evidence based management of atrial fibrillation

PROTECTPreventing AF-related stroke

GREGORY Y H LIP MD FRCP (Lond Edin Glasg) FACC FESC FEHRA

Price-Evans Chair of Cardiovascular Medicine, University of Liverpool, UK

National Institute for Health Research (NIHR) Senior Investigator

Distinguished Professor, Aalborg University, Denmark

Adjunct Professor, Yonsei University, Seoul;

Adjunct Professor, Seoul National University, South Korea.

………………………………………………………………………………..

©Prof GYH Lip

Declaration of Interests

• Guideline membership/reviewing: ESC Guidelines on Atrial Fibrillation, 2010 and Focused

Update, 2012; ESC Guidelines on Heart Failure, 2012; American College of Chest Physicians

Antithrombotic Therapy Guidelines for Atrial Fibrillation, 2012; NICE Guidelines on Atrial

Fibrillation, 2006 and 2014; NICE Quality Standards on Atrial Fibrillation 2015; ESC

Cardio-oncology Task Force, 2015; ESC Working Group on Thrombosis position documents

(2011-). Chairman, Scientific Documents Committee, European Heart Rhythm Association

(EHRA). Chairman, 2018 CHEST guidelines from American College of Chest Physicians

• Steering Committees/trials: Includes steering committees for various Phase II and III studies,

Health Economics & Outcomes Research, etc. Investigator in various clinical trials in

cardiovascular disease, including those on antithrombotic therapies in atrial fibrillation, acute

coronary syndrome, lipids, etc.

• Editorial Roles: Editor-in-Chief (clinical), Thrombosis & Haemostasis; Associate Editor,

Europace; Guest Editor, Circulation, American Heart Journal.

• Consultant/Advisor/Speaker:

– Consultant for Bayer/Janssen, BMS/Pfizer, Verseon, Boehringer Ingelheim, and Daiichi-

Sankyo.

– Speaker for Bayer, BMS/Pfizer, Boehringer Ingelheim and Daiichi-Sankyo

Contribution of AF to Incidence and Outcome of

Ischemic Stroke Population-Based L’Aquila StudyMarini et al Stroke 2005;36(6):1115-9.

Kaplan–Meier estimates of the

likelihood of recurrent stroke in

patients with and without AF

Annual Mortality Rates in Patients

With and Without AF:

At 1 year, AF 49.5% vs no AF,

27.5%

Increased mortality even up to 8 years

Recurrent stroke

Years after first stroke

Cu

mu

lati

ve

pro

bab

ilit

y

of

recu

rren

ce,

%

10

12

AF

No AF

8

6

4

2

00 2 4 6 8 10

P = 0.0398

Years post-stroke

Patients with AF

Patients without AF

An

nu

al m

ort

alit

y r

ate,

%

0

10

20

30

40

50

60

1 2 3 4 5 6 7 8

Mortality

Decision-making

interventions to stop

the global AF-related

stroke tsunami Cerasuolo … Lip et al

Int J Stroke 2017, 12(3) 222–228

(a) % population estimated to be alive

(65%), injured/ disabled (10%), and

dead (25%) within 30 days after the

2004 Boxing Day Tsunami in Aceh

Province.

(b) % AF patients without prior OAC

estimated to be alive and without

disability (25%), disabled (50%), and

dead (25%) 30 days after an AF-

related stroke.

(c) % AF patients receiving warfarin with

an INR > 2 estimated to be alive and

without disability (49%), disabled

(42%), and dead (9%) 30 days after an

AF-related stroke

Proportion alive, dependent, and dead in the Boxing

Day Tsunami and after an AF-related stroke with

and without prior anticoagulant treatment

The CHA2DS2-VASc score Lip et al Chest. 2010;137:263-72

Camm, Kirchhof, Lip et al

Eur Heart J 2010; 31, 2369–2429

CHA2DS2-VASc for

stroke in Asians with AFKorean Nationwide Sample

Cohort Study

Kim … Joung, Lip.

Stroke 2017 DOI:

10.1161/STROKEAHA.117.016926

Patients who were

categorized as low

risk consistently had

an event rate <1%

per year.

Event rates for different outcomes for non-

anticoagulated AF patients with less than 2 Non-

Gender Related stroke risk factors Fauchier … Lip. Stroke 2016 DOI: 10.1161/STROKEAHA.116.013253

0

1

2

3

4

5

Low risk

[CHA2DS2-

VASc 0 in males,

1 in females]

1 risk factor

[CHA2DS2VASc

1 in males; 2 in

females]

2.62(1.16-5.89)

3.21(1.11-9.26)

2.82 (1.32-6.04)

3.88 (2.51-6.0)

4.69 (1.88-11.6)

4.20(2.24-7.86)

Adjusted

HREv

ent

rate

%/y

ear

CHA2DS2-VASc Scores of

Patients With AF

±Ischemic Stroke:

Baseline, Follow-Up, Delta Chao, Lip et al

J Am Coll Cardiol. 2018;71(2):122–32.

Risk stratification and thromboprophylaxis made easy Lip and Lane Circ J 2014 June; Griffiths and Lip Circulation 2014;130(21):1837-9

Patient with atrial fibrillation

STEP 1 Is the patient 'low risk'?

'Low risk'’ = CHA2DS2-VASc score = 0 (male) or 1 (female)

STEP 2

Offer stroke prevention if ≥1 additional stroke risk factors*

NOAC VKA (eg. warfarin)

with Time in Therapeutic Range (TTR) >70%

If yes ...

No antithrombotic therapy

VKA, Vitamin K Antagonist

NOAC, non-Vitamin K

antagonist oral anticoagulant

.

* Use the HAS-BLED score to identify patients at ‘high risk’ of bleeding for more careful

review and followup, and to address reversible risk factors for bleeding. A high HAS-BLED

score (≥3) does not preclude use of OAC, and may help with NOAC dose selection

• CHA2DS2-VASc best to identify ‘low risk’

• Even 1 CHA2DS2-VASc factor confers risk of stroke

and death

• The NCB is +ve for OAC even with 1 stroke risk factor

How to apply guidelines into clinical practice

The default is stroke prevention*

unless ‘low risk’

*Stroke prevention means oral anticoagulation, whether as

well managed warfarin with good TTR or NOAC

10

The ‘3 –step’ [PS. It’s not a dance routine]

…. to streamline decision-making pathway for stroke

prevention in patients with atrial fibrillationLip et al. Thromb Haemost 2017; 117: 1230–1239

Step 2 Consider stroke

prevention (ie. oral

anticoagulant) in all AF

patients with ≥1 additional

stroke risk factors*

No

antithrombotic

treatment

SAMe-TT2R2 score >2Regular review/INR

checks/counselling for VKA

users

… or try a NOAC

SAMe-TT2R2 score 0–2Consider VKA treatment

(eg, warfarin)

*Calculate the HAS-BLED score. If HAS-BLED ≥3, address the modifiable

bleeding risk factors and ‘flag up’ for regular review and follow-up.

Calculate

SAMe-TT2R2 score

Low stroke risk

CHA2DS2-VASc

score:

0 in males

1 in females

Step 3

Decide on NOAC or

VKA with high time in

therapeutic range

Step 1 Identify low-

risk patients

Streamlining primary and secondary care

management pathways for stroke

prevention in AFCollaborative working and application of the simple

‘Birmingham 3-step’ approach Lip, Lane, Sarwar. Eur Heart J. 2017;38(40):2980-2982.

13

http://guidance.nice.org.uk/CG/Wave0/638/Consultation/Latest

…. the initial clinical decision step should use

the CHA2DS2-VASc score to determine the low

risk patients who do not require

antithrombotic therapy.

‘Low risk’ patients are defined as those with a

CHA2DS2-VASc score=0 if male, or a score=1,

if female.

Subsequent to this step, stroke prevention

should be offered to those AF patients with one

or more stroke risk factors.

http://guidance.nice.org.uk/CG/Wave0/638/Consultation/Latest

Anticoagulation

Control and

Prediction of

Adverse Events in

Patients With

Atrial Fibrillation

Wan et al

Circ Cardiovasc Qual

Outcomes. 2008;1:84-91

For retrospective studies, a 6.9%

improvement in the TTR

significantly reduced major

hemorrhage by 1 event per 100

patient-years of treatment (95%

CI, 0.29 to 1.71 events).

TTR negatively correlated with major

hemorrhage (r=-0.59; P=0.002) and

thromboembolic rates (r=-0.59;P=0.01).

How to best identify those

patients who would do well on

VKA with high TTR?

0

1

2

3

4

5

6

7

8

Ou

tco

me

even

ts r

ate

(per

10

0 p

atie

nt-

yea

rs, %

)

0 40 50 60 70 80 90

TTR (%)

Major haemorrhage

Thromboembolic

Linear (Major haemorrhage)

Linear (Thromboembolic)

Stroke/SERE-LY 0.66 (0.53–0.82)

ROCKET AF 0.88 (0.75–1.03)

ARISTOTLE 0.80 (0.67–0.95)

ENGAGE AF 0.88 (0.75–1.02)

Combined (random) 0.81 (0.73–0.91)

Major bleeding

RE-LY 0.94 (0.82–1.07)

ROCKET AF 1.03 (0.90–1.18)

ARISTOTLE 0.71 (0.61–0.81)

ENGAGE AF 0.80 (0.71–0.90)

Combined (random) 0.86 (0.73–1.00)

Secondary efficacy and safety outcomes

Efficacy Ischaemic stroke 0.92 (0.83–1.02)

Haemorrhagic stroke 0.49 (0.38–0.64)

MI 0.97 (0.78–1.20)

All cause mortality 0.90 (0.85–0.95)

Safety ICH 0.48 (0.39–0.59)

GI bleeding 1.25 (1.01–1.55)

Efficacy and safety of 4 high dose NOACs vs

warfarin: meta-analysis of phase III trialsRuff CT, et al. Lancet 2014;383:955–62

GI, gastrointestinal; ICH, intracranial haemorrhage; MI, myocardial infarction NOAC, non-VKA oral anticoagulant; SE, systemic embolism

There have been no head -to-

head studies between NOACs.

Conclusions about the relative

efficacy or safety of any the

NOACs cannot be drawn

from these data.

Favours NOAC

0.5 1.0

Favours warfarin Favours NOAC

0.5 1.0 2.0

Favours warfarin

Favours NOAC

0.2 0.5 2.0

Favours warfarin

1.0

2.0

Evolving Changes of the Use of Oral

Anticoagulants and Outcomes in Patients with

Newly-Diagnosed Atrial FibrillationChao .. .. Lip, Chen. Circulation 2018

The initiation rates

of OACs in newly

diagnosed AF

patients significantly

increased from

13.6% to 35.6%,

contemporaneous

with the introduction

of NOACs.

A lower risk of

ischemic stroke and

mortality was

temporally

associated with the

increasing

prescription rates of

OACs.

Oral Anticoagulation in Very Elderly Patients

with AF- A Nationwide Cohort Study Chao .. .. Lip Circulation 2018 10.1161/CIRCULATIONAHA.117.031658

Risks of ischemic stroke and ICH were compared between

11,064 AF and 14,658 non-AF patients aged ≥90 years

without antithrombotic therapy from year 1996 to 2011.

Oral Anticoagulation in Very Elderly Patients

with AF- A Nationwide Cohort Study Chao .. .. Lip Circulation 2018 10.1161/CIRCULATIONAHA.117.031658

From year 2012 to 2015, 768 AF patients aged ≥90

years treated with warfarin and 978 patients

treated with NOACs (dabigatran in 361,

rivaroxaban in 557 and apixaban in 60)

Risk of dementia in stroke-free patients diagnosed with

atrial fibrillation: data from a population-based cohort Kim .. Lip, Joung. Eur Heart J 2019 doi:10.1093/eurheartj/ehz386

Incident AF

was associated

with an

increased risk

of dementia,

independent of

clinical stroke

in an elderly

population.

OAC use was

linked with a

decreased

incidence of

dementia.

NICE guidelines (2014) …

led to the development of

NICE menu indicators,

which were adopted into the

Quality and Outcomes

Framework (QOF).

Use bleeding risk

assessment appropriately

and responsibly

• Bleeding risk assessment is to address

modifiable bleeding risk factors

• Then flag up ‘high risk’ patients for

early review and followup with a

bleeding risk score

• Bleeding risk is highly dynamic

• High bleeding risk score is not an

excuse to withhold OAC

– This is an education and

implementation issue

Patient-Centered Outcomes Research Institute

(PCORI) review ‘.. .. .. HAS-BLED provides the

best prediction for bleeding risk’

Patient with Atrial Fibrillation;

Eligible for Oral Anticoagulation

Identifies ‘at risk’ patients for more regular review and follow-up

For patients with an increased risk of bleeding the benefit of OAC usually, but not always, outweighs the bleeding risk; thus, regular review and careful monitoring of bleeding risk is important

Do not withhold OAC solely because the patient is at risk of falls

EHR and ‘electronic alerts’

Low risk=No action

High risk=Patient ‘flagged up’ for review

A ‘high risk’ bleeding risk score is not a

reason or excuse to withhold OAC

Review and address potentially reversible bleeding risk factors

- Uncontrolled hypertension

- Labile INRs (if on VKA)

- Concomitant use of aspirin and NSAIDs in anticoagulated patient

- Alcohol excess

Bleeding risk assessment

Bleeding Risk

Assessment in

AF: Observations

on the Use and

Misuse of

Bleeding Risk

Scores

Lip and Lane.

J Thromb Haemostat 2016

DOI: 10.1111/jth.13386.

We need a holistic approach to detection and improving

management of patients with AF

The patient pathway

… integrated care for managing atrial fibrillation

in a holistic manner

Cardiovascular risk factors & associated comorbidities

Symptoms? Rate control or rhythm control?

Stroke prevention

Real world

management

requires simple

and practical

decision making

processes

Improve

detection

of AF

A holistic approach to risk assessment and

management of patients with atrial fibrillation?

Secondary careNon-Cardiologists; Cardiologists (Non-AF vs AF)

Patients with AF

Primary Care

Awareness and improved

detection of atrial

fibrillation; allowing early

intervention

A holistic and integrated

approach to management

of AF patients

Patients with AF present to

GPs (often asymptomatically),

emergency rooms, non-

cardiologists (perioperatively,

ICU), cardiologists (non-

arrhythmia specialists and

arrhythmia specialists)

… and our AF patients need

a simple, streamlined

uniform and practical

approach to their care and

management

‘The patient pathway …’

‘The patient journey …’

The Atrial

Fibrillation Better

Care (ABC)

pathway for

integrated care

management

‘B’ Better symptom

management

Treat symptoms

‘Birmingham 3-step

Patient-centred and symptom-directed

decisions on rate versus rhythm control

• Manage hypertension, heart failure,

diabetes mellitus, cardiac ischaemia, and

sleep apnoea

• Lifestyle changes: obesity reduction,

regular exercise, and reduction of

alcohol and stimulant use

• Patient psychological mobidity

• Consider patient values and preferences

Step 1

• Identify low-risk patients

Step 3

• Decide on OAC (either a

VKA with well-managed

TTR or a NOAC

Step 2

• Offer stroke prevention

to patients with one or

more risk factors for

stroke

• Assess bleeding risk

‘A’ Avoid stroke

Optimise stroke

prevention

‘C’ Cardiovascular

and other

comorbidities

Manage risk factors

The Atrial fibrillation Better Care (ABC)

pathway for integrated management provides

a simple strategy that that streamlines primary

and secondary care of patients with AF.

The Atrial fibrillation Better Care (ABC) PathwayLip. Nat Rev Cardiol 2017 doi:10.1038/nrcardio.2017.153

Primary Care

Clinical Pathway

March 2018

CHA2DS2-VASc

HAS-BLED

SAMe-TT2R2

The ABC

of

Atrial Fibrillation

management

Detect, Protect, Perfect elements:• Detect more cases of AF,

• Protect with Anticoagulation and

modification of other CV risk factors

• Perfect the quality of therapy by

ensuring that patients are monitored

and followed up appropriately

https://bit.ly/2FhrwXQ

Integrated care management of patients with AF and risk of CV

events: The ABC (Atrial fibrillation Better Care) pathway in the

ATHERO-AF study cohort.Pastori .. .. Lip Mayo Clin Proc 2018 DOI: 10.1016/j.mayocp.2018.10.022

Multivariate modelHR for

MACE95% CI p value

‘ABC’ pathway

management0.44 0.24 0.80 .007

Female sex 0.62 0.42 0.91 .02

Paroxysmal AF 0.91 0.63 1.31 .59

Age ≥75 years 2.17 1.49 3.15 <.001

Prospective single-center cohort study including 907 consecutive patients with non-valvular

AF on VKAs from February 2008 to December 2016. Median followup 37 months

A, B and C groups were defined as follows:

• “A” by a Time in Therapeutic Range ≥65%; “B” by a European Heart Rhythm Association

(EHRA) symptom scale I-II; “C” as optimized cardiovascular comorbidity management.

• Primary endpoint was a composite outcome of CVEs.

HR 0.40, 95%CI 0.22-0.74

Integrated care

management of patients

with AF and risk of CV

events: The ABC pathway

in the ATHERO-AF study

Pastori .. Lip. Mayo Clin Proc 2018

DOI: 10.1016/j.mayocp.2018.10.022

Univariate model

HR for

CVEs

(95%CI)

p

value

Incidence rates

(%/year, 95%CI)p value

Study

groups

Control

groups

‘A’ group

(vs. TiTR<65%)

0.51

(0.35-0.75).001

2.7

(1.9-3.6)

5.2

(4.1-6.5)<.001

‘B’ group

(vs. EHRA III-IV)

0.58

(0.39-0.86).007

3.4

(2.7-4.2)

6.1

(4.3-8.6).003

‘C’ group

(vs. comorbidities)

0.38

(0.26-0.58)

<.00

1

2.1

(1.5-3.0)

5.5

(4.4-6.8)<.001

‘ABC’ group

(vs. any of ‘non-A’,

‘non-B’ or ‘non-C’)

0.40

(0.22-0.74).003

1.8

(0.9-3.0)

4.5

(3.7-5.5).001

AF confers a large healthcare burden from stroke

Stroke and bleeding risks are dynamic, and regular reassessment is needed.

Stroke prevention means oral anticoagulation, whether as VKA with high TiTR or

NOAC

Increase awareness and detection of AF in high risk groups

The default is stroke prevention unless ‘low risk’

– Use the simple, practical ‘3-step’ …. to streamline decision-making for stroke

prevention in AF

Additional decision steps should consider ....

- Symptom management, with regards to decisions on rate control or rhythm

control

- Cardiovascular and comorbidity risk management

Stroke prevention should be part of a proactive, integrated approach to

management of AF ... which can be simple as ABC

PROTECTPreventing AF-related stroke