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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

Rapid Response:

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

Thanks to Anne Szarewski (AS) and Diana Mansour (DM) for their concern about our new historical cohort study on non-oral hormonal contraception and venous thrombosis (1).

It is true, that our previous studies were criticised, but we actually made a very comprehensive response to this critique, published in BMJ last year, in which we addressed point by point all the concerns now repeated by AS and DM (2).
We suggest that AS and DM primarily read through this detailed response.

But again, briefly:

It is not biologically nonsensical that a combined vaginal ring delivering third generation progestogens confers the same risk of venous thrombosis as combined pills with the same third generation hormones. The opposite would have been a surprise.
In our opinion we controlled for relevant confounders, but not for all risk factors of venous thrombosis. That circumstance will not bias our results.

It is not an artefact that we censored women with levonorgestrel IUS after three years, and therefore left the >4 years category blank. Those categorised in the “1-4 years length of use” had actually taken hormonal contraception for 1-4 years, and levonorgestrel IUS at the time of their event. We censored these women after three years in order to be sure, that women categorised as users of this IUS had a high chance of actually being users of this product.

It is true that new products are often being prescribed to starters. But we compared starters with starters, and long term users with long term users, so the fact that there were more starters in one product group does not affect the results, as long as you adjust for differences in length of use.

The EURAS study showed a rate ratio of 1.0 before as well as after adjustment for BMI. In five further recent studies with access to this risk factor, adjustment for BMI did not change the estimates (3-7). The same studies confirmed an equal distribution of adipose women in users of different product groups.

It is true that women at risk of VTE are now recommended progestogen only contraception. That circumstance should decrease the risk of venous thrombosis in users of combined products, and not the opposite, as claimed by AS and DM. That levonorgestrel IUS may actually decrease the risk of venous thrombosis is biologically plausible, as this product, as the only one, decreases sex hormone-binding globuline (SHBG). SHBG is considered a surrogate marker for the risk of venous thrombosis (9). According to the same study, NuvaRing® increases SHBG more than the majority of combined pills.
The only other published study on the influence of NuvaRing® on the risk of venous thrombosis also demonstrated a significantly higher risk of venous thrombosis as compared with users of combined pills with levonorgestrel (7).

This consistency increases the credibility of studies based upon Danish health registries.

PS. It would be useful for readers of the J Fam Plann Reprod Health Care if you made a link to my response (in BMJ) to the critique by Dinger and Shapiro.

1. Szarewski A, Mansour D, rapid response to (1), 14th of May: http://www.bmj.com/content/344/bmj.e2990/rr/584507 letterBMJ[1].doc
2. 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
3. Lidegaard Ø, Edström B, Kreiner S. Oral contraceptives and venous thromboembolism. A five-year national case-control study. Contraception 2002; 65: 187-96.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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

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.

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