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Journal of Human Hypertension (2000) 14, 99–104  2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh ORIGINAL ARTICLE A randomised placebo controlled trial of the effects of on and in hypertensive women

G Lloyd1, E McGing1, A Cooper1, N Patel1, PJ Lumb2, AS Wierzbicki2 and G Jackson1 1Department of Cardiology and 2Chemical Pathology, Guys and St Thomas’ Hospital Trust, Lambeth Palace Road, London SE1 7EH, UK

The effects of replacement therapy in hyper- high-density lipoprotein (HDL)- by tensive women are controversial. This randomised pla- 21.7 ؎ 3.8% vs 2.4 ؎ 2.6% (P Ͻ 0.01) with tibolone as cebo controlled trial assessed the effect of tibolone opposed to placebo. No significant differences were 2.5 mg on blood pressure and fasting plasma lipids in observed in total cholesterol, low-density lipoprotein 29 hypertensive postmenopausal women over 6 months (LDL)-cholesterol and lipoprotein (a). Fibrinogen levels using a 2:1 randomisation to tibolone. The primary clini- were reduced by 13.6 ؎ 6.8% on tibolone compared to cal end-point was mean office blood pressure. At 6 a 19.3 ؎ 15.4% rise (P Ͻ 0.05) on placebo. This study months systolic blood pressure declined by suggests that tibolone has no deleterious effect on vs 4.94 ؎ 3.37% whilst diastolic blood blood pressure in women with hypertension but has 2.87% ؎ 5.30 -pressure declined 5.38 ؎ 2.65% vs 0.85 ؎ 3.69% on contrasting effects on biochemical risk factors. Large tibolone and placebo respectively. These differences scale studies are required to determine the overall effect were not statistically significant. of tibolone on cardiovascular morbidity and mortality. decreased by 33.3 ؎ 6.1% vs 7.6 ؎ 7.9% (P Ͻ 0.01) and Journal of Human Hypertension (2000) 14, 99–104

Keywords: hormone replacement; hypertension; lipids; trial

Introduction women with pre-existing hypertension on both blood pressure and biochemical cardiovascular The role of hormone replacement therapy (HRT) in risk factors. women with hypertension remains controversial. Oestrogen-based HRT remains underused in these women probably because of concerns about blood Materials and methods pressure deterioration in younger women taking the Study design oral contraceptive.1 However, the potentially ben- eficial effects of HRT in reducing coronary heart dis- The trial had a double-blind, randomised, placebo- ease (CHD) risk would suggest a role for it in the controlled format. Randomisation was 2:1 in favour management of hypertension.2,3 The loss of oes- of tibolone to increase the probability of demonstrat- trogen at the appears to be associated ing a treatment effect. The study received local ethi- with an overall rise in blood pressure.4 Little infor- cal approval and written informed consent was mation is available regarding the long-term effects obtained. At two baseline visits clinical details, of HRT in hypertensive women, but short duration baseline blood pressure, quality of life parameters studies in hypertensive women have demonstrated and fasting profiles were measured. Patients either a neutral or even modest hypotensive were reviewed monthly for continued blood press- effect.5–10 ure assessment. Baseline biochemical investigations Cyclical HRT preparations are unacceptable to were repeated at the final clinical visit after 6 most women suffering from coronary disease or months treatment. hypertension. Tibolone is a novel com- 11 pound, which controls menopausal symptoms, Eligibility inhibits postmenopausal loss12 and augments forearm blood flow.13 It does not induce endometrial Eligible patients had previously diagnosed hyper- hyperplasia or, usually, postmenopausal bleeding.14 tension on or off treatment with antihypertensives. We investigated the effect of introducing tibolone in All had three separate standard mercury sphygmo- manometer blood pressure readings greater than 160/90 mm Hg over 3 months or were taking long- Correspondence: Dr Guy Lloyd, Cardiothoracic Department, 6th term antihypertensive treatment. All were 1 or more Floor, East Wing, St Thomas’ Hospital, London SE1 7EH, UK years postmenopausal on clinical grounds. Received 24 May 1999; revised and accepted 3 September 1999 Exclusion criteria included, intrinsic renal disease, Tibolone randomised controlled trial G Lloyd et al 100 insulin-dependent diabetes or a past history of an at the final visit. Data were analysed using the SPSS oestrogen dependent tumour. Women who had used statistical package (version 6.0). Parametric data are sex steroid compounds including oral contracep- displayed as mean and standard error, non-para- tion, previous HRT, , tibolone or tamox- metric data as median and range while frequency ifen within the previous 3 months were excluded. data as value and percentage. Principal analysis was performed using ANOVA for repeated measures with unpaired t-testing for individual two-way com- Blood pressure measurement parisons between subjects allocated to tibolone or Blood pressure was measured as near as possible at placebo. Non-parametric data (lipoprotein (a) and the same time of the same day of the week by one triglycerides) were compared using the appropriate of two operators using the British Hypertension non-parametric test (Mann–Whitney) with contin- Society approved methods.15 For the purposes of gency table testing of frequency data (Yates’ conti- analysis the mean of the three recumbant blood nuity correction). P Ͻ 0.05 was considered statisti- pressure measurements was calculated. If blood cally significant. pressure exceeded 210/120 mm Hg on two separate visits, the patient left the study to allow modifi- cation of , otherwise all concomitant Results antihypertensive medication was left unchanged for Demographics the duration of the study. Major demographic features were similar in the active and placebo arms of the study (Table 1). The Plasma lipids and lipoproteins mean age of the women was 60.1 years in the active Blood samples were drawn in the recumbant pos- group and 62.7 years in the placebo group. Both ition after a 12-h fast. Samples were centrifuged groups were more than 10 years after the menopause immediately and stored at −70°C until subsequent (11.5 years tibolone and 16.1 years placebo). There analysis. Plasma lipid profiles were detained in a were non-significant statistical differences in other single batch by standard automated methods for patient characteristics and in concomitant total cholesterol, triglycerides and HDL on a Cobas . Fara II analyser. Low-density lipoprotein (LDL) was calculated by the Freidewald equation if triglycer- Blood pressure ides Ͻ4.5 mmol/L. Apolipoprotein (apo) A1, A2, B, lipoprotein (a) [Lp(a)] and fibrinogen were measured Study blood pressure readings are recorded in Fig- by immunoturbidimetric methods on the same ana- ure 1 and Table 2. The entry mean blood pressure lyser. Lp(a) samples were pre-treated by centrifug- was 161 ± 5.2/91 ± 1.8 mm Hg in the tibolone group ation and lipase treatment to reduce any and 157 ± 5.4/85 ± 2.4 mm Hg in the placebo. Base- interference with the assay. All methods used were line diastolic blood pressure was slightly but sig- validated against International Federation of nificantly higher in the active treatment arm (P Ͻ Clinical Chemistry standards and had standard 0.05) but the mean arterial pressure was not signifi- deviations of Ͻ2.5% for lipids, Ͻ4% for apolipo- cantly different (126.0 ± 3.2 vs 121.2 ± 3.6 mm Hg). , Ͻ6% for Lp(a) and Ͻ3% for fibrinogen for Systolic blood pressure fell by 5.2%, diastolic press- medium range calibrators. ure 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 Quality of life 148 ± 4.1/84 ± 3.2 mm Hg in the placebo arm. Quality of life was recorded at baseline and at 6 Neither absolute or percentage reductions in systolic months using the SF-36 General Health Question- and diastolic blood pressures were significantly dif- naire.16 This measures eight health concepts: physi- ferent at 6 months. Similarly the pulse pressure was cal functioning, physical and emotional role limi- unaffected by allocation to treatment arm. tations, bodily pain, general health, vitality, social functioning, mental health and reported health tran- Lipids, lipoproteins and fibrinogen sition. In each measure, a higher score indicates a better health state. 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 Statistical analysis tibolone and placebo groups. The reduction in total The study was powered to detect a change in mean cholesterol in the placebo group was however stat- blood of 15 mm Hg. A 2:1 randomisation was used istically significant (P = 0.04). LDL-cholesterol rose to increase the power to detect a treatment effect slightly by 1.2 ± 8.0% in the tibolone group com- while accepting an increased risk of a type I error. pared with a 5.3 ± 2.5% fall on placebo. High-den- In patients who dropped out of the study the blood sity lipoprotein (HDL) was significantly reduced pressure at the last visit was carried forward to suc- (21.7 ± 3.8%) falling from 1.40 ± 0.1 to cessive visits. Blood pressure data were analysed on 1.08 ± 0.1 mmol/L with tibolone compared to a an intention-to-treat basis but percentage change in 2.4 ± 2.6% rise in those on placebo. Similarly apoli- lipid values was calculated only for those patients poprotein A-1 fell by 20.4 ± 3.6% compared with a who finished the study and were taking medication 2.5 ± 2.1% rise on placebo but ApoAII levels

Journal of Human Hypertension Tibolone randomised controlled trial G Lloyd et al 101 Table 1 Patient characteristics

Tibolone (n = 19) Placebo (n = 11) Significance (P =)

Age 60.11 (1.28) 62.73 (1.79) 0.35 Current smoker 2 (11%) 1 (9%) 1.0 Never smoked 7 (39%) 8 (73%) 0.17 Non-caucasian 1 (6%) 1 (9%) 1.00 Duration of hypertension (years) 10.5 (2.20) 11.45 (2.86) 0.68 Last menstrual period (years) 11.5 (1.84) 16.10 (3.78) 0.30 Weight (kg) 77.77 (5.38) 77.11 (3.09) 0.40 Height 160.32 (4.10) 161.48 (2.23) 0.59 BMI 33.90 (5.99) 29.60 (1.30) 0.79 therapy ACE inhibitor 3 (16%) 2 (18%) 1.00 AT II antagonists 1 (5%) 1 (10%) 1.00 Beta-blockers 8 (44%) 9 (82%) 0.11 antagonists 5 (28%) 3 (27%) 1.00 Diuretics 5 (28%) 5 (46%) 0.57 Vastatin 2 (11%) 1 (9%) 1.00 No previous antihypertensives 6 (33%) 0 0.09 Previous HRT 3 (17%) 3 (27%) 0.83

No values significantly different at the 0.05 level.

declined less than ApoAI with tibolone therapy. Tri- were reduced by 33.4 ± 6.1% on tibolone compared to 7.6 ± 7.9% on placebo (P Ͻ 0.05). Fibrinogen was reduced on tibolone by 13.5 ± 6.8% but rose by 19.3 ± 15.4% on placebo (P Ͻ 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:

general health: 68.2 (5.0) vs 65.4 (4.9) tibolone, 66.1 (7.4) vs 71.7 (5.2) placebo; Figure 1 Effects of tibolone and placebo on systolic and diastolic physical functioning: 64.2 (9.1) vs 64 (6.9) tibolone, blood pressure. 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 Both tibolone and placebo were well tolerated. Four patients taking tibolone (22%) developed some compared with one (9%) in the pla- Figure 2 Effects of tibolone and placebo on the percentage change cebo arm; this difference was not statistically sig- on cardiovascular risk factors. („) Placebo, (í) Tibolone. nificant. One patient in the placebo group developed *P Ͻ 0.05. a major vaginal bleed resulting in hospitalisation

Journal of Human Hypertension Tibolone randomised controlled trial G Lloyd et al 102 0.85 (3.69) 4.94 (3.37) 7.87 (26.81) 4.38 (5.15) 7.37 (3.74) 2.04 (2.61) 2.47 (2.13) 2.75 (2.45) 5.29 (2.45) 2.42 (2.63) 7.61 (7.93) 6.75 (2.58) 15% (7.0–32.1) − − − − − − − − − − − − 10.05 (4.50) − − 1.55 (7.14) 5.38 (2.65) 5.30 (2.87) 8.31 (3.28) 9.78 (5.66) − − − − − 10.93 (20.74) 13.55* (6.81) 19.32 (15.37) 20.37* (3.57) 21.66* (3.78) 33.37* (6.06) − − − − − Baseline Month 6 Percent change from baseline Tibolone Placebo Tibolone Placebo Tibolone Placebo 11.1% (8.6–19.1) 19.6% (13.2–30.1) 13.2% (10.4–22.8) 13.5% (8.5–19.8) 18.6% (57.2–20.4) placebo. vs a Change in blood pressure, lipids, apolipoproteins and fibrinogen 0.05; Tribolone Ͻ P Framingham model for systolic blood pressure. Table 2 * a (mm Hg) Pulse pressure (mm Hg) 69.86 (4.45) 72.20 (5.28) 64.16 (3.08) 63.97 (4.87) (mm Hg) Diastolic blood pressure 91.11 (1.76) 85.11 (2.38)* 86.63 (3.38) 84.09 (3.11) Systolic blood pressure 160.97 (5.18) 157.30 (5.83) 151.39 (5.07) 148.06 (4.05) Fibrinogen 3.37 (0.20) 3.49 (0.43) 3.01* (0.19) 3.44 (0.15) Lipoprotein (a) 10 (7.5–23) 14 (5–66) 9 (6–33) 15 (4–16) Apo B: (A1–A2) ratio 1.30 (1.40) 1.50 (0.11) 1.88* (0.20) 1.28 (0.13) 46.10* (14.69) Apo B (mmol L) 1.39 (0.11) 1.47 (0.08) 1.44 (0.11) 1.31 (0.09) 3.42 (8.28) Apo AII (mmol L) 0.51 (0.03) 0.56 (0.01) 0.51 (0.02) 0.51 (0.03) Apo AI (mmol L) 1.67 (0.05) 1.54 (0.07) 1.32* (0.05) 1.56 (0.09) LDL: HDL ratio 2.86 (0.31) 3.21 (0.30) 4.02 (0.57) 2.76 (0.31) 30.41* (9.30) LDL-C (mmol L) 3.82 (0.36) 3.88 (0.33) 4.03 (0.41) 3.49 (0.39) 1.21 (8.00) HDL-C (mmol L) 1.40 (0.06) 1.24 (0.09) 1.08 (0.06) 1.28 (0.09) Triglycerides (mmol L) 1.54 (1.22–2.44) 2.11 (1.45–2.60) 1.23 (0.83–1.54) 1.31 (1.03–2.12) Total cholesterol (mmol L) 6.12 (0.38) 6.23 (0.27) 5.73 (0.39) 5.63 (0.38) 10-year cardiac risk

Journal of Human Hypertension Tibolone randomised controlled trial G Lloyd et al 103 and subsequent dilatation and curettage. Two relieves menopausal symptoms11 while preventing patients (11%) in the tibolone arm and two (18%) bone loss12 much like oestrogen. Tibolone augments in the placebo arm terminated the study early: two forearm11 and aortic blood flow,30 and alters aortic (one active and placebo) because of side effects distensibility,31 which suggest it may reduce blood (headache, nausea and flushing), one because of the pressure. It has also been reported to reduce myocar- development of an intercurrent pneumonia deemed dial ischaemia in women with angina.32 Further- not to be related to study medication, and one for more in an atherosclerotic rabbit model tibolone sig- personal reasons. nificantly reduced the development of new atherosclerotic plaque.33 It has androgenic effects on Discussion plasma lipids especially in reducing HDL. This study shows tibolone has no differential effect on The menopause may play a role in the acceleration HDL-cholesterol uptake and transfer as HDL and of hypertension in women. A rise in diastolic blood apoA1 levels were reduced in parallel. The effects pressure and a steepening of the time dependent rise of tibolone on HDL affect apoA1 more than apoA2, in systolic blood pressure occur in the postmeno- implying deleterious effects on reverse cholesterol pause.4 Concurrently other adverse changes occur in transport is HDL:A1 but not HDL:A1:A2 dependent. cardiac risk factors including rises in LDL and insu- It also may have differential effects on apoA gene lin resistance, falls in HDL, and changes in fat distri- expression as these genes are usually co-ordinately bution.17 Gender protection is lost so the incidence regulated. Alterations in lipid risk factors for CHD of CHD in women equals that in men by the age of such as triglycerides and Lp(a) may outweigh the 65.18 Hypertensive women in the Nurses Health effects of tibolone on HDL.34–36 Study had a 3.5-fold increase in risk of CHD with a It is of note that cholesterol levels fell significantly 2.6-fold increase in compared with non- in the placebo group. This is difficult to understand hypertensives.19 Despite circumstantial evidence of as no specific dietary advice was given and lipid- benefit, HRT has only rarely been prescribed in lowering therapy was held as a constant throughout hypertensive women, possibly due to the known the study. Presumably partaking in a clinical study hypertensive effects of oestrogen seen in women on caused subjects to have heightened awareness of car- the contraceptive pill.1 However oestrogen and pro- diac risk factors and pay more attention to diet and gestin supplementation may be beneficial in post- lifestyle issues. menopausal women with hypertension. Oestrogen This randomised placebo-controlled trial demon- acts as a vasodilator by restoring impaired endo- strated no clinically significant alteration in blood thelial function,20 inhibiting the vasoconstrictor pressure in hypertensive women taking tibolone for actions of endothelin-l21 and by inhibiting the influx 6 months. The study, though small, was powered to of Ca2+ into vascular smooth muscle cells.22 In detect a clinically relevant change in blood pressure addition oestrogen reduces circulating catecholam- that might affect clinical decision-making (15 ines levels23 and may act as an angiotensin-con- mm Hg). These results support the findings of a large verting inhibitor.24 In vivo administration of observational study of tibolone which found no rise oestrogen or natural progesterone can bring about an in blood pressure in 75 hypertensive menopausal acute drop in blood pressure.5,6 In hypertensive women over 14 months.37 The effects of tibolone on women a number of small studies have documented lipids were similar to those previously described an antihypertensive effect. Transdermal oestradiol with a 20–25% fall in HDL. The on can reduce daytime systolic pressure,7 achieve an the LDL:HDL, apoB: apoA1 and apoB:(apoA1-A2) absolute reduction in overall pressures8 and restore ratios imply that tibolone interfered with reverse a normal 24-h ambulatory blood pressure profile.9 cholesterol transport and for this reason may be del- Other studies have shown no effect of oestrogens on eterious. However, the 33% reduction in triglycer- blood pressure in the hypertensive population but a ides and 19% reduction in fibrinogen may counter- reduction in plasma renin and levels.10 balance this effect. In the most current model of The use of HRT alongside antihypertensive therapy cardiac risk derived from the Framingham study, can offset some of the adverse metabolic effects asso- incorporating TC, HDL-C and other risk factors, ciated with such as thiazides and beta-block- tibolone increased cardiac risk by about 18% but ers.25 Not all studies have shown encouraging this was not statistically significant and in this results. A study of a retirement community in the population represented a rise in absolute risk of USA found a relationship between the incidence of 2.6%.38 A fall in Lp(a) with tibolone has been noted hypertension and both dose and duration of oes- but this was not reproduced here.35 The measure- trogen use.26 Another small sequential series noted ment of Lp(a) is difficult to standardise and subject a rise in blood pressure associated with oestrogen to wide variation so both studies are likely to be use that returned to normal following termination of underpowered. Larger scale studies of the effects of oestrogen therapy.27 The PEPI study in normo- tibolone on Lp(a) are required. Tibolone was well tensive women showed that oestrogen plus various tolerated and did not significantly effect the quality progestins did not alter blood pressure significantly of life. over a 3-year period.2 Tibolone is a synthetic steroid with the unusual Conclusions property of differential in different organs. Hence it exerts a progesterone-like inhibi- Tibolone at a dose of 2.5 mg is safe to use in women tory effect on breast28 and uterine tissue29 and with treated or untreated hypertension, with mini-

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Journal of Human Hypertension