Stroke Prevention in Atrial

Fibrillation

Dato Dr Yap Lok Bin

Consultant Cardiologist

Structure

Atrial Fibrillation and OACs

Warfarin

Our experience of anticoagulants

Risk Scoring and Guidelines

Strategies for the management of AF

• Risk stratify: CHA2DS2VAS c or CHADS2 scores

• Anticoagulants (Warfarin or NOACs)

• Underutilized

Stroke prevention

• Adequate rate control defined as achievement of arbitrary heart rate target at rest and exercise

Ratecontrol

• Revert to Sinus Rhythm

• DCCV or Catheter Ablation

• Efficacy defined as “freedom from AF”

Rhythm control

Stroke

Stroke is 5 times more likely in patients with atrial fibrillation compared with those without.

A CVA during atrial fibrillation is twice as likely to cause death and disability compared with non embolic strokes

33% of acute strokes in elderly population are related to AF

Zhang L Stroke 2003

72.562.5

50

14.527.5

34

4.3 1.82.7

8.7 8.2 12.3

0%

20%

40%

60%

80%

100%

Thrift AG

Stroke 2001

North East

Melbourne

Zhang LF

Stroke 2003

China

Huang CY

Stroke 1990

Hong Kong

Ischemic

stroke

Intracerebral

hemorrhage

Undetermined

SAH

High Baseline ICH Risk in Asian

Hospital-based study

10 regions in China (Beijing, Shanghai, Guangzhou)

8,268 stroke patients

Ethnic Difference: Risk of Intracranial Hemorrhage with Warfarin for AF

Shen AY, et al. JACC 2007;50:309-15, n = 18,000 Rate of ICH is 20% in whites and 30% in Asians

Asian vs. White: ~4X risk of ICH with warfarin

Atrial Fibrillation and Anticoagulation

Prevalence: 5% of people over age 65

10% of people over age 80

Incidence of stroke with afib increases with age:

1.3 %/year in patients 50–59

2.2 %/year in 60–69

4.2 %/year in 70–79

5.1 %/year in 80–89

WARFARIN

Adjusted dose warfarin and antiplatelet agents have been shown to reduce the risk of stroke compared with control by 64% and 22%

Warfarin has been shown to be more effective than aspirin, in reducing stroke by 45%, but increasing the risk of bleeding

Warfarin and other oral anticoagulants (OAC) are recommended for patients at increased risk of stroke; and aspirin is recommended for patients at lower risk

Warfarin Antiplatelets

• Ann Intern Med 2007; 146: 857-67.

Warfarin vs Aspirin

-64

-22

-70-60-50-40-30-20-10

0

Risk Reduction in Stroke

(%) %

%

1930s

Heparin

1950s 1990s 20021970s

Warfarin LMWHs Factor Xa inhibitor

DTIs

ArgatrobanBivalirudinLepirudinIprivask

FondaparinuxEnoxaparinDalteparinTinzaparin

1980s

2010-12

DTI and Factor Xainhibitors

DabigatranRivaroxaban

Apixaban

Developmental History –Current FDA Approved

Anticoagulants

Unpredictable response

Routine coagulation monitoring

Slow onset/offset of action

Risk of BleedingComplications

Warfarin therapy has

several limitations

that make it difficult to

use in practice

Numerous drug-drug interactions

Numerous food-drug interactions

Frequent dose adjustments

Narrow therapeutic window (INR range 2-3)

Stroke Prevention in Atrial Fibrillation-Limitations of Warfarin Therapy in Atrial Fibrillation

• Warfarin was #1 in 2003 and 2004 in the number of mentions of “deaths for drugs causing adverse effects in therapeutic use”

• Warfarin caused 6% of the 702,000 ADEs treated in the ED/year; 17% required hospitalization

• J Thromb Thrombolysis 2008; 25: 52-60.

International Normalised Ratio (INR)

Target INR

(2.0-3.0)

<1.5 1.5–1.9 2.0–2.5 2.6–3.0 3.1–3.5 3.6-4.0 4.1-4.5 >4.50

20

40

60

80

Even

ts /

1000

pat

ient

yea

rs

Intracranial haemorrhageIschaemic stroke

The anticoagulant effect of vitamin K antagonists are optimized when therapeutic doses are maintained within a very narrow range

• N Engl J Med 2003; 349: 1019-26.

Stroke Prevention in Atrial Fibrillation-Limitations of Warfarin Therapy in Atrial Fibrillation-Narrow Therapeutic Window

NOACs

Advantages NOAC over Warfarin

No monitoring of PT/INR

Less incidence of intracranial haemorrhage

Lower rates of stroke and systemic embolism

Disadvantages of NOAC

High Cost

GI side effects

No antidote available (except Dabigatran)

Contraindicated in severe renal impairment

SPAF trials

Re-LY ROCKET-AF

ARISTOTLE

ENGAGE AF-TIMI 48

Drug Dabigatran Rivaroxaban Apixaban Edoxaban

Dose (mg)Freq

150, 110BID

20 (15*)QD

5 (2.5*)BID

60*, 30*QD

N 18,113 14,266 18,206 >21,000

Design PROBE 2x blind 2x blind 2x blind

AF criteria AF x 1< 6 mths

AF x 2(>1 in <30d)

AF or AFl x 2<12 mths

AF x 1 < 12 mths

% VKA naive 50% 38% 43% 40% goal

*Dose adjusted in patients with ↓drug clearance. **Max of 10% with CHADS-2 score = 2 and no stroke/TIA/SEEPROBE = prospective, randomized, open-label, blinded end point evaluation VKA = Vitamin K antagonist

Summary of NOACs

Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Mode of

Action

Vitamin K

antagonist

Direct

thrombin

inhibitor

Factor Xa

inhibitor

Factor Xa

inhibitor

Factor Xa

inhibitor

Half-life 40 h 14 h 5-9 h 8-13 h 5-13 h

Dose Once daily 110 mg twice

daily

150mg twice

daily

15 mg once

daily

20mg once

daily

2.5 mg twice

daily

5 mg twice

daily

30mg once

daily

60mg once

daily

Stroke

Prevention

(vs warfarin)

- Non-inferior

(110mg)

Superior

(150mg)

Non-inferior

(20mg)

Superior

(5mg)

Non-inferior

(30mg)

Non-inferior

(60mg)

Our Experience of NOAC vs Warfarin

IJN Study

IJN Study

What is our Experience of NOAC

compared to Warfarin?

Study of 1000 Clinical records

500 patients prescribed dabigatran vs 500 patients prescribed warfarin

Examined for stroke rates, adverse effects, bleeding risks with NOACs compared to warfarin

500 Patients on Warfarin –

Time in Therapeutic Range

Mean TTR for warfarin is 50%

Median TTR 53%

TTR subgroup analysis:

mean TTR by country

23

TTR = time in therapeutic range

Wallentin L et al. Lancet 2010;376:975–83

Mean T

TR (

%)

10

30

50

60

70

80

0

Country

20

40

Taiw

an

Mexic

o

Peru

Rom

ania

India

Colo

mbia

Russ

ia

Bra

zil

Chin

a

Kore

a

Gre

ece

Thaila

nd

Mala

ysi

a

Pola

nd

South

Afr

ica

Japan

Fra

nce

Slo

vakia

Port

ugal

Cze

ch R

epublic

Isra

el

Phili

ppin

es

Bulg

aria

Hungary

Hong K

ong

Turk

ey

Belg

ium

United S

tate

s

Aust

ria

Spain

Germ

any

Sw

itze

rland

Sin

gapore

Arg

entina

Neth

erlands

Norw

ay

Canada

United K

ingdom

Italy

Ukra

ine

Denm

ark

Aust

ralia

Fin

land

Sw

eden

4447 48 49 49

53 53 54 55 55 56 56 56 57 58 5860 60 61 62 64 64 64 64 64 65 65 66 66 66 67 68 68 70 70 70 71 71 72 72 72

74 7477Malaysia

Adverse Effects Analysis

Dabigatran Warfarin P value

Dyspepsia 20 (3.9%) 2 (0.4%) <0.01

Shortness of

Breath

6 (1.2%) 0 0.01

Leg oedema 5 (1%) 0 0.03

Palpitations 3 (0.6%) 0 0.13

Dizziness 3 (0.6%) 0 0.13

Chest pain 2 (0.4%) 0 0.16

headache 2 (0.4%) 0 0.16

Allergy 2 (0.4%) 2 (0.4%) 0.50

Flushing 0 2 (0.4%) 0.16

Bleeding Risk Analysis

Dabigatran Warfarin P value

Minor Bleeding

Haematuria 5 (1%) 3 (0.6%) 0.23

Gum bleeding 5 (1%) 1 (0.2%) 0.11

Gastrointestinal

bleed

0 3 (0.6%) 0.50

Subconjunctival

haemorrhage

2 (0.4%) 2 (0.4%) 0.69

Retinal haemorrhage 1 (0.2%) 0 0.75

Epistaxis 1 (0.2%) 0 0.75

Major Bleeding

Gastrointestinal

bleed

2 (0.4%) 2 (0.4%) 0.69

Haematuria 1 (0.2%) 0 0.75

Clinical Outcome

Follow-up Period

CVA Events Warfarin Dabigatran P value

CVA ischemic 4 (0.8%) 0 0.30

CVA

haemorrhagic

1 (0.2%) 1 (0.2%) 0.92

Warfarin Dabigatran

Average follow up 355 days (11.7

months)

Average follow up 315 days (10.4

months)

Reasons for Stopping Warfarin in our Study

Reasons for stopping warfarinSwitched to Dabigatran 42

Bleeding due to warfarin 10

Patient preference 7

INR subtherapeutic / not in range 6

Poor INR control 5

Doctors preference / recommendation 4

Post watchman device on dual anti-platelets 3

Deaths 3

Hot sensation 2

CVA 2

Poor compliance to warfarin 2

Allergy 2

Gastric upset and pain 2

Vomiting 1

Anxiety 1

Difficulty getting to INR clinic 1

Convenience (blood taking ) 1

Malaysian registry study supports the

positive efficacy and safety profile of

NOACs in Asia

Yap LB et al. J Thromb Thrombolysis. 2014;38:39–4428

• Observational cohort study

• National Health Institute in Malaysia

• 510 dabigatran users

– 31% switched from warfarin

– 60% taking 150 mg BID dose

– 315 days of follow-up (average)

“The rate of occurrences of adverse effects and bleeding

were lower than those seen in the RE-LY® trial”

OBSERVATION

• 1 haemorrhagic stroke

• 0 ischaemic strokes

• 2 major bleeding (GI)

• Dyspepsia 4%

• Withdrawal 18%

Current Guidelines

*Or moderate-to-severe left ventricular systolic dysfunction (left ventricular ejection fraction ≤40%)

TIA, transient ischaemic attack; SE, systemic embolism

Olesen et al. BMJ 2011

Increased risk of thromboembolism when CHA2D2s-VASc score ≥2

Add points

together

30

RISK FACTORS SCORE

Congestive heart failure 1

Hypertension 1

Age ≥ 75 2

Age 65-74 1

Diabetes mellitus 1

Stroke/TIA/thrombo-

embolism2

Vascular disease 1

Sex Female 1

Your score

CHA2DS2VASc

SCORE

ADJUSTED

STROKE RATE (%

year)

0 0%

1 1.3%

2 2.2%

3 3.2%

4 4.0%

5 6.7%

6 9.8%

7 9.6%

8 6.7%

9 15.2%

HAS-BLED Score

CLINICAL

CHARACTERISTIC

POINTS

AWARDED

Hypertension 1

Abnormal liver function 1

Abnormal renal function 1

Stroke 1

Tendency to bleed 1

Labile INRs 1

Elderly (Age >65) 1

Drugs 1

Alcohol 1

Your score

HAS

BLED

SCORE

NUMBER

OF

PATIENTS

No OF

BLEEDS

BLEEDS

PER

100

PATIENT

YEARS

0 798 9 1,13

1 1286 13 1,02

2 744 14 1,88

3 187 7 3,74

4 46 4 8,70

5 8 1 12,50

6 2 0 0

7 --- --- ---

8 --- --- ---

9 --- --- ---

Total 798 9 1,13

2012 ESC guidelines for the choice of anticoagulant in AFAntiplatelet therapy with ASA plus clopidogrel, or-less effectively-ASA only, should be considered in patients who refuse any OAC, or cannot tolerate anticoagulants for reasons unrelated to bleeding. If there are contraindications to OAC or antiplatelet therapy, left atrial appendage occlusion, closure or excision may be considered.

Line: solid=best option; dashed=alternative option

NOAC = novel oral anticogulant

CPG on Ischaemic Stroke 2012

• Older Asian Patients have higher risks of stroke

• Anticoagulation recommended for those with CHADSVASC score ≥ 2

• Our experience shows that NOACs are effective and safe when compared to warfarin

Summary

Additional Slides

Case 1 Mr Sidek A 67-year-old man presents to the clinic.

Past history : hypertension, hyperlipidemia,

Type 2 diabetes mellitus.

Current Medication: Bisoprolol 5mg daily, lisinopril 5 mg daily, metformin 500mg XR od, atorvastatin 20 mg daily, aspirin 150 mg daily

Social History: Mobile, independent, smokes 10/day, no alcohol. Works as a food vendor.

BP 120/80 mmHg, irregular pulse HR 70 bpm, eGFR > 60

ECG shows atrial fibrillation

CHADS2 score = 2

CHA2DS2-VASC score = 3

What drug should be given for stroke prevention?

Case 2

Mr Wong A 68-year-old man presents to the

clinic with breathlessness.

Past history : hypertension, PCI to LAD in 2008,

CCF, CVA 2012.

Current Medication: bisoprolol 2.5mg daily, Perindopril 4 mg daily, rosuvastatin 20 mg daily, spironolactone 12.5mg bd, aspirin 150 mg daily

Social History: Unemployed and unable to pay for medication.

ECG shows new atrial fibrillation. Rate 80 bpm. eGFR > 60

CHADS2 score = 4

CHA2DS2-VASC score = 7

What drug should be given for stroke prevention?

Case 3 Mr Jamal A 70-year-old man presents to the clinic

with palpitations

Past history : Hypertension, PCI to RCA 2013, GI bleed 2012 –OGD showed duodenal ulcer.

Current Medication: Aspirin 100mg od, Plavix 75 mg od, Omeprazole 20mg od, Atenolol 25mg od, Simvastatin 20mg od, Ramipril 5 mg od

Social History: Smoker 20/day, Alcohol 4x a week. Retired Health Professional.

ECG and monitoring showed paroxysmal AF

CHADS2 score = 1

CHA2DS2-VASC score = 3

HAS-BLED score = 4

What drug should be given for stroke prevention?