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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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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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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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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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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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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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)


systemic embolism in adult

patients with non-valvular

atrial fibrillation (NVAF)

(with at least one additional

risk factor)


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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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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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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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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≥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

http://firstport2/staff-support/coronary-heart-disease/Documents/Atrial%20Fibrillation%20Guideline.pdf

http://firstport2/staff-support/coronary-heart-disease/Documents/Atrial%20Fibrillation%20Guideline.pdf

https://www.nice.org.uk/guidance/cg180

http://www.nejm.org/toc/nejm/365/10/


