By: Dr. Geoffrey Modest
The BMJ just published a large analysis of the relationship between combined oral contraceptives OCPs and the risk of venous thromboembolism VTE (see BMJ 2015;350:h2135). They analyzed 2 nested case-control studies from 2 different UK databases, with a combined input from 1340 general practices, assessing the first diagnosis of VTE in women aged 15-49 from 2001-2013, and comparing this group to 5 controls matched for age, practice, and calendar year.
Results:
–10562 cases of VTE. mean age 38, 27% smokers in the VTE cases and 21% in controls, obesity in 27% vs 16% in controls. established risk factors for VTE were 47% vs 26% in controls
–odds ratio for incident VTE and use of OCPs in the previous year, adjusted for smoking, alcohol, ethnic group, BMI, comorbidities, and other contraceptives:
–current exposure to any OCP was associated with increased risk of VTE [odds ratio OR 2.97 (2.78-3.17)] vs no OCP exposure over the previous year, with breakdown as follows.
–newer OCPs:
–desogestrel OR 4.28 (3.66-5.01)
–gestodene OR 3.64 (3.00-4.43) –not available in the US
–drospirenone OR 4.12(3.43-4.96)
–cyproterone OR 4.27 (3.57-5.11) –not available in the US
–older OCPs (second generation)
–levonorgestrel OR 2.38 (2.18-2.59)
–norethisterone OR 2.56 (2.15-3.06) –not available in the US
–norgestimate OR 2.53 ( 2.17-2.96) –actually a third generation OCP which is partly metabolized to levonorgestrel, but is less androgenic than levonorgestrel and is actually considered a second generation one in Denmark.
–this translates to: the number of extra cases of VTE per year per women
–levonorgestrel was lowest at 6 (5-7), along with norgestimate at 6 (5-8)
–desogestrel was highest at 14 (11-17), along with cyproterone at 14 (11-17)
–overall, the risk associated with gestodene was 1.5x higher than levonorgestrel (the most commonly used in the UK), and those of desogestrel, drospirenone, and cyproterone was about 1.8x higher
–desogestrel had a slightly higher odds ratio for VTE with higher doses of estrogen. norethisterone and gestodene actually had slightly higher VTE rates at the lower estrogen dosages (these were not significant, which seems to support the primary association being with the progestin in these women already on lowish doses of estrogen)
So, most, but not all, studies over the past 2 decades have often shown increased VTE risk in the 3rd and 4th generation OCPs. The current very large UK groups, given the high quality of reporting, provides more information, though it is retrospective and observational. In terms of bias, one might think that since there have been older studies showing increased VTE risk with the newer agents, there might have been preselection bias to avoiding these agents in women surmised to be at somewhat increased risk, leading to understating the actual risk. Although I do not prescribe OCPs so often these past years, I must admit that I have been largely avoiding the newer agents because of the issue of increased VTE found in several of the earlier studies, and now confirmed here.