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DOAC – the story so far . . . Dr GM Benson
Director NI Haemophilia and Thrombosis Centre
BHSCT
A rose by any other name . .
Recommendation on the nomenclature for
oral anticoagulants: communication from the
SSC of the ISTH
The term NOAC has been used the longest,
and, recently, some have argued for use of the
term ‘non-VKA oral antagonists’ (NOACs), to
take advantage of the commonly used
abbreviation without using the terms novel
and new. However, identifying a class of drugs
by what they are not is scientifically
unappealing. Perhaps more importantly, there
is at least one reported account where the
term NOAC written in the medical record was
interpreted as meaning ‘No AntiCoagulation,’
potentially resulting in the patient not
receiving the critical therapy that was
intended
DOAC, 58.4%; TSOAC, 49.4%;
and NOAC, 39.0%.
TSOAC (target-specific oral anticoagulant), ODI (oral direct
inhibitor), and SODA (specific oral direct anticoagulant)
CHA2DS2-VASc scoring
for AF Eur Heart J (2013) doi:
10.1093/eurheartj/eht291
Risk factors
Score
Congestive Heart Failure +1
Hypertension +1
Age > 75 years +2
Diabetes Mellitus +1
Stroke/ TIA/TE +2
Vascular Disease +1
Age 65-74 years +1
Sex Category (female) +1
HAS-BLED score in AF
Eur Heart J (2013) doi: 10.1093/eurheartj/eht291
Risk factors
Score
Hypertension +1
Abnormal liver function +1
Abnormal renal function +1
Previous Stroke +1
Prior Major Bleeding or
Predisposition
+1
Labile INR (<60% of time in
therapeutic range)
+1
Age >65 years (Elderly) +1
Drugs Predisposing to Bleeding +1
Alcohol use (>8 drinks/week) +1
Journal of Thrombosis
and Haemostasis
Real-world variability in dabigatran levels in patients
with atrial fibrillation. Volume 13, Issue 6, June 2015, J.
Douxfils,
Bleeding risk in ‘real world’ patients with atrial
fibrillation: comparison of two established bleeding
prediction schemes in a nationwide cohort. Volume 9,
Issue 8, August 2011,J. B. OLESEN
Dabigatran adherence in atrial fibrillation patients
during the first year after diagnosis: a nationwide
cohort study. Volume 13, Issue 4, April 2015, A. Gorst-
Rasmussen,
Adherence to anticoagulant treatment with dabigatran
in a real-world setting. Volume 11, Issue 7, July 2013, S.
Schulman
Reasons for and consequences of vitamin K antagonist
discontinuation in very elderly patients with non-
valvular atrial fibrillation. Volume 14, Issue 11,
November 2016, G. Bertozzo
Thrombosis Haemostasis
Dabigatran in real-world atrial fibrillation . Meta-analysis of
observational comparison studies with vitamin K antagonists . J.
Carmo (1), 2016 116 4: 754-763
“Unreal world” or “real world” data in oral anticoagulant
treatment of atrial fibrillation . B. Freedman, 2016 116 4: 587-589
Dabigatran in ‘real-world’ clinical practice for stroke prevention in
patients with non-valvular atrial fibrillation . T. S. Potpara, 2015 114
6: 1093-1098
Rivaroxaban real-world evidence: Validating safety and
effectiveness in clinical practice . J. Beyer-Westendorf, 2016 116
Suppl. 2: S13-S23
Ischaemic stroke and bleeding rates in ‘real-world’ atrial
fibrillation patients . I. M. Ogilvie, 2011 106 1: 34-44
Real-world comparison of major bleeding risk among non-valvular
atrial fibrillation patients initiated on apixaban, dabigatran,
rivaroxaban, or warfarin . A propensity score matched analysis .
G. Y. H. Lip 2016 116 5: 975-986
Effectiveness and safety of apixaban versus warfarin in non-
valvular atrial fibrillation patients in “real-world” clinical practice .
A propensity-matched analysis of 76,940 patients . X. Li 2017 117 6:
1072-1082
Net clinical benefit of new oral anticoagulants (dabigatran,
rivaroxaban, apixaban) versus no treatment in a ‘real world’ atrial
fibrillation population: A modelling analysis based on a nationwide
cohort study . A. Banerjee 2012 107 3: 584-589
Key factors influencing choice of
anticoagulant
Licensing
Time in therapeutic range
INR testing
Efficacy
Patient education/choice
Frequency of dosing
Renal function
Extremes of BMI
GI adverse effects
Bleeding
Stability in compliance aids
Reversal
Monitoring
Food/drug interactions
Missed dose
Contraindications
Pregnancy/breastfeeding
“Bridging”
Assessing anticoagulation
control with vitamin K
antagonists NICE CG180, 2014
Calculate time in therapeutic range (TTR) at
each visit
Reassess anticoagulation for a person with
poor anticoagulation control:
2 INR values > 5 or 1 INR value > 8 within
the past 6 months
2 INR values < 1.5 within the past 6 months
TTR < 65%.
Patient Safety Alerts
The prescription of a DOAC must be preceded by a
thorough evaluation of patient characteristics,
including
age,
body weight,
history of renal or liver disease,
history of bleeding,
other co-morbidities and
use of concomitant drugs.
The results of laboratory tests, including full blood
count, PT and aPTT, serum creatinine, transaminases
and bilirubin, should be available and carefully
evaluated. CrCl should always be calculated using a
commonly available formula
This information will not only guide correct
prescription, but will also identify patients requiring
dose adjustments, which are recommended in fragile
patients such as elderly patients defined at increased
risk of bleeding and patients with moderated to severe
renal impairment.
CrCl
(ml/min)
Dabigatran Rivaroxaban▼
Apixaban Edoxaban ▼
≥ 50 Usual dose is 150mg
twice daily
Consider 110mg twice
daily in 75-80 year olds,
or with moderate renal
impairment, gastritis/
GORD or at increased
risk of bleeding
110mg twice daily in
patients >80 years or if
taking verapamil
20mg once
daily with food
5mg twice daily
Reduce to 2.5mg
twice daily in patients
with two or more of
the following:
o Age ≥80 years
o Body weight ≤60kg
o Serum creatinine
≥1.5mg/dL (133
micromoles/L)
60mg once daily
Reduce to 30mg
once daily in
patients with one or
more of the
following clinical
factors:
Low body weight
<60kg
Concomitant use of
ciclosporin,
dronedarone,
erythromycin or
ketoconazole
30 – 49 110-150 mg twice daily Reduce dose to
15mg daily
Use normal dose Reduce dose to
30mg daily 15 – 29 Do not use Reduce dose to 2.5mg
twice daily
< 15 Do not use
Dose reduction for DOACs
When prescribing a DOAC, the presence of
concomitant drugs potentially interfering with its
bioavailability should be carefully ascertained.
Some of these drugs (in particular verapamil for
dabigatran and clarithromycin or erythromycin for
rivaroxaban) may increase the risk of bleeding, and
their co-administration must be carefully evaluated,
also taking into account the individual risk profile.
Other drugs such as phenobarbital, carbamazepine or
phenytoin may decrease efficacy.
Finally, as for the vitamin K antagonists, the
concomitant administration of a DOAC with an
antiplatelet agent will increase the risk of bleeding and
the need for combined treatment should be reviewed.
Adequate counselling information must be provided
when the DOAC is prescribed. The patient should be
clearly informed about treatment indication, dosing
schemes, dosing instructions if one or more doses are
missed, risks associated with non-adherence and risks
associated with drug intake
Although patients treated with DOACs do not require
regular laboratory monitoring, a clinical monitoring
schedule should be planned with the patient, with
regular review of adherence and concomitant
medications. More frequent visits should be
considered for fragile patients based on their age,
body weight, presence of co-morbidities and
concomitant treatments. Laboratory monitoring of renal
function should be planned at least yearly, but possibly
more often in some high-risk patient categories such as
the elderly, patients with impaired renal function at
baseline, or patients with concomitant medications or
diseases potentially affecting renal function
Extremes of BMI International Society
on Thrombosis & Haemostasis
Standard dosing of DOACs in
patients with BMI ≤ 40kg/m2 and
weight ≤ 120kg for VTE treatment,
VTE prevention, and prevention of
ischaemic stroke and systemic
arterial embolism in non-valvular AF
DOAcs should not be used in patients
with BMI> 40kg/m2 or a weight
>120kg because there are limited
clinical data available for patients at
the extreme of weight
available PK/PD evidence suggests that
decreased drug exposures, reduced
peak concentrations and shorter half-
lives occur with increasing weight,
which raises concerns about
underdosing at extremes of weight
Bleeding and reversibility
Indication for reversibility
(Suspected) Bleed into a critical organ
Head
Eye
Spinal cord
Limb with compartment syndrome
Drop in Hb of greater than 20g/l
Need for surgery within 4 hours
VKA reversal
January to June 2016
62 patients received PCC for reversing an
anticoagulant. 44 VKA, 13 DOAC
Outcome at 24 hrs: Alive 55 Deceased 2
Outcome at 30 days: Alive 46 Deceased 11
DTI reversal
Xa inhibitior reversal
Prescribing trends/ challenges
Antiplatelet treatment
NICE CG180, 2014
Do not offer aspirin monotherapy
solely for stroke prevention to
people with AF.
No clear evidence of clinical
benefit of aspirin in reducing
mortality and systemic emboli.
Modest benefit in reducing
ischaemic stroke was partially
offset by a modest harm in
increased bleeding and
haemorrhagic stroke.
heavily dependent on results from
the SPAF1 study, which used 325 mg
aspirin/day
Trends in prescribing of DOACs in NI
0
5,000
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15,000
20,000
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30,000
35,000
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45,000
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Jun
2009
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2010
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Jun
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Ma
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12
Jun
2012
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Ma
r 20
13
Jun
2013
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p 2
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r 20
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Jun
2014
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2015
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p 2
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r 20
16
Jun
2016
Se
p 2
016
Dec 2
016
Ite
ms
Edoxaban Rivaroxaban Dabigatran Apixaban
Quarter ending
Increasing usage of OAC
Appropriate?
Need for safer patient selection and education
Need for safer clinician selection and education
Appropriate dosage selection for maximal stroke
prevention benefit
Anticoagulants reduce risk of clotting but with an
increased risk of bleeding.
Challenging choice of anticoagulant may lead to
challenging choice of reversal agents.