Robustness of placebo-controlled trials of extended-duration direct oral anticoagulant therapy for secondary venous thromboembolism prevention.

Direct oral anticoagulants (DOACs) have demonstrated efficacy in extended-duration secondary prevention in non-cancer patients with venous thromboembolism (VTE), but the robustness of these results has not been fully assessed. We performed a systematic review of phase 3 and 4 randomized placebo-controlled trials evaluating extended-duration DOACs therapy for secondary prevention of VTE. The primary outcome was symptomatic recurrent VTE in non-cancer patients. Secondary outcomes included major and clinically relevant non-major bleeding (CRNMB), number needed to treat (NNT), and number needed to harm (NNH). Fragility indices (FI) and quotients (FQ) were used to evaluate the robustness of trial findings. Four trials enrolling a total of 8,394 patients met the inclusion criteria. Extended-duration anticoagulation with DOACs consistently reduced recurrent VTE compared to placebo, with relative risk reductions of 80-93% and absolute risk reductions of 5-9%, yielding NNTs of 11-19. Extended DOACs therapy consistently showed net clinical benefit, with a pooled NNT of 14.4 versus an NNH of 116.2. Major bleeding was rare, while CRNMBs were slightly more common (although findings were statistically fragile across trials). Extended-duration DOACs therapy reduces recurrent VTE in non-cancer patients with a favourable safety profile compared to placebo in trial populations, supported by robust statistical evidence. These findings support DOACs as a preferred option for extended-duration secondary prevention of VTE.