A single-arm feasibility cohort study of rivaroxaban in antiphospholipid syndrome

Kimberly Legault, Mark Blostein, Marc Carrier, Susan Khan, Sam Schulman, Sudeep Shivakumar, Cynthia Wu, Mark A Crowther, Kimberly Legault, Mark Blostein, Marc Carrier, Susan Khan, Sam Schulman, Sudeep Shivakumar, Cynthia Wu, Mark A Crowther

Abstract

Background: There is uncertainty regarding the safety and effectiveness of direct oral anticoagulant agents in patients with antiphospholipid syndrome (APS). We performed a multicenter feasibility study to examine our ability to identify and obtain consent from eligible APS patients and to obtain 95% adherence with daily rivaroxaban administration, in order to inform and power a larger study. Clinical outcomes of bleeding and thrombosis were also collected.

Methods: APS patients with prior venous thromboembolism (VTE) were recruited over 2 years (Oct 2014-Sept 2016) and followed for ≥ 1 year. Patients were assessed clinically every 3 months and had pill counts performed every 6 months. Numbers of patients fulfilling study criteria, as well as those consenting to participate, were tracked, and percentage adherence based on pill counts was recorded. These data were compared against the feasibility endpoints. Rates of thrombosis and bleeding were calculated. Criterion for feasibility was obtaining consent from 135 of 150 identified APS patients over 2 years.

Results: Ninety-six eligible patients were identified, and 14 declined participation. Eighty-two patients were followed for a mean of 19 months, representing 129.8 patient-years. Average rivaroxaban adherence was 95.0%. During follow-up, there were 4 thromboembolic events (2 cerebrovascular and 2 VTE). There were no episodes of major bleeding.

Conclusions: Adequately powered comparative trials using patient-important outcomes in APS are unlikely to be successful due to inability to recruit sufficient numbers of study subjects. This study does not reveal a higher than expected risk of recurrent thromboembolic disease compared to historical cohorts; however, this is an uncontrolled study in relatively low-risk APS patients.

Trial registration: The study was registered with clinicaltrials.gov, identifier NCT02116036, April 16, 2014.

Keywords: Antiphospholipid syndrome; Feasibility studies; Hemorrhage; Rivaroxaban; Thromboembolism.

Conflict of interest statement

Competing interestsThis study received support from Bayer. MB has received advisory board fees and research support from Bayer. MC has received research funding from BMS and Leo Pharma and honoraria from Pfizer, Bayer, Leo Pharma, and Sanofi. SK has received advisory board fees from BMS, Pfizer, Sanofi, and Aspen. S. Shivakumar has received honoraria from Bayer and Pfizer. CW has received advisory board fees for Leo pharma and Pfizer. KL, MAC, S. Schulman declared no additional COI.

© The Author(s) 2020.

References

    1. Miyakis 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;4:295–306. doi: 10.1111/j.1538-7836.2006.01753.x.
    1. Hamsten A, Norberg R, Björkholm M, et al. Antibodies to cardiolipin in young survivors of myocardial infarction: an association with recurrent cardiovascular events. Lancet. 1986;1:113–116. doi: 10.1016/S0140-6736(86)92258-0.
    1. Bertero MT, Bazzan M, Carignola R, et al. Antiphospholipid syndrome in northwest Italy (APS Piedmont Cohort): demographic features, risk factors, clinical and laboratory profile. Lupus. 2010;21:806–809. doi: 10.1177/0961203312446974.
    1. Crowther 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;349:1133–1138. doi: 10.1056/NEJMoa035241.
    1. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e44S–e88S. doi: 10.1378/chest.11-2292.
    1. Ahmad Y, Lip GYH. Stroke prevention in atrial fibrillation: where are we now? Clin Med Insights Cardiol. 2012;6:65–78. doi: 10.4137/CMC.S8976.
    1. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499–2510. doi: 10.1056/NEJMoa1007903.
    1. Buller HR, Prins MH, Lensin AWA, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–1297. doi: 10.1056/NEJMoa1113572.
    1. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342–2352. doi: 10.1056/NEJMoa0906598.
    1. Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med. 1992;117:303–308. doi: 10.7326/0003-4819-117-4-303.
    1. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995;332:993–997. doi: 10.1056/NEJM199504133321504.
    1. Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165:1095–1106. doi: 10.1001/archinte.165.10.1095.
    1. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–694. doi: 10.1111/j.1538-7836.2005.01204.x.
    1. Connolly SJ, Eikelboom JW, Bosch J, et al. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet. 2018;391:205–218. doi: 10.1016/S0140-6736(17)32458-3.
    1. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015;74:1011–1018. doi: 10.1136/annrheumdis-2013-204838.
    1. Rudd P, Byyny RL, Zachary V, et al. Pill count measures of compliance in a drug trial: variability and suitability. Am J Hypertens. 1988;1:309–312. doi: 10.1093/ajh/1.3.309.
    1. Rudd P, Byyny RL, Zachary V, et al. The natural history of medication compliance in a drug trial: limitations of pill counts. Clin Pharmacol Ther. 1989;46:169–176. doi: 10.1038/clpt.1989.122.
    1. Jayaraman S, Rieder MJ, Matsui DM. Compliance assessment in drug trials: has there been improvement in two decades? Can J Clin Pharmacol. 2005;12:e251–e253.
    1. Finazzi 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;3:848–853. doi: 10.1111/j.1538-7836.2005.01340.x.
    1. Cohen 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–e436. doi: 10.1016/S2352-3026(16)30079-5.
    1. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132:1365–1371. doi: 10.1182/blood-2018-04-848333.
    1. Galli M, Luciani D, Bertolini G, et al. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003;101:1827–1832. doi: 10.1182/blood-2002-02-0441.

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