All contraceptive pills carry an increased risk for venous thromboembolism (VTE), but the newer ones are actually riskier, according to a combined population-based, nested case-control study published online May 26 in the BMJ.

Results of the study, the largest on this topic to date, showed that oral contraceptives containing a newer progestogen (desogestrel, gestodene, drospirenone, or cyproterone) had about double the risk of those containing an older one (levonorgestrel or norethisterone). The newer agent norgestimate was the exception.

“This study, based on national population and prescribing practices in the UK, has sufficient power to provide reliable comparative findings for different formulations of combined oral contraceptives,” write Yana Vinogradova, MSc, a research fellow in medical statistics, Division of Primary Care, University Park, in Nottingham, and colleagues.

“The results from our study and [a Danish national cohort study] provide evidence for relevant authorities concerned with prescribing guidelines or those involved with regulation of safety of medicines.”

In a journal news release, the researchers emphasize that oral contraceptives are remarkably safe and note that the observed elevation of VTE risk in the study is still far less than the up to 10-fold elevation of risk associated with pregnancy.

Current users of combined oral contraceptives “should not stop using them, but should consult their doctor and review their current type of pill at their next appointment if there are any concerns,” they recommend.

In an accompanying editorial, Susan S. Jick, DSc, a professor of epidemiology from the Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, Lexington, Massachusetts, writes, “[T]he results provide compelling evidence that these newer oral contraceptives are associated with a higher risk of venous thromboembolism than older options, despite attempts to develop safer hormonal contraceptives for women.”

She adds, “These results, combined with those published in [the similar Danish study], clarify inconsistencies in earlier studies and provide important guidance for the safe prescribing of oral contraceptives.”

Risk Increased Nearly Threefold

Vinogradova and colleagues analyzed data from UK general practices captured in the Clinical Practice Research Datalink and the QResearch primary care database. They identified 10,562 women aged 15 to 49 years who had a first VTE diagnosis between 2001 and 2013 and matched them by age, practice, and calendar year with 42,034 women who had not had a VTE.

In adjusted analyses, current users (those with use in the past 28 days, based on prescriptions) of any combined oral contraceptive had an elevated risk for VTE compared with counterparts with no such use in the past year (odds ratio, 2.97).

In drug-specific analyses, however, significantly greater elevations of risk were seen for current users of desogestrel (odds ratio [OR], 4.28), gestodene (OR, 3.64), drospirenone (OR, 4.12), and cyproterone (OR, 4.27) than for current users of levonorgestrel (OR, 2.38) and norethisterone (OR, 2.56) and norgestimate (OR, 2.53).

The absolute number of extra cases of VTE was lowest for levonorgestrel and norgestimate (six to seven per year per 10,000 exposed women for each) and highest for desogestrel and cyproterone (14 to 17 per year per 10,000 exposed women for each).

The study’s main findings were stronger when analyses were restricted to women experiencing a VTE who received prescriptions for anticoagulants and their control counterparts and to women who did not have any identifiable risk factors for VTE and their control counterparts. In addition, risk was elevated more for users aged 25 to 49 years than for younger users.

Analyses looking at the effect of estrogen dose in the contraceptive, possible only for norethisterone, desogestrel, and gestodene, did not show any significant association of dose with risk. In addition, analyses focusing on the duration of use showed a significantly higher risk for short-term users of levonorgestrel (using the pills for 84 days or less) compared with long-term users (using them for longer), but inconsistent results for the other drug types.

One coauthor is a professor of clinical epidemiology at the University of Nottingham and unpaid director of QResearch, a not-for-profit organization, which is a joint partnership between the University of Nottingham and EMIS (commercial IT supplier for 60% of general practices in the United Kingdom); she is also a paid director of ClinRisk, which produces open and closed source software to ensure the reliable and updatable implementation of clinical risk algorithms within clinical computer systems to help improve patient care. The other authors and Dr Jick have disclosed no relevant financial relationships.

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BMJ. Published online May 26, 2015.