Download Rivaroxaban and Dabigatran for the prevention of stroke and

Reduced Shared Care Protocol –remains open to review in light of any new evidence
Amber with guidance (Amber-G) = To be initiated and titrated to a stable dose by a specialist prescriber with follow up
prescribing by primary care
Rivaroxaban▼ and Dabigatran▼
Reduced shared care guideline for the use of rivaroxaban and dabigatran in the
prevention of stroke and systemic embolism in atrial fibrillation
Development Process
This guidance has been produced by Deborah Cooke, Lead Pharmacist, NHS Barnsley in liaison with Dr Jha,
Consultant Geriatrician and in consultation with the Barnsley Stroke Physicians, Cardiologists and
Haematologists. This guideline has been subject to consultation and endorsement by the Area Prescribing
Committee on 10th October 2012 and Local Medical Committee on 13th November 2012.
Introduction
Indication/Licensing Information
Warfarin remains the first-line option for anticoagulation in patients with atrial fibrillation (AF) at high risk of a
stroke. Rivaroxaban and dabigatran are new drugs and do not have the long term safety record of warfarin.
They do however offer substantial benefits in patients who are unable to take warfarin.
The North Trent Network of Cardiac Care have issued a policy statement outlining the place of the newer
anticoagulants.1 Rivaroxaban and dabigatran can be considered for the prevention of stroke and systemic
embolism in patients with non valvular AF, in whom warfarin is indicated, and who meet the following criteria:

A CHADS2* score of ≥ 2 AND meet the NICE criteria summarised below (TA256 and TA249) PLUS ONE
OF THE FOLLOWING


Warfarin is contraindicated or patient is unable to manage variable dosing with appropriate support
Poor control with warfarin (defined as one INR above 8, or 2 readings outside the range of 1.8 to 5 in a six
month period
* See appendix A table 1. Local specialists may use the CHA2DS2-VASc score instead of the CHADS2 score
and consider anticoagulation with rivaroxaban or dabigatran in patients with a score of 1 or more (see appendix
A table 2)
NICE TA 2562 recommends rivaroxaban as an option in patients with nonvalvular AF with one or more risk
factors such as:
 Congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, prior stroke or TIA
NICE TA 2493 recommends dabigatran as an option in patients with non valvular AF with one or more of the
following risk factors:
 Previous stroke, TIA or systemic embolism, left ventricular ejection fraction below 40%, symptomatic heart
failure of New York Heart Association class 2 or above, age 75 years or older, age 65 years or older with
diabetes mellitus, coronary artery disease or hypertension.
When a newer anticoagulant is indicated, rivaroxaban is the non vitamin K antagonist of choice.
Dabigatran is an option in patients in whom rivaroxaban is not suitable. There is a small cohort of patients
where dabigatran may be appropriate rather than rivaroxaban. One example is patients with new onset AF who
are not suitable for warfarin and are scheduled for cardioversion. There is an evidence base for dabigatran in
these patients but not for rivaroxaban.
Pharmacology
Rivaroxaban and dabigatran act at specific points in the clotting cascade; rivaroxaban is a factor Xa inhibitor
and dabigatran is a direct thrombin inhibitor.
Rivaroxaban and Dabigatran Reduced Shared Care Guideline
Date Prepared: August 2012
Review Date: August 2014
Page 1 of 9
Reduced Shared Care Protocol –remains open to review in light of any new evidence
Amber with guidance (Amber-G) = To be initiated and titrated to a stable dose by a specialist prescriber with follow up
prescribing by primary care
Dosage and Administration
Rivaroxaban
The recommended dose for the prevention of stroke and systemic embolism in patients with non valvular AF is
20mg once daily. Rivaroxaban tablets should be taken with food. A lower dose is required in patients with
renal impairment as detailed in the table below. There is no adjustment of dose for age. Rivaroxaban is
available as 15mg and 20mg tablets for the prevention of stroke and systemic embolism in AF.
Renal function
CrCl <15 ml/min
CrCl 15-29 ml/min
CrCl 30-49 ml/min
Recommended dose
DO NOT USE
15mg once daily
15mg once daily
Comments
Limited clinical data; use with caution
Conversion from warfarin
Warfarin should be stopped and treatment with rivaroxaban initiated when the INR is ≤ 3.0. When converting
patients from warfarin, INR values will be falsely elevated after the intake of rivaroxaban. The INR is not valid
to measure the anticoagulant activity of rivaroxaban and therefore should not be used.
Missed dose
If a dose is missed, a dose should be taken immediately, and then patients should continue the following day
with the once daily intake as recommended. Patients should not take a double dose to make up for a missed
dose.
Dabigatran
Dabigatran is given as a twice daily dose, the dose is dependent on the patient’s age, renal function and
concomitant medication as detailed in the table below. Dabigatran capsules must be swallowed whole, with or
without food. The capsules must not be opened as this may increase the risk of bleeding (oral bioavailability
may be increased by 75% compared to the capsule formulation if the pellets are taken without the capsule
shell). Dabigatran is available as 110mg and 150mg capsules for the prevention of stroke and systemic
embolism in AF.
Age / renal function /
concomitant medication
Adults <75 years
Recommended dose
Comments
150mg twice daily
Adults 75-80 years
150mg twice daily
Consider 110mg twice daily if high
bleeding risk or GI irritation.
If at low thromboembolic risk but high
bleeding risk consider 110mg twice daily.
Adults >80 years
CrCl <30 ml/min
CrCl 50-80 ml/min
CrCl 30-50 ml/min
110mg twice daily
DO NOT USE
150mg twice daily
150mg twice daily
+ Verapamil
110mg twice daily
Consider 110mg twice daily if high
bleeding risk or GI irritation.
Conversion from warfarin
Warfarin should be stopped and dabigatran started when the INR is below 2.0 (usually 3-5 days after
discontinuing warfarin for a patient with a stable INR 2.0-3.0).
Missed dose
A missed dose may be taken up to 6 hours prior to the next scheduled dose. From 6 hours prior to the next
scheduled dose on, the missed dose should be omitted. No double dose should be taken to make up for
missed doses.
Rivaroxaban and Dabigatran Reduced Shared Care Guideline
Date Prepared: August 2012
Review Date: August 2014
Page 2 of 9
Reduced Shared Care Protocol –remains open to review in light of any new evidence
Amber with guidance (Amber-G) = To be initiated and titrated to a stable dose by a specialist prescriber with follow up
prescribing by primary care
Responsibilities of the specialist initiating treatment
Responsibilities of the specialist initiating treatment
Summary
 To assess the suitability of the patient for treatment including checking for drug interactions with existing
medication and assessment of bleeding risk. A HAS-BLED bleeding risk score of ≥ 3 indicates high risk
and regular review of these patients is required (see appendix A table 3).
 To discuss the benefits and side effects of treatment with the patient/carer. The decision about whether to
start treatment with rivaroxaban or dabigatran should be made after an informed discussion with the patient
about the risks and benefits compared with warfarin.
 To counsel the patient/carer on the anticoagulant effect of rivaroxaban/dabigatran, the reason for starting
anticoagulation, the risk of bleeding, who to contact if adverse events occur, drug interactions and what to
do in case of surgery/dentistry and procedures.
 To supply the patient with a rivaroxaban/dabigatran patient alert card.
 To ensure that the patient/carer understands the importance of compliance and other patient/carer
responsibilities detailed below.
 To perform the baseline tests detailed below and communicate the results to the GP.
 To prescribe for at least the first 8 weeks of treatment and until the patient is stable and until the GP formally
agrees to shared care. Specialist to supply the first month of treatment and the second following a 4 week
review.
 To ask the GP whether they are willing to participate in shared care and to discuss the shared care
arrangement with the patient/carer.
 To provide the GP with a summary of information relating to the individual patient to support the GP in
undertaking reduced shared care (See shared care request form in Appendix B).
 To advise the GP of any dosage adjustments required, when to refer back, when and how to stop treatment
(if appropriate) and when the patient will next be reviewed by the specialist.
 To monitor the patient for adverse events and report to the GP and where appropriate Commission on
Human Medicines/MHRA (Yellow card scheme).
 To provide the GP with contact details in case of queries.
Baseline Tests
Renal function and liver function must be checked prior to initiating rivaroxaban or dabigatran.
Rivaroxaban and Dabigatran Reduced Shared Care Guideline
Date Prepared: August 2012
Review Date: August 2014
Page 3 of 9
Reduced Shared Care Protocol –remains open to review in light of any new evidence
Amber with guidance (Amber-G) = To be initiated and titrated to a stable dose by a specialist prescriber with follow up
prescribing by primary care
Responsibilities of other prescribers
Acceptance of Responsibility by the Primary Care Clinician
It is optional for GPs to participate in taking on responsibility for shared care for the patient. GPs will take on
shared care only if they are willing and able. Prescribing responsibility will only be considered for transfer to
primary care when a patient’s clinical management and treatment is demonstrably stable – free of side effects
(or side effects have been assessed), no signs of bleeding or anaemia and contraindications have been
excluded.
Summary
 To reply to the request for shared care as soon as possible.
 To prescribe and adjust the dose as recommended by the specialist.
 To ensure there are no interactions with any new medication initiated in primary care.
 To monitor renal function at least once a year or more frequently as clinical circumstances dictate when it
is suspected that the renal function could decline or deteriorate.
 To conduct an annual review as detailed below.
 To seek advice from the secondary care clinician if there is any significant change in the patient’s physical
health status.
 To refer back to the specialist where appropriate. For example:
o
Patient or general practitioner is not comfortable to continue with the existing regime due to either
change in condition or drug side effects.
o
Advice in respect of concordance.
o
Special situations (e.g. Pregnancy).
 To discontinue the drug as directed by the specialist if required.
 To identify adverse events if the patient presents with any signs and liaise with the hospital specialist
where necessary. To report adverse events to the specialist and where appropriate the Commission on
Human Medicines/MHRA (Yellow card scheme).
Routine Tests / Annual Review
Renal function should be checked at least annually or more frequently as clinical circumstances dictate when it
is suspected that the renal function could decline or deteriorate.
Patients should be reviewed at least annually and patients at high risk of bleeding (HAS-BLED score ≥ 3)
should be reviewed more frequently as the clinical situation dictates, assessing the continuing need for
anticoagulation against the risk of bleeding. Such a review must also be done after any reported bleeding,
initiating of interacting medication, change in clinical condition (e.g. renal/liver impairment etc). An
assessment should be made for new contraindications to ongoing anticoagulation treatment with rivaroxaban
or dabigatran. Where new contraindications are found, treatment should be reviewed and withdrawn if risks
are deemed to outweigh benefits.
Responsibilities of the patient/carer
Summary
 To take/administer rivaroxaban or dabigatran as prescribed. Dabigatran capsules must be swallowed
whole and not opened or chewed. Dabigatran should be kept in its original package until use.
 To carry patient alert card and inform other healthcare professionals (e.g. doctor, dentist, pharmacist,
nurse) that they are taking an anticoagulant.
 To attend for blood tests/review as advised by the specialist and/or GP.
 To report any adverse effects to the specialist and/or GP, particularly any of the following:
o Unexpected bruising or bleeding that lasts a long time e.g. unusual bleeding from the gums,
recurrent nose bleeds, unusual vaginal or heavier than normal menstrual bleeding, bleeding
that is severe or cannot be controlled, coughing up blood or blood in vomit
o Unexpected pain, swelling or joint pain
o Rash, itching, chest pain/tightness
 To seek medical attention following a fall or injury, especially if head is injured, due to the increased risk of
bleeding.

To report any changes in disease symptoms to GP and/or specialist.
Rivaroxaban and Dabigatran Reduced Shared Care Guideline
Page 4 of 9
Date Prepared: August 2012
s
Review Date: August 2014
Reduced Shared Care Protocol –remains open to review in light of any new evidence
Amber with guidance (Amber-G) = To be initiated and titrated to a stable dose by a specialist prescriber with follow up
prescribing by primary care
Adverse drug reactions, precautions, contraindications and interactions
The following information should be read in conjunction with the SPC for rivaroxaban/dabigatran.
Adverse Drug
Reactions
Bruising and bleeding - the overall risk of bleeding is similar to warfarin. In clinical
trials rivaroxaban and dabigatran caused less intracranial bleeding than warfarin but
more severe GI bleeds than warfarin. Rivaroxaban caused more nose bleeds and
haematuria than warfarin and dabigatran caused more dyspepsia than warfarin.
There is currently no antidote for dabigatran and rivaroxaban, treatment of bleeding is
therefore supportive (see protocol for management of bleeding complications).
Common adverse effects listed in the respective SPCs include:
Rivaroxaban – anaemia, epistaxis, tachycardia, hypotension, dizziness, headache, GI
tract haemorrhage, abdominal pain, dyspepsia, diarrhoea, nausea, vomiting and
pruritus.
Contraindications
Dabigatran – anaemia, epistaxis, GI haemorrhage, abdominal pain, diarrhoea,
dyspepsia, nausea
Rivaroxaban
Contraindications
 Hypersensitivity to the active substance or to any of the excipients.
 Clinically significant active bleeding.
 Hepatic disease associated with coagulopathy and clinically relevant bleeding
risk including cirrhotic patients with Child Pugh B and C
 Pregnancy and breast feeding
 Patients with CrCl <15 ml/min
 Concomitant systemic treatment with azole-antimycotics (such as
ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease
inhibitors (e.g. ritonavir)
Precautions
 Care is to be taken if patients are treated concomitantly with other drugs
affecting haemostasis such as NSAIDs or aspirin.
 Should be used with caution in patients with an increased bleeding risk
Dabigatran
Contraindications
 Hypersensitivity to the active substance or to any of the excipients
 Patients with CrCL <30 ml/min
 Active clinically significant bleeding
 Organic lesion at risk of bleeding
 Spontaneous or pharmacological impairment of haemostasis
 Hepatic impairment or liver disease expected to have any impact on survival
 Pregnancy and breast feeding
 Concomitant treatment with systemic ketoconazole, cyclosporin, dronedarone,
itraconazole and tacrolimus
 Concomitant treatment with any other anticoagulant e.g. heparin, oral
anticoagulants except under the circumstances of switching therapy to or from
dabigatran or when unfractionated heparin is given at doses necessary to
maintain an open central venous or arterial catheter
 Clinical conditions associated with a significant risk of major bleeding, such
as: current or recent gastrointestinal ulceration, malignant neoplasms, recent
brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent
intracranial haemorrhage, oesophageal varices, arteriovenous malformations,
vascular aneurysms, major intraspinal or intracerebral vascular abnormalities
Precautions
 Care is to be taken if patients are treated concomitantly with other drugs
affecting haemostasis such as NSAIDs or aspirin
Rivaroxaban and Dabigatran Reduced Shared Care Guideline
Date Prepared: August 2012
Review Date: August 2014
Page 5 of 9
Reduced Shared Care Protocol –remains open to review in light of any new evidence
Amber with guidance (Amber-G) = To be initiated and titrated to a stable dose by a specialist prescriber with follow up
prescribing by primary care
Interactions
Rivaroxaban
Interacting drug
Dronedarone
Systemic azole-antimycotics (such as
ketoconazole, itraconazole, voriconazole
and posaconazole) or HIV protease
inhibitors (e.g. ritonavir)
Anticoagulants
Antiplatelet drugs/ NSAIDs
St John’s wort/ rifampicin/
carbamazepine/ phenytoin/
phenobarbital
Comments
Limited data on combined use. Avoid
concomitant use.
May increase rivaroxaban blood levels
and increase bleeding risk.
Concomitant use with rivaroxaban is
not recommended
Increased risk of bleeding. Use with
caution. Detailed instructions for the
transitions with warfarin are given below.
May increase bleeding risk. Use with
caution.
May reduce rivaroxaban blood levels.
Use with caution.
Dabigatran
Interacting drug
St John’s wort/ rifampicin/
carbamazepine/ phenytoin/
Dronedarone
Systemic ketoconazole / itraconazole /
ciclosporin / tacrolimus
Posaconazole
Ritonavir
Verapamil
Amiodarone / quinidine / clarithromycin
SSRIs and SNRIs
Anticoagulants
Antiplatelet drugs/ NSAIDs
Rivaroxaban and Dabigatran Reduced Shared Care Guideline
Date Prepared: August 2012
Review Date: August 2014
Comments
May reduce dabigatran blood levels.
Avoid concomitant use.
Contraindicated with dabigatran.
Contraindicated with dabigatran.
No data on combined use. Concomitant
use not recommended.
No data on combined use. Concomitant
use not recommended.
Reduce dabigatran dose to 110mg twice
daily. Use with caution.
May increase dabigatran levels. Use
with caution.
Increased the risk of bleeding in RE-LY
in all treatment groups.
Increased risk of bleeding (see
contraindications section).
May increase the risk of bleeding. Use
with caution.
Page 6 of 9
Reduced Shared Care Protocol –remains open to review in light of any new evidence
Amber with guidance (Amber-G) = To be initiated and titrated to a stable dose by a specialist prescriber with follow up
prescribing by primary care
Communication
Specialist to GP
The specialist will inform the GP when they have initiated rivaroxaban or dabigatran. When the patient is near
completing the satisfactory initiation period, the specialist will write to the GP to request they take over
prescribing and where possible give an indication as to the expected length of treatment. The Specialist will
also send a shared care request form to support the GP in undertaking reduced shared care. (Appendix B)
GP to Specialist
If the GP has concerns over the prescribing of rivaroxaban or dabigatran, they will contact the specialist as
soon as possible.
Contact names and details
Contact Details
Telephone number
Email
Dr Pravin Jha, Consultant Geriatrician, Specialist
for Older People and Lead Clinician for Falls and
Bone Health Service and TIA/AF
Dr Al-Bazzaz, Consultant Stroke
Physician/Geriatrician. Lead Clinician for
Barnsley Stroke Services.
Dr Tahir, Consultant Cardiologist
01226 433387
[email protected]
01226 432035
[email protected]
01226 432572
[email protected]
Dr Etorki, Consultant Cardiologist
Dr Yousaf, Consultant Cardiologist
Dr Ng, Consultant Haematologist
Dr Chan-Lam, Consultant Haematologist
01226 432572
01226 432070
01226 432765
01226 432942
[email protected]
[email protected]
[email protected]
[email protected]
References
1. North Trent Network of Cardiac Care. NORCOM Policy Statement: Non Vitamin K Antagonists for the
prevention of stroke and TIA in patients with AF at increased risk of stroke. June 2012
2. NICE TA 256. Available at: http://guidance.nice.org.uk/TA256/Guidance/pdf/English
3. NICE TA 249. Available at: http://guidance.nice.org.uk/TA249/Guidance/pdf/English
4. Rivaroxaban SPC. Available at:
http://www.medicines.org.uk/EMC/medicine/25586/SPC/Xarelto+20mg+film-coated+tablets/
5. Dabigatran SPC. Available at:
http://www.medicines.org.uk/EMC/medicine/24839/SPC/Pradaxa+150+mg+hard+capsules/
Rivaroxaban and Dabigatran Reduced Shared Care Guideline
Date Prepared: August 2012
Review Date: August 2014
Page 7 of 9
Reduced Shared Care Protocol –remains open to review in light of any new evidence
Amber with guidance (Amber-G) = To be initiated and titrated to a stable dose by a specialist prescriber with follow up
prescribing by primary care
Appendix A – Risk Assessment Tables
Table 1
CHADS2 risk index
Condition
Congestive Heart Failure
Hypertension
Age ≥ 75
Diabetes Mellitus
Stroke/TIA (History of)
C
H
A
D
S2
Points
1
1
1
1
2
Table 2
CHA2DS2-VASc risk index
CHA2DS2-VASc Risk Category
Congestive Heart Failure or LV dysfunction ≤40%
Hypertension
Age 65 to 75
Diabetes Mellitus
Stroke/ TIA/ Thromboembolism
Vascular disease (MI, complex aortic plaque,
PAD)
Age ≥ 75
Sex (1 point awarded if female)
Points
1
1
1
1
2
1
2
1
Table 3
HAS-BLED bleeding risk score
Hypertension
Abnormal renal and liver
function
Stroke
Bleeding
Labile INRs
Elderly
Drugs/alcohol
>160mmHg
Chronic dialysis, renal
transplantation or creatinine
>200µmol/l
Chronic hepatic disease or
biochemical evidence (e.g.
bilirubin > 2 x ULN in
association with ALT or Alk
Phos > 3 x ULN)
Previous bleeding history and/or
predisposition to bleeding e.g.
bleeding diathesis, anaemia etc
Unstable/high INRs or poor time
in therapeutic range (e.g. <60%)
>65
Concomitant use of drugs such
as antiplatelets, NSAIDs or
alcohol abuse. etc
≥ 3 indicates high bleeding risk
1
1 or 2 (1 point each)
1
1
1
1
1 or 2
A score of 0-2 indicates low risk.
A score of ≥ 3 indicates high risk. This suggests that the bleeding risk is such that caution and/or
regular review is recommended.
Rivaroxaban and Dabigatran Reduced Shared Care Guideline
Date Prepared: August 2012
Review Date: August 2014
Page 8 of 9
Reduced Shared Care Protocol –remains open to review in light of any new evidence
Amber with guidance (Amber-G) = To be initiated and titrated to a stable dose by a specialist prescriber with follow up
prescribing by primary care
Appendix B – Reduced Shared Care (Amber-G) Request Form



Specialist to complete when requesting GP to enter a shared care arrangement.
GP to return signed copy of form.
Both parties should retain a signed copy of the form in the patient’s record.
From (Specialist):
To (GP):
Patient details
Name:
ID Number:
Address:
DOB:
Diagnosed condition:
Amber-G Drug details
Drug name:
Dose:
Date of initiation:
CHADS2 / CHA2DS2-VASc score (delete as applicable):
Telephone
for contact:
HAS-BLED number(s)
score:
Recommended frequency of review:
The patient will be reviewed by the Consultant on:
Consultant:
Date:
The patient should be reviewed by the GP by:
Communication
Consultant
Telephone number:
Fax number:
Email address:
Specialist Nurse
Telephone number:
Fax number:
Email address:
Confirmation of acceptance of shared care
Specialist name:
Specialist signature:
Date:
GP name:
GP signature:
Date:
Rivaroxaban and Dabigatran Reduced Shared Care Guideline
Date Prepared: August 2012
Review Date: August 2014
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