Transcript Use of direct oral anticoagulants

Use of direct oral
anticoagulants (DOACs) in
primary care
Julia Anderson
Consultant Haematologist
Royal Infirmary of Edinburgh
The ideal anticoagulant
• PREDICTABLE PHARMACOKINETICS and ANTICOAGULANT PROFILE
• FEW DRUG AND FOOD INTERACTIONS
• ORAL ADMINISTRATION
• NO NEED FOR MONITORING
• SIMPLE DOSING
• SHORT HALF-LIFE
• ANTIDOTE
New Direct Anticoagulants
ORAL
“DOACS”
PARENTERAL
TF/VIIa
TTP889
TFPI (tifacogin)
X
Rivaroxaban
Apixaban
Edoxaban
LY517717
YM150
DU-176b
TAK 442
Betrixaban
IX
VIIIa
APC (drotrecogin alfa)
sTM (ART-123)
IXa
Va
Xa
AT
II
Dabigatran
DX-9065a
Otamixaban
thrombin
Fibrinogen
Adapted from Weitz & Bates, J Thromb Haemost 2007
Fondaparinux
Idraparinux
Idrabiotaparinux
Fibrin
CHARACTERISTICS OF THE DIRECT ORAL ANTICOAGULANTS
Drug
Dabigatran
Rivaroxaban Apixaban
Edoxaban
Warfarin
Time to maximum
effect
1.5-2h
2h
1-2h
5 days
Half-life
12-17h
5-9h
8-15h
9-10h
36-48h
Plasma protein
binding
35%
92-95%
87%
40-59%
99%
Renal elimination
80%
33%
25%
35-39%
0%
Interactions
P-gp
P-gp,
CYP3A4
P-gp,
CYP3A4
P-gp,
CYP3A4
CYP2C9 (S)
CYP1A2 (R)
Food effect
Absorption
delayed
Required for No
absorption
No
Dark green
vegetables
etc
S3-4h
The direct oral anticoagulants exert effect almost immediately
- rivaroxaban and apixaban do not need initial overlap with heparin or LMWH
No need for bridging anticoagulation with heparin pre-operatively in view of half-life
- Stop 1-2 days before elective surgery if renal function is normal
Adapted from Schulman J Int Med 2014; 275 1-11
Lothian Adult Formulary:
approved indications for apixaban
• Non-valvular Atrial Fibrillation:
Prophylaxis of stroke and systemic embolism when warfarin
is not appropriate
• Deep vein thrombosis (DVT) and Pulmonary Embolism
(PE):
Acute Treatment of DVT and PE
Prevention of recurrent DVT and PE
• Patients undergoing Cardioversion and RF ablation
requiring anticoagulant cover where continuing warfarin is
not appropriate
DOACs should NOT be prescribed for:
• Mechanical heart valves – lack of efficacy
• Antiphospholipid antibody syndrome- unclear efficacy in
pts with VTE, and NOT for patients with arterial thrombosis
• Thrombosis in unusual sites – including axillary vein
thrombosis, splanchnic vein thrombosis and cerebral vein
thrombosis and in hereditary thrombophilias – efficacy
uncertain
• Acute PE/DVT with large bulk thrombus (e.g. saddle PE,
phlegmasia caerulea dolens: use IV UFH)
• Thrombosis in cancer patients – use LMWH
Commencing apixaban therapy: check
• Is the indication approved by NHS Lothian
• Does the benefit of anticoagulation outweigh the bleed?
• Does the patient have hepatic disease with coagulopathy?
• Does the patient have impaired renal function?
• Is the patient prescribed concomitant interacting medicines?
eg CYP3A4 inhibitors or inducers triazole and imidazole antifungals [except fluconazole],
protease inhibitors (HIV antiviral drugs); rifampicin, phenytoin, carbamazepine, St John’s Wort
• Is the patient prescribed concomitant antiplatelets /
anticoagulants / NSAIDs – usually need d/c but if ACS or PCI
must check with cardiology
Apixaban Dosing Guidance
Non-valvular AF
∙ 5mg twice daily if eGFR ≥ 30ml/min
∙ Reduce to 2.5mg twice daily if 2 or more of:
- Patient ≥ 80 yrs
- Body weight ≤ 60 Kg
- Creatinine ≥ 133 micromol/L
∙ Reduce to 2.5mg twice daily if eGFR is 15-29 ml/min
∙ Apixaban is not recommended if eGFR < 15ml/min or
dialysed patients
Apixaban Dosing Guidance
DVT/PE
Initial dosing
• 10mg twice daily for 7 days
• Then 5mg twice daily (maximum 6 months at this
dose)
Ongoing therapy after 6 months
• 2.5mg twice daily
• Apixaban is not recommended if eGFR <30ml/min
or dialysed patients
• (No dose reduction for weight or age)
Patient Education/Counselling
• Counselling sheet for NHS Lothian proposed,
with tick boxes to indicate information has
been given to patient/guardian
• Signed and dated by counsellor and patient
• Explain indication for therapy
• Explain expected duration of therapy
• Explain dose
• Administration:
- Swallow whole with water (with or without food)
- Take roughly at the same time each day
- Advise that a missed dose will increase the risk of further
blood clots and that strict compliance is essential
• Missed dose:
- Up to 6 hrs later than scheduled dose - Take as soon as
remembered then continue with the twice daily dose
- More than 6hrs later than scheduled dose - Wait and take
the next scheduled dose
• Advise of potential drug interactions
• Check with pharmacist before buying Over-The-Counter
medicines, alternative medicines, herbal remedies
• Always tell the doctor, dentist or pharmacist that you take
apixaban
• Bleeding risk:
- Advise patient of bleeding risk and lack of reversal
- Seek immediate medical attention if significant bleeding
or head injury
- Avoid risks from falls/injury ; need to take care with
hobbies/leisure activities and avoid contact sports
- Advise on the dangers of excess alcohol (increased risk of
fall and bleed)
Pregnancy and breastfeeding
• Apixaban must not be prescribed
• There is a lack of safety evidence for apixaban during
pregnancy / breastfeeding
• If patient becomes pregnant while taking apixaban
immediately contact haematology consultant at RIE or
SJH to arrange switch to LMWH and further obstetric
advice (RefHelp guide)
• Reliable contraception required: referral pathway to
Chalmers clinic being developed
Patient Information Sheets & Alert Cards
• Supply appropriate patient information leaflet
and alert card (in Apixaban tablet box)
https://www.eliquis.co.uk/resourcesforyourpatients/patientinformation/
Switching anticoagulants
• Switch from LMWH to apixaban
• Start apixaban when next dose of LMWH would have
been due
• Switch from warfarin to apixaban
• Check INR
• When INR < 2.0 start apixaban
Peri-operative Management
Timing for last dose of anticoagulant
96hrs
Xa inhibitors
Dabigatran
High risk and renal
Creat cl 30-49ml/min
48hrs
24hrs
High risk and/or
renal
Low risk
High risk or renal
Low risk and no
renal
Minor Procedures: NHS Lothian policies
• Endoscopy: protocol in place, follows BSG
guidance: withhold DOAC 24 hours in advance of
procedure
• Dental procedures: SDCEP guidance
• Working Group to advise on implementation in NHS Lothian
• Advocates no discontinuation of DOACs
Reversal
• Antidote to factor Xa inhibitors (Andexanet alfa) under
evaluation in clinical trials (modified recombinant
human fXa “decoy” molecule, Portola Pharmaceuticals)
• Currently no way to reverse anti-Xa effect, but short
lived effect; standard resuscitation measures,
compression of bleeding point and correction of
acquired coagulopathy
• Antidote to Dabigatran evaluated in REVERSE-AD trial,
and approved by FDA and being considered for
approval by EMA: Idarucizumab (Praxbind®)
SUMMARY
2 exciting new classes of oral anticoagulants
• Clear Advantages yet there are Limitations
• Challenges :–
–
–
–
the education of medical and nursing staff to avoid pitfalls
the education of patients regarding compliance
the development of protocols regarding anticoagulant switches
introduction of systems to inform lab staff if a patient is taking a
DOAC
– the development of protocols for peri-operative management and
management of bleeding
– understanding bleeding risk in specific patient populations outwith
trials