Position Statement: Diane-35 and Risk of Venous Thromboembolism (VTE)
Cyproterone acetate (2mg) combined with ethinylestradiol (35g) (CPA/EE), a product commercialized in Canada under the name of Diane-35, was introduced worldwide in 1978. CPA is a progestogen with strong anti-androgenic properties that may also be used as a mono substance in the dosage of 10 mg to 100 mg to treat women with moderate to severe signs of androgenization (hirsutism, acne).1,2 Men are also prescribed high doses of CPA (50-300 mg) for the treatment of prostate cancer.3 In Canada, CPA/EE was approved in September 1997 for the treatment of pronounced forms of acne, accompanied by seborrhoea, inflammation or formation of nodes, mild forms of hirsutism and for whom treatment with oral antibiotics or other available treatments has not worked.4,5 In addition to its effect on androgenic diseases, CPA/EE is known to be an effective combined hormonal contraceptive.6
Recently, there have been concerns about the relationship between CPA/EE and the risk of venous thromboembolic diseases (VTE) and related death. As a result, Health Canada issued an announcement that they would review the safety of the drug Diane-35 as of January 31, 2013.7
The absolute risk of blood clots for individual women is very low (4-5/10,000). The risk of getting a blood clot due to combined hormonal contraceptives is between 8-9 women per 10,000 pill users every year.8 Of 100 women who get a blood clot, it is estimated that one person will die, for a death rate of < 1 per 100,000 combined hormonal contraceptive users per year. Pregnancy carries a host of potential risks including higher rates of blood clots than that experienced by combined hormonal contraceptive users. Women who are overweight or pregnant have a risk of blood clots that is 2 to 40 times higher than the risk of blood clots associated with combined hormonal contraceptive use.9,10,11 To put the risks of combined hormonal contraceptive related deaths (0.5-0.9 per 100,000 users per year) into perspective, consider the following statistics12:
|Deaths/100,000 women per yr|
|Smoker (35 yr)||167|
|Per 100,000 combined hormonal contraceptive users with Leiden V||1.9 – 4|
|Per 100,000 combined hormonal contraceptive users||0.5 – 0.9|
|Background risk of fatal VTE for women aged 15-44||0.6|
The SOGC regularly reviews the scientific literature that addresses the risks of VTE with therapeutic products used in gynaecology and provides this update as of February 2013.
The ideal study to address the risk of VTE with a new product would compare VTE rates in similar women (similar age, weight, etc.) with similar risk factors (smoking, obesity, family history, etc.) initiating combined hormonal contraceptives for the first time (longer term users have lower risks than women starting the pills) with active follow-up (regular phone calls to identify any possible complications) and finally, with validation of any possible complications (by reviewing the actual medical record). Normally, this type of high quality information is only available when the study is planned in advance to address all these concerns in prospective fashion.
We have reviewed the published data on the issue of VTE and CPA/EE in the context of this recent “pill scare” about VTE risks associated with combined hormonal contraceptives. These studies include both prospective and retrospective studies of variable quality. Eight studies published from 1995 to 200413-20 included women using CPA/EE and other types of combined hormonal contraceptives related to VTE. As reviewed by WO Spitzer, professor of epidemiology at McGill University,21 the range of absolute incidence rates of VTE among CPA/EE users in these studies varied from 1.2 to 9.9 per 10,000 women-years. The absolute risk difference between CPA/EE users and conventional combined hormonal contraceptive users, called attributable risk, was not higher than 0.04%, indicating that CPA/EE users may have up to 0.04% more risk of getting a VTE than users of conventional combined hormonal contraceptives.21 In summary, except for one study exhibiting a small statistically significant benefit,13 there was no difference between the incidence rates of VTE among CPA/EE users and those among conventional combined hormonal contraceptive users.21
One study18 restricted its analysis to women with acne, hirsutism, and polycystic ovary syndrome (PCOS) and estimated the risk of VTE in users of CPA/EE and in users of conventional combined hormonal contraceptives. The authors reported a statistical difference in incidence rate of VTE, with an incidence rate of 8.05 per 10,000 women-years in CPA/EE users while it was 3.7 per 10,000 women-years in women using conventional combined hormonal contraceptives. Interestingly, two recent studies showed that women who suffer from PCOS were more likely to have VTE than women without PCOS.22,23
When examining the relationship between CPA/EE and VTE-associated risk, it is important to examine the strength of the evidence. Fear and confusion resulting from media coverage of rare events (death from combined hormonal contraceptive induced VTE of < 1/100,000) has the potential to create harm as inadvertent pregnancies are often the result of panic stopping of combined hormonal contraceptives and these pregnancies themselves carry greater risks for VTE.24 This situation occurred in 1995 following the publication of three articles in The Lancet.25-27 According to Mills,12 in the UK alone, there were 30,000 more conceptions in the 9 months following the “pill scare” (deliveries increased by 20-25% and abortions reached the highest level in 30 years with 10,000 more than anticipated). Mills and Edwards28 argued convincingly that “the constant negative drip of information from the lay press makes it impossible for the professionals and consumers to interpret true risks and benefits of drugs.” Combined hormonal contraceptives are known to reduce the risk of pelvic inflammatory disease, ectopic pregnancy, anemia, endometrial and ovarian cancer, and acne. CPA/EE, in particular, is one of the most effective and safest treatments for acne in women of reproductive age and because of its contraceptive efficacy, it does not carry the risk of teratogenesis associated with Accutane.
In conclusion, the risk of VTE with any combined hormonal contraceptives is increased over that of a non-pregnant, non-combined hormonal contraceptive user but is considerably lower than the risk of VTE in pregnancy and the postpartum period. Overall, the risk of VTE in users of these products is very low.29
- The risk of VTE in CPA/EE users is very low and comparable to that of other combined hormonal contraceptives. For the majority of women, the benefits outweigh the risks.
- Health-care providers should assess risk factors for VTE as one component of identifying the optimal choice of treatment for severe acne or other hyperandrogenism syndrome for a given woman.
- Health-care providers should understand that the risk of VTE in CPA/EE users, as well as in combined hormonal contraceptive users, is highest in the first months of use, falling towards baseline thereafter.
- Women should be counselled about the risk of VTE with any estrogen containing hormonal product and should be advised about signs and symptoms and what to do if these occur. To maintain perspective, it is useful to explain that the risk of VTE in pregnancy and the postpartum period is much higher than with CPA/EE use.
- Miller JA, Jacobs HS. Treatment of hirsutism and acne with cyproterone acetate. Clin Endocrin Metab 1986;15:373-89.
- Belisle S, Love EJ. Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multicentered Canadian study. Fertil Steril 1986;46:1015-20.
- Barradell LB, Faulds D. Cyproterone. A review of its pharmacology and therapeutic efficacy in prostate cancer. Drugs Aging 1994;5:59-80.
- Spona J, Huber J. Efficacy of low-dose oral contraceptives containing levonorgestrel, gestoden and cyproterone acetate. Gynecol Obstet Invest 1987;23(3):284-93.
- Heinemann LAJ, Dinger JC. Range of published estimates of venous thromboembolism incidence in young women. Contraception 2007; 75:328-336.
- Bergendal A, Bremme K, Hedenmanlm K, Lärfars G, Odeberg J, Persson I, Sundström A, Kieler H. Risk factors for venous thromboembolism in pre- and postmenopausal women. Thrombosis Research 2012 Oct;130(4):596-601.
- Heit JA. Kobbervig CE. James AH. Petterson TM. Bailey KR. Melton LJ 3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005; 143(10):697-706.
- Ros HS, Lichtenstein P, Belloco R, Petersson G, Cnattingius S. Increased risks of circulatory diseases in late pregnancy and puerperium. Epidemiology 2001; 12:456 –460.
- Mills A. Combined oral contraception and the risk of venous thromboembolism. Human Reproduction, 1997; 12(12): 2595-2598.
- Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995;346:1575-82.
- Pini M, Scoditti U, Caliumi F, Manotti C, Quintavalla R, Pattacini C et al. Risk of venous thromboembolism and stroke associated with oral contraceptives. Role of congenital Thrombophilias. Recenti Prog Med 1996;87:331-7.
- Farmer RD. Lawrenson RA. Todd JC. Williams TJ. MacRae KD. Oral contraceptives and venous thromboembolic disease. Analyses of the UK General Practice Research Database and the UK Mediplus database. Human Reproductive Update 1999;5:688-706.
- Farmer RD. Lawrenson RA. Todd JC. Williams TJ. MacRae KD. Tyrer F. Leydon GM. A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives. British Journal of Clinical Pharmacology. 49(6):580-90, 2000.
- Vasilakis- Scaramozza C, Jick H. Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives. Lancet 2001; 358: 1427-1429.
- Seaman HE, de Vries CS, Farmer RDT. The risk of venous thromboembolism in women prescribed cyproterone acetate in combination with ethinyl estradiol: a nested cohort analysis and case control study. Human Reproduction 2003; 18(3): 522-526.
- Lidegaard O. Absolute and attributable risk of venous thromboembolism in women on combined cyproterone acetate and ethinylestradiol. J Obstet Gynaecol Can 2003;25:575-7.
- Heuser P, Tonga K, Hopkins R, Henderson M, Weatherall M, Metcalfe S, Beasley R. Specific oral contraceptive use and venous thromboembolism resulting in hospital admission. New Zealand Medical Journal 2004 Nov 26;117(1206):U1176.
- Spitzer WO. Cyproterone acetate with ethinylestradiol as a risk factor for venous thromboembolism: an epidemiological evaluation. J Obstet Gynaecol Can 2003;25:1011-8.
- Okoroh EM, Hooper C, Atrash HK, Yusuf HR, Boulet SL.Is polycystic ovary syndrome anther risk factor for venous thromboembolism? United Staes 2003-2008. Am J Obstet Gynecol 2012;207:377.e1-8.
- Bird ST, Hartzema AG,Brophy JM, Etminan M, Delaney JAC.Risk of venous thromboembolism in women with polycystic ovary syndrome: a population based matched cohort analysis. CMAJ 2012; DOI:10.1503
- Reid RL. Oral Contraceptives and Venous Thromboembolism: Pill Scares and Public Health. JOGC 2011; 33(11):1150-1155.
- Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet 1995 Dec 1 6;346 (8990): 1575-82.
- Jick H, Jick SS, Gurewich V, Myers MW, Vasilakis C. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995 Dec 16;346(8990):1589-93.
- Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995 Dec 1 6;346(8990): 1593-6.
- Mills A, Edwards IR. Venous thromboembolism and the pill: The combined oral contraceptive pill— are poor communication systems responsible for loss of confidence in this contraceptive method? Human Reproduction, 1999; 14(1): 7-10.
- Raymond EG, Burke AE, Espey E. Combined hormonal contraceptives and venous thromboembolism: Putting the risks into perspective. Obstet Gynecol 2012; 119(5): 1039-1044.