Increased risk of thromboembolism in newer oral contraceptives
Published in Health News and Evidence
Date published: About this date
It is well established that oral contraceptives (OCs) carry a risk of venous thromboembolism (VTE), especially during the first year of use. Data are accumulating showing that some combined OCs containing new-generation and anti-androgenic progestogens have a higher risk of VTE than older drugs such as levonorgestrel. These new-generation contraceptives are being reviewed by the Therapeutic Goods Administration (TGA) for safety. Since other factors such as age and lifestyle factors influence the risk of VTE, health professionals are advised to take into account the possible increase in risk of VTE in new and existing users before prescribing.
- New data show that some combined OCs containing newer progestogens have a higher risk of VTE than older drugs.
- To address the possible additional risk of VTE, the TGA and European Medicines Agency (EMA) recently announced reviews of new-generation combined OCs, including the anti-androgenic Diane-35 and its generics.
- VTE is a rare adverse effect of all combined oral contraceptives. The risk is small and much lower than the risk of VTE during pregnancy, especially during the postpartum period.
- Health professionals are advised to weigh the clinical needs of their patients against the possible increase in risk of VTE when considering an oral contraceptive containing newer synthetic progestogens.
The cardiovascular side effects associated with use of hormonal contraception are well established and continuously revisited as the composition and use of contraceptives continue to evolve.1 Recently, regulatory authorities in the US, Europe and Australia released a series of advisory statements regarding the risk of VTE with some new-generation OCs.2–6 The TGA has advised it will closely monitor the risk of VTE and conduct a review of the safety information available for anti-androgenic combined OCs containing the synthetic progestogen cyproterone acetate.3 This follows recent TGA advisories regarding new-generation combined OCs containing drospirenone, desogestrel or gestodene.7,8 In Australia, only second-generation combined OCs are subsidised on the Pharmaceutical Benefits Scheme.
The safety advisories relate to a number of products approved for use in Australia (Table 1).9
Table 1. Combined oral contraceptives available in Australia
|Brand name||Progestogen dose
|Third generation||Marvelon||desogestrel 150||ethinyloestradiol 30||Oral contraceptive|
|Femoden||gestodene 75||ethinyloestradiol 30||Oral contraceptive|
|Minulet||gestodene 75||ethinyloestradiol 30||Oral contraceptive|
|Fourth generation||Yaz/Yaz-flex||drospirenone 3000||ethinyloestradiol 20||Oral contraceptive, treatment of moderate acne in women seeking oral contraception|
|Yasmin||drospirenone 3000||ethinyloestradiol 30||Oral contraceptive|
|Cyproterone||Diane-35, Brenda-35, Juliet-35, Estelle-35, Laila-35||cyproterone acetate 2000||ethinyloestradiol 35||Treament of severe acne and idiopathic hirsutism and oral contraception in this patient group|
A recent meta-analysis reported a greater risk of VTE in women taking new-generation combined OCs containing desogestrel, gestodene and drospirenone compared with those containing levonorgestrel, norgestrel or norgestimate.10 In addition, two large studies (one Dutch case–control study and one Danish cohort study) reported that the risk of VTE is nearly doubled in patients taking combined OCs containing desogestrel, gestodene and drospirenone compared with those taking levonorgestrel.11,12 The studies also confirmed a higher risk of VTE during the first year of OC use irrespective of the formulation11,12, with the risk more than halved in the second year of use.12
Although the influence of oestrogen dose on the risk of VTE appears to be well accepted, the risk attributed specifically to progestogens in these studies has been questioned. This was due to potential limitations related to misdiagnoses of VTE, a lack of control for duration of use of OCs and other bias and heterogeneity.13 Nevertheless, a reanalysis of the Danish cohort study with additional data confirmed a doubling of the risk of VTE with newer OCs.14
The safety reviews were prompted by recent epidemiological studies reporting a 2–3-fold increase in the risk of idiopathic cases of VTE in women taking OCs containing drospirenone compared with those taking levonorgestrel.2,15,16 However, other studies found no additional risk of VTE associated with drospirenone relative to other combined OCs17 or levonorgestrel formulations.18
In its safety alert, the US Food and Drug Administration (FDA) concluded that combined OCs containing drospirenone may be associated with a higher risk of VTE than other progestogen combined formulations but this effect could not be causally related.4 The FDA highlighted that a major limitation for most studies was the failure to consider risk-modifying patient characteristics, such as smoking status and body mass index, and lack of consistent estimates of the comparative risk of VTE between OCs containing drospirenone and those that do not.
A subsequent FDA-funded study comparing the risk of VTE in drospirenone-containing OCs compared with other low-dose combined OCs, including levonorgestrel, norethindrone acetate or norgestimate, found:
- there was about a 1.7-fold increased risk of VTE after adjusting for age, site and year of entry
- the increased risk of VTE was higher in younger people (aged 10–34 years), especially for new users of OCs or those switching to a drospirenone-containing OC
- the risk was significantly greater in the first year of use but did not differ from other low-dose combined OCs after 12 months of use.19
A recent French medicines agency (ANSM) review of the cyproterone acetate Diane-35 found a negative risk–benefit profile for the threat of VTE, which led to ANSM announcing that it will suspend the marketing authorisation of the medicine.3 Several cohort or case–control studies as well as meta-analyses have reported up to a twofold increase in risk of VTE in women taking OCs containing cyproterone acetate compared with those taking levonorgestrel.10–12,20 Compared with other combined OCs, the risk of VTE in women with signs of androgenisation, such as acne and hirsutism, treated with the cyproterone-acetate–ethinyloestradiol formulation is reported to be equivalent to the risk associated with its use as an oral contraceptive in all women.21
While Diane-35 has a contraceptive effect, it is not approved for that use in Australia.
A recent meta-analysis of studies published from 1967 to 2009 reported a 3–4-fold greater risk of VTE in women taking any OC compared with non-users.10 The latest FDA safety advisory reported a wider range of 3–9-fold for all users compared with 1–5-fold in non-users who are not pregnant and not taking hormones (per 10,000 woman years).4 If the increase in VTE risk reported for new-generation and anti-androgenic (e.g. Diane-35) combined OCs is accurate, the absolute risk of VTE is about 10 per 10,000 woman years for women taking OCs containing desogestrel, gestodene, drospirenone or cyproterone acetate.14,19 In comparison, the risk of pregnancy ranges from 5 to 20 per 10,000 woman years, rising to 40–65 during the postpartum period.4
- Consider the clinical needs of patients against the possible increase in risk of VTE when choosing any oral contraceptive.
- Advise patients of the possible increase in risk of VTE with OCs containing drospirenone and cyproterone acetate and educate patients to recognise the signs and symptoms of VTE.2,3
- OCs are contraindicated in women with severe or multiple risk factors for venous or arterial thrombosis. Care should be taken when prescribing OCs in women with risk factors that increase the risk of VTE, such as obesity, age over 35 years or smoking.9
- Advise patients to continue taking their OC and, if a patient is tolerating the regimen, there is generally no need to discontinue use at this time.
- Do not prescribe OCs in women with a previous history of VTE, coronary artery disease, cerebrovascular disease, uncontrolled hypertension, severely impaired liver function or malignancy of the breast or genital tract. Women with a history of VTE should be screened for thrombophilia before starting a combined OC.9
- Report all adverse events associated with all oral contraceptives to the TGA. For information about reporting adverse reactions, see the TGA website.
- 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. [PubMed]
- Therapeutic Goods Administration. Safety information alert: Oral contraceptives containing drospirenone (Yaz and Yasmin). 2011. http://www.tga.gov.au/safety/alerts-medicine-oral-contraceptives-110706.htm (accessed 31 January, 2013).
- Therapeutic Goods Administration. Safety information alert: Diane-35. Australian Government Department of Health and Ageing, 2013. http://www.tga.gov.au/safety/alerts-medicine-diane-35-130205.htm (accessed 5 February 2013).
- US Food and Drug Administration. Updated information about the risk of blood clots in women taking birth control pills containing drospirenone. FDA Drug Safety Communication: 2012. http://www.fda.gov/drugs/drugsafety/ucm299305.htm (accessed 31 January, 2013).
- European Medicines Agency. European Medicines Agency starts safety review of DIane-35 and its generics. 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/02/news_detail_001711.jsp&mid=WC0b01ac058004d5c1 (accessed 11 February 2013).
- European Medicines Agency. European Medicines Agency to review third- and fourth-generation combined oral contraceptives. 2013. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/01/WC500137933.pdf (accessed 31 January, 2013).
- Therapeutic Goods Administration. Venous thromboembolism with third generation oral contraceptives and cyproterone. Australian Adverse Drug Reactions Bulletin, 2002. http://www.tga.gov.au/pdf/aadrb-0206.pdf (accessed 31 January, 2013).
- Therapeutic Goods Administration. Oral contraceptives containing drospirenone (Yaz and Yasmin) and venous thromboembolism. Medicines Safety Update Australian Prescriber: 2011. http://www.tga.gov.au/pdf/msu-2011-05.pdf (accessed 31 January 2013).
- Therapeutic Guidelines Limited. eTG Complete. Oral contraceptive formulations available in Australia 2012. http://etg.hcn.com.au (accessed 31 January 2013).
- Manzoli L, De Vito C, Marzuillo C, et al. Oral contraceptives and venous thromboembolism: a systematic review and meta-analysis. Drug Saf 2012;35:191-205. [PubMed]
- Lidegaard O, Lokkegaard E, Svendsen AL, et al. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009;339:b2890. [PubMed]
- van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP, et al. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. BMJ 2009;339:b2921. [PubMed]
Shapiro S, Dinger J. Risk of venous thromboembolism among users of oral contraceptives: a review of two recently published studies. The journal of family planning and reproductive health care / Faculty of Family Planning & Reproductive Health Care, Royal College of Obstetricians & Gynaecologists 2010;36:33-8. [PubMed]
- Lidegaard O, Nielsen LH, Skovlund CW, et al. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 2011;343:d6423. [PubMed]
- Jick SS, Hernandez RK. Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data. BMJ 2011;342:d2151. [PubMed]
Parkin L, Sharples K, Hernandez RK, et al. Risk of venous thromboembolism in users of oral contraceptives containing drospirenone or levonorgestrel: nested case-control study based on UK General Practice Research Database. BMJ 2011;342:d2139. [PubMed]
- Dinger J, Assmann A, Mohner S, et al. Risk of venous thromboembolism and the use of dienogest- and drospirenone-containing oral contraceptives: results from a German case-control study. The journal of family planning and reproductive health care / Faculty of Family Planning & Reproductive Health Care, Royal College of Obstetricians & Gynaecologists 2010;36:123-9. [PubMed]
- Dinger JC, Heinemann LA, Kuhl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception 2007;75:344-54. [PubMed]
- US Food and Drug Administration. Combined oral contraceptives (CHCs) and the risk of cardiovascular disease endpoints. 2011. http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf (accessed 1 February 2013).
- Farmer RD, Lawrenson RA, Todd JC, et al. A comparison of the risks of venous thromboembolic disease in association with different combined oral contraceptives. British journal of clinical pharmacology 2000;49:580-90. [PubMed]
- Seaman HE, de Vries CS, Farmer RD. Venous thromboembolism associated with cyproterone acetate in combination with ethinyloestradiol (Dianette): observational studies using the UK General Practice Research Database. Pharmacoepidemiology and drug safety 2004;13:427-36. [PubMed]