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Table 4 Summary of completed and ongoing clinical trials of the use of DOACs in APS. Adapted from references [32, 70,71,72,73,74,75,76]

From: Antiphospholipid Syndrome Committee of the Brazilian Society of Rheumatology position statement on the use of direct oral anticoagulants (DOACs) in antiphospholipid syndrome (APS)

Trial Design Patient Population Intervention Comparison Primary Outcome Results/ ECD
RAPS (NCT02116036) Prospective, controlled, phase 2/3, non-inferiority RCT Primary or secondary thrombotic APS with previous isolated venous thromboembolism Rivaroxaban 20 mg once daily Warfarin (INR 2.0–3.0) Endogenous thrombin potential (ETP) Rivaroxaban did not reach the non-inferiority threshold
TRAPS (NCT02157272) Phase 3, open-label, multicenter, non-inferiority RCT with blinded end-point Triple positive thrombotic APS patients Rivaroxaban 20 mg once daily (CrCl> 50) or 15 mg daily (if CrCl 30–50) Warfarin (INR 2.0–3.0) Cumulative incidence of thromboembolic events, major bleeding and vascular death Terminated prematurely due to an excess of events in rivaroxaban arm
ASTRO-APS (NCT02295475) Prospective, open-label, blinded event, phase 4 pilot RCT Primary or secondary thrombotic APS. Exclusion: previous arterial events and recurrent venous thromboembolism when taking warfarin with INR of 2.0–3.0. Apixaban 2.5 mg twice a day (increased to 5 mg twice a day + brain MRI after protocol modification) Warfarin (INR 2.0–3.0) Rates of thrombosis and deaths caused by thrombosis/ major bleeding plus clinically relevant non-major bleeding over 1 year Protocol modification (2017): unanticipated excessive risk of arterial events during the first months in apixaban group.
ECD: December 2019.
Canadian RAPS (NCT02116036) Pilot phase 4, open-label RCT Primary or secondary thrombotic APS (history of arterial thrombosis allowed). Exclusion: arterial thrombosis or recurrent venous events while on anticoagulation. Rivaroxaban 20 mg daily None (single-arm) Rates of venous and arterial thrombosis and rates of minor, major and fatal bleeding Single-arm feasibility study;
Rates of thrombosis similar to warfarin studies
NCT02926170 Prospective, open-label, phase 3 RCT APS patients with previous arterial events and recurrent thrombosis Rivaroxaban 20 mg once daily (CrCl> 50) or 15 mg daily (if CrCl 30–50) Acenocoumarol (INR 2.0 to 3.0 or 2.5 to 3.5 if recurrent thrombosis) New thrombotic event or incidence of major bleeding (time frame: 36 months) Rivaroxaban did not reach the non-inferiority threshold
RISAPS (NCT03684564) Prospective, controlled, phase 2/3, non-inferiority RCT Primary or secondary thrombotic APS with previous stroke or other ischemic brain manifestations Rivaroxaban 15 mg twice a day Warfarin (INR between 3.0–4.0) Rate of chance in brain white matter hyperintensity volume on MRI (baseline and 24 months) ECD: October 2022
  1. APS antiphospholipid syndrome, CrCl creatinine clearance, DOACs Direct oral anticoagulants, ECD estimated completion date, INR international normalized ratio, RCT randomized clinical trial