Guidelines for the use of existing and New Oral Anticoagulants (NOAC) in the management of Atrial Fibrillation (AF)
Updated: September 2012
v2.0
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Medicines Management Team NHS Bolton
Document Control
Document Ref No.
MMGUID06
Title of document Guidelines for the use of existing and New Oral Anticoagulants (NOAC) in the management of Atrial Fibrillation (AF)
Author’s name Johanna Hulme Lesley Buxton
Author’s job title Acting Head of Medicines Management/Clinical Effectiveness Pharmacist, NHS Bolton Chronic Disease Management Pharmacist, NHS Bolton
Dept / Service Clinical Quality Directorate
Doc. Status FINAL v2.0
Based on GMMMG and GMCSN guidelines AF and NOACs
Signed off by Clinical Standards Board
Original Publication Date
N/A
Last Reviewed N/A
Next review date September 2014 or when relevant NICE guidance issued before this date
Distribution Trust wide
Has an Equality & Diversity Impact Assessment been completed? Yes
1. This guideline applies to all patients with a diagnosis of AF who are appropriate for treatment with anticoagulation.
2. AF can affect the entire population. 3. The guidance supports the use of new oral anticoagulants and
warfarin/Sinthrome® in AF. 4. The guidance aims to support management of all patients with a diagnosis of
AF, to maintain safe prescribing of NOACs where they are considered to be clinically appropriate for prescribing.
5. The guidance will improve clarity of patient care and provides clear information about which medication to use considering the licensed indications, the patient’s PMH and DH. The guidelines will have a positive impact on this group of patients. The medications used within this guideline can be prescribed in all faiths and cultures. Patients will continue to be monitored by their GP practice and/or Specialist (if they are under their care) to minimise the risk of adverse effects, unless the patient is prescribed warfarin/Sinthrome® (these patients will be monitored by the anticoagulation clinic or the GP practice where an anticoagulation service is commissioned).
Consultation History
NHS Bolton is the name used to refer to Bolton Primary Care Trust. The legal identity of the
organisation remains unchanged.
Version Date Consultation
Final v1.0 10/5/12 Approved document
Final v1.1 16/7/12 Minor amendments to GMMMG recommendations -Appendix 2
Draft v2.0 7/9/12 Amendments to document following GMMMG and GMCCSN guidance update
Draft v2.0 13/9/12 Clinical Standards Board – for approval
FINAL v2.0 13/9/12 CSB approved
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Contents
Section number Page Summary 4
1.0 Background 5 2.0 What is the picture in Bolton? 5
3.0 Managed entry of New Oral Anticoagulants (NOAC) – initiating and switching anticoagulant therapy safely
6
3.1 Acute setting (Bolton NHS FT) 6
3.2 Patients with a diagnosis of AF already prescribed warfarin (under the care of the anticoagulant clinic)
6
3.3 Patients with a diagnosis of AF already prescribed warfarin (under the care of the GP for anticoagulant monitoring)
7
3.4 Patients with a new diagnosis of AF, identified by the GP
8
Figure 2. Algorithm following
CHA2DS2-VASc 7
Appendix 1 Assessing a patient with AF for warfarin
therapy in Primary Care 9
Appendix 2 NOAC GMMMG recommendations 10
Appendix 3 Referral pathway 11
Appendix 4 Template letter sent from anticoagulant clinic to
GP 12
Appendix 5
Guideline for switching from Vitamin K
antagonists (VKA) e.g. warfarin to a new oral
anticoagulant therapy (NOAC)
13
Appendix 6 Choice of oral anticoagulant e.g. warfarin,
dabigatran, rivaroxaban 14-16
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Summary The flow chart below provides an overview of the current process for managing the use of the new oral anticoagulant treatments. This guidance document includes the most recent version of the GM guidance and therefore supersedes previous correspondence that may have been communicated.
* The time in therapeutic range (TTR) should be measured for individual patients using the Rosendaal method. Full information to support the above flow chart can be found in the GMMMG documents.
Patient is prescribed warfarin or Sinthrome®
Greater Manchester criteria for consideration of New Oral Anticoagulant drugs NOAC): 1) % of time INR in therapeutic range of 2-3, is less than 65%* OR 2) Unexplained INR greater than 5, more than 2 times (in 12 months) 3) NOAC should be available for patient who wish to take them despite clinical advice that
warfarin is first-line treatment (usually assessed by anticoagulant clinic/GP anticoagulant monitoring service)
Referral from NOAC advisor (Bolton anticoagulant clinic) to GP to consider anticoagulation (or choice if already prescribed)
(see appendix 3). GPs must action letter received from NOAC advisor (Michelle Grundy) and ensure close liaison occurs between the GP and NOAC advisor when switching oral
anticoagulants.
GP to undertake CHADS2 or CHA2DS2-VASC to identify if patient should be anticoagulated:
CHADS2 CHA2DS2-VASC** If result ≥2 If result ≥ 1
Anticoagulate:
Undertake full and informed discussion with the patient
Commence NOAC (if GM criteria met and drugs not contra-indicated)
Undertake CHA2DS2-VASC if: CHADS2 = 1 CHADS2 = 0
If: CHA2DS2-VASC = 0 (no treatment
required)
NB: GRASP-AF tool may need to be downloaded onto the practice computer system and ‘re-run’ to ensure most up-to-date scores for CHADS2 and CHA2DS2-VASC are achieved. ** Women with no other risk factor would score 1 on the CHA2DS2-VASC. this may be reasonable for women approaching 65, but younger women who have no other risk factors will have a lower absolute risk as there is a gradual increase with age. It therefore seems unreasonable to offer anticoagulation treatment to women < 60yrs if they have no other risk factor.
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Oral Anticoagulants (new and existing) for Atrial Fibrillation
1.0 Background
New oral anticoagulants (NOAC) have recently been licensed in the UK for the management of patients with Atrial Fibrillation (AF). NICE have reviewed the two currently licensed drugs:
Dabigatran (Pradaxa®) – NICE TA249 ‘Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation’
Rivaroxaban (Xarelto®) - NICE TA256 ‘Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation’
Apixaban - Expected April 2013 As these drugs are new to market, the full, long-term side effects of their use are not yet fully known. Concern with these drugs also includes a lack of known reversibility of the anticoagulation in those patients who present with major bleeding. Using NOAC therapy in all patients with AF would be prohibitively expensive. On this basis, the use of these drugs should be implemented carefully and monitored closely. To support this decisions appendix 1 provides guidance for ‘Assessing a patient with AF for warfarin therapy in Primary Care’. 2.0 What is the picture in Bolton?
The Greater Manchester Medicines Management Group (GMMMG) has been working closely with Greater Manchester and Cheshire Cardiac and Stroke Network (GMCCSN) to ensure there is a planned introduction for these drugs. Guidance documents have been developed and full documents are available on the GMMMG and GMCCSN websites. The documents are summarised individually below:
Guidance This provides guidance on the roles of the specific anticoagulant drugs when used in the management of AF. The guidance highlights which pre-treatment tests should be undertaking before considering prescribing an oral anticoagulant (warfarin or NOAC). This guidance is applicable to:
o All patients already prescribed oral anticoagulants for AF o Patients with newly diagnosed AF (to aid anticoagulant selection) o Patients who have previously had a diagnosis of AF, and who show on the
GRASP-AF tool as being appropriate for anticoagulant therapy. GRASP-AF should ideally be undertaken annually as patient risk factors are likely to change over time.
Available at: ‘Guidance on anticoagulation in atrial fibrillation’
Referral pathway Identifies the patient journey for patients who are currently prescribed warfarin/ sinthrome® who are inadequately controlled on warfarin/ sinthrome®, currently or historically. Available at: ‘see appendix 3’ or ‘Referral pathway for New Oral Anticoagulants (NOACs)’
Decision to refer for New Oral Anticoagulants (NOAC) - Proforma to consider whether a patient should be referred to the local anticoagulant clinic for review of their current anticoagulation therapy. The anticoagulation clinic will review the patient and send a letter including the proforma criteria to the GP. However, the anticoagulant clinic
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do not have access to the patient’s medical records or full list of current medication; in addition they also do not have the information to calculate the patient’s CHAD2 score. Available at: ‘Decision to refer for New Oral Anticoagulants (NOACs)’
3.0 Managed entry of New Oral Anticoagulants (NOAC) - Initiating and switching anticoagulant therapy safely
To ensure that prescribing of these new drugs is controlled and appropriate, it has been agreed at the Bolton Clinical Standards Board that the ‘Anticoagulation clinic’ based at Watersmeeting health centre and specifically Michelle Grundy, will be the ‘local advisor’ for recommendation to consider these new drugs.
3.1 Acute setting (Bolton NHS FT) Patients who are diagnosed with AF whilst an inpatient at Bolton NHS FT will not routinely be commenced on NOAC, however there will be occasions when NOAC will be indicated (e.g. warfarin skin necrosis). Patients suitable for slow loading of warfarin will be referred to the anticoagulant clinic as an outpatient. For those patients who require immediate loading of anticoagulation, warfarin will be commenced as an inpatient, as per existing protocols, with LMWH cover if giving higher loading doses to reduce the risk of anticoagulant therapy hypercoagulabililty. Patients who are commenced on warfarin for AF should have a CHA2DS2-VASC score ≥1.
3.2 Patients with a diagnosis of AF already prescribed warfarin (under the care of the anticoagulant clinic) The anticoagulant clinic will review patients currently prescribed warfarin/sinthrome® to identify those patients who are currently inadequately controlled and meet the criteria:
o The INR % of time in the therapeutic range of 2-3 less than 65% (as determined by the Rosendaal method) and/or
o Unexplained INR >5 more than 2 times (in 12 months) and/or o Other clinical considerations that must be specified in the referral to the GP
Examples include: Intolerance/adverse effect to warfarin/Sinthrome Other (to be specified)
Following review, these patients will be highlighted and a communication letter (see appendix 4) will be sent from the anticoagulant clinic to the GP. This will advise the GP to:
1. Undertake a CHA2DS2-VASC score 2. Follow the appropriate algorithm (see figure 2 below) dependent upon the patient’s
score 3. If the patient’s CHA2DS2-VASC score is ≥ 2 and warfarin/ sinthrome® treatment has not
lead to adequate control (as per GM criteria) a new oral anticoagulant agent (NOAC) should be commenced.
4. Patients’ medical history (e.g. renal impairment), concomitant drugs/interactions e.g. verapamil should be reviewed prior to commencing NOAC.
5. In the majority of cases patients will already be prescribed warfarin and will need to have therapy switched over. In all cases it is recommended that advice can be sought from the anticoagulant clinic. Michelle Grundy is the NOAC advisor and can be contacted on 01204 463040 or can be emailed for advice on [email protected].
6. To aid switching of anticoagulation to NOAC or commencement of NOAC, patient information leaflets are available for dabigatran and rivaroxaban, both containing a ‘patient alert card’ that the patient is advised to keep on their person and show to
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healthcare professionals prior to treatment. Anticoagulant clinic have stocks of these or they can be obtained directly from the manufacturer. In addition to ensure safe changeover of medication from warfarin/ sinthrome® to NOAC a summary checklist can be found in appendix 5.
7. A summary of the oral anticoagulants currently available for this indication can be found in appendix 6 to support treatment choice.
Figure 2: Algorithm following CHA2DS2-VASC (taken from full guidance)
3.3 Patients with a diagnosis of AF already prescribed warfarin (under the care of the GP for anticoagulant monitoring) For practices that undertake an anticoagulant monitoring service provision themselves, they should follow the guidance as set out in section 3.2 to ensure patients are managed via the same process, however the GP is responsible for identifying those patients who are inadequately controlled on warfarin. Michelle Grundy as the NOAC advisor should be informed whenever treatment with a NOAC is to commence.
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3.4 Patients with a new diagnosis of AF, identified by the GP Patients who have a new diagnosis of AF (with a CHA2DS2-VASC score ≥ 1) should be commenced on warfarin unless contraindicated. If after 3 months the patient has:
o The INR % of time in the therapeutic range of 2-3 less than 65% (as determined by the Rosendaal method) and/or
o Unexplained INR >5 more than 2 times (in 12 months) Guidance as above should be followed dependent upon whether the patient is under the care of the anticoagulation clinic or GP-led anticoagulation service.
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Appendix 1 – Assessing a patient with AF for warfarin therapy in Primary Care
Numerous clinical trials have provided an extensive evidence base for the use of oral anticoagulant therapy (OAC) e.g. warfarin in AF1. There is evidence however that OACs continue to be under-prescribed because of a perceived underestimate of the benefits and an overestimate of the risks, particularly the risk of bleeding2. It must be remembered that stoke risk is closely related to bleeding risk and as bleeding risk increases so does the risk of stroke. The decision whether to prescribe an oral anticoagulant must therefore take in to account the benefits from stroke prevention and the risk of bleeding. Advice re assessing risk factors for age, falls, peptic ulcer disease, uncontrolled hypertension and alcohol can be found in the GMCCSN guidance. This document states that the risk factors listed also apply to NOAC therapy. Current evidence points to similar bleeding risks with warfarin and NOAC (possibly a slightly lower risk with dabigatran 110mg compared with warfarin). For information on contra-indications/cautions drug interactions see appendix 6 and SPC.
Assessment of bleeding risk For assessing bleeding risk the European Society of Cardiology (ESC) highlight a new simple bleeding risk score HAS-BLED 3 (see table below). The ESC authors suggest that “It would seem reasonable to use the HAS-BLED score to assess bleeding risk in AF patients whereby a score of ≥ 3 indicates “high risk” and some caution and regular review of the patient is needed following the initiation of antithrombotic therapy. The HAS-BLED study authors suggest that for CHADS2 scores of 2 or more, if the HAS-BLED score exceeds the CHAD score then the risk of bleeding exceeds the potential benefit of the OAC. In the case of a CHADs2 score of 1, the HAS-BLED score must exceed 2 for the potential harm to offset the benefit. This recommendation has yet to be validated however.
Discussion with patient In all cases where OAC is considered, a discussion of the pros and cons with the patient, and an evaluation of the risk of bleeding complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences are necessary. The anticoagulant service will provide a 30 minute counselling session to all patients at their first visit which reiterates risk / benefit and ways to reduce harm / improve concordance.
1 The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology. Guidelines for the management of atrial
fibrillation. European Heart Journal 2010; 31 2369-2429. 2 Singh P, arrevad PS, Peterson GM, Bereznicki LR. Evaluation of antithrombotic usage for atrial fibrillation in aged care facilities. JClin Pharm and therapeutics Apr 2011; 36 (2): 166-171. 3Pisters R, Lane DA, Nieuwlaat R, De Vos CB, Crijns HJGM, Lip GYH. A novel user-friendly score (HAS-BLED) to assess one year risk of major bleeding in atrial fibrillation patient: The Euro Heart Survey. Chest 2010, March 18.
HAS-BLED
Clinical characteristic
Score
Hypertension (systolic BP > 160mmHg)
+1
Abnormal renal and liver function (1 point each)
+1 or 2
Stroke +1
Bleeding +1
Labile INRs +1
Elderly (age>65 years)
+1
Drugs or alcohol (1 point each)
+1 or 2
Key: Hypertension: if hypertension is controlled by medication score = 0) Abnormal renal function: chronic dialysis, renal transplantation or serum creatinine ≥ 200µmol/L. Abnormal liver function: chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic derangement e.g. bilirubin > 2 x upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatise > 3 x upper limit of normal etc. Stroke: previous history of stroke, especially deep brain (lacunar) stroke. Bleeding: previous bleeding history and/or predisposition to bleeding e.g. bacterial endocarditis, previous gastrointestinal bleeding, uncorrected major bleeding disorder – for example: thrombocytopenia, haemophilia, liver failure, renal failure. Potential bleeding lesions: active peptic ulcer, oesophageal varices, aneurysm, proliferative retinopathy, recent organ biopsy, recent trauma or surgery to head, orbit or spine. Labile INRs: unstable/high INRs or poor time in therapeutic range (e.g. < 60%). Drugs/alcohol use: Concomitant use of drugs, such as antiplatelet agents, NSAIDs, or alcohol abuse etc. NB: if patient’s NSAID is stopped or patient reduces alcohol consumption.
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Appendix 2- NOAC GMMMG recommendation
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Appendix 3 - Referral pathway (adapted for local use from the GMCCSN pathway)
In patient and not adequately controlled on
warfarin/Sinthrome & clinically appropriate to
commence NOAC
Patient meets Greater Manchester criteria for
new oral anticoagulants (NOAC)
Patient prescribed warfarin/ Sinthrome &
not adequately controlled. Patient to
be reviewed in anticoagulant clinic
(ACC)
Patient reviewed in secondary/tertiary care. Patient not adequately
controlled on warfarin/Sinthrome at present of historically (identifiable through
GRASP AF)
GP to have informed discussion with patient
Commence NOAC if appropriate
NOAC advisor (Michelle Grundy)
available for advice
Annual review and reassess risk
Hospital inpatients Anticoagulation clinic
patients
Outpatient department patients
Letter sent to GP
Refer patients to GP for review
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Appendix 4 – Template letter sent from anticoagulation clinic to GP
Waters Meeting HC Waters Meeting Road
Bolton BL1 8TU
Dr Jones The Practice Bolton BL1 1EH
Dear Dr Jones,
Re:
This patient is currently on warfarin/Sinthrome therapy (commenced on: DD/MM/YYYY) for stroke prevention in Atrial Fibrillation and meets criteria that make them eligible for consideration for NOAC therapy due to the reasons outlined below:
The INR % of time in the therapeutic range of 2-3 less than 65%. (TTR should be measured for individual patients using the Rosendaal method)
Y/N
Unexplained INR >5 more than 2 times (in 12 months) Y/N
Other clinical considerations:
Intolerance/adverse effect to warfarin/Sinthrome
Other – please state
Y/N Y/N
The review of anticoagulation therapy should be undertaken and patient considered for NOAC therapy following appropriate investigations and full informed discussion with the patient as described in the Greater Manchester (GM) guidance and local guidelines.
GM guidelines can be found at: http://gmccardiacnetwork.nhs.uk/cmsupload/Microsoft_PowerPoint_-_revised_GM_guidance_(1).pdf
Local guidelines can be found at: http://gp.boltonmlz.co.uk/documents/download/1298
If you wish to discuss this further I can be contacted at 01204 463032.
Yours Sincerely,
Michelle Grundy
Anticoagulant service manager / NOAC advisor
Mr T Bear 2030 The Spinney Fourth Avenue Bolton BL1 4LU
Hosp No: 1000000
NHS No: 46000000000
Date of Birth: 31/05/1921
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Appendix 5
Guideline for switching from Vitamin K antagonists (VKA) e.g. warfarin to a new oral anticoagulant therapy (NOAC)
GP is to discuss possible change with patient and explain reason – risks/benefits Consult with NOAC advisor if oral anticoagulant switching is required If patient consents to change:
Recent renal function / LFT required
Consider dose to be prescribed based on patient age/ renal function – see SPC/appendix 6
Review medications for potential drug interactions
Contact anticoagulant clinic and inform them of impending conversion
Give patient a prescription so that chemist can arrange supply
Vitamin K antagonist to be discontinued for 2 days
INR to be taken after 2 days omission
For dabigatran if INR <2 NOAC can commence
For rivaroxaban if INR <3 NOAC can commence
Give the patient an alert card and patient information leaflet for the NOAC
Ensure patient / carers are aware to send redundant VKA supply back to the chemist for safe destruction
Annual U&E
Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. (Adverse events should also be reported to Boehringer Ingelheim - Drug safety on 0800 328 1627 (freephone) for Dabigatran or Bayer plc on 01635563500 for Rivaroxaban.) Michelle Grundy NOAC advisor
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Appendix 6 – Choice of oral anticoagulant e.g. warfarin, dabigatran, rivaroxaban This summary provides an overview of the various oral anticoagulants now available. The individual Summary of Product characteristics should be utilised for full prescribing information when a specific drug is selected for prescribing.
Indication
Drug Warfarin Dabigatran (Pradaxa®) Rivaroxaban (Xarelto
®)
Indication (in relation to stroke
prevention)
Prophylaxis of systemic embolism in patients with rheumatic heart disease and atrial fibrillation.
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more of the following risk factors:
Hypersensitivity to the active substance or to any of the excipients
Previous stroke, transient ischemic attack, or systemic embolism (SEE)
Left ventricular ejection fraction < 40 %
Symptomatic heart failure, New York Heart Association (NYHA) Class 2
Age 75 years
Age 65 years associated with one of the following: diabetes mellitus, coronary artery disease or hypertension
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors:
Congestive heart failure
Hypertension
Age 75 years
Diabetes mellitus
Prior stroke or transient ischaemic attack
Dose, monitoring and formulation
Drug Warfarin Dabigatran (Pradaxa®) Rivaroxaban (Xarelto
®)
Dose
Variable dose (ONCE A DAY) generally at teatime. Dose dependent on INR and target range.
150mg TWICE A DAY
20mg ONCE A DAY (taken with food)
150mg TWICE A DAY (75-80years) if bleeding risk is high and thromboembolic risk low – physician can consider 110mg BD.
110mg BD (aged over 80 years)
Monitoring INR monitoring
Visible monitoring of patient for signs of bleeding and anaemia (no clinical monitoring available – INR not able to be used as different pathway of action)
Visible monitoring of patient for signs of bleeding and anaemia (no clinical monitoring available – INR not able to be used as different pathway of action)
Formulation 0.5mg, 1mg, 3mg and 5mg tablet
110mg and 150mg tablet 15mg and 20mg tablet
Contra-indications
Drug Warfarin Dabigatran (Pradaxa®) Rivaroxaban (Xarelto
®)
Contra-indications – See SPC
for full details and
drug interactions
section
Known hypersensitivity to warfarin or to any of the excipients
Haemorrhagic stroke
Clinically significant bleeding
Within 72 hours of major surgery with risk of severe bleeding
Within 48 hours postpartum
Pregnancy (first and third trimesters)
Drugs where interactions may lead to a significantly increased risk of bleeding
Hypersensitivity to the active substance or to any of the excipients
Patients with severe renal impairment (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
Concomitant treatment with systemic ketoconazole, cyclosporine, itraconazole, tacrolimus
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
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Cautions
Drug Warfarin Dabigatran (Pradaxa
®)
Rivaroxaban (Xarelto®)
Cautions/ Special
warnings for use
Therapy should be reviewed on a regular basis (most ADRs are due to over anticoagulation). All patients should have a ‘yellow’ anticoagulation booklet. Thrombophilia - patients with protein C or S deficiency. Thyroid disorders – closely monitor patients The following may increase bleeding risk: loss of weight, acute illness, cessation of smoking (doses may need to be reduced) The following may reduce efficacy: weight gain, diarrhoea, vomiting (doses may need to be increased) Genetic conditions in relation to CYP2C9 and VKORC1 – closer monitoring required
Patients with elevated liver enzymes > 2 ULN should not be prescribed dabigatran. Use with caution in conditions with an increased risk of bleeding.
See SPC for information on converting from warfarin/sinthrome to Rivaroxaban. Renal impairment: Mild: (CrCl 50-80ml/min) – no dose adjustment necessary Moderate: (CrCl 30-49ml/min) – 15mg ONCE A DAY Severe: (CrCl 15-29ml/min) – 15mg ONCE A DAY (use cautioned in these patients) Very severe: CrCl <15ml/min – not recommended in this group of patients
Drug interactions
Drug Warfarin Dabigatran (Pradaxa®)
Rivaroxaban (Xarelto
®)
Drug interactions
(see individual SPCs for
full details and action)
Pharmacodynamic and other interactions (avoid or use with caution):
Care with concomitant NSAIDs (including aspirin and COX-2s) and platelet aggregation inhibitors (e.g. clopidogrel)
Heparins (unless clinically indicated due to low INR)
Thrombin inhibitors e.g. bivalirudin, Dabigatran
Drugs inhibiting haemostasis, clotting or platelet action
Dipyridamole
Sulfinpyrazone
Fondaparinux, rivaroxaban
Glycoprotein IIb/IIIa receptor antagonists
Prostacyclin
SSRI/SNRI antidepressants
Concomitant glucosamine is not recommended
Generally interactions lead to an ↑ bleeding risk – patients should be monitored closely for signs of bruising, bleeding and anaemia (however will be guided by INR and anticoagulation clinic for dose variations)
Azole antifungals (e.g. ketoconazole, fluconazole)
Paracetamol
Methylphenidate
Zafirlukast
Fibrates
Statins (not pravastatin)
Generally interactions lead to an ↑ bleeding risk – patients should be monitored closely for signs of bleeding and anaemia.
Caution with concomitant other anticoagulants
Systemic azole-antimycotics e.g. ketoconazole, ciclosporin, itraconazole, tacrolimus are contra-indicated, also posaconazole (due to lack of available safety data for this combination)
Caution with concomitant strong P-gp inhibitors e.g. amiodarone, quinidine, verapamil
Caution concomitant use of amiodarone (nb: amiodarone has a long half-life and interaction may exist for weeks after discontinuation, especially in patients with mild-moderate renal impairment)
Caution concomitant use of quinidine especially in patients with mild-moderate renal impairment
Caution concomitant use of verapamil – dose
Interactions below lead to an ↑ bleeding risk – patients should be monitored closely for signs of bleeding and anaemia.
Concomitant use of systemic azole-antimycotics e.g. ketoconazole, itraconazole, voriconazole, posaconazole, HIV protease inhibitors
Concomitant use of dronedarone should be avoided
Caution with concomitant other anticoagulants
Caution with concomitant NSAIDs and platelet aggregation inhibitors (e.g. clopidogrel)
Interactions below lead to a ↓ in anticoagulant concentration therefore treatment may be suboptimal
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(prolonged use)
Allopurinol
Capecitabine
Erlotinib
Disulfiram
Omeprazole
Propafenone
Amiodarone
Tamoxifen
Erythromycin
Sulfamethoxazole
Metronidazole
Excessive alcohol consumption
Cranberry juice should be avoided
Interactions below lead to a ↓ in anticoagulant concentration therefore treatment may be suboptimal (however will be guided by INR and anticoagulation clinic for dose variations)
Barbiturates
Primidone
Carbamazepine
Griseofulvin
Oral contraceptives
Rifampicin
Azathioprine
Phe ytoin
St. John’s Wort – combination not supported
Large amounts of food containing vitamin K - i.e. sudden changes in diet of these products may affect anticoagulant control
Interactions below lead have variable effect
Corticosteroids
Nevirapine
Ritonavir
reduction advised from 150mg BD to 110mg BD in patients taking concomitant verapamil. Interaction more likely in patients with mild-moderate impairment)
Caution concomitant use of clarithromycin, especially in patients with mild-moderate renal impairment.
Protease inhibitors (e.g. ritonavir containing products) should not be prescribed concomitantly (due to lack of available safety data for this combination)
Interactions below lead to a ↓ in anticoagulant concentration therefore treatment may be suboptimal
Caution concomitant use of strong CYP3A4 inducers e.g. rifampicin, St. John’s Wort, carbamazepine, phenytoin
Caution concomitant use of strong CYP3A4 inducers e.g. phenytoin, carbamazepine, phenobarbital, St. John’s Wort)
Relevant resources
Drug Warfarin Dabigatran (Pradaxa®) Rivaroxaban (Xarelto
®)
Relevant resources (e.g. SPC)
Warfarin SPCs SPC – 150mg tablets SPC – 110mg tablets
SPC – 15mg tablets SPC – 20mg tablets