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RAPS

Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial

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Year of Publication: 2016

Authors: Hannah Cohen, Beverley J Hunt, Maria Efthymiou, ..., David A Isenberg

Journal: Lancet Haematol

Citation: Lancet Haematol 2016; 3: e426–36

Link: https://doi.org/10.1016/S2352-3026(16)30079-5

Clinical Question

Is rivaroxaban non-inferior to warfarin for anticoagulation in patients with antiphospholipid syndrome and previous venous thromboembolism?

Bottom Line

Rivaroxaban did not meet the non-inferiority threshold for endogenous thrombin potential compared to warfarin, but showed no increase in thrombotic risk and could be an effective and safe alternative in this patient population.

Major Points

  • Phase 2/3 non-inferiority trial comparing rivaroxaban 20mg daily vs standard-intensity warfarin in antiphospholipid syndrome
  • Primary endpoint was percentage change in endogenous thrombin potential (ETP) from baseline to day 42
  • ETP was significantly higher in rivaroxaban group (treatment effect 2.0, 95% CI 1.7-2.4, p<0.0001)
  • Peak thrombin generation was lower with rivaroxaban (treatment effect 0.6, 95% CI 0.5-0.8, p=0.0006)
  • No thrombotic events or major bleeding occurred in either group during 6 months
  • Quality of life visual analogue scores were significantly better with rivaroxaban

Design

Study Type: Randomised, controlled, open-label, phase 2/3, non-inferiority trial

Randomization: 1

Blinding: Open-label (no blinding)

Enrollment Period: June 5, 2013 to Nov 11, 2014

Follow-up Duration: 210 days

Centers: 2

Countries: UK

Sample Size: 116

Analysis: Modified intention-to-treat analysis using regression models adjusted for stratification variables and baseline values

Inclusion Criteria

  • Thrombotic antiphospholipid syndrome meeting international consensus criteria
  • At least one venous thromboembolic event when taking no or subtherapeutic anticoagulant therapy
  • Taking standard-intensity warfarin (target INR 2.5) for at least 3 months since last venous thromboembolic event
  • Age 18 years or older
  • Women using adequate contraception unless postmenopausal or sterilized

Exclusion Criteria

  • Previous arterial thrombotic events due to antiphospholipid syndrome
  • Recurrent venous thromboembolism when taking warfarin at therapeutic INR 2.0-3.0
  • Pregnancy or lactation
  • Severe renal impairment (creatinine clearance ≤29 mL/min)
  • Alanine aminotransferase more than twice upper limit of normal
  • Child-Pugh class B or C cirrhosis
  • Thrombocytopenia (platelets <75 × 10⁹/L)
  • Non-adherence to warfarin regimen
  • Taking prohibited medications (azole antifungals, protease inhibitors, strong CYP3A4 inducers, dronedarone)

Arms

FieldControlRivaroxaban
InterventionContinued standard-intensity warfarin with target INR 2.5 (range 2.0-3.0)20 mg oral rivaroxaban once daily (or 15 mg once daily if creatinine clearance 30-49 mL/min)
Duration180 days180 days

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Percentage change in endogenous thrombin potential (ETP) from randomisation to day 42Primary548 nmol/L per min (484-621)1086 nmol/L per min (957-1233)<0.0001
Peak thrombin generation at day 42Secondary85.7 nmol/L (72.3-101.5)55.6 nmol/L (46.8-66.1)0.60.00061
Thrombotic events at day 210Secondary00
Quality of life visual analogue scoreSecondary73 (1.8)80 (1.8)0.013
Major bleedingAdverse00
Clinically relevant bleedingAdverse2/55 (4%)3 (5%)
Serious adverse eventsAdverse3/55 (5%)4 (7%)

Subgroup Analysis

Exploratory post-hoc analysis showed no significant interactions between the effects of rivaroxaban and lupus anticoagulant positivity at baseline on thrombin generation parameters

Criticisms

  • Open-label design could introduce bias
  • Small sample size limits power for clinical endpoints
  • Short follow-up duration (6 months)
  • Excluded patients with arterial thrombosis and those needing higher-intensity anticoagulation
  • Primary endpoint was laboratory surrogate rather than clinical outcome
  • Single-country study limiting generalizability

Funding

Arthritis Research UK, Comprehensive Clinical Trials Unit at UCL, LUPUS UK, Bayer, National Institute for Health Research Biomedical Research Centre

Based on: RAPS (Lancet Haematol, 2016)

Authors: Hannah Cohen, Beverley J Hunt, Maria Efthymiou, ..., David A Isenberg

Citation: Lancet Haematol 2016; 3: e426–36

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