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Received: 30 August 2016    Revised: 27 October 2016    Accepted: 29 October 2016

DOI: 10.1111/jch.12992

O R I G I N A L PA P E R

Influence of high risk of obstructive sleep apnea on adherence

to antihypertensive treatment in outpatients

Camila G. Righi PhD1  | Denis Martinez MD, PhD1,2 | Sandro C. Gonçalves MD, PhD1,2 | 
Miguel Gus MD, PhD1,2 | Leila B. Moreira MD, PhD1,2 | Sandra C. Fuchs MD, PhD1  | 
Flavio D. Fuchs MD, PhD1,2

1
Graduate Studies Program in
Cardiology, School of Medicine, Universidade Abstract
Federal do Rio Grande do Sul, Porto Alegre, Obstructive sleep apnea (OSA) is a common cause of high blood pressure (BP). Many
RS, Brazil
2
patients, however, have uncontrolled BP because of nonadherence to antihyperten-
Division of Cardiology, Hypertension and
Sleep Clinics, Hospital de Clínicas de Porto sive medication. The possibility that OSA influences adherence has not been investi-
Alegre, Universidade Federal do Rio Grande
gated to date. The authors sought to explore the possible association between high
do Sul, Porto Alegre, RS, Brazil
risk of OSA and nonadherence. This study was carried out in a hypertension outpa-
Correspondence
tient clinic. Adherence to medication, high risk of OSA, and sleepiness were evaluated
Camila Gosenheimer Righi, PhD, Graduate
Studies Program in Cardiology Hospital de in a cross-­sectional study. These variables were identified using the eight-­item Morisky,
Clínicas de Porto Alegre (HCPA), Porto Alegre,
STOP-­Bang, and Epworth scales, respectively. A total of 416 patients with hyperten-
RS, Brazil.
E-mail: righicg@gmail.com sion were enrolled (32% male, aged 65±11 years). Nonadherence was identified in 71
Funding information (17%) individuals. The prevalence of high risk of OSA was 323 (78%) and of somno-
This paper was supported by the Research lence was 136 (33%). High risk of OSA was associated with nonadherence, showing a
Incentive Fund of the Hospital de Clínicas de
Porto Alegre (HCPA-­FIPE), the Coordination of prevalence ratio (PR) of 2.6 (95% confidence interval [CI], 1.3–5.6) and retained signifi-
Improvement of Higher Education Personnel cance after adjustment for sleepiness (PR, 2.3; 95% CI, 1.1–4.9 [P=.011]). Sleepiness
(CAPES), and the National Council of Scientific
and Technological Development (CNPq) was also associated with nonadherence (PR, 1.7; 95% CI, 1.1–2.6 [P=.003]). High risk
of OSA and sleepiness are associated with nonadherence. These conditions, if treated,
may allow for achieving better outcomes and improvement of adherence to
medication.

1 |  INTRODUCTION clinical characteristics and circumstances of each patient7 as nonad-

Every 34 seconds one person dies from cardiovascular disease.1 Nearly
9.4 million deaths throughout the world each year from cardiovascular
disease are due to high blood pressure (BP).2 More than one in three
individuals 25 years and older have high BP worldwide.3 Strict appli-
cation of the hypertension guidelines could be associated with avoid-
ance of 13 000 deaths from cardiovascular causes annually, resulting
in overall cost savings.4 However, despite the efficacy of the available
therapies, “drugs don’t work in patients who don’t take them.”5 Two
thirds of uncontrolled BP3 may be related to nonadherence to medica-
tion.6 This is not exclusive of patients with hypertension,3 since half of
patients with chronic conditions do not take their medications as pre-
5
scribed. Decisions about management of hypertension must consider
herence to treatment.8
A search with the terms “adherence or compliance to antihyper-
tensive medication” in the GoPubMed database, starting in 1970,
shows that in approximately the past 10 years this subject became a
matter of interest by researchers.9 Although nonadherence is an old
challenge, its study has boomed only recently, remaining the need to
explore it in depth. Adherence can also influence clinical prognosis and
is a relevant problem in the field of cardiovascular prevention.5
Systemic10 and resistant11 hypertension are about three and five
times more prevalent in patients with OSA, respectively. Patients who
fulfill criteria for resistant hypertension may have poor adherence in
53% of the cases.12 The prevalence of true resistant hypertension
is estimated in only 5% to 8% of the cases with unsatisfactory BP

J Clin Hypertens. 2017;1–6. wileyonlinelibrary.com/journal/jch ©2017 Wiley Periodicals, Inc.  |  1

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2       RIGHI et al.
control,13 while the greatest proportion of the remaining cases is due
to poor medication adherence.
Considering the association between OSA and uncontrolled BP,
and between uncontrolled BP and nonadherence to drug therapy,
it is reasonable to hypothesize that OSA can reduce adherence to
medication. The lack of studies on this subject and the importance of
the identification of factors related to adherence to antihypertensive
medication justifies exploratory analyses. The present study inves-
tigated the association between high risk of OSA and adherence to
antihypertensive treatment in an outpatient clinic for patients with
hypertension.
2 |  METHODS
2.1 | Procedure
The Strengthening the Reporting of Observational Studies in
Epidemiology (STROBE) checklist was used to guide the planning of
the study. This cross-­sectional study was performed in the hyper-
tension outpatient clinic of the Hospital de Clínicas de Porto Alegre,
RS, Brazil. Patients in this clinic were enrolled in a cohort to investi-
gate clinical and therapeutic aspects related to the management of
patients with hypertension.14 The study participants were consecu-
tively selected from September to December 2012. The inclusion cri-
teria were patients 18 years and older, of both sexes, taking treatment
with antihypertensive agents with more than one previous follow-­up
consultation.
The institutional review board approved the ethical and method-
ological aspects of the investigation under the number 120253. The
study complies with the Resolution 466/12 of the Brazilian National
Health Council, establishing the Guidelines and Standards for Research
Involving Humans, and with the 1964 Declaration of Helsinki and its
later amendments. All patients provided written informed consent to
participate.
2.2 | Study variables and measures
Patients completed a standardized interview covering demographics,
clinical, and social data, in addition to specific questionnaires. Office
BP was measured according to standard guidelines. Uncontrolled
hypertension was defined as an office BP ≥140/90 mm Hg at the day
7
of consultation. The high risk of OSA was assessed by the STOP-­
Bang instrument.15
A STOP-­Bang score of three or more defined high risk of OSA. The
letters of this acronym represent the following symptoms: snoring,
tiredness, observed apnea, high BP, body mass index ≥35 kg/m², age
50 years and older, neck circumference ≥40 cm, and male sex. Since
all patients had hypertension, we did not consider the item “P” related
to presence of high BP. The STOP-­Bang questionnaire was opted due
to a better sensibility (97%) than the Berlin questionnaire (71.5%) in
a sleep clinic sample.16 Nonadherence was defined by a score lower
than six in the eight-­item Morisky questionnaire.17 A score between
6 and <8 defined moderate adherence and a score of 8 defined good
adherence. Excessive daytime sleepiness was considered present
when the Epworth Sleepiness Scale18 score was >10.
2.3 | Statistical analysis
The sample size of 372 patients was calculated to detect a 15% dif-
ference in the prevalence of nonadherence to treatment between
patients with and without a high risk of OSA for a P α of 5% and power
of 80%. A 10% margin of additional enrollment was planned to com-
pensate for incomplete data and losses.
The variables were described as percentages or mean and standard
deviation. The chi-­square, Student t, Spearman bivariate correlation,
logistic regression, and Mann-­Whitney U tests were used to compare
each of the possible explanatory variables in groups of good and poor
adherence. Normal distribution was assessed by Kolmogorov-­Smirnov
test. Multivariate analysis was performed by Poisson regression.19 The
results were considered statistically significant when the probability of
α error was <0.05.
3 | RESULTS
The 416 participants included in this study represent the majority
of the attendances during the data collection period at the hyper-
tension outpatient clinic (Figure 1). The mean age of the sample was
65±11 years and 32% were men. Nonadherence was identified in 71
(17%) and BP was ≥140/90 mm Hg in 241 (58%) patients. High risk of
OSA indicated by the STOP-­Bang questionnaire was present in 323
(78%) of the sample and somnolence in 136 (33%). The characteristics
of the sample by adherence groups are shown in Tables 1 and 2.
The significant variables in univariate analyses associated with
nonadherence were diastolic BP, age, sleepiness, and high risk of
OSA (Tables 1 and 2 Figure 2). Although not statistically significant,
the adherent group tended to use the healthcare system, cost-­free
medication, and other resources more often than the nonadherent
group (Table 2). Absenteeism to consultation was not an indicator of
nonadherence, given the similarity between groups. The most com-
mon symptoms attributed to treatment were edema (19.5%), dizziness
(7.5%), headache (4.1%), dyspnea (2.6%), and pruritus (1.0%). None of
these side effects differed between groups.
Figure 2 shows the prevalence of sleepiness and high risk of OSA
by adherence groups. Poor adherence was significantly associated with
a greater prevalence of high risk of OSA and sleepiness. Regarding the
eight items from the STOP-­Bang questionnaire, observed apneas were
reported more frequently by nonadherent than adherent patients
(52% and 31%, respectively [P=.001]).
The prevalence of nonadherence was associated with sleepiness
only in patients with high risk of OSA (Figure 3). Daytime sleepiness
increased 2.03 times the odds for nonadherence (confidence inter-
val [CI], 1.17–3.54; P=.017). Patients without a high risk of OSA did
not show an association between sleepiness and nonadherence (OR,
.94; CI, 0.10–8.43 [P=.953]). The prevalence of sleepiness was 38%
in patients with high risk of OSA and 15% in patients without a high
RIGHI et al. |
      3

F I G U R E   1   Flow chart of the screened participants
BP-­lowering drugs. Our study also has shown that excessive daytime
sleepiness may affect adherence to medication. The results suggest
that the identification of high risk of OSA and/or excessive sleepi-
ness might lead the clinician to suspect OSA as a cause of insufficient
adherence to hypertension treatment.
In the original Morisky study (2008),17 the authors found a 32%
rate of low adherence. Comparatively, we found a lower prevalence
rate of nonadherence (17%) using the same cutoff point (<6 ques-
tions) in the Morisky questionnaire. The lower prevalence rate in
our study may be due in part to the fact it is a specialized outpa-
tient clinic, where patients are referred to follow a pharmacist con-
sultation specifically focused on strategies to improve adherence
levels.20

T A B L E   1   Clinical, Sociodemographic,
Variables Total (N=416) Nonadherent (n=71) Adherent (n=345) P Value
and Patient Characteristics of the Whole
Male sex 132 (32) 19 (27) 113 (33) .4 Sample and by Adherence Groups
Age, y 65±11 61±12 66±11 .002
2
BMI, kg/m 29.9±5.4 30.3±6.1 29.9±5.3 .56
Schooling, y 7±4 7±3 6.5±4 .21
Diabetes mellitus 128 (31) 18 (25) 110 (32) .35
Living with a 227 (55) 34 (48) 193 (56) .27
partner
Occupational 128 (31) 28 (41) 100 (29) .07
activities
White race 338 (81) 57 (80) 281 (81) .95
Black race 62 (15) 13 (18) 49 (14) .48
a
Smoking 169 (41) 22 (31) 147 (43) .09
Alcohol 112 (27) 16 (23) 96 (28) .44
consumption
Regular physical 143 (34) 21 (30) 122 (35) .43
activity
Target organ 185 (45) 32 (45) 153 (44) 1
damage
Alternative 77 (19) 58 (17) 19 (27) .07
medicine
Comorbidity 288 (69) 51 (72) 237 (69) .7

Data are reported as number (percentage) or means±standard deviation. Statistically significant prob-
abilities are shown in bold.
a
Current and past smoking. BMI indicates body mass index.

risk of OSA (P<.001). The prevalence ratio of the combined high risk
of OSA and sleepiness was 1.25, with a 95% CI of 1.14–1.37 (P<.001).
In multivariate analysis (Figure 4), the Poisson regression model
was employed to assess the association between high risk of OSA and
nonadherence. High risk of OSA increased the prevalence ratio to 2.3
(P=.029), even adjusting for daytime sleepiness.
4 | DISCUSSION
To the best of our knowledge, this is the first study to indicate that
patients with a high risk of OSA are more frequently nonadherent to
Our analysis shows that nonadherence is associated with younger age,
higher diastolic BP, sleepiness, and high risk of OSA. Each additional year
in age improves adherence in approximately 3% of patients (CI, 1.2–5.6%).
This finding is in agreement with studies demonstrating that age affects
adherence.21,22 Diastolic BP was significantly higher in the nonadherent
than in the adherent group. This might be due to younger age or nonadher-
ence itself. Average systolic BP was similar in both groups (>140 mm Hg;
Table 2). The Hawthorne effect23 could be a plausible explanation for this
unexpected result, since nonadherent patients may take their medication
before the consultation, producing a reduced BP when it is measured. On
the other hand, while BP was measured at the consultation day only, the
Morisky questionnaire refers to adherence during the past few days.
 |
4       RIGHI et al.

T A B L E   2   Clinical/Treatment and Healthcare System Variables in the Whole Sample and by Adherence Groups

Variables Total (N=416) Nonadherent (n=71) Adherent (n=345) P Value

Blood pressure
Systolic, mm Hg 144±23 142±19 144±24 .56
Diastolic, mm Hg 82±13 85±11 82±13 .04
Hypertension duration, y 20±12 19±12 21±13 .26
Drugs
No. prescribed 3.6±1.3 3.4±1.3 3.6±1.3 .33
3 or more 326 (78) 54 (76) 272 (79) .72
Dose frequency per d
Up to 2 253 (61) 48 (68) 205 (59) .25
Controlled by family members 44 (11) 8 (11) 36 (10) 1
Side effects 168 (40) 26 (37) 142 (41) .56
Healthcare system
Health insurance plans 135 (8) 14 (6) 31 (9) .48
Cost-­free drugs (government-­subsidized) 213 (51) 33 (47) 180 (52) .46
Visits to emergency (previous 12 mo) 216 (52) 33 (47) 183 (53) .38
Hospital admissions (previous 12 mo) 226 (54) 33 (47) 193 (56) .19
Absenteeism to consultations 22±18 20±17 22±19 .35

Data are reported as number (percentage) or means±standard deviations. Statistically significant probabilities are shown in bold.

The prevalence of sleepiness in this sample was 33% by the

Epworth scale result above 10 points. This percentage is similar to
the 27% found by Williams and coworkers.30 Considering that 42%
of the OSA patients aggregate in the sleepy cluster,31 the expected
percentage of sleepy participants in our sample would be exactly 33%.
The elevated prevalence of sleepiness in our sample, therefore, may
be fully explained by high risk of OSA.32 Daytime sleepiness is less
frequent in the community, around 18%.33,34 Excessive daytime sleep-
iness, a common apnea-­related symptom, may contribute to failure in
taking medication. Williams and colleagues also identified an associa-
tion between sleepiness and adherence.30 However, we have further
F I G U R E   2   Prevalence of obstructive sleep apnea and excessive evaluated the association between high risk of OSA and adherence.
daytime sleepiness by adherence groups
The present study shows that the effect of sleepiness on adherence is
mainly present in patients with high risk of OSA (Figure 3).
Using the STOP-­Bang questionnaire as a diagnostic tool, 78%
of the participants had a high risk of OSA. This prevalence in our
sample, with an average age of 65 years, agrees with the prevalence
identified in a previous report of patients in the same age range.24
In that study, the authors identified an apnea-­hypopnea index ≥5
by polysomnography in 72% of people of both sexes, aged 60 to
69 years.
OSA is a recognized cause of neurocognitive changes and leads to
brain structural and metabolic alterations related to memory.25 This
damage in brain may also be induced by sleepiness,26 which can be a
major cause of neurocognitive impairment in OSA.27 It may act directly
on the behavioral pattern of not taking medication. The behavior of
failure to take medication could be explored by apnea-­related symp-
toms and/or its consequences. The cognitive deficit related to hyper- F I G U R E   3   Prevalence of excessive daytime sleepiness by
tension28 also favors nonadherence.29 adherence levels in groups without and with obstructive sleep apnea
RIGHI et al.
Evidence implies a possible effect of memory on the behavior
29
of taking medication. Approximately 65% of individuals who did
not take their medications as prescribed reported that the reason
was their forgetfulness.35 In a population with heart failure,36 the
effect of daytime sleepiness on nonadherence to drug treatment
was attributed to attention impairment. However, Williams and col-
leagues30 reported preserved cognitive performance in hypertensive
patients. It is difficult to conclude on the memory-­nonadherence
issue, since reverse causality is a possibility, via the effect of higher
BP on memory.37
Verstraeten and colleagues27 pointed out sleepiness as the main
cause of neurocognitive loss in patients with OSA. The association
between OSA and hypertension is stronger when sleepiness is pres-
38
ent. Their results are in agreement with our findings, indicating that
sleepiness contributes to nonadherence and, therefore, favors high
BP. Daytime sleepiness should be assessed in the face of suspicion of
nonadherence to drug treatment.
39–41
Nonadherence can be explained by innumerable reasons.
However, it is also necessary to consider factors such as high risk
of OSA and sleepiness. Both conditions contribute to nonadherence
behavior. This is a hypothesis-­generating study. In order to reach
a higher level of evidence, it would be necessary to use polysom-
nography to confirm the effect of OSA on adherence. Moreover, an
intervention such as continuous positive airway pressure treatment
would be helpful to confirm causality between OSA and adherence.
However, a deeper evaluation in these terms is beyond the scope of
our study.
5 | STUDY LIMITATIONS AND STRENGTHS
This study has some limitations including the identification of high
risk of OSA by questionnaire. On the other hand, questionnaires are
a useful screening tool in clinical practice.24,42 Polysomnographic
evaluation is complex and would be unfeasible in this large sam-
ple study.24 Another potential limitation is the use of the Morisky
scale to assess nonadherence. However, measuring treatment
adherence is limited by direct and indirect methods. 6 The Morisky
scale is considered a practical and reliable tool when compared
with direct methods such as assessment of blood levels of drugs,
metabolites, and biomarkers. The measurement of dosages of
every drug in the blood would be impractical and expensive and
would not avoid the above-­cited Hawthorne effect. Even though
direct assessment methods of adherence are considered by some
to be the most accurate approach,5,6 a gold standard method has
|
      5
F I G U R E   4   Obstructive sleep apnea and
excessive daytime sleepiness are associated
with nonadherence by Poisson regression
analysis. CI indicates confidence interval;
PR, prevalence ratio
not been determined, since each method has its advantages and
disadvantages.6
Our results represent an advance in the understanding of the
determinants of nonadherence. They are not restricted to hyperten-
sion treatment in adults, but they may be useful in various other areas
in which improvement of adherence to drug therapy is essential. This
should be the object of future research on OSA mechanisms that
affect adherence to drug therapy.
6 | CONCLUSIONS
High risk of OSA and excessive daytime sleepiness are independent
risk factors for nonadherence to BP-­lowering treatment. Based on
these findings, studies on the impact of OSA treatment on adherence
to medication are warranted. Our results point out novel ­potentially
modifiable variables that can be targeted in future interventions
focusing on medication adherence.
AC KNOW L ED G M ENTS
We are grateful to Vania Hirakata, Math PhD, and Luciano for assis-
tance in the methods of Poisson regression, and to Aline Junqueira,
Ana Gabriela Neis, Eliese Denardi Cesar, Emerson Martins, Jamile
Dutra Correia, Marcelo Parra, Mariana Meister, Milena Cristofoletti,
Paola Perasso, Pedro Lopez, Victoria Prates, Roberta Horn, and
Yasmin Cecato for their important contribution in data collection.
D I S C LO S U R E O F P OT ENT I AL CO NFL I C TS O F I N T EREST
Dr Martinez has financial interest in a private sleep medicine clinic.
The other authors have no conflicts of interest to disclose.
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How to cite this article: Righi CG, Martinez D, Gonçalves SC,
et al. Influence of high risk of obstructive sleep apnea on
adherence to antihypertensive treatment in outpatients. J Clin
Hypertens. 2017;00:1-6. https://doi.org/10.1111/jch.12992