Department of Pharmacoepidemiology, Postgraduate Medical School (University of Surrey), Stirling House, The Surrey Research Park, Guildford GU2 7DJ, UK
1 To whom correspondence should be addressed. e-mail: h.seaman{at}surrey.ac.uk
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Abstract |
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Key words: acne/cyproterone acetate/ethinyl estradiol/polycystic ovary syndrome/venous thrombosis
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Introduction |
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Recent observational studies have suggested that CPA/EE may be associated with an increased risk of venous thromboembolism (VTE) compared with conventional combined oral contraceptives (COCs) (Farmer et al., 1999; Parkin et al., 2000
; Vasilakis-Scaramozza and Jick, 2001
; Lidegaard et al., 2002
). The use of CPA/EE in the UK more than doubled following the pill scare of 1995, possibly because women with androgenic skin conditions were switched to CPA/EE from COCs containing less androgenic progestogens (desogestrel and gestodene).
Because the VTE risk profile of women who have androgenic skin conditions (or PCOS) differs from that of other women of the same age, we conducted a cohort analysis and a casecontrol study to estimate the risk of VTE associated with CPA/EE in such women.
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Materials and methods |
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The study population was drawn from a cohort of women who had ever had a diagnosis of acne, hirsutism or PCOS. Women with PCOS were identified as those with an unequivocal diagnosis of PCOS or the identification of polycystic ovaries by ultrasound examination, and also any women with three or more markers for PCOS (acne, hirsutism/alopecia, obesity, anovulation/infertility, amenorrhoea/ oligomenorrhoea or endocrinological measures). From that population we selected women who at any time between January 1, 1992 and December 31, 1998 were aged 1539 years. Women who had a VTE (pulmonary embolism or deep vein thrombosis) confirmed by evidence of anticoagulant therapy were identified and the event date taken as the date on which the first symptoms were recorded. These symptoms included haemoptysis, shortness of breath, chest pain and swelling or redness of a limb. Prescriptions for conventional OCs and CPA/EE were identified and used to map drug use to each day in the study period (Farmer et al., 1999). We were thus able to ascertain for each case her OC exposure status on the VTE event date. Total exposure to CPA/EE and conventional OC products in terms of exposed women years was used to calculate rates of VTE stratified by age.
For the casecontrol study, up to seven controls were randomly selected from the study population matched to the case by event (index) date, general practice and year of birth. The GPRD records for cases and controls were reviewed and relevant medical and drug exposure information recorded. Women with chronic illness, which included diabetes, asthma, systemic lupus erythematosus, Crohns disease/ulcerative colitis and thyroid and renal disease, were identified. The use of conventional OCs and CPA/EE amongst controls was described with reference to the index date as before. The period of uninterrupted exposure prior to the event/index date for each case and control exposed to a conventional COC or CPA/EE was calculated. Also, because it appeared that the use of CPA/EE in the UK increased considerably following the pill scare of 1995 (Seaman et al., 2003), we partitioned the study population according to whether the event/index date was prior to or after 1995.
Differences in the length of time cases and controls were registered with practices contributing to the GPRD could have biased our observations with regard to assignation of acne status. In order to address this potential confounding we performed a sub-group analysis including only those cases and controls with at least 2 years (760 days) registration after the index date and at least 1 years (365 days) registration prior to the index date.
Conditional logistic regression models were built to provide risk estimates for VTE associated with CPA/EE adjusted for potential confounding.
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Results |
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Discussion |
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We have demonstrated an increased risk of VTE associated with the use of CPA/EE in women with acne, hirsutism or PCOS. The estrogen component of the CPA/EE formulation in current use and used by women in our study barely exceeds that of the majority of conventional COCs. To our knowledge no published research has associated CPA with VTE and as far as we are aware there is no biological plausibility for any such relationship. The depletion of susceptibles principle maintains that patients who remain on a drug are those who can tolerate it whilst those who cannot are selected out of the population at risk (Yola and Abenhaim, 1994). Thus risk per unit of time depends both on history of prior exposure and on duration of exposure. Whilst mindful of the limitations imposed by censoring of data held on the database (a patients medical and drug exposure experience prior to or after periods of registration with a contributing practice are unknown) and the small numbers of exposed cases, we found that, compared with long-term use (>6 cycles), there seemed to be an increased risk for VTE in short term users (
6 cycles) of conventional COCs but not users of CPA/EE. Thus we did not find evidence to support the possibility that the increased VTE risk in women using CPA/EE was associated with depletion of susceptibles, even when we restricted the analysis to CPA/EE-exposed cases and controls who had no evidence of prior oral contraceptive use. The growth of the GPRD in longitudinal data will allow us to explore further the duration of exposure issue in future work.
The observation that the use of CPA/EE in the UK increased considerably following the pill scare of 1995 should be considered in an assessment of VTE risk in women prescribed CPA/EE. As part of the analysis, therefore, the data were partitioned according to whether the VTE occurred prior to or after 1995conditional logistic regression analysis revealed no difference in the risk estimates for VTE associated with CPA/EE before or after the pill scare.
Women with an acne diagnosis at any time in the medical records contributed to our study population. Thus it was possible that if the time registered with practices contributing to the GPRD differed for cases and controls a bias could be introduced into the analysis with regard to acne status. We have described an acne period for patients with acne diagnoses on the GPRD (Seaman et al., 2003). That theoretical period began 2 years prior to a patients first acne diagnosis and ended 1 year after the last acne diagnosis. Based on that reasoning, to reliably assign acne status to cases and controls we performed a sub-group analysis including only those cases and controls with at least 2 years (760 days) registration after the index date and at least 1 years (365 days) registration prior to the index date. The results of the sub-group conditional logistic regression indicated a statistically significant association between VTE and exposure to CPA/EE (OR 3.87) and exposure to conventional COCs (OR 2.26). Thus it appears that at least part of the significantly elevated risk estimate for VTE in women prescribed CPA/EE may be accounted for by residual confounding with regard to acne status. The difference in risk between CPA/EE and conventional COCs was not significant, unlikely to be associated with ethinyl estradiol dose and could be a chance finding. The age-adjusted IRR for VTE associated with CPA/EE use versus use of conventional COCs was 2.2 and after adjustment in the sub-group casecontrol analysis this ratio was reduced to 1.7. Thus if complete adjustment for confounding could be achieved it is possible that no difference in risk between conventional COCs and CPA/EE would remain.
Our study population comprised women with acne, hirsutism or PCOS. It is possible that the morbidity associated with more severe symptoms in such women may include an elevated VTE risk. We cannot determine disease severity using routinely collected data such as that available on the GPRD and further work is planned to explore the underlying risk profiles of CPA/EE users.
In conclusion, it is likely that confounding by disease severity is an important component of the elevated VTE risk associated with CPA/EE exposure in women with acne, hirsutism or PCOS. Our findings suggest that CPA/EE remains a viable treatment option for women with hirsutism or acne which has proved unresponsive to other drugs. In addition the findings of this study suggest that, compared with other estrogen-containing products of a similar dose, CPA/EE does not increase a womans baseline VTE risk. Careful consideration should be given to the risks associated with CPA/EE versus other treatment options.
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Acknowledgements |
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References |
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Submitted on September 3, 2002; accepted on November 21, 2002.