Pharmacoepidemiology Unit, Postgraduate Medical School (University of Surrey), Guildford, Surrey, UK
1 To whom correspondence should be addressed at: Pharmacoepidemiology Unit, Postgraduate Medical School (University of Surrey), Stirling House, Stirling Road, Surrey Research Park, Guildford, Surrey GU2 7DJ, UK. e-mail: h.seaman{at}surrey.ac.uk
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Abstract |
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Key words: cyproterone acetate/ethinyl estradiol/oral contraception/utilization
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Introduction |
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Conventional medical treatments for acne act by reducing sebum production, unblocking pores, delivering antibiotics or suppressing the effects of androgens. Some combined oral contraceptives (COCs) may be helpful in alleviating acne. Whilst none of the progestogens in conventional COCs is anti-androgenic, desogestrel has low androgenic activity, as does gestodene (Speroff, 1993). Consequently, in women with acne, COC formulations containing desogestrel or gestodene are likely to be prescribed in preference to COCs containing the more androgenic progestogen, levonorgestrel.
In the UK, the anti-androgen cyproterone acetate (CPA 2 mg) combined with ethinyl estradiol (EE 35 µg) is licensed for the treatment of women with acne that is refractory to prolonged antibiotic therapy and women with moderately severe hirsutism; it also provides contraception. Acne and hirsutism are commonly associated with polycystic ovary syndrome (PCOS) (Rittmaster, 1997; Guzick, 1998
). Other common features of PCOS include obesity, secondary infertility, dyslipidaemia and insulin resistance, independent of obesity (Taylor, 1998
; Solomon, 1999
; Atiomo et al., 2000
; Kelly et al., 2000
). Some women with acne will exhibit other PCOS co-morbidities and thus present an intrinsically adverse cardiovascular risk profile.
In October 1995, the UK Committee on Safety of Medicines informed doctors and pharmacists that the risk of venous thromboembolism (VTE) amongst women using COCs containing desogestrel or gestodene was twice that amongst women using COCs containing other progestogens (Committee on Safety of Medicines, 1995). The use of COCs containing desogestrel and gestodene consequentially declined (Figure 1). Figure 2 illustrates a coincident increase in the COC market share occupied by CPA/EE (as a proportion of all COC cycle packs sold) from 1995. Trend lines for the periods 1987 to 1995 and 1995 to mid-year 2000 indicate a marked increase in CPA/EE market share after 1995.
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Materials and methods |
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The study population comprised women aged between 15 and 39 years who were registered with a general practitioner who provided data of research quality to the GPRD at any time during the study period (January 1, 1992 to December 31, 1998). Patients could join the study cohort (by registering with one of the contributing practices) or leave (by changing their doctor, as a result of death or by the doctor ceasing to contribute to the GPRD) at any time during the study period.
For each woman, her age (calculated as observation year minus year of birth) and the number of days on which was she was registered with the practice during each calendar year were calculated. The age-specific number of woman-years of observation [observed women years (OWY)] was aggregated in 5-year age bands (by summing the number of days on which each woman was registered during each calendar year of observation within each year of age and dividing by 365). COC and CPA/EE prescriptions for all women with at least 6 months prior data were identified and used to map drug use to each day in the study period (Farmer et al., 1999). Where there were prescriptions for the same product and the periods covered by the two prescriptions overlapped, the duration of overlap was added to the logical end date of the last overlapping script. Overlapping prescriptions were defined as two prescriptions where the start date of the second was within 14 days of the logical end-date of the first (represented by the start date plus duration of exposure). The 14-day period was used because any new prescription could ordinarily be started any time between 1 and 28 days after the day of issue. Non-overlapping scripts with a gap between them of more than 14 days were represented in the file as discontinuous periods of exposure, whether or not there was a change in product. In cases where there were overlapping prescriptions for different products, the exposure to the first product was truncated to the day of the switch and a new period of exposure to the switched product assumed from the subsequent day. Thus, all logically unused packs of oral contraceptives were discounted in the calculation of exposed women years (EWY).
Women with a diagnosis of acne, polycystic ovaries or PCOS were identified using appropriate OXMIS and Read codes. Because of its chronic nature, women were deemed to have acne in the year of an acne diagnosis, in the subsequent year, and in the 2 years prior to diagnosis. For women with more than one diagnosis of acne the acne period extended from 2 years prior to the first diagnosis until 1 year after the last. All women with a diagnosis of polycystic ovaries or PCOS at any time were included in the PCOS cohort. Also included were those women who at any time had three or more markers for PCOS (acne, hirsutism/alopecia, anovulation/infertility, amenorrhoea/oligomenorrhoea, obesity or endocrinological abnormalities).
A cohort of CPA/EE users was described by age and by presence of acne and/or PCOS as well as the proportionate use of CPA/EE amongst all COC use. Amongst all women with or without acne or PCOS, age-specific use of the different COCs was calculated.
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Results |
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A total of 32 889 women who had been prescribed CPA/EE between the ages of 15 and 39 years was identified. The medical record at the time of first prescription implied oral contraception as the indication in almost 44% of women; in about 35% the implied indication at the time of first prescription for CPA/EE was acne or disorders suggestive of PCOS. However, 66% of CPA/EE users had a diagnosis of acne on or at some time before the date of their first prescription for CPA/EE. Some 23% of women prescribed CPA/EE had no recorded indication for CPA/EE (an acne diagnosis, prescription for an acne treatment, PCOS-like condition) before or on the date of their first prescription for CPA/EE, and 21% had no recorded indication for CPA/EE treatment anywhere in the records. These data are limited by the data censoring imposed by registration periods on the GPRD, and may also be limited by the quality of recording. To explore the possibility that these observations might be affected by the data censoring issue, women prescribed CPA/EE for whom there was at least 2 years data prior to the first prescription for CPA/EE and at least 1 years data after the first prescription for CPA/EE were identified (n = 11 994). Of these women, 10 190 (85%) had a diagnosis of acne, PCOS or hirsutism at some time.
Altogether, 21% of women with a diagnosis of acne had been prescribed CPA/EE at some time (19 782/94 717). Of those women, 90% had a diagnosis of acne on or before the date of the first CPA/EE prescription, and the remainder had been prescribed an acne-specific treatment prior to the first CPA/EE prescription. In total, 9629 women had PCOS, and 2082 of these (22%) had been prescribed CPA/EE at some time between 1992 and 1998.
Table III shows the changes in the patterns of use of the major COC formulations and CPA/EE amongst women with and without acne. In 1994, the use of products containing levonorgestrel declined, particularly in younger women. Amongst women with and without acne there were similar patterns of use of products containing desogestrel and gestodene in all age groups. The use of CPA/EE in women with acne reached levels comparable with desogestrel and gestodene, although in women without acne the use of CPA/EE was much less. By 1996 there had been a sharp fall in the use of both gestodene- and desogestrel-based COCs by women both with and without acne and of all ages. In women with acne there was a rise in the use of levonorgestrel and CPA/EE, but the proportionate increase in the use of levonorgestrel was greater than that for CPA/EE. For example, there was a 3.6-fold increase in levonorgestrel use among 15- to 19-year-olds with acne between 1994 and 1998 compared with a 2.2-fold increase in the use of CPA/EE during the same period (P < 0.001). The proportionate increase in the use of levonorgestrel-based products was less amongst the women aged >20 years with a history of acne, but in each age group the proportionate increase in levonorgestrel use was greater than that for CPA/EE (P < 0.01). Between 1996 and 1998, the pattern changed: the use of levonorgestrel products altered little amongst women with acne, whereas the use of CPA/EE increased. In women without acne, similar increases in the use of products containing levonorgestrel by all age-groups were sustained through to 1998. The use of CPA/EE by women without acne increased only fractionally.
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Discussion |
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Several studies have found an apparent increased risk of VTE associated with exposure to CPA/EE (Farley et al., 1995; Farmer et al., 1999
; Lidegaard et al., 2002
; Parkin et al., 2000
; Vasilakis-Scaramozza and Jick, 2001
), although efforts to adjust those risk estimates for confounding have been mostly inadequate. Only in the last-mentioned study (Vasilakis-Scaramozza and Jick, 2001
) did the authors adjust for the presence of acne, hirsutism and PCOS. Because the investigators considered all CPA/EE users and a sample of levonorgestrel users, however, the population will have been a mixture of CPA/EE users more likely to have acne, hirsutism and PCOS than women prescribed COCs containing the more androgenic progestogen levonorgestrel. It is difficult to tell whether the adjusted analysis in that study would have adequately controlled for all potential confounding by acne, hirsutism and PCOS.
The present observations on changes in the pattern of CPA/EE sales and the issue of VTE risk raise important questions. First, is CPA/EE associated with an increased risk of VTE? If this is the case, then increased use of CPA/EE as a result of the pill scare would have been counterproductive. Second, is CPA/EE selectively prescribed to women with a higher intrinsic risk of VTE, associated with underlying co-morbidity and if so, will the results of the study by Vasilakis-Scaramozza and Jick have been adequately adjusted? The present analysis of secular trends in CPA/EE prescribing indicates that the proportion of CPA/EE prescribed to women with acne declined between 1992 and 1998. At the same time, the age-specific use of CPA/EE by the youngest women with a diagnosis of acne almost tripled. The proportion of CPA/EE prescribed to women with PCOS has remained fairly constant (except in older women), although the age-specific use of CPA/EE has increased considerably in younger women with PCOS.
Of particular interest are the secular trends in the use of COCs containing different progestogens in women with acne or PCOS. In younger women with acne in 1994, the age-specific use of CPA/EE and COCs containing desogestrel and gestodene was greater than the use of COCs containing levonorgestrel. In 1996, however, subsequent to the pill scare, the use of products containing levonorgestrel amongst those women with acne increased to levels comparable with CPA/EE. A similar trend was observed for women with PCOS.
The observation that in later years more CPA/EE was being prescribed to women without acne could be because the recording of acne was declining or it could also be an effect of the pill scarewomen with troublesome skin that had not been recorded as acne who, prior to October 1995 had been using the less androgenic COC formulations containing gestodene and desogestrel, switched to CPA/EE as a consequence of the pill scare.
It appears, therefore, that as a result of the pill scare women may have stopped using COCs containing desogestrel and gestodene in favour of COCs containing the more androgenic progestogen, levonorgestrel or CPA/EE. CPA/EE use has been associated with an increased risk of VTE compared with levonorgestrel (Vasilakis-Scaramozza and Jick, 2000), but it remains unclear whether this is a drug effect or because the women prescribed CPA/EE in this study have an inherently adverse VTE risk profile. The results of the present study clearly demonstrate that a large proportion of CPA/EE is prescribed to women with acne and/or PCOS, although this proportion appears to decrease with calendar time. This has implications for the evaluation of VTE risk associated with CPA/EE use: analyses should be stratified by use before versus after the pill scare, and the results should be adjusted for the presence of acne and/or PCOS. Investigators should be aware of the potential for residual confounding given that acne is probably under-recorded.
In conclusion, the morbidity of CPA/EE users needs to be more fully explored in order to understand the underlying risk profile of women prescribed CPA/EE and anticipate any future risk assessment of CPA/EE.
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References |
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Submitted on May 10, 2002; resubmitted on September 3, 2002; accepted on November 7, 2002.