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Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9

BMJ 2011; 343 doi: https://doi.org/10.1136/bmj.d6423 (Published 25 October 2011) Cite this as: BMJ 2011;343:d6423

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Authors' reply to Anne Szarewski et al.

Although repeated indefinitely, a risk factor is not the same as a
confounder. There is no evidence so far in any of the studies having
access to BMI, that this variable is a confounder despite how many times
it has proved to be a risk factor. A dose response relationship is an
argument for a variable being a risk factor, not a confounder. So far, no
study have demonstrated any confounding influence from BMI, as adjustment
for BMI in studies with this information did change the rate ratio between
COC with different progestogens only marginally or not at all1-5.

Therefore, it is rather unlikely, that especially Danish women in
this decade who smoke or are adipose or are predisposed for venous
thrombosis should preferentially be prescribed a certain pill rather than
another. Thus, we have good reasons to anticipate that confounding cannot
explain the Danish findings.
It is true that adjustment for age changed the Danish estimates much more
than age adjustment in the study of Dinger et al2. The reason for this
difference is quite simple: There were large age differences between users
of oral contraceptives with levonorgestrel and drospirenone, respectively
in our study, an age difference not found in the study by Dinger.

About preferential prescribing of third generation oral
contraceptives to women with family predisposition early after their
introduction, we dealt with that issue in our last answer to Szarewski
after our 2009 publication
(http://www.bmj.com/content/339/bmj.b2890.full/reply#bmj_el_270693). Our
opinion has not changed since then, except that we now have further new
studies confirming that no preferential prescribing is in effect according
to the risk factors mentioned by Anne Szarewski3, 5.

Therefore the conclusion by Szarewski et al. that our results should
be due to confounding is without any empirical support and against
substantial consistent epidemiological findings over the last decade.

1. Lidegaard O, Edstrom B, Kreiner S. Oral contraceptives and venous
thromboembolism. A five-year national case-control study. Contraception
2002; 65: 187-96.

2. Dinger JC, Heinemann LAJ, 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.

3. Vlieg AVH, Helmerhorst FM, Vandenbroucke JP, Doggen CJ, Rosendaal
FR. The venous thrombotic risk of oral contraceptives, effects of
oestrogen dose and progestagen type: results of the MEGA case-control
study. BMJ. 2009; 339: b2921.

4. Dinger J, Assmann A, Mohner S, Minh TD. Risk of venous
thromboembolism and the use of dienogest- and drospirenone-containing oral
contraceptives: Results from a German case-control study. J Fam Plann
Reprod Health Care 2010; 36: 123-9.

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.

Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that: Bayer Schering Pharma is thanked for covering the expenses of the analysis. All funding was given to Rigshospitalet, and the primary investigator received no salary for his work with this study, the EMA report or this manuscript. OL has within the last three years received honorariums for speeches on pharmacoepidemiological issues, including fees from Bayer Pharma Denmark and Novo Nordisk, and will be an expert witness for plaintiffs in a legal US case in 2011-2; FES received compensation for his work in the steering committee of the European Medicines Agency report.

03 November 2011
Ojvind Lidegaard
professor of obstetrics and gynaecology,
on behalf of Lars Hougaard Nielsen, Charlotte Wessel Skovlund, Finn Egil Skjeldestad, Ellen Lokkegaard
Gynaecological Clinic 4232, Rigshospitalet, University of Copenhagen, Denmark