Experts Confirm Favorable Benefit-risk Profile Of Combined Oral Contraceptives

Leading experts in the fields of gynecology, reproductive endocrinology, hematology and epidemiology have affirmed that for most women the low absolute risks of combined oral contraceptives (COCs) are outweighed by the well-established benefits of hormonal contraception.


Their consensus opinion has just been published in the Journal for Family Planning and Reproductive Health (J Fam Plann Reprod Health Care 2010; 36(3): 117 - 122)(1).


For most healthy women the benefits of COCs will outweigh the risks, but it is important to identify the individual risk factors for venous thromboembolism (VTE) the consensus opinion states.


Two publications(2,3) of 2007 dealing with venous thromboembolism in women using an ethinylestradiol / drospirenone-based COC (Yasmin®) were followed in 2009 by others(4,5) with conflicting findings about the risk of VTE with this product. This led Bayer Schering Pharma as the leading company in the field of oral contraception to convene a workshop in December 2009 in Berlin and invite experts in gynecology, reproductive endocrinology, hematology and epidemiology to critically review all recent publications in order to understand the reasons for divergent results.


Following the two-day symposium the experts issued the consensus paper now published by the Journal of Family Planning and Reproductive Health. The paper states that:



-- Modern COCs are reliable, well tolerated contraceptives which also offer a variety of non-contraceptive benefits ranging from regulation and reduction of both menstrual bleeding and dysmenorrhoea to treatment of premenstrual syndrome, acne and hirsutism. Long-term benefits include reduced rates of endometrial and ovarian cancer.



-- Modern COCs are well tolerated and serious side effects are rare in COC users.



-- VTE remains a rare but potentially serious complication of COC use. It is similar for all modern low dosed COCs.



-- The absolute risk of venous thromboembolism is low. The incidence of venous thromboembolism among women who do not take the COCs is about 4 to 5 per 10,000 women per annum. Among women who take COCs, this risk doubles to 9 to 10 cases of venous thromboembolism per 10,000 women per annum. By contrast, during pregnancy the risk rises to about 20 to 30 cases of venous thromboembolism per 10,000 women per annum and after childbirth to about 300 to 400 cases of venous thromboembolism per 10,000 women per annum.



-- As one of the most widely used and effective contraceptive methods, COCs reduce rates of unplanned pregnancies and actually decrease the overall rate of VTE for women in comparison to populations without access to effective contraception.















Controversial findings about VTE risk in different studies


Two studies published in the British Medical Journal in August 2009(4,5) suggested that COCs containing the progestogen drospirenone may have an increased risk of VTE compared to COCs containing levenorgestrel.


Participants of the workshop however found the results of both the Danish study by Lidegaard et al.(4) and the Dutch study by van Hylckama Vlieg et al.(5) could have resulted from methodological flaws and or misinterpretation of the findings.


According to the authors of the consensus paper the Dutch Mega Study showed hazard ratios for various COCs with wide and overlapping 95% confidence intervals indicating no statistically significant difference in the VTE risk between drospirenone-containing COCs and COCs with different progestogens. In recent revisions to the Yasmin product label in the USA, the Food and Drug Administration (FDA) has concluded: "The number of Yasmin cases [in the Dutch Mega Study] was very small (1.2% of all cases) making the risk estimates unreliable."


The authors of the consensus paper also identified several significant methodological weaknesses in the Danish National Cohort Study. Confounders such as obesity, surgery or a family history for VTE were not taken into consideration.


The experts also looked at the two studies published in 2007(3,4). Bayer sponsored as part of its post-approval commitments to EU regulatory authorities and the FDA for drospirenone-containing COCs, two large observational studies (EURAS(3) and Ingenix(4)) in Europe and the United States which were carried out by independent investigators. Both studies were specifically designed after extensive discussion with European and US health regulators to be sufficiently powered to assess differences between COCs with different progestogens with regard to the risk of VTE. EURAS controlled for confounding factors (e.g. Body Mass Index and personal or family history of VTE); Ingenix used recognized epidemiological methods (propensity score matching) to achieve balance between the cohorts. These studies encompassing more than 120,000 COC users confirm that users of low-dose COCs have a similarly low risk of VTE regardless of the progestogen used. The results of the EURAS and Ingenix trials, which were published in 2007, offer important information about the safety of COCs in a real-life setting.


Personal consultation is essential


The experts participating at the workshop emphasized the importance of the consultation which must precede any oral contraceptive prescription. Particularly when it comes to a patient's initial prescription, it is essential that healthcare professionals compile a thorough past medical history to establish a woman's risk profile. The decision on prescription of hormonal contraceptives has to be made based on an individual benefit-risk evaluation. Contraindications and precautions for use as indicated in the package insert also have to be taken into consideration. Known risk factors for VTE include individual or family history for VTE, coagulation disorders, advanced age, cigarette smoking, surgical procedures, long haul flights, obesity, pregnancy and time after child birth.


Studies mentioned in this release


References



1. Reid RL, Westhoff C, Mansour D, de Vries C, Verhaeghe J, Boschitsch E, Gompel A, Birkh?¤user M, Krepelka P, Dulicek P, Iversen O-E, Khamoshina M, Dezman LV, Fruzzetti F, Szarewski A, Wilken-Jensen C, Seidman D, Kaaja R, Shapiro S. Oral Contraceptives and Venous Thromboembolism. Consensus Opinion from an International Workshop held in Berlin, Germany in December 2009. J Fam Plann Reprod Health Care 2010: 36(3), 117 - 122



2. Dinger JC, Heinemann LAJ, K??hl-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 75 (2007) 344 - 354



3. Seeger JD, Loughlin J, Eng M, Clifford R, Cutone J, Walker AM, Risk of Thromboembolism in Women Taking Ethinylestradiol/Drospirenone and Other Oral Contraceptives, Obstetrics & Gynecology, Vol. 110, No. 3, September 2007, 587-593



4. Lidegaard O, L??kkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009:339:b2890.



5. van Hylckama Vlieg A, Helmerhorst FM, Vandenbroucke JP , Doggen CJM, Rosendaal FR. 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


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Source: Bayer Schering Pharma