Challenges of defining a non-inferiority margin: a case study of non-inferiority randomized controlled trials of oral anti-thrombolytic agents for prophylaxis of venous thromboembolic events after orthopedic surgery

Methods We searched in Pubmed and Cochrane-central-registerfor-controlled-trials for all NI RCTs of direct thrombin inhibitors (DTI) and direct inhibitors of factor Xa (DXAI) for prophylaxis of VTE. All NI trials had enoxaparin as their active comparator. Using the draft FDA guidelines for NI trials, we determined an NI margin, referred to as the reference NI margin, based on all published placebo-controlled trials on enoxaparin for the same indication, identified in PubMed and Cochranecentral-register-for-controlled-trials. We used preservedeffects of 50% and 67% to calculate the reference NI margin.