Download Amber Initiation Guideline

313FM.5 DABIGATRAN, RIVAROXABAN, EDOXABAN AND APIXABAN FOR ATRIAL
FIBRILLATION (AF)
Amber initiation guideline
1.
2.
3.
SUMMARY ................................................................................................................................... 1
BACKGROUND FOR USE ........................................................................................................... 2
CRITERIA FOR USE .................................................................................................................... 2
3.1 NEW patients generally suitable to start NOAC.................................................................... 2
3.2 EXISTING WARFARIN patients generally NOT suitable to start NOAC ............................... 3
3.3 EXISTING patients who may be suitable to consider a NOAC or warfarin ............................ 3
3.4 EXISTING patients generally suitable to start NOAC ........................................................... 3
4. TABLE OF CONSIDERATIONS WHEN DECIDING WHICH NOAC FOR AF ............................... 3
5. CONTRAINDICATIONS AND PRECAUTIONS ............................................................................ 4
5.1 Absolute contraindications to warfarin and NOACs .............................................................. 4
5.2 Relative contraindications to both warfarin and NOACs ....................................................... 4
5.3 Contraindications for NOACs but not for warfarin ................................................................. 5
6. RESPONSIBILITIES..................................................................................................................... 5
6.1 NOAC Specialist Pharmacist responsibilities ....................................................................... 5
6.2 GP responsibilities ............................................................................................................... 6
6.3 Patient/carer’s responsibilities .............................................................................................. 6
7. PRE-TREATMENT ASSESSMENT BY GP .................................................................................. 6
8. ONGOING MONITORING SCHEDULE BY GP ............................................................................ 7
9. SUPPORTING INFORMATION FOR INDIVIDUAL NOACs .......................................................... 7
9.1 Dabigatran ........................................................................................................................... 7
9.2 Rivaroxaban ......................................................................................................................... 9
9.3 Apixaban ............................................................................................................................ 11
9.4 Edoxaban........................................................................................................................... 13
10.
MANAGEMENT OF OVERDOSE AND BLEEDING ................................................................ 15
11.
BACK-UP INFORMATION/ADVICE ........................................................................................ 16
12.
REFERENCES ....................................................................................................................... 16
13.
Appendices ............................................................................................................................. 18
Appendix A: Care Pathways ............................................................................................................. 19
i)
New AF patient from primary care ...................................................................................... 19
ii)
Patients initiated on NOAC by BHNHST ............................................................................ 20
iii) Anticoagulation pathway for existing patients on warfarin .................................................. 21
Appendix B: Referral Form 1 – GP to NOAC Clinic .......................................................................... 22
Appendix C: Referral Form 2 – Hospital AF Referrals to NOAC Clinic .............................................. 23
Appendix D: Creatinine Clearance (ml/min) using Cockcroft & Gault Equation ................................. 24
1.
SUMMARY
This guideline provides prescribing and monitoring guidance for anticoagulation with new
oral anticoagulants (NOACs) in AF treatment for adults. It should be read in conjunction with
the shared care responsibilities document, the Summary of Product Characteristics (SPC)
available on http://www.medicines.org.uk/emc and the BNF.
1.1
1.2
1.3
1.4
AF is a condition which results in an increased risk of stroke. Warfarin has always been the
main anticoagulant used in the UK for primary and secondary prevention of stroke in patients
with AF.
In 2012, dabigatran, the first of the NOACs, was approved by NICE as an option for
anticoagulation in non-valvular AF for stroke prevention.
Subsequently, rivaroxaban.
apixaban and edoxaban have also been approved by NICE for this indication. These new oral
anticoagulants (NOACs) are unlike warfarin as they are not vitamin K antagonists and do not
require regular INR monitoring.
Each of the NOACs has a different side effect profile.
None of the NOACs as yet has a licensed antidote.
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1.5
1.6
1.7
1.8
1.9
1.10
1.11
All anticoagulants, whether vitamin K antagonists or NOACs, are associated with serious
bleeding risks and require careful risk assessment of the patient prior to initiation.
The decision about whether to start treatment with a NOAC should be made after an informed
discussion between the clinician and the patient about the risks and benefits of NOACs
compared with warfarin. For patients who are taking warfarin, the potential risks and benefits
of switching to a NOAC should be considered in light of their level of INR control.
For the majority of patients, the risk assessment, informed discussion and decision about
choice of anticoagulant is made in the NOAC clinic where treatment is initiated.
Those patients started on warfarin by the NOAC clinic are referred to the anticoagulant clinic
which usually provides the monitoring service for GP practices.
Those patients started on a NOAC are reviewed at 2 weeks by the NOAC clinic and
discharged to their GP for ongoing prescribing and monitoring unless there are significant
concerns or toxicities.
If side effects or concerns, make a further review of anticoagulation options by the NOAC
clinic necessary, the patient is reassessed by the NOAC clinic. At this point, anticoagulation is
either stopped, an alternative anticoagulant is prescribed or a referral is made to Cardiology.
There is no long term experience of using NOACs. New side effects are still being
recognised. There are clear risks and benefits with these agents. As a general rule, NOACs
are only considered for prescribing when warfarin is not suitable according to local criteria.
2.
BACKGROUND FOR USE
2.1
Anticoagulation is recommended in patients with AF with a CHA2DS2-VASc ≥1 for men or ≥2
for women. Where a patient presents with a transient ischaemic attack (TIA) or stroke, in the
absence of alternative causes and where paroxysmal AF cannot be ruled out, anticoagulation
is considered.
Warfarin has been used for over 60 years for anticoagulation and is monitored using INR
allowing individualised dosing and reinforcement of compliance. The practicalities of
monitoring and adherence with complex dosage regimens, especially for patients with multiple
co-morbidities, makes warfarin challenging for some patients. Thus many patients who could
benefit from anticoagulation do not receive it.
In line with NICE Guidelines for the NOACs they may be considered as alternatives to
warfarin in patients with AF, in whom oral anticoagulation is indicated CHA2DS2-VASc ≥1 for
men or ≥2 for women.
NOACs do not require INR monitoring. The reduced monitoring and dosage adjustment
requirements need to be weighed against the lack of long term safety data, antidote, and
limited data at extremes of age, weight, renal or liver function.
All anticoagulants can cause significant bleeding risk. Before starting any anticoagulant
careful consideration of bleeding risk should be undertaken. Tools such as the HAS-BLED
score should be used to help quantify the bleeding risk.
The CHA2DS2-VASc and HAS-BLED scores share risk factors and, as a result, patients at
high risk of stroke (high CHA2DS2-VASc score) often also have a high HAS-BLED score.
Steps should be taken to reduce the bleeding risk through a reduction in modifiable risk
factors for bleeding such as uncontrolled blood pressure (BP).
2.2
2.3
2.4
2.5
2.6
3.
CRITERIA FOR USE
Warfarin remains the first line option for initiation of anticoagulation unless the criteria below
are met.
3.1
3.1.1
3.1.2
3.1.3
3.1.4
NEW patients generally suitable to start NOAC
High risk of interactions with warfarin leading to unacceptable INR fluctuations which cannot
be addressed.
Co-morbidities which make INR control challenging (clinically unstable or medically complex),
e.g. unstable severe chronic obstructive pulmonary disease (COPD), uncontrolled left
ventricular failure (LVF), recurrent cellulitis.
Adherence to variable dosage regimens is likely to be poor, e.g. learning disabilities.
Secondary prevention of AF patients with recent stroke or TIA to be initiated by a consultant in
the secondary care stroke service. Initiated at least 2 weeks after the stroke or TIA when
there has been associated brain infarction.
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3.2
3.2.1
3.2.2
3.2.3
EXISTING WARFARIN patients generally NOT suitable to start NOAC (to remain on
warfarin)
Good INR control assessed by time in therapeutic range (TTR) >70% - patients should be
advised that there is no clear data to support switching to NOAC in patients with good INR
control. There are clear disadvantages/risks associated with NOAC as described above.
Patients taking warfarin for indications other than anticoagulation in non-valvular AF, unless
licensed in these groups.
Patients with mitral valve disease or mechanical heart valve replacements (unlicensed in this
group even if the patient has co-existing AF).
3.3
EXISTING patients who may be suitable to consider a NOAC or warfarin
3.3.1 Moderate INR control (TTR 60 to 69%) despite evidence of compliance – patients should be
advised that the benefit from switching to a NOAC is unclear. Efforts should be made to find
and resolve underlying causes of reduced control. If this proves impossible then a switch to a
NOAC may be considered but NOAC disadvantages/risks as described above should first be
discussed.
3.4
3.4.1
3.4.2
EXISTING patients generally suitable to start NOAC
Poor INR control (TTR <60%), despite evidence of compliance and adequate vitamin K intake.
Allergy to or intolerable side effects from warfarin which would require warfarin withdrawal.
4.
TABLE OF CONSIDERATIONS WHEN DECIDING WHICH NOAC FOR AF
General principle: When all considerations are equal, priority will be given to the product with the
greatest experience of use and lowest long term costs.
Characteristic
Drug choice
Rationale
NOACs
contraindicated
NOACs effectively contraindicated. Recent REALIGN phase lll
dose ranging study of dabigatran in patients with mechanical
valves was terminated early due to an increase in adverse
events including stroke, MI, bleeding and valve thrombosis.
Severe renal
impairment
(CrCl <30 mL/min)
NOACs not
recommended
Dabigatran contraindicated. Apixaban, rivaroxaban and
edoxaban – lower doses have been approved for patients with
CrCl 15 - 30 mL/min, however these are largely based on
pharmacokinetic data, rather than clinical trial data use with
caution.
Moderate renal
impairment
(CrCl 30 - 50 mL/min)
Rivaroxaban or
apixaban or
edoxaban
Factor Xa inhibitors less affected by impaired renal function
than dabigatran (renal excretion 80% for dabigatran, 50% for
edoxaban, 33% for rivaroxaban and 25% for apixaban).
Apixaban
Higher rates of GI bleeding with dabigatran, rivaroxaban and
edoxaban compared to warfarin. Apixaban only agent to show
a reduction in GI bleeding in addition to an overall reduction in
bleeding rates when compared with warfarin.
Mucous membrane
bleeding (includes
nosebleeds,
haematuria, vaginal
bleeding)
Dabigatran
Mucous membrane bleeding is more common with factor Xa
inhibitors (apixaban, edoxaban and rivaroxaban) compared
with warfarin. Mucous membrane bleeding risk is similar with
dabigatran and warfarin.
Recent ischaemic
stroke on warfarin
Dabigatran
Dabigatran (at a dose of 150 mg twice daily) is the only NOAC
shown to be superior to warfarin in reducing ischaemic stroke.
Rivaroxaban
Small increase in MI with dabigatran (although subsequent
analysis has suggested this apparent increase is not
statistically significant). Rivaroxaban has demonstrated benefit
in patients with recent ACS (ATLAS ACS 2TIMI 51 trial).
Apixaban has demonstrated neither benefit nor harm.
Mechanical valve or
valvular AF
Increased risk of GI
bleed
Recent acute
coronary syndrome
(ACS)
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Characteristic
Drug choice
Rationale
Moderate or severe
heart failure
Dabigatran
Concurrent treatment
of deep vein
thrombosis (DVT)
and/or pulmonary
embolism (PE) or
prevention of
recurrent DVT and/or
PE
Dabigatran or
rivaroxaban or
apixaban or
edoxaban
Poor compliance with
twice daily dosing
Rivaroxaban or
edoxaban
Only NOACs that are once daily administration.
Patient requiring a
compliance aid, e.g.
dosette box
Rivaroxaban or
apixaban or
edoxaban
Dabigatran not stable in a compliance aid.
Administration via
enteral feeding tube
Rivaroxaban or
apixaban
Dabigatran capsules need to be swallowed whole. Opening
the capsules results in a significant increase in bioavailability.
5.
Peripheral oedema can occur with rivaroxaban, apixaban and
edoxaban.
CONTRAINDICATIONS AND PRECAUTIONS
All clinical contraindications to warfarin anticoagulation are also contraindications to NOACs.
5.1
Absolute contraindications to warfarin and NOACs
5.1.1 Known large oesophageal varices.
5.1.2 Significant thrombocytopenia (platelet count <50 x 109/L) - refer to haematologist.
5.1.3 Within 72 hours of major surgery with risk of severe bleeding - defer and reassess risk postoperatively.
5.1.4 Previously documented hypersensitivity to either the drug or excipients – consider Cardiology
opinion.
5.1.5 Acute clinically significant bleed - defer and reassess stroke versus bleeding risk within 3
months.
5.1.6 Decompensated liver disease or deranged baseline clotting screen (INR ≥1.5) – refer to
Gastroenterology/Hepatology. Contraindication applies to oral anticoagulants only.
5.1.7 Pregnancy or within 48 hours postpartum - seek urgent haematological advice.
Contraindication applies to oral anticoagulants only.
5.1.8 Severe renal impairment. Contraindication applies to dabigatran with CrCl <30 mL/min
and to apixaban, rivaroxaban and edoxaban with CrCl <15 mL/min.
5.2
5.2.1
5.2.2
5.2.3
Relative contraindications to both warfarin and NOACs
Previous history intracranial haemorrhage - some AF patients especially those considered at
higher stroke risk (i.e. CHADS2 score ≥3) may benefit from antithrombotic therapy, seek the
opinion of a stroke specialist.
Recent major extracranial bleed within the last 6 months where the cause has not been
identified or treated –decision for oral antithrombotic therapy should be deferred.
Recent documented peptic ulcer (PU) within last 3 months – decision for oral antithrombotic
therapy should be deferred until treatment for PU completed. In all cases with history of PU,
give proton pump inhibitor (PPI) cover whilst on antithrombotic.
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5.2.4
Recent history recurrent iatrogenic falls in patient at higher bleeding risk.
A patient at higher bleeding risk is assessed by having 3 or more of the following risk
factors:
 Age >65 years.
 Previous history bleed or predisposition to bleeding (e.g. diverticulitis).
 Uncontrolled hypertension.
 Severe renal impairment (i.e. serum creatinine >200 micromol/L, GFR <30 mL/min/1.73 m2
or on dialysis).
 Acute hepatic impairment (e.g. bilirubin >2 x ULN + LFTS >3 x ULN), chronic liver disease
(e.g. cirrhosis).
 Low platelet count <80 x 109/L or a thrombocytopenia or anaemia of undiagnosed cause.
 On concomitant drugs associated with an increased bleeding risk, e.g. selective serotonin
reuptake inhibitors (SSRIs), oral steroids, non-steroidal anti-inflammatory drugs (NSAIDs),
methotrexate or other immune-suppressant agents.
N.B. A risk of falls is not a contraindication to initiating oral anticoagulation (e.g. a
patient with an annual stroke risk of 5% (CHADS2 score 2 - 3) would need to fall 295 times for
fall risk to outweigh stroke reduction benefit of warfarin).
5.2.5 Dementia or marked cognitive impairment with poor medicines compliance and no access to
carer support.
5.2.6 Chronic alcohol abuse – especially if associated with binge drinking.
5.3
5.3.1
5.3.2
Contraindications for NOACs but not for warfarin
Severe renal impairment (CrCl <30 mL/min for dabigatran; CrCl <15 mL/min for rivaroxaban or
apixaban).
Hepatic impairment (elevated ALT >2 x ULN) for dabigatran or edoxaban. Liver disease
resulting in a coagulopathy or expected to have any impact on survival for any NOAC.
6.
RESPONSIBILITIES
6.1
6.1.1
6.1.2
NOAC Specialist Pharmacist responsibilities
To accept referral from primary and secondary care.
To confirm a diagnosis of AF documented on the referral or medical notes, and
anticoagulation indicated.
To check or confirm anticoagulation is not contraindicated, including review of BP, U&Es,
FBC, LFTs and baseline INR.
To decide/confirm benefits of anticoagulation outweigh risks and agree the need for
anticoagulation.
To decide on the most appropriate anticoagulant, if any, and initiate treatment following an
informed discussion with the person/carer about the risks and benefits of NOAC compared
with warfarin, as per local criteria for NOAC use. Where an informed discussion is not
possible due to the patient’s medical condition, the decision will be made as considered in the
best interests of the patient. This initiation may be undertaken by the secondary care stroke
service rather than by the NOAC clinic, for secondary prevention of stroke or TIA to prevent
delay in treatment prior to review by the NOAC service. Cardiologists may prescribe a NOAC
for urgent anticoagulation after 17:00 on Fridays, after it is confirmed that the patient cannot
be seen by the NOAC Clinic that day, so there is no delay in initiation over the weekends.
These patients will have a CHADS-VASc of greater than or equal to 5. All patients started on
a NOAC by stroke physicians or by cardiologists over the weekend must be referred promptly
to the NOAC service for follow up.
To counsel patients or their carer wherever possible.
To list concurrent medications and inform patient/carer and GP if any changes are advised.
Patients referred for review of anticoagulation for insufficient TTR on warfarin will have the
reasons explored and addressed wherever possible. If these cannot be resolved then NOAC
will be initiated.
To complete an ICRP request for approval for funding under the exceptional cases process
(ICRP) from the CCG prior to initiation for patients requiring NOAC for whom use would be
unlicensed.
6.1.3
6.1.4
6.1.5
6.1.6
6.1.7
6.1.8
6.1.9
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6.1.10 To prescribe the first month’s anticoagulant treatment.
6.1.11 To refer those patients initiated on warfarin to their usual anticoagulation service for ongoing
monitoring and dosage adjustment.
6.1.12 To contact patients or their carers two to three weeks following initiation of a NOAC to assess
the tolerability of the drug and to review if any problems have occurred which can be rectified.
6.1.13 To communicate non-attendance or inability to carry out a follow up to GP.
6.1.14 If the NOAC is stopped or changed to an alternative anticoagulant, the GP will be informed in
writing of the change and reason for change. The NOAC service will normally prescribe the
first month’s supply of the new agent.
6.1.15 To supply data for all patients seen by the NOAC service and specify which anticoagulant
drug they were prescribed.
6.1.16 If the GP is requested to prescribe the first prescription for a NOAC then the CCG will be
informed so that they are not billed for the NOAC.
6.1.17 To ensure an audit/NICE compliance form is completed by the clinician or NOAC service clinic
clearly documenting the reasons why the NOAC is being tried, including the time in
therapeutic range while on warfarin (if the patient has tried warfarin) and all information
required by the CCG for audit purposes (as stated in separate contract document) prior to
dispensing of NOAC. This will provide ongoing audit information for all patients. No NOAC
will be dispensed without such a form being presented with the prescription.
6.1.18 To give support and advice to the primary care and secondary care healthcare professionals
as needed.
6.1.19 To report serious adverse effects to the MHRA/CHM for dabigatran and all side effects for
black triangle NOACs (rivaroxaban, apixaban and edoxaban).
6.1.20 Provide audit data (specified in the contract) to Aylesbury Vale and/or Chiltern Clinical
Commissioning Groups.
6.2
6.2.1
6.2.2
6.2.3
6.2.4
GP responsibilities
The GP should assess the patient using the locally agreed criteria (above) and refer patients
into the specialist service if they feel a new oral anticoagulant agent may be suitable. The
referral to the NOAC clinic should state which criteria are met. It is not recommended to refer
in patients who are well controlled on warfarin.
The GP should provide recent U&Es and weight (within the last 3 months). FBC within the
last 12 months and LFTs and INR if there is any reason to suspect it is abnormal.
The GP should provide a patient summary when referring into the NOAC clinic, including time
in range for INR if known for those monitored by the practice, allergies, past medical history,
current and past medication over the last 3 to 6 months, alcohol use (if known), recent BP,
CHA2DS2-VASc score and HAS-BLED score. Forms are available for GP referral (see
appendix B) and hospital internal referral (see appendix C).
To prescribe the first months NOAC if requested to do so by the NOAC service. After the first
month of treatment provided by the specialist, the GP should:
 Continue to prescribe the NOAC as indicated.
 Undertake ongoing review of the patient to ensure they continue to meet the criteria for
anticoagulation and NOACs in particular. This review should include monitoring of renal
function using Cockcroft and Gault formula, BP, clinical review, as indicated by the
patient’s condition and compliance assessment.
6.3
6.3.1
6.3.2
6.3.3
6.3.4
Patient/carer’s responsibilities
To attend all appointments with the patient’s GP and specialist.
To report any adverse effects to their specialist or GP whilst under treatment.
To share any concerns they have in relation to treatment.
Ask the specialist or GP if they do not have a clear understanding of their treatment.
7.
PRE-TREATMENT ASSESSMENT BY GP
7.1
7.2
U&Es and weight within the last 3 months, (to allow CrCl to be calculated) - see appendix D.
FBC within last 12 months but recent results are required for patients who have been acutely
unwell.
If previous history suggests any likelihood of abnormal LFTs and/or INR these should also be
checked and provided in the referral letter.
7.3
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8.
ONGOING MONITORING SCHEDULE BY GP
8.1
If a switch to warfarin or an alternative NOAC is considered necessary, the patient will need to
be referred into the usual anticoagulant pathway on switching from NOAC to warfarin.
Rivaroxaban, apixaban and edoxaban are monitored intensively by the MHRA and CHM and
all adverse reactions should be reported via the yellow card system. Serious adverse
reactions should be reported to the MHRA/CHM for dabigatran.
8.2
U&E, including assessment of
renal function
BP
FBC including Hb
Re-check stroke versus bleeding
risk, i.e. CHA2DS2-VASc exceeds
HAS-BLED score
Annually, but more frequently if clinical status changes.
Only re-check if any reason to suspect abnormal. If ALT exceeds
2 x ULN seek advice from NOAC service or haematologist.
LFTs
9.
Annually. More frequently if patient unwell or declining renal
function suspected, e.g. loop diuretic dose needs increasing.
Annually. More frequently if systolic close to or above 160 mmHg.
Only re-check FBC if anaemia is suspected clinically.
SUPPORTING INFORMATION FOR INDIVIDUAL NOACs
9.1
Dabigatran
9.1.1 Dabigatran dosage
110 mg and 150 mg capsules licensed for stroke prevention in non-valvular AF.
Indication
Prevention of
stroke in
patients with
non-valvular AF
and with a
CHA2DS2VASc
of 1 or more for
males.
CHA2DS2VASc
of 2 or more for
females.
Dose



150 mg twice daily is the usual dose, preferably with or after food to minimise
gastrointestinal side effects.
Some patients may require a reduced dose of 110 mg twice daily, e.g. if high
risk of bleeds, CrCl 30 - 50 mL/minute, over 75 and considered a moderate risk
of a bleed, over 80, very low body weight, taking verapamil, concurrent
antiplatelet agents - clinical discretion and individual patient factors should be
taken into account.
Doses should not be added to monitored dosage systems as it is hygroscopic.
9.1.2 Missed doses
A forgotten dabigatran dose may be taken up to 6 hours after the last scheduled dose. From 6 hours
prior to the next scheduled dose onwards, the missed dose should be omitted. No double dose
should be taken to make up for missed doses.
9.1.3 Switching from warfarin to dabigatran (usually done in secondary care)
In patients taking warfarin, stop the warfarin then the timing of starting dabigatran depends upon the
INR:
Most recent INR (in last
Action
month or more recently)
<2
Stop warfarin and start dabigatran the same day
2-3
Stop warfarin and start dabigatran the next day
>3
Ensure INR is <3 before starting dabigatran (see above)
9.1.4 Switching from dabigatran to warfarin
9.1.4.1 Warfarin should only be started by an expert in anticoagulation. GPs are expected to refer
patients into their usual local anticoagulation pathway.
9.1.4.2 The full effect of warfarin is only seen after at least a few days and up to 10 days. Unless
immediate cessation is necessary the following schedule should be followed:

CrCl ≥50 mL/min, start warfarin 3 days before discontinuing dabigatran etexilate.

CrCl ≥30 - <50 mL/min, start warfarin 2 days before discontinuing dabigatran etexilate.
9.1.4.3 Because dabigatran can contribute to an elevated INR, INR testing should not be performed
until dabigatran has been stopped for at least 2 days.
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9.1.5 Dabigatran time to response
Full anticoagulation is expected within 2 hours of initiation.
9.1.6 Dabigatran side effects and actions to be taken (see SPC for full list)
Please report serious suspected side effects through the yellow card system. The following table
covers the common side effects listed in the SPC. For uncommon and rare effects - see SPC to
determine if they could be due to the drug and seek advice if severe.
Side Effects
Dyspepsia, abdominal pain, nausea
and diarrhoea are all common
GI bleeds
Risk of bleeding
Anaemia
Hepatic enzymes elevated
Nose bleeds
Myocardial infarction (MI) or
ischaemic heart disease (IHD): There
was a statistically insignificant
increased number of MIs in the
dabigatran arm of RE-LY.
Guideline 313FM.5
Action
These side effects may improve over time if the patient persists
with treatment. Reinforce need to take with food or a full glass of
water. A PPI or H2 antagonist may need to be initiated or the
existing PPI dose may need to be increased. If significant
symptoms review choice of anticoagulant.
Major GI bleed risk was twice as high with dabigatran 150 mg
twice daily than with warfarin in RE-LY. Dabigatran cannot be
reversed with vitamin K. Its effect wears off over 1 - 2 days. For
full management see Trust Guideline 34FM Dabigatran:
Guidance for Management of Overdose and Bleeding.
The mainstay of treatment is to stop the drug and provide
supportive care. Severe bleeds may require hospital admission.
Patients who bleed do not respond to vitamin K and so the
majority of the management is supportive care see Trust
Guideline 34FM Dabigatran: Guidance for Management of
Overdose and Bleeding.
The drug is renally excreted and will accumulate and potentially
cause toxicity if prescribed in patients with a CrCl <30 mL/min.
Dabigatran is contraindicated if CrCl <30 mL/min - stop the drug
and review alternative choices of anticoagulation.
An MHRA safety alert (Dec 2011) confirmed dabigatran is
associated with increased bleeding risks when given in moderate
and severe renal impairment.
Interacting drugs may also increase dabigatran levels and risk of
a bleeding.
If Hb <80 g/L do not start anticoagulation until anaemia has been
treated and resolved.
If Hb 80 – 100 g/L review the urgency of anticoagulation and seek
advice if there is a need to anticoagulate quickly.
If Hb 101 g/L or more it is safe to anticoagulate, although
treatment of any underlying reasons for anaemia is
recommended.
If small increase re-test. If LFTs exceed 2 x ULN stop dabigatran
and seek advice.
These are common. Check and exclude raised BP as
contributory factor. In most patients it is safe to continue
treatment. If clinically concerned about acute or recurrent
epistaxis please seek further advice.
Ideally avoid dabigatran use in patients with a past history if IHD;
review benefits versus risks if there is a compelling need to treat,
warfarin may be a safer option.
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9.1.7 Dabigatran notable drug interactions (refer to BNF and SPC)
Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system and have
no in vitro effects on human cytochrome P450 enzymes. Dabigatran is however a substrate at Pglycoprotein receptors (P-gp) and clinically relevant interactions can occur.
Class
Strong P-gp
inhibitors
Drugs
Dronedarone
Ketoconazole
Itraconazole
Ciclosporin
Tacrolimus
Posaconazole
Effect
Action
Levels of dabigatran
increased by ~150%
for ketoconazole and Combination contraindicated.
~100% for
dronedarone.
Amiodarone
Other strong PQuinidine
gp inhibitors
Verapamil
Levels of dabigatran
increased by ~50 60%
Moderate P-gp Clarithromycin
inhibitors
Erythromycin
Rifampicin
Carbamazepine
P-gp inducers
Phenytoin
St John’s Wort
Aspirin
Clopidogrel
NSAIDs
Levels of dabigatran
increased by ~20%
SSRIs
Others
Prasugrel
Ticagrelor
Protease
inhibitors, e.g.
ritonavir
Levels of dabigatran
decreased
Increased risk of
bleeding
Increased risk of
bleeding
Increased risk of
bleeding
May increase or
decrease risk of
bleeding
Reduce dose to 110 mg twice daily. Please note
that due to the long half-life of amiodarone, the
potential for interaction may persist for several
weeks after stopping amiodarone. Reduce dose
to 110 mg twice daily, advise patient to take
simultaneously, monitor carefully. Largest
increase in dabigatran levels observed when
verapamil administered one hour prior to
dabigatran with no significant increase when
administered two hours after dabigatran.
No dose reduction required. Monitor closely.
Consider use of azithromycin (safer alternative).
Combination contraindicated.
Combination not recommended. Consider GI
protection. Close monitoring for signs of
bleeding.
If combination is needed then consider GI
protection if not already prescribed.
Avoid combination.
Avoid combination.
9.2
Rivaroxaban
9.2.1 Dosage
Rivaroxaban is licensed for stroke prevention in non-valvular AF.
Indication
Prevention of stroke in patients
with non-valvular AF and with a
CHA2DS2-VASc of 1 or more for
males. CHA2DS2-VASc of 2 or
more for females.
Dose



Rivaroxaban 20 mg daily is the usual dose
If CrCl 15 – 49 mL/minute 15 mg daily is the recommended dose
The dose is best taken with or after food to increase bioavailability
9.2.2 Rivaroxaban missed doses
A forgotten rivaroxaban dose may be taken as soon as the patient remembers, on the same day. No
double dose should be taken to make up for missed doses.
9.2.3 Switching from warfarin/dabigatran to rivaroxaban
This is undertaken under secondary care supervision.
9.2.4 Rivaroxaban time to response
Full anticoagulation is expected within 2 - 4 hours of initiation.
Guideline 313FM.5
9 of 24
Uncontrolled if printed
9.2.5 Rivaroxaban side effects and actions to be taken (see SPC for full list)
Rivaroxaban is a new drug and is marked  in the BNF which signifies intensive monitoring by the
MHRA. Please report all suspected side effects through the yellow card system. There is a lack of
long term follow up data available. The following table covers the common side effects listed in the
SPC. For uncommon and rare effects see SPC to determine if they could be due to the drug and
seek advice if severe.
Side Effects
Risk of bleeding
Oedema
Action
Patients who bleed do not respond to vitamin K and so the majority of the
management is supportive care - see Guideline 240FM Rivaroxaban and
Apixaban: Guidance for Management of Overdose and Bleeding.
The drug is 33% renally excreted and will accumulate and potentially cause
toxicity if prescribed in patients with a severe renal failure. Rivaroxaban is
contraindicated if CrCl <15 mL/min - stop the drug and review alternative
choices of anticoagulation.
Review, especially if increasing shortness of breath or oedema.
If Hb <80 g/L do not start anticoagulation until anaemia has been treated and
resolved.
If Hb 80 – 100 g/L review the urgency of anticoagulation and seek advice if
Anaemia
there is a need to anticoagulate quickly.
If Hb 101 g/L or more it is safe to anticoagulate, although treatment of any
underlying reasons for anaemia is recommended.
Review anticoagulation options. Severe symptoms can result in falls and
Dizziness, headache,
inability to drive. Even if mild symptoms, because they do not improve with
syncope
time, it will affect compliance.
Eye haemorrhage,
haematuria, vaginal
Treat symptomatically, seek expert advice if necessary.
bleeding
Tachycardia
Unless clinically worrying does not require action.
These side effects may improve over time if the patient persists with
Dyspepsia, abdominal
treatment. Reinforce need to take with food or a full glass of water. A PPI or
pain, nausea and
H2 antagonist may need to be initiated or the existing PPI dose may need to
diarrhoea are all
be increased. If significant symptoms continue, rivaroxaban should be
common
stopped. Review choice of anticoagulant.
Pruritis can occur with or without rash and usually requires a review of
Skin reactions
treatment. Minor rashes do not warrant treatment discontinuation, but more
severe reactions do. An alternative treatment may be required.
Pain in extremities
May be a sign of haemorrhage or may be idiopathic.
It is not known if these symptoms are caused by the drug or not, but they have
Fever
been described in association with rivaroxaban.
Malaise, somnolence,
Review if timeline suggests it may be due to rivaroxaban as likely to negatively
decreased energy/
impact on compliance.
strength
These are twice as common with rivaroxaban as with warfarin. Exclude raised
Epistaxis
BP as contributory factor. Review depending on severity. Seek specialist
advice if necessary.
Guideline 313FM.5
10 of 24
Uncontrolled if printed
9.2.6 Rivaroxaban notable drug interactions (refer to BNF and SPC)
Rivaroxaban is metabolised by cytochrome P450 and is also a substrate for P-glycoprotein.
Class
Strong P-gp
inhibitors and
CYP3A4 inhibitors
Moderate CYP3A4
inhibitor
Drugs
Dronedarone
Ketoconazole
Itraconazole
Voriconazole
Posaconazole
HIV protease
inhibitors, e.g.
ritonavir
Fluconazole
Effect
Levels of rivaroxaban
increased by up to 160%
Contraindicated
Levels of rivaroxaban
increased by 40%
Not considered clinically significant
Strong CYP3A4 and
moderate P-gp
Clarithromycin
inhibitor
Levels of rivaroxaban
increased by 50%
Moderate CYP3A4
and P-gp inhibitor
Levels of erythromycin
increased by 30%
CYP3A4 inducer
Others
Erythromycin
Rifampicin
Carbamazepine
Phenobarbital
Phenytoin
St John’s Wort
Aspirin
Clopidogrel
NSAIDs
SSRIs
Prasugrel
Ticagrelor
Action
Reduces area under
curve (AUC) of
rivaroxaban by 50%
causing a reduced
anticoagulation effect
Not considered clinically significant.
No dose reduction required. Monitor
closely. Consider use of
azithromycin (safer alternative).
Not considered clinically significant.
No dose reduction required. Monitor
closely. Consider use of
azithromycin (safer alternative).
Contraindicated
Combination not recommended.
Increased risk of bleeding Consider GI protection. Close
monitoring for signs of bleeding.
If combination is needed then
Increased risk of bleeding consider GI protection if not already
prescribed.
Increased risk of bleeding Avoid combination
9.3
Apixaban
2.5 mg and 5 mg tablets are licensed for stroke prevention in non valvular AF (NVAF).
9.3.1 Dosage
Indication
Prevention of stroke in
patients with non-valvular AF
and with a CHA2DS2-VASc
score of 1 or more for males.
CHA2DS2-VASc of 2 or more
for females.
Dose
 Apixaban 5 mg twice daily is the usual dose.
 All patients with creatinine clearance 15 – 29 mL/min should receive
2.5 mg twice daily of apixaban. In addition, if they meet two of the
following criteria they should receive the lower dose:
Serum creatinine ≥133 micromol/L, age ≥80 years or body weight
≤60 kg.
9.3.2 Apixaban missed doses
A forgotten apixaban dose may be taken up to 6 hours after the last scheduled dose. From 6 hours
prior to the next scheduled dose onwards, the missed dose should be omitted. No double dose
should be taken to make up for missed doses.
9.3.3 Switching from warfarin to apixaban (usually done in secondary care)
In patients taking warfarin, stop the warfarin and start apixaban once INR is less than 2.
9.3.4 Switching from apixaban to warfarin
When converting patients from apixaban to warfarin therapy, continue administration of apixaban for
at least 2 days after starting warfarin therapy or until INR ≥2. The switching should only be carried
out by a specialist.
Guideline 313FM.5
11 of 24
Uncontrolled if printed
9.3.5 Apixaban time to response
Apixaban is rapidly absorbed with maximum concentrations (Cmax) appearing 3 to 4 hours after tablet
intake.
9.3.6 Apixaban side effects and actions to be taken (see SPC for full list)
Apixaban is a new drug and is marked  in the BNF which signifies intensive monitoring by the
MHRA. Please report all suspected side effects through the yellow card system. There is a lack of
long term follow up data available. The following table covers the common side effects listed in the
SPC. Other than hypersensitivity reactions and contusions no other adverse reactions are listed in
the SPC for apixaban. However experience in real world patients has found similar side effects to
rivaroxaban. Please also see adverse reactions listed in the SPC for rivaroxaban to determine if they
could be due to the drug and seek advice if severe.
Side Effects
Risk of bleeding
Eye haemorrhage,
haematuria,
vaginal bleeding,
respiratory tract
haemorrhage (e.g.
alveolar)
Anaemia
Contusions,
dizziness,
syncope
Skin reactions
Action
Patients who bleed do not respond to vitamin K and so the majority of the
management is supportive care - see Trust Guideline 240FM Rivaroxaban and
Apixaban: Guidance for Management of Overdose and Bleeding.
The drug is 25% renally excreted and will accumulate and potentially cause
toxicity if prescribed in patients with a severe renal failure. Apixaban is
contraindicated if CrCl <15 mL/min - stop the drug and review alternative choices
of anticoagulation.
Treat symptomatically, seek expert advice if necessary.
If Hb <80 g/L do not start anticoagulation until anaemia has been treated and
resolved.
If Hb 80 – 100 g/L review the urgency of anticoagulation and seek advice if there
is a need to anticoagulate quickly.
If Hb 101 g/L or more it is safe to anticoagulate, although treatment of any
underlying reasons for anaemia is recommended.
Dizziness and syncope are not listed as side effects but these are side effects
with rivaroxaban, another factor Xa inhibitor, and it is possible that blows to the
skin as result of these are the cause of the contusions which are a side effect
listed in the SPC. Review anticoagulation options. Severe symptoms can result
in falls and inability to drive. Even if dizziness and syncope are mild, because
they do not improve with time may affect compliance.
Pruritis can occur with or without rash and usually requires a review of treatment.
Minor rashes do not warrant treatment discontinuation, but more severe reactions
do. An alternative treatment may be required.
Malaise,
somnolence,
decreased
energy/strength
Review if timeline suggests it may be due to apixaban, as likely to negatively
impact on compliance. An alternative anticoagulant may be required.
Epistaxis
More common with apixaban than warfarin. Review depending on severity. Seek
specialist advice.
Guideline 313FM.5
12 of 24
Uncontrolled if printed
9.3.7 Apixaban notable drug interactions (refer to BNF and SPC)
Apixaban is metabolised by cytochrome P450 and is also a substrate for P-glycoprotein. In theory,
other interactions are possible but many remain unstudied.
Class
Strong CYP3A4
and P-gp
inhibitors
Other moderate
or weak
inhibitors of
CYP3A4, P-gp
inhibitors or both
Strong CYP3A4
and P-gp
inducers
Drugs
Dronedarone
Ketoconazole
Itraconazole
Voriconazole
Posaconazole
HIV protease inhibitors, e.g. ritonavir
Diltiazem
Naproxen
Amiodarone
Verapamil
Quinidine
Rifampicin
Phenytoin
Carbamazepine
Phenobarbital
St. John's Wort
Effect
Action
Levels of apixaban
increased by 100% for
some of these whilst no
data is available for
others.
Contraindicated
Levels of apixaban
increased but to a
lesser extent than with
the strong inhibitors.
Monitor for signs of
bleeding, no dose
adjustment
required.
Levels of apixaban
reduced, 50%
reduction with
rifampicin.
Combination
contraindicated.
Aspirin
Clopidogrel
NSAIDs
Increased risk of
bleeding.
SSRIs
Increased risk of
bleeding.
Prasugrel
Ticagrelor
Increased risk of
bleeding.
Avoid combination.
Consider GI
protection. Close
monitoring for signs
of bleeding.
If combination
needed, consider
GI protection if not
prescribed.
Others
9.4
9.4.1
Avoid combination.
Edoxaban
Dosage (see SPC for more detailed information)
Recommended dose 60 mg once daily
Dose recommendation for patients with one or more of the following clinical factors:
Renal impairment
Moderate or severe (CrCL 15 – 50 mL/min)
Low body weight
≤60 kg
30 mg once daily
P-gp Inhibitors
Ciclosporin, dronedarone, erythromycin, ketoconazole
NOTE: A trend towards decreasing efficacy with increasing creatinine clearance was observed for
edoxaban compared to well-managed warfarin, therefore, edoxaban should only be used in patients
with NVAF and creatinine clearance above 100 mL/min after a careful evaluation of the individual
thromboembolic and bleeding risk.
9.4.2 Edoxaban missed doses
A forgotten edoxaban dose may be taken as soon as the patient remembers, on the same day. No
double dose should be taken to make up for missed doses.
9.4.3 Switching from warfarin to edoxaban
This is undertaken under secondary care supervision.
In patients taking warfarin, stop the warfarin and start edoxaban once INR is ≤2.5.
Guideline 313FM.5
13 of 24
Uncontrolled if printed
9.4.4 Switching from edoxaban to warfarin
When converting patients from edoxaban to warfarin therapy, continue administration of edoxaban at
50% of previous dose until INR ≥2, (i.e. from 60 mg daily to 30 mg daily OR 30 mg daily to 15 mg
daily).
Loading doses of warfarin loading should NOT be administered when switching from edoxaban to
warfarin. The switching should only be carried out by a specialist.
9.4.5 Time to response with edoxaban
Full anticoagulation is expected within 1 - 2 hours of initiation.
The half-life is 10 - 14 hours and so its effects will completely wear off in 3 days.
9.4.6 Edoxaban side effects and actions to be taken (see SPC for full list)
Edoxaban is a new drug and is marked  in the BNF which signifies intensive monitoring by the
MHRA. Please report all suspected side effects through the yellow card system. There is a lack of
long term follow up data available. The following table covers the common side effects listed in the
SPC.
Side Effects
Risk of bleeding
Mucosal bleeding (e.g.
epistaxis, gastrointestinal,
genitourinary)
Anaemia
Dizziness
Skin reactions
Malaise, somnolence,
decreased energy/strength
Epistaxis
Guideline 313FM.5
Action
Patients who bleed do not respond to vitamin K and so the majority of
the management is supportive care - seek Haematology advice.
The drug is 50% renally excreted and will accumulate and potentially
cause toxicity if prescribed in patients with a severe renal failure.
Edoxaban is contraindicated if CrCl <15 mL/min - stop the drug and
review alternative choices of anticoagulation.
Mucosal bleedings are seen more frequently during long term
edoxaban treatment compared with vitamin K antagonist treatment.
Treat symptomatically, seek expert advice if necessary.
If Hb <80 g/L do not start anticoagulation until anaemia has been
treated and resolved.
If Hb 80 – 100 g/L review the urgency of anticoagulation and seek
advice if there is a need to anticoagulate quickly.
If Hb 101 g/L or more it is safe to anticoagulate, although treatment of
any underlying reasons for anaemia is recommended.
Dizziness is not listed as a side effect but this is a side effect with other
factor Xa inhibitors. Monitor for this side effect. Severe symptoms can
result in falls and inability to drive. Even if dizziness and syncope are
mild, because they do not improve with time may affect compliance.
Pruritis can occur with or without rash and usually requires a review of
treatment. Minor rashes do not warrant treatment discontinuation, but
more severe reactions do. An alternative treatment may be required.
Review if timeline suggests it may be due to edoxaban, as likely to
negatively impact on compliance. An alternative anticoagulant may be
required.
More common with edoxaban than warfarin. Check BP to exclude as
contributory cause. Review depending on severity. Seek specialist
advice if necessary.
14 of 24
Uncontrolled if printed
9.4.7 Edoxaban notable drug interactions (refer to BNF and SPC)
Edoxaban is metabolised by hydrolysis and cytochrome P450 and is also a substrate for Pglycoprotein. In theory, other interactions are possible but many remain unstudied.
Class
Strong CYP3A4 and
P-gp inhibitors
Drugs
Ciclosporin,
dronedarone,
erythromycin, or
ketoconazole
Effect
Action
Levels of edoxaban
increased
Requires dose reduction to
30 mg once daily
Strong CYP3A4 and
P-gp inhibitors BUT
no clinical data
Itraconazole
Voriconazole
Posaconazole
HIV protease inhibitors,
e.g. ritonavir
Likely increased levels
Contraindicated
Other moderate or
weak inhibitors of
CYP3A4, P-gp
inhibitors or both
Quinidine, verapamil,
or amiodarone
Increased levels of
edoxaban
Does not require dose
reduction based on clinical
data
Strong CYP3A4 and
P-gp inducers
Rifampicin
Carbamazepine
Phenobarbital
Phenytoin
St John’s Wort
Levels of edoxaban
Use with caution
reduced, 35%.
Aspirin
Clopidogrel
NSAIDs
Others
SSRIs
Prasugrel, ticagrelor
10.
Combination not
recommended. Consider
GI protection. Close
monitoring for signs of
bleeding.
If combination is needed
then consider GI protection
if not already prescribed.
Increased risk of
bleeding
Increased risk of
bleeding
Increased risk of
bleeding
Avoid combination
MANAGEMENT OF OVERDOSE AND BLEEDING
For overdose and bleeding, please see the following guidelines:
Guideline 34FM Dabigatran: Guidance for Management
Emergency/Elective Surgery.
of
Overdose,
Bleeding
and
Guideline 240FM Rivaroxaban and Apixaban: Guidance for Management of Overdose, Bleeding and
Emergency/Elective Surgery
For edoxaban seek Haematologist’s advice.
Guideline 313FM.5
15 of 24
Uncontrolled if printed
11.
BACK-UP INFORMATION/ADVICE
Contact Details
New Oral
Anticoagulant
(NOAC) Service
Cardiology
Haematology
Stroke
Specialists
Medicines
Information
Switchboard
12.
1.
2.
3.
4.
5.
6.
7.
8.
Wycombe and Amersham Hospitals
Stoke Mandeville Hospital
Satinder Bhandal, Consultant Pharmacist – Anticoagulation
[email protected]
Tel: 01494 425590
Fax: 01494 425495
Dr Piers Clifford
Dr Andrew Money-Kyrle
[email protected]
andrew.moneyTel: 01494 425004
[email protected]
Tel: 01296 315543
Dr Soroosh Firoozan
Tel: 01494 425004
Dr Punit Ramrakha
Fax: 01494 425908
[email protected]
Tel: 01296 315675
Fax: 01296 315672
01494 425224 (secretaries)
01296 315516 (leave message for
In an emergency contact Consultant
Consultant call back)
Haematologist on-call 01494 526161
In an emergency contact Consultant
Haematologist on-call 01296 315000
Dr Matthew Burn
Dr Chris Durkin
[email protected] [email protected]
Tel: 01494 425908
Tel: 01296 316542
Dr Amulya Misra
[email protected]
Tel: 01494 426302
Dr Simmie Manchanda
[email protected]
s.uk
Tel:01484 426304
01494 425355
Dr Dennis Briley
[email protected]
Tel: 01296 315688
Amersham: 01494 434411
Wycombe: 01494 526161
01296 315000
REFERENCES
NICE March 2012. Atrial fibrillation – dabigatran elexilate (TA 249) available at www.NICE.org.uk
<accessed 12/02/14>
SPC for Pradaxa 150 mg strength www.medicines.org.uk last updated December 2015
<accessed 19/02/15>
SPC for Pradaxa 110 mg available at www.medicines.org.uk last updated September 2015
<accessed 16/10/15>
SPC for Lixiana 60mg available at https://www.medicines.org.uk/emc/medicine/30506 last
updated July 2015 <accessed 16/10/15>
SPC for Lixiana 30mg available at https://www.medicines.org.uk/emc/medicine/30512 last
updated July 2015 <accessed 16/10/15>
SPC for Lixiana 30mg available at https://www.medicines.org.uk/emc/medicine/30513 last
updated July 2015 <accessed 16/10/15>
Connolly SJ et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation (Re-LY study). N
Engl J Med 2009; 361:1139-115.
http://www.nejm.org/doi/full/10.1056/NEJMoa0905561
Healthcare Improvement Scotland.
Professional summary on dabigatran Aug 11
http://www.scottishmedicines.org.uk/files/advice/dabigatran_Pradaxa_FINAL_August_2011_Ame
nded_05.09.11_for_website.pdf
Guideline 313FM.5
16 of 24
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9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
Healthcare Improvement Scotland. Frequently Asked Questions Aug 11.
http://www.healthcareimprovementscotland.org/programmes/cardiovascular_disease/dabigatran/
dabigatran_consensus.aspx
Anon. Dabigatran and risk of acute coronary events. Drug and Therapeutics Bulletin DTB Select
March 2012 No 89 http://dtb.bmj.com/content/early/2012/03/06/dtb.2012.03.0089.full <link only
works for subscribers>
Dabigatran – Risk of serious haemorrhage. MHRA Drug Safety Update July 2012 Vol 5 Issue
12. http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/index.htm
New oral anticoagulants apixaban (Eliquis▼), dabigatran (Pradaxa) and rivaroxaban (Xarelto▼):
risk of serious haemorrhage - clarified contraindications apply to all three medicines. MHRA Drug
Safety Update. October 2013.
http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON322347
Dabigatran (Pradaxa): contraindicated in patients with prosthetic heart valve(s) requiring anticoagulant treatment, because of the risk of thrombosis and haemorrhage. MHRA Drug Safety
Update March 2013.
http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON252010
Rivaroxaban for the prevention of stroke and systemic embolism in people with AF (NICE TA
256), May 2012. Available at www.NICE.org.uk <accessed 13/01/14>
Patel M. et al. Rivaroxaban versus warfarin in non-valvular AF (Rocket AF) New Engl J Med,
Sept 2012: 365: 863-891.
SPC for Xarelto® 20 mg and 15 mg strengths. Available at www.medicines.org.uk last updated
November 2013 <accessed 13/02/14>
Granger CB et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. (ARISTOTLE). N
Engl J Med, 2011; 365:981-992.
SPC for Eliquis® 5 mg and 2.5 mg strengths. Available at www.medicines.org.uk last updated
September 2013 <accessed 20/02/14>
Tanaka K.A., Szlam F. Treatment of massive bleeding with prothrombin complex concentrate:
argument for. J Thromb Haemost 2010; 8: 2589-91.
Heidbuchel H, Verhamme P, Alings M et al. European Heart Rhythm Association Practical Guide
on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation. Europace
2013;15:625651.
NICE clinical guideline 180. Atrial Fibrillation: The management of atrial fibrillation. Published
June 2014
http://www.nice.org.uk/guidance/cg180/evidence/atrial-fibrillation-update-full-guideline243739981
National Institute for Health and Care Excellence. NICE technology appraisal guidance TA 355:
edoxaban for preventing stroke and systemic embolism in people with non-valvular atrial
fibrillation. September 2015.
National Institute for Health and Care Excellence. NICE technology appraisal guidance TA 249:
dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation. March
2012.
National Institute for Health and Care Excellence. NICE technology appraisal guidance TA 275:
apixaban for preventing stroke and systemic embolism in people with nonvalvular atrial
fibrillation. February 2013.
National Institute for Health and Care Excellence. NICE technology appraisal guidance TA 256:
rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation.
May 2012.
Scottish Medicines Compendium. Rivaroxaban 15 and 20mg film-coated tablets (Xarelto®). SMC
756/12. February 2012.
Scottish Medicines Compendium. Edoxaban tosilate 15mg, 30mg, 60mg film-coated tablets
(Lixiana®) 1095/15. November 2015.
Scottish Medicines Compendium. Dabigatran etexilate 110mg and 150mg capsules (Pradaxa®)
672/11. September 2011.
Scottish Medicines Compendium. Apixaban 2.5mg and 5mg film-coated tablets (Eliquis®) 836/13.
February 2013.
Guideline 313FM.5
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13.
Appendices
Appendix A: Care Pathways:
i) New AF patient from primary care
ii) Patients initiated on NOAC by Buckinghamshire Healthcare NHS Trust (BHNHST)
iii) Existing patients on warfarin
Appendix B: Referral Form 1 - GP to NOAC Clinic
Appendix C: Referral Form 2 - Hospital AF referrals to NOAC Clinic
Appendix D: Creatinine Clearance (mL/min) using Cockcroft & Gault Equation
See also:
Guideline 34FM
Dabigatran: Guidance for Management of Overdose, Bleeding and
Emergency/Elective Surgery
Guideline 240FM Rivaroxaban and Apixaban: Guidance for Management of Overdose, Bleeding
and Emergency/Elective Surgery
Guideline 295FM Dabigatran, Rivaroxaban, Apixaban and Edoxaban for Deep Vein
Thrombosis/Pulmonary Embolism
Title of Guideline
Guideline Number
Version
Effective Date
Review Date
Original Version Published
Approvals:
Formulary Management Group
Bucks Area Prescribing Committee
Clinical Guidelines Subgroup
Author/s
Dabigatran, Rivaroxaban, Edoxaban and Apixaban for Atrial
Fibrillation (AF)
313FM
5
June 2016
June 2019
June 2012
nd
st
2 September and 21 October 2015
th
14 April 2016
th
27 April 2016
Satinder Bhandal, Consultant Anticoagulation Pharmacist
Dr Jonathan Pattinson, Consultant Haematologist
Maire Stapleton, Formulary Manager, BHNHST
Sarah Crotty, Interface Pharmacist, AV& Chiltern CCGs
SDU(s)/Department(s) responsible Pharmacy (Primary and Secondary Care)
for updating the guideline
Haematology
th
Uploaded to Intranet
15 June 2016
Buckinghamshire Healthcare NHS Trust/Aylesbury Vale and Chiltern Clinical Commissioning Groups
Guideline 313FM.5
18 of 24
Uncontrolled if printed
Appendix A: Care Pathways
i)
New AF patient from primary care
GP diagnoses patient with AF
and refers to NOAC service
NOAC clinic decides on
anticoagulation option for patient
in line with Bucks criteria
Start warfarin treatment,
provide prescription,
counsel patient, provide
anticoagulation therapy
pack
Refer into usual
warfarin anticoagulant
clinic for patients from
that GP practice
Guideline 313FM.5
 Start NOAC, provide
prescription, counsel
patient, provide
Anticoagulant Alert
Card
 Letter to GP

If warfarin and NOAC
unsuitable, consider
referral to cardiologist
Second patient contact by NOAC clinic usually by phone
at 2 weeks:



Address issues/concerns
Highlight importance of compliance
Discharge to care of GP for ongoing anticoagulation
with NOAC

If NOAC to be switched to different NOAC, reassess
anticoagulation risk benefit and options and repeat
previous steps

If NOAC not to be continued inform GP

If patient needs to be switched to warfarin, refer into
usual anticoagulation clinic for patients from that GP
practice
19 of 24
Uncontrolled if printed
ii)
Patients initiated on NOAC by BHNHST
Patient potentially requiring NOAC (as inpatient or outpatient) identified
Non-urgent Refer to
NOAC clinic
Urgent: Recent TIA or
stroke
Consultant stroke physician
starts NOAC and then refers
patient to NOAC clinic
Urgent (non stroke):
CHA2DS2-VASc ≥5
Consultant refers to NOAC
clinic for urgent same day or
next working day initiation of
NOAC
Urgent (non stroke)
CHA2DS2-VASc ≥5
at weekends
Cardiologist starts and
then refers patient to
NOAC clinic
NOAC clinic decides/reviews anticoagulation
options for patient in line with Bucks criteria
Start warfarin treatment,
provide prescription, counsel
patient, provide
anticoagulation therapy pack
Refer into usual
warfarin anticoagulant
clinic for patients from
that GP practice
Guideline 313FM.5
 Start/continue NOAC,
provide prescription if
necessary, counsel patient,
provide Anticoagulant Alert
Card
 Letter to GP

If warfarin and first choice
NOAC unsuitable, consider
other options or referral
Second patient contact by NOAC clinic usually by phone at 2
weeks:



Address issues/concerns
Highlight importance of compliance
Discharge to care of GP for ongoing anticoagulation with
NOAC

If NOAC not tolerated, reassess risk benefit and treatment
options.

Repeat steps in flow chart following receipt of referral

If NOAC not to be continued or changed to an alternative
anticoagulant inform GP

If patient needs to be switched to warfarin, refer into usual
anticoagulation clinic for patients from that GP practice
20 of 24
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iii)
Anticoagulation pathway for existing patients on warfarin
Warfarin anticoagulant clinic identifies patient with poor INR control.
A standard letter will be sent to ask the GP to consider referring to NOAC
clinic by BHNHST warfarin anticoagulant clinic.
GP refers to NOAC clinic if patient potentially meets Bucks criteria for NOAC
NOAC clinic decides on anticoagulation option
for patient in line with Bucks criteria

Continue warfarin after
counselling


If warfarin and NOAC
unsuitable, consider
referral to cardiologist
Second patient contact by NOAC clinic usually by phone
at 2 weeks:



Guideline 313FM.5
Start NOAC, provide
prescription, counsel patient,
provide Anticoagulation Alert
Card
Letter to GP
Address issues/concerns
Highlight importance of compliance
Discharge to care of GP for ongoing
anticoagulation with NOAC

If NOAC not tolerated, reassess risk benefit and
treatment options

Repeat steps in flow chart following receipt of referral

If NOAC not to be continued or changed to an
alternative anticoagulant inform GP

If patient needs to be switched to warfarin, refer into
usual anticoagulation clinic for patients from that GP
practice
21 of 24
Uncontrolled if printed
Appendix B: Referral Form 1 – GP to NOAC Clinic
GP Referral to New Oral Anticoagulant Service at BHNHST
Atrial Fibrillation
Patient name:
DoB:
NHS No:
Address:
Sex:
GP Name:
Address:
Postcode:
Tel (day):
Tel (mobile):
Patient email:
Patient requires transport:
Postcode:
Practice code:
Patient needs interpreter:
Tel:
Language:
Ethnicity:
Fax:
Reason for referral: …………………………………………………………………
On warfarin
Time in range
OR warfarin naive
Renal function info must be supplied:
Date
creatinine
and weight
Known history of poor compliance?
kg
Give details:
In addition please provide a Patient Summary which details:

Allergies, PMH, current medication and recent past medication, alcohol use if known, recent
BP, FBC.

LFTs and INR (if any reason to suspect may be abnormal from history)
Please ring the scores for your patient:
Points
C
H
A2
D
S2
V
A
Sc
LVF/LVD dysfunction
Hypertension
>75 years
Diabetes mellitus
Prior stroke or TIA
Vascular disease
Age 64 – 74
Female
Total
1
1
2
1
2
1
1
1
Signed.................................................. (GP)
Preferred clinic:
Amersham
H
A
S
B
L
E
D
Clinical Characteristic
Hypertension
Renal or LFTs abnormal
Stroke
Bleeding
Labile INRs
>65 years
Drugs or alcohol >8 U/week
Points
1
1 or 2
1
1
1
1
1 or 2
Total
Print………………………Date………………………
Wycombe
Stoke Mandeville
(please circle)
FAX ALL REFERALS TO: 01494 425495. TELEPHONE NUMBER: 01494 425590.
Guideline 313FM.5
22 of 24
Uncontrolled if printed
Appendix C: Referral Form 2 – Hospital AF Referrals to NOAC Clinic
Hospital AF Referrals to New Oral Anticoagulant (NOAC) Clinic
Addressograph or
Name/Address/MRN/DOB/NHS No.
Consultant
Hospital
Outpatient Clinic or Ward
Name of referrer
Bleep
Signature
Date
Telephone
Mobile
Please prescribe and monitor anticoagulant therapy for:
Atrial Fibrillation
Other: ……………………………………………..
Binge drinking
Poor compliance
Poor cognition
Uncomplicated AF
Valvular AF
Cardioversion
STROKE TEAM ONLY or Cardiologists
weekends for CHADS-VASc >/= 5
TIA Yes / No
Stroke Yes/ No
If yes to either give date of most recent event:
Bleeding history
Details:
Metal valves
For ablation
LVF
When do you want anticoagulation to start:
If prescription has been issued state date so timely
follow up can be organised:


at
BLOODS WITHIN LAST 2 WEEKS
N.B: If unavailable, they must be requested. Referral cannot be accepted without them.
Blood Test
Creatinine
Hb
Platelets
Baseline INR
LFTs normal
Y/N
Date
Comments
Please circle the scores for your patient:
Points
C
H
A2
D
S2
V
A
Sc
LVF/LVD dysfunction
Hypertension
>75 years
Diabetes mellitus
Prior stroke or TIA
Vascular disease
Age 64 – 74
Female
Total
1
1
2
1
2
1
1
1
H
A
S
B
L
E
D
Clinical Characteristic
Hypertension
Renal or LFTs abnormal
Stroke
Bleeding
Labile INRs
>65 years
Drugs or alcohol >8 U/week
Points
1
1 or 2
1
1
1
1
1 or 2
Total
PATIENTS ALREADY ON WARFARIN (NEW OR CONTINUATION) MUST BE REFERRED TO
THE ANTICOAGULANT CLINICS FOR MONITORING. THIS FORM IS FOR INITIATION OF
ANTICOAGULATION AND REVIEW OF OPTIONS ONLY.
Preferred clinic:
Amersham

Wycombe

Stoke Mandeville 
F all referrals to: 01494 425495 TELEPHONE NUMBER: 01494 425590
Guideline 313FM.5
23 of 24
Uncontrolled if printed
Appendix D: Creatinine Clearance (mL/min) using Cockcroft & Gault Equation
Female ≥60 kg* creatinine clearance mL/min
age
serum
creatinine
50
60
70
80
90
100
110
120
130
140
150
160
170
180
190
200
40
45
50
55
60
65
70
75
80
85
90
95
100
120
100
86
75
67
60
55
50
46
43
40
38
35
33
32
30
114
95
81
71
63
57
52
48
44
41
38
36
34
32
30
29
108
90
77
68
60
54
49
45
42
39
36
34
32
30
28
27
102
85
73
64
57
51
46
43
39
36
34
32
30
28
27
26
96
80
69
60
53
48
44
40
37
34
32
30
28
27
25
24
90
75
64
56
50
45
41
38
35
32
30
28
26
25
24
23
84
70
60
53
47
42
38
35
32
30
28
26
25
23
22
21
78
65
56
49
43
39
35
33
30
28
26
24
23
22
21
20
72
60
51
45
40
36
33
30
28
26
24
23
21
20
19
18
66
55
47
41
37
33
30
28
25
24
22
21
19
18
17
17
60
50
43
38
33
30
27
25
23
21
20
19
18
17
16
15
54
45
39
34
30
27
25
23
21
19
18
17
16
15
14
14
48
40
34
30
27
24
22
20
18
17
16
15
14
13
13
12
Male ≥70 kg* creatinine clearance mL/min
age
serum
creatinine
50
60
70
80
90
100
110
120
130
140
150
160
170
180
190
200
40
45
50
55
60
65
70
75
80
85
90
95
100
168
140
120
105
93
84
76
70
65
60
56
53
49
47
44
42
160
133
114
100
89
80
73
67
61
57
53
50
47
44
42
40
151
126
108
95
84
76
69
63
58
54
50
47
44
42
40
38
143
119
102
89
79
71
65
60
55
51
48
45
42
40
38
36
134
112
96
84
75
67
61
56
52
48
45
42
40
37
35
34
126
105
90
79
70
63
57
53
48
45
42
39
37
35
33
32
118
98
84
74
65
59
53
49
45
42
39
37
35
33
31
29
109
91
78
68
61
55
50
46
42
39
36
34
32
30
29
27
101
84
72
63
56
50
46
42
39
36
34
32
30
28
27
25
92
77
66
58
51
46
42
39
36
33
31
29
27
26
24
23
84
70
60
53
47
42
38
35
32
30
28
26
25
23
22
21
76
63
54
47
42
38
34
32
29
27
25
24
22
21
20
19
67
56
48
42
37
34
31
28
26
24
22
21
20
19
18
17
The SPCs for all NOACs specify that creatinine clearance CrCl (Cockroft & Gault) should be used for
dosing decisions, not eGFR. The tables should not be used for patients in acute renal impairment, who
are dehydrated or if under the stated weights when CrCl should be calculated individually (manually or
on, e.g. SystmOne>clinical tools>renal calculations, available in the CCG).
CrCl = [140 – age (yrs)] x ideal body weight or actual if less (kg) x 1.2 for males
Serum creatinine (micromol/L)
*average ideal body weight
Guideline 313FM.5
24 of 24
Uncontrolled if printed