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

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.

Drug therapy in anticoagulation: which drug for which patient?

“…A randomised clinical study comparing rivaroxaban and warfarin in over 100 APS patients with previous VTE showed the endogenous thrombin potential to be increased but the peak thrombin to be reduced in the rivaroxaban arm after 42 days of treatment. 41 The clinical significance of these results is not yet known. No data are available on NOACs in APS patients with arterial thrombosis; warfarin remains the anticoagulant of choice for both venous and arterial thrombosis in the APS setting.…”

Recurrent Thrombosis in Patients with Antiphospholipid Syndrome Receiving Newer Oral Anticoagulants: A Case Report and Review of Literature

“…Ongoing clinical trials to determine the safety and efficacy of NOACs in APS may lead to additional clarity. 14,18 This uncertainty should be discussed with the patients who should also be involved in the decisionmaking process.…”

“…The results of the RAPS trial, a randomized controlled, open label non-inferiority trial that compared rivaroxaban with warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS) 14 was recently published. The investigators concluded that the NOACs are non-inferior to VKAs.…”

Direct Oral Anticoagulants in Patients with Thrombophilia: Challenges in Diagnostic Evaluation and Treatment

“…The primary endpoint, the percentage change in endogenous thrombin potential (ETP) from randomization to day 42, was higher in the rivaroxaban group together with markedly lower peak thrombin generation, the most sensitive marker of thrombin formation. No VTE episodes or serious bleeding were reported, leading to the conclusion that rivaroxaban "could be an effective and safe alternative" in thrombotic APS [47]. Although the size of the study groups was limited and the observation period short, the RAPS study provided valuable confirmation that the impact of rivaroxaban on blood coagulation is comparable to warfarin with a target INR of 2.5 in patients with various forms of APS.…”

“…An open-label, randomized, controlled trial -rivaroxaban in antiphospholipid syndrome (RAPS) study, performed on thrombotic APS patients allocated to warfarin or rivaroxaban 20 mg daily, was published in September 2016 [47]. The primary endpoint, the percentage change in endogenous thrombin potential (ETP) from randomization to day 42, was higher in the rivaroxaban group together with markedly lower peak thrombin generation, the most sensitive marker of thrombin formation.…”