Abstract
SummaryBackgroundRivaroxaban is established for the treatment and secondary prevention of venous thromboembolism, but whether it is useful in patients with antiphospholipid syndrome is uncertain.MethodsThis randomised, controlled, open-label, phase 2/3, non-inferiority trial, done in two UK hospitals, included patients with antiphospholipid syndrome who were taking warfarin for previous venous thromboembolism, with a target international normalised ratio of 2·5. Patients were randomly assigned 1:1 to continue with warfarin or receive 20 mg oral rivaroxaban daily. Randomisation was done centrally, stratified by centre and patient type (with vs without systemic lupus erythematosus). The primary outcome was percentage change in endogenous thrombin potential (ETP) from randomisation to day 42, with non-inferiority set at less than 20% difference from warfarin in mean percentage change. Analysis was by modified intention to treat. Other thrombin generation parameters, thrombosis, and bleeding were also assessed. Treatment effect was measured as the ratio of rivaroxaban to warfarin for thrombin generation. This trial is registered with the ISRCTN registry, number ISRCTN68222801.FindingsOf 116 patients randomised between June 5, 2013, and Nov 11, 2014, 54 who received rivaroxaban and 56 who received warfarin were assessed. At day 42, ETP was higher in the rivaroxaban than in the warfarin group (geometric mean 1086 nmol/L per min, 95% CI 957–1233 vs 548, 484–621, treatment effect 2·0, 95% CI 1·7–2·4, p<0·0001). Peak thrombin generation was lower in the rivaroxaban group (56 nmol/L, 95% CI 47–66 vs 86 nmol/L, 72–102, treatment effect 0·6, 95% CI 0·5–0·8, p=0·0006). No thrombosis or major bleeding were seen. Serious adverse events occurred in four patients in each group.InterpretationETP for rivaroxaban did not reach the non-inferiority threshold, but as there was no increase in thrombotic risk compared with standard-intensity warfarin, this drug could be an effective and safe alternative in patients with antiphospholipid syndrome and previous venous thromboembolism.FundingArthritis Research UK, Comprehensive Clinical Trials Unit at UCL, LUPUS UK, Bayer, National Institute for Health Research Biomedical Research Centre.
Highlights
Thrombotic antiphospholipid syndrome is a potentially fatal and devastating disorder
Antiphospholipid syndrome is classified as a rare disease,[4] but a systematic review suggests that antiphospholipid antibodies are present in 10% of patients with deep vein thrombosis,[5] which suggests possible underdiagnosis of antiphospholipid syndrome
In the Rivaroxaban in Antiphospholipid Syndrome (RAPS) non-inferiority trial, we aimed to confirm the usefulness of rivaroxaban in secondary prevention of venous thromboembolism in patients with antiphospholipid syndrome
Summary
Thrombotic antiphospholipid syndrome is a potentially fatal and devastating disorder. The mainstay for secondary prevention of venous thromboembolism is anticoagulation with warfarin or other vitamin K antagonists.[1,2] Approximately 15% of patients with systemic lupus erythematosus have thrombotic antiphospholipid syndrome, which severely worsens the outlook.[3] Antiphospholipid syndrome is classified as a rare disease,[4] but a systematic review suggests that antiphospholipid antibodies are present in 10% of patients with deep vein thrombosis,[5] which suggests possible underdiagnosis of antiphospholipid syndrome. Direct oral anticoagulants, including rivaroxaban,[6] are licensed for the treatment and secondary prevention of venous thromboembolism and are established as therapeutic alternatives to low-molecular-weight heparins and vitamin K antagonists. Patients with antiphospholipid syndrome were probably included in phase 3 randomised controlled trials of direct oral anticoagulants, but, because antiphospholipid antibody status was not systematically documented in these trials, confirmation of the usefulness of direct oral anticoagulants in these patients is required
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