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Original Article
Ambulatory Blood Pressure Monitoring and Cardiovascular Risk in
Resistant Hypertensive Women
Monica Maria Ferreira Magnanini1, Armando da Rocha Nogueira2, Marilia Sá Carvalho4, Katia Vergetti Bloch1,3
Instituto de Estudos em Saúde Coletiva1; Hospital Universitário Clementino Fraga Filho2; Departamento de Medicina Preventiva - Faculdade de
Medicina – UFRJ3; Escola Nacional de Saúde Pública Sérgio Arouca – Programa de Computação Científica FIOCRUZ4, Rio de Janeiro, RJ - Brazil
Summary
Background: Few studies have explored the prognostic value of ambulatory blood pressure (ABP) in resistant hypertensive
patients, a high-risk group.
Objective: To investigate the prognostic value of uncontrolled daytime ABP in resistant hypertensive women.
Methods: We followed 382 resistant hypertensive women, aged 24-92 years, from a hypertension unit of a university
hospital, for up to 8.9 years (mean 3.9). Patients were classified as controlled (office BP≥140/90mmHg and daytime ABP
<135/85 mmHg) or uncontrolled (office BP≥140/90mmHg and daytime ABP ≥135/85 mmHg). We analyzed a combined
endpoint, consisting of cardiovascular mortality, ischemic heart disease, stroke and nephropathy. Cox proportional
hazard models were used to estimate the risk for cardiovascular events, adjusting for potential confounders.
Results: The total event rate was 5.0 per 100 women-years. In the controlled and uncontrolled groups, the rates were 3.7
vs. 5.8 events respectively, p=0.06. The relative risks adjusted for age and current smoking status associated with a 10
mmHg increment in systolic ABP were greater than the ones associated with a 5 mmHg increment in diastolic ABP. Nondipper patients had a higher risk for cardiovascular events than dipper patients (RR = 1.42 (0.87 – 2.32)), although this
association had no statistical significance. Uncontrolled daytime blood pressure (yes/no) was a stronger independent
risk factor, 1.67 (1.00-2.78).
Conclusions: There was a 67% increase in the risk of a cardiovascular event if daytime ambulatory blood pressure was
uncontrolled in women with resistant hypertension. Therefore, it is mandatory to use ABP to evaluate control and to
guide therapeutic strategies in resistant hypertensive patients. (Arq Bras Cardiol 2009; 92(6) : 448-453)
Key words: Blood pressure monitoring, ambulatory; hypertension; cardiovascular diseases; prognosis.
Introduction
women than men die annually of cardiovascular diseases2.
Cardiovascular diseases are the main cause of mortality
all over the world and an important contributing factor is the
difficulty in blood pressure (BP) control. Despite the fact that
pharmacological therapy of hypertension is widely spread,
the proportion of patients with BP lower than 140/90 mmHg
after treatment ranges from 6% to 25%1.
In Brazil, there was a 500% increase in the elderly
population in 40 years. There will be 32 millions of elderly
subjects by the year 2020. Life expectancy has been rising, and
in an overwhelming majority of countries, women outnumber
men in later life. However, although females have higher life
expectancy than males, they live proportionally fewer years
in good health3,4.
In the USA, there were no significant changes in the rates
of hypertension control for women between 1988 to 1994
and 1999 to 2004, with the rates remaining under 50%, while
50% of men aged 60 and older achieved hypertension control.
Possible explanations for the poor blood pressure control seen
in women may be the fact that physicians are less likely to
suggest preventative measures for women than men, as they
significantly minimize the cardiovascular risk status of women
when compared with men, as they are not aware that more
Mailing address: Monica Maria Ferreira Magnanini •
Rua Carolina Santos, 53 casa 13, Méier, 20.720-310, Rio de Janeiro,
RJ - Brazil
E-mail: [email protected]
Manuscript received June 06, 2008; revised manuscript received
August 13, 2008, accepted September 05, 2008.
448
Evidence indicates that ambulatory BP (ABP) measurements
are more closely related to target organ damage than office BP
measurements5-9. Although some studies have explored the
prognostic value of ABP in treated hypertensive subjects10-12,
few investigated this issue in resistant hypertensive patients13,
a high-risk group that challenges clinical practice.
The aim of this study was to evaluate the cardiovascular
outcome in a cohort of resistant hypertensive women,
comparing the ones with controlled daytime ABP with the
non-controlled ones.
Methods
The present study design is a cohort of 382 women
referred to an outpatient hypertension clinic due to resistant
Magnanini et al
Cardiovascular risk in resistant hypertensive women
Original Article
hypertension. The exposure was uncontrolled daytime
ABP at the entrance of the study and the endpoint was any
cardiovascular event.
Resistant hypertension was defined as office BP persistently
higher than 140/90 mmHg in spite of triple or more intensive
antihypertensive therapy.
Patients gave their informed consent. The study was in
accordance with the second Declaration of Helsinki and was
approved by the Institutional Review Board.
Clinical evaluation
All patients underwent clinical evaluation, electrocardiography,
routine laboratory tests and echocardiographic examination.
After optimization of the therapeutic regimen, patients were
submitted to ABP monitoring. Secondary hypertension was
an exclusion criterion.
The physician measured the patient’s office blood
pressure in the sitting position, using a calibrated mercury
sphygmomanometer with an appropriately-sized cuff. Two
BP measurements were taken during the visit (at least 5
min apart) and the second one was used. Weight, height,
and waist circumference were determined for each subject;
waist circumference was measured at the narrowest diameter
between the costal margin and the iliac crest. Body mass index
(BMI) was calculated by the weight in kilograms divided by
the square of the height in meters.
Risk factors evaluated were: diabetes (two fasting glycemias
≥ 6.9 mmol/L or under treatment), dyslipidemia, current
smoking status, overweight/obesity (overweight defined as
BMI ≥25 kg/m2 and obesity as BMI≥30 kg/m2), sedentary
lifestyle (no regular physical activity at least 30 min per day,
on most days of the week).
The American Society of Echocardiography criteria for left
ventricular hypertrophy (LVH), which considers hypertrophy
as a left ventricular mass index (LVMI) >104 g/m2 for women,
was used14. LV mass was calculated according to Devereux15
and normalized for body surface area to obtain the LVMI.
Follow-up
Patients were followed at the outpatient clinics
(Hypertension, Internal Medicine, Cardiology, and Geriatrics)
of the same hospital. Patients’ characteristics and the
occurrence of cardiovascular events were recorded during
follow-up visits. Patients that did not return after one year and
that could not be contacted by telephone were searched at
the Mortality Information System.
reading was taken every 10 min throughout the day and
every 20 min at night. The data were considered adequate
when a minimum of 70 valid records were obtained in 24
h, with at least two records per hour during the nighttime.
Patients registered their sleep patterns, so that an individual
nighttime pattern could be entered into the software for each
patient16. The following parameters were evaluated: average
24-h, daytime and nighttime systolic BP (SBP) and diastolic
BP (DBP); pulse pressure (PP) was calculated as systolic minus
diastolic BP. Patients were defined as nondippers if they had
a reduction in BP less than 10% from daytime to nighttime,
or as dippers, when otherwise. Women were classified
either as having controlled daytime ABP (white coat resistant
hypertension), office BP≥140/90mmHg and daytime ABP
<135/85mmHg, or as having uncontrolled daytime ABP (true
resistant hypertension), office BP ≥140/90mmHg and daytime
ABP ≥135/85 mmHg7.
Statistical analysis
Data were expressed as mean ± standard deviation or
percentage. Baseline characteristics were compared with
Mann-Whitney test for continuous variables and Đ 2 tests for
categorical variables. For the participants who experienced
multiple events, the analysis included only the first event.
Event rates are expressed as the number of events per 100
patient-years based on the ratio of the observed number of
events to the total number of patient-years exposure up to the
terminating event or censor. Survival curves were estimated
using the Kaplan-Meier product-limit method and were
compared by the log-rank test. Variables that had a p value less
or equal to 0.20 were included in the multivariate analysis as
potential confounders. The independent effect of uncontrolled
daytime ABP was tested using multivariate Cox proportionalhazard models. The confounding effect was assessed by
the change each variable produced in the point estimate
and hazard ratio (relative risk) of the categorical variables
controlled /uncontrolled daytime ABP. Effect modification
was investigated using a heterogeneity test for an interaction
term included in the model. Analyses were carried out using
STATA 9.0 (StataCorp, Texas, USA).
Results
Ambulatory BP monitoring
Of the 382 patients analyzed, 162 (42.4%) were classified
as presenting controlled daytime ABP, and 220 (58.6%) as
presenting uncontrolled daytime ABP. The main clinical
characteristics and BP values of the patients in each group are
shown in Table 1. The controlled group was older and more
dyslipidemic than the uncontrolled group, whereas body mass
index and circumference waist were higher in the uncontrolled
group. Afro-Brazilian patients were slightly more frequent
in the uncontrolled group. All others characteristics were
similar between the groups. The blood pressure parameters
were higher in the uncontrolled group than in the controlled
group, except for the pulse pressure that was higher in the
controlled group.
Ambulatory BP was recorded using the Oscar (SunTech
Medical) or DYNAMAPA equipments, both of which have
been approved by the British Society of Hypertension8. A
Eighty-eight percent of the patients had been prescribed
three or four antihypertensive drugs and twelve percent were
prescribed more than four. All patients were taking diuretics.
Cardiovascular events included fatal and nonfatal coronary
disease (myocardial infarction, bypass surgery or angioplasty),
cerebrovascular disease (stroke, corroborated by physical
exam and/or CT scans), and hypertensive nephropathy
(proteinuria >500 mg/24 h and/or creatinine clearance <50
ml/min and/or microalbuminuria of 30–299 mg/day).
Arq Bras Cardiol 2009; 92(6) : 448-453
449
Magnanini et al
Cardiovascular risk in resistant hypertensive women
Original Article
The most frequently used drugs were ACE inhibitors (89.3%),
B-blockers (79.1%) and calcium channel blockers (49.0%).
The latter was more frequently used by the controlled patients
than by the uncontrolled ones. The most frequently used
therapeutic regimen in each group is shown in Table 1.
Forty-two subjects (11.0%) were lost to follow-up, 14.6%
from the uncontrolled group and 6.2% from the controlled
group, p=0.01.
A total of 73 new cardiovascular events were recorded
during a mean follow-up period of 3.9 years, ranging from 1
month to 8.9 years, with 1,474.0 person-years at risk. There
were 25 fatal and 48 non-fatal cardiovascular events. The
total event rate per 100 women-years was 5.0. The incidence
rate of events was lower for the controlled group than for the
uncontrolled one (3.7 vs. 5.8 events per 100 women-years;
p=0.06). The probability of event-free survival is presented in
Figure 1. The comparison of survival curves among the groups
showed that the survival was lower for the uncontrolled than
for the controlled group, although the difference was not
statistically significant (log-rank p= 0.10). No race/ethnicbased difference in survival was observed.
Only age and current smoking status were considered
confounders for the association between daytime ABP control
and cardiovascular events in this population.
The relative risks adjusted for age and current smoking
status associated with a 10 mmHg increment in systolic ABP
and with a 5 mmHg increment in diastolic ABP are reported in
Table 2. The relative risks associated with increments in systolic
BP were greater than the ones associated with increments in
diastolic BP.
Non-dipper patients had a higher risk for cardiovascular
events than dipper patients (RR = 1.42 (0.87 – 2.32)), mainly
for the uncontrolled patients (RR = 1.70 (0.93 – 3.10)) when
compared to the controlled ones (RR = 0.92 (0.40 – 2.15)),
although these associations had no statistical significance.
There was no interaction between dipper pattern and BP
control (p=0.34).
Cox regression analysis showed that daytime ABP control
was an independent risk factor for new cardiovascular events,
RR = 1.67 (Table 3).
Discussion
The results of our prospective study with resistant hypertensive
women showed that, after adjustment for traditional risk
factors, the daytime ABP control provided additional prognostic
information concerning cardiovascular events.
The incidence rates as well as the survival curve showed a
worst risk profile for the uncontrolled patients, although this
unadjusted analysis did not show a striking difference. The
relative risk after adjustment for age and current smoking status
was almost 70% higher in the group with higher daytime BP.
Although the uncontrolled patients had higher BMI and
larger waist circumference, these characteristics were not
450
Arq Bras Cardiol 2009; 92(6) : 448-453
Table 1 - Characteristics of the population according to controlled/
uncontrolled daytime ABP
Parameter
Uncontrolled
Controlled
220 (57.6)
162 (42.4)
Age (years)
59.1 (12.0)
61.9 (10.8)
0.029
Afro-Brazilian, n (%)
112 (50.9)
68 (42.0)
0.069
Body mass index (kg/m2)
31.5 (6.1)
30.5 (6.8)
0.026
Current smokers, n (%)
19 (8.7)
10 (6.3)
0.383
Physical inactivity, n (%)
168 (77.4)
119 (74.8)
0.561
Diabetes, n (%)
90 (40.9)
61 (38.4)
0.618
Dyslipidemia, n (%)
132 (61.4)
117 (74.1)
0.010
169 (83.3)
118 (78.7)
0.275
6.8 (3.0)
6.5 (2.3)
0.855
Triglyceride (mmol/L)
1.8 (1.4)
1.7 (0.96)
0.887
HDL (mmol/L)
1.2 (0.31)
1.2 (0.32)
0.668
Circumference waist (cm)
101.9 (12.9)
99.1 (12.9)
0.042
Metabolic syndrome, n (%)
51 (31.5)
63 (28.6)
0.55
Systolic (mmHg)
189.2 (30.8)
178.2 (23.8)
0.001
Diastolic (mmHg)
103.3 (19.8)
96.4 (15.7)
0.002
Systolic daytime (mmHg)
153.5 (16.3)
122.3 (8.9)
<0.001
Diastolic daytime (mmHg)
87.2 (12.6)
70.7 (7.5)
<0.001
Systolic nighttime (mmHg)
143.1 (22.1)
112.8 (13.6)
<0.001
N (%)
P value
Demographic variables
Risk factors
Subclinical organ damage
LV Hypertrophy, n (%)
Factors for MetS
Glucose (mmol/L)
Office blood pressure
Ambulatory blood pressure
Diastolic nighttime (mmHg)
77.9 (14.3)
62.8 (9.3)
<0.001
Systolic 24-h (mmHg)
151.4 (16.5)
120.4 (8.9)
<0.001
Diastolic 24-h (mmHg)
85.2 (12.6)
69.1 (7.4)
<0.001
Pulse Pressure 24-h
(mmHg)
50.2 (8.8)
64.0 (13.4)
<0.001
Dipper, n (%)
113 (51.4)
84 (52.2)
0.876
0.022
Therapeutic regimen
Diur + ACEI + BB
58 (26.4)
39 (24.1)
Diur + ACEI + CCB
25 (11.4)
20 (12.3)
Diur + ACEI + BB + CCB
23 (10.5)
36 (22.2)
Diur + ACEI + BB + VD
32 (14.5)
15 (9.3)
Others
82 (37.3)
52 (32.1)
Data are presented as mean ± SD or number (%); LV - left ventricular hypertrophy;
HDL - high density lipoprotein; Diur - diuretics; ACEI - angiotensin-converting
enzyme inhibitors; BB - B-blockers; CCB - calcium channel blockers; VD direct vasodilators
Magnanini et al
Cardiovascular risk in resistant hypertensive women
Original Article
Table 2 – Adjusted relative risks per 10 mm Hg increase in systolic
blood pressures and per 5 mm Hg increase in diastolic blood
pressures for the combined end point
Blood Pressures
RR (95% CI)
P value
Ambulatory
24h-SBP
1.16 (1.03-1.30)
0.02
24h-DBP
1.08 (0.97-1.20)
0.17
Daytime SBP
1.15 (1.02-1.29)
0.03
Daytime DBP
1.07 (0.97-1.18)
0.22
Nighttime SBP
1.12 (1.02-1.23)
0.03
Nighttime DBP
1.08 (0.99-1.19)
0.09
Pulse Pressure (1 mm Hg)
1.02 (1.01-1.04)
0.02
SBP
1.04 (0.96-1.13)
0.26
DBP
0.97 (0.90-1.04)
0.38
Office
Relative Risks are adjusted for age and current smoking status; SBP
– systolic blood pressure; DBP - diastolic blood pressure.
Table 3 – Relative risks of cardiovascular events associated with
daytime ABP uncontrolled: crude and adjusted for age and current
smoking status
RR (95% CI)
p value
Crude
1.52 (0.92 – 2.51)
0.10
Adjusted
1.67 (1.00 – 2.78)
0.05
RR - relative risk ; CI - confidence interval
associated with cardiovascular risk in this population, probably
because these measures were very high in both groups.
The lack of association between dyslipidemia and
cardiovascular risk may be due to a survival bias at baseline.
Patients with dyslipidemia would be underrepresented in the
uncontrolled group, as they would have died earlier.
Calcium channel blocker agents were more frequently used
by the controlled patients (older ones), but this agents were
not an independent cardiovascular risk factor.
Our results suggest that a dipper pattern may be associated
with lower cardiovascular risk, and this association seems to be
stronger in patients already at a higher risk due to increased BP
levels. Effect modification is plausible and we may not have
had the power to detect it.
Our results are in line with other studies carried out in
treated hypertensive populations to investigate the prognostic
impact of ABP10-13.
Redon et al13 studied 86 patients with DBP> 100 mmHg
using three or more antihypertensive drugs, including a diuretic.
After 49 months of follow-up, the risk of a cardiovascular event
was significantly higher for patients who had a higher daytime
diastolic BP at baseline (RR = 6.2; 95%CI = 1.38-28.1).
Verdecchia et al10 showed that ABP control (daytime) is
superior to office BP control when predicting cardiovascular
outcome in treated hypertensive patients receiving single,
double or multiple therapy. The event rate was lower (0.71
events/100 person-years) among patients with controlled ABP
than among those with uncontrolled ABP (1.87 events/100
person-years), p=0.003. When both office and ABP controls
were forced into the same model, only ABP control achieved
significance, with an adjusted relative risk of 0.36 (95%CI
0.18-0.70).
Figure 1 - Probability of event-free survival in women with resistant hypertension grouped as controlled/uncontrolled daytime ABP.
Arq Bras Cardiol 2009; 92(6) : 448-453
451
Magnanini et al
Cardiovascular risk in resistant hypertensive women
Original Article
Clement et al11 used a cutoff of 135 mmHg for 24-h
systolic BP, and not for daytime BP, as the normal limit for
ABP and did not use the diastolic BP. They found a higher
risk of cardiovascular events for the patients with mean 24-h
systolic BP of 135 mmHg or higher, with an adjusted relative
risk (including office BP) of 1.74 (95%CI 1.15-2.48).
Pierdomenico et al12 reported that age, diabetes, previous
events and true nonresponsive hypertension (office BP ≥ 140
or 90 mmHg and daytime BP ≥ 135 or 85 mmHg) resulted
in independent predictors of outcome in Caucasian patients.
The relative risk for true vs. false nonresponders (office BP ≥
140 or 90 mm Hg and daytime BP< 135 or 85 mm Hg) found
was 2.33 (95%CI 1.14-4.77).
17
Verdecchia et al studied subjects diagnosed with essential
hypertension and found a strong significant independent
association between blunted nocturnal reduction in BP and
cardiovascular morbidity in women, but not in men. The
association we found was weaker, especially after adjustment
for 24-hour BP values, which can suggest that for this
population, a higher average BP over the 24 hours explains
part of the higher risk in the nondippers.
Hajar et al18 showed that in stroke-free older adults,
those with uncontrolled hypertension had an increased
risk of incident disability, whereas those with controlled
hypertension had a similar risk of incident disability as those
without hypertension. They found that, compared with men,
women are particularly at an increased risk of developing
disability from hypertension. The authors credited the
increased predisposition to disability in women to the fact
that hypertension is more prevalent among them.
As far as we are concerned, this is the first study focused on
resistant hypertensive women. Our results reinforce the need of
a more aggressive therapeutic strategy towards blood pressure
control in this particular group. Physicians should not downgrade
the cardiovascular risk status of women, especially in a high risk
population as the one studied here. The role of ABP monitoring
to guide therapeutic approaches has been definitely established
and the method should be included in the assessment of BP
control in resistant hypertensive patients routinely.
Some limitations of our study should be pointed out. There
were more losses in the non-controlled group than in the
controlled group. This may have produced an underestimated
relative risk, so we believe that the differences found could
be even bigger without the losses.
Conclusions
This study suggests an association between elevated daytime
ABP and cardiovascular risk in resistant hypertensive women.
Therefore, to achieve the goal of decreasing cardiovascular
morbidity and mortality in this population, the decisions
should be based on the control of ABP and not on the control
of office blood pressure.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was
reported.
Sources of Funding
This study was partially funded by FINEP/Petrobrás/
Cnpq.
Study Association
This article is part of the thesis of doctoral submitted by
Monica Maria Ferreira Magnanini, from Escola Nacional de
Saúde Pública Sérgio Arouca - FIOCRUZ.
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Cardiovascular risk in resistant hypertensive women
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