Drospirenone-containing oral contraceptives may increase the risk of venous thromboembolism
- Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, Lexington, Massachusetts, USA
- Correspondence to: Dr Susan S Jick, Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, 11 Muzzey Street, Lexington, MA 02421, USA;
Implications for practice and research
The risk of arterial thrombosis (AT) is very low in all oral contraceptive pills (OCPs)
Risks of venous thromboembolism (VTE) vary according to the progestin type
Drospirenone OCPs confer a higher risk of VTE than levonorgestrel OCPs
That OCPs increase the risk of venous and arterial thrombosis has been well recognised and well researched since OCPs were first marketed. Since the earliest reporting of the high risk of VTE (deep vein thrombosis and pulmonary embolism) in OCP users, the doses and formulations of both the oestrogen and progestin components of OCPs have changed, initially resulting in a decrease in the risk of thrombotic events, and later leading to differences in risk between OCPs. However, the following questions remain: what are the risks of thrombotic events with today's OCPs? And do these risks vary between different preparations?
To address these questions for the newer drospirenone OCPs, Wu and colleagues reviewed all 13 available comparative studies in relation to the risk of both VTE and AT, published between 2007 and 2012.
The authors concluded that there is insufficient data to determine whether drospirenone-containing OCPs confer an increased risk of AT compared to other OCPs, but that they may increase the risk of VTE in comparison to users of any OCP (range of risk estimates: 0.9–6.4) and more specifically to users of levonorgestrel-containing OCPs (range of risk estimates:1.0–3.3).
AT is very rare in healthy young women, thus data on AT risk are sparse, there are no well-powered studies of OCPs in relation to AT and available results are conflicting. The absolute risk for AT is very low in an OCP-using population and the benefits of OCPs are believed to outweigh the minimal risk. However, with regard to VTE, published studies have found varying results for drospirenone OCPs compared to other OCPs ranging from a finding of no increased risk to risks greater than three-fold. Wu and colleagues posited that these differences can be explained by variation in methods. Indeed, they found differences between studies, highlighting the importance of accurate and thorough presentation of results to aid interpretation of findings. First, the comparison groups differed across studies: some included third generation OCPs in the comparison group, some used levonorgestrel and others had a non-exposed referent. In the review the comparator description was usually limited to ‘unexposed to drospirenone’, which would include exposures to no OCP, third-generation OCP or a levonorgestrel OCP. Each of these comparators yields a different magnitude of effect, as each one confers a different risk of VTE. Third-generation OCPs have been shown to increase the risk of VTE compared to levonorgestrel OCPs, consequently, including them as a comparator would lead to a lower relative risk of drospirenone OCPs. Thus, without knowing the comparator, the reader cannot properly assess the relative effect of drospirenone compared to other OCPs.
Case definition is also important and this differed across studies. Some studies included all cases of VTE (including people with prior VTE or other cardiovascular disease), others included only idiopathic cases (those with no other proximate causes such as recent surgery or lower leg injury) and others included some, but not all, non-idiopathic cases. These important differences could explain the range of results in the reviewed studies, yet the necessary details were not provided or discussed in the review and the tables failed to fully describe the inclusion and exclusion criteria for each study. Therefore, direct comparisons between the studies could not be made. Finally, data related to the study size was misleading and difficult to interpret as some studies were cohort studies that included many people but yielded relatively few cases, while the case–control studies had comparatively fewer people but more cases and thus more relevant information. The information presented in the tables was inadequate to fully appreciate the true differences between the studies.
Ultimately, it was not clear, given the lack of critical assessment of the varied methods, how the authors came to the conclusion that ‘drospirenone-containing OCPs may increase the risk of VTE compared with levonorgestrel-containing OCPs and non-use of OCPs’. Perhaps a more accurate and useful conclusion would have been that compared with levonorgestrel OCPs, drospirenone OCPs yield an increased risk of VTE.
Despite the higher risk of drospirenone OCPs, VTE is rare in healthy young women and the risks of VTE in pregnancy and postpartum are substantially higher than in OCP users. Thus, preventing unintended pregnancies must remain a high priority and women should have multiple contraceptive options and be informed of each of their risks. Regardless of whether the thrombotic risk of drospirenone OCs compared to levonorgestrel OCs is increased by 1.5-fold or threefold, the absolute risk is still low.
Competing interests None.