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Antithrombotic treatment failures in antiphospholipid syndrome: the new anticoagulants?

H. Cohen and SJ Machin
Lupus 2010 19: 486
DOI: 10.1177/0961203310361355

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 Lupus (2010) 19, 486–491
http://lup.sagepub.com

REVIEW

Antithrombotic treatment failures in antiphospholipid syndrome:

the new anticoagulants?
H Cohen and SJ Machin
Department of Haematology, University College London, London, UK

Anticoagulation with oral vitamin K antagonists (VKA) is the mainstay of the treatment of
venous and/or arterial thromboembolism in patients with antiphospholipid syndrome (APS),
although the optimal intensity of anticoagulation remains controversial. The limitations of
existing anticoagulants have driven a search for novel agents. Dabigatran etexilate
(PradaxaÕ ), a direct thrombin inhibitor (DTI), and rivaroxaban (XareltoÕ ), the first in a
new class of drugs, the oral direct factor Xa (FXa) inhibitors, are both fixed-dose orally
administered agents. They are now licensed in the UK and Europe for the prevention of
venous thromboembolism (VTE) in adult patients undergoing elective total hip replacement
(THR) or total knee replacement (TKR). Prospective randomized clinical trials suggest that
these agents, and also apixaban, a further oral direct anti-Xa inhibitor, may have potential in
other areas including the treatment of acute VTE, prevention of stroke or systemic embolism
in patients with atrial fibrillation (AF) and acute coronary syndromes. Here, we summarize
current indications for these agents and address the potential for their use in patients with
thrombotic APS. Lupus (2010) 19, 486–491.

Key words: Dabigatran; Rivaroxaban; Antiphospolipid syndrome; Thrombosis;

arterial,venous

Current anticoagulant therapy in thrombotic some patients with APS a target INR of 2.5 (2.0–
antiphospholipid syndrome 3.0) is insufficient.
There is no consensus on the optimal manage-
Venous and/or arterial thromboembolism are char- ment of patients who develop recurrent or progres-
acteristic features of the antiphospholipid syn- sive thrombosis despite therapeutic oral VKA
drome (APS), with the current mainstay of the therapy. Current strategies include increasing the
treatment of thromboembolism anticoagulation target therapeutic INR range, the addition of
with oral vitamin K antagonists (VKAs). low-dose aspirin, or substitution of oral VKA by
Prospective, randomized controlled trials suggest subcutaneous (SC) therapeutic dose low molecular
that high-intensity warfarin (target International weight heparin (LMWH).3
Normalized Ratio [INR] 3.5) is not superior to Warfarin has a slow onset of action of 3–5 days
moderate-intensity (target INR 2.5)1,2 in these and a narrow therapeutic window. This, as well as
cases. However, the optimal intensity of anticoagu- its numerous drug and dietary interactions, and
lation with oral VKA remains disputed, particu- potential for a variation of action with alcohol,
larly in patients with a high risk of recurrent intercurrent illness, exercise and smoking, necessi-
venous thrombosis, who were not included in tates frequent monitoring of the INR, which is
these trials, and those with arterio-thrombotic inconvenient and has resource implications.
stroke and recurrent cerebral infarction who were Over-anticoagulation with warfarin is associated
probably under-represented. It is likely that for with a risk of bleeding and under-anticoagulation
is associated with a risk of thrombosis.
VKA monitoring in patients with antiphospholi-
pid antibodies (aPL) can be complicated by the
Correspondence to: Dr Hannah Cohen, Department of Haematology, variable responsiveness of thromboplastins to
University College London Hospitals NHS Foundation Trust, 250
Euston Road, London NW1 2PJ, UK.
lupus anticoagulants (LA) which may in turn
Email: hannah.cohen@uclh.nhs.uk potentially influence the validity of the
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prothrombin time (PT)-INR in monitoring oral
VKA treatment in patients with APS. A multicen-
tre study of laboratory INR testing concluded that
the effect of LA interference on the PT-INR mea-
sured with the majority of commercial thrombo-
plastins is not enough to cause concern if
insensitive thromboplastins, properly calibrated to
assign them an instrument-specific International
Sensitivity Index, are used. The investigators also
suggested that new thromboplastins, especially
those made of relipidated tissue factor, should be
checked to see if they are insensitive to the effects of
aPL before they are used to monitor oral anticoa-
gulant treatment in patients with APS.4 Whilst
these procedures are generally routine in specialist
centres, they may not be as easily observed in other
institutions, and thus, as a result, the INR may not
accurately reflect the true anticoagulation intensity.
In a subset of APS patients, probably up to 10%,
point-of-care (POC) INR testing may produce fal-
sely elevated results. Where there is concern about
the validity of INR testing, either based on labora-
tory or POC testing, an alternative method, i.e. a
single coagulation factor such as a chromogenic
factor X, may be a suitable method to monitor
the VKA effect.5,6 The potential effect of LA
on the INR may also be associated with apparent
instability of the INR, necessitating frequent antic-
oagulant monitoring with the attendant inconve-
nience to the patient and the costs. LA detection
in patients on VKA may be problematic because of
the prolonged basal clotting time.7 This limits the
ability to diagnose APS in patients on VKA and
also monitoring of aPL status in those with an
established diagnosis.
LMWHs require SC administration. Further-
more, LMWH may induce heparin-induced throm-
bocytopenia (HIT) and their long-term use may be
associated with osteoporosis. Fondaparinux, used
chiefly as an alternative to LMWHs, also requires
SC administration. The limitations of existing
anticoagulants highlight the unmet need for an
agent which fulfils the criteria of an ‘ideal’ antic-
oagulant safely, and this has driven a search for
novel agents.
Pharmacology of the new oral anticoagulants
The coagulation system is centrally involved in the
formation of both arterial and venous thrombi.
Existing anticoagulants such as unfractionated
heparin (UFH), LMWH and warfarin, act on a
number of targets whereas the newer agents have
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Antithrombotic treatment failures in antiphospholipid syndrome: the new anticoagulants?
H Cohen and SJ Machin
487
been designed to be selective for a single target in
the coagulation mechanism.
Dabigatran etexilate
Dabigatran etexilate (PradaxaÕ ) (Boehringer
Ingelheim) is a potent, competitive, reversible
direct thrombin (activated factor IIa) inhibitor
which binds to thrombin and blocks its interaction
with substrates, thus preventing fibrin formation,
thrombin-mediated activation of factors V, VIII,
XI and XIII and thrombin-induced platelet aggre-
gation. Dabigatran etexilate is a pro-drug which is
rapidly absorbed following oral administration and
completely converted into the active form dabiga-
tran in plasma and the liver. The terminal half-life
is 14–17 h and in healthy volunteers peak plasma
concentrations of dabigatran are reached within
0.5–2 h of oral administration. Eighty percent of
the drug is excreted unchanged renally.
As a direct thrombin inhibitor (DTI), dabigatran
has the following potential advantages over UFH/
LMWH: (a) the ability to inhibit free and
clot-bound thrombin, whereas UFH and LMWH
are indirect thrombin inhibitors and therefore have
limited capacity to limit propagation of thrombus;
(b) DTIs do not bind to plasma proteins and should
offer a more predictable anticoagulant response
compared with heparin; (c) DTIs do not bind to
platelet factor 4 (PF4) and should be unaffected
by the release of PF4 from platelet-rich thrombi.
Heparin-type induced thrombocytopenia asso-
ciated with dabigatran should therefore be unlikely.
Rivaroxaban
Rivaroxaban (XareltoÕ ; Bayer HealthCare AG) is a
highly selective, reversible, competitive and
dose-dependent direct oral FXa inhibitor.
Rivaroxaban is rapidly and almost completely
absorbed (absolute bioavailability 80–100%) and
the plasma concentration peaks at 2–4 h after oral
intake (SPC Xarelto). Only one-third of the admin-
istered rivaroxaban dose is eliminated unchanged (in
the urine) with a mean terminal half-life of 7–11 h.
The action of rivaroxaban is independent of
antithrombin (AT), in contrast to the indirect
FXa inhibition by heparin and LMWH, fondapar-
inux and idraparinux. In vitro studies show that
rivaroxaban inhibits free FXa, FXa within the pro-
thrombinase complex and clot-associated FXa
which is an advantage over UFH and LMWH.
Theoretical considerations suggest that FXa may
represent a better target for inhibition than throm-
bin. Blood coagulation involves a biological ampli-
fication system with the sequential activation of
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 Antithrombotic treatment failures in antiphospholipid syndrome: the new anticoagulants?
H Cohen and SJ Machin
488

coagulation proteins which culminates in the gen- non-inferior to enoxaparin 50 mg daily. In the third
eration of thrombin. FXa is the primary site of trial dabigatran etexilate at 150 mg daily or 220 mg
amplification and a rate limiting step in thrombin daily failed to show non-inferiority compared with
generation. Therefore, anti-Xa inhibition is poten- enoxaparin (RE-MOBILIZE).11 Meta-analysis of
tially a more effective strategy for anticoagulation RE-NOVATE and RE-MODEL supported the
than targeting downstream thrombin, as smaller conclusions of the individual trails that dabigatran
doses of anticoagulant are required to block coag- etexilate was non-inferior to enoxaparin 40 mg
ulation progression earlier in the sequence of reac- daily.12
tions. Thrombin is also the principal activator of
platelets at sites of injury, whereas factor Xa has no Rivaroxaban
direct effect on platelet activation.8 Rivaroxaban has been compared with SC enoxa-
parin 40 mg daily in four double-blind, randomized
Other new oral anticoagulants
controlled trials in approximately 12,500 patients
These include apixaban (Bristol-Myers SquibbTM), undergoing hip or knee replacement surgery. Three
an oral direct factor Xa inhibitor of free and of the trials used enoxaparin once daily dosing13–15
cell-bound factor Xa and activated prothrombi- and the fourth used enoxaparin twice-daily dosing.15
nase, DU-176b, YM-150 and betrixaban. The primary efficacy outcome was the same in all of
these studies, the percentage risk reduction in a com-
Clinical efficacy in phase III trials posite of DVT (venographic or symptomatic),
A number of phase III clinical trials using the new non-fatal PE, or death from any cause up to 42
anticoagulants have been completed and these are days in the hip trials or 17 days in the knee trials.
detailed below. Table 1 summarizes the develop- Rivaroxaban 10 mg daily was superior to enoxa-
mental status of dabigatran, rivaroxaban and parin with regard to the primary efficacy outcome
apixaban. in patients undergoing elective total hip or knee
replacement (RECORD 1, 2 and 3).13–15 In a
fourth trial, significantly fewer patients on rivarox-
aban 10 mg daily experienced VTE than those on
Major lower limb orthopaedic surgery
enoxaparin 30 mg twice daily (RECORD 4).16
Dabigatran etexilate
Dabigatran etexilate has been compared with enox- Acute venous thromboembolism
aparin in three non-inferiority double-blind, rando-
mized controlled trials in approximately 8300 A randomized, double-blind, non-inferiority trial in
patients undergoing major lower limb orthopaedic patients with acute VTE (the RE-COVER trial) ini-
surgery. The primary efficacy outcome (a composite tially given parenteral anticoagulation for a median
of total venous thromboembolism (VTE) events, of 9 days and, oral dabigatran 150 mg twice daily
defined as DVT (venographic or symptomatic) versus warfarin to achieve a target INR of 2.5
and/or symptomatic PE and all-cause mortality showed that the 6-month incidence of recurrent symp-
during treatment) was the same in all three trials. tomatic, objectively confirmed VTE was similar
In the first two trials, in patients undergoing elec- (2.4% and 2.1% respectively).17 In a randomized,
tive total hip replacement (RE-NOVATE)9 or knee double-blind, placebo-controlled, superiority evalu-
replacement (RE-MODEL),10 dabigatran etexilate ated therapy, rivaroxaban 20 mg daily for a mean
150 mg daily and 220 mg daily were judged to be duration of about 6 months after completion of

Table 1 Development status of rivaroxaban, apixaban and dabigatran20

Rivaroxaban Apixaban Dabigatran

Venous thromboembolism (VTE) Phase III completed Phase III ongoing Phase III completed
prevention orthopaedic surgery (Licensed for use) (Licensed for use)
Stroke prevention in atrial fibrillation (AF) Phase III ongoing Phase III ongoing Phase III completed
Acute coronary syndrome (ACS) Phase III ongoing Phase II completed Phase II ongoing
VTE prevention in medical inpatients Phase III ongoing Phase III ongoing No study in progress
VTE treatment Phase III ongoing Phase III ongoing Phase III completed
Einstein-Extend Study completed

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12 months treatment with VKA following acute VTE,
was associated with significantly fewer recurrent
confirmed symptomatic VTE events compared
with placebo (7.1% versus 1.3%, p < 0.0001;
Einstein-Extension Study).18
Prevention of stroke and systemic embolism in
atrial fibrillation
In this randomized, non-inferiority trial approxi-
mately 18,000 patients who had AF and a risk of
stroke were randomized to receive, in a blinded fash-
ion, dabigatran 110 mg or 150 mg daily, or in an
unblinded fashion, adjusted-dose warfarin (target
INR 2.5; the RE-LY trial). The primary outcome
was stroke or systemic embolism and the median
duration of follow up 2 years. Rates of the primary
outcome were 1.69% per year in the warfarin group,
compared with 1.53% in the dabigatran group that
received 110 mg, with dabigatran judged to be
non-inferior. However, in the group that received
150 mg dabigatran daily, the rate of the primary out-
come was lower at 1.11% per year (relative risk,
0.66; 95% confidence interval (CI), 0.74–1.11;
p < 0.001). There was no significant difference in
mortality between the three groups. The efficacy of
dabigatran 110 mg daily was non-inferior to that of
warfarin with lower rates of major haemorrhage.
Dabigatran 150 mg daily was associated with lower
rates of stroke and systemic embolism, but similar
rates of major haemorrhage (see the next section).19
Bleeding complications
In the three dabigatran orthopaedic thrombopro-
phylaxis trials, major haemorrhage occurred in less
than 2% in both dabigatran etexilate and enoxa-
parin groups, while a meta-analysis of the dabiga-
tran 200 mg dose in the two trials using enoxaparin
40 mg daily estimated that the relative risk of major
bleeding with dabigatran etexilate was 1.24 (95%
CI 0.75–2.05; p ¼ 0.41).12 Pooled data from the
three trials comparing rivaroxaban to once-daily
enoxaparin showed a similar rate of major bleeding
(0.2% for both at 2 weeks and 0.3% versus 0.2%,
respectively, at the end of the planned medication
period)21. It should be noted in the dabigatran stu-
dies, bleeding from surgical sites was included
within the definition of major bleeding whereas in
the rivaroxaban trials, such bleeding was not clas-
sified as major unless it was fatal or necessitated
re-operation.
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Antithrombotic treatment failures in antiphospholipid syndrome: the new anticoagulants?
H Cohen and SJ Machin
489
In the dabigatran acute VTE treatment trial,
major bleeding occurred in 1.6% of patients on
dabigatran and 1.9% of those on warfarin with the
incidence of any bleeding 16.1% and 21.9%, respec-
tively (NS).17 In the rivaroxaban Einstein-Extension
Study, there was a low incidence of major bleeding
(0.7%) although a 5% incidence of clinically signif-
icant bleeding was associated with rivaroxaban.18
In the dabigatran AF trial, the rate of major bleed-
ing per year was significantly lower in the group ran-
domized to dabigatran 110 mg compared with that in
patients on warfarin (2.71% versus 3.36%, respec-
tively; p < 0.001), and the rate of haemorrhagic
stroke per year was significantly lower in patients
receiving both doses of dabigatran (0.38% in the war-
farin group and 0.12% in the dabigatran 110 mg daily
group [p < 0.001] and 0.10% in the dabigatran 150 mg
daily group [p < 0.001]). The rate of gastrointestinal
bleeding was increased in the dabigatran 150 mg daily
group compared with that in patients on warfarin
(1.51% versus 1.02%, respectively; p <0.001).19
There are currently no clinical pharmacological
antidotes to either dabigatran etexilate or rivaroxa-
ban. Dabigatran etexilate is predominantly renally
excreted and adequate diuresis is therefore recom-
mended. It is dialyzable, although there is currently
no clinical experience to demonstrate the efficacy of
this approach. Rivaroxaban is highly plasma protein
bound and is not expected to be dialyzable although
the use of activated charcoal to reduce absorption
may be considered. Limited animal data suggest
that the anticoagulant effects of high-dose rivaroxa-
ban were almost completely reversed by prothrom-
bin complex concentrate (PCC; 50 U/kg) when
administered to bleeding animals. This suggests
that PCC may have the potential to be used as an
antidote to high-dose rivaroxaban.22
Other unwanted effects
There were no significant differences in the incidence
of elevation of serum aspartate or alanine transami-
nases in the phase III clinical trials. Of note, in the
dabigatran AF trial the rate of myocardial infarc-
tion was significantly increased in the dabigatran
150 mg daily group compared with that in patients
on warfarin (0.74% and 0.53%, respectively;
p < 0.048). In the dabigatran VTE trial, the
number of acute coronary syndromes was similar
in the two groups. In the dabigatran acute VTE
treatment and AF trials, dabigatran was associated
with an increased incidence of dyspepsia (2.9% and
11.8% in the dabigatran groups compared with
0.6% and 5.8% with warfarin, respectively).17,19
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 Antithrombotic treatment failures in antiphospholipid syndrome: the new anticoagulants?
H Cohen and SJ Machin
490

Contraindications and cautions VTE, approximately 10% have APS, and therefore
it is likely that patients with APS were included
Dabigatran etexilate and rivaroxaban are contrain- with the study population in the dabigatran and
dicated in severe renal impairment (CrCl less than rivaroxaban VTE trials.17,18
30 ml/min and less than 15 ml/min, respectively). As Adequately powered prospective randomized
with other antithrombotic agents, caution should be controlled multicentre clinical trials are required
exercised with the use of other agents which inhibit to compare the efficacy of the new oral anticoagu-
haemostasis, such as concurrent aspirin or lants versus oral VKA in patients with thrombotic
non-steroidal anti-inflammatory drugs. Dabigatran APS. Consideration should be given to the inclu-
etexilate, dabigatran and rivaroxaban are not meta- sion of patients with a history of VTE, those with
bolized by the cytochrome P450 system, limiting the recurrent or progressive thrombosis despite thera-
potential for drug interactions. However, azole anti- peutic VKA therapy, and also patients with
fungals (such as ketoconazole and itraconazole arterio-thrombotic stroke or recurrent cerebral
although fluconazole can be co-administered with infarction, in such trials. Currently, as discussed
caution) and HIV protease inhibitors (such as rito- above, it remains unknown as to whether the
navir), are all strong inhibitors of both CYP3A4 and INR in thrombotic APS patients on oral VKA
P-glycoprotein and concurrent use with rivaroxaban accurately reflects the intensity of anticoagulation
is not recommended due to the increased risk of in these patients. Assessment of global coagulation
bleeding. Rifampicin, phentoin, carbamazepine, activation by the measurement of plasma thrombin
phenobarbitol or St John’s wort may reduce the generation as well as of fibrinolytic activation as a
plasma concentration of rivaroxaban. There are no response to fibrin formation by the measurement of
adequate data for the use of either agent in preg- plasma D-dimer is likely to give a representative
nancy and animal studies have demonstrated repro- estimate of thrombogenic potential. A phase III
ductive toxicity, therefore, neither drug should be trial should be preceded by a pilot study of one of
used during pregnancy or breastfeeding. the new oral anticoagulants in patients with throm-
botic APS both to ensure acceptability in this
patient group and to determine the optimal thera-
peutic dose(s). Consideration should also be given
Laboratory monitoring as to whether a DTI (dabigatran) or direct anti-Xa
inhibitor (rivaroxaban) would be preferable for
As fixed-dose oral anticoagulants, both dabigatran clinical trials in thrombotic APS, based on the
and rivaroxaban do not appear to require labora- potential advantages and risks of these agents.
tory monitoring. In the RE-COVER and RE-LY
trials, laboratory monitoring of dabigatran was
not reported, and the former study investigators Disclosure Statement
concluded that laboratory monitoring was not
required.17 The effect of dabigatran may be assessed
Professor Machin has been on a UK Advisory
using a sensitive ecarin clotting time (ECT). A com-
Board for Boehringer Ingelheim and the depart-
mercially available coamatic heparin assay, based
ment has received unrestricted eduational grants
on the principle of one-stage detection, may be suit-
from Bayer.
able for monitoring rivaroxaban in the range of 0–
500 ng/ml, with a pre-dilution step in the high
range.23
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