Another flawed database analysis of VTE risk and hormonal contraceptives

Lidegaard O, Nielson LH, Skovlund CW, Lokkegaard E. Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10 BMJ 2012;344:e2990 doi: 10.1136/bmj.e2990 (Published 10 May 2012)

This is basically a companion paper to the one published last year in the BMJ, which concentrated on the Pill and was comprehensively criticised in the January issue of the Journal (Dinger & Shapiro 2012), to which readers are referred, as well as to the Rapid Responses posted on the BMJ website. This analysis, also from the Danish registry looks at the EVRA patch NuvaRing, Implanon and the levonorgestrel-releasing intra-uterine system (Mirena IUS). All the previous issues of confounding, lack of information regarding smoking, BMI, and family history, and not comparing like with like apply here.

It is important to compare new users with new users, as a well-established fact is that the risk of VTE is highest in the first 6 months of use of oestrogen-containing contraceptives. It is therefore important to look at the launch dates of contraceptive products. NuvaRing was launched in Denmark in late 2001 / early 2002, while the EVRA patch was launched there in September 2003. Meanwhile combined pills containing levonorgestrel have been in use since the 1970s, and those containing norgestimate since the mid 1980s. Thus, since the study period began in 2001, all users of NuvaRing and EVRA must have been new users, and so also more likely to be first time users / women with risk factors. Meanwhile, the users of the comparator COCs were more likely to be long term users and therefore at lower risk, since the high risk women in those groups will have been weeded out within the first 6 months of use – before the study began (ie attrition of susceptibles). The effect of duration of use is most clearly seen with NuvaRing in Table 4, where compared with non-users of hormonal contraceptives,  the relative risk becomes appreciably lower with increasing duration of use, declining from 8.36 for <1 year of use to 3.83 for use of 1 to 4 years. In addition, the numbers in each duration category are small, leading to random variability.  For the patch (6 exposed women) and the implant (5 women) not even the overall numbers are adequate.

With regard to the two progestogen only methods under study, not surprisingly neither was associated with a significantly increased risk of VTE – progestogen only methods have not been implicated in VTE risk, since this is related to oestrogen (Reid et al, 2010). Indeed, progestogen only methods are advised for women with risk factors for VTE (Blanco-Molina et al 2012). However, in the abstract, the authors misleadingly state that ‘the relative risk was increased in women who used subcutaneous implants’ and yet their relative risk of 1.4 had confidence intervals of 0.6 – 3.4, ie not even approaching statistical significance.  For the IUS, not only was the relative risk not increased, it was significantly decreased at 0.6 (95% CI 0.4 – 0.8). This has no biological plausibility and simply highlights the lack of credibility of the analysis.

Anne Szarewski, Editor-in-Chief, J Fam Plann Reprod Health Care

Diana Mansour, Consultant in Community Gynaecology and Reproductive Health Care, Head of Sexual Health Services, Newcastle Upon Tyne,


Dinger JC, Shapiro S. Combined oral contraceptives, venous thromboembolism, and the problem of interpreting large but incomplete datasets  J Fam Plann Reprod Health Care 2012;38:2–6. doi:10.1136/jfprhc-2011-100260

Reid RL, Westhoff C, Mansour D, de Vries C, Verhaeghe J, Boschitsch E,et al.   Oral Contraceptives and Venous Thromboembolism: Consensus Opinion from an International Workshop held in Berlin, Germany in December 2009  J Fam Plann Reprod Health Care 2010; 36(3): 117–122

Blanco-Molina MA, Lozano M, Cano A, Cristobal I, Pallardo LP, Lete I. Progestin-only contraception and venous thromboembolism Thrombosis Research 129 (2012) e257–e262