Comparison of alprazolam versus captopril in high blood pressure: A randomized controlled trial
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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
1Department of Emergency Medicine and 2Department of Psychiatry, Faculty of Medicine, Kocaeli University, Turkey
Abstract
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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 consent-
ing 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
For personal use only.
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
contributes to left ventricular hypertrophy and to the
Many patients present to the emergency department commonly associated metabolic abnormalities of
(ED) with high blood pressure (BP), but only a small insulin resistance and hyperlipidaemia. The mecha-
proportion of these will require emergent antihyper- nisms of increased long-term cardiac risk attribut-
tensive therapy. The primary goal of the emergency able to mental stress and psychiatric illness are not
physician is to determine which patients with acute entirely clear, but activation of the sympathetic ner-
hypertension are exhibiting symptoms of end-organ vous system seems to be of prime importance (4). A
damage. In contrast, patients presenting with elevated meta-analysis of 2024 patients who received psycho-
BPs (systolic BP, SBP ⬎ 200 mmHg or diastolic BP, social treatment vs 1156 control subjects found that
DBP ⬎ 120 mmHg) without symptoms, and whose the psychosocially treated patients showed greater
BP remains high until ED discharge should begin reductions in psychological distress, SBP, heart rate
antihypertensive therapy as an outpatient with close and cholesterol levels (5). Another meta-analysis of
follow-up (1). The cause of hypertension is not known 37 studies found that psychoeducational (health edu-
in many patients, but includes pheochromocytoma, cation and stress management) programmes for
renal artery stenosis, severe pain, cerebrovascular dis- coronary heart disease patients yielded lower BP, car-
ease, acute renal failure, medications and illegal drugs, diac mortality and recurrence of myocardial infarc-
withdrawal of antihypertensive treatment, and panic tion (6).
attack or phobic anxiety (2,3). Although the above long-term studies have found
Anxiety is known to trigger sympathetic discharge treatment for anxiety to have cardiovascular benefits,
that may lead to elevated BP (2). Sympathetic studies of anxiety levels and acute BP control in ED
activation, in addition to the elevated BP, also likely 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: serkanyilmaz@kocaeli.edu.tr
(Received 12 October 2010 ; accepted 6 December 2010 )
ISSN 0803-7051 print/ISSN 1651-1999 online © 2011 Scandinavian Foundation for Cardiovascular Research
DOI: 10.3109/08037051.2011.5539342 S. Yilmaz et al.
diazepam was as effective as captopril in treating a unblinded)
. 0.5 mg alprazolam (Xanax®, Eczacıbaşı
hypertensive episode but anxiety levels were not A.S., Istanbul, Tü. rkiye) or 25 mg captopril (Kapto-
measured (3). If anxiolytic treatment for selected ril®, Deva A.S., Istanbul, Türkiye).
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 Assessments and measurements
might need to be altered. Patients with high anxiety BP measurement. JNC-7 recommendations (7) for
scores may benefit more from anxiolytics than antih- accurate BP measurement in the office were used to
pertensives. The present study investigated the rela- noninvasively (oscillometric method) measure BP
tionship between anxiety and BP and compared the with a calibrated and validated instrument (Vista®
effects of alprazolam vs captopril in acutely lowering monitor, Draeger Medical Systems, Inc., Danvers,
BP and anxiety levels in ED patients. 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.
Methods The second BP measurement was performed after
10 min. Measurement of BP was repeated at 1 and
Study design
2 h after administration of the study medication.
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This single-blind, prospective, randomized, con-
trolled clinical trial compared oral alprazolam with
Psychometric assessments. The State Trait Anxiety
captopril in the treatment of elevated BP in ED
Inventory (STAI) was used to measure the anxiety
patients without end organ damage. Our study design
levels of the patients in both groups at baseline and
and implementation were approved by our university
1 and 2 h after medication administration. The STAI
ethics committee.
has two subscales, 40 questions and uses a 4-point
Likert scale for responses (8). One of the subscales
Study setting aims to measure the current level of anxiety (STAI-S,
For personal use only.
state anxiety), the other subscale measures the char-
Study participants were recruited from the ED of a acteristic or enduring level of anxiety (STAI-T, trait
university hospital with an annual census of approx- anxiety). This test has excellent validity (levels up to
imately 40,000 adult visits. All subjects provided r ⫽ 0.80), reliability (r ⫽ 0.77) and internal consis-
written informed consent. tency (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
Selection of participants
score of 39–40 was considered an abnormal state of
Consecutive ED patients over 18 years old who had anxiety (9,10). In addition, a self-reported 100-mm
an initial SBP ⱖ 160 or DBP ⱖ 100 mmHg and visual-analogue scale for the measurement of acute
repeat high BP after a 10-min resting period were anxiety (VAS-A) was used at baseline, and 1 and 2
approached for participation in the study (7). Exclu- h after medication administration.
sion criteria included a history of secondary hyper-
tension, malignant hypertension, acute left cardiac
failure, chronic renal failure, acute coronary syn- Outcome
drome, aorta dissection, cerebrovascular event, con- The main outcome measures were BP and anxiety
ditions requiring analgesics use, known allergy to levels, as measured at 1 and 2 h after administration
captopril or alprazolam, and pregnancy. Data from of the study medications. The secondary outcome
patients with end organ damage, as determined by measure was the association between anxiety and BP
history, physical examination, electrocardiography, over the course of the study.
serum creatinine, electrolytes, urinalysis and fundos-
copy, were excluded from analysis.
Data analysis
All statistical analyses were performed with SPSS
Interventions
version 16.0 for Windows (SPSS Inc. Chicago, USA).
The authors generated the allocation sequence using The Shapiro–Wilk test was used to evaluate if the
a random numbers table before the study. Partici- data were normally distributed. Socio-demographic
pants were given details about the study. The patients variables were assessed with either independent sam-
were enrolled and assigned to a study group accord- ples t-test for continuous variables or chi-square test.
ing to the previously established table by a senior Yates’ corrected chi-square was used for all the other
resident. Following baseline measurement of BP and 2 ⫻ 2 tables. After Box’s M test for equality of cova-
psychometric assessments as described below, riance matrices and Mauchly’s test of sphericity, a
patients received (patients blinded, medical staff repeated-measures analysis of variance (ANOVA)Anxiety and hypertension 3
with repeated contrasts was performed on three con- 106.81 ⫾ 12.74; for the captopril group, 108.30 ⫾
secutive measurements of BP to explore the differ- 12.63; t ⫽ ⫺ 0.43, df ⫽ 51, p ⫽ 0.67). As measured
ences in pattern and magnitude between the by the STAI test, trait anxiety was present (a score
alprazolam and captopril groups. If sphericity could over 40) in 96.2% (n ⫽ 51) of patients and 81.1%
not be assumed, the multivariate analysis of variance (n ⫽ 43) had state anxiety (a score over 40). The mean
(MANOVA) approach was used to test the signifi- state and trait anxiety scores were not significantly
cance of F values. Following a significant global F different between the treatment groups However,
test, univariate ANOVA with Greenhouse–Geisser baseline VAS-A scores of the two groups were signifi-
adjustment was then performed. In addition, a cantly different (Table I).
repeated measure of analysis of covariance (ANCOVA)
with the same statistical procedures mentioned above
was performed for evaluating the effect of baseline Treatment effect on BP
STAI scores as covariates on change in BP. The sig- Since Mauchly’s test indicated that the assumption of
nificance level was set at 0.05. As a measure of effect sphericity had been violated for the main effects of
size, partial eta-squared (η2) was also reported in the BP (χ2 ⫽ 7.68, df ⫽ 2, p ⫽ 0.021), we used the
main ANOVAs. MANOVA approach after Box’s M test (Box
M ⫽ 24.38, df1 ⫽ 21, df2 ⫽ 9535.83, p ⫽ 0.442) for
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evaluating the effect of medication on BP and VAS-A.
Results There was no significant association between change
of BP and baseline STAI-T (F(1.43, 71.29) ⫽ 0.28,
Characteristics of study subjects
p ⫽ 0.933) or STAI-S (F(1.43, 71.29) ⫽ 1.028, p ⫽ 0.341)
Patient recruitment and flow in the study are shown scores. As shown in Figure 2, SBP dropped signifi-
in Figure 1. Demographics, clinical characteristics of cantly from baseline in both alprazolam and captopril
patients and comparisons are shown in Table I. Of the groups (F(1.42, 72.46) ⫽ 113.41, p ⬍ 0.0005, η2 ⫽ 0.69),
53 patients granting consent to participate in the but the mean change in SBP was not significantly
study, 27 were males (50.9%); 27 patients (50.9%) different between the two groups (F(1.42, 72.46) ⫽ 0.36,
For personal use only.
received captopril and 26 patients (49.1%) received p ⫽ 0.626, η2 ⫽ 0.007). SBP was significantly cor-
alprazolam. Treatment groups were not significantly related with VAS-A scores (F(2,51) ⫽ 5.00, p ⫽ 0.010).
different in gender, age and history of psychiatric dis- Both groups had a significant drop from baseline in
order or hypertension. All patients had high SBP but VAS-A (F(1.84, 93.87) ⫽ 86.18, p ⬍ 0.0005, η2 ⫽ 0.63),
44 patients (83%) had concomitantly high DBP. with the VAS-A scores decreasing more in the alpra-
However, baseline SBP was significantly higher in the zolam group than in the captopril group (F(1.84,
captopril group (for alprozolam group, 187.46 ⫾ 18.34; 93.87) ⫽ 9.67, p ⬍ 0.0005, η ⫽ 0.159). A contrasts
2
for the captopril group, 199.85 ⫾ 20.72; t ⫽ ⫺ 2.30, analysis in MANOVA found no difference in change
df ⫽ 51, p ⫽ 0.025), but the baseline DBP values of of VAS-A score between the baseline and first hour
the two groups were similar (for alprozolam group, 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.
Alprazolam group Captopril group Statistical values
Female gender 46.2% (n ⫽ 14) 53.8% (n ⫽ 12) χ2 ⫽ 0.2 df ⫽ 1, p ⫽ 0.89
Age (mean ⫾ SD) (years) 53 ⫾ 11 57 ⫾ 11 t ⫽ ⫺ 1.17, df ⫽ 51, p ⫽ 0.25
History of any anxiety disorder 26.9% 18.5% χ2 ⫽ 0.16, df ⫽ 1, p ⫽ 0.69
History of hypertension 46.2% 59.3% χ2 ⫽ 0.46, df ⫽ 1, p ⫽ 0.5
VAS-A 84 ⫾ 16 70 ⫾ 24 t ⫽ 2.45, df ⫽ 51, p ⫽ 0.02
STAI-S 49 ⫾ 12 50 ⫾ 10 t ⫽ ⫺ 0.31, df ⫽ 51, p ⫽ 0.76
STAI-T 52 ⫾ 7 50 ⫾ 5 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.
significant difference at the second hour measure- majority of our patients had high levels of state and
ment between the treatment groups in favor of alpra- trait anxiety upon presentation to the ED. The effect
zolam (F(1, 51) ⫽ 9.89, p ⫽ 0.003). of anxiolytics on BP has been investigated in a few
earlier studies. Grossman et al. (3) compared oral
diazepam and sublingual captopril without measur-
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ing anxiety levels in ED patients with elevated BP,
Discussion
and found that both agents were similarly effective in
We found that ED patients with high BP but no end lowering BP. In contrast to that study, we measured
organ damage have high levels of anxiety, and as anx- anxiety with both the STAI test and VAS-A. In addi-
iety is relieved, BP falls accordingly. BP falls in a tion, we used alprazolam because of its more rapid
similar fashion whether one uses an anxiolytic or anti- onset of action and shorter duration of activity com-
hypertensive agent, but anxiety is relieved more effec- pared with diazepam. These characteristics render it
tively with alprazolam. Anxiety, including panic attack a more appropriate agent for use in ED, and we
and hyperventilation, has been shown to increase BP obtained results similar to the mentioned study.
For personal use only.
(2,10). Up to 18% of anxiety disorder patients have Although alprazolam was found to lower anxiety
hypertension according to studies performed in psy- levels more than captopril, the mechanism by which
chiatry and/or primary healthcare units (11). How- captopril lowers anxiety is unclear. Captopril’s ability
ever, the associations between anxiety and medical to reduce VAS-A scores might be related to a placebo
problems have not been explored in ED patients. The 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 5
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