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Pii: s0378-5122(01)00255-9Effect of postmenopausal hormone replacement on Peter Angerer *, Stefan Sto¨rk, Wolfgang Kothny, Clemens von Schacky Klinikum der Uni6ersita¨t Mu¨nchen, Institut und Poliklinik fu¨r Arbeits- und Umweltmedizin, Medizinische Klinik-Innenstadt, Ziemssenstraße 1, 80336 Mu¨nchen, Germany Received 26 January 2001; received in revised form 9 July 2001; accepted 16 July 2001 Abstract
Objecti6es: On the basis of epidemiological and experimental data, it has been supposed that hormone replacement therapy (HRT) inhibits atherosclerosis in postmenopausal women. This randomized controlled trial examinedwhether 1 mg 17b-estradiol daily, combined cyclically with 0.025 mg gestodene in every month (HRT 1), or in everythird month (HRT 2) slows the increase of intima-media thickness in femoral arteries compared with no HRT.
Methods: Healthy postmenopausal women (n = 321) with an increased risk for future vascular disease as indicated by\1 mm of intima-media thickness in the carotid arteries were equally randomized to one of the three groups for 48weeks. Ultrasound scans of femoral arteries were recorded at study start and study end, together with a thoroughclinical examination and laboratory work-up. Results: Complete scans were obtained in 260 of the 264 subjects whoparticipated until study end. Mean maximum intima-media thickness of four femoral artery segments (common andsuperficial, both sides) was 0.93 90.37 mm (mean9S.D.) at study start. It increased by 0.0290.05, 0.0290.05, and0.03 90.05 mm in the HRT 1, HRT 2 and no HRT groups, respectively (HRT 1 versus no HRT, HRT 2 versus noHRT; both P \0.2). Compared with no HRT, HRT significantly lowered follicle stimulating hormone, low-densitylipoprotein cholesterol, and fibrinogen. Conclusions: In this 1-year trial, irrespective of the progestogen dose used,HRT with 1 mg 17b-estradiol did not inhibit progression of femoral artery atheroslerosis in postmenopausal womenwith subclinical vascular disease. 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: 17b-Estradiol; Hormone replacement therapy; Atherosclerosis; Femoral arteries; Intima-media thickness; Randomizedcontrolled trial Abbre6iations: ABI, ankle/brachial (systolic blood pressure) index; CAD, coronary artery disease; FSH, follicle stimulating hormone; HDL, high-density lipoprotein cholesterol; HRT, hormone replacement therapy; IMT, intima-media thickness; LDL,low-density lipoprotein cholesterol; PAD, peripheral arterial disease.
* Corresponding author. Tel.: + 49-89-5160-2440; Fax: + 49-89-5160-4444.
E-mail address: (P. Angerer).
0378-5122/02/$ - see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 7 8 - 5 1 2 2 ( 0 1 ) 0 0 2 5 5 - 9 P. Angerer et al. / Maturitas 41 (2002) 51 – 60 1. Introduction
against Atherosclerosis (PHOREA) trial was ran-domized, controlled, observer blind, and con- Although several investigations have addressed ducted according to the International Conference the question of whether hormone replacement for Harmonisation — guidelines for Good Clini- therapy (HRT) for postmenopausal women slows cal Practice (ICH-GCPP). PHOREA investigated progression of atherosclerosis, the answer still re- the effect of two different HRT regimens com- mains unclear. Some epidemiological studies sug- pared with no HRT on intermediate endpoints of atherosclerotic disease and on risk factors for significant coronary artery disease , and for atherogenesis. The primary outcome measure of atherosclerosis in the carotid arteries [2 – 4], the part of the trial that examined progression of whereas others observed no beneficial effect of atherosclerosis was the averaged change of in- HRT . Randomized controlled trials demon- tima-media thickness (IMT) of six segments of the strated that oestrogen alone or combined with carotid arteries. The change of IMT in the different doses of progestogen does not inhibit femoral arteries was the secondary outcome mea- progression of atherosclerosis in coronary or sure. The study design and the results of the carotid arteries of postmenopausal women [6,7].
primary outcome measure have been reported in Data on HRT and atherosclerosis in peripheral arteries of postmenopausal women are scarce. Re- Eligibility criteria included female gender, post- cently, in the Rotterdam Study, a lower risk for menopausal status as defined by last regular haemodynamically relevant peripheral arterial dis- bleeding or surgical menopause \1 year ago; or, ease in previous long-term users of HRT was in the case of hysterectomy, follicle stimulating observed . However, in the randomized Heart hormone (FSH) levels \40 IU/l, age between 40 and Oestrogen/Progestogen replacement study and 70 years, and IMT \1 mm in at least one of (HERS), peripheral arterial disease (PAD) events the predefined segments of the carotid arteries as were not reduced by HRT . PAD is frequent in detected by high-resolution ultrasound. Excluded postmenopausal women, increasing with age were women with malignant disease, those for [8,10]. It causes pain [8,11] and it indicates a whom HRT was necessary or was intolerable, substantially increased cardiovascular mortality women with myocardial infarction within the past . Involvement of proximal (e.g. femoral) arter- 6 months or with coronary artery disease (CAD) ies was associated with a higher mortality than that required treatment for angina, history of involvement of distal (e.g. tibial) arteries .
ischaemic cerebrovascular disease, blood pressure In this randomized, controlled trial, we investi- greater than 200/110 mmHg after 5 min rest, with gated the effect of 17b-estradiol combined with any other contraindication against HRT or with standard dose and with low dose progestogen any other serious illness. All subjects gave in- (gestodene) on progression of atherosclerosis dur- formed consent. The study was approved by the ing 48 weeks as monitored by serial ultrasound ethics committee of the faculty of medicine of the measurements. In the present paper, we report on the progression of atherosclerosis in the femoral Subjects were randomly allocated to three arteries. The hypothesis was that the increase of groups. The HRT 1 group received tablets con- intima-media thickness would be smaller in both taining 1 mg 17b-estradiol each day, with addition HRT groups compared with the control group.
of 0.025 mg gestodene on days 17 – 28 of each4-week cycle (standard dose progestogen). TheHRT 2 group received oestrogen following the 2. Methods
same regimen, but gestodene was added in eachthird cycle only (low dose progestogen). The no HRT group received no oestrogen and noprogestogen at all. The duration of treatment was 48 weeks, corresponding to 12 cycles. An indepen- P. Angerer et al. / Maturitas 41 (2002) 51 – 60 dent clinical research organization (Biometrisches IMT in sufficient quality, i.e. clear blood- Zentrum fu¨r Therapiestudien, Munich, Germany) intima and media-adventitia boundaries over the monitored the adherence to the study protocol, full length of the segment, was recorded digitally.
verified all source data, and provided the verified The examination was repeated at study end ac- database. It also ensured blinding of the ultra- cording to the same protocol, using the same angles of interrogation. Only the far wall was Subjects were seen in the university hospital considered for calculation of outcome measures outpatient centre at study start, and in weeks 12, since ultrasound measurement of the near wall 22, and 48. At study start and study end, arterial underestimates the true histological thickness and IMT was documented by ultrasound examination.
proper visualization is often difficult [5,15]. The At each visit, history was taken and a physical measurement of the carotid IMT has been de- examination was performed, including blood pres- scribed previously . In brief, for the common sure measurements in recumbent position at rest and internal carotid artery and the carotid and extensive laboratory work-up. General health bifurcation, left and right side, the maximum IMT advice and advice for treatment of risk factors of the far wall was determined at study start and followed the guidelines of the American Heart at study end, using the same angles of interroga- Association . The study medication was dis- pensed at each visit, and all blisters and all re- To ensure blindness of sonographers with re- maining tablets were collected during subsequent spect to treatment, their contact with the partici- visits. Subjects documented daily study drug in- pant was limited to the ultrasound examination.
take and vaginal bleeding in a diary. Com- On all recordings, a five-digit random number pliance with medication was assessed by this di- replaced the name of the subject and the date of ary, by FSH measurement, and by pill count. The examination. The keyed list containing names, intention-to-treat population was defined as all dates and five-digit numbers was stored at the randomized subjects who completed both ultra- clinical research organization until the end of the trial. Sonographers (W.K. and P.A.) had com- ulation was defined as all subjects who did not pleted a training program with more than 1000 violate any eligibility criteria at randomization or scans of carotid and femoral arteries prior to the during the study, took at least 91.7% (11 cycles)of the study medication and did not use any trial. All readings were carried out by W.K. to additional HRT (including topical application) avoid interobserver variation. In addition, to as- sess reproducibility, scans were performed in 30subjects in identical manner as already described within 1 week after the baseline or follow-up scanand evaluated blindly. Reproducibility for the Atherosclerosis was measured as thickness of femoral arteries, expressed as the mean difference the intimal and medial layers of the artery as between two measurements and its standard devi- visualized by high-resolution 7.5 MHz ultrasound ation , was: mean maximum IMT, − 0.01 9 (Apogee CX Color; ATL, Bothel, WA, USA) .
0.06 mm; single maximum IMT, − 0.01 90.06 An RMI 413 tissue-mimicking phantom was used to monitor instrument performance. Subjects IMT was measured twice from the digitized rested recumbent for the examination. For the image, at the site of its maximum thickness within measurement of the femoral IMT, the probe was each segment, and both results were averaged.
held in an anterior – posterior position, and two The software NIH-Image (National Institutes of segments were visualized at both sides: the distal Health, Bethesda, USA) was used, on a Power 10 mm of the common femoral artery, and the Macintosh 8100/80 with a high-resolution screen.
proximal 10 mm of the superficial femoral artery.
The mean of the maximum far wall IMT values The optimal longitudinal view of the maximum for both femoral artery segments on both sides P. Angerer et al. / Maturitas 41 (2002) 51 – 60 was calculated as mean maximum IMT per sub- able. In the no HRT group, 72 subjects were ject. The highest IMT of all femoral segments was considered as valid cases, 69 in the HRT 1 group, the single maximum IMT per subject. In addition, and 73 in the HRT 2 group (i.e. 214 of 264) the mean of the maximum far wall IMT values of according to the criteria described in Section 2 both sides was calculated for the common and the (valid case population). Of these 214, 210 had superficial femoral artery per subject separately.
complete femoral artery ultrasound scans.
Fifty-seven subjects ended participation prema- turely. Compared with subjects who completedthe trial in the respective groups, those who Sample size estimation was based on similar stopped in the no HRT group had a higher num- ber of hysterectomies and longer duration of pre- atherosclerosis progression : with reference to vious HRT, and those who stopped in the HRT 2 what had been demonstrated in another primary group had a lower number of hysterectomies and prevention trial, the annual atherosclerotic pro- shorter duration of previous HRT. At baseline, in gression rate of IMT was estimated to be 0.04 9 the femoral arteries mean maximum IMT was estimated to result in a 50% slowing of progres- 1.51 90.82 mm. In the carotid arteries, the re- sion. To achieve a power of 90% and a P value of spective values were 1.18 90.19 and 1.8990.55 0.05, 80 subjects per group were required, result- mm. Thus, participants who discontinued did not ing in 320 subjects altogether after adding the differ from those who completed the trial until estimated drop-out rate of 33% .
Normality and homogeneity of variances of the Among the 264 subjects who participated until outcome measures were assessed by Lilliefors’ test study end, no difference between treatment and Levene’s test, respectively. Differences be- groups was observed at study start, except for tween HRT 1 and no HRT, and between HRT 2 fewer hysterectomies in the no HRT and HRT 2 group compared with HRT 1 (Table 1).
sample t-test or chi-squared test, according to thenature of the data. For the analysis of the ultra- sound outcome measures, the P value was ad-justed for multiple comparisons according to the At baseline, 166 subjects (64%) had a femoral Bonferroni – Holm method. For other outcome measures, no adjustment was made since the anal- segments examined. In the intention-to-treat anal- ysis was exploratory. A P value B0.05 was ysis, overall mean maximum IMT increased by defined as significant. All calculations were per- 0.023 90.050 mm (mean of all groups). All differ- formed on a Power Macintosh 7600/120 using ences of change of the femoral IMT as presented SPSS 6.1.1 (SPSS Inc., Chicago, IL, USA).
in Table 2 were not statistically significant (all Pvalues \0.2).
Results of the valid case analysis of the femoral 3. Results
artery outcome measures were almost identical tothe results of the intention-to-treat analysis (data Of 321 subjects randomized, 264 remained in the study and had a second ultrasound examina- tion after 48 weeks (intention-to-treat popula-tion). Their baseline characteristics are presented No subject reported symptoms suggestive of in Table 1. In 260 of 264 subjects, both scans of PAD (e.g. claudication), neither at study start nor the femoral artery IMT were completed and read- P. Angerer et al. / Maturitas 41 (2002) 51 – 60 (Table 3): FSH decreased by approximately one- More subjects in the no HRT group took anti- third in the HRT groups, whereas it increased hypertensive medication during follow-up com- slightly in the no HRT group. Low-density lipo- pared with HRT 1. Fewer subjects in the HRT 1 protein cholesterol (LDL) and fibrinogen de- group compared with the no HRT group were current smokers at study end. Changes of other slightly in the no HRT group. High-density lipo- factors with a potential effect on IMT (plasma protein cholesterol (HDL) decreased slightly in all glucose, blood pressure, physical activity, and groups with a significantly smaller change in the lipid lowering medication) were similarly dis- HRT 2 group. There was a small increase in tributed among treatment groups during follow- weight in the no HRT group, whereas weight Table 1Baseline data, intention-to-treat population Subjects on antihypertensive drugs, n Subjects on lipid lowering drugs, n Data with plus–minus values are means 9S.D. CA, Carotid arteries; FA, femoral arteries; P, plasma; S, serum. * Comparison ofno HRT versus HRT 1, PB0.001; comparison of HRT 1 versus HRT 2, P=0.050.
P. Angerer et al. / Maturitas 41 (2002) 51 – 60 Table 2Femoral artery IMT: absolute change from study start to study end DMean maximum IMT, common femoral artery, mm DMean maximum IMT, superficial femoral artery, mm Study end minus study start (positive values indicate increase), intention-to-treat analysis. HRT 1 versus no HRT and HRT 2 versusno HRT, all comparisons P\0.2. Data with plus–minus values are means9S.D.
3.4. Exploratory subgroup analysis had vascular risk factors. LDL and fibrinogendecreased by HRT within the expected range. No In order to detect any influence of uneven difference in progression was observed between distribution of baseline characteristics on change the standard dose and the low dose progestogen of IMT in femoral arteries, exploratory analysis was performed in the following subgroups: previ- Subjects in this study had atherosclerosis but ous hysterectomy (yes/no), history of current less than 3% had experienced any clinical event smoking (yes/no), antihypertensive medication at (e.g. myocardial infarction or coronary interven- any time during the study (yes/no), and lipid tion). From the clinical point of view, this repre- lowering medication at any time during the study sents a primary prevention situation. However, (yes/no). In any subgroup, change of femoral these subjects carry a high risk for future vascular disease events [19,20]. On the basis of epidemio- logical observations, it was suggested that healthywomen at increased cardiovascular risk might 3.5. Relationship between progression of carotid benefit most from HRT . For women with manifest CAD, two large randomized interventiontrials Change of the mean maximum IMT of the six equine estrogens combined with medroxyproges- carotid segments and of the two femoral segments terone acetate do not prevent cardiovascular correlated significantly, in all subjects (r = 0.36, events  and do not slow progression of angio- P B0.001): in HRT 1, r=0.30, P=0.007; in graphically observed coronary atherosclerosis .
HRT 2, r = 0.44, P B0.001; in no HRT, r=0.39, The latter finding was independent from the addi- tion of medroxyprogesterone acetate , whichhas been accused of antagonizing the beneficialeffect of estrogens [21 – 23]. In response to these 4. Discussion
new findings, the perspective has shifted to HRTas a means of primary prevention . However, Combined sequential HRT with 17b-estradiol there are no trials with clinical endpoints to cor- and gestodene for 48 weeks did not slow progres- roborate this concept. We and other workers have sion of subclinical atherosclerosis in femoral ar- recently shown that HRT does not slow progres- teries. In this randomized controlled trial, all sion of carotid atherosclerosis in clinically healthy subjects were at increased risk for vascular disease women [7,25]. Pooled data from randomized trials events as defined by the inclusion criterion of \1 that focused mostly on bone-related outcome mm IMT in at least one segment of the carotid measures in primarily healthy women showed a arteries [19,20]. In addition, 64% of subjects had non-significantly higher odds ratio for cardiovas- \1 mm IMT of the femoral arteries and most cular events in women taking HRT compared P. Angerer et al. / Maturitas 41 (2002) 51 – 60 with those taking placebo . Peripheral artery gression could be explained by carotid artery IMT atherosclerosis is an established independent in- termediate endpoint for cardiovascular morbidity To the best of our knowledge, the present study and mortality [13,27,28]. The lack of a favourable is the only randomized trial to date that examined effect in the present trial contributes to the recent the effect of HRT on femoral artery atherosclero- findings that do not support the use of HRT in sis. It is in line with the results of HERS where no primary prevention of cardiovascular disease.
reduction of incident peripheral arterial events In addition to its role as intermediate end point was found . Our results did not confirm obser- for vascular disease mortality, atherosclerosis of vations from the epidemiological Rotterdam the lower extremities is a disease entity of its own.
Study that HRT given for at least 1 year was The highly significant correlation between pro- associated with a decreased likelihood for PAD as gression of carotid and femoral IMT indicates defined by a low ankle/ brachial systolic blood that both can be understood as sequelae of a pressure index (ABI) . Potential bias in epi- common generalized disease. However, only 13% demiological studies would exaggerate the benefit (r2) of the variation of femoral artery IMT pro- of HRT . Alternatively, since ABI compares Table 3Other characteristics: absolute change from study start to study end DBlood pressure systolic, mmHg −6.5911.0 Mean of all follow-up visits minus study start unless otherwise indicated (positive values indicate increase). Data with plus–minusvalues are means 9S.D.
P. Angerer et al. / Maturitas 41 (2002) 51 – 60 systolic blood pressure in the tibial artery and in a slightly smaller decrease of LDL, a small de- the brachial artery, it may be influenced by several crease or no change of HDL, but a more desirable mechanisms as there is proximal atherosclerotic change in fibrinogen. The biological effects of the lumen narrowing, perfusion through collateral ar- HRT used in the present trial are thus comparable teries, and stiffening of the artery that must be compressed by the blood pressure cuff . HRT Other limitations of our study have been dis- may influence some of these processes by vasodi- cussed in detail previously  and are therefore lation, by improved endothelial function or by only briefly mentioned: subjects and the physi- reduced arterial stiffness [30 – 32]. Stiffness seems cians taking care of them in the outpatient clinic to be especially altered in smokers , who ac- were not blinded, but the ultrasound scans were count for a large proportion of women with PAD performed and read by blinded personnel, thus . The lower prevalence of pathological ABI was reducing the likelihood of bias to a minimum.
observed in women who predominantly had used Visible thickening of the arterial wall and reduc- unopposed oestrogen . In our study, an antago- tion of lumen by atherosclerosis is one, although nizing action of progestogen is unlikely to be important, pathomechanism of atherosclerotic responsible for oestrogen’s lack of effect since no disease. However, we did not study endothelial difference was demonstrated in the group that function or other phenomena that may also be important for the pathology of the vessel wall and progestogen. The favourable influence on LDL may be favourably influenced by oestrogen .
and fibrinogen was similar in both HRT regimens.
In conclusion, for healthy postmenopausal However, the increase of IMT in femoral arter- women at increased risk for vascular disease ies was somewhat smaller in the HRT groups than events, this randomized trial demonstrated that in the no HRT group. Sample size had been HRT with 1 mg 17b-estradiol did not slow pro- estimated for the expected change of IMT in the gression of atherosclerosis of femoral arteries.
carotid arteries, which was the primary outcome Conversely, HRT decreased LDL and fibrinogen measure . Consequently, if we speculate that as expected. This negative finding is in line with atherosclerosis in femoral arteries progresses more other recent randomized trials. Thus, evidence is slowly than in carotid arteries, a larger sample mounting that oestrogen replacement does not size or a longer duration of treatment would have substantially slow progression of atherosclerosis.
been necessary. If we hypothesize that the ob-served difference was not explained by chance (aswe assume on the basis of the P value), a sample Acknowledgements
size of 500 subjects per group would have beennecessary to obtain a power of 90%. Thus, our study may have missed an unexpectedly slow ef- fect of HRT on femoral atheroslerosis.
made possible by Schering AG, Berlin. The study The dose of 17b-estradiol recommended for medication was also provided by Schering AG.
postmenopausal HRT is 1 or 2 mg . Lipo-protein changes are similar with large or small References
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