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

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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.