effects of a fixed combination of low dose nifedipine and acebutolol on essential hypertension:...
TRANSCRIPT
CLIN. AND EXPER.-THEORY AND PRACTICE, A7(11), 1541-1552 (1985)
EFFECTS OF A FIXED COMBINATION OF LOW DOSE NIFEDIPINE AND ACEBUTOLOL ON ESSENTIAL HYPERTENSION :
COMPARISON WITH STANDARD DOSE ACEBUTOLOL
Ph. Lejeune l, W. GunselmannY2, I. Hoppe 3, P. Mummel,$, B. Peter~en,~, E. Winkler,%
G. Gfrerer7, U. Schreiber8.
1. Medical Research, BAYER AG, Postfach 101709, D-5600 Wuppertal 1. (Address for correspondence) 2. Inst. of biometry, BAYER AG, Postfach 101709,
D-5600 Wuppertal 1. 3. BismarckstraBe 6 0 , D-4690 Herne. 4. GoethestraBe 8, D-5804 Herdecke. 5. Dr. Ruer Platz 1, D-4630 Bochum. 6. CastroperstraBe 357, D-4690 Herne.
7. Deutschland Abt. Med. Wiss., BAYER AG, D-4600 Dortmund. 8. Deutschland Abt. Med. Wiss., BAYER AG, D-5060 Leverkusen.
Key words:
Calcium entry blocker, Beta adrenergic blocking agent, Combination
therapy, Essential hypertension, Double-blind controlled clinical
study, Low dose treatment.
ABSTRACT
114 patients from four clinics participated in a double blind study designed to assess the efficacy of a nifedipine-acebutolol fixed combination -10 mg + 100 mg - as compared with acebutolol -200 mg- in essential hypertension. During the ten week study the mean blood pressure readings (s.d.) 1-3 h after treatment decreased from 179.2/104.8 (10.2/6.2) to 150.3/87.7 (9.817.7) in
Copyright 0 1985 by Marcel Dekker, Inc.
1541
0730-0077/85/07 11-1541 $3.50/0
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1542 LEJEUNE ET AL.
the combination group and from 181.71106.5 (14.4/7.0) to 150.4189.0 (15.0/10.4) in the acebutolol group. The mean systolic and diastolic blood pressures were also decreased after exertion (load) and 24 hours after treatment at the end of the 6th week of the study. A doubling of the dose from week 7 to 10 did not change these figures. These results reveal the possibility of treating essential hypertension with a low dose of beta-adrenergic blocking agents in combination with 10 mg nif edipine. Both drugs were well tolerated. 3 patients ( 5 %) in the combination group and 3 patients in the acebutolol group were withdrawn from the study because of headache and dizziness.
INTRODUCTION
Nifedipine and acebutolol are established antihypertensive
drugs [1,21. Their free combination is more effective than
either drug alone [ 3 , 4 ] . Moreover this combination may be
desirable, particulary in patients with coexisting hypertension
and angina [51.
beta-adrenergic blocking agent in a combination without any loss
of efficacy in the treatment of angina [61. The same could be
true in hypertension. A low dose nifedipine/acebutolol (10 mg/lOO mg) combination tablet was available. This tablet is
effective in hypertension in comparison with a standard dose
nifedipine therapy [7 1.
It was possible to reduce the dose of a
The aim of this double blind study was to test the efficacy
of a low dose beta-blocker combination in hypertension by
comparing its effect with a 200 mg acebutolol tablet, either
drug given once a day for four weeks and twice a day for four
additional weeks. A 200 mg instead of a 100 mg acebutolol tablet was chosen as reference drug, as the former tablet is already in
current use €or hypertension in several countries and as it was
the intention to compare a potential new treatment for
hypertension with an established one.
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NIFEDIPINE/ACEBUTOLOL COMBINATION IN HYPERTENSION 1 5 4 3
METHODS
The Drug
BAY 1 5240 is a fixed combination of nifedipine and
acebutolol with interesting nifedipine kinetic parameters. The
10 mg nifedipine in this fixed combination has a Cmax of 61.5 2 7.0 pg/l and a Tmax of 0.9 2 0.1 h while a 10 mg nifedipine
tablet given separately to the same volunteers had a Cmax of only 27.4 - + 4.1 pg/l and a Tmax of 1.4 - + 0.2 h. Acebutolol
kinetics in this fixed combination were similar to those of
acebutolol given separately.
fixed combination behaves more like nifedipine in capsules than
like nifedipine in tablets.
The nifedipine compound in this
Study Design
The study was carried out in four clinics in West Germany
from May 1983 to January 1984.
being informed and giving their consent. After randomization,
one female patient refused to continue the study and one male
patient broke his leg and was withdrawn by a physician not
involved with the study.
116 patients were included after
The main criteria for inclusion were: a recumbent systolic
blood pressure (SBP) of more than 159 mm Hg and a recumbent
diastolic blood pressure (DBP) of more than 94 mm Hg on three
different days before the study, a heart rate between 50 and 100
beats/min on three different days before the study, a body mass
index (kg/m ) less than 25, and age for females: 21 to 65 and
for males: 45 to 65. Different minimal ages for males and
2
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1544 LEJEUNE ET AL.
females with a unique DBP value limit were chosen to produce sex
groups of the same cardiovascular risk [ 8 ] . Blood pressures were
measured using a calibrated mercury sphygmomanometer fitted with
the appropriated cuff. Measurements were taken after a 5 min.
rest in the recumbent position in a quiet room.
SBP was registered at Korotkoff I and DBP at Korotkoff V. In
each clinic, the same observer measured blood pressures
throughout the complete study. No attempt was made to achieve standardization of observers between clinics. All
antihypertensive treatment had to be discontinued before the
study. The initial medical assessment included an EGG and
laboratory tests, to ensure that there were no secondary
hypertension, renal impairment, uncontrolled diabetes and that
there were no disorders to preclude treatment with acebutolol.
On two occasions during the study the coordinating centre sent plasma samples to assess the inter-laboratory variability.
Three patients were included in the analysis, although their
heart rate exceeded 100 beats/min at one of the three prestudy
measurements. Twelve patients were also included in the
analysis, although the previous antihypertensive treatment was
only withdrawn at the beginning of period 1 (run-in period).
Patients were randomized in 2 groups and treated for 10
consecutive weeks.
period 1 with 1 acebutolol tablet in the morning and 1 placebo tablet in the evening for 2 weeks, during period 2 with 1 combination tablet in the morning and 1 placebo tablet in the evening for 4 weeks and during period 3 with 1 combination
tablet in the morning and 1 combination tablet in the evening
for 4 weeks. The acebutolol group was treated during period 1
with 1 acebutolol tablet in the morning and 1 placebo tablet in the evening for 2 weeks, during period 2 with 1 acebutolol
tablet in the morning and 1 placebo tablet in the evening for 4
The combination group was treated during
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NIFEDIPINE/ACEBUTOLOL COMBINATION IN HYPERTENSION 1545
weeks and during period 3 with 1 acebutolol tablet in the
morning and 1 acebutolol tablet in the evening for 4 weeks. The
patients were evaluated at the end of each study period. SBP,
DBP and HR were registered in the recumbent (SBP or DBP) and
standing (SBP or DBP standing) positions, as well as after
exertion (load) by executing 20 rapid knee bends (SBP or DBP
after exertion). These measurements were taken before the
morning treatment and 1-3 h thereafter. This was followed by
venepuncture for the laboratory tests. Laboratory tests were
performed before the study and at the end of each period. These
data were recorded on standardised forms. Volunteered adverse
effects were recorded with their duration, intensity and
relation to the treatment. Countermeasures and the
investigators' remarks were also documented.
Statistical methods
To check homogeneity age, weight and height were analysed
separately for male and female patients by multivariate analyses
of variance [ 91 using "treatment group" and "investigator" as
main factors, (Programme BMD P4V from UCLA). Sex distribution
was checked by X test per investigator and summation over
investigators.
2
A s main target criterion the DBP was analyzed during
treatment periods by a repeated measures design incorporating
the between factors 'treatment' and 'investigator', the within
factors 'period (Znd, 3rd)' and 'time to medication (before,
1-3h, after)' and adjusting for DBP at the end of the period 1 (analysis of co-variance; Programme BMD P2V from UCLA). The
effect of non-standardization of blood pressure measurement
techniques between clinics is accounted for in the analysis by
using the investigator as between factor. Within factors may be
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1546 LEJEUNE ET AL.
T A B L E 1 Study Population at Inclusion
Male n (%) Female n (%) Age in years
Male: Median (Range) Female: Median (Range)
Male: Median (Range) Female: Median (Range)
Male: Median (Range) Female: Median (Range)
Body mass index (kg/m2> Smoker n (%) Systolic blood pressure
mm Hg: Median (Range) Diastolic blood pressure
mm Hg: Median (Range) Heart rate
bpm: Median (Range)
Height in cm
Weight in kg
BAY 1 5240 group (n = 57)
Acebutolol group (n = 57)
18 39
54 56
179 168
75 64
22.9 10
180
105
76
(32) 25 (68) 32
( 45-63 56 (27-64) 55
(156-189) 178 (156-179) 167
(51-84) 76 (52-72) 63 (20.6-25.0) 23.1 (18) 11
(160-212) 180
(95-120) 110
( 64- 1 15 ) 76
(44) (56)
(46-64) (34-65)
(159-196) (155-176)
(58-92) (55-72) (20.5-25.0) (19)
(160-240)
(95-120)
(68-100)
overestimated due to correlation.
RESULTS
The "check of homogeneity" on the 114 patients indicated a statistical difference for age, height and weight between the
populations per investigator for males (p = 0.002) but not for females (p = 0.05). However, when total study groups were
considered, no statistical significance was seen (Table 1). During the ten week study the mean blood pressure readings
(s.d.1 1-3 h after medication decreased from 179.2/104.8
(10.2/6.2) before the study (inclusion) to 150.3/87.7 (9.8/7.7) at the end of the study (end period 3) in the combination group
and from 181.7/106.5 (14.4/7.0) to 150.4/89.0 (15.0/10.4) in the
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NIFEDIPINE/ACEBUTOLOL COMBINATION IN HYPERTENSION 1547
mmHg groupeffect p = O 2 4 periodeffecl p-006 beforeionereffect p-COO1 m
Bay I 5240 group n = 57 acebutolol group 13.57
- wefore - I -3 n oner medicotion __ Imd
penad1 perm2 period3 p e m I per1ad2 period3
60 inclusion end end end inclusion end end end
Figure 1
Blood pressures lying before and after medication.
Blood pressures after exertion.
Mean + sd -
acebutolol group. Both treatments were equally effective on
blood pressure (fig 1).
The mean SBP 1 to 3 hours after medication decreased by 13.1 mm Hg in the combination group and by 10.2 mm Hg in the
acebutolol group from the end of period 1 to the end of period 2. The mean DBP decreased by 7.4 mm Hg and 6.4 mm Hg respectively.
The mean SBP 24 hours after medication decreased by 14.1 mm Hg
in the combination group and by 10.4 mm Hg in the acebutolol
group during period 2. The mean DBP decreased by 8.0 mm Hg and 6.1 mm Hg respectively. Similar decreases were observed after
exertion as well before as after treatment. The heart rate
changes were similar in both groups. Heart rate decreases of
less than 5 beats/min were observed.
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1548 LEJEUNE ET AL.
All blood pressures showed an additional moderate decrease after doubling the dose of either drug for four additional weeks
from the end of period 2 to the end of period 3 (additional
decreases: range SBP 1.9 to 2.4 mm Hg in the combination group
and 1.7 to 3.3 mm Hg in the acebutolol group and range DBP 1.1
to 1.8 mm Hg in the combination group and 0.4 to 1.4 mm Hg in
the acebutolol group).
SBP lower than 160 mm Hg and DBP lower than 95 nrm Hg were
observed in 25 patients (46 % > in the combination group and in
30 patients (56 %) in the acebutolol group before treatment (24
hours after the last tablet) at the end of period 2. After
period 3 (12 hours after the last tablet) the respective figures
were 32 (59 %) and 33 (61 %I. within three minutes after transition from the recumbent to the
standing position did not reveal any orthostatic reactions.
Blood pressure readings taken
The statistical analysis of the DBP before exertion did not
differ significantly between treatments (p = 0.24). A
significant effect was observed for the factor "investigator"
(p (0.01), "time after medication" (p (0.001) and the
interaction ''time after medication x investigator" ( p (0.001) - i.e. values after medication are significantly lower than
before-medication values -.
No relevant changes in the laboratory values were observed. Both regimes were well tolerated (fig 2). Nine patients (16 % >
in the combination group and 7 patients (12 % > in the acebutolol
group complained of side effects, some for several reasons.
Headache was reported by six patients in the combination group
and by six patients in the acebutolol group. Vasomotor symptoms
were reported by four patients in the combination group and by
five patients in the acebutolol group. Three patients in the
combination group and three patients in the acebutolol group
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NIFEDIPINE/ACEBUTOLOL COMBINATION IN HYPERTENSION 1549
Figure 2
Side-effects. 1 symbol per investigator and 1 letter
within investigator's group.
per pati .ent
were withdrawn from the study because of headache and dizziness.
DISCUSSION
The antihypertensive efficacies of acebutolol and the low
The response t o acebutolol was dose combinaton were similar.
comparable to the one seen by others 1101 even if 400 mg
acebutolol was used [ll]. The response to the low dose
combination was also similar to the one seen after free
combination [3,41.
the combination was maintained over 24 hours, since the observed difference of about 2.5 mm Hg between DBP before and 1 to 3 h
after medication is of questionable clinical relevance. Moreover
a separate analysis per investigator showed that this difference
originated from one investigator only; the three others giving
no substantial difference between the values recorded before and
1-3h after medication. As reported elsewhere this long lasting effect was not observed with nifedipine monotherapy 111. The
Our results also show that the efficacy of
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1550 LEJEUNE ET AL.
acebutolol component could b e r e spons ib l e f o r t h e e f f i c a c y of
t h e combination during t h e second h a l f of t he day, but t h e study
was not designed t o answer t h i s quest ion. The r e s u l t s a l s o
showed t h e a b i l i t y of e i t h e r t reatment t o e f f e c t i v e l y c o n t r o l
t he blood p res su re a f t e r e x e r t i o n as was descr ibed i n o t h e r
r e p o r t s [12]. Only a minimal blood pressure decrease between
period 1 and per iod 2 was observed.
adverse e f f e c t s were s i m i l a r i n both groups.
The type and frequency of
These r e s u l t s support t h e p o t e n t i a l of t r e a t i n g e s s e n t i a l
hypertension with a low dose of beta-adrenergic blocking agent
i n combination with 10 mg n i f ed ip ine . W e conclude t h a t t h e
n i f ed ip ine /acebu to lo l combination is an e f f e c t i v e and s a f e
an t ihype r t ens ive drug, t h e e f f i c a c y of which i s maintained over
a 24-hour per iod, a l s o a f t e r e x e r t i o n b u t which does not produce
o r t h o s t a t i c hypotension.
ACKNOWLEDGEMENTS
We thank D r . J. Priive f o r i s a s s i s t a n c e i n preparing the d a t a
€ o r ana lys i s .
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Date Accepted 9/25/85
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