Newer oral anticoagulants

This bulletin principally discusses the use of the

three newer oral anticoagulants licensed for use in Summary
the UK – dabigatran etexilate, apixaban▼, and
 The benefits and risks of anticoagulation should
rivaroxaban▼ – for the prevention of stroke and
be carefully assessed using validated tools.
systemic embolism in patients with non-valvular
atrial fibrillation (AF). It also contains information  An informed discussion, of risks and benefits
likely to be of use when managing patients relative to warfarin, should take place with the
prescribed these medicines for other licensed patient if a newer anticoagulant is to be used.
indications.  Patients who are already well controlled on
warfarin should not have their therapy changed.
The newer oral anticoagulants have been developed  Renal function should be measured prior to
in an attempt to address some of the perceived initiation of the newer anticoagulants and
limitations of anticoagulation with vitamin K periodically thereafter; where required, the dose
antagonists, specifically warfarin, including: should be adjusted as recommended.
 a longer onset and offset of action,  It should be noted that significant drug-drug
necessitating bridging therapy with parenteral interactions may occur with the newer agents.
agents for some indications,
 Switching from warfarin to a newer agent and
 variability in dosing requirements and a narrow vice versa should be done with care and
therapeutic window, requiring routine monitoring of renal function and international
anticoagulant monitoring, normalised ratio (INR) where appropriate.
 food-drug and drug-drug interactions, requiring
dietary precautions, restrictions on use with
certain other medicines, and/or the requirement Some useful pharmacology
for additional monitoring.1 Dabigatran etexilate is an inactive pro-drug,
In Wales, over 890 000 prescriptions for oral which is converted in vivo into the direct thrombin
anticoagulants were dispensed in primary care in inhibitor dabigatran; apixaban and rivaroxaban
the year to August 2013; newer agents accounted are both direct inhibitors of factor Xa.
for less than 1% of the total, but this is increasing.2
Approximately 80% of active dabigatran, 25% of
Licensed indications the apixaban dose, and one-third of the rivaroxaban
dose are excreted unchanged in the urine. It is
Dabigatran etexilate, apixaban, and rivaroxaban essential to assess kidney function using creatinine
have been accepted by the National Institute for clearance (CrCl) prior to initiation; serum
Health and Care Excellence (NICE) as an option creatinine should be measured and the Cockcroft-
for use within the NHS for the following licensed Gault formula used. The dose should then be
indications.3-9 All are licensed for the prevention of adjusted as recommended.1,10-13 Renal function
stroke and systemic embolism in patients with non- should be monitored periodically thereafter – the
valvular AF with one or more cardiovascular risk product literature for dabigatran etexilate suggests
factor/s (which vary very slightly between agents) at least annually in most patients, but more frequent
and the prophylaxis of venous thromboembolism monitoring is recommended in certain situations
following knee or hip surgery. Rivaroxaban is where renal function may decline or deteriorate
additionally licensed for the treatment – and (e.g. dehydration, hypovolaemia, co-administration
prevention of recurrent – deep vein thrombosis and of medicines affecting the kidney, etc.).11,14
pulmonary embolism.

November 2013
Dabigatran does not undergo substantial As apixaban and rivaroxaban undergo hepatic
metabolism via the hepatic pathway, but both metabolism, predominantly via the CYP3A4/3A5
apixaban and rivaroxaban are metabolised in the pathway; inhibitors and inducers of this system
liver.1,15 Liver function tests are required before may respectively increase or decrease plasma
initiating apixaban.12 Changes to dose and/or levels. Dabigatran has a low potential for
contraindications and cautions in hepatic interactions through the hepatic pathway but is
impairment vary between agents.11-13 likely to be affected to a greater extent than
apixaban and rivaroxaban by combinations of
The newer agents are not without associated drug- medicines affecting the kidney. All three agents are
drug interactions and, as they enter more routine substrates of P-glycoprotein and co-administration
practice, it is likely that others will be identified. with medicines that inhibit or induce this pathway
Table 1 illustrates some of the medicines which can respectively increase or decrease plasma
may interact. concentration.1,15
Table 1. Examples of possible drug-drug interactions with the newer anticoagulants10-13
Drugs directly Drugs affecting Inducers of Inhibitors of Inducers of Inhibitors of
affecting bleeding the kidney hepatic hepatic P-glycoprotein P-glycoprotein
risk metabolism metabolism
other diuretics rifampicin azole rifampicin, dronedaroneB,F
anticoagulantsA NSAIDs St John’s Wort antifungalsB,E,F St John’s Wort, quinidineD
NSAIDs ACE inhibitors carbamazepine verapamilC carbamazepine, azole
antiplatelets angiotensin-II- phenytoin amiodaroneD phenytoin, antifungalsB,E,F
thrombolytic receptor phenobarbital ciclosporinB phenobarbital amiodaroneD
agents antagonists tacrolimusB diltiazem
selective serotonin HIV protease verapamilC
re-uptake inhibitors inhibitorsE,F clarithromycin
serotonin-
ticagrelor
noradrenaline re-
uptake inhibitors HIV protease
inhibitorsE,F
A. Contraindicated except when switching between agents. D. Dose adjustment of dabigatran etexilate required in orthopaedic use.
B. Contraindicated with dabigatran etexilate. E. Not recommended with apixaban.
C. Dose adjustment of dabigatran etexilate required. F. Not recommended with rivaroxaban.

Prophylaxis in atrial fibrillation Box 1. CHADS2 scoring system

Antithrombotic therapy should be considered for the Risk factor Score
prophylaxis of embolism in all patients with AF.16 C Congestive HF 1
The choice of treatment depends on individual risk H Hypertension 1
assessment for both stroke and bleeding, together A Age ≥ 75 1
with an informed discussion with the patient.
D Diabetes mellitus 1

Patients at the highest risk of stroke are likely to S2 Stroke/TIA/thromboembolism 2

derive most benefit from anticoagulation. NICE

Box 2. CHA2DS2-VASc scoring system
recommends that antiplatelet therapy may be
considered for low risk patients. However, the Risk factor Score
European Society of Cardiology (ESC) 2012 C Congestive HF/left-ventricular dysfunction 1
guideline recommends that an anticoagulant is H Hypertension 1
considered for all patients other than those at ‘truly A2 Age ≥ 75 2
low risk’, i.e. aged under 65 years with lone AF, who D Diabetes mellitus 1
should receive no antithrombotic.17
S2 Stroke/TIA/thromboembolism 2

The Quality and Outcomes Framework (QOF) for V Vascular disease (prior myocardial infarction, 1
peripheral artery disease, or aortic plaque)
Wales (2013-14) recommends the use of the
A Age 65 - 74 1
CHADS2 tool (see Box 1) to assess stroke risk in
patients with AF.18 Anticoagulation should be Sc Sex category, i.e. female gender 1
considered in patients with a score of ≥ 2.19 The
CHA2DS2-VASc tool (see Box 2) includes more risk An assessment of bleeding risk using a tool such as
factors for stroke and may be used for patients with a HAS-BLED (see Box 3) should be undertaken before
CHADS2 score of 0 or 1 to identify those at truly low anticoagulation. In general, if the HAS-BLED score
risk; it is at least as good as CHADS2 at identifying ≥ 3, caution and regular review is advised.17,20
patients who develop stroke and thromboembolism.17 Modifiable risk factors should be addressed.

2 WeMeReC Bulletin, November 2013

Box 3. HAS-BLED bleeding risk score Choosing an anticoagulant in AF
Risk factor Score The All Wales Medicines Strategy Group (AWMSG)
H Hypertension (systolic > 160 mmHg) 1 currently advises warfarin as first-line therapy for the
A Abnormal renal/hepatic function* (1 each) 1 or 2 majority of patients where the decision has been
S Stroke 1 made to start an anticoagulant in AF (see guidance at
B Previous or predisposition to bleeding 1
www.awmsg.org).19 Patients who are already well
controlled on warfarin should not have their therapy
L Labile INR (unstable/high/poor TTR) 1
changed.19 However, in certain carefully selected
E Elderly (age > 65 years) 1
patients, e.g. those taking warfarin but unable to
D Drugs or alcohol (1 each) (e.g. antiplatelets, 1 or 2 maintain an INR within the target therapeutic range
NSAIDs, or alcohol ≥ 8 units/week)
despite good adherence, the newer agents may be
* Abnormal renal function: chronic dialysis, transplantation, or serum
creatinine ≥ 200 µmol/l. Abnormal hepatic function: chronic disease
considered. In such cases an informed discussion
(e.g. cirrhosis) or significant biochemical derangement (e.g. bilirubin should take place between the patient and clinician
> 2x upper limit of normal, in association with aminotransferase/ regarding the risks and benefits of the newer agent
alanine aminotransferase/alkaline phosphatase > 3x upper limit of
normal, etc.). relative to warfarin.4,6,8,19 When monitoring warfarin
therapy it is important to use a computer dosing
Social and clinical risk factors should also be system that is capable of measuring time in
assessed.19 It is useful to ask questions such as: therapeutic range (TTR). The TTR should not be
 Is the patient registered with a GP? assessed within the first one to three months post-
 Any investigations for cancer? initiation; an assessment period of six months
 Is the patient taking over-the-counter medicines? following this initiation phase is a better indication of
 Any evidence of trips and falls?
ability to maintain target INR.19
 Any sensory, visual, or literacy deficits? Poor adherence to any anticoagulant is
 Alzheimer’s or problems with mental capacity? likely to be associated with an increased risk
 Is the patient of child-bearing age?21 of thrombosis or bleeding.19

Evidence suggests that warfarin is not an effective

Benefits and risks of newer agents in AF intervention when TTR < 58%.19 If there are extreme
The three key clinical trials comparing the newer spikes in INR and/or TTR is below this threshold, the
agents with warfarin in patients with AF were based issue of adherence should be explored. Poor
on a non-inferiority design, i.e. they were designed to adherence alone is not an indication that one of the
show equivalence within specified limits for the newer agents will be suitable; indeed, the newer
primary endpoint of stroke and systemic embolism. agents have comparatively short half-lives and it has
been suggested that missed doses could lead to a
Non-inferiority versus warfarin was demonstrated for greater risk of thrombosis compared with missed
all three of the newer agents.22-24 Dabigatran etexilate doses of warfarin.1 Prescribers should make efforts to
110 mg twice daily was associated with a slightly understand and address reasons for warfarin non-
lower risk of major bleeding, and at 150 mg twice adherence before considering a switch.19
daily there was a decrease in the risk of stroke and
systemic embolism with no difference in the rate of Prescribing responsibility
major bleeding compared with warfarin.22 The
The decision to initiate one of the newer agents
apixaban trial also reported a decrease in the risk of
should be on the advice of a secondary care specialist
stroke and systemic embolism but with a lower rate
but this should not preclude primary care prescribing
of major bleeding compared with warfarin.23 The
where appropriate; a first prescription may be issued
rivaroxaban trial reported similar rates of stroke and
in primary care on the advice of a specialist.19 For
systemic embolism and major bleeding to warfarin.24
people with existing AF in whom the decision is
made to switch from current therapy to dabigatran
A systematic review and meta-analysis of efficacy
etexilate, apixaban, or rivaroxaban it may be
and safety data from 12 phase II and III trials of four
appropriate for practices providing level 3 and 4
newer anticoagulants (one not licensed in the UK)
anticoagulation services to make the switch if the
suggested a small advantage over warfarin in terms of
clinician is familiar with the use of these agents.19
stroke and systemic embolism and all-cause
mortality.25 Intracranial bleeding rates were lower In the year to July 2013, the MHRA received 33
than seen with warfarin but the risk of major bleeding Yellow Cards regarding the newer anticoagulants
was similar. These results provide a limited estimate from within Wales.27 To report suspected adverse
of clinical efficacy.26 effects, go to www.yellowcardwales.org.

WeMeReC Bulletin, November 2013 3

 Table 2. Initiation of newer anticoagulants and switching from and to warfarin in AF10-13
Initiation doses in AF Switching from warfarin in AF Switching to warfarin in AF
Dabigatran 150 mg twice daily, or Stop warfarin and start If CrCl ≥ 50ml/min, start warfarin 3 days
etexilate 110 mg twice daily if: dabigatran etexilate when INR prior to dabigatran withdrawal.
patient > 80 years, at higher risk of < 2.0. If CrCl ≥ 30 to < 50ml/min, start warfarin
bleeding, or receiving verapamil 2 days prior to dabigatran withdrawal.
Contraindicated if: Dabigatran etexilate can affect INR; do
CrCl < 30 ml/min not measure until 48h after withdrawal.
▼
Apixaban 5 mg twice daily, or Stop warfarin and start Co-administer apixaban and warfarin
2.5 mg twice daily if: apixaban when INR < 2.0. for two days, then measure INR.
CrCl 15-29 ml/min, or at least two of: Warfarin can be continued as
age ≥ 80 years, weight ≤ 60kg or, monotherapy when INR ≥ 2.0.
serum creatinine ≥ 1.5mg/dL. Apixaban can affect the INR; measure
Not recommended if: at least 24h after the previous dose but
CrCl < 15ml/min prior to the next dose.
▼
Rivaroxaban 20 mg daily, or Stop warfarin and start Co-administer rivaroxaban and warfarin
15 mg daily if: rivaroxaban when INR ≤ 3.0. until INR ≥ 2.0.
CrCl 30-49 ml/min Rivaroxaban can affect the INR;
CrCl 15-29 ml/min (use with caution) measure at least 24h after the previous
Not recommended if: dose but prior to the next dose.
CrCl < 15ml/min

Monitoring activity Managing bleeding

One of the postulated advantages of the newer agents Experience with the newer agents is still limited and
is that there is no need for routine coagulation managing bleeding should concentrate on prevention,
monitoring and this may be of benefit to many. i.e. prescribing the correct dose to a suitable patient.
However, the lack of the ability to monitor these Special care should be taken when prescribing the
agents using routine tests may be of concern to some. newer agents to patients with co-morbidities,
undergoing procedures, or with other medicines,
All three of the newer agents prolong the activated which may increase the risk of bleeding.30 Careful
partial thromboplastin time (aPTT) and the INR to attention should also be paid to renal function and to
some extent; thrombin time is increased by the contraindications, posology, and warnings for use
dabigatran and prothrombin time by the factor Xa specific to each agent, together with the individual’s
inhibitors. With an appropriate reagent, the aPTT risk factors for bleeding.30
may be used to indicate whether anticoagulation is
supratherapeutic, therapeutic, or subtherapeutic, but There is no specific antidote for any of the newer
cannot determine plasma concentration.14,15,28 Such agents – product information should be consulted for
urgent qualitative assessment may be useful: advice on treatment in the event of a bleed.30 Local
 before surgery or invasive procedures guidelines may also exist and all prescribers should
be familiar with these. Bleeding patients should be
 when a patient is bleeding
rapidly assessed for haemodynamic stability, source
 if a patient has overdosed of bleeding, time elapsed since last dose, and renal
 if a patient has developed renal failure function. All three agents have comparatively short
 when a patient has a thrombosis on treatment.14 half-lives and minor bleeding such as epistaxis,
ecchymosis, and menorrhagia may be controlled with
The ecarin clotting time and diluted thrombin time local haemostatic measures, possibly combined with
can be used to measure the effect of dabigatran, and a short cessation of therapy with due regard given to
specifically calibrated anti-factor Xa assays may be thrombotic risk. Patients with moderate and
used with rivaroxaban and apixaban.14,28 However, severe/life-threatening bleeding should be urgently
the relationship of these tests with the thrombotic referred to secondary care.31
event risk and bleeding risk remains to be
established29 and availability is variable. These less Again, local guidelines may exist regarding the peri-
urgent quantitative tests may be useful: operative management of anticoagulation with the
 for patients with deteriorating renal function newer agents. The risk of bleeding from the
 where interacting medicines are to be given procedure, together with renal function, should be
taken into account – as should the risk of thrombosis
 for patients at extremes of body weight.14 if anticoagulation is to be temporarily withdrawn.29,32
Consult Summaries of Product Characteristics for full prescribing information.

Welsh Medicines Resource Centre

All Wales Therapeutics & Toxicology Centre
Academic Building, University Hospital Llandough,
Penarth, Vale of Glamorgan CF64 2XX

Tel: 029 2071 6117 Web: www.wemerec.org

Email: [email protected]
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