Rivaroxaban to treat thrombotic antiphospholipid syndrome
Authors: Rolf T Urbanus
Journal: The Lancet Haematology (2016)

Thrombosis is one of the clinical hallmarks of antiphospholipid syndrome, a heterogeneous autoimmune disorder associated with the presence of antiphospholipid antibodies.1Miyakis S Lockshin MD Atsumi T et al.International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS).J Thromb Haemost. 2006; 4: 295-306Crossref PubMed Scopus (5155) Google Scholar Thrombosis can occur in any vascular bed, but most patients present with venous thrombosis or ischaemic stroke.2Cervera R Piette JC Font J et al.Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients.Arthritis Rheum. 2002; 46: 1019-1027Crossref PubMed Scopus (1656) Google Scholar Patients with antiphospholipid syndrome have a high risk of recurrent thrombotic events. The standard treatment for secondary prevention of venous thromboembolism is vitamin K antagonists. The intensity of anticoagulation needed to optimise prevention of secondary events has been debated, with arguments against and for high-intensity anticoagulation (international normalised ratio [INR] 3·0–4·0). Two randomised controlled trials showing that standard-intensity anticoagulation (target INR 2·0–3·0) is non-inferior to high-intensity treatment3Crowther MA Ginsberg JS Julian J et al.A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome.N Engl J Med. 2003; 349: 1133-1138Crossref PubMed Scopus (782) Google Scholar, 4Finazzi G Marchioli R Brancaccio V et al.A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS).J Thromb Haemost. 2005; 3: 848-853Crossref PubMed Scopus (476) Google Scholar lessened the debate, but with the arrival of direct oral anticoagulants targeting either thrombin or activated coagulation factor X, the discussion has restarted. The reported safety of direct oral anticoagulants combined with an increase in patients' wellbeing due to reduced need for monitoring are important arguments in favour of the use of these drugs for secondary prevention of venous thromboembolism. Case reports of patients with antiphospholipid syndrome who have had thrombosis while taking direct oral anticoagulants, however, have raised some concerns.5Win K Rodgers GM New oral anticoagulants may not be effective to prevent venous thromboembolism in patients with antiphospholipid syndrome.Am J Hematol. 2014; 89: 1017Crossref PubMed Scopus (57) Google Scholar, 6Schaefer JK McBane RD Black DF Williams LN Moder KG Wysokinski WE Failure of dabigatran and rivaroxaban to prevent thromboembolism in antiphospholipid syndrome: a case series of three patients.Thromb Haemost. 2014; 112: 947-950Crossref PubMed Scopus (78) Google Scholar Randomised controlled trials are urgently needed to resolve these issues. In The Lancet Haematology, Hannah Cohen and colleagues7Cohen H Hunt BJ Efthymiou M et al.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.Lancet Haematol. 2016; 3: e426-e436Summary Full Text Full Text PDF Scopus (260) Google Scholar provide evidence that similar anticoagulation status can be achieved with rivaroxaban or warfarin in patients with antiphospholipid syndrome. They did a randomised controlled trial involving patients who were taking warfarin for previous venous thromboembolism, with a target INR of 2·5. After 6 months of follow-up during which anticoagulation status was assessed, only small differences in anticoagulation were found, leading the authors to conclude that rivaroxaban is non-inferior to warfarin. The primary endpoint of the study was a laboratory comparison of the efficacy of warfarin and rivaroxaban. These two drugs have notably different effects on the coagulation system: warfarin essentially decreases the concentrations of several coagulation factors, whereas rivaroxaban alters coagulation reaction kinetics by interfering with the prothrombinase complex. Thus the drugs cannot by compared directly for efficacy. For this reason, Cohen and colleagues compared anticoagulation intensity, assessed with calibrated automated thrombography, which is a holistic test of coagulation that measures thrombin generation rather than fibrin formation. Of note, though, the inherent differences between warfarin and rivaroxaban remain apparent in this assay, making it difficult to interpret the reported findings. The endogenous thrombin potential (the parameter most frequently reported in the literature for calibrated automated thrombography), indicated inferiority of rivaroxaban. By contrast, peak thrombin concentrations, which Cohen and colleagues argue more accurately reflects thrombotic risk than endogenous thrombin potential, suggested non-inferiority, supporting their conclusion of non-inferiority of rivaroxaban. Probably the most compelling evidence for the similar anticoagulant effects with rivaroxaban and warfarin was that the plasma concentrations of in-vivo markers of coagulation, thrombin–antithrombin complexes, D-dimers, and prothrombin fragment 1.2, were slightly raised in only a few patients in both treatment groups. The most pressing question that needs to be answered in relation to the use of direct oral anticoagulants for prevention of venous secondary thrombosis in patients with antiphospholipid syndrome is whether rivaroxaban is non-inferior to warfarin and other vitamin K antagonists clinically as well as in the laboratory. With 54 patients in the rivaroxaban group and 56 patients in the warfarin group, the study by Cohen and colleagues7Cohen H Hunt BJ Efthymiou M et al.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.Lancet Haematol. 2016; 3: e426-e436Summary Full Text Full Text PDF Scopus (260) Google Scholar did not have sufficient power to investigate the clinical efficacy of rivaroxaban. Nevertheless, no thrombotic recurrences or major bleeds were reported in the 6-month follow-up period, which suggests that this drug could be a safe and effective alternative for warfarin in a larger number of patients. Nevertheless, some caution should be applied because antiphospholipid syndrome is a highly heterogeneous disorder in terms of clinical presentation and risk profiles. Although Cohen and colleagues recruited a well defined, homogeneous group of patients, those with the high risk triple-positive phenotype (positive for lupus anticoagulant and antibodies against β2 glycoprotein I and anticardiolipin8Pengo V Ruffatti A Legnani C et al.Clinical course of high-risk patients diagnosed with antiphospholipid syndrome.J Thromb Haemost. 2010; 8: 237-242Crossref PubMed Scopus (432) Google Scholar) were under-represented. Moreover, patients who had had recurrent venous thromboembolism while taking standard-intensity warfarin were excluded. Whether treatment with rivaroxaban would be equally efficacious in these subgroups of patients needs to be assessed. Although the findings of Cohen and colleagues are hopeful,7Cohen H Hunt BJ Efthymiou M et al.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.Lancet Haematol. 2016; 3: e426-e436Summary Full Text Full Text PDF Scopus (260) Google Scholar the efficacy of rivaroxaban treatment for secondary prevention of thrombosis in patients with antiphospholipid syndrome remains unclear. The outcomes of larger clinical trials investigating these questions are eagerly awaited. I declare no competing interests. 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 trialETP 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. Full-Text PDF Open Access