Clinical Decision Making

for Oral Anticoagulation

Iain Speirits

Pharmacist Clinical Cardiology

Friday 08th September 2017

Overview

• Epidemiology

• ESC

• Mechanisms of Action

• Comparison with VKA

• Treatment Considerations

• Choice of DOAC

• Case Studies

Atrial Fibrillation

• Most common sustained

cardiac arrhythmia

– Scottish prevalence

considered ~1.6%

(84,720)

– increases sharply aged ≥

65 years (85% diagnoses)

• Men more commonly affected

• Predicted to increase 23.6%

between 2011 and 2021

• EU prevalence predicted to

more than double from 2010

to 2060

Prevalence of AF by Age and Sex

Disease Burden

Risk ratio 4.8

2-y

ear

ag

e a

dju

ste

d in

cid

en

ce o

f str

oke/1

000

Risk of stroke in AF andnon-AF patients

AF patients Non-AF patients

One-year mortality after ischaemic stroke in AF and non-AF patients

12,500 strokes estimated to be caused directly by AF in UK annually

8,500 deaths within year of first stroke estimated attributable to AF

10

0

20

30

40

50

AF patients have a near 5-fold increased risk of

ischaemic stroke

5x

Fatal,49.5%

Non-fatal,50.5%

Fatal,27.1%

Non-fatal,72.9%

Strokes in AF Non-AF strokes

Oral Anticoagulants Underused

• SSNAP (2014) highlights lack of effective

stroke prevention in UK

– 3,790 patients identified as being in AF prior to

admission

– 41.2% of AF patients admitted to hospital with

stroke on OAC prior to admission

– 15.1% of patients not on OAC had justifiable

reason not to be receiving one

– 34% taking only antiplatelet drugs, considered

ineffective for patients in AF

RE-LY ROCKET-AF ARISTOTLE ENGAGE AF

Drug Dabigatran Rivaroxaban Apixaban Edoxaban

N 18,113 14,264 18,201 21,105

Dose (mg)

Frequency

150, 110

BID

20

OD

5

BID

60, 30

OD

Initial dose

adjustmentNo 20 → 15 mg 5 → 2.5 mg 60 → 30 mg

Dose adj (%) 0 21 5 25

Dose

adjustment

after

randomisation

No No No Yes

Design PROBE 2x blind 2x blind 2x blind

RE-LY ROCKET-AF ARISTOTLE ENGAGE AF

Randomised, n 18,113 14,264 18,201 21,105

Age, years 72 ± 9 73 (65–78) 70 (63–76) 72 (64–78)

Female, % 37 40 36 39

Mean CHADS2 score 2.1 3.5 2.1 2.8

Paroxysmal AF, % 32 18 15 25

Prior stroke/TIA, % 20 55 19 28

VKA-naive, % 50 38 43 41

Aspirin use, % 40 36 31 29

Median follow-up, years 2.0 1.9 1.8 2.8

Median TTR, % 64 58 66 68

CHADS2

2

3–6

0–1

Edoxaban 60 mg* vs other NOACs for prevention of stroke and systemic embolism in patients with CHADS2 score ≥ 2 at baseline

Risk ratio (95% CI)

Rivaroxaban 0.90 (0.70–1.16)

Dabigatran 150 mg 1.26 (0.97–1.64)

Dabigatran 110 mg 0.95 (0.74–1.22)

Apixaban 1.08 (0.86–1.37)

0 1.0 3.00.5 1.5 2.0 2.5

Favours edoxaban 60mg Favours other treatments

Edoxaban - Efficacy

Risk ratio (95% CI)

Rivaroxaban 0.76 (0.66–0.89)

Dabigatran 150 mg 0.72 (0.61–0.84)

Dabigatran 110 mg 0.83 (0.71–0.98)

Apixaban 1.08 (0.91–1.28)

0 1.0 3.00.5 1.5 2.0 2.5

Favours edoxaban 60mg Favours other treatments

Edoxaban 60 mg* vs. other DOACs for reduction of major bleeding†

in patients with CHADS2 score ≥ 2 at baseline

Edoxaban - Safety

Study Relative risk (95% CI)

DOAC

events

Warfarin

events

RE-LY (dabigatran)*0.66 (0.53–0.82)

P = 0.0001134/6,076 199/6,022

ROCKET AF

(rivaroxaban)†

0.88 (0.75–1.03)

P = 0.12269/7,081 306/7,090

ARISTOTLE (apixaban)‡ 0.80 (0.67–0.95)

P = 0.012212/9,120 265/9,081

ENGAGE AF-TIMI 48

(edoxaban)§

0.88 (0.75–1.02)

P = 0.10296/7,035 337/7,036

Combined# 0.81 (0.73–0.91)

P < 0.0001911/29,312 1107/29,229

Comparative Efficacy

0.5 1.0 1.5

Favours DOAC Favours warfarin

Secondary Efficacy

Outcome Relative risk (95% CI)

DOAC

events

Warfarin

events

Ischaemic stroke

0.92 (0.83–

1.02)

P = 0.10

665/29,292 724/29,221

Haemorrhagic

stroke

0.49 (0.38–

0.64)

P < 0.0001

130/29,292 263/29,221

Myocardial

infarction

0.97 (0.78–

1.20)

P = 0.77

413/29,292 432/29,221

All-cause mortality

0.90 (0.85–

0.95)

P = 0.0003

2,022/29,29

2

2245/29,22

1

0.5 1.0 1.5

Favours DOAC Favours warfarin

Comparative Safety

Study Relative risk (95% CI)

DOAC

events

Warfarin

events

RE-LY (dabigatran)*0.94 (0.82–1.07)

P = 0.34375/6,076 397/6,022

ROCKET AF (rivaroxaban)† 1.03 (0.90–1.18)

P = 0.72395/7,111 386/7,125

ARISTOTLE (apixaban)‡ 0.71 (0.61–0.81)

P < 0.0001327/9,088 462/9,052

ENGAGE AF-TIMI 48

(edoxaban)§

0.80 (0.71–0.90)

P = 0.0002444/7,012 557/7,012

Combined# 0.86 (0.73–1.00)

P = 0.061,541/29,287

1,802/29,21

1

0.5 1.0 1.5

Favours DOAC Favours warfarin

Outcome Relative risk (95% CI)

DOAC

events

Warfarin

events

Intracranial

haemorrhage

0.48 (0.39–

0.59)

P < 0.0001

204/29,28

7

425/29,21

1

Gastrointestinal

bleeding

1.25 (1.01–

1.55)

P = 0.043

751/29,28

7

591/29,21

1

Secondary Safety

0.0 1.0 2.01.50.5

Favours DOAC Favours warfarin

HIS June 2017 - Efficacy

• No direct DOAC comparisons identified

• Apixaban 5mg, edoxaban 60mg and

dabigatran 150mg similar

• Rivaroxaban 20mg less effective than

dabigatran 150mg

• Absolute risk of SSE for patients treated

with standard dose DOAC lowest for

dabigatran 150mg

HIS June 2017 - Safety

• Apixaban 5mg fewer major bleeding

events than dabigatran 150mg or

rivaroxaban 20mg

• ICH similar for all standard dose DOACs

• Apixaban 5mg fewer GI bleeding events

than dabigatran 150mg or rivaroxaban

20mg

• Absolute risk of major bleeding lowest in

patients receiving apixaban 5mg

Special Considerations

• Edoxaban 30mg associated with more

SSE than standard dose DOACs

• Edoxaban 30mg associated with fewer

major bleeding events and fewer GI

bleeding events than all DOACs except

apixaban 5mg

• Dabigatran 110mg and edoxaban 30mg

associated with fewer ICHs than

rivaroxaban 20mg

DOAC CrCl 15 –

29 mL/min

CrCl 30 – 49

mL/min

Issues to

Consider

Dabigatran

Etexilate

(150mg bd)

Contra-

indicated

Standard

unless other

risk factors

≥80 years

Verapamil

GORD

Rivaroxaban

(20mg od)

15mg

once daily

15mg

once daily

Dose to be

taken after

food

Apixaban

(5mg bd)

2.5mg

twice daily

Standard

unless other

risk factors

Serum Cr

≥133µmol/L

Edoxaban

(60mg od)

30mg

once daily

30mg

once daily

-

Dose Reduction

Study Patient Dose Reduction Frequency

Dabigatran RE-LY 6,015/18,113 (33.2%), 110 mg

6,076/18,113 (33.5%), 150 mg

Twice daily

Rivaroxaban ROCKET-AF 7,111/14,246 (50%)

randomised to either

20 mg or 15 mg

Once daily

Apixaban ARISTOTLE 428/9,120 (4.7%), 2.5mg Twice daily

Edoxaban ENGAGE AF-TIMI

48

5,330/21,105 (25.3%) at

randomisation 30 mg

Once daily

Once Daily Regimen

- Better Adherence?A

dh

ere

nt

pa

tie

nts

, %

P < 0.001

P < 0.001

Chronic medications1*

Ad

here

nt

pa

tie

nts

, %

β-blockers2

P < 0.001 P = 0.004

Two retrospective claims analyses compared adherence to once daily vs twice daily regimens (chronic medications1* and β-blockers2) among NVAF patients

Patient Preference

Patient preference Consider once daily formulation Riva, Edox

High risk of bleeding,

e.g. HAS-BLED 3; very old

Consider agent/dose with the lowest

incidence of bleeding

Dabi 110,

Edox, Apix

CAD, previous MI or high-risk

for ACS/MI

Consider agent with a positive effect

in ACS Riva?

High risk of ischaemic

stroke, low bleeding risk

Consider agent/dose with the best

reduction of ischaemic strokeDabi 150

Concomitant CYP inhibitorConsider agents with no/little

metabolism via CYP systemDabi, Edox

Renal impairmentConsider agent least dependent on

renal function

Apix, Edox DR 30

Riva 15

Sp

ec

ific

pa

tie

nt

ch

ara

cte

risti

cs

Previous stroke

(secondary prevention)

Consider best investigated agent or

greatest reduction of secondary stroke

Riva, Apix,

Edox

Treatment Choices

Thank you

Questions?

Case Study One

Female RW (85 years)

Relevant Medical History

• L breast CA (15.06.2015)

• pAF (30.03.2015); pre-op ECG 130bpm

• Rectal CA (12.03.2015)

• Osteoporosis (24.01.2014)

• Rheumatoid arthritis (07.08.2013)

• Hypothyroidism (06.02.2004)

Current Drug Therapy

Alendronic acid 70mg weekly, bisoprolol

1.25mg, fluoxetine 20mg, folic acid 5mg,

letrozole 2.5mg, levothyroxine 100µg,

methotrexate 20mg weekly, simvastatin

40mg and Theical-D3® daily

Condition and Treatment Considerations

• CHA2DS2-VASc = 3

– ≥75 years (2), female (1)

• Annual Risks:

– Stroke (3.2%) and SSE (4.6%)

Investigations

Occasional palpitations, exertional dyspnoea

BP 132/75mmHg, pulse 72bpm regular

Weight 62kg, serum Cr 77µmol/L

eGFR >60mL/min/1.73m2

Cockcroft-Gault CrCl 47mL/min

Treatment Outcomes

Commenced on apixaban 5mg twice daily

No effect on previous recurrent bleeding

(following surgery and radiotherapy)

Case Study Two

Male JT (87 years)

Relevant Medical History

• Asbestos-induced pleural plaque (14.10.2016)

• COPD - MRC 2 (20.05.2016)

• Pernicious anaemia (19.11.2014)

• pAF (11.04.2014)

• POCS (27.10.2013)

• Hypertension (03.02.2004)

Current Drug Therapy

Bisoprolol 2.5mg daily

Candesartan 16mg daily

Clopidogrel 75mg daily

Simvastatin 40mg daily

Condition and Treatment Considerations

• CHA2DS2-VASc = 5

– ≥75 years (2), hypertension (1), stroke (2)

• Annual Risks:

– Stroke (7.2%) and SSE (10%)

Investigations

No cardiovascular symptoms, though TATT

BP 177/73mmHg, pulse 44bpm regular

Weight 82kg, serum Cr 85µmol/L

eGFR >60mL/min/1.73m2

Cockcroft-Gault CrCl 63mL/min

Treatment Outcomes

Commenced on edoxaban▼ 60mg daily

Bisoprolol dose reduced to 1.25mg daily

Candesartan dose increased to 32mg daily

Follow-up (One)

• Renal function re-checked eight days after

review following candesartan dose increase:

U+Es N, K+ 4.8mmol/L

• BP 157/73mmHg, pulse 54bpm regular

Follow-up (Two)

Discussed tolerance to edoxaban at clinic

review; patient now feeling well, denies any

difficulties, bruising and bleeding

• BP 148/81mmHg, pulse 52bpm regular