep
apnea (OSA). However, there is little evidence about the effect of continuous positive airway
pressure (CPAP) treatment on blood pressure in patients with resistant hypertension.
OBJECTIVE To assess the effect of CPAP treatment on blood pressure values and nocturnal
blood pressure patterns in patients with resistant hypertension and OSA.
DESIGN, SETTING, ANDPARTICIPANTS Open-label, randomized, multicenter clinical trial of
parallel groups with blinded end point design conducted in 24 teaching hospitals in Spain
involving 194 patients with resistant hypertension and an apnea-hypopnea index (AHI) of 15
or higher. Data were collected fromJune 2009 to October 2011.
INTERVENTIONS CPAP or no therapy while maintaining usual blood pressure control
medication.
MAINOUTCOMES AND MEASURES The primary end point was the change in 24-hour mean
blood pressure after 12 weeks. Secondary end points included changes in other blood
pressure values and changes in nocturnal blood pressure patterns. Both intention-to-treat
(ITT) and per-protocol analyses were performed.
RESULTS A total of 194 patients were randomly assigned to receive CPAP (n = 98) or no CPAP
(control; n = 96). The mean AHI was 40.4 (SD, 18.9) and an average of 3.8 antihypertensive
drugs were taken per patient. Baseline 24-hour mean blood pressure was 103.4 mmHg;
systolic blood pressure (SBP), 144.2 mmHg; and diastolic blood pressure (DBP), 83 mmHg.
At baseline, 25.8%of patients displayed a dipper pattern (a decrease of at least 10%in the
average nighttime blood pressure compared with the average daytime blood pressure). The
percentage of patients using CPAP for 4 or more hours per day was 72.4%. When the changes
in blood pressure over the study period were compared between groups by ITT, the CPAP
group achieved a greater decrease in 24-hour mean blood pressure (3.1 mmHg [95%CI, 0.6
to 5.6]; P = .02) and 24-hour DBP (3.2 mmHg [95%CI, 1.0to 5.4]; P = .005), but not in
24-hour SBP (3.1 mmHg [95%CI, 0.6 to 6.7]; P = .10) compared with the control group.
Moreover, the percentage of patients displaying a nocturnal blood pressure dipper pattern at
the 12-week follow-up was greater in the CPAP group than in the control group (35.9%vs
21.6%; adjusted odds ratio [OR], 2.4 [95%CI, 1.2 to 5.1]; P = .02). There was a significant
positive correlation between hours of CPAP use and the decrease in 24-hour mean blood
pressure (r = 0.29, P = .006), SBP (r = 0.25; P = .02), and DBP (r = 0.30, P = .005).
CONCLUSIONS AND RELEVANCE Among patients with OSA and resistant hypertension, CPAP
treatment for 12 weeks compared with control resulted in a decrease in 24-hour mean and
diastolic blood pressure and an improvement in the nocturnal blood pressure pattern. Further
research is warranted to assess longer-termhealth outcomes.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00616265
JAMA. 2013;310(22):2407-2415. doi:10.1001/jama.2013.281250
Author Affiliations: Author
affiliations are listed at the end of this
article.
Corresponding Author:
Miguel-ngel Martnez-Garca, MD,
PhD, Servicio de Neumologa,
Hospital Universitario y Politcnico La
Fe, Valencia, Bulevar Sur s/n,
46026Valencia, Spain
(mianmartinezgarcia@gmail.com).
Research
Original Investigation
2407
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S
ystemic hypertension is one of the most treatable car-
diovascular riskfactors.
1
Between12%and27%of all hy-
pertensive patients require at least 3 antihypertensive
drugs for adequate bloodpressure control andare considered
patients with resistant hypertension.
2-4
Patients with resis-
tant hypertensionare almost 50%more likely to experience a
cardiovascular event than hypertensive patients without re-
sistant hypertension, andthe incidence of resistant hyperten-
sion is expected to increase.
5
Obstructivesleepapnea (OSA) affects 4%to6%of thegen-
eral middle-aged population
6,7
and increases with age.
8
It is
characterizedbytherepeatedcollapseof theupper airwaydur-
ing the night, causing intermittent hypoxemia and sleep dis-
ruption, whichinturnare
associated with an in-
creasedriskfor neurocog-
nitive and cardiovascular
morbidities.
9
Recent stud-
ies have shown that OSA
may contribute to poor
control of bloodpressure
10
and that a very high per-
centage (>70%) of resis-
tant hypertension patients have OSA.
11
Accordingly, interna-
tional guidelines now recognize OSA as one of the most
common risk factors of resistant hypertension.
4
Continuous positive airway pressure (CPAP) is the treat-
ment of choice for severe or symptomatic OSA.
12
A meta-
analysis suggests that CPAP treatment reduces blood pres-
surelevels toaclinicallymeaningful degree,
13
but whether this
positive effect is more pronounced in patients with resistant
hypertensionis unclear becausestudies onthis issuearescarce
and based on single-center approaches.
14-16
The objective of
our study was to conduct a randomized, multicenter clinical
trial to assess the effect of CPAP treatment on blood pressure
values andnocturnal bloodpressure patterns of patients with
resistant hypertension and OSA.
Methods
Study Design
This studywas approvedbythe ethics committee of eachpar-
ticipatingcenter. All theparticipants providedinformedsigned
consent to participate in the study. Our study was an open-
label, randomized, multicenter clinical trial of parallel groups
witha blindedendpoint designconductedin24teachinghos-
pitals in Spain in patients diagnosed with resistant hyperten-
sionandOSA. Patients wererandomlyassignedtoeither CPAP
or no therapy (control) and maintained their usual, unmodi-
fied blood pressure control medication.
Selection of Patients
Patients were consecutively recruited from the Hypertension
Clinical Units of the participating centers. Patients were ini-
tially eligible for participation in the study if they had pri-
mary resistant hypertension, were aged 18 to 75 years, and
signed the informed consent to participate. All the major
causes of resistant hypertension were ruled out in each
Hypertension Clinical Unit including primary aldosteronism,
renal artery stenosis, and renal insufficiency. Initial exclusion
criteria also included pregnancy, disabling hypersomnia
requiring urgent treatment (defined as an Epworth Sleepiness
Scale [ESS] 18), current use of CPAP treatment, poor adher-
ence with antihypertensive treatment, long-term treatment
with oral corticosteroids or nonsteroidal anti-inflammatory
drugs, renal insufficiency (creatinine concentration higher
than 1.5 mg/dL [to convert to micromoles per liter, multiply
by 88.4] in peripheral blood sample), a cardiovascular event
in the month prior to the inclusion in the study, and the regu-
lar use of sedative drugs such as benzodiazepines, major opi-
ates, and antipsychotics, which could significantly modify
the results of sleep studies and alcohol intake (more than 100
grams of alcohol per day).
Procedures
Initial Visit
At the initial visit, all the patients completed a standardized
protocol that included general and anthropometric data, his-
toryof cardiovascular diseases, current medications, andclini-
cal history related to OSA. The ESS was used to quantify day-
time somnolence. Good adherence to the antihypertensive
treatment was verifiedbymeans of the Haynes-Sackett test.
17
This test is amethodfor assessingself-reportedadherence. Pa-
tients were alsoaskedtobring the emptyblister packs of their
antihypertensive pills to check the number of tablets missed
per month. Goodadherencewas consideredtooccur whenthe
percentage of doses taken was between 80%and 120%of the
prescribed dose (some patients took more than the pre-
scribed dose).
Sleep Studies
All the included patients underwent attended respiratory
polygraphy
18
in the sleep laboratory of each center. Respira-
torypolygraphyincludedcontinuousrecordingof oronasal flow
and pressure, heart rate, thoracic and abdominal respiratory
movements, and oxygen saturation (SaO
2
). Polygraphy data
were scored manually by trained personnel. Apnea was de-
fined as an interruption of oronasal airflow for more than 10
seconds. Hypopnea was definedas a 30%to90%reductionin
oronasal airflowfor more than10seconds, associatedwithan
oxygen desaturation of 4%or higher. Apnea-hypopnea index
(AHI) was definedas thenumber of apneas plus hypopneas per
hour of recording, and TSat
90
was defined as the percentage
of recordingtimewithSaO
2
less than90%. Thosetests inwhich
thepatients claimedtosleepless than4hours or inwhichthere
were less than 5 hours of nocturnal recording were repeated.
Central sleepapnea was definedas at least 50%of respiratory
events having a pattern of apnea or hypopnea without respi-
ratory effort.
24-Hour Ambulatory Blood Pressure Monitoring
All patients with an AHI of 15 or higher underwent an initial
24-hour ABPM measurement to ascertain the presence of re-
sistant hypertension and its control in accordance with stan-
dard recommendations.
19,20
AHI apnea-hypopnea index
ABPM ambulatory blood pressure
monitor
CPAP continuous positive airway
pressure
DBP diastolic blood pressure
OSA obstructive sleep apnea
SBP systolic blood pressure
Research Original Investigation CPAP for Resistant Hypertension
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The summary values in the ABPM report of each patient
inthedata analysis wereused. Data relatedtotheaverageday-
time and nighttime systolic blood pressure (SBP), diastolic
bloodpressure(DBP), andmeanbloodpressure(definedas [
DBP value] + [SBP value])
21
; types of nocturnal blood pres-
sure patterns (according to the increase [riser], decrease [dip-
per], or absence of a difference [nondipper] of at least 10%in
the value of the average nighttime bloodpressure levels com-
paredtotheaveragedaytimelevels);
20
variabilityof bloodpres-
sure (defined as the standard deviation of the 24-hour mean
bloodpressure); heart rate; andbothSBPandDBP24-hour peak
and valley values (defined as the maximum[peak] and mini-
mum[valley] 24-hour blood pressure values) were recorded.
Bloodpressurelevels weremeasuredevery20minutes inboth
the daytime and nighttime periods.
The sleeping and awaking periods were determined by
instructing the patients to record the approximate times
when they fell asleep and woke up. The 24-hour ABPM cri-
teria used to define resistant hypertension were blood pres-
sure that remained above goal (ie, average SBP 130 mm Hg,
average DBP 80 mm Hg, or both) in spite of concurrent use
of at least 3 antihypertensive medication agents prescribed
at doses that provide optimal benefit1 of them being, ide-
ally, a diuretic, if no contraindication exists.
4
Patients not
fulfilling resistant hypertension criteria were excluded from
the study.
Main Outcome Measures
The primary end point was the change in the 24-hour ambu-
latorymeanbloodpressure frombaseline to12 weeks of CPAP
or control. Secondary end points included changes in other
bloodpressurevalues, especiallydiurnal andnoctunal SBPand
DBP, and changes in nocturnal blood pressure patterns.
RandomAllocation
Patients with an AHI of 15 or higher in whomresistant hyper-
tension was confirmed were eligible for randomization. The
clinicianresponsibleuseda specific softwaredesignedfor this
study (Random function of JavaScript math package) to de-
termine the group allocation for patients. Randomallocation
stratified by site was used without any other restriction. The
software only revealed the allocation group when an investi-
gator providedthe data of a fully eligible patient, whichguar-
anteed the concealment of the randomization sequence.
CPAP Pressure Titration
For those patients randomized to CPAP treatment, optimal
CPAP pressure was titrated in the sleep laboratory on a sec-
ond night by an auto CPAP device (REMstar Pro MSeries with
C-Flex, Philips Respironics) within a period of less than 15
days after the diagnostic study to obtain a fixed CPAP pres-
sure value, according to a previous validation by the Spanish
Sleep Network.
22
The optimal pressure was determined by 2
blinded expert researchers, based on the visual evaluation of
the raw data recording from the night study, with no signifi-
cant leaks (less than 0.40 L/s). This fixed pressure was then
maintained throughout the study in those patients assigned
to the CPAP group.
Follow-up
Treatment with CPAP was continued for 3 months, during
which the patient had direct contact with the research team
at all times for clinical problem-solving issues. Medical ap-
pointments were scheduled for all patients (with or without
CPAP) 2 weeks after randomizationand, subsequently, at 4, 8,
and 12 weeks. We considered adherence as adequate if the
mean CPAP use was at least 4 hours per night. Every medical
appointment involvedprotocol-basedassessments of the fol-
lowing: adherence to CPAP and antihypertensive treatment,
appearanceof anynoteworthynewmedical circumstances (es-
peciallychanges intreatments, clinical or anthropometricvari-
ables, or newvascular events), and reevaluation of the exclu-
sion criteria. At the last medical appointment, after 12 weeks
of treatment, a repeat 24-hour ABPMtest was conductedinall
patients. The CPAP device used was able to store all the data
from the 3 months of use and record the residual AHI, leaks,
and other information for each night for analysis using spe-
cific software (Encore Pro, Philips Respironics). Data were col-
lected fromJune 2009 to October 2011.
Statistical Analysis
Continuous variables were expressed as mean (SD), while
categorical variables were reported as absolute numbers
and percentages. The normality of the distribution of vari-
ables was tested using the Kolmogorov-Smirnov test. Calcu-
lation of the sample size aimed to detect a reduction of 4
mm Hg or more in 24-hour mean blood pressure, assuming
a pooled standard deviation of 8.7,
23
an error of 5%, and a
statistical power of 80%, with a total of 70 patients needed
per randomized treatment group, including both an
intention-to-treat (ITT) analysis (analyzed data from all ran-
domized patients) and a per-protocol analysis (analyzed
data only from patients with adequate adherence to CPAP
who finished the study).
The intragroup differences from the beginning to the
end of the study were evaluated with a paired t test. Inter-
group comparisons of the change in blood pressure were
assessed by analysis of covariance (ANCOVA) to adjust for
baseline blood pressure values. The hospital of inclusion
and all the clinically relevant cardiovascular risk factors that
differed significantly at baseline were also included as
covariates. The validity of the models was assessed by the
coefficient of determination R
2
. Also, graphical examination
was performed in order to confirm the assumptions of lin-
earity and normality of the residuals. The
2
test was used to
compare dichotomous variables. Multiple imputation tech-
niques were used to estimate values for those patients with-
out valid measurements of blood pressure after the 12-week
follow-up. The multiple imputation method is implemented
under the assumption that the missing data are missing at
random. For the 20 patients with missing follow-up blood
pressure measurements, imputed values of these measure-
ments were generated on the basis of baseline blood pres-
sure values, sex, age, AHI, ESS, and number of initial antihy-
pertensive drugs. This was generated using multiple
imputation by chained equations, the ice command in Stata
(StataCorp), version 11.
CPAP for Resistant Hypertension Original Investigation Research
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Logistic regressionanalysis was usedtoestimate the odds
ratio(OR) of having a dipper or riser patterninthe CPAPgroup
compared with the control group. Baseline status was in-
cluded as a covariate. Appropriate 95% CIs were also calcu-
lated. A 2-sided P value less than .05 was considered signifi-
cant. Data management and statistical analyses were
performedusing Stata, version11, andSPSS predictive analyt-
ics software (IBM), version 21.
Results
Of the initial 266 recruited patients, 194 were randomized,
98 to the CPAP group and 96 to the control group (ITT popu-
lation), and 174 (87 CPAP, 87 control) of these completed
the study and had valid 24-hour ABPM measurements
(Figure 1). Of the 194 randomized patients, 133 patients
(68.6%) were men. The mean (SD) for age was 56.0 (9.5)
years; body mass index (BMI; calculated as weight in kilo-
grams divided by height in meters squared), 34.1 (5.4); AHI,
40.4 (18.9) events per hour (96.1% of events were obstruc-
tive); and antihypertensive drugs taken per patient, 3.8
(0.9). Patients showing an AHI of 30 or higher were 63.9%;
an ESS of 10 or higher, 43.2%. The mean ESS was 9.1 (SD, 3.7;
range, 1-18). No patient had central sleep apnea. The mean
(SD) for baseline 24-hour mean blood pressure was 103.4
(9.6) mm Hg; SBP, 144.2 (12.5) mm Hg; and DBP, 83.0 (10.5)
mm Hg. Patients with a nondipper blood pressure nocturnal
pattern were 42.8%; riser, 31.4% (Table 1). Ten patients were
not taking a diuretic as antihypertensive treatment because
of adverse effects. The use of antihypertensive medication
is detailed in Table 2. Patients who did not complete the
follow-up were similar to those who completed it, except
that they took slightly more antihypertensive medication at
baseline (4.3 incomplete study vs 3.7 completed study;
P = .02).
The average use of CPAP treatment was 5 (1.9) hours per
night, with71 patients (72.4%) usingit at least 4hours per night.
The mean CPAP pressure used was 8.5 (2.1) mm Hg. The re-
sidual AHI following the application of CPAP during the titra-
tion study was 4.1 (3.8) mmHg.
Intention-to-Treat Analysis
For the ITT analysis, imputed values for blood pressure
measurements were calculated for the 20 patients with
missing follow-up blood pressure measurements due to fail-
ure to complete the protocol or an invalid 24-hour ABPM
study. When the changes in blood pressure during the study
period were compared between study groups by ITT (98
patients in the CPAP group; control group, 96 patients), the
CPAP group achieved a greater decrease in 24-hour mean
blood pressure (3.1 mm Hg [95% CI, 0.6 to 5.6]; P = .02) and
24-hour DBP (3.2 mm Hg [95% CI, 1.0 to 5.4]; P = .005), but
not 24-hour SBP (3.1 mm Hg [95% CI, 0.6 to 6.7]; P = .10)
compared to the control group (Table 3). The differences
appeared greater for nocturnal blood pressure than for day-
time blood pressure, although the 95% CIs for changes in
nocturnal and daytime blood pressure overlapped. The
model did not change when it was adjusted for potential
confounders (baseline blood pressure, AHI, ESS, nocturnal
blood pressure pattern, and previous cardiovascular events)
except for the statistically significant reduction observed in
SBP values not seen in the unadjusted model (Table 3).
Regarding nocturnal patterns, the percentage of patients
displaying a nocturnal blood pressure dipper pattern at the
12-week follow-up was greater in the CPAP group than
in the control group (35.9% CPAP vs 21.6% control; adjusted
OR, 2.4 [95% CI, 1.2 to 5.1]; P = .02). (Table 4). Also, fewer
patients in the CPAP group displayed a nocturnal riser pat-
tern at the end of the study compared to the control
group (adjusted OR, 0.45 [95% CI, 0.23 to 0.91]; P = .03)
(Table 4).
There were no differences in the percentage of patients
reaching a normotensive range inthe ABPM(<130/80mmHg)
between the CPAP group and control group at the end of the
study (18.4%CPAP vs 13.8%control; P = .41).
Analysis According to CPAP Tolerance
(Per-Protocol Analysis)
In a per-protocol analysis (71 patients in the CPAP group;
control group, 87 patients), patients in the CPAP group
showed a statistically significant decrease in 24-hour mean
blood pressure of 4.4 mm Hg (95% CI, 1.8-7), P = .001; SBP,
4.9 mm Hg (95% CI, 1.2-8.6), P = .01; and DBP, 4.1 mm Hg
(95% CI, 1.9-6.4), P < .001. This difference was more evident
during the night, with a decrease of 7.1 mm Hg (P = .003) in
nocturnal SBP and 4.1 mm Hg (P = .003) in nocturnal DBP.
Moreover, the proportion of patients who had a dipper pat-
tern at the end of follow-up was greater in the CPAP group
Figure 1. Flowchart of the Study
266 Patients assessed for eligibility
72 Excluded
39 Normal ABPM values
24 AHI <15
2 Refused to participate
2 Unable to contact
5 Missing AHI
194 Randomized
98 Included in intent-to-treat analysis
11 Missing data imputed
96 Included in intent-to-treat analysis
9 Missing data imputed
98 Randomized to receive CPAP
98 Received CPAP as randomized
96 Randomized to receive no therapy
96 Received no therapy as
randomized
1 Lost to follow-up
9 Discontinued intervention
7 Refused to continue
2 Changed antihypertensive
treatment
3 Lost to follow-up
4 Discontinued intervention
2 Refused to continue
2 Changed antihypertensive
treatment
87 Completed follow-up
1 Invalid final 24-hour ABPM
87 Completed follow-up
2 Invalid final 24-hour ABPM
ABPMindicates ambulatory blood pressure monitor; AHI, apnea-hypopnea
index; and CPAP, continuous positive airway pressure.
Research Original Investigation CPAP for Resistant Hypertension
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(OR, 2.8 [95%CI, 1.3-6.3]; P = .01). Also, fewer patients in the
CPAP group displayed a nocturnal riser pattern at the end of
the study compared to the control group (OR, 0.43 [95%
CI, 0.20-0.91]; P = .03).
Figure 2 shows a positive linear correlation between the
number of hours of CPAPuseandthedecreasein24-hour mean
bloodpressure (r = 0.29, P = .006); SBP, (r = 0.25; P = .02); and
DBP, ; (r = 0.30, P = .005). Linear regressionanalysis shows an
improvement of blood pressure figures of 1.3 mmHg (95%CI,
0.4 to 2.2) for mean blood pressure; SBP, 1.9 mm Hg (95% CI,
0.6to3.3); andDBP, 1.0mmHg (95%CI, 0.1 to1.8) for eachad-
ditional hour of CPAP use.
Discussion
Thereis clinical evidencethat OSAis a riskfactor for thedevel-
opment and poor control of systemic hypertension.
10,24,25
Nevertheless, great variabilityhas beenobservedwithrespect
to the effect of treatment with CPAP on blood pressure, prob-
ably on account of the multifactorial nature of systemic
hypertension.
5-22,24-29
This has led to an increasing interest in
theanalysisof subgroupsof patientswhocouldpotentiallyben-
efit fromtheCPAPtreatment. Obstructivesleepapneais highly
prevalent inpatients withresistant hypertension, regardless of
Table 1. Baseline Characteristics of All Randomized Patients
Mean (SD)
All Patients Control Group CPAP Group
Patients, No. 194 96 98
Age, y 56.0 (9.5) 58.2 (9.6) 57.8 (9.5)
Men, No. (%) 133 (68.6) 62 (64.6) 71 (72.4)
BMI 34.1 (5.4) 33.6 (6.9) 34.3 (5.7)
30, No. (%) 113 (79.6) 52 (76.4) 61 (82.4)
Neck circumference, cm 42.2 (4.9) 41.5 (4.7) 42.9 (5.1)
Epworth Sleepiness Scale 9.1 (3.7) 9.3 (4.0) 8.9 (4.0)
10, No. (%) 76 (43.2) 43 (47.3) 33 (38.9)
Years since diagnosis of
resistant hypertension
12.8 (8.6) 13.1 (8.0) 12.5 (9.2)
No. of systemic hyperten-
sion drugs
3.8 (0.9) 3.9 (0.9) 3.7 (0.9)
Past cardiovascular events,
No. (%)
42 (21.4) 24 (25) 18 (18)
Apnea-hypopnea index,
event/h
40.4 (18.9) 39.5 (19.2) 41.3 (18.7)
30, No. (%) 124 (63.9) 56 (58.3) 68 (69.4)
TSat
90
, median (IQR) 9 (2-20) 8 (2-19) 9.5 (4-22)
Mean O
2
saturation, % 92.0 (3.8) 92.0 (4.8) 91.9 (2.5)
24-h mean blood pressure,
mm Hg
103.4 (9.6) 102.9 (9.6) 103.9 (9.6)
24-h SBP, mm Hg 144.2 (12.5) 143.5 (13.2) 144.9 (11.7)
Diurnal 146.1 (12.7) 145.1 (13.3) 147.2 (12.1)
Nocturnal 140.8 (16.3) 140.4 (16.8) 141.2 (15.8)
24-h DBP, mm Hg 83.0 (10.5) 82.6 (10.0) 83.4 (11.1)
Diurnal 85.2 (11.0) 84.6 (10.4) 85.7 (11.6)
Nocturnal 78.6 (11.7) 78.6 (11.1) 78.5 (12.4)
Nocturnal blood pressure
pattern, No. (%)
Dipper 50 (25.8) 25 (26.0) 25 (25.5)
Nondipper 83 (42.8) 37 (38.5) 46 (46.9)
Riser 61 (31.4) 34 (35.4) 27 (27.6)
Variability, mm Hg 11.7 (3.1) 11.6 (3.5) 11.7 (3.6)
Heart rate, beats/min 71.8 (11.3) 73.3 (11.1) 70.3 (11.7)
Valley blood pressure,
mm Hg
24-h SBP 111.5 (14.7) 111.0 (14.3) 111.9 (15.4)
24-h DBP 64.2 (12.2) 60.3 (11) 59.6 (11.6)
Peak blood pressure,
mm Hg
24-h SBP 160.9 (17.7) 160.2 (17.3) 161.8 (18)
24-h DBP 93.5 (13.1) 92.8 (12.4) 93.9 (13.7)
Abbreviations: BMI, body mass index
(calculated as weight in kilograms
divided by height in meters squared);
CPAP, continuous positive airway
pressure; DBP, diastolic blood
pressure; IQR, interquartile range;
SBP, systolic blood pressure; TSat
90
,
nighttime spent with an oxygen
saturation below90%.
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otherconfoundingvariablessuchasthepresenceof obesity,
11,30,31
thus suggestingthis subgroupof hypertensivepatients is a po-
tential worthwhile population for CPAP treatment.
International guidelineshavepointedout that evenminimal
reductions inthe blood pressure levels (to the order of 2-3 mm
Hgof SBP) couldhaveaclinicallysignificant effect bygreatlyre-
ducing subsequent cardiovascular mortality (between 6%-8%
forstrokeand4%-5%forcoronaryheartdisease).
32
Veryfewstud-
ieshaveassessedtherolefor CPAPtreatment inpatientswithre-
sistant hypertensionandOSA. Theavailablestudies havefound
clinically significant reductions inbloodpressure levels, espe-
ciallyduringthenight andparticularlyinpatients withgoodad-
herencetoCPAPtreatment. However, all of thesestudieshadsig-
nificantmethodological limitations(eg, lackofrandomization
14,15
and small cohorts)
14-16
leading their authors to emphasize the
needfor further studieswithrigorousstudydesigns. Inlinewith
thepublishedevidence, our results confirmthat thereis aclini-
callyandstatisticallysignificant reductioninboth24-hour mean
anddiastolic bloodpressure levels, especially during the night
and inthose patients with acceptable CPAP adherence.
Table 3. Effect of Continuous Positive Airway Pressure Treatment on Blood Pressure Levels in the Intention-to-Treat Population
Mean (SD)
Intergroup
Crude
a
Differences
(95% CI)
P
Value
Intergroup
Adjusted
b
Differences
(95% CI)
P
Value
CPAP Group
(n = 98)
Control Group
(n = 96)
Baseline Follow-up Baseline Follow-up
BP variables,
mm Hg
c
24-h mean BP 103.9 (9.6) 99.8 (14.6) 102.9 (9.6) 102.1 (18.2) 3.1 (0.6 to 5.6) .02 3.9 (1.3 to 6.6) .004
24-h SBP 144.9 (11.7) 140.2 (13.1) 143.5 (13.2) 142.3 (17.1) 3.1 (0.6 to 6.7) .10 4.2 (0.4 to 8.0) .03
Diurnal 147.2 (12.1) 144.0 (13.7) 145.1 (13.3) 142.5 (16.2) 0.3 (4.0 to 3.5) .89 1.1 (2.9 to 5.2) .59
Nocturnal 141.2 (15.8) 134.6 (16.4) 140.4 (16.8) 137.8 (19.4) 3.7 (0.8 to 8.2) .11 5.8 (1.1 to 10.5) .02
24-h DBP 83.4 (11.1) 79.5 (11.5) 82.6 (10.0) 82.1 (12.7) 3.2 (1.0 to 5.4) .005 3.8 (1.4 to 6.1) .002
Diurnal 85.7 (11.6) 82.7 (12.5) 84.6 (10.4) 83.2 (13.2) 1.5 (0.8 to 3.9) .20 2.3 (0.1 to 4.8) .07
Nocturnal 78.5 (12.4) 75.4 (11.7) 78.6 (11.1) 77.5 (13.5) 2.1 (0.6 to 4.7) .13 3.3 (0.5 to 6.1) .02
Valley BP
24-h SBP 111.9 (15.4) 106.2 (17.8) 111.0 (14.3) 103.3 (20.2) 2.6 (7.9 to 2.6) .32 0.4 (6.0 to 5.3) .90
24-h DBP 59.6 (11.6) 57.4 (11.1) 60.3 (11.0) 58.4 (13.1) 0.5 (2.3 to 3.3) .71 2.2 (0.7 to 5.1) .14
Peak BP
24-h SBP 161.8 (18.0) 150.5 (25.1) 160.2 (17.3) 149.6 (28.9) 0.3 (8.0 to 7.4) .93 0.5 (7.5 to 8.6) .89
24-h DBP 93.9 (13.7) 88.4 (14.2) 92.8 (12.4) 92.8 (14.0) 5.0 (1.8 to 8.3) .003 5.7 (2.3 to 9.2) .001
BMI 34.3 (5.7) 34.5 (5.2) 33.6 (6.9) 33.6 (6.0) 0.4 (1.8 to 1.0) .54 0.1 (0.4 to 0.7) .64
ESS 8.9 (4.0) 5.5 (4.1) 9.3 (4.0) 9.0 (4.5) 3.3 (2.3 to 4.2) <.001 3.4 (2.4 to 4.3) <.001
Heart rate,
beats/min
70.3 (11.7) 70.1 (14.8) 73.3 (11.1) 73.0 (11.7) 0.9 (2.3 to 4.0)
.59
0.6 (2.8 to 3.9)
.74
Variability 11.7 (3.6) 11.9 (4.4) 11.6 (3.5) 12.6 (4.3) 0.8 (0.5 to 2.0) .24 0.4 (0.8 to 1.6) .52
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided
by height in meters squared); BP, blood pressure; CPAP, continuous positive
airway pressure; DBP, diastolic blood pressure; ESS, Epworth Sleepiness Scale;
SBP, systolic blood pressure.
a
Adjusted by baseline BP values.
b
Adjusted by baseline BP, AHI, ESS, dipper or riser status, and previous
cardiovascular events.
c
Crude differences calculated as (change in CPAP group) (change in control
group).
Table 2. Use of Prescribed Antihypertensive Medication in Randomized Patients
No. (%)
All Patients
Treatment
Control Group CPAP Group
Patients, No. 194 96 98
Diuretic
a
184 (94.8) 89 (93.7) 95 (96.9)
Calcium channel blockers 142 (72.4) 69 (71.9) 73 (73)
Angiotensin II receptor
blockers
132 (67.3) 64 (66.7) 68 (68)
-Blockers 112 (57.1) 54 (56.3) 58 (58)
Angiotensin-converting
enzyme inhibitor
75 (38.3) 38 (39.6) 37 (37)

1
-Blockers 65 (33.1) 32 (33.3) 33 (33)
Renin blockers 21 (10.7) 8 (8.3) 13 (13)
Others 8 (4.1) 4 (4.2) 4 (4)
Abbreviation: CPAP, continuous
positive airway pressure.
a
Ten patients were not taking
diuretic treatment due to adverse
effects.
Research Original Investigation CPAP for Resistant Hypertension
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The recovery of the dipper nocturnal pattern with antihy-
pertensive treatment may be advantageous because the pres-
enceof nondipper or riser bloodpressurenocturnal patternshas
emerged as an independent cardiovascular risk factor. In our
study, more than 70%of patients had a nondipper or riser pat-
tern and CPAP treatment normalized the blood pressure noc-
turnal patterninasignificant percentageof thesepatients. More-
over, CPAP provided protection against having a riser pattern
at the end of the study compared to the control group. This is
an important point because patients with a riser blood pres-
sure pattern exhibit the highest cardiovascular risk.
33,34
Some authors have reportedthat the effect of CPAP treat-
ment onbloodpressurelevels depends onthenumber of hours
of CPAPuse.
28
Our study corroborates this finding, witha sig-
nificant correlation between the hours of CPAP use (espe-
ciallyinpatients withat least 4hours of use per night) andthe
decrease in blood pressure levels. Adherence to CPAP treat-
ment was good in the present study, with more than 70% of
patients using CPAP for 4 or more hours per night, an adher-
ence rate similar to that reported in other large studies of pa-
tients with OSA.
35
In our study we chose not to use shamCPAP as a placebo
becausestudies haveshownthat excessiveair leakingandlow
air pressure(necessarytodeliver averylow, noneffectivepres-
sure of 2-3 cm H
2
O), along with the persistence of symptoms
such as snoring or breathing pauses, makes the patients real-
ize that theyare not receiving aneffective treatment.
23,36
Sev-
eral studies have reportedlower CPAP compliance withsham
CPAP compared to optimal CPAP, suggesting that this device
fails to function as a true placebo.
37,38
The major strength of our study is its randomized multi-
center clinical trial design with a sample size sufficient to en-
able bothanITTandper-protocol analyses. Inaddition, resis-
tant hypertensionwas establishedbymeans of 24-hour ABPM,
as recently recommended to provide more accurate esti-
mates of bloodpressure inthese patients.
19
Nevertheless, this
studyhasseveral limitations. First, respiratorypolygraphydoes
not permit any quantification of the duration of sleep. This is
unlikelytoaffect our conclusions becausepatients inour study
had an average AHI of more than 40 events per hour (severe
OSA). Indeed, thecorrelationbetweentheAHI calculatedfrom
respiratory polygraphy and the AHI derived from full poly-
somnographyis veryhighinsevereOSA.
39
Second, inthis trial,
we opted for titration of a fixed pressure by means of an auto
CPAPdeviceandthenusedthis target pressurefor the3months
of thestudy. This approachwas usedbecausefixedCPAPpres-
sure is the most common method applied to OSA patients in
Spain. Moreover, a recent studyfailedtodemonstrate anydif-
ferences inbloodpressure levels whenusing fixedCPAPpres-
sure in comparison to auto CPAP devices.
40
Conclusions
Among patients with OSA and resistant hypertension, CPAP
treatment for 12 weeks, comparedto control, resultedina de-
crease in 24-hour mean and diastolic blood pressure and an
improvement in the nocturnal blood pressure pattern. Fur-
ther research is warranted to assess longer-term health out-
comes.
Figure 2. Correlation Between Changes in 24-Hour Mean, Systolic, and Diastolic Blood Pressure and Number of Hours of Continuous Positive Airway
Pressure Use
40
0
20
20
m
m

H
g
CPAP Use, h/d
0 7 5 6 4 3 2 8 9 1
n =87
Change in diastolic blood pressure
40
0
20
m
m

H
g
CPAP Use, h/d
20
0 7 5 6 4 3 2 8 9 1
n =87
Change in systolic blood pressure
40
0
20
m
m

H
g
CPAP Use, h/d
20
0 7 5 6 4 3 2 8 9 1
n =87
Change in 24-h mean blood pressure
Correlation between continuous positive airway pressure (CPAP) use and change in blood pressure in the patients of the CPAP group who finished the follow-up.
Table 4. Effect of Continuous Positive Airway Pressure Treatment on Prevalence of Blood Pressure Patterns
No. (%)
OR (95% CI)
a
P Value
CPAP Group
(n = 98)
Control Group
(n = 96)
Baseline Follow-up Baseline Follow-up
Prevalence dipper
pattern
25 (25.5) 35 (35.9) 25 (26.0) 21 (21.6) 2.4 (1.2-5.1) .02
Prevalence riser
pattern
27 (27.6) 20 (20.5) 34 (35.4) 35 (36.8) 0.45 (0.23-0.91) .03
Abbreviations: CPAP, continuous positive airway pressure; OR, odds ratio.
a
Adjusted for baseline status. Control group data were reference values. Odds
ratio (95%CI) of dipper or riser pattern 12 weeks after CPAP treatment relative
to the control group.
CPAP for Resistant Hypertension Original Investigation Research
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ARTICLE INFORMATION
Author Affiliations: Respiratory Department,
Hospital Universitario y Politcnico La Fe, Valencia,
Spain (Martnez-Garca); Respiratory Department,
Hospital Universitario Virgen del Rocio, Sevilla,
Spain (Capote); Respiratory Department, Hospital
Universitario Valme, Sevilla, Spain
(Campos-Rodrguez); Respiratory Department,
Hospital Universitario Vall Hebrn, Barcelona, Spain
(Lloberes); Respiratory Department, Hospital
Universitario 12 de Octubre, Madrid, Spain (Daz de
Atauri); Respiratory Department, Consorcio
Sanitario de Terrassa, Barcelona, Spain (Somoza);
Respiratory Department, Hospital Universitario San
Pedro de Alcntara, Cceres, Spain (Masa);
Respiratory Department, Hospital Universitario
Marqus de Valdecilla, Santander, Spain (Gonzlez);
Respiratory Department, Hospital de Villajoyosa,
Alicante, Spain (Sacristn); Institut de Recerca
Biomdica, IRB Lleida, Spain (Barb); Bio-Araba
Research Institute, Vitoria, Spain (Durn-Cantolla,
Aizpuru); Clinical Research Unit, Hospital
Universitario Araba, Vitoria, Spain (Durn-Cantolla,
Aizpuru); Respiratory Department, Hospital
Universitario Ramn y Cajal, Madrid, Spain (Maas);
Respiratory Department, Hospital Universitario
Mutua de Terrassa, Barcelona, Spain (Barreiro);
Respiratory Department, Hospital Universtario
Xeral, Vigo, Spain (Mosteiro); Respiratory
Department, Hospital Costa del Sol, Mlaga, Spain
(Cebrin); Respiratory Department, Hospital
Universitario Son Espases, Palma de Mallorca, Spain
(de la Pea); Respiratory Department, Hospital
Universitario La Paz, IdiPAZ, Madrid, Spain
(Garca-Ro); Respiratory Department, Hospital Son
Llatzer, Palma de Mallorca, Spain (Maim);
Respiratory Department, Hospital de Igualada,
Barcelona, Spain (Zapater); Respiratory
Department, Hospital Universitario de Las Palmas,
Gran Canaria, Spain (Hernndez); Respiratory
Department, Hospital del Mar, Barcelona, Spain
(Grau SanMarti); Respiratory Department, Hospital
Clinic-IDIBAPS, Barcelona, Spain (Montserrat).
Author Contributions: Drs Martnez-Garca and
Aizpuru 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.
Study concept and design: Martnez-Garca,
Lloberes, Somoza, Masa, Barb, Cebrin, de la
Pea, Garca-Ro.
Acquisition of data: Martnez-Garca, Capote,
Campos-Rodrguez, Lloberes, Daz de Atauri,
Somoza, Masa, Gonzlez, Sacristn, Barb,
Durn-Cantolla, Maas, Barreiro, Mosteiro, Cebrin,
de la Pea, Garca-Ro, Maim, Zapater, Hernndez,
Grau, Montserrat.
Analysis and interpretation of data:
Martnez-Garca, Capote, Campos-Rodrguez,
Lloberes, Masa, Barb, Durn-Cantolla, Aizpuru,
Montserrat.
Drafting of the manuscript: Martnez-Garca,
Capote, Campos-Rodrguez, Lloberes, Masa, Barb,
Durn-Cantolla, Aizpuru, Montserrat.
Critical revision of the manuscript for important
intellectual content: Martnez-Garca, Capote,
Campos-Rodrguez, Lloberes, Daz de Atauri,
Somoza, Masa, Gonzlez, Sacristn, Barb,
Durn-Cantolla, Aizpuru, Maas, Barreiro, Mosteiro,
Cebrin, de la Pea, Garca-Ro, Maim, Zapater,
Grau, Montserrat.
Statistical analysis: Aizpuru.
Obtained funding: Capote, Barb, Zapater,
Hernndez, Montserrat.
Administrative, technical, or material support:
Martnez-Garca, Capote, Campos-Rodriguez,
Lloberes, Masa, Barb, Montserrat.
Study supervision: Martnez-Garca, Capote,
Campos-Rodrguez, Lloberes, Daz de Atauri,
Somoza, Masa, Gonzlez, Sacristn, Barb,
Durn-Cantolla, Maas, Barreiro, Mosteiro, Cebrin,
de la Pea, Garca-Ro, Maim, Zapater, Hernndez,
Grau, Montserrat.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Formfor
Disclosure of Potential Conflicts of Interest and
none were reported.
Funding/Support: The study received a grant from
Philips-Respironics, Sociedad Espaola de
Neumologa, Instituto de Salud Carlos III, and
Sociedad Valenciana de Neumologa.
Role of the Sponsor: The sponsors had no role in
the design and conduct of the study; collection,
management, analysis, and interpretation of the
data; preparation, review, or approval of the
manuscript; and decision to submit the manuscript
for publication.
CIBERde Enfermedades Respiratorias (CIBERES)
Investigators: Miguel-Angel Martnez-Garca, MD,
PhD, Patricia Lloberes, MD, PhD, Mara Josefa Daz
de Atauri, MD, PhD, Juan F. Masa, MD, PhD, Ferrn
Barb, MD, PhD, Joaqun Durn-Cantolla, MD, PhD,
Francisco Garca-Ro, MD, PhD, Josep Mara
Montserrat, MD, PhD.
Group Information: The Spanish Sleep Network
members are Juan Jose Soler, MD, PhD, and Pablo
Cataln, MD(Hospital de Requena, Valencia); Irene
Valero, MD, and Mara Jos Selma, MD(Hospital
Universitario y Politcnico La Fe, Valencia); Antonio
Grilo-Reina, MD(Hospital Valme, Sevilla); Carmen
Carmona, MD, ngeles Snchez Armengol, MD, and
Pedro Maas Escorza, MD(Hospital Virgen del
Roco, Sevilla); Gabriel Sampol, MD, PhD(Hospital
Vall Hebrn, Barcelona); Trinidad Daz Cambriles,
MD(Hospital 12 de Octubre, Madrid); Carles
Sanjun, MD, PhD, and MA Flez, MD(Hospital del
Mar, Barcelona); Cristina Embid, MD(Hospital
Clinic-IDIBAPS, Barcelona); Jaime Corral, MD, PhD,
and Estefana Garca-Ledesma, MD(Hospital San
Pedro de Alcntara, Cceres); Mara Pilar Cuellar,
MD(Hospital de Marbella, Mlaga); Javier Pierola,
PhD(Hospital Son Espases, Palma de Mallorca); MJ
Muoz Martnez, MD(Hospital Universitario Xeral
de Vigo); Manuel de la Torre, PhD, Gerard Torres,
MD, and Silvia Gmez, MD(Institut de Recerca
Biomdica, IRB Lleida); Alberto Torre, MD; Ral
Gaera, MD, and David Romero, MD(Hospital
Universitario La Paz, Madrid); Juan Bauz
Deroulede, MD(Hospital Son Llatzer, Palma de
Mallorca); Rosa Esteban, MD, PhD(Hospital
Universitario Ramn y Cajal, Madrid); Rosa Gmez,
MD, PhD(Hospital Gregorio Maran, Madrid);
Mara ngeles Martnez, MD, and Olga Cantalejo,
MD(Hospital Marqus de Valdecilla, Santander);
Vicenc Esteve, MD(Consorcio Sanitario de
Terrassa); Ramn Caracho, MD, Cristina
Martnez-Null, PhD, Carlos Egea, MD, PhD, and
Laura Cancelo, MD(Hospital Universitario Araba,
Vitoria); Amaia Latorre Ramos, MD, and Erika
Miranda Serrano, MD(Unidad Investigacin
Osakidetza, Araba). All members are fromSpain.
Previous Presentation: The results of the present
study were presented in the annual Congress of the
European Respiratory Society in Vienna (2012) as a
thematic poster and in the annual congress of
American Thoracic Society in Philadelphia (2013).
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