Authors: Sandeep Dhanda 1, 2 Vicki Osborne 1, 2, Saad Shakir 1, 2

Affiliations: 1 Drug Safety Research Unit, 2 University of Portsmouth

Background

Women receiving anticoagulation are susceptible to the added risk of gynaecological bleeding (GB). This may occur in premenopausal women who experience physiological bleeding related to the ovulatory cycle and for whom the risk is greater, or postmenopausal women. Thus, the use of anticoagulation in women requires special consideration in terms of GB risk. It may be that DOACs overall or a particular DOAC are the wrong choice of treatment for women at risk.

Objectives

To examine the association between DOACs and GB in women, by comparing risk in users of DOACs to users of standard anticoagulant (AC) therapy (e.g. vitamin K antagonists (VKAs)).

Methods

4 databases were searched (July 2018) for clinical trials (CTs) and observational studies (OS) reporting GB in women taking DOACs or a comparator of standard AC therapy for any indication. Abstracts were screened followed by full review of a subset for eligibility. Studies reporting GB with DOACs but with no standard AC comparator were excluded. Due to a high degree of heterogeneity between studies in terms of study design, indications, outcome measures and use of different denominators, a meta-analysis was not performed.

Results

Records identified n=594; 16 eligible for inclusion (CTs n=7, OS n=9). Of the 6 studies specifically designed to evaluate GB in women with DOACs v. standard AC, 3 reported a significantly increased risk of this outcome with DOACs v. standard AC (rivaroxaban (riva) n=2 (HR 2.13; 95% CI [1.57, 2.89], risk ratio 2.3; p=0.009), and edoxaban (edox) n=1 (HR 1.7; 95% CI [1.1, 2.5])). Conversely, no significant difference for 2 studies (riva n=1, apixaban (apix) n=1) and a lower risk for 1 (dabigatran (dabi)) was observed (OR 0.59; 95% CI [0.30, 0.90]). The remaining 10 studies were not designed to evaluate GB with DOACs but reported this within study results; 1 reported a higher risk of GB with dabi v. standard AC (HR 2.27; 95% CI [1.32, 3.90]), and for the remaining 9, results were inconclusive due to non-significant/lack of hypothesis test results.

Conclusions

Gynaecological bleeding appears to be a common complication of DOACs, however, there is variability between DOACs. More evidence is available for riva, in which the risk of GB appears to be higher than with standard AC. Although limited, evidence suggests a higher risk with edox, lower risk with dabi and no difference with apix v. standard AC. Further research including head-to-head CTs and OS specifically investigating GB is needed to draw firm conclusions on which class of ACs (VKAs v. DOACs) are more favourable for women and the difference in risk between individual DOACs.