Download New oral anticoagulants

New oral anticoagulants:
an update
Julian Holmes
H+T Pharmacist NUH
[email protected]
Problems with warfarin
Variable dose
 INR affected by diet, illness etc
 Drug interactions can be problematic
 Narrow therapeutic index
 BUT – its cheap!
 AND – the INR is a good measure of
compliance
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The clotting cascade
New agents
Ideally need:
 Once daily constant dose for all patients
 Predictable kinetics and anticoagulant
effect
 No problematic drug interactions
 Several new agents – dabigatran,
rivaroxaban and apixaban are most
advanced three
Dabigatran in AF
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RELY trial
Oral direct thrombin inhibitor
Half life 12-17 hours
No reversal agent
Contraindicated if CrCl<30ml/min
Substrate of efflux transporter P-glycoprotein so
levels affected by inducers (St Johns Wort) or
inhibitors (amiodarone, quinidine (C/I),
verapamil, clarithromycin) of this
Dabigatran in AF
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Mortality and haemorrhagic stroke rates
favoured dabigatran
Time in range ~64% for warfarin pts
Dabigatran slightly more effective than warfarin
at the higher dose
Higher MI and GI bleed rates with dabigatran
Drop out trial rate of ~10% with dyspepsia with
dabigatran
Now licensed in UK
NICE TA249 Mar 2012 – can be used as a
treatment option
Dabigatran in AF
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Dose is 150mg twice daily reduced to 110mg
twice daily if:
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Creatinine clearance 30-50ml/min
Over 80 years
Body weight <50kg
Increased bleeding risk
On verapamil
Patients with gastritis, oesophagitis or
gastoesophageal reflux
– Patients continuing to take aspirin to manage a
chronic condition
Why Xa inhibitors over TI?
Less complicated dosing regimen
 Reduced MI rate
 Less GI S/E
 MDS issue with dabigatran
 ?easier to reverse
 Dabigatran only licensed for AF and not
VTE treatment
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Rivaroxaban in AF
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Dose 20mg daily (15mg daily if CrCl 3049ml/min or HASBLED score over 3) in ROCKET
trial vs warfarin in 14,264 patients
Primary end point of stroke or systemic
embolism
Rates of primary outcome 1.7% per year
rivaroxaban and 2.2% per year warfarin
Bleeding rates 14.9% per rivaroxaban and
14.5% per year warfarin
Time in range for warfarin ~55%
Rivaroxaban in AF
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Intracranial and fatal bleeds favoured
rivaroxaban
Rivaroxaban non inferior to warfarin
C/I if - CrCl less than 30ml/min, active bleeding,
hepatic disease (Child’s Pugh B and C),
pregnancy and breast feeding
Adverse effects – anaemia, dizziness, headache,
epistaxis, GI s/e, haemorrhage
License application for Dec 2011 and NICE
appraisal May 2012
Rivaroxaban
Half life 7-11 hours
 Review use of agents affecting haemostasis (e.g.
NASIDS and anti platelets)
 Metabolised by CYP3A4 so interactions could be
problematic:
 Inducers – barbiturates, carbamazepine, phenytoin,
rifampicin, St Johns Wort – avoid use of strong inducers
 Inhibitors – clarithromycin, ciclosporine, danazol,
dlitiazem, erythromycin, fluconazole, fluoxetine,
fluvoxamine, indinavir, isoniazid, ritonavir, verapamil
 Avoid itraconazole, ketoconazole, voriconazole
and protease inhibitors
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Rivaroxaban in DVT (instead of
warfarin/enoxaparin)
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Patients must have a recommendation from a Haematology
specialist dose is 15mg BD for 3 weeks then 20mg daily
Allergy to warfarin
Unstable INR control
Intravenous drug users
Liver disease (N.B. All anticoagulants are contraindicated in established liver
cirrhosis including rivaroxaban)
Anticoagulation in malignancy
– In this patient group LMWH’s are first line, warfarin and rivaroxaban should only
be used if LMWH’s are contraindicated
– Newly diagnosed patients with active malignancy should not be warfarinised until
their treatment plan is agreed as control is often very unstable in these patients.
– Patients with chronic malignant conditions eg. prostate cancer may be suitable
for warfarin, but treatment should be reviewed by the specialist team if liver
metastases are present.
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Unable to comply with variable dosing (e.g dementia but with no support in
community)
Rivaroxaban for SPAF new pts
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Patients must fit the criteria in the Nottinghamshire
guidance (see http://www.nottsapc.nhs.uk) and have a
recommendation from a secondary care Consultant
Haematologist, Consultant in Stroke Medicine , or
Consultant Cardiologist. Excluded patient groups are those
with significant valvular disease and patients suitable for
cardioversion
Patients requiring domiciliary phlebotomy
Known unpredictable alcohol excess (N.B. All anticoagulants are
contraindicated in established liver cirrhosis including rivaroxaban)
Unable to comply with variable dosing schedule
Contraindications to warfarin – N.B. many contraindications for
warfarin will be contraindications to anticoagulation in general, and
thus are likely to be contraindications for rivaroxaban also
Rivaroxaban switch in pts on
warfarin
Patients must fit the criteria in the
Nottinghamshire guidance (see
http://www.nottsapc.nhs.uk) and have a
recommendation from a secondary care
Consultant Haematologist, Consultant in Stroke
Medicine, or Consultant Cardiologist. Excluded
patient groups are those with significant valvular
disease and patients suitable for cardioversion
 TTR<60% after 4 months of VKA in presence of
compliance
 Intolerant of VKA (e.g. side effects etc)
 INR>8 without any strong cause (e.g. interacting meds)
 History of significant bleed associated with poor warfarin
control
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Rivaroxaban
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Classed as amber drug for DVT and AF
Secondary care supply first month then
continues in primary care
Rebate scheme available
Can refer pts to NUH anticoag for counselling etc
(as per warfarin)
No INR’s needed – monitor U+E’s according to
baseline renal function – see APC guideline
Rivaroxaban and elective surgery
Stop rivaroxaban at least 24 hours before
intervention. If procedure cannot be delayed
until at least 24 hours post dose, the increased
risk of bleeding should be assessed against the
urgency of the intervention. This should be
discussed with a haematologist.
 Rivaroxaban should be re-started post procedure
when risk of bleeding is judged to be low
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Rivaroxaban and emergency
surgery/haemorrhage
No reversal agent
 Can use charcoal if ingested within 1 hr
 Emergency surgery – measure INR
(neoplastin) or Xa level – if low proceed if
not delay or give octaplex
 Haemorrhage – as above and use
haemorrhage control
measures/tranexamic acid/octaplex
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Monitoring rivaroxaban
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Rivaroxaban does not routinely require monitoring of
therapeutic response (unlike warfarin). However, if a
patient has an episode of bleeding or requires an
invasive procedure, measurement of an anticoagulant
effect may be advantageous.
A standard clotting screen has not been validated for
assessing the degree of anticoagulation in a patient
taking Rivaroxaban and should not be used for this
purpose
A prothrombin time using a sensitive reagent such as
neoplastin plus or a specific anti Xa can be used to
measure the effect only after discussion with a
haematologist.
Effect of NOAC on clotting screens
Dabigatran, rivaroxaban and apixaban are new
oral anticoagulants that are alternatives to
coumarins (e.g. warfarin) in selected groups of
patients for certain indications. All drugs
accumulate in renal impairment.
 A standard clotting screen has not been
validated for assessing the degree of
anticoagulation in a patient taking these agents
and should not be used for this purpose. Consult
haematology for advice
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Daily costs
Dabigatran and rivaroxaban – community
~£2.60, hospital ~£1.60
 Warfarin - (+costs of drug, INR,
monitoring, dosing etc) approx £0.67-0.83
daily
 Apixaban likely to be similar other new
agents
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Ongoing trials
Rivaroxaban in DVT/PE licensed - as effective as
warfarin and NICE TA – dose is 15mg BD for 3
weeks and then 20mg daily
 Dabigatran now C/I in MHV after trial halted
 Apixaban (10mg BD for 5 days then 5mg BD for
6 months then 2.5mg BD) and Dabigatran
(150mg BD after 5 days of LMWH) now
approved for DVT/PE
 Cardioversion trial riva vs warfarin
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Apixaban
in AF
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New oral Xa inhibitor
Behind dabigatran and rivaroxaban in
development
More effective than aspirin in stroke reduction
C/I if CrCl less than 25ml/min
ARISTOTLE trial – apixaban 5mg twice daily
(reduced to 2.5mg BD if any 2 of 3 of: >80yrs,
<60kg, Cr>133) vs warfarin in 18, 201 patients
Primary endpoint of stroke and systemic
embolism
Apixaban in AF
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Warfarin time in range 62%
Rates of primary outcome 1.27% per year
apixaban and 1.6% per year warfarin –
statistically significant
Major bleeds 2.13% per year apixaban and
3.09% warfarin
Apixaban superior for stroke prevention and
causes less bleeding
Drug interactions as per riva avoid strong
inhibitors of CYP3A4 or p-gp
But for all new meds
Higher costs
 How do we reverse if patient is actively
bleeding and/or needs emergency surgery
(both companies recommend rVIIa/PCC –
no real in vivo data)?
 Difficult to measure level of
anticoagulation (dabigatran ECT/TT,
rivaroxaban PT) which may vary according
to RF
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But for all new meds
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How do we measure compliance with new agents?
(given data suggests approx 43% average patient
compliance with new meds – NUH coag service has
approx 70% of pts in therapeutic range)
Peri-operative and emergency surgery issues
(cardioversion and emergency surgery) – new agents
have shorter half lives so may be able to stop day before
pre op
Pts will need to carry alert cards and be counselled
(register pts in DAWN) by coag – need to be referred
Both C/I for AF treatment if CrCl<30ml/min – what do
we do if AKI?
Will need to go back onto warfarin if do not tolerate new
agents for AF
Current situation
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Only using rivaroxaban in selected patients (~400) and those unable
to tolerate warfarin – DVT and AF
Apixaban now has NICE TA and better data for AF – for use in
selected patients as above only by cardiology/stroke
All NOAC C/I in MHV
May decide to use riva in DVT and PE if pts on for up to 6-12
months – but ?if long term
Apixaban (10mg BD for 5 days then 5mg BD for 6 months then
2.5mg BD) and Dabigatran (150mg BD after 5 days of LMWH) now
approved for DVT/PE
Rivaroxaban vs warfarin in cardioversion
NOAC to amber 3 shortly
What do we need to do?
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Check pt has had correct bloods (U+E/LFT/clotting/FBC)
pre starting and 3 weeks after then according to
guidelines
(http://www.nottsapc.nhs.uk/attachments/article/3/APC
%20statement%20re%20NICE%20CG180%20%20Atrial
%20fibrillation.pdf
Check dose ok according to pts renal function
Pt information given and alert card
Counselling/DVD – side effects, missed doses,
procedures etc
Check interacting meds (antiplatelets)
Questions?