It's time for head-to-head trials with direct oral anticoagulants.

Direct oral anticoagulants (DOACs) have become the recommended first choice anticoagulant agent for treatment of acute venous thromboembolism (VTE) in non-cancer patients and are increasingly prescribed worldwide. They have not only intrinsic advantages, such as rapid onset of action and wide therapeutic windows, but also a lower risk of major, intracranial and fatal bleeding in VTE patients compared to vitamin K antagonists. Even though DOACs are often referred to as uniform drug class, there is growing evidence that each DOAC has a specific risk profile. Indirect comparisons and retrospective cohort studies suggest that apixaban may be associated with a lower risk of major bleeding than other DOACs, but there are no head-to-head trials with DOACs. Therefore, current guidelines do not recommend one DOAC over another and the choice of a specific DOAC is mainly based on physician and patient preferences, reimbursement and availability. Retrospective cohort studies and VTE registries are important to identify potential differences in efficacy and safety between DOACs; but they are methodologically too limited to inform the optimal choice of oral anticoagulant agent. Randomized controlled trials are crucial to inform sound treatment recommendations, because proper randomization is the key to unprejudiced treatment allocation and minimization of unmeasured and unknown confounding. Given increasing evidence of differences in safety profiles of DOACs from indirect comparisons and observational studies, it's time for head-to-head trials with DOACs.