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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

(Continued from part 2)
Risk according to length of use.
Most previous studies have demonstrated a decreasing risk of VTE with increasing length of use, so that the risk is elevated about 50% the first year, and thereafter is almost constant.

We were also able to demonstrate such an overall trend by time. When you stratify current users into 16 different user groups, each with confirmed and non-confirmed events, and thereafter further subdivide your exposure time into four categories according to length of use, you cannot expect to find an equal decrease for all sub-groups by time. We nevertheless found a small although significant decrease for users of OCs with DRSP when comparing use for less than a year with use for a year or longer (2). The difference in the relative risk estimates by time of use for OCs with DRSP between our 2009 and 2011 publications are probably a result of the different censoring rules applied in the two analyses. Actually we have found no other study demonstrating a decreasing trend by time for specifically OCs with drospirenone. On the contrary, the FDA study (4) and an Israeli study (5) did not find any consistent trend in risk of VTE by duration of use for OCs with DRSP.
Surprisingly, Dinger did not report any risk estimates according to length of use in his EURAS publication or his German case-control study from 2010.

JD & SS write (page 3 second column) that “...the investigators stipulated rules based on several assumptions, in order to minimise the impact of the lack of precise exposure information..” This statement is wrong. The detailed set of allocation rules was a result of exceptionally precise exposure information. Therefore we had to decide how we would define e.g. continuous use, new use, re-started use and switched use, all made possible due to the very precise exposure information. These rules were not made on assumptions, but were established by the Steering Committee in order to ensure the highest possible validity of the risk estimates.

Confounding by BMI and family disposition.
Of nine existing studies examining the risk of VTE in users of OCs with DRSP, five had access to BMI. In none of these studies did confounder control for BMI change the risk estimates or rate ratios between OCs with DRSP versus LNG significantly, and in four of five not at all (5-9). Two of these studies were conducted by Dinger. The average BMI in his first study was 22.0 among users of OCs with LNG and 22.9 among users of OCs with DRSP (6). The proportion of women with BMI ≥30 was (read from Fig 1 in (6)) 5.3% in users of LNG OCs and 8.2% among users of DRSP OCs, but users of DRSP OCs were also slightly older than the users of LNG OCs. Dinger stated ““..the differences were small, and the preferential prescribing pattern identified here could only slightly increase the incidence of VTE … for the DRSP cohort” (6). As BMI did not influence the risk estimates materially in any of these five studies, it is difficult to understand why JD & SS continues to insist that our data should be invalid due the this missing information. The same studies have documented that users of DRSP are not selected according to BMI or other risk factors of VTE.

Similar arguments can be made concerning the postulated confounding influence from family disposition. Despite being a definite risk factor for VTE, in no study over the last 10 years was it found to be a confounder.

So despite being repeated by JD & SS again and again, there is no scientific evidence at all, suggesting that the lack of confounder control for BMI or family disposition distorted our results or rate ratios.

Audit
After we had delivered our EMA report, Bayer-Pharma asked us whether we were willing to participate in an external audit of our study. That request was not made by the Steering Committee. We accepted this audit on the condition that if it was used by Bayer-Pharma in any external connection, we should have the right to comment on the audit-report. With the statements about this audit made by JD & SS in their critique, Bayer-Pharma has violated this agreement. It should be noted, however, that the audit pertains to documentation of procedures, not the reliability of the results. Secondly we asked that the audit team not only analysed our scientific process but also our actual scientific results. This request was refused by Bayer-Pharma. The conclusion of the audit report was that certain formal recordkeeping procedures set forth in a set of accreditation rules, many of which are applicable in clinical trial settings rather than rules for use of a government national registry, were not followed, but that the auditors had no reason to doubt the qualifications of the investigator team or the validity of the results. We could add that no specific procedural rules were agreed to in advance of our study, and that we were working to meet specific time constraints making it difficult to fulfil some accreditation rules e.g. that two independent statisticians should have done all the analyses for comparison.

Several of the statements made by JD & SS concerning this audit are objectively wrong. E.g. there was a detailed signed protocol describing the statistical analysis strategy before the analysis was commenced. The audit team had access to all our data and all our analyses – so transparency was definitively present.
Concerning transparency, it is also important to be aware of the fact, that Danish registries are available for any (qualified) scientist who want to investigate a scientific issue. Thus any other researcher could get access to the same data as based our analyses, as these data belongs to the state and not to any particular scientist.
Finally the willingness to conduct a re-analysis of our 2009 study, and our agreement after the conclusion of the re-analysis to an external audit, prove more than anything else our scientific openness and wish to ensure transparency. Few researchers can claim to have accepted such oversight, nor have any of Bayer’s company sponsored studies been subjected to such scrutiny.
On the authors behalf
Øjvind Lidegaard

References
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.
4. 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.
5. 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.
6. Dinger JC, Heinemann LAJ, Kühl-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.
7. 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.
8. Dinger J, Assmann A, Möhner 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.
9. 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: 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
Oejvind Lidegaard
Professor in Obstetrics and Gynaecology
Rigshospitalet, University of Copenhagen
Blegdamsvej 9, 2100 Copenhagen Ø