CoChat
Sign Up
Cited by 410Systemic Lupus Erythematosus ResearchVenous Thromboembolism Diagnosis and ManagementBlood Coagulation and Thrombosis Mechanisms

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

Open access
Cohen, Hannah, Hunt, Beverley J, Efthymiou, Maria, Arachchillage, Deepa R J, Mackie, Ian J, Clawson, Simon, Sylvestre, Yvonne, Machin, Samuel J +6 more·2016·The Lancet Haematology
DOI 10.1016/s2352-3026(16)30079-5PMC PMC5010562
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: Rivaroxaban is established for the treatment and secondary prevention of venous thromboembolism, but whether it is useful in patients with antiphospholipid syndrome is uncertain. METHODS: This 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. FINDINGS: Of 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. INTERPRETATION: ETP 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. FUNDING: Arthritis Research UK, Comprehensive Clinical Trials Unit at UCL, LUPUS UK, Bayer, National Institute for Health Research Biomedical Research Centre.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/s2352-3026(16)30079-5

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In a post-hoc analysis of antiphospholipid syndrome patients in three RCTs of dabigatran versus warfarin and one RCT of rivaroxaban versus warfarin in venous thrombotic antiphospholipid syndrome, there were no differences in outcomes between direct oral anticoagulants and vitamin K antagonists for venous thrombosis.

    “In a post-hoc analysis of patients with APS included in three RCTs of dabigatran versus warfarin,26 and in one RCT of rivaroxaban versus warfarin in patients with venous thrombotic APS,27 there were no differences in outcomes between treatment with DOACs and VKA for venous thrombosis”

    From EULAR recommendations for the management of antiphospholipid syndrome in adults (2019) · cites this paper as [27]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 30

  1. [1]Erkan D Aquiar C Andrade D 14th International Congress in Antiphospholipid Antibodies Task Force report on antiphospholipid syndrome treatment trends Autoimmun Rev 13 2014 685 696 24468415
  2. [2]Ruiz-Irastorza G Cuadrado MJ Ruiz-Arruza I Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies Lupus 20 2011 206 218 21303837
  3. [3]Ruiz-Irastorza G Egurbide MV Ugalde J Aguirre C High impact of antiphospholipid syndrome on irreversible organ damage and survival of patients with systemic lupus erythematosus Arch Intern Med 164 2004 77 82 14718326
  4. [5]Andreoli L Chighizola CB Banzato A Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction and deep vein thrombosis: a critical review of the literature Arthritis Care Res (Hoboken) 65 2013 1869 1873 23861221
  5. [7]Eichinger S Gregor H Kollars M Kyrle PA Prediction of recurrent venous thromboembolism by endogenous thrombin potential and D-dimer Clin Chem 54 2008 2042 2048 18948369
  6. [8]Conway EM Bauer KA Barzegar S Rosenberg RD Suppression of hemostatic system activation by oral anticoagulants in the blood of patients with thrombotic diatheses J Clin Invest 80 1987 1535 1544 3680513 PMC442421
  7. [9]Hemker HC Al Dieri R De Smedt E Béguin S Thrombin generation, a function test of the haemostatic-thrombotic system J Thromb Haemost 96 2006 553 561 17080210
  8. [10]Brodin E Seljeflot I Arnesen H Hurlen M Applebom H Hansen JB Endogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment Thromb Res 123 2009 573 579 18474393
  9. [11]Gerotziafas GT Dupont C Spyropoulos AC Hatmi M Samama MM Differential inhibition of thrombin generation by vitamin K antagonists alone and associated with low-molecular-weight heparin Thromb Haemost 102 2009 42 48 19572066
  10. [12]Gerotziafas GT Elalamy I Depasse F Perzborn E Samama MM In vitro inhibition of thrombin generation, after tissue factor activation, by the oral, direct factor Xa inhibitor rivaroxaban J Thromb Haemost 5 2007 886 888 17388799
  11. [13]Green L Lawrie AS Patel S The impact of elective knee/hip replacement surgery and thromboprophylaxis with rivaroxaban or dalteparin on thrombin generation Br J Haematol 151 2010 469 476 20950405
  12. [14]Eerenberg ES Kamphuisen PW Sijpken MK Meijers JC Buller HR Levi M Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossfover study in healthy subjects Circulation 124 2011 1573 1579 21900088
  13. [15]Cohen H Doré CJ Clawson S Rivaroxaban in antiphospholipid syndrome (RAPS) protocol: a prospective, randomized controlled phase II/III clinical trial of rivaroxaban versus warfarin in patients with thrombotic antiphospholipid syndrome, with or without SLE Lupus 24 2015 1087 1094 25940537 PMC4527976
  14. [17]Cockcroft DW Gault H Prediction of creatinine clearance from serum creatinine Nephron 16 1976 31 41 1244564
  15. [18]Winter ME Basic clinical pharmacokinetics 4th edn. 2004 Lippincott Williams & Wilkins Philadelphia
  16. [19]Keeling D Mackie I Moore GW Greer IA Greaves M British Committee for Standards in Haematology. Guidelines on the investigation and management of antiphospholipid syndrome Br J Haematol 157 2012 47 58 22313321
  17. [21]Hochberg M Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus Arthritis Rheum 40 1997 1725 9324032
  18. [22]Tripodi A Chantarangkul V Clerici M Negri B Galli M Mannucci PM Laboratory control of anticoagulant treatment by the INR system in patients with the antiphospholipid syndrome and lupus anticoagulant Br J Haematol 115 2001 672 678 11736953
  19. [23]Arachchillage DR Efthymiou E Mackie IJ Lawrie AS Machin SJ Cohen H Rivaroxaban and warfarin achieve effective anticoagulation, as assessed by inhibition of TG and in-vivo markers of coagulation activation, in patients with venous thromboembolism Thromb Res 135 2015 388 393 25555316
  20. [24]Dargaud Y Luddington R Gray E Effect of standardisation and normalisation on imprecision of calibrated automated thrombography: an international multicentre study Br J Haematol 135 2007 303 309 17897307
  21. [25]Efthymiou M Lawrie AS Mackie I Thrombin generation and factor X assays for the assessment of warfarin anticoagulation in thrombotic antiphospholipid syndrome Thromb Res 135 2015 1191 1197 25895847
  22. [26]Cohen H Baglin T Plasma, plasma products and indications for their use Contreras M ABC of transfusion medicine 4th edn. 2009 British Medical Journal Books (Wiley-Blackwell) 40 47
  23. [27]Dargaud Y Luddington R Gray E Standardisation of thrombin generation test—which reference plasma for TGT? An international multicentre study Thromb Res 125 2010 353 356 19942257
  24. [28]Kubitza D Becka M Voith B Zuehlsdorf M Wensing G Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor Clin Pharmacol Ther 78 2005 412 421 16198660
  25. [29]Perzborn E Strassburger J Wilmen A In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor J Thromb Haemost 3 2005 514 521 15748242
  26. [30]Gerotziafas GT Elalamy I Depasse F Perzborn E Samama MM In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban J Thromb Haemost 5 2007 886 888 17388799
  27. [31]Arachchillage DRJ Mackie IJ Efthymiou M Isenberg DA Machin SJ Cohen H Interactions between rivaroxaban and antiphospholipid antibodies in thrombotic antiphospholipid syndrome J Thromb Haemost 13 2015 1264 1273 25850997
  28. [32]Crowther MA Ginsberg JS Julian J A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome N Engl J Med 349 2003 1133 1138 13679527
  29. [33]Finazzi G Marchioli R Brancaccio V 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 3 2005 848 943 15869575
  30. [34]Mueck W Lensing AW Agnelli G Decousus H Prandoni P Misselwitz F Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention Clin Pharmacokinet 50 2011 675 686 21895039

Cited by

Sorted by citations

Authors
Cohen, H., Hunt, B. J., Efthymiou, M., Arachchillage, D. R. J., Mackie, I. J., Clawson, S., Sylvestre, Y., Machin, S. J., Bertolaccini, M. L., Ruiz-Castellano, M., Muirhead, N., Doré, C. J., Khamashta, M., & Isenberg, D. A.
Affiliations
  • University College Hospital (GB)
  • St Thomas' Hospital (GB)
  • University College London (GB)
  • Guy's Hospital (GB)
Corresponding author
Cohen, Hannah
ORCID
Venue
The Lancet Haematology
Publisher
Elsevier BV
Published
2016-09
Volume
3
Issue
9
Pages
e426-e436
ISSN
2352-3026 (ISSN-L)
DOI
10.1016/s2352-3026(16)30079-5
PMC
PMC5010562
OpenAlex
W2514539105
Cited by
410
References
3
Citations by year
2026: 21 · 2025: 22 · 2024: 40 · 2023: 28 · 2022: 29 · 2021: 48 · 2020: 61 · 2019: 62 · 2018: 56 · 2017: 35 · 2016: 7 · 2015: 1
FWCI
56.75
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Haematology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, cc-by)
Funders
Versus Arthritis (19708)
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Internal Medicine › Venous Thromboembolism Diagnosis and Management
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Keywords
rivaroxaban, warfarin, thrombotic antiphospholipid syndrome, systemic lupus erythematosus, endogenous thrombin potential, thrombin generation, venous thromboembolism, anticoagulation, bleeding risk, non-inferiority, oral anticoagulants, thrombosis risk
MeSH terms
Rivaroxaban, Equivalence Trials as Topic, Anticoagulants, Female, Follow-Up Studies, United Kingdom, Humans, Lupus Erythematosus, Systemic, Male, Middle Aged, Thrombosis, Warfarin, Prevalence, Survival Rate, Antiphospholipid Syndrome, Treatment Outcome, Factor Xa Inhibitors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review