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Summary
Background Rivaroxaban is established for the treatment and secondary prevention of venous thromboembolism, but Lancet Haematol 2016;
whether it is useful in patients with antiphospholipid syndrome is uncertain. 3: e42636
See Comment page e403
Methods This randomised, controlled, open-label, phase 2/3, non-inferiority trial, done in two UK hospitals, included *Senior authors
patients with antiphospholipid syndrome who were taking warfarin for previous venous thromboembolism, with a Department of Haematology
target international normalised ratio of 25. Patients were randomly assigned 1:1 to continue with warfarin or receive (H Cohen MD) and Department
of Rheumatology
20 mg oral rivaroxaban daily. Randomisation was done centrally, stratied by centre and patient type (with vs without (Prof D A Isenberg MD),
systemic lupus erythematosus). The primary outcome was percentage change in endogenous thrombin potential University College London
(ETP) from randomisation to day 42, with non-inferiority set at less than 20% dierence from warfarin in mean Hospitals NHS Foundation
percentage change. Analysis was by modied intention to treat. Other thrombin generation parameters, thrombosis, Trust, London, UK;
Haemostasis Research Unit,
and bleeding were also assessed. Treatment eect was measured as the ratio of rivaroxaban to warfarin for thrombin Department of Haematology
generation. This trial is registered with the ISRCTN registry, number ISRCTN68222801. (H Cohen, M Efthymiou PhD,
D R J Arachchillage MD,
I J Mackie PhD,
Findings Of 116 patients randomised between June 5, 2013, and Nov 11, 2014, 54 who received rivaroxaban and 56 who
Prof S J Machin FRCP),
received warfarin were assessed. At day 42, ETP was higher in the rivaroxaban than in the warfarin group (geometric Comprehensive Clinical Trials
mean 1086 nmol/L per min, 95% CI 9571233 vs 548, 484621, treatment eect 20, 95% CI 1724, p<00001). Unit (S Clawson BSc,
Peak thrombin generation was lower in the rivaroxaban group (56 nmol/L, 95% CI 4766 vs 86 nmol/L, 72102, Y Sylvestre MSc,
N Muirhead PhD,
treatment eect 06, 95% CI 0508, p=00006). No thrombosis or major bleeding were seen. Serious adverse events
Prof C J Dor BSc), and Centre
occurred in four patients in each group. for Rheumatology, Division of
Medicine (Prof D A Isenberg),
Interpretation ETP for rivaroxaban did not reach the non-inferiority threshold, but as there was no increase in University College London,
London, UK; Department of
thrombotic risk compared with standard-intensity warfarin, this drug could be an eective and safe alternative in
Thrombosis and Haemophilia
patients with antiphospholipid syndrome and previous venous thromboembolism. (Prof B J Hunt MD) and Lupus
Research Unit
Funding Arthritis Research UK, Comprehensive Clinical Trials Unit at UCL, LUPUS UK, Bayer, National Institute for (M Ruiz-Castellano MD,
Prof M Khamashta MD), Guys
Health Research Biomedical Research Centre.
and St Thomas Hospitals NHS
Foundation Trust, London, UK;
Copyright The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. and Department of
Haematology (Prof B J Hunt),
Academic Department of
Introduction Direct oral anticoagulants, including rivaroxaban,6 are Vascular Surgery,
Thrombotic antiphospholipid syndrome is a potentially licensed for the treatment and secondary prevention Cardiovascular Division,
fatal and devastating disorder. The mainstay for of venous thromboembolism and are established as Faculty of Life Sciences and
secondary prevention of venous thromboembolism is therapeutic alternatives to low-molecular-weight heparins Medicine (M L Bertolaccini PhD),
and Lupus Research Unit,
anticoagulation with warfarin or other vitamin K and vitamin K antagonists. Patients with antiphospholipid Division of Womens Health
antagonists.1,2 Approximately 15% of patients with syndrome were probably included in phase 3 randomised (Prof M Khamashta), Kings
systemic lupus erythematosus have thrombotic controlled trials of direct oral anticoagulants, but, College London, London, UK
antiphospholipid syndrome, which severely worsens because antiphospholipid antibody status was not Correspondence to:
the outlook.3 Antiphospholipid syndrome is classied systematically documented in these trials, conrmation Dr Hannah Cohen, Haemostasis
Research Unit, Department of
as a rare disease,4 but a systematic review suggests of the usefulness of direct oral anticoagulants in these
Haematology, University College
that antiphospholipid antibodies are present in 10% patients is required. London, 1st Floor, 51 Chenies
of patients with deep vein thrombosis,5 which Generation of thrombin via the tissue factor pathway is Mews, London WC1E 6HX, UK
suggests possible underdiagnosis of antiphospholipid integral to the blood coagulation process. Markers of in- hannah.cohen@ucl.ac.uk
syndrome. Appropriate management of thrombotic vivo coagulation activation provide information about an
antiphospholipid syndrome is crucial to minimise its individuals thrombogenic potential,7 and their concen-
harmful eects. trations should be reduced after anticoagulation.8
Research in context
Evidence before this study When assessed by endogenous thrombin potential ([ETP] ie,
We searched MEDLINE and PubMed with the following phrases: the are under curve) alone, rivaroxaban was inferior to warfarin
antiphospholipid syndrome, systemic lupus erythematosus, in terms of anticoagulation intensity, but peak thrombin
venous thromboembolism, new oral anticoagulants, novel generation favoured rivaroxaban. Warfarin aects all thrombin
oral anticoagulants, direct acting oral anticoagulants, direct generation parameters equally, whereas rivaroxaban mainly
inhibitors of coagulation, non-vitamin K antagonist oral aects the initiation and propagation phases of thrombin
anticoagulants, warfarin, coumadin, vitamin K generation. Formation of the prothrombinase complex is
antagonists, dabigatran, rivaroxaban, apixaban, delayed and lag time and time to peak thrombin generation are
edoxaban, thrombin generation, and in vivo coagulation prolonged and, therefore, the ETP is greater than would be
activation markers. Further information was also requested expected for the degree of anticoagulation. Thus, the overall
from the manufacturers of the individual direct oral thrombogram indicated no increase in thrombotic risk with
anticoagulants. Thrombotic antiphospholipid syndrome is a rivaroxaban. This conclusion was supported by concentrations
potentially fatal and devastating disorder. Although the disorder of in-vivo coagulation activation markers being increased in
is rare, antiphospholipid antibodies are thought to be present in only a few patients in both treatment groups, and the absence
10% of patients with deep vein thrombosis, suggesting possible of new thrombotic events during 6 months of treatment.
underdiagnosis of thrombotic antiphospholipid syndrome. No major bleeding episodes were noted, and rivaroxaban was
Warfarin and other vitamin K antagonists are the standard of signicantly associated with improved quality of life.
care for the secondary prevention of venous thromboembolism Additionally, we found no evidence in in-vitro studies of
in patients with thrombotic antiphospholipid syndrome. antiphospholipid antibodies interfering with the anticoagulant
These drugs, however, can be particularly problematic in action of rivaroxaban.
patients with thrombotic antiphospholipid syndrome because
Implications of all the available evidence
of variable sensitivity of thromboplastins to lupus anticoagulant,
Rivaroxaban seems to oer an eective, safe, and convenient
which is present in many of these patients. Consequently, the
alternative to warfarin in patients with thrombotic
international normalised ratio (INR), which is used to monitor
antiphospholipid syndrome who have had previous venous
warfarin treatment, might not accurately reect anticoagulation
thromboembolism requiring standard-intensity warfarin therapy
intensity. Two randomised controlled trials in thrombotic
(ie, target INR 25, range 2030). The RAPS ndings are
antiphospholipid syndrome have reported no benets with
applicable to this group of patients due to the homogeneity of the
high-intensity versus standard-intensity warfarin in the
study population. An alternative to warfarin would be welcomed
prevention of recurrent thrombosis. Rivaroxaban and other
by these patients and their treating clinicians, particularly because
direct oral anticoagulants are eective and safe compared with
of issues with variable sensitivity of thromboplastins to lupus
warfarin for the treatment and secondary prevention of venous
anticoagulant and unstable INR needing frequent and
thromboembolism. Although antiphospholipid antibody status
unpredictable anticoagulant monitoring. Warfarin is also
was not systematically documented in randomised controlled
associated with risks of thrombosis or bleeding due to
trials of direct oral anticoagulants, it is likely that patients with
underanticoagulation and overanticoagulation, respectively.
antiphospholipid syndrome were included. In the Rivaroxaban in
The RAPS trial, however, was designed with a laboratory surrogate
Antiphospholipid Syndrome (RAPS) non-inferiority trial,
outcome measure that reects the mechanisms of action of the
therefore, we aimed to conrm the usefulness of rivaroxaban in
interventions because the large-scale, long-term clinical trials
secondary prevention of venous thromboembolism in patients
needed to assess recurrent venous thromboembolism are not
with antiphospholipid syndrome.
feasible in patients with antiphospholipid syndrome. The absence
Added value of this study of new thrombosis or major bleeding and the low rate of clinically
RAPS is slightly larger than the two previous randomised relevant bleeding indicate low risks in the subgroup of patients
controlled trials in patient with thrombotic antiphospholipid assessed and puts into context anecdotal reports in case studies
syndrome, and our inclusion criteria enabled recruitment of a and small case series of recurrent thrombosis after switching from
more homogeneous study population, that is, only patients warfarin to a direct oral anticoagulant in patients with
with previous venous thromboembolism needing antiphospholipid syndrome. The small but signicant
standard-intensity warfarin and none with arterial thrombosis improvement in the quality of life visual analoge score seen with
related to antiphospholipid syndrome, which is not a licensed rivaroxaban in RAPS is encouraging. Further studies are needed to
indication for direct oral anticoagulants. Because thrombotic dene the role of direct oral anticoagulants in the treatment of
antiphospholipid syndrome is clinically heterogeneous, the patients with antiphospholipid syndrome, including those who
homogeneity of our study population maximises the clinical need higher-intensity anticoagulation after recurrent
applicability of our results. Thrombin generation allows thrombotic events while they were taking standard-intensity
assessment of the anticoagulant eects of warfarin and anticoagulation, and those with stroke or other arterial
rivaroxaban despite these drugs dierent modes of action. thrombosis.
Thrombin generation triggered by tissue factor, therefore, or recurrent venous thromboembolism when taking
seems to be a relevant marker.9 Thrombin generation acts warfarin at a therapeutic INR of 2030 and those who
as a global measure of anticoagulation and can show the were younger than 18 years. Other exclusion criteria were
anticoagulant eects of warfarin and rivaroxaban despite pregnancy or lactation; severe renal impairment (creatinine
these drugs having dierent modes of action on the clearance calculated with the Cockcroft and Gault
coagulation mechanism. The thrombin generation curve formula17,18 29 mL/min); alanine aminotransferase more
is quantied in terms of the lag time, time to peak than twice the upper limit of normal; Child-Pugh class B or
thrombin generation, peak thrombin generation, and C cirrhosis; thrombocytopenia (platelets <75 10/L);
endogenous thrombin potential (ETP), which is the area non-adherence to warfarin regimen (based on clinical
under the curve. Warfarin reduces the ETP by 3050% of assessment); taking azole class antifungals, protease
that before warfarin or that in normal controls.10,11 inhibitors (eg, ritonavir) for HIV, strong CYP3A4 inducers
Rivaroxaban inhibits thrombin generation in whole blood (eg, rifampicin, phenytoin, carbamazepine, phenobarbital,
and platelet-rich plasma,12 and the ETP may be used as a or St Johns wort), or dronedarone; and refusal to give
measure of anticoagulation intensity.13,14 consent for the study site to inform a family doctor or
We did the Rivaroxaban in Antiphospholipid Syndrome health-care professional responsible for anticoagulation
(RAPS) trial to investigate whether rivaroxaban would care about participation.
provide anticoagulation non-inferior to that achieved All patients enrolled met the international consensus
with standard-intensity warfarin in patients with criteria for antiphospholipid syndrome,16 with testing for
antiphospholipid syndrome and previous venous antiphospholipid antibodies done in accordance with
thromboembolism, with or without systemic lupus national and international guidelines (appendix
erythematosus. The study protocol has been published15 pp 6, 7).16,19,20 All patients with systemic lupus ery- For the RAPS protocol see
and is available online. thematosus were classied according to the revised http://discovery.ucl.ac.
uk/1472201/
criteria of the American College of Rheumatologists21
Methods and reviewed in lupus clinics by experienced clinicians,
Study design according to standard activity and damage assessment
RAPS was a randomised, controlled, open-label, phase 2/3, indices, although the results were not part of this study.
non-inferiority clinical trial in patients with thrombotic We did not apply any performance status criteria for
antiphospholipid syndrome who were receiving trial entry, and all patients included in the trial were
standard-intensity warfarin for venous thromboembolism outpatients. We did not anticipate that mortality during
(appendix p 3). We recruited patients from specialist follow-up would dier from that in the general population. See Online for appendix
haematology and rheumatology clinics at University
College London Hospitals and Guys and St Thomas Randomisation and masking
Hospitals NHS Foundation Trusts, London, UK. Enrolled Randomisation was performed by a web-based
patients provided informed written consent after independent randomisation service (Sealed Envelope,
discussion with a hospital study investigator or a delegate. London, UK) to ensure allocation concealment. The
The trial was overseen by an independent trial steering schedule was created using permuted blocks with a
committee (appendix p 5). An independent data random block length, stratied by centre and patient
monitoring committee (appendix p 5) provided oversight type (with vs without systemic lupus erythematosus).
and monitored trial progress. Ethics approval was Participants were randomised 1:1 to remain on standard-
obtained from the University College London Hospitals intensity warfarin with target INR 25 (range 2030)
NHS Foundation Trust research and development oce, or to switch to 20 mg oral rivaroxaban once daily (or
having been approved by the National Research Ethics 15 mg once daily depending on local clinical care and
Service Committee South Central-Oxford A (reference following the summary of product characteristics in
12/SC/0566). patients with creatinine clearance 3049 mL/min) for
180 days (appendix pp 8, 9).6
Patients The trial was open label to ensure optimum warfarin
Eligible patients had thrombotic antiphospholipid dosing, as the variable sensitivity of thromboplastins to
syndrome (appendix p 3)16 and at least one venous lupus anticoagulant22 can lead to INR instability. This and
thromboembolism when taking no or subtherapeutic other factors, such as changing medication, can necessitate
anticoagulant therapy (appendix p 3), and had been frequent anticoagulant monitoring with unpredictable
taking standard-intensity warfarin (target international time intervals. Additionally, the management of bleeding
normalised ratio [INR] 25) for at least 3 months since events diers between patients receiving warfarin and
the last venous thromboembolic event. Women had to be rivaroxaban. Masking of treatment allocation was also not
using adequate contraception (appendix p 3) unless they possible in the RAPS central laboratory because dierent
were postmenopausal or had undergone sterilisation. tests were needed for the two anticoagulants, and samples
We excluded patients with previous arterial thrombotic taken at baseline and day 42 were tested simultaneously to
events (appendix pp 3, 4) due to antiphospholipid syndrome minimise variability between assays.
Data for the treatment groups are number (%) or geometric mean (95% CI) unless stated otherwise. ETP=endogenous thrombin potential. FEU=brinogen equivalent units.
N/A=not applicable. ED-EQ-5L=ve-level EuroQol-5D. VAS=visual analogue score. SAE=serious adverse events. SAR=serious adverse reactions. SUSAR=suspected unexpected
serious adverse reaction. *Except for one patient who withdrew before day 42 in the warfarin group. Estimated as ratio of rivaroxaban to warfarin for thrombin generation
and as the dierence between treatments (rivaroxabanwarfarin) for other outcomes. Regression models are adjusted for stratication variables and baseline values of each
variable. Includes only patients with at least three international normalised ratio measurements. Includes patients with bleeding episodes at more than one site; only most
severe reported here. Four patients (two withdrawals, one lost to follow-up, and one death) in the warfarin group did not reach day 210. ||Not judged to be related to
treatment; the event pre-dated the trial. **SAE grades are described in the main text.
Table 2: Results from regression models of thrombin generation parameters, in-vivo coagulation activation markers, and quality of life, adherence, and
clinical and safety measures in all patients assigned treatment*
9
with concentrations lower than 160 g/L, eight were
between 50 and 100 g/L, and six were lower than the
NR 285529 NR 285529 lower limit of detection of 50 g/L. Blood samples for
5
measurement were taken at 24 h after treatment in 39
3 (70%) of 56 patients, and within 6 h in all except four
patients (range 824 h).
Amidolytic factor X in patients taking warfarin
B correlated positively with ETP at day 42 (r=05, 95% CI
0307). Correlations between INR and ETP were
55
Time to peak thrombin generation (min)
3000
NR 13082291 NR 13082291 a background of chronic post-thrombotic lower limb
swelling following a previous femoral deep vein
thrombosis. A lower limb venous doppler scan showed
1100 changes related to the previous femoral vein deep vein
thrombosis but no new thrombosis. Rivaroboxan was
stopped while the patient received treatment with
450 therapeutic dose low-molecular-weight heparin, then
restarted (grade 2). This episode was reported as an SAE
because of the potential seriousness of the situation. The
170 second of these SAEs was intestinal perforation (grade 4).
Warfarin (R) Warfarin (W) Rivaroxaban Warfarin Four SAEs were reported in patients taking warfarin,
three of which were judged to be unrelated to the trial
Figure 2: Thrombin generation parameters at baseline (left) and day 42 (right)
drug: one patient had an acute exacerbation of asthma
Solid lines indicate medians, dotted lines indicate limits of normal ranges. NR=normal range. Warfarin
(W)=patients receiving warfarin at baseline who continued taking warfarin after randomisation. Warfarin associated with an upper respiratory tract infection
(R)=patients receiving warfarin at baseline who were switched to rivaroxaban at randomisation. (grade 3), one had sepsis (grade 4), and one developed
Discussion
When anticoagulation intensity was assessed by 0
percentage change in ETP alone, rivaroxaban was inferior
to warfarin in patients with antiphospholipid syndrome B
200
and previous venous thromboembolism. However, peak
thrombin generation was lower with rivaroxaban and,
therefore, the overall thrombogram indicated no
dierence in thrombotic risk. This conclusion is 150
Thrombin generation (nmol/L)
A limitation of RAPS is that it was not designed to been dened for clinical use. Population pharma-
conrm clinical ecacy and long-term safety. Rather, cokinetics indicate that peak rivaroxaban concentrations
the trial was designed with a laboratory surrogate are in the range 160360 g/L.34 29 (51%) of 57 RAPS
outcome measure to assess the mechanism of action of patients had peak therapeutic concentrations of at least
the interventions in these patients. A trial with a primary 160 g/L, and three of these had concentrations greater
endpoint of recurrent thrombosis would require a than 360 g/L. Six (11%) patients had peak
sample of several thousand patients, which is unfeasible concentrations lower than 50 g/L and were possibly
for patients with thrombotic antiphospholipid syn- non-adherent.
drome, and a much longer follow-up period. There was The absence of new thrombotic events during 6 months
an intended selection bias because we excluded patients of treatment in RAPS justies our selection of this
who had had venous thromboembolism and developed subgroup of patients with antiphospholipid syndrome
recurrent events while taking standard-intensity anti- and puts into context anecdotal case reports and ndings
coagulation (ie, needing higher-intensity anticoagul- in small case series of recurrent thrombosis after
ation) and those with arterial events. Thus, our cohort switching patients from warfarin to a direct oral
seemed to have antiphospholipid antibodies that caused anticoagulant. Of note, 28% of patients in RAPS had
clinical disease at the less aggressive end of the range triple positivity for lupus anticoagulant and antibodies
seen in patients with thrombotic antiphospholipid against cardiolipin and 2GPI at baseline and, therefore,
syndrome. Nevertheless, limiting the selection of had a particularly high-risk antibody prole.35
patients to those with thrombotic antiphospholipid Our ndings suggest that in patients with anti-
syndrome and previous venous thromboembolism phospholipid syndrome who have had previous venous
leading to treatment with standard intensity warfarin thromboembolism and need standard-intensity anti-
ensured a clinically homogeneous study population coagulation (ie, target INR 25) the overall thrombotic
which is in contrast to two previous, slightly smaller, risk, based on the overall thrombogram, in-vivo
randomised controlled trials.32,33 This feature is an coagulation activation markers and clinical outcomes, is
important strength of RAPS. Thrombotic antiphospho- not increased with rivaroxaban compared with that
lipid syndrome is clinically heterogeneous, with the risk related to warfarin. The absence of new thrombosis or
of recurrent thrombosis and intensity of anticoagulation major bleeding and low rate of clinically relevant bleeding
being dependent on the clinical phenotype.2 Thus, trials, supports this conclusion. Further studies are required
such as RAPS, that involve clinically homogeneous to dene the role of direct oral anticoagulants in
thrombotic antiphospholipid syndrome populations, antiphospholipid syndrome patients, including those
maximise clinical applicability for subgroups of patients. with venous thromboembolism who need higher-
We caution, therefore, that our results are not applicable intensity anticoagulation (ie, those without recurrent
to patients with antiphospholipid syndrome and venous venous thromboembolism while taking standard-
thromboembolism who need greater than standard- intensity anticoagulation) or antiphospholipid syndrome
intensity anticoagulation or with stroke or other arterial patients with stroke or other arterial thrombosis. Overall,
thrombosis. rivaroxaban seems ecacious and safe, and might oer a
Direct oral anticoagulants have several advantages convenient alternative to warfarin in this subgroup of
compared with warfarin. They avoid the need for patients with antiphospholipid syndrome.
routine anticoagulation monitoring, which is Contributors
particularly relevant to antiphospholipid syndrome HC was the chief investigator and BJH, MK and DAI were principal
patients because thromboplastins have variable investigators. HC, BJH, MK, and DAI conceived the study. HC, BJH,
SC, YS, SJM, NM, CJD, MK, and DAI designed the protocol. HC and
sensitivity to lupus anticoagulants and, therefore, the DAI obtained funding for the study. Data were collected by HC, BJH,
INR might not accurately reect anticoagulation ME, DRJA, MLB, MR-C, MK, and DAI, and all authors were involved in
intensity.22 If INR instability develops, frequent the interpretation of the data. ME and DRJA did the assays. IJM
anticoagulant monitoring will be needed with supervised the RAPS central laboratory. YS and CJD did the statistical
analysis. HC wrote the rst draft of the Article and all authors
unpredictable time intervals, and the risk of thrombosis contributed to the revisions.
or bleeding will be increased due, respectively, to
Declaration of interests
undercoagulation or overcoagulation. The percentage HC has received institutional research support from Bayer, with
of time in the therapeutic range for patients in the honoraria for lectures and participation on an advisory board being
RAPS warfarin group was only 55% up to day 180. This diverted to a local charity. DRJA has received honoraria from Bayer for
nding highlights that the predictable anticoagulant participation in an international meeting. The other authors declare no
competing interests.
eect of rivaroxaban oers a potential advantage in
antiphospholipid syndrome patients, but ecacy is Acknowledgments
We thank the patients involved in the trial, the RAPS trial investigators
dependent upon adherence to the treatment regimen. for recruiting patients to the study, the research sta who assisted with
Unlike treatment with warfarin, where anticoagulation patient recruitment, data collection, and data management, and
is constant, rivaroxaban leads to peaks and troughs. No members of the trial oversight committees (appendix pp 5, 3032).
Heather Short, Comprehensive Clinical Trials Unit, University College
range of therapeutic rivaroxaban concentrations have
London, London, UK, took over from SC as the trial manager from 18 Winter ME. Basic clinical pharmacokinetics, 4th edn. Philadelphia:
April 20, 2015. The National Institute of Biological Standards and Lippincott Williams & Wilkins, 2004.
Control (NIBSC), Potters Bar, UK, kindly provided the thrombin 19 Keeling D, Mackie I, Moore GW, Greer IA, Greaves M.
generation reference plasma. British Committee for Standards in Haematology. Guidelines on
the investigation and management of antiphospholipid syndrome.
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