(Moexipril) and Hormonal Replacement Therapy in Postmenopausal Women

Journal of Human Hypertension (1999) 13, 337–342  1999 Stockton Press. All rights reserved 0950-9240/99 $12.00 http://www.stockton-press.co.uk/jhh ORIGINAL ARTICLE Co-administration of an ACE-inhibitor (moexipril) and hormonal replacement therapy in postmenopausal women

B Koch1, S Oparil2 and M Stimpel1 1Department of Clinical Research, Schwarz Pharma AG, Monheim, Germany; 2University of Alabama School of Medicine, Birmingham, Alabama, USA

Co-administration of antihypertensive drug therapy and and diastolic BP from baseline than placebo (−12.2/ hormonal replacement therapy (HRT) is frequent in post- −9.9 mm Hg vs −1.6/−4.3 mm Hg, P Ͻ 0.001). Metabolic menopausal women but it is not known whether HRT parameters were not affected by treatment with moexi- interacts with concomitant antihypertensive therapy. pril: mean levels of triglycerides, total cholesterol, The present study was designed to investigate efficacy HDL, LDL, total cholesterol/HDL ratio and glucose and safety of the ACE inhibitor moexipril in comparison remained unchanged throughout the study. Fibrino- to placebo in hypertensive, postmenopausal women gen, an independent cardiovascular risk factor, on HRT. increased after placebo (+35.0 mg/dl) and decreased After a 4-week placebo run-in phase, 95 postmeno- after treatment with moexipril (−33.6 mg/dl), the differ- pausal women (35–74 years of age) who had a sitting ence, however, was not statistically significant. Moexi- diastolic blood pressure (BP) of 95–114 mm Hg and pril was well-tolerated by postmenopausal women were treated with HRT were randomised to a 12-week using HRT. The most frequent adverse events included treatment with moexipril 15 mg or placebo. Efficacy and headache (21.3%), cough (12.8%) and rhinitis (10.6%) safety were assessed by measuring changes in sitting and there were no significant differences in the num- BP and metabolic parameters associated with cardio- ber and severity of adverse events between the moexi- vascular disease including triglycerides, total choles- pril and placebo groups. terol, HDL, LDL, total cholesterol/HDL ratio and glucose. This study indicates that moexipril is effective and Adverse events were recorded continuously. well tolerated in the treatment of hypertensive, post- After 12 weeks of treatment, moexipril 15 mg was menopausal women and can safely be co-administered significantly more effective in reducing sitting systolic to HRT.

Keywords: moexipril; hormonal replacement therapy; postmenopausal women

Introduction it may cause hypertension, perhaps under the mis- taken impression that HRT has the same side effects One very important question facing postmenopausal as the first generation of steroid contraceptives. A women today is whether or not to take hormone number of newer case-control and prospective stud- replacement therapy (HRT). Its benefits include ies have demonstrated that HRT does not exacerbate reduced risk of cardiovascular disease and osteop- hypertension in postmenopausal women and that orosis as well as control of postmenopausal symp- 1–4 cardiovascular mortality of postmenopausal women toms. Otherwise, risk of endometrial cancer is gre- on HRT decreases by approximately one-half.7–9 atly increased with unopposed oestrogen treatment, Unfortunately up to now very little is known about and breast cancer is increased with both forms of 5,6 the interaction of HRT and antihypertensive drug HRT (oestrogen alone or oestrogen plus progestin). treatment. Therefore the present placebo-controlled The risk/benefit ratio of HRT has yet to be assessed study was designed to answer the question whether in prospective trials. the new angiotensin-converting enzyme (ACE) Despite the benefits of HRT in relieving meno- inhibitor, moexipril, can effectively and safely be pausal symptoms, there continues to be anxiety co-administered to HRT in the antihypertensive about its use in women who also have hypertension. drug treatment of postmenopausal women. The Although there is overwhelming evidence that HRT compatibility of both drug therapies was studied reduces the incidence, many physicians assume that with respect to blood pressure (BP), metabolic parameters and special clotting factors.

Correspondence: Professor Michael Stimpel, MD, Schwarz Patients and methods Pharma Deutschland GmbH, Alfred-Nobel-Straβe 10, 40789 Monheim, Germany Patients Received 8 October 1998; revised 31 December 1998; accepted 8 This randomised, double-blind, parallel, placebo- February 1999 controlled study was conducted at 12 centres in the Moexipril and HRT in postmenopausal women B Koch et al 338 United States. The study population consisted of at baseline and at week 4 and 12 of the double-blind postmenopausal women with mild to moderate treatment period. Specimens were taken for hypertension (sitting diastolic BP between 95 and measurement of triglycerides, total cholesterol, 114 mm Hg) who were treated with HRT. The HDL-cholesterol, LDL-cholesterol, total cho- majority of patients received oestrogen therapy lesterol/HDL ratio and fasting serum glucose. Blood alone (54/95) or a combination of oestrogen and pro- samples also were evaluated for special coagulation gestin (33/95), as prescribed by their physician. studies, eg, plasminogen activator inhibitor-1 (PAI- Patients had to be free of secondary hypertension 1), lipoprotein (a), antithrombin III, protein C, pro- or any significant cardiovascular, haematologic, tein S and fibrinogen. endocrinologic, hepatic or renal disease. Patients were also excluded for alcohol or drug abuse, concomitant medication that influenced BP, any abnor- Adverse experiences malities that may interfere with absorption or contraindication to treatment with any of the Adverse experiences as well as pre- vs post-treat- study drugs. ment results of physical examination, ECG and laboratory tests (biochemistry, haematology, urinalysis and special clotting factors) were included in the Study design safety evaluation. Adverse events were assessed at Before entering the study, all patients signed a writ- each visit and graded by the investigator as ‘serious’ ten informed consent form, approved by the review or ‘non-serious’, and ‘mild’, ‘moderate’ or ‘severe’ boards of the participating institutions. At this and the relationship to the study medication was point, all previous antihypertensive medications, characterised as ‘none’, ‘likely’, ‘possible’, ‘probable’ when applicable, were discontinued in a 1 week or ‘highly probable’. wash-out period with the use of appropriate taper- ing procedures. This was followed by a 4 week single-blind placebo period. At the conclusion of the Statistical methods placebo period, 95 patients with a sitting diastolic BP between 95 to 114 mm Hg were randomised to Continuous variables were summarised with receive moexipril 15 mg or placebo. The patients descriptive statistics (eg, number, mean, median, were followed-up in the clinic at weekly intervals standard deviation, minimum and maximum). during the wash-out and placebo period and every Treatment comparisons were inferentially analysed 2 or 4 weeks during the 12 week double-blind treat- using a two-way analysis of variance model ment phase. Initial and final visit evaluations (ANOVA) with fixed effects for site, treatment, and included a medical history, physical examination treatment per site interaction. Changes in sitting sys- with a fundoscopy, laboratory evaluations and a 12 tolic and diastolic BP and heart rate were analysed lead ECG. Blood pressure and heart rate were meas- by analysis of covariance (ANCOVA) with factors for ured at each of the seven visits. The study drugs— site, treatment, and treatment per site interaction, moexipril or matching placebo—were taken once using the baseline measure as a covariate. Response daily, approximately at the same time of the day, rates were analysed by using the Cochran-Mantel- compliance was assessed by pill counting. HRT was Haenszel Test for general association. The primary continued unchanged throughout the study. analyses as well as the assessment of the adverse events were performed on an intent-to-treat basis. Blood pressure measurement Comparison between treatment groups for each cate- gory of adverse events was performed using the Blood pressure measurement was conducted in Fisher’s Exact Test. All tests were two-sided and P- accordance with the American Society of Hyperten- values Ͻ0.05 were considered significant. sion recommendations with a standard mercury sphygmomanometer. Triplicate BP measurements were taken in the sitting position after 5 min of rest. Results The recorded BP was an average of these three read- ings. Standing BP was determined immediately fol- Baseline demographics lowing standing up from the sitting position and repeated 2 min later while still remaining upright. Of 129 postmenopausal women initially screened Phase I and V of the Korotkoff sounds were used as for study entry, 95 met the entry criteria and were the determinants of systolic and diastolic BP, randomised to treatment with moexipril 15 mg (47 respectively. Pulse was also recorded once in the sit- patients) or placebo (48 patients). Seventy-eight (78) ting and once in the standing position. Blood pres- patients completed the 12 week double-blind per- sure and heart rate were assessed for all visits at iod; 12 patients from the placebo group and five similar times of day, preferably in the morning patients from the moexipril group discontinued the 24 ± 2 h after the prior days dose. Efforts were made study. Table 1 displays baseline demographics and to ensure the consistency of the environment. vital signs of the randomised patients. The distribution of race and age was similar in the two assigned treatment groups. Patients ranged in age Laboratory measurements from 35 to 74 years and the majority were white Twelve hour fasting blood specimens and a urinaly- (72% and 73% in the moexipril and the placebo sis were obtained at the start of the placebo period, group, respectively) and of medium frame size. Moexipril and HRT in postmenopausal women B Koch et al 339 Table 1 Summary of demographic and baseline characteristics

Moexipril (n = 47) Placebo (n = 48) P-value

Age (years)* 56.1 ± 8.0 57.0 ± 6.8 0.493 Race, number (%) white 34 (72) 35 (73) 0.657 black 5 (11) 4 (8) other 0 9 (19) Weight (kg)* 73.1 ± 10.3 71.2 ± 11.8 0.516 Height (cm)* 163.6 ± 7.1 162.6 ± 5.6 0.527 Aetiology of menopause, number (%) bilateral oophorectomy 21 (45) 20 (42) 0.681 naturally postmenopausal 26 (55) 28 (58) Sitting systolic blood pressure (mm Hg) 154.6 ± 11.8 158.5 ± 13.6 0.129 Sitting diastolic blood pressure (mm Hg) 99.5 ± 3.8 100.0 ± 3.7 0.835 Sitting pulse (bpm) 72.7 ± 7.7 72.4 ± 6.3 0.435

*Data as mean and s.d.

Efficacy throughout the study. Moexipril treated patients showed a moderate decrease in mean levels of Mean baseline systolic and diastolic BPs were fibrinogen compared to patients receiving placebo 154.6/99.5 mm Hg for the moexipril group and (−33.6 mg/dl vs +35.0 mg/dl) (Table 3); the differ- 158.5/100.1 mm Hg for the placebo group. After 12 ence however was not statistically significant. No weeks of treatment, moexipril reduced both the dias- significant changes in plasminogen activator inhibi- tolic BP (−9.9 mm Hg vs −4.3 mm Hg, P Ͻ 0.001) and tor (PAI), lipoprotein (a), antithrombin III, protein C the systolic BP (−12.2 mm Hg vs −1.6 mm Hg, P Ͻ or protein S were observed in either treatment 0.001) to a statistically significantly greater extent group. ECHO and physical examination results indi- than did placebo (Figure 1). Changes in systolic and cated no significant changes from baseline for either diastolic BP in the standing and 2-min standing pos- group, nor significant differences between both itions were similar to those seen in the sitting pos- groups at either baseline or week 12. ition. Also the response rates for moexipril and pla- Moexipril was well tolerated by postmenopausal cebo differed significantly. Response rates are women using HRT. Adverse event rates for moexi- classified as excellent if the patient has a sitting pril and placebo were in general similar. The overall diastolic BP Ͻ90 mm Hg and as good if the sitting percentages of patients who had one or more labora- diastolic BP is у90 mm Hg but a BP reduction of tory adverse events during the double-blind period у10 mm Hg is achieved. Fifty-one percent (51%) of were 19.1% for moexipril and 16.7% for placebo. the patients treated with 15 mg moexipril had an For clinical adverse events the overall percentages excellent response to treatment and good response were 70.2% for moexipril and 58.3% for placebo. was seen in 2%. The respective values were 25% The most frequent adverse events included head- and 11% in the placebo group. ache (21.3%), cough (12.8%) and rhinitis (10.6%) for moexipril and headache (27.1%) and pharyngitis Safety (8.3%) for placebo. There were no significant differences in the number or severity of adverse events Table 2 displays the laboratory data for the treat- between the moexipril and placebo groups, except ment groups. Moexipril in general did not affect for increased cough (12.8% of moexipril patients vs metabolic parameters. Mean levels of triglycerides, no placebo patients). total cholesterol, HDL, LDL, total cholesterol/HDL ratio and glucose remained relatively unchanged Discussion After losing the protective effect of oestrogens, postmenopausal women are at an increased risk of developing cardiovascular diseases, osteoporosis and metabolic disturbances such as dyslipidae- mia.10–12 Long-term administration of HRT may reduce the risk of developing these conditions via favourable effects on bone metabolism and cardiovascular risk factors (ie, raising HDL, lowering of LDL, total cholesterol, fibrinogen and PAI-1,1,13–16). Additionally, HRT relieves postmenopausal symptoms such as vaginal dryness, loss of libido, hot 1–4 Figure 1 Adjusted mean charge from baseline in sitting systolic flushes and depression. Although results from and diastolic BP at study end-point (mm Hg). some studies in women on opposed or unopposed Moexipril and HRT in postmenopausal women B Koch et al 340 Table 2 Baseline and 12-week values of metabolic parameters

Moexipril (n = 47) Placebo (n = 48)

baseline week 12 baseline week 12

Total cholesterol (mm/dL)* 216.6 ± 33.2 219.0 ± 37.5 224.7 ± 37.9 218.9 ± 31.2 Triglycerides (mg/dL)* 154.4 ± 63.7 155.7 ± 71.7 183.8 ± 124.8 153.0 ± 64.9 HDL-cholesterol (mg/dL)* 60.5 ± 14.4 60.0 ± 14.6 61.6 ± 16.7 61.1 ± 13.5 LDL-cholesterol (mg/dL)* 124.8 ± 32.4 127.5 ± 35.7 127.4 ± 34.9 126.7 ± 31.2 Total cholesterol/HDL ratio* 3.8 ± 1.2 3.9 ± 1.2 3.8 ± 1.4 3.8 ± 1.1 Glucose (mg/dL)* 93.2 ± 17.2 91.3 ± 12.4 96.4 ± 21.4 93.3 ± 15.6

*Data as mean and s.d.

Table 3 Baseline and 12 week values of coagulation factors

Moexipril (n = 47) Placebo (n = 48)

baseline week 12 baseline week 12

PAI–1 (mg/dL)* 14.8 ± 4.4 15.5 ± 5.4 16.1 ± 4.9 15.2 ± 5.9 Lipoprotein (a) (%)* 20.8 ± 22.3 22.6 ± 24.8 23.9 ± 28.2 31.1 ± 33.4 Antithrombin III (activity, %)* 117.4 ± 15.6 113.7 ± 20.8 119.2 ± 20.4 117.1 ± 17.3 Protein C (activity, %)* 113.3 ± 26.4 114.7 ± 33.3 125.5 ± 44.3 119.4 ± 39.4 Protein S (activity, %)* 86.6 ± 6.8 85.5 ± 7.1 81.5 ± 14.5 85.4 ± 9.5 Fibrinogen (mg/dL)* 319.4 ± 110.1 286.3 ± 101.9 297.0 ± 89.7 345.8 ± 113.2

*Data as mean and s.d.

postmenopausal oestrogen therapy also showed a and fibrinogen levels when studied in postmeno- slight beneficial effect of HRT on high BP,17 most pausal women over different periods of time up to studies indicate that HRT has little effect on BP in 1 year.1–4 This short-term study, however, failed to either normotensive or hypertensive subjects.1,9 show any significant positive effect on lipid and glu- Therefore for postmenopausal women suffering cose metabolism in its placebo-treated patients as all from hypertension, concomitant long-term treat- patients were stable on their individual HRT treatment with HRT and antihypertensive drugs may be ment prior to start of study. Moreover, the current required. Up to now no data exists about the effects study showed that addition of moexipril did not of co-administrated HRT and antihypertensive drug affect any metabolic parameter. ACE inhibitors like treatment. Therefore the current study concentrated moexipril in general are not associated with any on the effect of the new ACE inhibitor moexipril vs metabolic abnormalities22–24 and this study proved placebo on BP, cardiovascular risk factors and the that this is also true in combination with HRT. Mean safety profile in women co-treated with HRT. An levels of triglycerides, total cholesterol, HDL, LDL, ACE inhibitor was chosen for investigation as ACE total cholesterol/HDL ratio and glucose remained inhibitors seem to be preferred drugs in postmeno- relatively unchanged throughout the study which pausal women as they are effective, well-tolerated indicates that with regard to cardiovascular risk fac- and free of metabolic adverse events. tors both drugs can safely be co-administered. Patients receiving moexipril for the 12-week study After menopause the haemostatic balance shifts period had statistically significant and clinically rel- towards a latent hypercoagulable state and evant mean decreases from baseline in systolic and especially fibrinogen and PAI-1, a primary inhibitor diastolic BP (−12.2/−9.9 mm Hg). These reductions of fibrinolysis, appear to rise. Both clotting factors were comparable to those reported previously for are positively linked to the risk of coronary heart the same dose of moexipril18–20 and were statisti- disease.25,26 Postmenopausal women receiving HRT cally significantly greater than for placebo (−1.6/−4.3 showed to have more favourable plasma levels of the mm Hg; P Ͻ 0.001). Compared to placebo, greater haemostatic factors PAI-1 and fibrinogen than did numbers of moexipril patients (51% vs 25%) had a those not receiving therapy.16,27,28 Thus, the putative response rate categorised as excellent. These results beneficial effect of HRT on the risk of coronary heart are similar to those obtained with moexipril in pla- disease may be partly mediated through the proven cebo controlled studies in other patient popu- changes in clotting factors and the fibrinolytic sys- lations18,21,22 and thereby indicate moexipril as tem. Changes in special coagulation parameters effective in reducing BP in postmenopausal women evaluated in this study did not reveal any statistical who concomitantly receive HRT. The effects of HRT significance neither in patients treated concomi- per se on BP were not assessed in the study, as HRT tantly with moexipril nor in patients receiving regimens were held constant throughout all of the placebo and no significant difference was observed experimental period. in the between-treatment evaluations. Nevertheless, Previous studies have demonstrated slightly mean fibrinogen levels seen in the moexipril treated favourable metabolic effects of HRT on HDL, LDL patients were moderately decreased compared to Moexipril and HRT in postmenopausal women B Koch et al 341 patients receiving HRT only (−33.6 mg/dl vs tion after oestrogen and oestrogen-progestogen replace- +35.0 mg/dl). The difference was not statistically ment. Br J Obstet Gynaecol 1992; 99 (10): 821–828. significant. As the plasma fibrinogen level is associa- 3 Hazzard WR. Interdisciplinary review of estrogen ted with both the severity and the extent of coron- replacement therapy: Estrogen replacement and car- ary, cerebral and peripheral atherosclerosis,4,26,29 diovascular disease: Serum lipids and blood pressure these results may indicate that co-administration of effects. Am J Obstet Gynecol 1989; 161 (6S): 1847– 1853. moexipril and HRT is of possible protective effect 4 Nait M, Hayashi T, Iguchi A. New approaches to the regarding that. Fibrinogen levels, however, are posi- prevention of atherosclerosis. Drugs 1995; 50: 440– tively correlated with age, smoking behaviour, dia- 453. betes, hypertension, obesity and hypercholesterolae- 5 Schneider HP, Birkhaüser M. Does HRT modify risk mia whereas alcohol intake and oestrogen of gynecological cancers? Int J Fertil Menopausal Stud replacement therapy are associated with lower 1995; 40 (Suppl 1): 40–53. fibrinogen concentrations.30–32 Therefore, further 6 Mayeaux EJ Jr, Johnson C. Current concepts in post- evaluations are necessary to ensure that this interest- menopausal hormone replacement therapy. J Fam ing finding is of real clinical relevance. Neverthe- Pract 1996; 43: 69–75. less, the fact that other investigators also showed a 7 Samsioe G. Hormone replacement therapy and cardio- favourable effect of ACE inhibitors on fibrinogen vascular disease. Int J Fertil Menopausal Stud 1993; levels33 seems to be encouraging. 38: 23–29. Overall, moexipril was well tolerated among post- 8 Lip G, Beevers M, Churchill D, Beevers DG. Do clin- icians prescribe HRT for hypertensive postmenopausal menopausal women using HRT, the adverse event 18–22 women? Br J Clin Pract 1995; 49: 61–64. rate was similar to previous moexipril studies 9 Lip GY, Beevers M, Churchill D, Beevers DG. Hormone and no new safety risks were identified during the replacement therapy and blood pressure in hyperten- course of this study. Especially, no effect of moexi- sive women. J Hum Hypertens 1994; 8: 491–494. pril on the typical postmenopausal symptoms could 10 Sarubbi B, Ducceschi V, Russo B, Di Micco G, Iacono be observed. The percentage of clinical adverse A. Sex hormones, glycolipid metabolism, and athero- events, however, was slightly higher in the moexi- genesis. Minerva Med 1995; 86: 265–273. pril than in the placebo group (70% vs 58%). The 11 Renard E, Bringer J, Jaffiol C. Sex steroids. Effects on difference may be due in part to the incidence of the carbohydrate metabolism before and after meno- cough in moexipril-treated patients. Increased pause. Presse Med 1993; 22: 431–435. cough was the only adverse event for which any sig- 12 Kleerekoper M, Sullivan JM. Osteoporosis as a model nificant difference was demonstrated between the for the long-term clinical con-sequences of the menopause. Prog Cardiovasc Dis 1995; 38: 181–188. groups (12.8% of moexipril patients vs no placebo 13 Lip GY, Beevers G, Zarifis J. Hormone replacement patients). Cough is a well documented side effect of therapy and cardiovascular risk: the cardiovascular ACE inhibitors and an expected adverse event for physicians’ viewpoint. J Intern Med 1995; 238: 389– 34–37 moexipril in the whole population. 399. Although the ability is limited to extrapolate the 14 Tonstad S et al. Efficacy of sequential hormone findings to other HRT groups than those examined, replacement therapy in the treatment of hypercholes- this study indicates that moexipril is effective and terolaemia among postmenopausal women. J Intern well-tolerated in the treatment of hypertensive, post- Med 1995; 238: 39–47. menopausal women and can safely be co-adminis- 15 Habiba M, Akkad A, al-Azzawi F. Effect of a new cycli- tered to individuals taking HRT. Nevertheless, the cal sequential postmenopausal HRT on lipoprotein, interaction of ACE inhibition and HRT during long- apoprotein and thrombophilia profile. Eur J Obstet term administration in postmenopausal women Gynecol Repord Biol 1995; 62: 89–94. remains an outstanding topic which requires 16 Scarabin PY et al. Haemostatic variables and menopausal status: influence of hormone replacement ther- further research. apy. Thromb Haemost 1993; 70: 584–587. 17 Dallongeville J et al. 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