Use of hormone therapy in the Hong Kong public health sector after the Women’s Health Initiative trial

K.Y. Leunga,*, M. Lingb, G.W.K. Tanga

a Department of Obstetrics & Gynaecology, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR

b Chief Pharmacist’sOffice, Hospital Authority, Hong Kong SAR

Correspondence to:

Dr. K.Y. Leung

Department of Obstetrics & Gynaecology,

The University of Hong Kong,

QueenMaryHospital.

Pokfulam Road, Hong Kong SAR.

Telephone: (852) 28553913

Fax: (852) 25173278

Email:

Abstract

Objectives: To determine the impact of Women Health Initiative (WHI) trial on the use of hormone therapy (HT) in the Hong Kong public health sector. Methods: The central prescription database of the Hospital Authoritywas used to describe the half-yearly trend in the use of HT between July2000 and December 2003.The data of hysterectomy was retrieved from another clinical database. Results: Before the publication of the WHI trial in July 2002, there was a modest decline by about 9-15% in the total number of HT usersbetween 1 July 2000 to 30 June 2002. After the publication, the decline was similar (14.4%) in the first six monthsbecauseother combined estrogens /progestogen products or tibolone was used to replace combined conjugated equine estrogens (CEE) /progestogen products. The decline was more substantial (32.4%) in the second six months, and there was no more decline in the third six months.Relative to the first half of 2002, prescriptions in the first half of 2003 declined by 69.8% for combined CEE/ progestogen products and 46.9% for CEE alone therapy. The decline was more than 46% in women aged 50 to 69, and more than 36% in women aged 35 to 50. The decline was greater in women with a history of hysterectomy (60.3%) than women without (38.6%), but was similar between gynaecology specialty (41.7%)and non-gynaecology specialty (43.9%). Conclusions: A substantial decline in the use of HT was observed after the publication of the WHI trial, though not immediately. The decline varied by formulation and women’s characteristics.

Keywords: Hormone replacement therapy; menopause; women; Hong Kong

Introduction

After the publication of the Women’s Health Initiative (WHI) trial [1] and the Million Women Study [2], there were a lot of media reporting, and many guidelines issued by boards of experts and regulatory institutions in different countries suggest a change in paradigm in prescribing hormone (HT)[3-6]. While treatment of menopausal symptoms remains the primary indication for HT, it should be used for the shortest duration and at the lowest possible dose [3]. Severe doubts exist that long-term HT is a valid option for the prevention of osteoporosis considering the risk/benefit ratio [3-6]. As a result, there has been an immediate impact on the use of HT in various countries. In the U.S., the HT prescriptions declined by 38% in July 2003 relative to months prior to July 2002 [7]. Conjugated equine estrogens (CEE) and its related products accounted for 80% of the overall decline [7]. The discontinuation of HT increased almost immediately, from 2.5% at baseline (September 1, 1999, to June 30, 2002) to 13.8% in October 2002 [8]. In New Zealand, 58% of the current users stopped taking HT [9]. In Australia, current HT user rate dropped from 28% in women over 50 years in 2000 to 10.2% in 2002 [10].

In the English literature, we have not found any report on the use of HT after WHI in theChinese population. The objective of this study was to determine the impact of the WHI trial on the use of HT in the Hong Kong public health sector, and whether the pattern of use differ by women’ s characteristics, type of HT and prescribing specialty.

Methodology

In Hong Kong, the Hospital Authority is the largest public healthcare organization that provides all inpatient and specialist outpatient clinic services to the Hong Kongpopulation. This study used data retrieved from the prescription database of the Hospital Authority, the Corporate Drug Dispensary History (CDDH) which has been described previously [11]. It includes demographic data, prescribing department, and detailed pharmaceutical information on all medications prescribed and dispensed in 36 specialist outpatient clinics of the Hospital Authority. This is a central database of the Hospital Authority and records every patient medication in a longitudinal manner. The pharmaceutical information included prescribing clinicians, drug names, dosages, formulations, quantities dispensed, dates and durations of dispensed prescriptions. All prescriptions were checked by hospital pharmacies and verified with prescribing clinicians in case of doubt.

As the WHI report was released in July 2002, all women who received at least one dispensed prescription of estrogens between July 2000 and December 2003 were selected from the CDDH. The dates of their first dispensed prescriptions of estrogens were termed the index dates. Women who received no prescriptions of estrogen forone year before the index dates were included in the study, and were observed up to March 2004.

We defined exposure to HT as at least one dispensed prescriptionof oral, transdermal or vaginal estrogens. The quantity of estrogens per prescription varied from three to nine months. The following estrogens with or without combination with progestogens were included: premelle (Wyeth, U.S., each tablet containing conjugated equine estrogens 0.625mg and medroxyprogesterone acetate 2.5mg), kliogest (Novo Nordisk, Denmark, each tablet containing estradiol 2mg and norethisterone acetate 1mg), femoston (Solvay Pharmaceuticals, Canada, one tablet containing estradiol 2mg for the first 14 days, followed by one tablet containing estradiol 2mg and dydrogesterone 10mg for the next 14 days), dilena (Organon, The Netherlands, one tablet containing estradiol valerate 2mg for the first 11 days, followed by one tablet containing estradiol valerate 2mg and medroxyprogesterone acetate 10mg for the next 10 days), premelle cycle (Wyeth, U.S., one tablet containing conjugated equine estrogens 0.625mg for the first 14 days, followed by one tablet containing conjugated equine estrogens 0.625mg and medroxyprogesterone acetate 5mg for the next 14 days), prempak (Wyeth, U.S., one tablet containing conjugated estrogens 0.625mg for the first 11 days, followed by one tablet containing conjugated estrogens 0.625mg and one tablet containing medrogesterone 5mg for the next 10 days), premarin (Wyeth, U.S., each tablet containing conjugated equine estrogens 0.3mg, 0.625mg or 1.25mg), estrofem (Novo Nordisk, Denmark, each tablet containing estradiol 2mg), progynova (Schering AG, Germany, each tablet containing estradiol valerate 2mg), Estraderm (Novartis, Switzerland, transdermal continuous estradiol 25 or 50 μg/day), estracomb (Novartis, Switzerland, transdermal continuous estradiol 50 μg/day with norethisterone acetate 0.25mg during the last 14 days of a 28 days cycle), dermestril (Rotta Pharmaceuticals, Italy, transdermal continuous estradiol 50 μg/day), oestrogel (Besins International, Belgium, transdermal continuous estradiol 50 μg/day), evista (Eli Lily, U.S., each tablet containing raloxifene HCL 60mg), livial (Organon, The Netherlands, each tablet containing tibolone 2.5mg), vaginal premarin cream (Wyeth, U.S. each tube containing 42.5g oestrogens conjugated vaginal cream) and dienoestrol (Cilag, Switzerland, each tube containing 78 g vaginal cream 0.01%).

From the prescription database, we collected data of variables including age, types of hormones, routes of delivery, and dose of estrogen, prescribing specialty at the index date, and Hong Kong identity number (ID). By inputting the personal ID, a unique identification number, into the Clinical Management System database which is a routine clinical information system of the Hospital Authority, we checked whether the procedure coding of hysterectomy was added before the prescription of HT. The procedure coding was directly entered by medical staff into the Clinical Management System.

Statistical analysis

We used PC version 10.1 of the Statistical Package for Social Science for statistical analysis. The number of HT users was reported in 6-month intervals. For analysis, HT preparations were classified into eight groups: (a) conjugated equine estrogens (CEE) including premarin 0.3mg, 0.625mg and 1.25mg; (b) other oral estrogens including progynova and estrofem; (c) oral combined therapy with CEE including premelle, premelle cycle, and prempak; (d) other oral combined therapy including dilena, activelle, trisequens, femoston, and kliogest; (e) Tibolone, (f) Raloxifene; (g) transdermal estrogens containing estraderm 25 and 50, estracomb, dermestril, and estrogel; and (h) vaginal estrogen cream. In each 6-month interval, the age group, history of hysterectomy, prescribing specialty, and the group of HTwere reported.

Results

The prescription pattern

In examining half-yearly trends in the HT users, four phases of prescription practice patterns are apparent (Table 1 and Figure 1). From 1 July 2000 to 30 June 2002, there was a modest decline by about 9-15% in the total number of HT users in every 6-month. After the publication of WHI trial in July 2002, the decline was similar (14.4%; 95% CI, 12.9% - 15.9%) in the first six months, but more substantial (32.4%; 95%CI, 30.3% - 34.5%) in the second six months. There was no more decline in the third six months.

Relative to the first half of 2002, the decline in the HT prescriptions in the first half of 2003 was more than 46% in women aged 50-69, and more than 36% in women aged 35-50 (Figure 2). Besides, the decline was greater in women with a history of hysterectomy (54.5%; 95% CI, 46.7%- 62.3%) than women without (41.6%; 95%CI, 39.4%- 43.8%). However, the decline in HT prescriptions by gynaecology specialty (41.7%; 95% CI, 39.4%- 44.0%) was similar to that by non-gynaecology specialty (43.9%; 95% CI, 41.4% - 46.5%).

Types and doses of hormone therapy

The decline in HT prescriptions varied by types and doses (Table 2 and Figure 3). From 1 July 2000 to 1 July 2002, oral estrogens, in particular, CEE and its related products dominated HT prescribing for it had been the main HT prescribed in the Hospital Authority [11]. Following the release of WHI trial in July 2002, there was a substantial decline by 43.5% in the prescriptions of combined CEE/ progestogen products and a modest declineby 22.4% in the prescriptions of CEE alonetherapy in the second half of 2002. On the other hand, there was a substantial increase in prescription by 57.5% and 61.1% in other combined HT preparations and tibolone respectively. The vaginal prescriptions remained relatively constant. In the first half of 2003, a decline in the prescriptions of all preparations except raloxifene was observed. There was a further substantial decline by 44.7% in the prescriptions of combined CEE/ progestogen products and a declineby 31.6% in the prescriptions of CEE alone therapy. In the second half of 2003, there was a substantialincrease by 100.0% in the prescriptions of raloxifenebut the absolute numbers were small (Table 2). There was a small increase by 13.8% in the prescriptions of combined CEE/ progestogens products. On the other hand, there was a further decline by 29.9% in the use of other combined HT preparations. As a result, oral estrogens, in particular CEE and its related products,still dominated HT prescribing, though to a much less extent than before.In addition, the percentage of low dose HT increased from 1.7% in the first half of 2002 to 3.4% in the second half of 2003.

Relative to the first half of 2002, prescriptions in the first half of 2003 declined by 69.8% for combined CEE/ progestogen products and 46.9% for CEE alone therapy. These two groups of products alone accounted for 72.0% of the overall decline in HT prescriptions observed over the same period.

Discussion

Consistent with the studies on Caucasians [7, 12], the release of data from Heart and Estrogen/Progestin replacement Study (HERS) [13,14] was associated with a modest decline in the number of new HT users in the Hong Kong public health sector, whereas the release of the principal findings from the WHI trial was associated with a more substantial decline. We agree with the explanations given by Jennifer et al [12]. First, the WHI findings were more widely publicized than the HERS findings, and were intended for healthy postmenopausal women. Second, WHI trial was stopped prematurely suggesting more negative impact while HERS was conducted for the entire study period. Third, the dissemination of new evidence (the HERS findings followed by WHI findings) may be cumulative, particularly when the evidence conflicts with current practices. Fourth, in contrast to the HERS investigators, the WHI investigators were more decisive and definite in their conclusion: ‘this regimen should not be initiated or continued for primary prevention of coronary heart disease’ [1].

Interestingly, after the publication of the WHI trial in July 2002, the decline in the number of HT users was modest (14.4%) in the first six months, but substantial (32.4%) in the second six months, and then no more decline in the third six months. In contrast to other studies [7-10], the substantial decline in the use of HT in Hong Kongdid not occur immediatelybecause the initial response was to use alternative combined estrogens /progestogen products or tibolone. This response was similar to the practice in Belgium in which physicians tend to prescribe another HT regimento replace CEE and medroxyprogesterone [15]. The more marked decline in the use of HT in the second six months might be due to the realization by doctors that there is no evidence to support the safety of other HT. Besides, it might take time for new evidence to sink in.

Our findings suggest a rapid response to clinical trial evidence and revised guidelines. Physicians rapidly abandon well established therapies when studies show harm [16,17 ]. Like another study [7], relative to the first half of 2002, prescriptions in the first half of 2003 declined by 69.8% for combined CEE/ progestogen products and 46.9% for CEE alone therapy. There was an increase in the use of low-dose HT probably for the relief of symptoms and raloxifene for the management of osteoporosis.

In contrast to other studies [18], there was no increase in the use of transdermal estrogens. The latter was not preferred probably because of the hot and humid climate in Hong Kong which may account for adverse skin reaction [11]. There might be a cosmetic reason for not wishing to have a patch on the body [11].

Although results from the WHI and similar trials cannot be extrapolated to women with premature menopause before the age of 45, and there is no need at present to change our usual practice of prescribing HT to these women [19], we found a pronounced decline in the use of HT among women older than 50 as well as women aged 35 to 50. The decline in the use of HT in women younger than 40will result not only in the suffering of menopausal symptoms, but also the increased risk for osteoporotic fracture. The implication is great especially in the Asia population in which osteoporosis is a growing problem.

Although the WHI findings apply to women taking continuous estrogen and progestin regimens, we found a substantial decline (60%) in the use of CEE alone therapy as well and a pronounced decline in the percentage of HT (typically unopposed estrogen) prescribed to women with a history of hysterectomy. These findings may reflect women’s choice of not starting HT, or doctors’ conservative attitudes towards prophylactic oophorectomy [20].The publication of estrogen-only arm of WHI in April 2004 [21]might swing the pendulum in the use of HT in hysterectomised women and prophylactic oophorectomy.

It seems that the impact on the use of HT in Hong Kongdiminished 12 months after the publication of WHI trial. The latter was no longer reported in the local media. In the second half of 2003, the number of HT users remained relatively constant compared to the first half of 2003. In addition, a small increase in the prescriptions of combined CEE/ progestogens products was observed. CEE and its related products, constituting about 70% of all oral HT, still dominated HT prescribing, though to a less extent than before (more than 80% in the second half of 2002). The level of use of HT may reflect the need of the preparation to treat hot flush and dry vagina. Reflected by the percentage increase in the prescription of vaginal cream (Table 2), dry vagina would be an important indication for HT so as to improve the quality of life.

Previously we [11] and another investigator [22] reported that better compliance rate was observed when HT was prescribed by gynaecologists rather than family physicians. One of the possibilitiescould be that women felt that gynaecologists have knowledge and tools to detect major side effects and their reassurance might translate into better information on risks and benefits [22]. However, in the present study, thedecline in HT prescriptions by the gynaecology specialty was similar to that by non-gynaecology specialty after the release of WHI trial.We postulate that there was no much difference in the quantity and quality of information given to women after the publication of WHI trial between gynaecologists and non-gynaecologists.

There are limitations in the Hospital Authority dispensary database to (a) identify the reasons for taking HT, (b) differentiate between starting and maintaining HT, and (c) retrieve detailed clinical information. In the present study, we did not investigate the reasons for discontinuation of HT. Only the spatial relationship between the use of HT and the release of WHI report is examined.

In conclusion, after the publication of the WHI trial in July 2002, the decline in the number of users of HT in the Hong Kong public health sector was modest (14.4%) in the first six months, but substantial (32.4%) in the second six months, and then no more decline in the third six months.Relative to the first half of 2002, prescriptions in the first half of 2003 declined by 69.8% for combined CEE/ progestogen products and 46.9% for CEE alone therapy. The decline varied by formulation,women’s age and history of hysterectomy.
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    Table 1

Hormone therapy (HT) users by characteristics and by 6-month interval (from 1 Jul 2000 to 31 Dec 2003)