Download Comparison of alprazolam versus captopril in high blood pressure

Blood Pressure, 2011; Early Online, 1–5
ORIGINAL ARTICLE
Comparison of alprazolam versus captopril in high blood pressure:
A randomized controlled trial
SERKAN YILMAZ1, MURAT PEKDEMIR1, ÜMIT TURAL2 & MECIT UYGUN1
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1Department
of Emergency Medicine and 2Department of Psychiatry, Faculty of Medicine, Kocaeli University, Turkey
Abstract
Objective. Anxiety is an important cause of acute blood pressure (BP) elevation. However, the role of anxiolysis in this
situation is still controversial. In this study, the relationship of anxiety with BP and the effect of anxiolytic treatment on
BP were investigated. Methods. Emergency department (ED) patients with an initial systolic BP (SBP) ⱖ 160 mmHg or
diastolic BP (DBP) ⱖ 100 mmHg but no end organ damage were approached for inclusion in the study. In those consenting to participate, anxiety levels were measured using the State-Trait Anxiety Index (STAI) and Visual Analog Scale for
Anxiety (VAS-A). Patients were randomly assigned to receive oral alprazolam 0.5 mg or captopril 25 mg. BP and anxiety
levels were measured at baseline and at 1 and 2 h after administration of the study medication. Results. Of 133 patients
meeting inclusion criteria, 53 patients agreed to participate. Of these, 27 patients (50.9%) received captopril and 26 patients
(49.1%) received alprazolam. The majority of the patients had a high-level trait (96.2%, n ⫽ 51) and state anxiety (81.1%,
n ⫽ 43). The mean SBP and VAS-A values of both patient groups dropped significantly over the 2 h, with no significant
difference between the two groups. A significant association between SBP and VAS-A scores was found (F(2,50) ⫽ 6.27,
p ⫽ 0.004). Conclusion: A significant association exists between the level of BP and anxiety in hypertensive ED patients.
Alprazolam is as effective as captopril in lowering BP in ED patients with an initial SBP ⬎ 160 mmHg.
Key Words: Alprazolam; anxiety; captopril; emergency department; high blood pressure
Introduction
Many patients present to the emergency department
(ED) with high blood pressure (BP), but only a small
proportion of these will require emergent antihypertensive therapy. The primary goal of the emergency
physician is to determine which patients with acute
hypertension are exhibiting symptoms of end-organ
damage. In contrast, patients presenting with elevated
BPs (systolic BP, SBP ⬎ 200 mmHg or diastolic BP,
DBP ⬎ 120 mmHg) without symptoms, and whose
BP remains high until ED discharge should begin
antihypertensive therapy as an outpatient with close
follow-up (1). The cause of hypertension is not known
in many patients, but includes pheochromocytoma,
renal artery stenosis, severe pain, cerebrovascular disease, acute renal failure, medications and illegal drugs,
withdrawal of antihypertensive treatment, and panic
attack or phobic anxiety (2,3).
Anxiety is known to trigger sympathetic discharge
that may lead to elevated BP (2). Sympathetic
activation, in addition to the elevated BP, also likely
contributes to left ventricular hypertrophy and to the
commonly associated metabolic abnormalities of
insulin resistance and hyperlipidaemia. The mechanisms of increased long-term cardiac risk attributable to mental stress and psychiatric illness are not
entirely clear, but activation of the sympathetic nervous system seems to be of prime importance (4). A
meta-analysis of 2024 patients who received psychosocial treatment vs 1156 control subjects found that
the psychosocially treated patients showed greater
reductions in psychological distress, SBP, heart rate
and cholesterol levels (5). Another meta-analysis of
37 studies found that psychoeducational (health education and stress management) programmes for
coronary heart disease patients yielded lower BP, cardiac mortality and recurrence of myocardial infarction (6).
Although the above long-term studies have found
treatment for anxiety to have cardiovascular benefits,
studies of anxiety levels and acute BP control in ED
patients have been few. In one study of 36 patients,
Correspondence: Serkan Yılmaz, Kocaeli Üniv. Tıp Fakültesi, Acil Tıp Anabilim Dalı, Umuttepe, Kocaeli, 41380 Turkey. Tel: ( ⫹90) 262 3038548. Fax: ( ⫹90)
262 3038003. E-mail: [email protected]
(Received 12 October 2010 ; accepted 6 December 2010 )
ISSN 0803-7051 print/ISSN 1651-1999 online © 2011 Scandinavian Foundation for Cardiovascular Research
DOI: 10.3109/08037051.2011.553934
2
S. Yilmaz et al.
diazepam was as effective as captopril in treating a
hypertensive episode but anxiety levels were not
measured (3). If anxiolytic treatment for selected
patients with severe hypertension is found to be
effective without serious side-effects, our approach
to treating these patients in the short- or long-term
might need to be altered. Patients with high anxiety
scores may benefit more from anxiolytics than antihpertensives. The present study investigated the relationship between anxiety and BP and compared the
effects of alprazolam vs captopril in acutely lowering
BP and anxiety levels in ED patients.
Methods
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Study design
This single-blind, prospective, randomized, controlled clinical trial compared oral alprazolam with
captopril in the treatment of elevated BP in ED
patients without end organ damage. Our study design
and implementation were approved by our university
ethics committee.
Study setting
Study participants were recruited from the ED of a
university hospital with an annual census of approximately 40,000 adult visits. All subjects provided
written informed consent.
Selection of participants
Consecutive ED patients over 18 years old who had
an initial SBP ⱖ 160 or DBP ⱖ 100 mmHg and
repeat high BP after a 10-min resting period were
approached for participation in the study (7). Exclusion criteria included a history of secondary hypertension, malignant hypertension, acute left cardiac
failure, chronic renal failure, acute coronary syndrome, aorta dissection, cerebrovascular event, conditions requiring analgesics use, known allergy to
captopril or alprazolam, and pregnancy. Data from
patients with end organ damage, as determined by
history, physical examination, electrocardiography,
serum creatinine, electrolytes, urinalysis and fundoscopy, were excluded from analysis.
unblinded)
0.5 mg alprazolam (Xanax®, Eczacıbaşı
.
A.S., Istanbul, Tü. rkiye) or 25 mg captopril (Kaptoril®, Deva A.S., Istanbul, Türkiye).
Assessments and measurements
BP measurement. JNC-7 recommendations (7) for
accurate BP measurement in the office were used to
noninvasively (oscillometric method) measure BP
with a calibrated and validated instrument (Vista®
monitor, Draeger Medical Systems, Inc., Danvers,
MA, USA). Before BP measurements, the patients
were seated quietly for at least 5 min in a chair, with
feet on the floor and arm supported at heart level.
The second BP measurement was performed after
10 min. Measurement of BP was repeated at 1 and
2 h after administration of the study medication.
Psychometric assessments. The State Trait Anxiety
Inventory (STAI) was used to measure the anxiety
levels of the patients in both groups at baseline and
1 and 2 h after medication administration. The STAI
has two subscales, 40 questions and uses a 4-point
Likert scale for responses (8). One of the subscales
aims to measure the current level of anxiety (STAI-S,
state anxiety), the other subscale measures the characteristic or enduring level of anxiety (STAI-T, trait
anxiety). This test has excellent validity (levels up to
r ⫽ 0.80), reliability (r ⫽ 0.77) and internal consistency (0.89 for state anxiety, 0.91 for trait anxiety).
The reliability and validity of the Turkish version of
the test has been previously established (9). A cut off
score of 39–40 was considered an abnormal state of
anxiety (9,10). In addition, a self-reported 100-mm
visual-analogue scale for the measurement of acute
anxiety (VAS-A) was used at baseline, and 1 and 2
h after medication administration.
Outcome
The main outcome measures were BP and anxiety
levels, as measured at 1 and 2 h after administration
of the study medications. The secondary outcome
measure was the association between anxiety and BP
over the course of the study.
Data analysis
Interventions
The authors generated the allocation sequence using
a random numbers table before the study. Participants were given details about the study. The patients
were enrolled and assigned to a study group according to the previously established table by a senior
resident. Following baseline measurement of BP and
psychometric assessments as described below,
patients received (patients blinded, medical staff
All statistical analyses were performed with SPSS
version 16.0 for Windows (SPSS Inc. Chicago, USA).
The Shapiro–Wilk test was used to evaluate if the
data were normally distributed. Socio-demographic
variables were assessed with either independent samples t-test for continuous variables or chi-square test.
Yates’ corrected chi-square was used for all the other
2 ⫻ 2 tables. After Box’s M test for equality of covariance matrices and Mauchly’s test of sphericity, a
repeated-measures analysis of variance (ANOVA)
Anxiety and hypertension
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with repeated contrasts was performed on three consecutive measurements of BP to explore the differences in pattern and magnitude between the
alprazolam and captopril groups. If sphericity could
not be assumed, the multivariate analysis of variance
(MANOVA) approach was used to test the significance of F values. Following a significant global F
test, univariate ANOVA with Greenhouse–Geisser
adjustment was then performed. In addition, a
repeated measure of analysis of covariance (ANCOVA)
with the same statistical procedures mentioned above
was performed for evaluating the effect of baseline
STAI scores as covariates on change in BP. The significance level was set at 0.05. As a measure of effect
size, partial eta-squared (η2) was also reported in the
main ANOVAs.
Results
Characteristics of study subjects
Patient recruitment and flow in the study are shown
in Figure 1. Demographics, clinical characteristics of
patients and comparisons are shown in Table I. Of the
53 patients granting consent to participate in the
study, 27 were males (50.9%); 27 patients (50.9%)
received captopril and 26 patients (49.1%) received
alprazolam. Treatment groups were not significantly
different in gender, age and history of psychiatric disorder or hypertension. All patients had high SBP but
44 patients (83%) had concomitantly high DBP.
However, baseline SBP was significantly higher in the
captopril group (for alprozolam group, 187.46 ⫾ 18.34;
for the captopril group, 199.85 ⫾ 20.72; t ⫽ ⫺ 2.30,
df ⫽ 51, p ⫽ 0.025), but the baseline DBP values of
the two groups were similar (for alprozolam group,
3
106.81 ⫾ 12.74; for the captopril group, 108.30 ⫾
12.63; t ⫽ ⫺ 0.43, df ⫽ 51, p ⫽ 0.67). As measured
by the STAI test, trait anxiety was present (a score
over 40) in 96.2% (n ⫽ 51) of patients and 81.1%
(n ⫽ 43) had state anxiety (a score over 40). The mean
state and trait anxiety scores were not significantly
different between the treatment groups However,
baseline VAS-A scores of the two groups were significantly different (Table I).
Treatment effect on BP
Since Mauchly’s test indicated that the assumption of
sphericity had been violated for the main effects of
BP (χ2 ⫽ 7.68, df ⫽ 2, p ⫽ 0.021), we used the
MANOVA approach after Box’s M test (Box
M ⫽ 24.38, df1 ⫽ 21, df2 ⫽ 9535.83, p ⫽ 0.442) for
evaluating the effect of medication on BP and VAS-A.
There was no significant association between change
of BP and baseline STAI-T (F(1.43, 71.29) ⫽ 0.28,
p ⫽ 0.933) or STAI-S (F(1.43, 71.29) ⫽ 1.028, p ⫽ 0.341)
scores. As shown in Figure 2, SBP dropped significantly from baseline in both alprazolam and captopril
groups (F(1.42, 72.46) ⫽ 113.41, p ⬍ 0.0005, η2 ⫽ 0.69),
but the mean change in SBP was not significantly
different between the two groups (F(1.42, 72.46) ⫽ 0.36,
p ⫽ 0.626, η2 ⫽ 0.007). SBP was significantly correlated with VAS-A scores (F(2,51) ⫽ 5.00, p ⫽ 0.010).
Both groups had a significant drop from baseline in
VAS-A (F(1.84, 93.87) ⫽ 86.18, p ⬍ 0.0005, η2 ⫽ 0.63),
with the VAS-A scores decreasing more in the alprazolam group than in the captopril group (F(1.84,
2
93.87) ⫽ 9.67, p ⬍ 0.0005, η ⫽ 0.159). A contrasts
analysis in MANOVA found no difference in change
of VAS-A score between the baseline and first hour
measurements (F(1, 51) ⫽ 2.70, p ⫽ 0.107), but a
Figure 1. Flow diagram of patient selection.
4
S. Yilmaz et al.
Table I. Demographic and historical information, and baseline anxiety levels of 53 consecutive emergency department patients with
systolic blood pressure ⬎ 160 mmHg.
Female gender
Age (mean ⫾ SD) (years)
History of any anxiety disorder
History of hypertension
VAS-A
STAI-S
STAI-T
Alprazolam group
Captopril group
Statistical values
46.2% (n ⫽ 14)
53 ⫾ 11
26.9%
46.2%
84 ⫾ 16
49 ⫾ 12
52 ⫾ 7
53.8% (n ⫽ 12)
57 ⫾ 11
18.5%
59.3%
70 ⫾ 24
50 ⫾ 10
50 ⫾ 5
χ2 ⫽ 0.2 df ⫽ 1, p ⫽ 0.89
t ⫽ ⫺ 1.17, df ⫽ 51, p ⫽ 0.25
χ2 ⫽ 0.16, df ⫽ 1, p ⫽ 0.69
χ2 ⫽ 0.46, df ⫽ 1, p ⫽ 0.5
t ⫽ 2.45, df ⫽ 51, p ⫽ 0.02
t ⫽ ⫺ 0.31, df ⫽ 51, p ⫽ 0.76
t ⫽ 0.85, df ⫽ 51, p ⫽ 0.40
VAS-A, visual analogue scale for anxiety; STAI-S, State-Trait Anxiety Index, state anxiety; STAI-T, trait anxiety.
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significant difference at the second hour measurement between the treatment groups in favor of alprazolam (F(1, 51) ⫽ 9.89, p ⫽ 0.003).
Discussion
We found that ED patients with high BP but no end
organ damage have high levels of anxiety, and as anxiety is relieved, BP falls accordingly. BP falls in a
similar fashion whether one uses an anxiolytic or antihypertensive agent, but anxiety is relieved more effectively with alprazolam. Anxiety, including panic attack
and hyperventilation, has been shown to increase BP
(2,10). Up to 18% of anxiety disorder patients have
hypertension according to studies performed in psychiatry and/or primary healthcare units (11). However, the associations between anxiety and medical
problems have not been explored in ED patients. The
majority of our patients had high levels of state and
trait anxiety upon presentation to the ED. The effect
of anxiolytics on BP has been investigated in a few
earlier studies. Grossman et al. (3) compared oral
diazepam and sublingual captopril without measuring anxiety levels in ED patients with elevated BP,
and found that both agents were similarly effective in
lowering BP. In contrast to that study, we measured
anxiety with both the STAI test and VAS-A. In addition, we used alprazolam because of its more rapid
onset of action and shorter duration of activity compared with diazepam. These characteristics render it
a more appropriate agent for use in ED, and we
obtained results similar to the mentioned study.
Although alprazolam was found to lower anxiety
levels more than captopril, the mechanism by which
captopril lowers anxiety is unclear. Captopril’s ability
to reduce VAS-A scores might be related to a placebo
effect or a pathophysiological process. Based on the
Figure 2. Mean systolic (SBP) and diastolic blood pressure (DBP) (mmHg) and mean visual analogue scale for anxiety (VAS-A, on a
0–100 mm scale) scores in 53 consecutive emergency department patients with SBP ⬎ 160 mmHg, before and 1 and 2 h after a single
oral dose of alprazolam or captopril.
Anxiety and hypertension
results of our study with a small number of patients,
studies with more hypertensive patients are needed
in order to recommend the use of anxiolytics as standard treatment.
Limitation
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The effect size of the study was high for general comparisons, but the effect size of subgroup analysis in
BP was low. Our results represent those from a single
institution; therefore our study should be repeated in
other healthcare settings. Interviews with the patients
for diagnostic purposes and detailed psychiatric measurements could enhance the interpretations of
future findings when studying the relationship
between BP and anxiety.
Conclusion
Patients applying to ED with moderate elevations in
BP are frequently anxious. Oral captopril and alprazolam lower BP to a similar degree in these patients,
but alprazolam lowers anxiety to a greater degree
than captopril. Further studies with placebo and
treatment groups will help clarify medical management options in these patients.
Competing interests
None to declare.
5
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