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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: (Published 25 October 2011) Cite this as: BMJ 2011;343:d6423

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

Jürgen Dinger (JD) and Samiel Shapiro (SS) have published in the Journal of Family Planning and Reproductive Health Care a critique (1) of our new study published in BMJ online on October 25, 2011, in which we described the risk of venous thromboembolism (VTE) in users of different types of oral contraceptives (OCs)(2). Permit us to go through each of the critique points raised by JD and SS roughly in the same order as they appear in their critique.

The BMJ publication was not an abbreviated version of the report made for the European Medicines Agency (EMA). On the one hand, the EMA report was a priori restricted in its aim, e.g. we were limited to include results defined in the protocol and by the Steering Committee. Where the EMA report analysed six different product groups, the BMJ publication reported 16 different product groups. Thus results on low-dose (20 µg oestrogen) OCs with drospirenone (DRSP) first published in the BMJ paper, were not included in the EMA report. On the other hand, the EMA report included many supplementary tables, not included in the BMJ publication. The BMJ publication was based on analyses conducted by the author team, with no influence from parties other than the authors. The authors had the aim of reporting all relevant results on all types of oral contraceptives, to calculate relative risks with non-users as a reference, and to present rate ratios between different types of OCs according to oestrogen dose, progestogen types and duration of use. It is our opinion that all relevant results were presented in the paper and its appendices.

Relevance and presentation of different analyses
First JD & SS state that users of OCs with DRSP could only have commenced their OC use in 2001. This is wrong. While DRSP was introduced to the market in 2001, the majority of DRSP users had taken other OCs before 2001. Therefore, users of OCs with either LNG or DRSP could have used OCs long before 2001. Therefore the “attrition of susceptibles” would be in effect for users in either group.
Secondly, it was decided in the protocol to conduct sub-analyses stratified into starters, new-users (defined as users with at least 12 weeks of pause before the new use), re-starters (4-12 weeks of pause) and switchers (less than 4 weeks of pause). The results demonstrated significantly increased rate ratios of VTE between users of OCs with DRSP and levonorgestrel (LNG) ranging from 1.96 to 2.69 for the different user categories. These results were reported in appendix 4 (2).
Third, no studies on OCs and VTE (to our knowledge), including the studies by Dinger et al. have ever required exclusion of every woman who used any type of OCs before the beginning of the study period. The reason that no studies use this criteria is obvious; such a requirement would not provide a sufficient number of exposed women or a sufficient number of events to ensure reliable estimates. Further, the pharmacologic effect of OCs on coagulation disappears within days rather weeks after cessation. Therefore, no scientific reason exists to support such an exclusion criteria
Nevertheless, SS (not the Steering Committee) insisted upon seeing a sub-analysis in which all users were not only starters after 2001 but also women who had never used OCs at any time prior to 2001. As expected the rate ratio estimates between OCs with drospirenone versus OCs with LNG were unstable and ranged from 0.5 to 1.9 for different duration categories, with an overall estimate of 1.0. We concluded this finding was due to chance as a result of the low number of events in users of OCs with LNG (n=11). This interpretation was confirmed by the rate ratio of 2.05 for all starters and new users as defined in the study.

Note that we conservatively required a pause of at least 12 weeks for a woman to be considered a new user in our study. No scientific evidence suggests that previous use before a pause of at least 12 weeks influences the risk of thrombosis with new use. Based upon the instability caused by the few cases contained in the sub-analysis of non-users before 2001, the lack of scientific basis for such an exclusion criteria and the inconsistency of these results when compared to our rationally designed comparison of starters and new users, we did not include the SS requested analysis in our BMJ paper. It simply did not add any reliable or relevant information to what already was included in Appendix 4. Further, as no previous study has adopted the requirement of no previous use of any OCs, all evidence suggests that the different results achieved in different studies have nothing to do with the speculations JD & SS have about this issue. We are confident that our inclusion of previous users of OCs before 2001 is a valid design decisions. It is also transparent as we do present in our paper rate ratios of the different user categories. As authors of a scientific paper it is our responsibility to present reliable data and not to report unsustainable results.
And fourth: If the speculations from JD & SS had the slightest relevance, you should expect a difference in risk between the older 3rd generation OCs with desogestrel or gestodene and the newer OCs with DRSP. However, the risk of VTE with use of OCs with DRSP was similar to the risk of VTE in users of 3rd generation pills. In addition, by allocating continuous users at start of study in the correct “duration category”, the study gained power in rate ratio analysis for longer duration of use categories.
Fifth, in Dingers own study (3), he stressed that the risk by length of use was constant after the first year, which contradicts the proposal of “attrition of susceptibles” in their critique.
And finally sixth, if previous use of OCs was a relevant issue, you should expect a differential rate ratio in risk of VTE according to comparable length of use categories. However, even in the group of more than four years of use, the rate ratio DRSP versus LNG was 2.31.
So for at least six good reasons there is no evidence of any differential influence from previous use of OCs on the risk estimates of VTE achieved in our new study among users of OCs with DRSP versus LNG.
On the authors behalf Øjvind Lidegaard
(continues in part 2 and part 3)
1. Dinger J, Shapiro S. Combined oral contraceptives, venous thromboembolism, and the problem of interpreting large but incomplete datasets. J Fam Plann Reprod Health Care 2011.doi:10.1136/fjprhc-2011-100260.
2. Lidegaard O, Nielsen LH, Skovlund CV, Skjeldestad FE, Lokkegaard 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.
3. Dinger J, Thai DM, Moehner S. The Risk of Venous Thromboembolism in OC Users: Time Patterns after Initiation of Treatment. Pharmacoepidemiology and Drug Safety, 2010; 19: S214-215.

Competing interests: The primary investigator received no salary for his work with this study, the EMA report or the manuscript. OLi 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. The other authors had nothing to declare.

07 December 2011
Øjvind Lidegaard
Professor in Obstetrics and Gynaecology
Gynaecological Clinic, Rigshospitalet
Blegdamsvej 9, 2100 Copenhagen, Denmark