NHS Lanarkshire Guidance on Anticoagulant treatment for ... · mitral stenosis should be treated...
Transcript of NHS Lanarkshire Guidance on Anticoagulant treatment for ... · mitral stenosis should be treated...
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review Date: November 2019
NHS Lanarkshire Guidance on Anticoagulant treatment for patients with
non-valvular atrial fibrillation
Atrial fibrillation (AF) affects about 1.2% of the population in the United Kingdom and accounts for
20% of all strokes. AF is the most common sustained cardiac arrhythmia and if left untreated AF is a
significant risk for stroke and other morbidities. For detailed guidance on management of atrial
fibrillation please refer to NHS Lanarkshire Guideline on Management of Atrial Fibrillation1.
Aim
The aim of this document is to support prescribers in identifying and managing appropriate patients
with AF for whom anticoagulation with warfarin or Direct acting Oral Anticoagulant (DOAC) would be
a beneficial and cost effective treatment for reducing stroke and systemic embolism risk in non-
valvular AF (NVAF) . The recommendations are based on NICE CG180, July 20142. NVAF includes all
cases of AF in which the patients do not have a prosthetic metallic valve that normally requires
anticoagulation or mitral stenosis.
Risk assessment for patients with atrial fibrillation
Stroke and bleeding risk should be assessed in all patients with AF. Use CHA2DS2-VASc score to
assess stroke risk and HAS-BLED to assess the risk of bleeding in patients who are going to be started
on an anticoagulant.
General key points about anticoagulants
For most patients the benefit of anticoagulation outweighs the bleeding risk.
For people with an increased risk of bleeding, the benefit of anticoagulation may not always
outweigh the bleeding risk and careful monitoring of bleeding risk is important.
Do not withhold anticoagulation solely because the person is at risk of having a fall.
Do not offer aspirin (or clopidogrel) monotherapy solely for stroke prevention to people with
AF.
Anticoagulation
If considering anticoagulation, the options include Warfarin or DOACs. Discussion of anticoagulation
treatment options with the patient will help them make an informed decision.
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October2017 Review date: November 2019
Following a diagnosis of AF, the patient will need to make an informed decision regarding whether
to commence anticoagulation or not. In most cases the decision to start immediate anticoagulation
is not necessary. The patient should be given a few days to reflect and to talk over with family,
friends or other healthcare professionals before making their decision.
Choice of anticoagulant
Warfarin is the first choice anticoagulant in NHSL. However , DOACs offer an alternative choice and
the decision regarding the choice of anticoagulant in AF should be made with the patient and is also
dependent upon patients’ clinical features and preferences. The risks and benefits of treatment
options should be presented to the patient in an easily understandable and unbiased manner.
The DOACs dabigatran3, rivaroxaban 4, apixaban5 and edoxaban6 have not been directly compared in
the same clinical trials, so it is not possible to say which one is better based on a head to head
analysis. They share some of the same advantages and disadvantages compared to warfarin but
because they work slightly differently, they also have some unique characteristics that make them
better suited for different types of patients.
Although the different DOACs have not been directly compared in the same clinical setting and
potentially all the four DOACs which have SMC approval could be used as an alternative to warfarin,
it was felt that making all of them available at the same time would cause confusion with regards to
the choice of DOAC and it would be best to have preferred DOACs. The decision making committee
developing this guidance decided to recommend apixaban and edoxaban for inclusion in NHSL
formulary based on their overall efficacy, cost effectiveness and risk profile .
The clinical benefits of DOACs compared to warfarin diminish with improving INR control. In existing
patients, where warfarin treatment is well controlled (TTR >65%) the use of DOACs may be less
favourable and there is no need to consider a change. Clinicians will need to take the level of INR
control into consideration when assessing the benefits of a potential change to DOAC.
Key points relating to apixaban and edoxaban
Apixaban 5mg twice daily and edoxaban 60mg once daily (standard doses) have similar
efficacy in preventing stroke and systemic embolism
The incidence of intracranial haemorrhage is similar for standard dose apixaban and
edoxaban
Apixaban and edoxaban in standard dose are associated with reduced risk of major bleeding
compared to warfarin
In analysis of absolute rather than relative risk, the absolute risk of major bleeding for NVAF
patients treated with standard dose DOAC was lowest in patients receiving apixaban 5mg
twice daily
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
Edoxaban 30mg once daily was associated with more strokes and systemic embolism than
standard dose edoxaban and apixaban
Patients for consideration of DOAC:
New patients
Patients already on warfarin who have poor INR control (poor control is defined as
TTR<65%)
Warfarin allergy or intolerance (eg.alopecia)
Significant problems with INR monitoring and/or accessing anticoagulant clinics
Frequent medication changes or need for medication that interact with warfarin eg.
Antibiotics
Requirement for compliance aid such as blister pack or dosette box
Unable to regularly attend anticoagulant clinic
Antiplatelets and anticoagulation
Antiplatelets may be indicated in combination with the anticoagulants, for other conditions
associated with AF such as acute cardiac ischaemic events or PCI/stenting .
The co-prescription of an antiplatelet with an anticoagulant confers an additional bleeding risk. The
combination of dual antiplatelet therapy plus anticoagulant (referred to as ‘triple therapy’) increases
the risk of bleeding events by about 2-4 times compared to anticoagulant or aspirin alone.
If a patient is on an antiplatelet because of pre-existing ischaemic heart disease (or
cerebrovascular disease), the antiplatelet agent should be reviewed with a view to
discontinuation.
Patients with stable coronary artery disease (no acute ischaemic event or PCI/stent in
preceding 12 months) and concurrent AF can be managed with anticoagulation alone.
The period of dual antiplatelet therapy plus anticoagulant should be as short as possible
after PCI/stenting (e.g. not exceeding 6 months for patients at low risk of bleeding or 4
weeks for patients at high risk of bleeding). This can be followed by single antiplatelet
therapy plus anticoagulant for up to 12 months and then lifelong anticoagulant. The
decision regarding length of combined antiplatelet and anticoagulant therapy should be
clearly documented by treating Cardiologist in each case.
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
The use of P2Y12 inhibitors (ticagrelor or prasagrel) in combination with anticoagulants is
not recommended due to increased risk of major bleeding.
Key points: Warfarin
Warfarin has been prescribed for more than 50 years.
Warfarin remains an established and cost effective treatment option for anticoagulation in
patients.
Patients with prosthetic valves requiring anticoagulation (normally metallic valves) and
mitral stenosis should be treated only with warfarin and not a DOAC.
Unlike DOACs, Warfarin may be considered in patients with prosthetic heart valves requiring
anticoagulation, mitral stenosis and/or hepatic impairment.
The benefits of DOACs over Warfarin decline as the TTR for Warfarin increases.
INR gives clinicians a guide to patient compliance.
Effective and familiar use of antidote with Vitamin K should a severe bleed occur whilst
being treated.
Clearance of warfarin is not affected by renal function.
Clinicians may choose to use warfarin in patients for whom the ability to readily or
objectively monitor the extent of anticoagulation is paramount.
For patients who may miss an occasional dose of warfarin, the long time to onset and offset
of action, maybe advantageous as the anticoagulant effect of warfarin will persist for a few
days after the last dose.
× In Warfarin, time to peak effect ranges from 3-5 days and life averaging 40 hours.
× Warfarin is known to interact with certain foods e.g. cranberries, alcohol and other food
containing high amounts of Vitamin K.
× Patients may have difficulty around complying with or accessing INR monitoring.
Key points: DOACs
No requirement for INR monitoring.
DOACs provide immediate anticoagulant effect (time to peak effect ranges from 1-4 hours).
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
DOACs currently have no known food interactions.
× The sole responsibility of anticoagulation remains with the prescriber without the support of
anticoagulant clinic services.
× DOACs have shorter half life and missed doses may result in more time without any
anticoagulation and greater risk of thromboembolic complications.
× Adherence can be a challenge for patients managing anticoagulants.
× Each DOAC has considerably higher acquisition cost than Warfarin (Warfarin cost per year
£50, average NOAC cost per year £500-£620).
× Renal function should be assessed and monitored using Cockcroft and Gault formula to
calculate the creatinine clearance, especially in patients with extreme BMI.
× DOAC s do also require baseline tests and ongoing monitoring intermittently.
Cockcroft and Gault formula
Estimated Creatinine Clearance (ml/min)= (140-age) X Ideal body weight X constant
Serum Creatinine
Age (years)
Weight (Kg)
Constant
o 1.23 men
o 1.04 women
In patients with average body weight and height laboratory estimated eGFR can be similar to
calculated creatinine clearance values according to Cockcroft and Gault formula
However a calculation of creatinine clearance is recommended according to SPC of DOACs
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
Appendix I
Anticoagulation in NVAF
The following algorithm is intended as a guide to support clinicians and should
not replace individual clinical decisions.
Is the patient:
1. Poorly controlled by warfarin (TTR <65%)?2. Predicted to have a lot of interacting medicines (e.g. COPD
patients requiring frequent courses of antibiotics)?3. Unable or unwilling to take warfarin for other reasons
(e.g. difficulty with monitoring requirements or unable tocope with variable dosing)?
Warfarin
Is patient’s creatinine clearance
<30ml/min
Consider a DOAC
Weight >60Kg and Creatinine
clearance >59ml/min
HAS BLED ≥ 3 or previous GI bleed
+ / - upper GI symptoms
Edoxaban 60mg
once daily*
Apixaban 5mg twice daily*
2.5mg twice daily if two or more of
≥80 years, ≤60kg, serum creatinine
>133 µmol/l
* for full prescribing details please refer to SPC or BNF
No
Yes
Yes
No
Yes Yes No
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
Appendix II
Choice of Anticoagulant in AF based on Patient Characteristics
Patient Characteristics Preferred Drug Choice Rationale
Mechanical Heart Valve Warfarin DOACs not studied in this
patient population or inferior to
warfarin (Dabigatran)
Valvular Disease (mitral stenosis or
metallic valves)
Warfarin DOACs not studied in this
patient population
Moderate hepatic impairment
(Child-Pugh B)
Warfarin Apixaban or Edoxaban should
be used with caution
Severe hepatic impairment (Child-
Pugh C)
Warfarin DOACs either contraindicated
or not studied in this patient
population
Stable on warfarin
(TTR>65%, no allergy or alopecia)
Warfarin A switch not required unless
change in patient
characteristics (concomitant
new drug having significant
interaction with warfarin,
unable to attend anticoagulant
clinic)
CrCl <30 ml/min Warfarin preferred
If using Apixaban, dose
should be reduced to 2.5
mg twice daily
Very few patients with CrCl<30
ml/min included in DOAC trials.
ESC guidelines recommend
against use of DOAC in this
population
Recent gastrointestinal bleed Warfarin or apixaban Less bleeding risk with apixaban
but warfarin can be reversed
easily if further bleeding
Extremes of weight
(<50kg or >120kg)
Warfarin Limited trial data for DOACs
Frequent illness or health status
change without significant
deterioration in renal function
Apixaban or Edoxaban Increased risk of under or over
anticoagulation with warfarin
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
Frequent medication changes or
need for medication that interact
with warfarin such as antibiotics
Apixaban or Edoxaban Increased risk of under or over
anticoagulation
Previous intracranial bleed
(decision to anticoagulate as per
specialist advice)
Apixaban or Edoxaban Risk of intracranial bleeding less
with DOACs than warfarin.
Patients with previous
intracranial bleed generally
excluded from trials
Requirement for compliance aid
such as blister pack/dosette box
Apixaban or Edoxaban Warfarin not normally
dispensed in sealed compliance
box (due to variable dosing)
Unable to regularly attend
anticoagulant clinic
Apixaban or Edoxaban Additional resource required
for home visits
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
Appendix III
The following information is a summary guide for prescribers- for additional
information consult individual SPCs.
Warfarin Apixaban Edoxaban
Licensed
indications
Prevention of stroke and
systemic embolism in
adult patients with non-
valvular atrial fibrillation
(NVAF) (with at least
one additional risk factor)
Prevention of stroke and
systemic embolism in adult
patients with non-valvular
atrial fibrillation (NVAF)
(with at least one additional
risk factor)
Prevention of stroke and
systemic embolism in adult
patients with non-valvular
atrial fibrillation (with one
or more risk factors)
Doses As per INR
5mg twice daily
(CrCL 15-29ml/min –
2.5mg twice daily)
Patients with 2 or more of
the following give 2.5mg
twice daily:
-age >80 years
-body weight <60kg
-serum Cr>133micromole/l
60mg once daily
(For CrCl 50-80 ml/min)
For patients with one or
more of the following
clinical factors give
30mg once daily
CrCl 15-50ml/min
Body weight <60kg
Concomitant P-
glycoprotein inhibitors-
ciclosporin, dronedarone,
erythromycin,
ketoconazole
Interactions
(list not exhaustive
– refer to current
SPC)
Multiple
interactions
requiring
increased INR
monitoring
Cranberry juice,
alcohol, foods
with high amount
of vitamin K e.g.
leafy green veg
such as cabbage,
spinach, Brussel
sprouts and
broccoli
Avoid concomitant
use with strong
inhibitors of both
CYP3A4 and P-gp e.g.
ketoconazole,
intraconazole,
voriconazole or HIV
protease inhibitors.
Caution with strong
CYP3A4 inducers e.g.
rifampicin,
phenytoin,
carbamazepine,
Phenobarbital or St.
John’s Wort as they
may lead to reduced
apixaban
concentrations
There are no known food
interactions
Concomitant use
with P-gp
inhibitor (e.g.
ketoconazole,
ciclosporin,
dronedarone or
erythromycin)
requires dose
reduction to 30mg
once daily
Use with caution
when co-
administered with
P-gp inducers (e.g.
phenytoin,
carbamazepine,
phenobarbital or
St. John’s Wort)
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
Warfarin Apixaban Edoxaban
Contraindications
(List not
exhaustive, refer
to current SPC)
Hypersensitivity
A lesion or condition,
if considered a
significant risk factor
for major bleeding
Hepatic disease
associated with
coagulopathy and
clinically relevant
bleeding risk
Anticoagulant in use
(except during
switching – see
below)
CrCL<15ml/min
Hypersensitivity
Clinically
significant active
bleeding
Hepatic disease
associated with
coagulopathy and
clinically relevant
bleeding risk
Lesion or
condition, if
considered a
significant risk
factor for major
bleeding
Uncontrolled
severe
hypertension
Anticoagulant in
use (except during
switching – see
below)
End stage renal
failure , patients
undergoing
dialysis
Efficacy for stroke
prevention
Superior to warfarin
(ARISTOTLE)
Non-inferior to
warfarin (ENGAGE
AF-TIMI 48)
Poor adherence Can monitor
adherence by
checking INR
Not recommended Not
recommended
Dosing intervals Once daily Twice a day dosing Once daily
Missed dose Missed dose
should be taken
immediately and
then continue
once daily with
dose adjustment
depending on INR
Missed dose should
be taken
immediately and
then continued with
twice a day as before
Do not double dose
within the same day
to make up for
missed dose
Missed dose
should be taken
immediately and
then continued
the following day
with once daily
intake as before
Do not double
dose within the
same day to make
up for missed
dose
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
Warfarin Apixaban Edoxaban
Compliance aid Not suitable for
compliance aids
due variable
dosing
Shelf life of 3 years
and no special
storage requirement-
can be used with
compliance aids
Shelf life of 3
years and no
special storage
requirement-can
be used with
compliance aids
Extremes of BMI Dose adjustment
according to INR
Exposure of DOAC
may vary by 20-30%
at extremes of
bodyweight (<50kg
or >120 Kg). This may
be problematic given
the difficulties in
monitoring
therapeutic effects.
Exposure of DOAC
may vary by 20-
30% at extremes
of bodyweight
(<50kg or >120
Kg). This may be
problematic given
the difficulties in
monitoring
therapeutic
Renal impairment Can be used with
caution in renal
impairment (not
excreted by
kidneys)
Patients must have a
baseline renal
function test before
initiating DOAC.
Renal function can
decline while on
treatment hence
monitor annually or
more often in high
risk patients.
eGFR and CrCL are
not interchangeable
but in practice eGFR
can be used as a
guide in most
patients (>18years)
with average height
and weight.
The SPC of each
DOAC recommends
that ‘Cockcroft and
Gault formula’ is
used for dosing and
monitoring
Patients must
have a baseline
renal function test
before initiating
DOAC. Renal
function can
decline while on
treatment hence
monitor annually
or more often in
high risk patients.
eGFR and CrCL are
not
interchangeable
but in practice
eGFR can be used
as a guide in most
patients
(>18years) with
average height
and weight.
The SPC of each
DOAC
recommends that
‘Cockcroft and
Gault formula’ is
used for dosing
and monitoring
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
Warfarin Apixaban Edoxaban
Hepatic
impairment
Should be used
with caution
Avoided in severe
hepatic
impairment
(especially is
prothrombin time
is prolonged)
Not recommended in
patients with
elevated liver
enzymes >twice
upper limit of normal
Contraindicated in
patients with hepatic
disease associated
with coagulopathy
and clinically
relevant bleeding risk
Not
recommended in
severe hepatic
impairment
Contraindicated in
patients with
hepatic disease
associated with
coagulopathy and
clinically relevant
bleeding risk
Age No dose
adjustment
specified
Consider dose
reduction in >80yrs-
2.5mg twice daily
No dose reduction
is required
pregnancy Not
recommended
Not recommended Not
recommended
Major bleed risk
compared to
warfarin
Reduced risk
compared to
warfarin
Reduced risk
compared to
warfarin
Intracranial bleed
risk
Small risk Reduced risk
compared to
warfarin
Reduced risk
compared to
warfarin
GI bleeding risk
compared to
warfarin
Similar risk to
warfarin
Increased risk with
high dose (60mg
daily)
Risk of
dyspepsia/upper
GI side effects
Non reported Non reported Non reported
Reversibility Can be reversed There is currently no
antidote
There is currently
no antidote
Conversion from
warfarin to DOAC
Discontinue warfarin
and start apixaban
when INR <2
Discontinue
warfarin and start
edoxaban when
INR ≤2.5
Conversion from
DOAC to warfarin
Continue with
apixaban for at least
2 days after starting
warfarin therapy
Check INR and
continue co-
administration until
INR >2.0
For patients on
edoxaban 60mg,
reduce dose to 30
mg daily (reduce
to 15mg for
patients on 30mg)
Co-administer
appropriate dose
warfarin until INR
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017 Review date: November 2019
≥2
Before surgery If the procedure can
not be delayed the
increased risk of
bleeding should be
assessed against
urgency of
intervention
Discontinue at least
48 hours prior to
elective surgery or
invasive procedures
with a moderate or
high risk of bleeding
Discontinue at least
24 hours prior to
elective surgery or
invasive procedures
with low risk of
bleeding
If the procedure
can not be
delayed the
increased risk of
bleeding should
be assessed
against urgency of
intervention
Edoxaban should
be stopped at
least 24 hours
before elective
procedure
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017Review date: November 2019
Appendix IV
Check list for patients starting on a DOAC
Tick when completed
Explain the purpose of anticoagulation in AF
Explain how the drug works i.e. ‘blood takes longer to clot, not
thinner’
Explain the intended duration of therapy
Explain the pros and cons of warfarin versus DOAC including
dosing regimen
Explain the risk of bleeding/bruising and what action to take in the
event of bleeding, fall or head injury (currently no antidote for
apixaban)
Explain follow up arrangements to assess compliance, side-effects,
bleeding and monitoring
(frequency of follow up blood tests depends on creatinine
clearance or illness affecting LFTs)
Explain the risk of potential drug interactions
Explain to the patient how to take medication
The frequency of administration
Importance of compliance and to take regularly
What to do if a dose is missed
To seek help if extra dose is taken accidentally
Not to stop taking medication
Advise patient to always inform any healthcare professionals,
including doctors, nurses, pharmacists and dentists that they are
taking an anticoagulant
Ensure patients carry a patient alert card and provide other
available information to support DOAC use i.e. locally produced
patient information leaflets
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Guidance prepared by: M Malekian Approved by: ADTC Version date: October 2017Review Date: November 2019
References:
1. http://firstport2/staff-support/coronary-heart-disease/Documents/Atrial Fibrillation
Guideline.pdf
2. https://www.nice.org.uk/guidance/cg180
3. Connolly et al., Dabigatran versus warfarin in in patients with atrial fibrillation, N Engl J
Med 2009; 361:1139-1151
4. Manesh et al, Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation, N Engl J
Med 2011; 365:883-891
5. Granger et al., Apixaban versus Warfarin in Patients with Atrial Fibrillation, N Engl J
Med 2011; 365:981-992
6. Giugliano et al., Edoxaban versus Warfarin in Patients with Atrial Fibrillation, N Engl J
Med 2013; 369:2093-210