Download RIVAROXABAN for the prevention of stroke and systemic

RIVAROXABAN for the prevention of stroke and systemic embolism
in non-valvular atrial fibrillation: supporting practical guidance for primary care
(NCL Joint Formulary Committee website – NOAC - http://ncl-jfc.org.uk/noac-prescribing-guides.html)
1.0 Introduction: indication and licensing
1
NICE TA 256 recommended rivaroxaban (Xarelto®) as an option for the prevention of stroke and systemic
embolism within its licensed indication i.e. in adult patients with non-valvular atrial fibrillation with one or more risk
factors such as:
• congestive heart failure
• hypertension
• age ≥ 75 years
• diabetes mellitus
• prior stroke or transient ischaemic attack
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Rivaroxaban is an orally active direct Anti-Xa inhibitor. ROCKET-AF was a large, prospective, randomised controlled
trial in over 14,000 patients with CHADS2 score > 2 that compared rivaroxaban to adjusted dose warfarin (INR range
2.0 to 3.0). Patients with CrCL < 30mL/min as estimated by Cockcroft & Gault were excluded from the trial. The
primary efficacy outcome was the composite of stroke (ischemic or hemorrhagic) and systemic embolism whilst the
principal safety end point was a composite of major and non-major clinically relevant bleeding events.
ROCKET-AF demonstrated non inferiority with in the primary endpoint (composite of ischaemic or haemorrhagic
stroke and systemic emboli) with incidences of 1.7% per-100 patient years in the rivaroxaban arm versus 2.2% in the
warfarin arm; p < 0.001. Major and non-major clinically relevant bleeding was not significantly different between the
two groups. Intracranial haemorrhage occurred less often with rivaroxaban (0.5% versus 0.7%, HR 0.67; 95% CI 0.47
to 0.93; P = 0.02), as did fatal bleeding (0.2% per year vs. 0.5% per year, P = 0.003). Major GI bleeding was more
common with rivaroxaban (3.2%) than with warfarin (2.2%, P<0.001), as were bleeds requiring transfusion (1.6% per
year for rivaroxaban vs 1.3% per year for warfarin; p=0.04).
2.0 Use across North Central London (NCL)
The new oral anticoagulants (NOAC) such as rivaroxaban, dabigatran and apixaban, are all NICE approved and are
considered alternatives to warfarin (currently standard treatment) for the prevention of stroke and systemic
embolism in patients diagnosed with non-valvular AF, with CHA2DS2VASc > 1 (excluding female gender) and assuming
that NCL criteria are fulfilled (summarised in table below). Rivaroxaban is the preferred agent as per the NCL Joint
Formulary Committee, although dabigatran or apixaban can be used where clinically justified
NCL criteria
Known allergy / intolerance to warfarin or other vitamin K
antagonist
Significant technical difficulties with INR monitoring and/or
accessing A/C clinic that raises safety concerns
Patient-time in range < 65% once established on warfarin
(not due to wilful non-compliance).
Comments
e.g. alopecia with no other cause (such as iron
deficiency anaemia, hypothyroidism etc)
Consider alternatives such as community A/C
services, domiciliary monitoring/input or self-testing
Non-compliance is not a reason to switch to NOAC.
Consider alternatives such as community A/C
services, domiciliary monitoring/input or self-testing
INR ≥ 8.0 on 1 occasion or INR > 5.0 on 2 occasions over a
period of 6 months (once A/C is established), with a high
likelihood of recurrence (i.e. unsafe)
Phenindione supply issues
Awaiting DC-cardioversion or urgent AF ablation within 4
weeks [dabigatran only]
Dabigatran is the only NOAC currently licensed for
DC-cardioversion. All NOAC are unlicensed for AF
ablation. If ongoing anticoagulation required post
procedure (regardless of rhythm), then switch to
warfarin unless any of the other criteria listed in this
table are fulfilled.
Specific clinical indication as per locally designated
consultant in stroke medicine / thrombosis / cardiology
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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3.0 Patient pathway – an overview (See appendix 1 for complete AF NOAC pathway)
Governance structures are required to ensure the safe and robust introduction of NOAC into routine clinical practice.
The use of secondary care anticoagulation clinics would fulfil this requirement and is the model agreed by NCL for
initiation of NOAC.
Decision to
anticoagulate
and NOAC
criteria fulfilled
GP*refers pt
to local AC
clinic using
NOAC referral
proforma
Hospital AC
clinic initiates,
prescribes and
monitors
NOAC for 2
months**
After 2
months, GP
takes over
prescribing &
monitoring
GP to re-refer
to local A/C
clinic if needed
*If urgent, then secondary care can directly refer patients to his/her local AC clinic for outpatient initiation
** Referral pathways may be subject to local variation, but the minimum requirements are outlined above
4.0 Roles and Responsibilities
4.1 Referring clinician to:
• Calculate CHA2DS2VASc score (see appendix 2)
• Risk assess patient for anticoagulation (including the HAS-BLED score – see appendix 2)
• Check routine biochemistry (FBC, U&E, LFT), calculate CrCL (using Cockcroft & Gault equation, appendix 3),
check coagulation screen and blood pressure
• Confirm that NOAC is appropriate, in line with NCL guidance
• Discuss risks vs. benefits of anticoagulation with the patient
• Complete the NOAC referral proforma and refer patient to his/her local anticoagulation clinic for NOAC
counselling and initiation
• For patients identified in secondary care requiring anticoagulation for AF:
o Outpatients: GP to refer to local anticoagulation clinic
o Outpatient stroke neurologists/physicians, or designated cardiologists/haematologists may refer patient to
his/her local A/C clinic directly in cases where urgent anticoagulation is required (as is done currently);
these patients may be on a low molecular weight heparin as an interim measure
o Inpatients: If urgent, IP team to refer to patient’s local anticoagulation clinic for OP initiation. Otherwise,
patient to be referred to the local anticoagulation clinic by GP
• In general, NOACs should only be initiated by secondary care anticoagulation clinics, to ensure that robust
governance processes will be followed
4.2 Anticoagulation (A/C) clinic to:
• Check baseline bloods as per normal practice: FBC, U&E, LFTs, coagulation screen (if not on A/C) or INR (if on
warfarin)
• Select appropriate NOAC after review of clinical data provided on referral proforma (rivaroxaban is the preferred
agent as per the NCL Joint Formulary Committee, although dabigatran or apixaban can be used where clinically
justified)
• Scan referral proforma into electronic records (or file in medical notes if former not possible)
• Deliver standardised verbal counselling as per NCL/local checklist (patient to sign)
• Provide (1) written information about the drug and (2) a patient alert card (available from the drug company)
• Arrange an initial supply of 4 weeks (month 1) and provide a follow-up A/C clinic appointment within 4 weeks
• Inform GP (standard NCL letter) that patient has been initiated on NOAC
• Review the patient within 4 weeks to assess tolerability and compliance. Assuming no concerns, arrange the
second month's prescription (NB: if there are concerns, clinic to liaise with referring clinician / local
haematologist)
• After the second visit (when month 2’s prescription is issued) and assuming that patient will remain on NOAC,
immediately inform GP via standard transfer of care letter (fax and phone to confirm receipt of information) to
ensure continuity of care and NOAC supply
• GP should aim to take over care as from the start of month 3. A/C clinic to ensure that GP agreement has been
received (and scanned onto electronic records or the equivalent) before discharging patient from the clinic
• Ensure patient understands the transfer process and how to obtain further supplies
• Enter details on local A/C database
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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4.3 GP responsibilities
• As per points listed under 4.1 if referring the patient
Also:
• Update GP practice records, detailing that NOAC has been initiated (with months 1 and 2 being supplied by
secondary care)
• During month 2 of treatment, sign the transfer of care form to confirm agreement for ongoing prescribing and
monitoring as from the start of month 3, and fax back to the anticoagulation clinic
• Reiterate the importance of patient compliance and review on a regular basis to avoid accidental stoppage.
Reiterate the need to carry the patient alert card at all times
• Undertake appropriate clinical monitoring (section 11.0) and be aware of possible drug interactions
• Notify other healthcare professionals if patient is to undergo any invasive treatments (e.g. dental or elective
surgery)
• Undertake an annual review regarding the ongoing appropriateness of anticoagulation, including a review of the
cautions and contraindications to rivaroxaban
• Refer back to the local anticoagulation clinic if there are any clinical concerns
5.0 Contraindications and exclusion criteria to rivaroxaban
In October 2013, the MHRA strengthened the contraindications for all NOACs (dabigatran, rivaroxaban and
3a
apixaban) . Patients listed in the categories below, should not receive rivaroxaban.
Contraindications / exclusions to use (not exhaustive – refer to Xarelto® SPC3)
Lesion or condition, if considered to be a significant risk factor for major bleeding. This may include:
• Current/recent upper or lower GI ulceration; oesophageal varices (known or suspected); malignant
neoplasms at high risk of bleeding
• Surgery/trauma or bleed affecting head/brain, eyes or spine within last 4 weeks
• AV malformations, vascular aneurysms or major intraspinal / intracerebral vascular abnormalities
• Stroke in last 14 days/severe stroke in last 6 months (unless advised by designated stroke neurology cons)
• Uncontrolled hypertension (systolic BP > 180mmHg and/or diastolic BP > 100mmHg), vascular retinopathy
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic
patients with Child Pugh B and C
• CrCL < 15mL/min (calculated as per C&G formula)
Pregnancy and lactation (crosses placenta and into breast milk)
Indications not covered by licence e.g. prosthetic heart valve(s) requiring anticoagulation; INR range higher
than 2.0-3.0 required
Contraindicated: concomitant treatment with other anticoagulants, except when switching to or from
rivaroxaban (as advised by A/C clinic, haematology SpR or haemostasis consultant), or when unfractionated
heparin is given at doses necessary to maintain an open central venous or arterial catheter
Not recommended: systemic ketoconazole, itraconazole, posaconazole, voriconazole, HIV protease inhibitors
Avoid: dronedarone
6.0 Cautions
Patients falling into the following categories should be discussed with the local haematologist.
Cautions to use (not exhaustive – refer to Xarelto® SPC3)
History of previous major bleed on anticoagulation / antiplatelet therapy
Thrombocytopenia (e.g. platelets < 75)
Abnormal baseline coagulation screen (repeat and investigate before initiation of NOAC)
Weight < 50 kg or > 120kg
Abnormal liver function tests (2 x upper limit of normal)
Myeloproliferative disease / sickle sell disease (limited evidence on use)
Congenital or acquired bleeding disorders
3
Antiplatelets, NSAIDs, rifampicin, phenytoin, phenobarbitone, carbamazepine, St John’s Wort – refer to SPC
and table 2
Age > 75 years; discuss with local haematologist if additional risk factors for bleeding
Excessive alcohol intake
High risk of recurrent falls resulting in significant injury
Patients < 18 years (unlicensed – discuss with haematologist)
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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Note: the concomitant use of aspirin or other antiplatelets with rivaroxaban significantly increases the
risk of major bleeding. All antiplatelet (and NSAID) use must be reviewed prior to initiating
rivaroxaban. See sections 7.0 and 8.0
7.0 Dose and administration
•
•
•
•
•
•
•
•
The standard licensed dose of rivaroxaban for AF is 20mg OD (15mg OD in specific circumstances – see below)
CAUTION: the 10mg rivaroxaban tablet is licensed for VTE thromboprophylaxis in elective hip or knee
replacement surgery. Please ensure that only the 15mg/20mg strength tablets are prescribed or dispensed for
AF, to minimise drug errors and patient confusion
Note that plasma levels and excretion of rivaroxaban are affected by many variables including renal function and
drug interactions – see below for further information and for advice re dose adjustments
Rivaroxaban must be taken with food to maximise bioavailability
Both the 20mg and the 15mg tablets are film-coated, but are not modified or controlled release. Crushing the
tablets for patients who are unable to swallow would not be expected to affect the release characteristics per se,
but would make it an unlicensed administration method (clinical decision and responsibility)
If a dose is missed, then the patient should take rivaroxaban as soon as it is remembered (- local practice at
UCLH is to limit this to within 8 hours). Continue with the next dose the following day as usual.
The dose should not be doubled within the same day to make up for a missed dose
The tablets can be dispensed into medication reminder devices if appropriate
Formulation contains lactose: avoid in patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption
Table 1: Rivaroxaban dosing for specific patient groups
Usual standard dose for AF: Rivaroxaban 20mg OD
Plasma levels and excretion of rivaroxaban can be affected by many variables including renal function and drug
interactions. If there are a number of risk factors for bleeding, then reconsider the overall risk vs benefit
of treatment with rivaroxaban
Risk factors for bleeding with rivaroxaban
Rivaroxaban dosing comments (refer to SPC3)
HAS-BLED score > 3 and where anticoagulation is
appropriate
Consider 15mg OD in line with recommendations from The
4
European Society of Cardiology (ESC)
History of gastritis, oesophagitis or
gastro-oesophageal reflux disease and where
anticoagulation is appropriate
Low bodyweight (e.g. < 50kg)
Increased risk of major GI bleeding compared to VKA
If rivaroxaban appropriate, then PPI cover advised.
Renal impairment* CrCL 15-49mL/min
Reduce dose to 15mg OD (SPC for AF)
(NB: limited clinical data with CrCL 15-29mL/min; plasma
concentrations significantly ↑)
Do NOT use rivaroxaban (SPC)
Renal impairment* CrCL < 15mL/min
Antiplatelet agents
NSAIDS
SSRIs (Selective Serotonin Re-uptake Inhibitors) /
SNRIs (Selective Norepinephrine Re-uptake Inhibitors)
Certain drug interactions
*estimated CrCL using C&G formula (appendix 3)
Limited data available - discuss with local haematologist
Concomitant use of antiplatelet agents increases the risk of
major bleeding - see table 2 for further information
Increased risk of bleeding - see table 2
May increase risk of bleeding – see table 2
See table 2
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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8.0 Drug interactions with rivaroxaban3
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. It is also a substrate of the
transporter proteins P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp)
• Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp,
are expected to increase rivaroxaban plasma concentrations to a lesser extent, than those strongly inhibiting
both pathways
3
Table 2: Drug interactions with rivaroxaban (NB: list is NOT exhaustive)
3
3
Drugs (examples)
Effect (SPC ) with examples
Action (SPC )
•
Systemic azole
antimycotics, such as:
ketoconazole
itraconazole
voriconazole
posaconazole
(These are strong inhibitors
of both CYP3A4 and P-gp
pathways)
HIV protease inhibitors e.g.
ritonavir
(Strong inhibitor of both
CYP3A4 and P-gp pathways)
Dronedarone
Potent CYP3A4 and
moderate P-gp inhibitors
e.g. clarithromycin /
telithromycin)
Strong CYP3A4 inducers
Rifampicin
Phenytoin Carbamazepine
Phenobarbitone
St. John's Wort (Hypericum
perforatum)
Anticoagulants such as
unfractionated heparin,
LMWH (dalteparin,
enoxaparin etc),
fondaparinux, other oral
anticoagulants (warfarin,
dabigatran, apixaban etc)
Thrombolytic agents,
GPIIb/IIIa inhibitors
↑ rivaroxaban plasma concentrations expected,
leading to increased risk of bleeding
Ketoconazole ↑ AUC (2.6 fold) and ↑ Cmax (1.7
fold)
NB: fluconazole is a moderate CYP3A4
inhibitor and its interaction with rivaroxaban
is not considered to be clinically relevant
↑ rivaroxaban plasma concentrations expected,
leading to increased risk of bleeding
Ritonavir ↑ AUC (2.5 fold) and ↑ Cmax (1.6 fold)
Limited available clinical data
Possible ↑ plasma concentration in patients
with renal impairment (from pharmacokinetic
modelling studies)
↓ rivaroxaban plasma concentrations expected.
Rifampicin ↓mean AUC of rivaroxaban by
approximately 50 %.
Other strong CYP3A4 inducers (examples given),
may also lead to ↓ rivaroxaban plasma
concentrations.
Increased risk of major bleeding
Increased risk of major bleeding
Aspirin / clopidogrel
Increased risk of major bleeding
Other antiplatelet agents
(e.g. Ticlodipine / prasugrel
/ ticagrelor)
NSAIDs
Likely increased risk of major bleeding
SSRIs (Selective serotonin reuptake inhibitors) / SNRIs
(selective norepinephrine
re-uptake inhibitors)
Concomitant use is not recommended
Increased risk of bleeding
May increase risk of GI bleeding
Concomitant use is not recommended
Avoid concomitant use
Use with caution
Use with caution
Combination contraindicated, except when
switching therapy to or from rivaroxaban (as
advised by A/C clinic / haemostasis SpR or
Consultant), or when unfractionated heparin
is given at doses necessary to maintain a
patent central venous or arterial catheter
Interaction not specifically mentioned in the
SPC, but advise avoid combination – d/w
haemostasis consultant should the situation
arise
Stop antiplatelet agents UNLESS another
specific clinical indication (other than AF)
exists. If concomitant therapy unavoidable
(and a careful risk-benefit assessment has
been made) then review the most appropriate
drug combination. PPI cover advised. Close
clinical monitoring required
Interaction not specifically mentioned in SPC;
combination not recommended
Avoid if at all possible. Careful risk-benefit
assessment required. If benefit of chronic
NSAID outweighs risk of bleeding, then PPI
cover advised. Close clinical monitoring
required
Interaction not specifically mentioned in the
SPC - use with caution. If other risk factors for
bleeding present, then consider GI cover;
close clinical monitoring required
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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9.0 Converting from VKA or low molecular weight heparin (LMWH) to rivaroxaban
Secondary care anticoagulation clinics will switch patients to rivaroxaban. GPs should not do this please.
3
Recommendations from the SPC are outlined below for information only:
Vitamin K Antagonist (VKA e.g. warfarin) to rivaroxaban
• Stop warfarin
3
• Start rivaroxaban when the INR is < 3.0 (NB: a different recommendation exists for VTE patients – refer to SPC )
LMWH to rivaroxaban i.e. patients on longterm therapeutic dose LMWH being switched to rivaroxaban.
(For anticoagulation around elective procedures, refer to section 12.0)
• Stop LMWH
• Start rivaroxaban 0 to 2 hours before the time of the next scheduled administration of SC LMWH
10.0 Adverse effects
•
•
•
•
•
•
As would be expected, rivaroxaban increases the risk of bleeding during treatment and patients should be
monitored for signs of bleeding/anaemia
Patients should be advised to seek medical advice if persistent or frequent episodes of bleeding occur; he/she
should seek urgent medical attention if severe bleeding is experienced. Note that there is currently no
pharmacological antidote to rivaroxaban.
In case of intolerance to rivaroxaban, patients should be instructed to consult their doctor as soon as possible so
that treatment can be reviewed and alternative options considered. Discussion with the local haematology
consultant / local anticoagulant clinic is advised
3
Common side effects (≥ 1/100 to < 1/10) as listed in the SPC include: dyspepsia, diarrhoea, nausea, vomiting,
hypotension, oedema and dizziness (not exhaustive - refer to the current BNF or SPC for further information)
From various phase 3 studies (different indications), mucosal bleeding (e.g. epistaxis, gingival, gastrointestinal,
genitourinary) and anaemia were seen more frequently during long term rivaroxaban treatment compared with
3
warfarin/VKA .
2
Specifically from ROCKET-AF :
o Rivaroxaban 20mg OD (15mg OD for CrCL 30-49mL/min), resulted in similar rates of major bleeding
compared to warfarin (3.6% vs 3.4%, p=0.58). The rate of critical organ bleeding was less with rivaroxaban
(0.8% vs 1.2%, p= 0.007), as were both the risk of intracranial haemorrhage (0.5% vs 0.7%, p = 0.02) and the
risk of fatal bleeding (0.2% vs 0.5% p=0.003).
o Decreases in haemoglobin levels of > 2 g/dL and major bleeding requiring transfusions were more common
among rivaroxaban patients, as was major bleeding from a gastrointestinal site (3.2% vs 2.2%, p <0.001).
o Epistaxis (10.1% vs 8.6%) and haematuria (4.2% vs 3.4%) occurred more frequently with rivaroxaban than
with warfarin (p< 0.05). (All stats quoted as event rate no./100 patient-yr)
IMPORTANT: Long-term safety/tolerability is not yet known. These ‘black triangle’ drugs and are being
intensively monitored. All suspected adverse drug reactions should be reported to the MHRA either using
the BNF ‘yellow card’ system or online at www.mhra.gov.uk/yellowcard
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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11.0 Recommended monitoring for rivaroxaban for primary care
Monitoring parameter
FBC, U&Es, LFTs, blood pressure and HAS-BLED score
Comment
Prior to referral to local A/C clinic.
(NB: these will be reviewed by the anticoagulation team)
Thereafter, as clinically indicated (minimum annually) but
see below for renal function.
Review if LFTs > 2 x upper limit of normal, platelets <100,
or uncontrolled hypertension
Renal function: once initiated, monitor as suggested in
adjacent column (NB: patients > 75 years may require
more frequent monitoring)
Reassess when decline suspected (e.g. hypovolaemia,
dehydration, certain co-medications etc.)
est. CrCL (C&G formula)
CrCL > 80mL/min
Suggested monitoring frequency
Annually
CrCL 50-79mL/min
CrCL 30-49mL/min
6-12 monthly
Close monitoring at discretion of
clinician (minimum 3 monthly)*
Close monitoring at discretion of
clinician (minimum 3 monthly)*
Do not use
CrCL 15-29mL/min
CrCL < 15mL/min
*dose reduction required for AF: refer to Xarelto SPC
Ongoing clinical surveillance, including:
1) Checking to avoid accidental NOAC stoppage
2) Checking for possible interactions with new medicines
3) Reinforcing the importance of carrying the
rivaroxaban ‘patient alert’ card at all times
Annual clinical review to:
1) Assess the continuing need for antithrombotic therapy
2) Asses the risk vs. benefit of anticoagulation i.e.
o History of stroke / TIA
o Bleeding risk using the HAS-BLED score,
including any bleeding episodes.
NB: Routine anticoagulation monitoring is NOT required
3
Throughout the treatment period and in line with general
anticoagulation practice
Consider whether current dose remains optimal or
whether dose reduction / referral back to specialist is
required.
Standard coagulation parameters (e.g. Activated partial
thromboplastin time (APTT) and prothrombin time (PT), may be
affected to varying degrees, but do not provide quantitative
information on the intensity of anticoagulation effect.
12.0 Management around elective invasive procedures / surgical interventions
•
•
Note that clinical experience with rivaroxaban and bridging around surgical procedures is limited
The management of anticoagulation around elective procedures should be in accordance with the appropriate
local secondary care management guidelines - liaise with the local haematologist/anticoagulation clinic
In general, steps to follow include:
• Several weeks pre-op, inform surgeon / other clinician undertaking procedure that patient is taking rivaroxaban
for AF. Additional useful information from primary care includes CHA2DS2VASc score and patient’s bleeding
history.
•
Rivaroxaban will need to be stopped at least 24 hours prior to the intervention, depending on renal function /
proposed intervention (secondary care to advise). The T1/2 is 5-9 hours in young healthy individuals, increasing
3
to 11-13hours in the elderly .
•
Post procedure and depending on risks of bleeding vs thrombosis, secondary care may advise initial post-op
management with thromboprophylactic doses of LMWH, escalating to therapeutic dose LWMH (or rivaroxaban
– see below) when surgeons happy and as per local bridging guidelines.
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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•
Rivaroxaban to restart when there are no concerns re surgical haemostasis, patient is eating and drinking and
reinitiation of therapeutic anticoagulation is appropriate (peak levels usually reached approx 2-4hours post
3
dose with steady state reached within approx 2-3 days with normal renal function).
How to switch from LMWH to rivaroxaban (only in the context of management of anticoagulation around
elective procedures). For the routine switch from longterm LMWH to new rivaroxaban, refer to section 9.0
o
o
Stop LMWH
Start rivaroxaban approx. 12hrs after last dose of prophylactic LMWH, 12hrs after last dose of
therapeutic LMWH if in divided BD dose (e.g. dalteparin 100 units/kg SC BD) or 24hrs after last
therapeutic once daily LMWH dose (e.g. dalteparin 200units/kg SC OD).
•
For minor procedures including dental procedures under LA/GA and at LOW RISK of bleeding: restart
therapeutic dose rivaroxaban (preadmission dose) 6hrs post procedure, then 24hrly thereafter. This assumes
surgical haemostasis is secured, oral absorption is assured and immediate therapeutic A/C is safe to resume.
Peak levels reached 2-4 hrs post dose. Note: If there are concerns re therapeutic anticoagulation, consider
prophylactic dose LMWH and d/w local haematologist.
•
For urgent acute interventions: contact local haematologist for advice.
13.0 Additional NCL information to support this document
NCL Joint Formulary Committee website – NOAC - http://ncl-jfc.org.uk/noac-prescribing-guides.html
• NCL position statement on the use of NOAC for the prevention of stroke and systemic embolism in patients
diagnosed with non-valvular atrial fibrillation at increased risk of stroke (AF)
• NCL Summary treatment pathway for Anticoagulation and AF
• NOAC referral proforma
• GP NOAC notification and transfer of care forms
• Guidelines for bleeding (rivaroxaban) - trusts to write local guidelines
14.0 Appendices
•
•
•
•
Appendix 1: Summary treatment pathway: anticoagulation for the prevention of stroke and systemic embolism
in non-valvular AF
Appendix 2: Risk assessment: CHA2DS2-VASc and HAS-BLED scoring systems (AF patients)
Appendix 3: Cockcroft & Gault (C&G)formula (to estimate CrCL)
Appendix 4: Rivaroxaban counselling checklist
15.0 References
1.
2.
3.
3.
4.
5.
6.
7.
8.
NICE technology appraisal guidance 256. Rivaroxaban for the prevention of stroke and systemic embolism in people with
atrial fibrillation. May 2012
Patel MR et al. and the ROCKET AF Steering Committee for the ROCKET AF Investigators. Rivaroxaban versus warfarin in
nonvalvular atrial fibrillation (and supplementary appendix). N Engl J Med 2011; 365: 883-91.
(a) MHRA Drug Safety Update 2013; Vol 7 (3). New oral anticoagulants, apixaban (Elquis▼), dabigatran (Pradaxa▼) and
rivaroxaban (Xarelto▼): risk of serious haemorrhage – clarified contraindications apply to all three medicines
Summary of product Characteristics. Xarelto 20mg & 15mg film coated tablets. Bayer Pharma AG. Date of first
authorisation/renewal of authorisation: 30/09/08. Date of revision June 2013. Available from: www.emc.medicines.org.uk
Camm AJ et al. 2012 focussed update of the ESC guidelines for the management of atrial fibrillation. Eur. Heart J. 2012. 33:
2719-2747
Lip et al. Refining clinical risk stratification for predicting stroke and thromboembolism in Atrial Fibrillation using a novel risk
factor-based approach. The Euro Heart Survey on Atrial Fibrillation. Chest 2010; 137(2):263–272
Pisters R et al. A novel user-friendly score (HAS-BLED) to assess 1 year risk of major bleeding in patients with AF: The Euro
heart survey. Chest 2010; 138: 1093-1100
Cockcroft DW and Gault H. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16: 31-41.
Basic Clinical Pharmacokinetics 4th edition; 2004. Michael Winter. Editor: DB Troy. Lippincott Williams& Wilkins, Philadelphia
Document written on behalf of NCL by:
•
Ms Carolyn Gates, Lead pharmacist, Thrombosis & Anticoagulation, UCLH NHS Foundation Trust
•
Dr Hannah Cohen, Consultant haematologist, UCLH NHS Foundation Trust
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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Appendix 1: Summary treatment pathway: Anticoagulation for the prevention of
stroke and systemic embolism in non-valvular atrial fibrillation (AF)
ALL referrers (primary & secondary care)
Risk assess for stroke prevention
(CHA2DS2VASc) and bleeding (HASBLED)
Warfarin
Complete warfarin
referral proforma as
per local procedures
Monitoring and
follow up by Local AC
services
NOAC
Decision made to anticoagulate
Referrer to indicate Warfarin or NOAC
(taking into consideration NCL NOAC criteria*)
Warfarin remains the current standard
of treatment across NCL. Note that all referral
proformas will be reviewed by the
haematologist to ensure appropriateness;
referrer may be contacted
Complete NOAC
referral proforma as
per local procedures
Rivaroxaban is preferred
NCL agent. Dabigatran /
apixaban can be used
where clinically justified
NCL NOAC criteria* summary (refer to points 1-5 for further explanation)
Existing AC patients
fulfilling NCL NOAC
criteria: Refer back to
AC clinic for review
NCL NOAC criteria*
1. Alopecia, rash etc with no other
cause
2. Significant technical difficulties
with INR monitoring or accessing
the AC clinic; housebound
patients, where INR monitoring
or clinic attendance would
adversely affect quality of life /
raise safety concerns. Note:
consider alternatives such as
community AC services,
domiciliary monitoring, review of
medicines management and selftesting
3. Proportion of patient-time in
range of < 65% once AC
established (not due to wilful
non-compliance); INR ≥ 8.0 on 1
occasion or INR > 5.0 on 2
occasions over a period of 6 mths
(once A/C established), with a
high likelihood of recurrence; VKA
supply issues (e.g. phenindione)
4. Unlicensed indication, short term
use only of dabigatran by
individual centres. If AC required
long term post DCCV (regardless
of rhythm), then switch to
warfarin unless NCL criteria
applicable
5. Locally designated consultants in
Stroke medicine, thrombosis or
cardiology
•
•
•
•
•
1
Documented warfarin/VKA allergy or specific intolerance
2
Unable to comply with warfarin/VKA specific monitoring requirements
3
Unable to achieve satisfactory INR control
4
Awaiting DCCV or urgent AF ablation (within 4 weeks)
5
Specific clinical indication as advised by locally designated consultants
Non-compliance is NOT a reason to switch to NOAC
Primary care
Secondary care
Secondary care
Complete NOAC
referral proforma
• Routine outpatients or inpatients: letter
to GP requesting
referral to local
AC clinic
• Non NCL
patient: refer
back to GP for
local pathway
• Urgent outpatients or inpatients: direct
referral to
patient’s local
AC clinic for OP
initiation;
complete NOAC
referral
proforma
• Non NCL
Secondary care anticoagulation (AC) clinic
• Select appropriate NOAC and dose
• Counsel and initiate treatment
• Review for tolerance and adherence at one month; issue second
month’s prescription
• Transfer care to GP with appropriate paperwork; GP to take over from
start of month 3
NB: referral pathways may be subject to local variation
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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Appendix 2: Risk assessment with CHA2DS2-VASC and HAS-BLED scoring systems (AF patients)
CHA2DS2-VASC score for AF patients
5
Compared to the older CHADS2 score, the CHA2DS2-VASc score is able to discriminate those patients who are truly at
‘low risk’ from AF (i.e. CHA2DS2-VASc = 0, which is essentially patients <65years with lone AF and no additional risk
factors). For these patients, no antithrombotic therapy is generally the preferred option.
Patients with one or more risk factors (i.e. CHA2DS2-VASc score of > 1, but excluding female sex), should be
considered for anticoagulation.
Risk Factor
C
Congestive heart failure / LV dysfunction < 40%
H
Hypertension
A2
Age > 75 years
D
Diabetes Mellitus
S2
Stroke / TIA/ Systemic embolism
V
Vascular disease (e.g. prior MI, peripheral artery
disease, aortic plaque)
A
Age 65-74 years
Sc
Sex category (i.e. female)
Maximum score
Score
1
1
2
1
2
1
1
1
9
CHA2DS2VASc
score
Adjusted
stroke rate
(%/year)
0
1
2
3
4
5
6
9
0%
1.3%
2.2%
3.2%
4.0%
6.7%
9.8%
15.2%
Ref 5
HAS-BLED score (validated for AF patients)
The risk of bleeding should be assessed before starting anticoagulation and at least annually (with the annual review
6
of AF). The HAS-BLED scoring system has been validated as a practical tool that can be used to assess the bleeding
risk in patients with AF and can therefore support the clinical decision making process regarding antithrombotic
therapy.
Risk Factor
H
Hypertension (systolic BP > 160mmHg)
A
Abnormal renal and liver function (1 point each)
• Abnormal renal function: chronic dialysis, renal
transplantation or serum Cr > 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
AST/ALT/ALP > 3x upper limit of normal)
S
Stroke
B
Bleeding (previous bleeding history and/or
predisposition to bleeding e.g. bleeding diathesis,
anaemia etc)
L
Labile INR’s (unstable/high INR’s or poor time in
therapeutic range e.g. < 60%)
E
Elderly (e.g. age > 65years)
D
Drugs (i.e. medications) or alcohol (1 point each)
e.g. concomitant use of antiplatelets, NSAIDs, or alcohol
abuse
Maximum score
Score
1
1 or 2
1
1
HASBLED
score
Major bleed s
per 100 pt
years
0
1
2
3
4
5
6-9
1.13
1.02
1.88
3.74
8.70
12.50
Insufficient
data
Ref 6
1
1
1 or 2
9
A HAS-BLED score of > 3 indicates that the patient is at high risk of bleeding and some caution and regular review of
the patient is required following the initiation of antithrombotic therapy. Efforts should be made to correct
potentially reversible risk factors for bleeding. A high HAS-BLED score per se, should not be used to exclude patients
from anticoagulant therapy.
References
5. Lip et al. Chest 2010; 137(2):263–272
6. Pisters R et al. Chest 2010; 138: 1093-1100
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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Appendix 3: Cockcroft & Gault (C&G) formula
•
•
•
The creatinine clearance (CrCL mL/min) as estimated using the C&G formula, is the parameter most often
used in clinical trials and by drug manufacturers to determine dose adjustments for renally eliminated
medications.
There are inherent inaccuracies however when the C&G formula is used to estimate CrCL in certain patient
populations i.e. the very elderly, those with low body weight, very high body weight, reduced muscle mass
or with poor nutritional status.
Caution is therefore advised when using C&G to estimate renal function for these patient groups, and
dosing advice should be sought as appropriate from the local anticoagulation teams.
Cockcroft and Gault formula7 (C&G) in μmol/L
Estimated CrCL (mL/min) = (140 – age) x weight*(kg) [x 1.23 if male] or [x 1.04 if female]
serum creatinine (µmol/L)
CrCl is creatinine clearance (mL/min) corrected for body weight
*Calculate weight as follows (steps 1 and 2)
8
1. Estimate ideal body weight (IBW) kg
• Males:
IBW = 50 kg + 2.3 kg for each inch over 5 feet
• Females:
IBW = 45.5 kg + 2.3 kg for each inch over 5 feet
2. Compare IBW to patient’s total body weight (TBW) kg (as measured using weighing scales)
a.
If TBW is 120% or less of the IBW then use TBW in the C&G formula
b.
If TBW is more than 120% of the IBW, then calculate the adjusted body
8
weight (ABW) kg, and use ABW in the C&G formula
Adjusted body weight (ABW) = IBW + 0.4 x (TBW-IBW)
References
7. Cockcroft DW and Gault H. Nephron 1976;16: 31-41.
8. Basic Clinical Pharmacokinetics 4th edition; 2004. Michael Winter. Editor: DB Troy. Lippincott Williams& Wilkins, Philadelphia
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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Trust logo
Hospital Number:
Patient Name:
Appendix 4: Rivaroxaban counselling record (file/scan in medical notes) Date of Birth:
This patient has been counselled on the following areas of rivaroxaban therapy, by a doctor, pharmacist
or Anticoagulant clinical nurse specialist in accordance with the guidance overleaf
Counselling point
1.
Indication for rivaroxaban
2.
Alternative anticoagulation options
3.
Benefits and disadvantages of rivaroxaban compared to warfarin
4.
Expected duration of therapy (specify if known)
5.
Basic mode of action
6.
Dose
7.
How to take:
Signature
Comments
• Must be taken with food to improve amount absorbed
• Aim to take at the same time of day
8.
What to do if a dose is missed:
• If taking 20mg (or 15mg) OD: Take one tablet as soon as it is remembered and
then take the next tablet the following day (and continue). Do not take two
tablets in one day to make up for the missed dose
• If taking 15mg BD (e.g. acute VTE): take one tablet as soon as remembered.
Do not take more than two 15mg tabs in a single day (but can take 2 tablets at
the same time to make a total of 30mg on one day). Continue with one 15mg
tablet BD on the next day
Extra dose taken accidentally? Contact doctor or healthcare team
9.
Importance of compliance:
10.
• Fairly rapid fall in drug levels (and therefore loss of efficacy) if poorly compliant
• Ways of remembering to take the tablets e.g. calendar
Monitoring (e.g. renal function) and how often
11.
Side effects of rivaroxaban (and what to do if experienced)
• Signs/symptoms of excess anticoagulation: bleeding or bruising
• Recurrence of thromboembolism (if relevant)
12.
Potential for drug interactions: paracetamol is the preferred analgesic
13.
Alcohol intake
14.
Contraception, pregnancy, and hormone replacement therapy (if relevant)
15.
Surgical procedures (inc. day surgery /dental treatment & hospital admission)
16.
Hobbies and leisure activities (including flying)
17.
Injections (including immunisation) – inform nurse that pt is anticoagulated
18.
How to obtain further supplies of rivaroxaban
19.
Who to contact for advice/ further information
The patient must receive a rivaroxaban patient information booklet and patient alert card.
The alert card MUST be fully completed and the patient advised to keep it with him/her at all times
Counselled by: (Sign & print name): ............................................................................ Bleep / Extn:…………………..…….Date: ……………………..
Patient’s signature: …………….……………………………….……………................................…..…………………………………………..…..… Date:………………………..
Rivaroxaban – stroke and systemic embolism prevention in non-valvular AF; practical guidance for NCL. 18.10.13
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Rivaroxaban Counselling Guidelines
Provide patient with the Xarelto patient information booklet and go through it with him/her, ensuring that the points below
are covered. Complete the patient alert card -if unsure of any sections, check with the doctor. The patient alert card should
be kept with the patient at all times.
1. Indication: licensed for: (a) Prevention of stroke and systemic embolism in adult patients with non-valvular AF with
additional risk factors (b) Treatment of DVT/PE (c) prevention of recurrent DVT/PE in adults.
2. Alternative anticoagulants: warfarin (and other oral vitamin K antagonists), low molecular weight heparin (e.g. dalteparin),
other newer oral anticoagulants (e.g. dabigatran, apixaban).
• For AF, rivaroxaban was shown to be as effective as warfarin for the prevention of stroke and systemic embolism, with a
similar rate of major bleeding, but with a lower risk of intracranial haemorrhage. There was a higher rate of GI bleeding,
epistaxis and haematuria with rivaroxaban compared to warfarin.
• For the treatment of acute DVT /PE: rivaroxaban was shown to be as effective as warfarin (plus initial SC enoxaparin) in
preventing symptomatic recurrent VTE, with a similar (DVT trial) or lower (PE trial) rate of major bleeding.
3. Advantages (vs. warfarin): fixed dose, no routine coagulation monitoring, more stable anticoagulation control, lower risk of
intracranial haemorrhage (AF pts); Disadvantages (vs. warfarin): unable to routinely monitor coagulation, not as easy to
reverse compared to warfarin (no formal drug antidote), limited long-term data
4. Expected duration of therapy – if unsure, check with Doctor.
5. Basic mode of action: belongs to a group of medicines called antithrombotic agents; blocks a blood clotting factor (factor
Xa) and thus reduces the tendency of the blood to form clots.
6. Dose: Non-valvular AF: 20mg OD*; Acute VTE: 15mg BD for 3 wks, then 20mg OD*. *review dose if CrCL 15 - 49mL/min see SPC
7. How to take: For rivaroxaban doses > 15mg, the dose must be taken with food to improve absorption; aim to take at the
same time each day.
9. Compliance: Rivaroxaban has a shorter half-life than warfarin and efficacy more likely to be affected if poorly compliant.
10. Monitoring: the dose will need to be reduced / stopped if renal function deteriorates. Frequency of monitoring depends
on the level of renal function and may vary from minimum 3monthly to 6-12monthly. Also, FBC and LFTs, minimum annually
11. Side effects of rivaroxaban (and what to do if experienced)
• For VTE patients: recurrence of thromboembolism: contact doctor if original symptoms recur
• Bloody stools or urine, nose bleeds (lasting for > 5-10mins or if pt does not usually suffer from nose bleeds), blood shot eye,
coughing or vomiting blood, severe or spontaneous bruising, unusual headaches, excessive vaginal bleeding, cuts that take
longer than 5 minutes to stop bleeding. Seek medical attention.
• If involved in major trauma, suffer a significant blow to the head or are unable to stop bleeding – seek immediate medical
attention
• Any other side-effects: discuss with GP or anticoagulant clinic
12. Potential for drug interactions: may be affected by some medicines / herbal preparations (see SPC for Xarelto).
Therefore:
• Patient should always let doctor/dentist/pharmacist know that s/he is on rivaroxaban
• Not to take aspirin unless prescribed by doctor, as increased risk of bleeding ( - combination to be reviewed; will need GI
protection). Avoid OTC painkillers such as ibuprofen, aspirin, diclofenac etc (paracetamol is preferred)
• If admitted to hospital, to inform staff that s/he is taking a new oral anticoagulant (to avoid duplication of therapy with
standard VTE thromboprophylaxis).
13. Alcohol intake: alcohol is not expected to affect rivaroxaban levels per se. However, excess alcohol consumption and
binge drinking are generally not advised for anticoagulated patients, due to the risks of alcohol associated acute injuries (e.g.
head injuries) and chronic liver disease (which may affect coagulation).
14. Contraception, pregnancy, and hormone replacement therapy (if relevant): Women should not become pregnant nor
breast feed whilst taking rivaroxaban. Reliable contraception is required. If patient is currently taking HRT/OCP then
discussions are required regarding stopping or appropriate choice (generally avoid oestrogen-containing preparations;
progesterone only ones are preferred). For women taking rivaroxaban who may be pregnant, discussion with the Haemostasis
SpR is required ASAP so that pt can be seen by a haematologist / obstetrician for discussion re potential implications. If
planning to become pregnant, then pt should discuss with GP for onward referral to a haematologist.
15. Surgical procedures (including dental treatment) and hospital admission: patient must inform healthcare professional that
s/he is taking rivaroxaban especially as (1) patient will need management of anticoagulation around procedures and (2) VTE
thromboprophylaxis (e.g. LMWH) is often prescribed on admission to hospital.
16. Hobbies and leisure activities: avoid contact sports (e.g. boxing) and other higher risk sports (e.g. skiing and horse riding),
as increased risk of bruising/bleeding. Inform Dr/anticoagulant clinic if flying in the near future.
18. Obtain further supplies of rivaroxaban from the hospital (or GP once care transferred). Not to run out of supplies,
especially when on holiday.
19. Further advice/info from local A/C clinic, GP, Hospital pharmacy medicines info dept or in an emergency, A&E dept
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