Women are still significantly under-represented in clinical trials for treatment of acute VTE, despite improvements in recent decades, new research shows.

In a short communication published in Contemporary Clinical Trials, a group of experts stressed that a multifaceted approach will be crucial to improving understanding of the problem and increasing female participation in both observational studies and randomised controlled trials, “so that high-quality knowledge reduces treatment disparities and improves patient outcomes”.

The review looked at data on representation of women in RCTs underpinning the regulatory approval of direct oral anticoagulants (DOACs) for acute VTE, as an illustrative example of the issue.

While it was reassuring that each RCT included at least 40% of women in the studied cohorts, the pooled proportion of women was only 43%, which, the authors noted, was far less than that seen in large multicentre VTE registries such as RIETE (50.5% female) and GARFIELD-VTE (49.6% female).

The picture was similar for extended VTE treatment; the proportion of women included in results of the RE-MEDY and RE-SONATE trials for dabigatran was just 39% and 45%, respectively, while for AMPLIFY-EXT, which assessed apixaban, it was 42.6%.

Crucially, none of the pivotal trials for acute VTE treatments included any pregnant or lactating women, a particularly pertinent finding “given the unknown risks of teratogenicity and transfer into breast milk with these agents”, the authors emphasised.

Trials for thromboprophylaxis in pregnancy: A global failure 

Professor Beverley Hunt, a Haematology Consultant at Guy’s and St. Thomas’ Hospitals NHS Foundation Trust and review author, told the limbic that “While representation of women in leadership committees of clinical trials, grant agencies and journals seems very good in the UK, we face the global failure of doing trials around thrombosis prevention and management in pregnancy and the puerperium.

“Indeed, despite the widespread use of thromboprophylaxis in pregnancy, there have never been RCTs looking at efficacy and safety of thromboprophylaxis in pregnancy or puerperium.”

The authors stressed that prevention and treatment of VTE should be among the research priorities in pregnancy, which is already being addressed in the UK; an NIHR funded UK team, led by Sarah Davis from the School of Health and Related Research at the University of Sheffield, is currently  exploring the possibility of trials in this area.

Specifically, the team is seeking to determine the value of undertaking a study to determine the clinical and cost-effectiveness of risk stratification tools for the prediction of VTE and the provision of thromboprophylaxis for women in pregnancy and after delivery, with the research due for completion next month.

Elsewhere, the review authors highlighted that a “multitude of barriers” could be preventing equitable participation and representation of women in VTE trials and registries, including a lack of public awareness of the burden of VTE in women and/or ongoing studies, a lack of representation of women in leading research, concerns over including complex subgroups such as pregnant or lactating women – two subgroups at particular risk of VTE – in trials, and the under-reporting of sex-specific findings in completed studies.

“Novel and multifaceted interventions are urgently needed to change this status quo,” they said. In the first instance, a holistic systematic assessment of the scope of the problem based on sex differences is needed. As such, a group investigators, including the authors of this review, will undertake a systematic assessment of representation of women across recent VTE trials and registries.

Also, public awareness on the burden of VTE needs to be raised, and women need to be involved at various stages of research, including on academic committees and investigative teams and in leadership positions that shape research agendas and trial designs. Patients, both women and men should also be “actively engaged as research partners in the development of research studies, rather than mere study subjects”.

Researchers must also take into account participation obstacles that are specific to women when designing trials, including logistical and accessibility barriers, fertility concerns, and concerns about privacy and issues related to stigma, particularly in transgender women and those from marginalised or isolated communities, they said.

The authors also highlighted the need for studies to be designed with the aim of identifying sex-specific and differentiating mechanisms that influence outcomes, including collection of sex-related biological data, and that trial data is analysed and reported separately for male and female study participants.