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Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10

BMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e2990 (Published 10 May 2012) Cite this as: BMJ 2012;344:e2990

Re: Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10

Mary E Gaffield et al. (MEG) are concerned that published scientific evidence will have an effect on prescribing practices (1). My question is: If published scientific evidence does not influence our prescribing practices, then what should guide us in counselling our patients?

Our clinical recommendation is not to abandon hormonal contraception, but rather to make clinicians aware of a rather big difference in the risk of venous thrombosis according to the type of progestogen, included in combined hormonal products. Such knowledge should influence our contraceptive choices. I see no reason to suppress such scientific information due to the third generation pill scare. In my opinion, the so-called third generation pill scare was caused primarily by a discrepancy between the non-scientifically based safety claims made by drug companies when they introduced third generation pills (that is combined oral contraceptives with desogestrel or gestodene) versus the real thrombotic risk of these products as established by the first independent scientific studies. At that time, the drug companies’ argument against a difference in risk of venous thrombosis was that women at risk were preferentially prescribed the new combined pills. While some preferential prescribing did actually occur during the first years after launch of third generation pills, these small preferential prescribing practices did not explain the higher risk of venous thrombosis in users of these products. Now, nearly 20 years after launch, use of third generation pills still appear to double the risk of venous thrombosis compared to the older 2nd generation pills with levonorgestrel.

MEG refers to a critique by Dinger & Shapiro which claims that our lack of control for BMI and family disposition invalidates our results. But again, these well known risk factors are unlikely to be confounders, because the proportion of adipose women has been found to be similar among women using different product types (2-6). We have dealt in detail with the concerns expressed by Dinger & Shapiro, and refer to this reply (7)

In regard to incidence rates, the incidence rate of venous thrombosis depends largely upon the inclusion criteria used in the study. Studies may og may not include women of certain age groups, those with a history of of prior thrombotic events, women who are pregnant, or women who use hormonal contraceptives. These circumstances to a large extent explain the differences in incidence figures published.

Next MEG et al. proclaim national databases in particular to be unreliable for scientific purposes. I do not agree with this claim. In my opinion, the method of data storage does not affect its validity. All studies are initially based upon discharge diagnoses. These diagnoses are not 100% accurate. The fact that Denmark collects these discharge diagnoses and store them in a central database does not make them any more or less reliable than discharge diagnoses gathered from hospitals or insurance companies in some other manner. The important issue is the method used to validate these diagnoses. We did so by identifying women with a discharge diagnosis of venous thrombosis, and then assessing whether they underwent succeeding anticoagulation therapy for at least four weeks, as such a therapy is generally not given to women who have no venous thrombosis. After using this validation procedure, we then restricted our statistical analysis to these confirmed events. We thereby ensured a 99% positive predictive value for our diagnoses of a true venous thrombosis (8).

While we acknowledge the many benefits of hormonal contraception, the majority of these benefits are also available from products with a low risk of venous thrombosis. Therefore, in my opinion, these benefits are not an argument in support of prescribing a high risk product as a first choice.

Finally about biological plausibility. Transdermal patches have been found to confer a 60% higher plasma level of oestrogen as compared to the combined pill with the same type of progestogen (norgestimate)(9), and to increase sex hormone-binding globulin (SHBG) significantly more than combined pills of any type (10). So the higher risk of venous thrombosis with transdermal patches is not only confirmed in several epidemiological studies (11-13), but also is in good agreement with biological evidence.

1. Lidegaard Ø, Edström B, Kreiner S. Oral contraceptives and venous thromboembolism. A five-year national case-control study. Contraception 2002; 65: 187-96.
2. Vlieg AVH, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal FR. The venous thrombotic risk of oral contraceptives, effects of estrogen dose and progestagen type: results of the MEGA case-control study. BMJ. 2009; 339: b2921.
3. Parkin L, Sharples K, Hernandez RK, Jick SS. 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: 340: d2139.
4. 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; 340: d2151.
5. Food and Drug Adminidsration, Office of surveillance and epidemiology. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints. FDA 2011: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM277384.pdf.
6. Gronich N, Lavi I, Rennert G. Higther risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study. CMAJ 2011; DOI:10.1503/cmaj.110463.
7. Repy to critique by Jürgen Dinger and Samuel Shapiro. Part I-III. BMJ 2011, December 7, http://www.bmj.com/content/343/bmj.d6423?tab=responses
8. Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study 2001-9. BMJ 2011;343:d6423.
9. Van den Heuvel MW, van Bragt AJM, Alnabawy A, Kaptein MC. Comparison of ethinylestradiol pharmacokinetics in the transdermal patch, and an oral contraceptive. Contraception 2005;72:168-74.
10. Raps M, Helmerhorst F, Fleischer K, Thomassen S, Rosendaal F, Rosing J, Balleux B, Vliet Hv. Sex hormone-binding globulin as a marker for the thrombotic risk of hormonal contraceptives. J Thromb Haemost 2012; Doi 10.1111/ j.1538-7836.2012.04720.x
11. Cole JA, Horman H, Doherty M, Walker AM. Venous thromboembolism, myocardial infarction, and stroke among transdermal contraceptive system users. Obstet Gynecol 2007;109:339-46.
12. Jick SS, Hagberg KW, Kaye JA. Ortho EVRA® and venous thromboembolism: an update. Contraception 2010;81:452-3.
13. Dore DD, Norman H, Loughlin J, Seeger JD. Extended case-control study results on thromboembolic outcomes among transdermal contraceptive users. Contraception 2010;81:408-13.

Competing interests: The author has within the last three years received honoraria for speeches in pharmacoepidemiological issues, including fees from Bayer Pharma Denmark, MSD Denmark, and Theramex, Monaco, and has been expert witness for plaintiff in a legal US case in 2011.

25 May 2012
Øjvind Lidegaard
Professor
Gynaecological Clinic, Rigshospitalet, University of Copenhagen
Blegdamsvej 9, 2100 Copenhagen