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Review
Non-vitamin K antagonist oral anticoagulants
(NOACs): clinical evidence and therapeutic
considerations
Karan Saraf,1 Paul Morris,1,2 Pankaj Garg,1 Paul Sheridan,1,2 Robert Storey1,2
1
Department of Cardiology,
Sheffield Teaching Hospitals
NHS Foundation Trust,
Northern General Hospital,
Sheffield, UK
2
Department of Cardiovascular
Science, University of Sheffield,
Medical School, Sheffield, UK
Correspondence to
Dr Karan Saraf, Department of
Cardiology, Sheffield Teaching
Hospitals NHS Foundation
Trust, Northern General
Hospital, Herries Road,
Sheffield S5 7AU, UK;
[email protected]
Received 1 February 2014
Revised 16 July 2014
Accepted 18 July 2014
Published Online First
1 August 2014
ABSTRACT
Warfarin, a vitamin K antagonist, is the most widely
used oral anticoagulant in the world. It is cheap and
effective, but its use is limited in many patients by
unpredictable levels of anticoagulation, which increases
the risk of thromboembolic or haemorrhagic
complications. It also requires regular blood monitoring
and dose adjustment. New classes of drugs, non-vitamin
K antagonist oral anticoagulants (NOACs), are now
supported as alternatives to warfarin. Three NOACs are
licensed: dabigatran, a direct thrombin inhibitor, and
rivaroxaban and apixaban, antagonists of factor Xa.
NOACs do not require routine blood monitoring or dose
adjustment. They have a rapid onset and offset of action
and fewer food and drug interactions. Current
indications include treatment and prophylaxis of venous
thromboembolism and prevention of cardioembolic
disease in non-valvular atrial fibrillation. Effective
antidotes are lacking and some caution must be used in
severe renal impairment, but favourable trial evidence
has led to their widespread adoption. Research is
ongoing, and an increase in their use and indications is
expected in the coming years.
INTRODUCTION
▸ http://dx.doi.org/10.1136/
postgradmedj-2013-132474
▸ http://dx.doi.org/10.1136/
postgradmedj-2014-132950
To cite: Saraf K, Morris P,
Garg P, et al. Postgrad Med
J 2014;90:520–528.
520
Warfarin remains the most widely used vitamin K
antagonist (VKA) for the prevention and treatment
of thromboembolic disease. For decades it has
remained the gold standard anticoagulant in the
treatment of deep venous thrombosis (DVT) and
pulmonary embolism (PE), and for the prevention
of cardiac thromboembolic disease such as stroke in
patients with atrial fibrillation (AF).
However, its use is complicated by a variety of
food and drug interactions and its narrow therapeutic range and variable patient dose-response
require regular laboratory monitoring and careful
dose titration. Even with frequent, meticulous monitoring, it can still be difficult to achieve stable
anticoagulation in many patients.1 According to the
international normalised ratio (INR) monitoring,
control in the UK is among the best in the world,
with an average time in therapeutic range of
approximately 65%.2–4 In the remaining 35%,
two-thirds of INRs are below the therapeutic
window, predisposing to thromboembolism, and a
third are above the therapeutic window, increasing
the risk of bleeding.1 Therefore, warfarin is both
inconvenient and exposes patients to periods of
undertreatment and overtreatment with the subsequent risk of complications. Additionally, regular
monitoring of warfarin treatment consumes significant health resources.
Over the last decade, several alternative oral
anticoagulants have been developed that have a
direct and reversible inhibitory effect on either
thrombin or factor Xa. A plethora of clinical trials
have demonstrated the efficacy and safety of these
newer generation anticoagulants. Until recently,
they were designated ‘novel oral anticoagulants’,
with the abbreviation non-vitamin K antagonist
oral anticoagulants (NOACs). However, the
European Society of Cardiology Working Group
on Thrombosis task force on anticoagulants in
heart disease recommends that ‘NOACs’ should
denote ‘Non-vitamin K antagonist Oral AntiCoagulants’, when referring to these direct inhibitors of single coagulation factors.5 NOACs are
effective alternatives to VKAs for the treatment and
prevention of thromboembolic disease. These
agents do not require monitoring or dose adjustment and thus represent a more convenient option
for both patients and physicians.
The UK National Institute of Health and Care
Excellence (NICE) has undertaken several technology appraisals that have resulted in three NOACS
being recommended as an alternative to VKAs and
even first-line oral anticoagulants.
It is, therefore, important for physicians to be
familiar with the mechanisms of action, efficacy
and safety data, cost-effectiveness and current
NICE recommendations for the available NOACs.
This article examines each of these topics and presents some practical considerations in the use of
NOAC drugs as an alternative to warfarin.5
MECHANISMS OF ACTION
The mechanisms of action of NOACs differ from
that of the VKAs (figure 1), and understanding
these differences aids decision making when choosing an anticoagulant for individual patients.
Vitamin K antagonists
In order to contribute effectively to the coagulation
cascade, factors II ( prothrombin), VII, IX and X
must first be carboxylated, allowing their binding
to the surface of activated platelets and vascular
endothelium. This process is dependent upon the
enzymatic recycling of vitamin K. By inhibiting this
with a VKA, newly synthesised clotting factors are
rendered biologically inactive. As the circulating
active clotting factors degrade over hours and days,
normal coagulation is inhibited and anticoagulation
achieved.6 This explains the long VKA half-life
(approximately 40 h for warfarin). There is significant heterogeneity in the rate of VKA metabolism
(mainly due to genetic variations), which results in
Saraf K, et al. Postgrad Med J 2014;90:520–528. doi:10.1136/postgradmedj-2014-132605
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Review
Figure 1 Mechanism of action of
vitamin K antagonists and non-vitamin
K antagonist oral anticoagulants
(adapted from Steffel and
Braunwald.32 Reproduced with kind
permission from Oxford University
Press).
a variable and unpredictable period until a stable INR is
achieved and maintained thereafter.1 VKAs include warfarin,
acenocoumarol and dicoumarol. However, in the context of the
current article, only warfarin is considered because it is, by far,
the most commonly used VKA and is the drug upon which all
relevant clinical evidence is based.
Non-vitamin K antagonist oral anticoagulants
There are currently two main types of NOACs: direct thrombin
inhibitors (ie, dabigatran) and factor Xa inhibitors (ie, rivaroxaban, apixaban). Unlike warfarin, NOACs inhibit a single coagulation factor, have short half-lives and do not require either
monitoring or dose titration.
Dabigatran etexilate (Pradaxa) acts via direct inhibition of
thrombin (factor II), leading to potent anticoagulation.7
Thrombin performs several crucial roles in the coagulation
cascade. It promotes platelet activation, which in turn facilitates
further thrombin generation, and activates multiple factors in
the final step of coagulation, including the cleavage of fibrinogen to fibrin, thus having the dominant role in the stabilisation
of a clot.
Rivaroxaban (Xarelto) and apixaban (Eliquis) are direct inhibitors of factor Xa. In doing so, they disrupt both the intrinsic
and the extrinsic coagulation pathways, preventing the formation of thrombin and subsequent clotting.8
Because NOAC effect is determined solely by plasma concentration rather than by inhibition of clotting factor synthesis,
they have a rapid onset of action once absorbed into the circulation. The half-life of dabigatran is approximately 12–17 h, rivaroxaban 7–11 h and apixaban 9–14 h. Cessation of
administration results in a relatively rapid return to baseline
physiology.8 Unlike warfarin, all three NOACs are associated
with a consistent and predictable dose-response and time taken
to reach steady state. Haematological monitoring and dose
adjustment are therefore unnecessary.9
EVIDENCE FOR EFFICACY AND SAFETY OF NOACs
In terms of evidence base, warfarin is the current gold standard
in the treatment of venous thromboembolism (VTE) and in the
prevention of stroke and systemic embolism in patients with AF,
reducing stroke rate by two-thirds.2 New anticoagulants must
not only have practical advantages (eg, lack of need for monitoring), but must demonstrate at least equal efficacy and safety profiles before they can be considered as alternatives. The following
sections review some of the landmark randomised controlled
trials that have compared NOACs with warfarin, focusing on
the primary efficacy (deleterious events avoided by treatment)
and safety (adverse events as a result of treatment) end points in
comparison with standard treatment with warfarin.
PREVENTION OF STROKE AND SYSTEMIC EMBOLISM
IN PATIENTS WITH NON-VALVULAR AF
Up to 20% of acute strokes occur as a consequence of AF with
cardiac thromboembolism.2 Once identified, those at increased
risk should be established on lifelong anticoagulation in order
to reduce the risk of this debilitating complication. Trials evaluating NOACs in patients with AF have looked at a primary efficacy end point of reduction in stroke or systemic embolism and
primary safety end points of mortality and bleeding, particularly
intracranial haemorrhage. RE-LY7 is the largest prospective, multicentre randomised controlled trial comparing dabigatran, at
two doses of 110 or 150 mg twice-daily, with standard warfarin
therapy. In total, 18 113 patients with AF and at least two risk
factors for stroke were enrolled and followed up for 2 years.
The lower dose of dabigatran was comparable in efficacy with
warfarin (1.53% events per year vs 1.69%, p<0.001). The
higher dose was superior (1.11% events per year vs 1.69%,
p<0.001) to the lower dose. Major bleeding was reduced in
those receiving dabigatran 110 mg (2.71% per year vs 3.36%,
p<0.001) and was similar to warfarin in the higher dose group
(3.11%, p=0.31). Compared with warfarin, haemorrhagic
stroke was also reduced in both the low-dose and high-dose
groups (0.12% and 0.1% vs 0.38%, respectively, p<0.001 for
both comparisons). There were higher rates of dyspepsia in both
dabigatran groups (11.8% in the 110 mg and 11.3% in the 150
mg dabigatran groups vs 5.8% in the warfarin group, p<0.001
for both comparisons). This study was extended for a further
2 years (RELY-ABLE10) in order to gain more data to compare
the two doses of dabigatran, and followed up 48% of the original dabigatran-treated groups. Stroke or systemic embolism
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occurred in 1.46% (150 mg) and 1.6% per year (110 mg), with
major bleeding in 3.74% and 2.99% per year, respectively, confirming that, compared with the lower dose of dabigatran, the
higher dose was more efficacious, but resulted in more bleeding.
Similar in design to RE-LY, ROCKET-AF11 is the largest trial
comparing rivaroxaban 20 mg once-daily with warfarin. In
total, 14 264 patients with AF were enrolled, 10% of whom
had at least two risk factors, and 90% of whom had at least
three risk factors for stroke. Rivaroxaban was comparable with
warfarin in preventing stroke or systemic embolism (1.7% vs
2.2% per year, p<0.001). While there were no significant differences in the rates of major and non-major bleeding, there were
fewer intracranial (0.5% vs 0.7%, p=0.02) and fatal haemorrhages (0.2% vs 0.5%, p=0.003) with rivaroxaban.
ARISTOTLE,8 the last of these three landmark trials, compared warfarin with apixaban 5 mg twice-daily in 18 201
patients with AF and at least one risk factor for stroke. Stroke or
systemic embolism was reduced in the apixaban group (1.27%
vs 1.6% per year), showing superiority ( p<0.01) over warfarin
therapy. Furthermore, there were fewer major bleeding events
(2.13% vs 3.09%, p<0.001) and haemorrhagic strokes (0.24%
vs 0.47%, p<0.001) in the apixaban group. Apixaban was also
better tolerated than warfarin, with fewer drug discontinuations.
In contrast to the other studies, all-cause mortality was significantly reduced in the apixaban group (3.52% vs 3.94%,
p=0.047). Apixaban was, therefore, superior to warfarin in preventing stroke, embolic events, bleeding of any kind and death.
In summary, in these trials, NOACs were either comparable
with (dabigatran 110 mg and rivaroxaban) or superior (dabigatran 150 mg and apixaban) to warfarin in preventing stroke or
systemic embolism and demonstrated either a similar (dabigatran
150 mg and rivaroxaban) or superior (dabigatran 110 mg and
apixaban) safety profile, with reductions in major and minor
bleeding rates. A significant concern with using any anticoagulant is the risk of intracranial haemorrhage because even a
modest bleed can result in significant and permanent morbidity
or even death. However, all three agents were associated with a
statistically significant reduction in the rates of intracranial
haemorrhage compared with warfarin.
VENOUS THROMBOEMBOLISM
Prospective trials evaluating the treatment of VTE or VTE
prophylaxis following high-risk procedures such as orthopaedic
surgery have demonstrated similarly positive results in favour of
NOACs.
Treatment of VTE
Suboptimal INR control in patients with DVT or PE is associated with recurrent thrombosis and increased morbidity and
mortality, all of which places a significant burden upon limited
healthcare resources. In VTE (acute DVT or PE) treatment,
NOACs were compared with standard care, that is, acute subcutaneous low-molecular-weight heparin (enoxaparin) followed
by warfarin. Enoxaparin was discontinued when the patient was
established on warfarin with a therapeutic and stable INR; treatment in both groups continued for a standardised period. The
primary end points were recurrent DVT or PE within the treatment period. The RE-COVER II trial found dabigatran 150 mg
twice-daily to be comparable with standard treatment
( p<0001), with similar major bleeding event rates and lower
overall bleeding rates.12 Rivaroxaban was evaluated in two
studies. In EINSTEIN-DVT,13 rivaroxaban (15 mg twice-daily
for 3 weeks, then 20 mg once-daily) was comparable with standard treatment for acute DVT (2.1% vs 3%, p<0.001) with a
522
similar safety profile. The EINSTEIN-PE trial14 involved a
similar comparison, this time for the treatment of acute PE.
Rivaroxaban was again comparable with standard therapy in
preventing the primary end point. Major or clinically relevant
non-major bleeding rates were similar between the two groups,
but there were significantly fewer major bleeds in the rivaroxaban group. The AMPLIFY trial15 showed that apixaban (10 mg
twice-daily for 1 week, then 5 mg twice-daily) demonstrated
comparable efficacy to standard therapy in treatment of acute
DVT and PE. Apixaban had a superior safety profile with major
bleeding occurring in 0.6% of patients compared with 1.8% in
the conventional treatment group ( p<0.001).
Prophylaxis of VTE following orthopaedic surgery
Many orthopaedic operations, particularly procedures involving
the hip and lower limb, increase the risk of thromboembolism
in the postoperative period. Appropriate patients, therefore,
receive a once-daily administration of low-molecular-weight
heparin (enoxaparin) for a standardised period determined by
the nature of the procedure. In the RE-MODEL trial,16 dabigatran 150 or 220 mg once-daily was found to be comparable
with enoxaparin with a similar safety profile. The RECORD
trials17 18 compared rivaroxaban 10 mg once-daily with enoxaparin and demonstrated superiority of rivaroxaban with similar
rates of bleeding. In ADVANCE-2, apixaban 2.5 mg twice-daily
was superior in preventing VTE, with similar bleeding rates.19
Although not exhaustive, this review includes the most significant ‘landmark’ trials that are representative of the trial evidence
to date in these areas. Similarly positive results have been
demonstrated for dabigatran, rivaroxaban and apixaban in
almost all other large-scale trials not highlighted by our
review.20–24
LICENSING AND COST-EFFECTIVENESS
Since February 2013, all three NOACs have been licensed by
NICE for the following indications:
▸ The prevention of VTE in adults undergoing elective total
hip or knee replacement surgery.
▸ The prevention of stroke or systemic embolism in adults with
non-valvular AF and one or more of the following risk
factors: previous stroke, transient ischaemic attack or systemic embolism; left ventricular ejection fraction <40%;
symptomatic heart failure≥New York Heart Association class
2; age ≥75 years; age ≥65 years associated with one of the
following: diabetes mellitus, coronary artery disease or
hypertension.
In addition, rivaroxaban is licensed for both the treatment of
acute DVT and chronic prophylaxis of recurrent DVT and/or PE
in adults following an initial diagnosis of DVT.
Full technology appraisals for the three NOACs undertaken
by NICE25–28 resulted in their recommendation as first-line
agents for the indications listed above, on the basis that they
provide a superior or at least equal efficacy and safety profile to
warfarin, while providing a more convenient treatment regimen
with fewer limitations (monitoring, dose adjustment,
interactions).
NOACs are significantly more expensive than warfarin.
However, several economic evaluations have deemed their use
as first-line agents to be cost-effective in the long term, given
that patients treated with NOACs require fewer healthcare
resources, due to a reduction in adverse events (bleeding, stroke
and VTE) and the lack of need for monitoring and dose adjustment compared with warfarin.29–32 However, few of these
reports are based on prospective trial data with most being
Saraf K, et al. Postgrad Med J 2014;90:520–528. doi:10.1136/postgradmedj-2014-132605
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generated by decision analysis models and further work is
required to provide a definitive answer. Importantly, NICE concludes that NOACs are indeed cost-effective alternatives to warfarin and that cost should not be a barrier to the initiation of, or
conversion to, an NOAC.25–28
POTENTIAL COMPLICATIONS WITH NOACs
There are a number of considerations before prescribing an
NOAC.
Side effects
In addition to the risk of bleeding (common with all anticoagulants), NOACs are uncommonly associated with nausea, vomiting, diarrhoea and dizziness. There is stronger association
between dabigatran and dyspepsia (approximately 11%) and,
although not an absolute contraindication, it should be used
with caution in those with gastroesophageal reflux disease.7 33
Chronic kidney disease
Warfarin does not require dose modification in renal impairment. However, all NOACs are at least partially renally excreted
(dabigatran 80%, rivaroxaban 35%, apixaban 27%).
Considerable trial data support their use in mild-to-moderate
chronic kidney disease (CKD), with dose reduction in some
cases (table 1). Limited data are available regarding use in
patients with advanced CKD or severe acute kidney injury.
Consequently, NOACs are not licensed for use in severe renal
impairment and should be discontinued if significant acute
kidney injury develops while on the medication. Dabigatran is
contraindicated in patients with a creatinine clearance <30 mL/
min. Rivaroxaban is also contraindicated, for the specific indication of VTE, if creatinine clearance is <30 mL/min but can be
used for AF with dose reduction. Apixaban is considered the
safest drug for use in patients with renal impairment because it
has the lowest dependency upon renal excretion. It can be continued until creatinine clearance declines to 15 mL/min.9 NOAC
trials are yet to generate long-term follow-up data, but many
patients require lifelong anticoagulation. Renal impairment may
develop or deteriorate over time, resulting in drug accumulation
and increased risk of haemorrhage. Monitoring of renal function should be undertaken in patients receiving these drugs to
ensure their safety profile remains at least equivalent to warfarin
over time (yearly in most patients; 6 monthly in CKD3; 3
monthly in CKD4).9
Drug interactions
NOACs are associated with far fewer drug interactions than warfarin and have no known interactions with foods. The combination of NOAC therapy with certain antiepileptic, antifungal,
macrolide antibiotic and antiarrhythmic drugs can result in
increased NOAC plasma levels that necessitates either dose
modification or contraindicates their use (see table 1). A detailed
list of contraindications is included in the European Heart
Rhythm Association practical guide to NOACs.9
Emergency management of bleeding or overdose
The principles of managing major bleeding in patients receiving
warfarin therapy are well established. When required,
VKA-associated anticoagulation can be readily reversed with
vitamin K and/or prothrombin complex concentrate. Currently,
there are no antidotes for NOAC-induced anticoagulation and
only little experience in the management of overdose or haemorrhage when urgently reversing the anticoagulant effect
becomes necessary. However, NOACs have comparatively short
half-lives, and a combination of local measures, such as compression, and cessation of drug administration are often
Table 1 NOAC dosing recommendations and considerations9
Licensed dose
Stroke prevention in AF
VTE prophylaxis
VTE treatment
Kidney disease
CrCl >50 mL/min
CrCl 30–49 mL/min
CrCl 15–29 mL/min
CrCl <15 mL/min
Caution
Dabigatran
Rivaroxaban
Apixaban
150 mg BD
220 mg OD
N/A
20 mg OD
10 mg OD
15 mg BD 21 days, then 20 mg OD
5 mg BD
2.5 mg BD
N/A
No dose modification
Consider 110 mg BD (AF)
Consider 150 mg OD (VTE)
Not recommended
No dose modification
15 mg OD (AF)
No modification (VTE)
15 mg OD (AF)
Not recommended (VTE)
Not recommended
No dose modification
No dose modification
Age >80
Weight <60 kg
Macrolide antibiotics
Amiodarone
Age >80
Weight <60 kg
Macrolide antibiotics
Carbamazepine
Phenytoin
Age >80
Weight <60 kg
Diltiazem
Ketoconazole
Itraconazole
Carbamazepine
Phenytoin
Dronedarone
Ketoconazole
Itraconazole
Ketoconazole
Itraconazole
Carbamazepine
Phenytoin
Not recommended
2.5 mg BD
Not recommended
Contraindicated
AF, atrial fibrillation; BD, twice-daily regimen; CrCl, creatinine clearance as calculated by Cockcroft–Gault formula; NOAC, non-vitamin K antagonist oral anticoagulant; OD, once-daily
regimen; VTE, venous thromboembolism.
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Figure 2 European Society of Cardiology guidelines on management of bleeding in patients taking non-vitamin K antagonist oral anticoagulant
(adapted from Heidbuchel et al.9 Reproduced with kind permission from Oxford University Press). aPCC, activated prothrombin complex concentrate;
NOAC, non-vitamin K antagonist oral anticoagulant; PCC, prothrombin complex concentrate; RBC, red blood corpuscles; rFVIIa, recombinant
activated factor VII.
sufficient to reverse the anticoagulant effect in the context of
non-life-threatening bleeding, with normal coagulation being
achieved within 24 h. This is a slightly longer time course when
compared with the administration of vitamin K for a patient
anticoagulated with warfarin (approximately 12 h). Evidence
supporting anticoagulation reversal with these agents in major
life-threatening bleeding is limited to controlled trials conducted
in healthy human subjects largely yielding mixed results.34
Dabigatran elimination may be achieved via haemofiltration or
charcoal haemoperfusion. The effects of the factor Xa inhibitors
(rivaroxaban and apixaban) may be, at least partially, reversed
with the co-administration of prothrombin complex concentrate
(25–50 UI/kg) and recombinant factor VIIa (90 μg/kg). These
measures need further evaluation, particularly in the setting of
major bleeding (figure 2). At least one specific antidote to factor
Table 2 Effect of NOACs on coagulation tests (adapted from
Gavillet and Angelillo–Scherrer.35 Reprinted with kind permission
from EMH Swiss Medical Publishers Ltd.)
PT
APTT
INR
D-Dimer
Fibrinogen
Anti-Xa
Antithrombin
Dabigatran
Rivaroxaban
Apixaban
Decreased
Increased
Increased
Same
Same
Same
Increased
Decreased
Increased
Increased
Same
Same
Increased
Same
Decreased
Increased
Increased
Same
Same
Increased
Same
INR, international normalised ratio; NOAC, non-vitamin K antagonist oral
anticoagulant.
524
Xa inhibitors has been shown to be effective in early animal
models, and more sophisticated agents are in development, but
further evidence is required before these can be made available
for clinical use.35 36 Hospitals should issue local protocols for
the management of bleeding associated with NOAC treatment.
While routine monitoring is not required, there are situations
where quantitative evaluation of anticoagulant effect may be
desirable, for example, preoperatively. This is possible with new
assays for antithrombin and antifactor Xa. Widespread availability of these tests remains limited at the current time. A further
consideration is the effect these drugs have on standard laboratory coagulations assays that are outlined in table 2.35
CURRENT RESEARCH AND THE FUTURE
Evidence now supports NOAC use for treatment and prevention
of VTE in certain patients with non-valvular AF and in those
undergoing elective hip or total knee replacement. Current
research is focused on identifying other potential roles in conditions such as the acute coronary syndromes (ACSs), AF with
associated valvular heart disease and in those who require anticoagulation because of a mechanical prosthetic heart valve. It is
likely that the range of indications for NOAC use will widen
over time.
Acute coronary syndromes
Trials evaluating the efficacy of NOACs in ACSs when added to
standard therapy have produced mixed results. In the placebocontrolled ATLAS ACS 2-TIMI 51 study, low-dose rivaroxaban
(2.5 or 5 mg twice-daily) was associated with a reduction in
stroke and cardiovascular mortality when added to standard
medical therapy ( p=0.008), but increased the rate of major
bleeding ( p<0.001).37 The APPRAISE-2 trial for apixaban was
aborted prematurely due to a significant increase in major
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Table 3 NOAC overview1 9
Mechanism of action
Half-life
Renal excretion
Renal failure (table 1)
Clinical trials
AF
VTE prophylaxis
VTE treatment
Outcomes (vs gold standard)*
Efficacy in AF
Efficacy in VTE prophylaxis
Efficacy in VTE treatment
Bleeding in AF
Bleeding in VTE
Licence date (NICE)
Stroke prevention in AF
VTE
Indications (NICE)
Stroke prevention in AF
VTE prophylaxis (preoperative/postoperative)
VTE treatment (DVT/PE)
Drug cost/month (warfarin=£1)
Dabigatran
Rivaroxaban
Apixaban
Direct thrombin inhibitor
12–17 h
80%
Caution
Direct factor Xa inhibitor
7–11 h
35%
Caution
Direct factor Xa inhibitor
9–14 h
27%
Best
Re-LY
RE-MODEL
RE-COVER
RE-COVER II
ROCKET-AF
RECORD I-IV
EINSTEIN-DVT
EINSTEIN-PE
ARISTOTLE
ADVANCE I-III
AMPLIFY
Better (150 mg)
Equal (110 mg)
Equal
Equal
Better
Equal
Equal
Better
Better
Equal
Equal
Equal
Better
Better
Better
Better
15 March 2012
24 September 2008
21 May 2012
22 April 2009
27 February 2013
25 January 2012
✓
✓
×
110 mg BD=£65.90
150 mg BD=£65.90
✓
✓
✓
10 mg OD=£63
15 mg OD=£58.80
15 mg BD (21 days)=£88.20
20 mg OD=£58.80
✓
✓
×
2.5 mg BD=£65.90
5 mg BD=£61.50
*Gold standard = warfarin (stroke prevention in AF), enoxaparin (VTE prophylaxis) or both (VTE treatment).
AF, atrial fibrillation; DVT, deep venous thrombosis; NICE, National Institute of Health and Care Excellence; NOAC, non-vitamin K antagonist oral anticoagulant; PE, pulmonary
embolism; VTE, venous thromboembolism; BD, twice-daily regimen; OD, once-daily regimen.
bleeding events without a decrease in ACS events.38 Phase III
trial development for dabigatran in ACS has also ceased because
of safety concerns. The future role of NOACs in ACS therefore
remains uncertain, and further research is underway. NICE guidance on the prevention of adverse outcomes in the management
of ACS is expected in March 2015, including recommendations
for the role of NOACs (table 3).
Valvular heart disease
Although the original ARISTOTLE trial8 excluded patients with
significant mitral stenosis or valve prosthesis, those with mitral
regurgitation, less significant mitral stenosis, aortic stenosis,
aortic regurgitation, tricuspid regurgitation or previous valve
surgery were included. In a post hoc subanalysis, the results in
these patients were consistent with the positive overall results,
that is, apixaban was associated with a similar reduction in
stroke, major bleeding events and all-cause mortality in those
with or without valve disease (excluding significant mitral stenosis and/or prosthetic valve).39 Given that patients with valve
disease and AF are known to suffer worse outcomes with
respect to thromboembolism than those without, it is, therefore,
likely that this group will also gain a recommendation for
NOAC therapy in the near future. The role for NOACs in those
with prosthetic valves also requires further evaluation.
Prosthetic valve patients anticoagulated with dabigatran were
shown to be at increased risk of valve thrombosis and haemorrhage compared with warfarin in the RE-ALIGN trial.40 It is
hoped that the role of NOACs in this group will be further
clarified by the DAWA study, which is currently assessing the
efficacy and safety of dabigatran in patients with prosthetic
heart valves.41
Other NOACs
The desire for effective, convenient and safe anticoagulants and
the large potential market size has driven research in this area,
which is now very active and dynamic. Other NOACs are being
developed and assessed. Edoxaban, another factor Xa inhibitor,
has been tested in stroke prevention for AF and for VTE
prophylaxis with favourable outcomes, and indeed has already
been licensed for VTE prophylaxis in orthopaedic surgery in
Japan.42 43 In addition, a host of novel inhibitors, targeted at
factors IX and XII, are under development and it is almost
certain that the number of NOACs and their indications will
increase over the coming years.44
CONCLUSION
In appropriate patients, NOACs offer safe, efficacious and predictable anticoagulation. Efficacy and safety are at least equivalent to warfarin and in certain groups appear superior. Because
NOACs do not require monitoring or dose titration to achieve
optimal anticoagulation, and have fewer food and drug interactions, shorter half-lives and simpler dosing regimens, they are
far more convenient for doctors and patients compared with
warfarin. NOACs are redefining how we approach VTE prophylaxis and treatment. In line with NICE guidance, many centres
have already adopted NOACs as first-line anticoagulants. In
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patients who are well established on warfarin, with stable INRs
in the therapeutic range, there may be little or no additional
clinical benefit from changing to NOAC therapy. Patients in
whom over-anticoagulation or under-anticoagulation is particularly risky or those with labile INRs, poor drug compliance or
difficulty attending for INR monitoring may benefit from conversion from warfarin to NOAC therapy.
Antidotes for NOACs are still not available and there remain
concerns about use in those with severe renal impairment.
Therefore, NOACs are not a ‘one size fits all’ solution, and
patients should be carefully selected in order to maximise
benefit while minimising the risk of adverse events. These decisions should be aided by the use of risk analysis tools such as
the CHA2DS2VASc and HASBLED scores, which can be used to
balance potential benefit versus risk.25–28
Uptake and adoption of NOACs is accelerating. They are
quickly becoming the first-choice anticoagulant for many
patients and for many doctors. It is important that clinicians are
familiar with the presented topics to enable appropriate anticoagulant prescribing. Furthermore, physicians should be aware
that the literature concerning this class of drugs is expanding, as
are the indications for NOAC use.
Main messages
▸ Warfarin, the most commonly used anticoagulant, is limited
by multiple food and drug interactions, the necessity for
regular monitoring and dose adjustment and an often
unpredictable anticoagulant effect.
▸ Non-vitamin K antagonist oral anticoagulants (NOACs)
(dabigatran, rivaroxaban and apixaban) have fewer
interactions, require no monitoring, have simple dosing
regimens and predictable anticoagulation and are more
convenient to use than warfarin.
▸ NOACs are at least as effective as warfarin at preventing
thromboembolic events and have fewer associated bleeding
events.
▸ There is no antidote for these NOACs. In non-life-threatening
bleeding, local measures and cessation of drug is enough to
achieve haemostasis. Hospitals should have their own
protocols for management of life-threatening bleeding.
▸ Choice of anticoagulant must be tailored to the individual
patient—NOACs are particularly useful in those with poor
compliance with healthcare appointments, labile
international normalised ratios and those in whom bleeding
is of greater concern.
Management of patients on NOACs4
When to choose an NOAC over warfarin:
Clinicians are at present more comfortable with prescribing
warfarin, but NOACs need not just be considered as second-line
agents. They may be initiated as first-line anticoagulation.
However, certain patient groups that may benefit from NOAC
therapy over warfarin include those who may not be presented
with regular international normalised ratio (INR) checks, those
with cognitive impairment who may not be able to remember
variable dosing with warfarin, those already on warfarin who
have labile INRs and those whose stroke and bleeding risks may
be similar (as calculated using the CHA2DS2VASc and HASBLED
scores), therefore requiring agents that are associated with
fewer bleeds to increase benefit over risk. Cautions for starting
NOAC therapy: at least moderate chronic kidney disease (CKD)
and specific drug–drug interactions (table 1).
What to check at follow-up appointments:
Compliance, thromboembolic or bleeding events, side effects,
other medications that may interact with NOAC (table 1), and
blood testing (FBC, LFT, U&E): 1 yearly (CKD1–2); 6 monthly
(CKD3) or 3 monthly (CKD4).
To switch from warfarin to NOAC (eg, labile INR, drug
interactions):
Stop warfarin and check INR. Start apixaban/dabigatran when
INR <2, rivaroxaban when INR <3.
To switch from NOAC to warfarin (eg, new or worsening renal
function):
Administer NOAC and warfarin concomitantly until INR >2.
Ensure INR checks done prior to NOAC dose, and 24 h post
monotherapy with warfarin.
Advice to patient if missed a dose:
Take missed dose up to 6 h (in twice daily regimen) or 12 h (in
once daily regimen) after scheduled dose. Otherwise, continue
from next scheduled dose. No double doses.
526
Current research questions
▸ Are NOACs suitable for the primary/secondary prevention of
acute coronary syndrome?
▸ Do patients with atrial fibrillation (AF) and valve disease
derive similar benefit from NOAC therapy as those with
non-valvular AF?
▸ Are NOACs a safe replacement for warfarin in patients who
require anticoagulation prior to cardioversion for AF? Data
are only available for dabigatran currently, which has shown
equal efficacy to warfarin.
▸ Can a safe NOAC antidote be developed for use in
NOAC-associated haemorrhage?
▸ Are NOACs efficacious and safe for use in patients who
require a greater level of anticoagulation, for example, those
with prosthetic heart valves?
Key references
▸ Heidbuchel H, Verhamme P, Alings M, et al. European Heart
Rhythm Association Practical Guide on the use of new oral
anticoagulants in patients with non-valvular atrial
fibrillation. Europace 2013;15:625–51.
▸ Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus
warfarin in patients with atrial fibrillation. N Engl J Med
2009;361:1139–51.
▸ Granger CB, Alexander JH, McMurray JJ, et al. Apixaban
versus warfarin in patients with atrial fibrillation. N Engl J
Med 2011;365:981–2.
▸ Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus
warfarin in nonvalvular atrial fibrillation. N Engl J Med
2011;365:883–91.
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Review
REFERENCES
Self assessment questions
1
1. Which statements are true regarding the safe use of an
NOAC with the respective renal function (as expressed as
creatinine clearance)?
A. Dabigatran at normal dose in a patient with AF and
creatinine clearance 51 mL/min
B. Dabigatran at reduced dose in a patient with AF and
creatinine clearance 28 mL/min
C. Rivaroxaban at normal dose in a patient with acute DVT
and creatinine clearance 31 mL/min
D. Apixaban at reduced dose in a patient with AF and
creatinine clearance 15 mL/min
2. The following drugs are safe to prescribe (but must be
monitored closely) in patients taking phenytoin or
carbamazepine:
A. Dabigatran
B. Warfarin
C. Rivaroxaban
D. Apixaban
3. The following drugs are currently licensed for use in
anticoagulation of patients with AF who are awaiting
direct-current cardioversion:
A. Rivaroxaban
B. Warfarin
C. Apixaban
D. Warfarin
4. The following are recommended methods for reversal of
anticoagulation in the context of major bleeding:
A. Intravenous vitamin K in a patient anticoagulated with
warfarin
B. Intravenous prothrombin complex concentrate in a
patient anticoagulated with a NOAC
C. Intravenous prothrombin complex concentrate and
recombinant factor VIIa in a patient anticoagulated with
a NOAC
D. Intravenous vitamin K and prothrombin complex
concentrate in a patient anticoagulated with warfarin
5. The following statement are true regarding efficacy and
safety of NOACs when compared with warfarin:
A. Apixaban has largely been shown to be superior in both
efficacy and safety when compared with warfarin for
the prevention of stroke and systemic embolism in
patients with AF
B. Rivaroxaban has been shown to be superior to warfarin
in efficacy, and comparable in safety for the prevention
of stroke and systemic embolism in patients with AF
C. Rivaroxaban was equal in both efficacy and safety when
compared with warfarin in the treatment of acute DVT
or PE
D. Dabigatran high dose (150 mg twice daily) was superior
to warfarin in both efficacy and safety for prevention of
stroke or systemic embolism in patients with AF
2
Contributors All authors conducted a literature review, formulated the first draft
and were all involved in subsequent revisions and alterations to the manuscript.
Competing interests RS declares receiving institutional grants from AstraZeneca,
Eli Lilly/Daiichi Sankyo, and Merck; research support from Accumetrics; honoraria
from AstraZeneca, Eli Lilly/Daiichi Sankyo, Merck, Novartis, Iroko, Sanofi-Aventis,
Bristol Myers Squibb, Accumetrics and Medscape; and consultancy fees from
AstraZeneca, Merck, Novartis, Accumetrics, PlaqueTec and Roche.
Provenance and peer review Not commissioned; externally peer reviewed.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Saraf K, et al. Postgrad Med J 2014;90:520–528. doi:10.1136/postgradmedj-2014-132605
Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin
K antagonists: the seventh ACCP conference on anti- thrombotic and thrombolytic
therapy. Chest 2005;127:415–16.
Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant over
antiplatelet therapy in atrial fibrillation depends on the quality of international
normalized ratio control achieved by centers and countries as measured by time in
therapeutic range. Circulation 2008;118:2029–37.
Mitka M. FDA advisory decision highlights some problems inherent in pragmatic
trials. JAMA 2011;306:1851–2.
Rose AJ, Ozonoff A, Henault LE, et al. Warfarin for atrial fibrillation in
community-based practise. J Thromb Haemost 2008;6:1647–54.
Husted S, de Caterina R, Andreotti F, et al. Non-vitamin K antagonist oral
anticoagulants (NOACs): no longer new or novel. Thromb Haemost 2014;111:781–2.
Whitlon DS, Sadowski JA, Suttie JW. Mechanism of coumarin action: significance of
vitamin K epoxide reductase inhibition. Biochemistry 1978;17:1371–7.
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients
with atrial fibrillation. N Engl J Med 2009;361:1139–51.
Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients
with atrial fibrillation. N Engl J Med 2011;365:981–2.
Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association
Practical Guide on the use of new oral anticoagulants in patients with non-valvular
atrial fibrillation. Europace 2013;15:625–51.
Connolly SJ, Wallentin L, Ezekowitz MD, et al. The long term multicentre
observational study of dabigatran treatment in patients with atrial fibrillation
(RELY-ABLE) study. Circulation 2014;128:237–43.
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular
atrial fibrillation. N Engl J Med 2011;365:883–91.
Schulman S, Kakkar AK, Schellong SM, et al. A randomized trial of dabigatran
versus warfarin in the treatment of acute venous thromboembolism (RE-COVER II).
American Society of Hematology 2011 Annual Meeting; 12 December, 2011; San
Diego, CA. Abstract 205.
Bauersachs R, Berkowitz SD, Brenner B, et al.; EINSTEIN Investigators. Oral
rivaroxaban for symptomatic venous thromboembolism. N Engl J Med
2010;363:2499–510.
Buller HR, Prins MH, Lensin AW, et al.; EINSTEIN-PE Investigators. Oral rivaroxaban
for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:
1287–97.
Agnelli G, Buller HR, Cohen A, et al. Apixaban for the treatment of acute venous
thromboembolism. N Engl J Med 2013;369:799–808.
Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous
enoxaparin for the prevention of venous thromboembolism after total knee
replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178–85.
Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for
thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358:2776–86.
Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for
thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358:2765–75.
Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for
thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double
blind trial. Lancet 2010;375:807–15.
Conolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation.
N Engl J Med 2011;364:806–17.
Lassen MR, Gallus A, Raskob JE, et al. Apixaban versus enoxaparin for
thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487–98.
Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for
prevention of venous thromboembolism after total hip replacement: a randomised,
double-blind, non-inferiority trial. Lancet 2007;370:949–65.
Cohen AT, Spiro TE, Buller HR, et al. Rivaroxaban for thromboprophylaxis in acute ill
medical patients. N Engl J Med 2013;368:513–28.
Romualdi E, Donadini MP, Ageno W. Oral rivaroxaban after symptomatic venous
thromboembolism: the continued treatment study (EINSTEIN extension study). Expert
Rev Cardiovasc Ther 2011;9:841–4.
http://guidance.nice.org.uk/TA249 (accessed 23 May 2014).
http://guidance.nice.org.uk/TA256 (accessed 23 May 2014).
http://guidance.nice.org.uk/TA261 (accessed 23 May 2014).
http://guidance.nice.org.uk/TA275 (accessed 23 May 2014).
Kansal AR, Sorensen SV, Gani R, et al. Cost-effectiveness of dabigatran etexilate for
the prevention of stroke and systemic embolism in UK patients with atrial
fibrillation. Heart 2012;98:573–8.
Harrington AR, Armstrong EP, Nolan PE, et al. Cost-effectiveness of apixaban,
dabigatran, rivaroxaban and warfarin for stroke prevention in atrial fibrillation.
Stroke 2013;44:1676–81.
Lee S, Anglade MW, Pham D, et al. Cost-effectiveness of rivaroxaban compared to
warfarin for stroke prevention in atrial fibrillation. Am J Cardiol 2012;110:
845–51.
Steffel J, Braunwald E. Novel oral anticoagulants: focus on stroke prevention and
treatment of venous thrombo-embolism. Eur Heart J 2011;32:1968–76.
http://www.ema.europa.eu/ema (accessed 19 Nov 2013).
527
Downloaded from pmj.bmj.com on September 4, 2014 - Published by group.bmj.com
Review
34
35
36
37
38
39
40
41
42
528
Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and
dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled,
crossover study in healthy subjects. Circulation 2011;124:1573–9.
Gavillet M, Angelillo-Scherrer A. Quantification of the anticoagulatory effect of noval
anticoagulants and management of emergencies. Cardiovasc Med 2012;15:170–9.
Lu G, DeGuzman FR, Karbarz MJ, et al. Reversal of rivaroxaban mediated
anticoagulation in animal models by a recombinant antidote protein (r-antidote,
PRT064445). Eur Heart J 2011;32:640–1.
Mega JL, Braunwald E, Wiviott S, et al. Rivaroxaban in patients with recent acute
coronary syndrome. N Engl J Med 2012;366:9–19.
Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after
acute coronary syndrome. N Engl J Med 2011;365:699–708.
http://news.bms.com/press-release/partnering-news/new-eliquis-apixaban-posthoc-subanalysis-phase-iii-aristotle-trial-de (accessed 23 May 2014).
Eikelboom JW, Conolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in
patients with mechanical heart valves. N Engl J Med 2013;369:1206–14.
http://clinicaltrials.gov/ct2/show/NCT01868243 (accessed 23 May 2014).
Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients
with atrial fibrillation. N Engl J Med 2013;369:2093–104.
43
Kawaji H, Ishii M, Tamaki Y, et al. Edoxaban for prevention of venous
thromboembolism after major orthopedic surgery. Orthop Res Rev 2012;4:53–64.
De Caterina R, Husted S, Wallentin L, et al. General mechanisms of coagulation and
targets of anticoagulants (section i). Position paper of the ESC working group on
thrombosis—task force on anticoagulants in heart disease. Thromb Haemost
2013;109:569–79.
44
Answers
1.
2.
3.
4.
5.
A-T, B-F, C-T, D-T
A-F, B-T, C-T, D-F
A-F, B-T, C-F, D-T
A-F, B-F, C-T, D-T
A-T, B-F, C-T, D-F
Saraf K, et al. Postgrad Med J 2014;90:520–528. doi:10.1136/postgradmedj-2014-132605
Downloaded from pmj.bmj.com on September 4, 2014 - Published by group.bmj.com
Non-vitamin K antagonist oral
anticoagulants (NOACs): clinical evidence
and therapeutic considerations
Karan Saraf, Paul Morris, Pankaj Garg, et al.
Postgrad Med J 2014 90: 520-528 originally published online August 1,
2014
doi: 10.1136/postgradmedj-2014-132605
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