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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