Re: Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10
In the Danish study the fundamental principle that exposure groups should be compared over the same time intervals is violated. The investigators state that follow-up was from 2001 to 2010. In fact, for women who were contraceptive users as of 2001, follow-up of COCs containing levonorgestrel (LNG) could actually have commenced as early as 1994, whereas for patch (EVRA) users follow-up could only have commenced in 2003, and for vaginal ring (NuvaRing) users in 2001 (the dates of introduction in Denmark). Only the occurrence of VTE was determined from 2001 to 2010.
For these reasons, with LNG-containing COCs as the reference, the duration-adjusted relative risks (RRs) of venous thromboembolism (VTE) for the patch (RR, 2.31) and vaginal ring (RR, 1.90) are not valid. Between 1994 and 2010, there were major advances in the detection and diagnosis of VTE (e.g., Duplex ultrasound), as well as increasing awareness of VTE risk among COC users. Moreover, women who had used LNG from as far back as 1994 without developing VTE would by 2001 have been at exceedingly low risk (depletion of susceptibles). Still further, the risk of VTE is highest in the first 3 months of COC use, followed by a decline to a lower but still elevated level thereafter1-3. Hence, in a valid comparison of different COCS it is essential to compare women who have not used COCs for at least 6 months (‘new users’) – and preferably, to compare women who have never used a COC previously (‘first-time-ever users’). And further still, the markedly reduced incidence of VTE in non-users of hormonal contraceptives (2.1 per 10 000 woman years) indicates that VTE was underascertained1-3, further augmenting the likelihood of bias.
The increased risk of VTE is a class effect dependent on the estrogen dose3, and it was predictable that a comparison of women who could have commenced use 7 or more years apart, and who also differed in the proportions of new and first-time-ever users, would have resulted in spuriously elevated RRs for the most recently introduced products.
The failure to control major confounding further invalidates the evidence. Body mass index and age are powerful determinants of VTE risk, and their combined effects are more than additive1,2. A family history of VTE is also a powerful determinant. The absence of data on these variables indicates that the Danish registry is an unsuitable resource for the evaluation of VTE risk.
1. Dinger JC Shapiro S. Combined oral contraceptives, venous thromboembolism, and the problems of interpreting large but incomplete datasets. J Fam Plann Reprod Health Care 2012;38:2-6.
2. Dinger JC, Heinemann LAJ, Kuhl-Habisch D. The safety of a drospirenone-containing contraceptive: final results of the European Active Surveillance study on oral contraceptives based on 142 475 women-years of observation. Contraception 2007;75:344-354.
3. Reid RL, Weshoff C, Mansour D, et al. Oral contraceptives and venous thromboembolism. Consensus opinion from and international workshop held in Berlin, Germany in December 2009. J Fam Plann Reprod Health Care 2010;36:117-122.
Competing interests: The author presently consults and in the past has consulted with manufacturers of hormonal contraceptives, including NuvaRing. In the past he has consulted with the manufacturer of EVRA.