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

Thanks to Dr. Alfred R Pauls for his rapid response to our paper on oral contraceptives (OC) and venous thrombosis (1).

First Dr. Pauls think I did wrong in using the term “accusations”. This term should be seen on the background of eight circumstances:

1. Samuel Shapiro and Jürgen Dinger published about half a year after our primary publication in 2009 (2) a critique in which they concluded that our study was invalid for mainly three reasons: a) left censorship, b) missing confounder control for BMI, c) lack of validation of our end points (VTE). We were never presented for this critique before publication, but refused all these three critique points as a possible explanation of the increased risk of VTE in users of OC with drospirenone as compared with users of OC with levonorgestrel (3).

2. Before publishing their critique, Shapiro and Dinger participated in so called “expert meeting” in Berlin, arranged by Bayer Pharma, in which the Danish and the Dutch studies were criticised according to the same points as in their paper. None of the authors of the Danish or Dutch studies were invited to ensure the possibility of defence of our study methods.

3. We accepted after a request from the European Medicines Agency to conduct a new analysis of Danish registry data. Shapiro planned as a member of the steering committee the protocol of this new analysis, and signed and approved the protocol. The new study a) eliminated left censorship, b) stated that BMI has not been a (significant) confounder in any study with access to this information and c) validated all end points. The new results demonstrated a rate ratio between users of OC with drospirenone versus users of OC with LNG of 2.1 (1.6-2.8)(1).

4. Nowhere in the protocol of the new study it was stated, that an analysis should be conducted in which the women were not allowed to have used hormonal contraception at any time before the study period. This wish was a tertiary wish from Shapiro, after he realised the results of the new analysis.

5. Contrary, it was clearly stated in the protocol, that we should make an analysis restricted to starters and new users, where new users were defined as women with at least 12 weeks pause before current use. These results were presented as planned in appendix 4 of our BMJ paper.

6. We conducted dozens of stratified supplementary analyses in the report to the European Medicines Agency. All these sub-analyses showed the same rate ratio of about 2. But there is a limit to how tiny sub-stratifications you can do, before you drown in stochastic noise. That is so few events that coincidence and chance are more prevalent than valid estimates. The request by Shapiro was such an example. With exclusion of 94% of the exposure time and 93% of the VTE events in users of OC with levonorgestrel you simply have too little power to make valid and reliable estimates. I could add that I could deliver several other small samples demonstrating larger rate ratios than two. As author you have the responsibility to present reliable results, not stochastic noise. This has nothing to do with censoring results for you or anybody else.

7. No other study to my knowledge has limited included women to women who have never used any type of hormonal contraception before current use. Neither the EURAS study by Dinger et al. in which Shapiro was also in the steering committee.

8. All these things have we explained Samuel Shapiro in writing and verbally several times. So he is and was fully aware of these scientific facts.

Perhaps “accusations” was not the most appropriate word, - I take the full responsibility for that – but that choice could be influenced by an approaching saturation point of an apparently endless critique from Samuel Shapiro, despite how many times we prove his critique points wrong.
Next Dr. Pauls talks about “true first-ever users” with reference to two studies by Suissa et al. (4) and by Dinger et al. (5), respectively. However, in the study by Suissa, as I read it, the inclusion criteria was that 2nd and 3rd generation users of OC were first time users of these products, not first time users of any hormonal contraception. In the study of Dinger et al. (which by the way was just an abstract) they defined starters as women with a pause of at least 4 weeks before current use. By way of comparison we had at least 12 weeks of pause. So nothing in the two references Dr. Pauls refers to indicates that our starters were less “true” than starters in previously conducted studies.

And further. If Dr. Pauls think women should have been without hormonal contraceptive use for a longer period than 12 weeks before current use, what should then be the scientific argument for that? I have seen no study demonstrating or even suggesting that previous use more than 12 weeks ago should have any influence on risk estimates of VTE with new use. If such study exists, I would be grateful for a reference.

Finally concerning John Tukey: Why not choose an exact answer to a right question?

Øjvind Lidegaard

1. 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.

2. Lidegaard O, Lokkegaard E, Svendsen Al, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009; 339: b2890.

3. Lidegaard Ø. Critique of a Danish cohort study on hormonal contraception and VTE. J Fam Plann Reprod Health Care 2010;36:103-104 doi:10.1783/147118910791069303

4. Suissa S, Blais L, Spitzer WO, Cusson J, Lewis M, Heinemann L. First-time use of newer oral contraceptives and the risk of venous thromboembolism. Contraception 1997; 56(3):141-6.

5. 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: 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.

21 November 2011
Ojvind Lidegaard
professor of obstetrics and gynaecology
Gynaecological Clinic 4232, Rigshospitalet, University of Copenhagen, Denmark
oejvind.lidegaard@rh.regionh.dk