Stroke Prevention in Atrial Fibrillation Trial Data are Supported by Clinical Experience

Dr. MUHAMMAD SYUKRI, Sp JP

PUSAT JANTUNG Regional

Stroke Prevention in Atrial Fibrillation

Trial Data are Supported by Clinical Experience

BAGIAN KARDIOLOGI DAN KEDOKTERAN VASKULAR FKUA/PUSAT JANTUNG RS. DR. M

DJAMIL, PADANG

Topics of Discussion

Burden and Management of AF Challenges and limitation of ASA and VKA New Oral Anti Coagulants ( NOACs) Results of the studies with NOACs, RELY and

RELY-ABLE Results of RELY among Asian population What the Guideline Says The goal of OAC therapy Summary

Burden and Management of AF

Chowdhury P, et al. Cleve Clin J Med. 2009;76:543–550

Thrombus (clot)

Affectedportion of the brain

Atrial fibrillation is a supraventricular arrhythmia characterized by chaotic and uncoordinated contraction of the atrium

Sinus Rhytm

Atrial Fibriillation

The Stroke Association: www.stroke.org.uk. Base on: Office of National Statistics Health Statistics Quarterly, Winter 2001 "Stroke incidence and risk

factors in a population based cohort study“. The Stroke Association estimate that 5,000 people per year have a stroke in

Northern IrelandScottish Stroke Care Audit 2005/2006.

David Bloom's silent killer.David Bloom was an American television journalist covering Iraq war who died suddenly in 2003 after a pulmonary embolism.


Prevention of complications,

including thromboembolism

(particularly ischaemic stroke) and heart failure

Relief of symptoms

Choice of antithrombotic therapy should be tailored to the patient based on:

Risk of thromboembolism Risk of bleeding

ESC guidelines: Camm J et al. Eur Heart J 2010;31:2369–429;ACCF/AHA/HRS Focused Update Guidelines: Fuster V et al. J Am Coll

Cardiol 2011;57:e101–9


Superior Efficacy Profile of OAC vs ASA

to Prevent Stroke in Patients With

Non Valvuler AF

Hart et al, Ann Intern Med 2007;146:857–867


Friberg, Rosenqvist & Lip Eur Heart J 2012

Similar safety profile of OAC and ASA

in intracranial bleeding and major bleeding


Challenges and limitations of ASA and VKA

Camm AJ et al. Eur Heart J 2012;33:2719–47; Aspirin Tablets BP 300 mg: SmPC, 2013; Ansell J et al. Chest 2008;133;160S–198S; Nutescu

EA et al. Cardiol Clin 2008;26:169–87; Umer Ushman MH et al. J Interv Card Electrophysiol 2008;22:129–37

13

Is there any NEW,Better & Ideal Antithrombotic Agent?

At least as effective as warfarinPredictable responseWide therapeutic windowLow incidence and severity of adverse effectsOral fixed doseNo need for routine anticoagulation monitoringLow potential for food or drug interactionsFast onset and offset of action

Lip GY et al. EHJ Suppl. 2005;7:E21–25

Requirements ??

?

?

?

?

?

?

?

Guidelines ?

Long term safety profile ?

NOACs approved forprevention of systemic embolism or stroke in

patients with non-valvular AF

17

Dabigatran ® 150 mg twice daily is proven to provide superior Ischaemic Stroke prevention vs. Warfarin1

24% risk reduction in Ischaemic Stroke

Result of New OAC Clinical Studies RE-LY ® Results: Primary Endpoint

RRR24%

Haemorrhagic Stroke

Both dosages of Dabigatran® dramatically reduced the risk of haemorrhagic stroke compared with warfarin:1

RRR69%

RRR74%

18

RE-LY ® Results: Secondary EndpointLife-Threatening Bleeding

Rates

Intracranial Bleeding

Both doses of Dabigatran ®

Significantly reduced the riskof life threatening bleedingcompared with warfarin1

Both doses of Dabigatran ® substantially reduced the riskof intracranial bleedingcompared with warfarin1

RRR33%

RRR20%

RRR70%

RRR59%

25

Result of New OAC Clinical Studies(stroke ischemic)

The objective is to

reduce

Ischemic Stroke…

27

Result of New OAC Clinical Studies(Intracranial Hemorrhage)

… and minimizing the

risk of

Intracranial

Haemorrhage

Results of the studies with NOACs(CV Mortality)

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011Not head-to-head comparison – for illustrative purposes only

RE-LY® ROCKET-AFARISTOTLE

c

Results of RELY among Asian populationEfficacy outcomes (Asia vs. non-Asia)

RE-LY® Asia

Stroke or SEE Asia Non-Asia Ischemic stroke Asia Non-Asia Hemorrhagic stroke Asia Non-AsiaMyocardial infarction Asia Non-AsiaDeath from any cause Asia Non-Asia

Dabigatran 150mg bidvs. Warfarin


Rate (%/year)

110mg bidWarfarin

Dabigatran

1.0 2.00Warfarin better

HR (95%CI)

Dabigatran better

1.391.06

1.120.81

0.170.09

0.500.86

4.013.57

3.061.48

2.020.98

0.750.32

0.580.65

5.093.96

Interactionp value

Interactionp value

0.0853

0.1977

0.7590

0.3782

0.4244

150mg bid

2.501.37

2.051.14

0.110.12

0.510.88

5.013.53

0.5597

0.5959

0.2729

0.3761

0.5929

1.0 2.00Dabigatran better Warfarin better

HR (95%CI)

Results of RELY among Asian populationSafety outcomes (Asia vs. non-Asia)

RE-LY® Asia

Major bleeding Asia Non-Asia GI major bleeding Asia Non-Asia Life threatening bleeding Asia Non-Asia Intracranial bleeding Asia Non-AsiaMinor bleeding Asia Non-AsiaMajor or minor bleeding Asia Non-Asia



Rate (%/year)

150mg bid 110mg bidWarfarin

Dabigatran

1.0 2.00Warfarin betterDabigatran better

HR (95%CI)Interaction

p valueInteraction

p value

2.173.52

0.961.69

1.281.52

0.450.29

12.4315.27

13.9917.02

3.823.53

1.411.01

2.201.79

1.100.71

19.6615.81

22.0317.74

2.222.99

1.151.14

0.911.29

0.230.23

10.1213.69

11.7215.27

0.0079

0.0089

0.1749

0.9509

<0.0001

<0.0001

0.0705

0.3379

0.0738

0.4561

<0.0001

<0.0001

1.0 2.00Dabigatran better Warfarin better

HR (95%CI)

20

RELY-ABLE®

The RELY-ABLE® study: Long-term multi-centre extension of dabigatran treatment in patients with atrial fibrillationStudy design

RELY-ABLE®: Extension of RE-LY®

AF and ≥1 additional risk factor for stroke

Absence of contraindications

Warfarin (INR 2.0–3.0)

n=6022

Dabigatran etexilate

110 mg BIDn=6015


150 mg BIDn=6076


110 mg BIDN=2914


150 mg BIDN=2937

RELY-ABLE®

RE-LY®

R

OBJECTIVE:Evaluate long-term safety of dabigatran etexilate (two doses) in patients with AF

BID = twice daily

RELY-ABLE® goals, design and summary

Goals To describe the long-term efficacy and safety of ongoing

dabigatran therapy following RE-LY®

Methods Patients eligible at completion of RE-LY® study if:

▪ Alive and still receiving study dabigatran▪ Being followed at centre participating in RELY-ABLE®

Dabigatran blinded dose continued in RELY-ABLE® for 2.3 years

Analysis Two follow-up periods described

▪ RELY-ABLE® (post-RE-LY®)▪ RE-LY® + RELY-ABLE® (beginning of RE-LY® to end of RELY-

ABLE®)

RELY-ABLE® goals, design and summary

In patients who continued treatment on dabigatran after RE-LY®, the rates of stroke and major bleeding remain low

There were no new safety signal observed during this extended follow up period

The results from RELY-ABLE® are highly consistent with those observed in RE-LY®

What the Guideline Says: ESC 2012

Atrial fibrillation

Valvular AF*

Assess risk of stroke

CHA2DS2-VASc score

No antithrombotictherapy NOAC VKA

0 1

No (i.e. nonvalvular)

Yes

≥2

Oral anticoagulant therapy

<65 years and lone AF (including females)

Assess bleeding risk (HAS-BLED score)

Consider patient values and preferences to choose right dose

No

Yes

Recommended Optional

No room for Antiplatelet

Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253

What the Guideline Says: ESC 2012(Risk of stroke)

Update strongly recommends a practice shift towards identification of ‘truly low risk’ patients with AF (i.e. age <65 years and lone AF) who do not need antithrombotic therapy

CHADS2 does not reliably identify ‘truly low risk’ patients

CHA2DS2-VASc: inclusive of the most

common stroke risk factors

validated in multiple cohorts

better than CHADS2 at identifying ‘truly low risk’ patients

As good as CHADS2 in identifying patients who develop stroke and thromboembolism


What the Guideline Says: ESC 2012(Risk of bleeding)

HAS-BLED score:• allows clinicians to

make informed assessment of bleeding risk

• makes clinicians think of the correctable risk factors for bleeding

• has been validated in several independent cohorts

• correlates well with ICH risk

High HAS-BLED score per se should not be used to exclude patients from OAC therapy


28

2012

ESC Guidelines 2012for the management of AF

29 *Pending approval; INR = international normalized ratio; OAC = oral anticoagulation; VKA = vitamin K antagonist Camm AJ et al. Eur Heart J doi:10.1093/eurheartj/ehs253

Recommendation Class Level

In patients with CHA2DS2-VASc score ≥2, OAC therapy with:•a dose-adjusted VKA (INR 2–3); or•a direct thrombin inhibitor (dabigatran); or•an oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban*)… is recommended unless contraindicated

I A

In patients with CHA2DS2-VASc score 1, OAC therapy with:•a dose-adjusted VKA (INR 2–3); or•a direct thrombin inhibitor (dabigatran); or•an oral Factor Xa inhibitor (e.g. rivaroxaban, apixaban*)… should be considered, based upon an assessment of the risk of bleeding complications and patient preferences

IIa A

THE GOAL of OAC therapy

“I need to maximize risk

reduction at the same time as

minimizing harm to the patient… “ - PCP CPA Study

1. Circulation. 2008; 118 : 2029-2037. 2. Connoly SJ et al. N Engl J Med 2009; 361(12): 1139-1151

34

Is there any NEW,Better & Ideal Antithrombotic Agent?

At least as effective as warfarinPredictable responseWide therapeutic windowLow incidence and severity of adverse effectsOral fixed doseNo need for routine anticoagulation monitoringLow potential for food or drug interactionsFast onset and offset of action

Lip GY et al. EHJ Suppl. 2005;7:E21–25

Requirements Dabigatran SUPERIOR

YES

YES

YES

YES

YES

YES

YES

Guidelines ACCP, ESC, AHA/ASA, NICE, CCS, PERDOSSI

Long term safety profile RELY-ABLE, PMS(FDA and EMA)

Summary AF confers an increased risk of stroke, which is

dependant upon the presence of various stroke risk factors All NVAF patient with ≥ 1 risk of stroke should receive

anticoagulation - ASA is not an alternative, availability of NOACs has led to revisions in treatment guidelines

The net clinical benefit balancing ischaemic stroke vs intracranial bleeding favors Dabigatran from RE-LY®

Net clinical benefit was consistently in favor of DE for both doses compared with warfarin, in both Asians and non-Asians

Give right dose for the right patient (150mg or 110mg): Age, HASBLED, renal function and drug interactions

Dabigatran provides long-term safety data in this setting (RELY-ABLE, PMS EMA and FDA)

Documents

Stroke Prevention in Atrial Fibrillation Trial Data are Supported by Clinical Experience