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Journal of Human Hypertension (2000) 14, 99–104
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ORIGINAL ARTICLE
A randomised placebo controlled trial of
the effects of tibolone on blood pressure
and lipids in hypertensive women
G Lloyd1, E McGing1, A Cooper1, N Patel1, PJ Lumb2, AS Wierzbicki2 and G Jackson1
1
Department of Cardiology and 2Chemical Pathology, Guys and St Thomas’ Hospital Trust, Lambeth
Palace Road, London SE1 7EH, UK
The effects of hormone replacement therapy in hypertensive women are controversial. This randomised placebo controlled trial assessed the effect of tibolone
2.5 mg on blood pressure and fasting plasma lipids in
29 hypertensive postmenopausal women over 6 months
using a 2:1 randomisation to tibolone. The primary clinical end-point was mean office blood pressure. At 6
months systolic blood pressure declined by
5.30 ⴞ 2.87% vs 4.94 ⴞ 3.37% whilst diastolic blood
pressure declined 5.38 ⴞ 2.65% vs 0.85 ⴞ 3.69% on
tibolone and placebo respectively. These differences
were not statistically significant. Triglycerides
decreased by 33.3 ⴞ 6.1% vs 7.6 ⴞ 7.9% (P ⬍ 0.01) and
high-density
lipoprotein
(HDL)-cholesterol
by
21.7 ⴞ 3.8% vs 2.4 ⴞ 2.6% (P ⬍ 0.01) with tibolone as
opposed to placebo. No significant differences were
observed in total cholesterol, low-density lipoprotein
(LDL)-cholesterol and lipoprotein (a). Fibrinogen levels
were reduced by 13.6 ⴞ 6.8% on tibolone compared to
a 19.3 ⴞ 15.4% rise (P ⬍ 0.05) on placebo. This study
suggests that tibolone has no deleterious effect on
blood pressure in women with hypertension but has
contrasting effects on biochemical risk factors. Largescale studies are required to determine the overall effect
of tibolone on cardiovascular morbidity and mortality.
Journal of Human Hypertension (2000) 14, 99–104
Keywords: hormone replacement; hypertension; lipids; trial
Introduction
The role of hormone replacement therapy (HRT) in
women with hypertension remains controversial.
Oestrogen-based HRT remains underused in these
women probably because of concerns about blood
pressure deterioration in younger women taking the
oral contraceptive.1 However, the potentially beneficial effects of HRT in reducing coronary heart disease (CHD) risk would suggest a role for it in the
management of hypertension.2,3 The loss of oestrogen at the menopause appears to be associated
with an overall rise in blood pressure.4 Little information is available regarding the long-term effects
of HRT in hypertensive women, but short duration
studies in hypertensive women have demonstrated
either a neutral or even modest hypotensive
effect.5–10
Cyclical HRT preparations are unacceptable to
most women suffering from coronary disease or
hypertension. Tibolone is a novel steroid compound, which controls menopausal symptoms,11
inhibits postmenopausal bone loss12 and augments
forearm blood flow.13 It does not induce endometrial
hyperplasia or, usually, postmenopausal bleeding.14
We investigated the effect of introducing tibolone in
Correspondence: Dr Guy Lloyd, Cardiothoracic Department, 6th
Floor, East Wing, St Thomas’ Hospital, London SE1 7EH, UK
Received 24 May 1999; revised and accepted 3 September 1999
women with pre-existing hypertension on both
blood pressure and biochemical cardiovascular
risk factors.
Materials and methods
Study design
The trial had a double-blind, randomised, placebocontrolled format. Randomisation was 2:1 in favour
of tibolone to increase the probability of demonstrating a treatment effect. The study received local ethical approval and written informed consent was
obtained. At two baseline visits clinical details,
baseline blood pressure, quality of life parameters
and fasting lipid profiles were measured. Patients
were reviewed monthly for continued blood pressure assessment. Baseline biochemical investigations
were repeated at the final clinical visit after 6
months treatment.
Eligibility
Eligible patients had previously diagnosed hypertension on or off treatment with antihypertensives.
All had three separate standard mercury sphygmomanometer blood pressure readings greater than
160/90 mm Hg over 3 months or were taking longterm antihypertensive treatment. All were 1 or more
years postmenopausal on clinical grounds.
Exclusion criteria included, intrinsic renal disease,
Tibolone randomised controlled trial
G Lloyd et al
100
insulin-dependent diabetes or a past history of an
oestrogen dependent tumour. Women who had used
sex steroid compounds including oral contraception, previous HRT, progesterone, tibolone or tamoxifen within the previous 3 months were excluded.
Blood pressure measurement
Blood pressure was measured as near as possible at
the same time of the same day of the week by one
of two operators using the British Hypertension
Society approved methods.15 For the purposes of
analysis the mean of the three recumbant blood
pressure measurements was calculated. If blood
pressure exceeded 210/120 mm Hg on two separate
visits, the patient left the study to allow modification of medication, otherwise all concomitant
antihypertensive medication was left unchanged for
the duration of the study.
Plasma lipids and lipoproteins
Blood samples were drawn in the recumbant position after a 12-h fast. Samples were centrifuged
immediately and stored at −70°C until subsequent
analysis. Plasma lipid profiles were detained in a
single batch by standard automated methods for
total cholesterol, triglycerides and HDL on a Cobas
Fara II analyser. Low-density lipoprotein (LDL) was
calculated by the Freidewald equation if triglycerides ⬍4.5 mmol/L. Apolipoprotein (apo) A1, A2, B,
lipoprotein (a) [Lp(a)] and fibrinogen were measured
by immunoturbidimetric methods on the same analyser. Lp(a) samples were pre-treated by centrifugation and lipase treatment to reduce any triglyceride
interference with the assay. All methods used were
validated against International Federation of
Clinical Chemistry standards and had standard
deviations of ⬍2.5% for lipids, ⬍4% for apolipoproteins, ⬍6% for Lp(a) and ⬍3% for fibrinogen for
medium range calibrators.
Quality of life
Quality of life was recorded at baseline and at 6
months using the SF-36 General Health Questionnaire.16 This measures eight health concepts: physical functioning, physical and emotional role limitations, bodily pain, general health, vitality, social
functioning, mental health and reported health transition. In each measure, a higher score indicates a
better health state.
Statistical analysis
The study was powered to detect a change in mean
blood of 15 mm Hg. A 2:1 randomisation was used
to increase the power to detect a treatment effect
while accepting an increased risk of a type I error.
In patients who dropped out of the study the blood
pressure at the last visit was carried forward to successive visits. Blood pressure data were analysed on
an intention-to-treat basis but percentage change in
lipid values was calculated only for those patients
who finished the study and were taking medication
Journal of Human Hypertension
at the final visit. Data were analysed using the SPSS
statistical package (version 6.0). Parametric data are
displayed as mean and standard error, non-parametric data as median and range while frequency
data as value and percentage. Principal analysis was
performed using ANOVA for repeated measures
with unpaired t-testing for individual two-way comparisons between subjects allocated to tibolone or
placebo. Non-parametric data (lipoprotein (a) and
triglycerides) were compared using the appropriate
non-parametric test (Mann–Whitney) with contingency table testing of frequency data (Yates’ continuity correction). P ⬍ 0.05 was considered statistically significant.
Results
Demographics
Major demographic features were similar in the
active and placebo arms of the study (Table 1). The
mean age of the women was 60.1 years in the active
group and 62.7 years in the placebo group. Both
groups were more than 10 years after the menopause
(11.5 years tibolone and 16.1 years placebo). There
were non-significant statistical differences in other
patient characteristics and in concomitant
medications.
Blood pressure
Study blood pressure readings are recorded in Figure 1 and Table 2. The entry mean blood pressure
was 161 ± 5.2/91 ± 1.8 mm Hg in the tibolone group
and 157 ± 5.4/85 ± 2.4 mm Hg in the placebo. Baseline diastolic blood pressure was slightly but significantly higher in the active treatment arm (P ⬍
0.05) but the mean arterial pressure was not significantly different (126.0 ± 3.2 vs 121.2 ± 3.6 mm Hg).
Systolic blood pressure fell by 5.2%, diastolic pressure by 3.6% and mean arterial pressure by 4.6%.
After 6 months the blood pressures were
151 ± 5.5/87 ± 3.4 mm Hg in the active and
148 ± 4.1/84 ± 3.2 mm Hg in the placebo arm.
Neither absolute or percentage reductions in systolic
and diastolic blood pressures were significantly different at 6 months. Similarly the pulse pressure was
unaffected by allocation to treatment arm.
Lipids, lipoproteins and fibrinogen
Biochemical data from the trial are presented in
Table 2 and Figure 2. Total cholesterol fell in both
arms of the study with no difference between
tibolone and placebo groups. The reduction in total
cholesterol in the placebo group was however statistically significant (P = 0.04). LDL-cholesterol rose
slightly by 1.2 ± 8.0% in the tibolone group compared with a 5.3 ± 2.5% fall on placebo. High-density lipoprotein (HDL) was significantly reduced
(21.7 ± 3.8%)
falling
from
1.40 ± 0.1
to
1.08 ± 0.1 mmol/L with tibolone compared to a
2.4 ± 2.6% rise in those on placebo. Similarly apolipoprotein A-1 fell by 20.4 ± 3.6% compared with a
2.5 ± 2.1% rise on placebo but ApoAII levels
Tibolone randomised controlled trial
G Lloyd et al
101
Table 1 Patient characteristics
Age
Current smoker
Never smoked
Non-caucasian
Duration of hypertension (years)
Last menstrual period (years)
Weight (kg)
Height
BMI
Drug therapy
ACE inhibitor
AT II antagonists
Beta-blockers
Calcium antagonists
Diuretics
Vastatin
No previous antihypertensives
Previous HRT
Tibolone (n = 19)
Placebo (n = 11)
60.11
2
7
1
10.5
11.5
77.77
160.32
33.90
(1.28)
(11%)
(39%)
(6%)
(2.20)
(1.84)
(5.38)
(4.10)
(5.99)
62.73
1
8
1
11.45
16.10
77.11
161.48
29.60
(1.79)
(9%)
(73%)
(9%)
(2.86)
(3.78)
(3.09)
(2.23)
(1.30)
0.35
1.0
0.17
1.00
0.68
0.30
0.40
0.59
0.79
3
1
8
5
5
2
6
3
(16%)
(5%)
(44%)
(28%)
(28%)
(11%)
(33%)
(17%)
2
1
9
3
5
1
0
3
(18%)
(10%)
(82%)
(27%)
(46%)
(9%)
1.00
1.00
0.11
1.00
0.57
1.00
0.09
0.83
(27%)
Significance (P =)
No values significantly different at the 0.05 level.
declined less than ApoAI with tibolone therapy. Triglycerides were reduced by 33.4 ± 6.1% on tibolone
compared to 7.6 ± 7.9% on placebo (P ⬍ 0.05).
Fibrinogen was reduced on tibolone by 13.5 ± 6.8%
but rose by 19.3 ± 15.4% on placebo (P ⬍ 0.05).
Median Lp(a) rose nonsignificantly in both groups
during the study but final levels were similar.
Quality of life
There were no significant differences within the
tibolone and placebo groups between baseline and
6-month follow-up:
Figure 1 Effects of tibolone and placebo on systolic and diastolic
blood pressure.
general health: 68.2 (5.0) vs 65.4 (4.9) tibolone, 66.1
(7.4) vs 71.7 (5.2) placebo;
physical functioning: 64.2 (9.1) vs 64 (6.9) tibolone,
66.1 (10.8) vs 71.9 (6.2) placebo;
physical role: 58.3 (16.7) vs 58.3 (13.2) tibolone, 62.5
(18.3) vs 78.1 (14.5) placebo;
emotional role: 81.5 (11.3) vs 96.9 (3.0) tibolone.
62.5 (18.3) vs 70.83 (15.9) placebo;
social functioning: 90 (5.2) vs 80.1 (7.7) tibolone,
70.3 (9.7) vs 80.4 (10.2) placebo;
bodily pain: 70.3 (8.2) vs 65.3 (8.3) tibolone, 68.7
(11.13) vs 71.5 (11.4) placebo;
vitality: 52.8 (8.8) vs 51.9 (6.2) tibolone, 52.5 (8.8)
vs 52.1 (8.9) placebo;
mental health: 78.7 (3.9) vs 81.0 (3.4) tibolone, 66.5
(9.3) vs 65.6 (9.1) placebo.
There were also no significant differences between
the tibolone and placebo group at baseline or
6-month follow-up.
Adverse events
Figure 2 Effects of tibolone and placebo on the percentage change
on cardiovascular risk factors. (쏔) Placebo, (쐽) Tibolone.
*P ⬍ 0.05.
Both tibolone and placebo were well tolerated. Four
patients taking tibolone (22%) developed some
vaginal bleeding compared with one (9%) in the placebo arm; this difference was not statistically significant. One patient in the placebo group developed
a major vaginal bleed resulting in hospitalisation
Journal of Human Hypertension
Journal of Human Hypertension
(5.28)
(0.27)
(1.45–2.60)
(0.09)
(0.33)
(0.30)
(0.07)
(0.01)
(0.08)
(0.11)
(5–66)
(0.43)
(13.2–30.1)
72.20
6.23
2.11
1.24
3.88
3.21
1.54
0.56
1.47
1.50
14
3.49
19.6%
69.86
6.12
1.54
1.40
3.82
2.86
1.67
0.51
1.39
1.30
10
3.37
11.1%
(4.45)
(0.38)
(1.22–2.44)
(0.06)
(0.36)
(0.31)
(0.05)
(0.03)
(0.11)
(1.40)
(7.5–23)
(0.20)
(8.6–19.1)
85.11 (2.38)*
157.30 (5.83)
Placebo
91.11 (1.76)
160.97 (5.18)
*P ⬍ 0.05; Tribolone vs placebo.
a
Framingham model for systolic blood pressure.
Systolic blood pressure
(mm Hg)
Diastolic blood pressure
(mm Hg)
Pulse pressure (mm Hg)
Total cholesterol (mmol L)
Triglycerides (mmol L)
HDL-C (mmol L)
LDL-C (mmol L)
LDL: HDL ratio
Apo AI (mmol L)
Apo AII (mmol L)
Apo B (mmol L)
Apo B: (A1–A2) ratio
Lipoprotein (a)
Fibrinogen
10-year cardiac riska
Tibolone
Baseline
Table 2 Change in blood pressure, lipids, apolipoproteins and fibrinogen
64.16
5.73
1.23
1.08
4.03
4.02
1.32*
0.51
1.44
1.88*
9
3.01*
13.2%
(3.08)
(0.39)
(0.83–1.54)
(0.06)
(0.41)
(0.57)
(0.05)
(0.02)
(0.11)
(0.20)
(6–33)
(0.19)
(10.4 –22.8)
86.63 (3.38)
151.39 (5.07)
Tibolone
Placebo
63.97
5.63
1.31
1.28
3.49
2.76
1.56
0.51
1.31
1.28
15
3.44
13.5%
(4.87)
(0.38)
(1.03–2.12)
(0.09)
(0.39)
(0.31)
(0.09)
(0.03)
(0.09)
(0.13)
(4 –16)
(0.15)
(8.5–19.8)
84.09 (3.11)
148.06 (4.05)
Month 6
(7.14)
(5.66)
(6.06)
(3.78)
(8.00)
(9.30)
(3.57)
(3.28)
(8.28)
(14.69)
(20.74)
(6.81)
(57.2–20.4)
−10.05
−6.75
−7.61
−2.42
−5.29
−2.75
−2.47
−2.04
−7.37
−4.38
−7.87
19.32
−15%
(4.50)
(2.58)
(7.93)
(2.63)
(2.45)
(2.45)
(2.13)
(2.61)
(3.74)
(5.15)
(26.81)
(15.37)
(7.0–32.1)
−0.85 (3.69)
−5.38 (2.65)
−1.55
−9.78
−33.37*
−21.66*
1.21
30.41*
−20.37*
−8.31
3.42
46.10*
−10.93
−13.55*
18.6%
−4.94 (3.37)
Placebo
−5.30 (2.87)
Tibolone
Percent change from baseline
Tibolone randomised controlled trial
G Lloyd et al
102
Tibolone randomised controlled trial
G Lloyd et al
and subsequent dilatation and curettage. Two
patients (11%) in the tibolone arm and two (18%)
in the placebo arm terminated the study early: two
(one active and placebo) because of side effects
(headache, nausea and flushing), one because of the
development of an intercurrent pneumonia deemed
not to be related to study medication, and one for
personal reasons.
Discussion
The menopause may play a role in the acceleration
of hypertension in women. A rise in diastolic blood
pressure and a steepening of the time dependent rise
in systolic blood pressure occur in the postmenopause.4 Concurrently other adverse changes occur in
cardiac risk factors including rises in LDL and insulin resistance, falls in HDL, and changes in fat distribution.17 Gender protection is lost so the incidence
of CHD in women equals that in men by the age of
65.18 Hypertensive women in the Nurses Health
Study had a 3.5-fold increase in risk of CHD with a
2.6-fold increase in stroke compared with nonhypertensives.19 Despite circumstantial evidence of
benefit, HRT has only rarely been prescribed in
hypertensive women, possibly due to the known
hypertensive effects of oestrogen seen in women on
the contraceptive pill.1 However oestrogen and progestin supplementation may be beneficial in postmenopausal women with hypertension. Oestrogen
acts as a vasodilator by restoring impaired endothelial function,20 inhibiting the vasoconstrictor
actions of endothelin-l21 and by inhibiting the influx
of Ca2+ ions into vascular smooth muscle cells.22 In
addition oestrogen reduces circulating catecholamines levels23 and may act as an angiotensin-converting enzyme inhibitor.24 In vivo administration of
oestrogen or natural progesterone can bring about an
acute drop in blood pressure.5,6 In hypertensive
women a number of small studies have documented
an antihypertensive effect. Transdermal oestradiol
can reduce daytime systolic pressure,7 achieve an
absolute reduction in overall pressures8 and restore
a normal 24-h ambulatory blood pressure profile.9
Other studies have shown no effect of oestrogens on
blood pressure in the hypertensive population but a
reduction in plasma renin and aldosterone levels.10
The use of HRT alongside antihypertensive therapy
can offset some of the adverse metabolic effects associated with drugs such as thiazides and beta-blockers.25 Not all studies have shown encouraging
results. A study of a retirement community in the
USA found a relationship between the incidence of
hypertension and both dose and duration of oestrogen use.26 Another small sequential series noted
a rise in blood pressure associated with oestrogen
use that returned to normal following termination of
oestrogen therapy.27 The PEPI study in normotensive women showed that oestrogen plus various
progestins did not alter blood pressure significantly
over a 3-year period.2
Tibolone is a synthetic steroid with the unusual
property of differential metabolism in different
organs. Hence it exerts a progesterone-like inhibitory effect on breast28 and uterine tissue29 and
relieves menopausal symptoms11 while preventing
bone loss12 much like oestrogen. Tibolone augments
forearm11 and aortic blood flow,30 and alters aortic
distensibility,31 which suggest it may reduce blood
pressure. It has also been reported to reduce myocardial ischaemia in women with angina.32 Furthermore in an atherosclerotic rabbit model tibolone significantly reduced the development of new
atherosclerotic plaque.33 It has androgenic effects on
plasma lipids especially in reducing HDL. This
study shows tibolone has no differential effect on
HDL-cholesterol uptake and transfer as HDL and
apoA1 levels were reduced in parallel. The effects
of tibolone on HDL affect apoA1 more than apoA2,
implying deleterious effects on reverse cholesterol
transport is HDL:A1 but not HDL:A1:A2 dependent.
It also may have differential effects on apoA gene
expression as these genes are usually co-ordinately
regulated. Alterations in lipid risk factors for CHD
such as triglycerides and Lp(a) may outweigh the
effects of tibolone on HDL.34 –36
It is of note that cholesterol levels fell significantly
in the placebo group. This is difficult to understand
as no specific dietary advice was given and lipidlowering therapy was held as a constant throughout
the study. Presumably partaking in a clinical study
caused subjects to have heightened awareness of cardiac risk factors and pay more attention to diet and
lifestyle issues.
This randomised placebo-controlled trial demonstrated no clinically significant alteration in blood
pressure in hypertensive women taking tibolone for
6 months. The study, though small, was powered to
detect a clinically relevant change in blood pressure
that might affect clinical decision-making (15
mm Hg). These results support the findings of a large
observational study of tibolone which found no rise
in blood pressure in 75 hypertensive menopausal
women over 14 months.37 The effects of tibolone on
lipids were similar to those previously described
with a 20–25% fall in HDL. The adverse effect on
the LDL:HDL, apoB: apoA1 and apoB:(apoA1-A2)
ratios imply that tibolone interfered with reverse
cholesterol transport and for this reason may be deleterious. However, the 33% reduction in triglycerides and 19% reduction in fibrinogen may counterbalance this effect. In the most current model of
cardiac risk derived from the Framingham study,
incorporating TC, HDL-C and other risk factors,
tibolone increased cardiac risk by about 18% but
this was not statistically significant and in this
population represented a rise in absolute risk of
2.6%.38 A fall in Lp(a) with tibolone has been noted
but this was not reproduced here.35 The measurement of Lp(a) is difficult to standardise and subject
to wide variation so both studies are likely to be
underpowered. Larger scale studies of the effects of
tibolone on Lp(a) are required. Tibolone was well
tolerated and did not significantly effect the quality
of life.
103
Conclusions
Tibolone at a dose of 2.5 mg is safe to use in women
with treated or untreated hypertension, with miniJournal of Human Hypertension
Tibolone randomised controlled trial
G Lloyd et al
104
mal effects on blood pressure. The balance between
its adverse effects on HDL and the beneficial effects
on triglycerides and fibrinogen should be the subject
of further study in women at risk of CHD.
19
20
Acknowledgements
The authors would like to thank Organon Laboratories LTD for the supply of the study medications
and for an educational grant towards this study, and
The Peel Medical Research Trust.
21
22
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