Υπέρταση, Κολπική μαρμαρυγή και νέα αντιθρομβωτικά...

Director of Cardiology Dept, Asklepeion General Hospital,

Athens Greece.

New Generation of Anticoagulant Drugs In Cardiovascular Diseases

Athanasios J. Manolis

Congress set aside $ 1.1 billion last year for head-to-head testing of drugs and treatment to determine which work best and for which type of patient

AF is the Most Common Cardiac Arrhythmia

AF affects 1 in 25 adults >60 years1 1 in 10 adults >80 years1

6.8 million patients with AF in EU and US*1,2

* EU 2001, US 2006, both cited in 2006 guidelines1. Go AS et al. JAMA 2001;285:2370-2375

2. Fuster V et al. J Am Coll Cardiol 2006;38:1231-1265

4.5 million

2.3 million

0 1 2 3 4 5

US

EU

Risk Factor for the Development of AF

38-year follow-up of the Framingham study

Risk factors

Age

adj

uste

d od

ds r

atio

Cigarettes

1

2

3

4

0

Diabetes ECG LVH Hypertension BMI Alcohol

AF Increases Risk Along the Cardiovascular Continuum

LVH = Left Ventricular Hypertrophy; RAAS = Renin-Angiotensin-Aldosterone System.1. Benjamin EJ et al. JAMA 1994;271:840-844; 2. Krahn AD et al. Am J Med 1995;98:476-484;

3. Nakashima H et al. Circulation 2000;101:2612-2617; 4. Tsai CT et al. Circulation 2004;109:1640-1646

Risk factors(diabetes,

hypertension)

Atrial Fibrillation1,2

MI

Atherosclerosisand LVH

Remodelling Ventriculardilation

Heart failure

End-stage microvascular

andheart disease

Death

26/04/23 05:24 a.m.11760 M11760 M

ESH/ESC Guidelines and Search for ESH/ESC Guidelines and Search for Subclinical Organ DamageSubclinical Organ Damage

20032003GLsGLs

20072007GLsGLs

SCr (> 1.4-1.5 mg/dl)SCr (> 1.4-1.5 mg/dl) eCrCl / GFReCrCl / GFRMAMAEKG †EKG †

SCr (> 1.4-1.5 mg/dl)SCr (> 1.4-1.5 mg/dl)EKG †EKG †

LVH (Echo)LVH (Echo)Concentric LVHConcentric LVHLA enlargementLA enlargementCA thickening / plaquesCA thickening / plaquesAnkle/Brachial ratioAnkle/Brachial ratioArterial stiffening (PWV)*Arterial stiffening (PWV)*

LVH (Echo)LVH (Echo)CA thickening / plaquesCA thickening / plaquesMAMA

Routine RecommendedSearch for Search for multiorgan ODmultiorgan ODOD assessed before OD assessed before and during Tand during T

* * Depending on availability / also shown by high SBP / low Depending on availability / also shown by high SBP / low DBPDBP† † LVH / MI-ischemia / ArrhythmiasLVH / MI-ischemia / Arrhythmias

What is Atrial Fibrillation?

In AF, Control of the Heart Rhythm is Taken Away from the Sinus Node

Veenhuyzen et al. CMAJ sept 28, 2004;171(7)

Normal electrical pathways

Abnormal electrical pathways

Sinus Rhythm Atrial Fibrillation

Multiple co-existing wavelets cause rapid and irregular atrial activity (400-600 bpm)

Sinus node

The Conclusive Sign of AF is the Absenceof P Waves on an ECG

On the ECG, rapid oscillations, or fibrillatory waves that varyin amplitude, shape, and timing, replace consistent P waves

There is an irregular ventricular response that is rapid when conduction is intact

Atrial Fibrillation

P T

QS

R

ACC/AHA/ESC 2006 guidelines J Am Coll Cardiol 2006;48:854-906

Sinus Rhythm

P wave

R-R Interval

AF Duration

AF is a Progressive Disease

Paroxysmal

Trigger dependent(Initiation)

Permanent

Substrate dependent

(Maintenance)Rel

ativ

e Im

port

ance

Khan IA Int J Card. 2003;87:301-302

Persistent

Over Time AF Causes Atrial Remodelling

Contractile remodelling-Reduced atrial contractility-Sets the stage for thrombus

formation-May lead to atrial dilation

further altering electrophysiologic properties

-Occurs rapidly

Structural remodelling-Histologic changes-Left atrium and left atrial

appendage enlargement-Decrease in cardiac output-Occurs after a period of

weeks to months

Shortened refractory

period

-80 mV

Electrical remodelling-Shortening of atrial

refractory periods-Occurs rapidly (within

several days) and contributes to the increased stability of AF

Van Gelder et al. Europace 2006;8:943-949

Cardiac Output Decreases and the Risk of Thromboembolism Increases

Atrial stasis

Loss of atrial systole compromises ventricular filling

Ventricle only ejects its contents

Risk of thromboembolism

Mainly in the left atrial appendage

Decrease in ventricular filling: about 20%

Decrease in cardiac output

Rapid and irregular

ventricular rate

Coronary flow is diastolic

Diastole shortens due to tachycardia

Oxygen consumption increases

Supply decreases


Loss of atrial contraction

(atrial systole)

What are the consequences of AF?

AF is an Independent Risk Factor for Stroke

AF patients have a near 5-fold increased risk of stroke1

1 in every 6 strokes occursin a patient with AF2

Ischemic stroke associatedwith AF is typically more severe than stroke due to other etiologies3

Stroke risk persists evenin asymptomatic AF4

1. Wolf et al. Stroke 1991;22:983-9882. Fuster V et al. Circulation 2006;114:e257-e354 3. Dulli DA et al. Neuroepidemiology 2003;22:118-1234. Page RL et al. Circulation 2003;107:1141-1145

AF Increases the Risk of Stroke Recurrence andPost-Stroke Mortality

AF patients Non-AF patients

1-year stroke recurrence 23% 8% p<0.001

30-day post stroke mortality 25% 14%

OR 1.84 (95% CI, 1.04 to

3.27)1-year post stroke mortality 63% 34% p<0.001

Lin HJ et al. Stroke 1996;27:1760-1764

Framingham

What are the current treatment strategies

for AF?

Atrial fibrillation is easy to find,

but evidence on how best to treat it isn’t

Current Treatment Strategies for AF

Prevention of thrombo-embolism

Rhythm control

Rate control


Effect of hypertension on anticoagulated patients with atrial fibrillation

Rates of stroke/SEE rate in SPORTIF III and V by quartiles of individual patient mean SBP values (84.0-122.6, 122.7-131.3, 131.4-140.7, and 140.8-191.7mmHg)

Lip G. et al., Eur Heart J 2007

0

1

2

3

SPORTIF III-V

XimelagatranQ1Q2Q3Q4

Warfarin Q1Q2Q3Q4

Eve

nt ra

te (%

PY)

1.52

1.061.47

2.52

1.061.47

1.77

2.26

AF Increases Risk Along the Cardiovascular Continuum

RAAS can impact the progression of AF and inhibition of RAAS can have some beneficial effects3,4

LVH = Left Ventricular Hypertrophy; RAAS = Renin-Angiotensin-Aldosterone System.1. Benjamin EJ et al. JAMA 1994;271:840-844; 2. Krahn AD et al. Am J Med 1995;98:476-484;

3. Nakashima H et al. Circulation 2000;101:2612-2617; 4. Tsai CT et al. Circulation 2004;109:1640-1646

Risk factors(diabetes,

hypertension)

Atrial Fibrillation1,2

MI

Atherosclerosisand LVH

Remodelling Ventriculardilation

Heart failure

End-stage microvascular

andheart disease

Death

Meta-analysis: Inhibition of renin-angiotensin system prevents new-onset atrial fibrillation

95% CI

RR Lower Limit Upper Limit % Weight

Hypertension trials

CAPPP 0.87 0.68 1.11 23.6

STOP-2 1.12 0.95 1.32 26.4

LIFE 0.66 0.54 0.81 25.2

VALUE 1.20 0.97 1.48 24.8

Pooled RR 0.94 0.72 1.23

Post-myocardial infarction trialsGISSI-3 0.92 0.83 1.01 60

TRACE 0.52 0.31 0.87 40

Pooled RR 0.73 0.43 1.26

Heart failure trialsVal-HeFT 0.67 0.54 0.83 38.7

SOLVD 0.22 0.12 0.43 21.9

CHARM 0.82 0.68 1.00 39.4

Pooled RR 0.57 0.37 0.89

Kishlay A. et al., Am. Hear J 2006; 152:217-22.

How Did RAS Blockers Reduce the Risk of Stroke “Beyond Blood Pressure”?

Cardiac remodeling/Cardiac remodeling/enlargementenlargement

Endothelial dysfunctionEndothelial dysfunction

Prothrombotic stateProthrombotic state

Vascular remodelingVascular remodeling

Reduced ECG–LVH

Improved endothelial function

Inhibition of platelet aggregationReduced proaggregatory factors

Inhibited atherosclerosis formationReduced carotid artery hypertrophy Reduced gluteal artery hypertrophy

Anti-thrombotic Therapy is Essential forReducing Risk of Stroke

Current clinical practice recommends that anticoagulation should be continued for life in patients at high risk of thrombo-embolism or with risk factors for atrial fibrillation recurrence

The CHADS2 (Cardiac Failure, Hypertension, Age, Diabetes, Stroke [Doubled]) is a points based system for predicting risk of stroke in AF, based on key risk factors and serves as a guideline for anticoagulation treatment

Prior stroke or TIA 2 pointsAge >75 years 1 pointHypertension 1 pointDiabetes mellitus 1 point Heart failure 1 point

CHADS2 Stroke Risk Stratification SchemeFor Patients With Nonvalvular AF

Risk Factors Score

C Recent congestive heart failure 1H Hypertension 1

A Age ≥ 75 y 1D Diabetes mellitus 1S2 History of stroke or transient ischemic attack 2

CHADS2 Score

Stro

ke R

ate

%

20

15

10

5

0

1.92.8

4.0 5.98.5

12.5

18.2

1 2 30 4 5 6

Relationship between CHADS2 score and annual risk of stroke

Stroke Risk Assessment in AF:CHA2DS2-VASC*

Stroke Risk Factors Score

Congestive heart failure / LV dysfunction

1

Hypertension 1

Age ≥75 yrs 2

Diabetes mellitus 1

Stroke / TIA / TE 2

Vascular disease

(prior MI, PAD, or aortic plaque)

1

Age 65-74 1

Sex category (i.e., female sex) 1

AF-related stroke is preventable

2/3 of strokes due to AF are preventable with appropriate anticoagulant therapy with a vitamin-K-antagonist (INR 2-3)1

Anticoagulation with a vitamin-K-antagonist (VKA) is recommended for patients with more than 1 moderate risk factor (age,HBP, CHF or LVD, Diabetes)

A meta-analysis of 29 trials in 28,044 patients showed that adjusted-dose warfarin results in a reduction in ischaemic stroke and in all-cause mortality1

Stroke Death

67% 26%

1. Hart RG et al. Ann Intern Med. 2007;146:857-867 2. Fuster V, et al. JACC. 2006; 48: 854-906

Effect of VKA compared to placebo

Oral VKAs

Advantages of warfarin

Used for more than 60 years

Well studied

Fairly effective if INR kept in therapeutic range

Well-known and defined drug and food interactions

Relatively inexpensive

Easy to reverse

Disadvantages of warfarin

Requires frequent monitoring to keep in therapeutic range

Multiple medication adjustments often required

Significant interactions with multiple medications and foods

Patient reluctance

Bad reputation among healthcare providers

Underuse of oral anticoagulants in AF:A Systematic Review

Ogilvie I et al Am J Med 2010;123:638

Underuse of oral anticoagulants for high-risk atrial fibrillation patients was found in most of the 54 studies (1998-2008) reporting both patient stroke risk and patients treated.

Over two thirds of studies of atrial fibrillation patients with prior stroke or transient ischemic attack reported treatment levels of under 60% of eligible patients.

Most studies based on CHADS2 score reported oral anticoagulant treatment levels of high-risk subjects below 70%.

Key features of a “new contender” in the prevention of CV events in AF

Freedom from coagulation monitoring

Simpler kinetic profile

More rapid onset and offset

Reduced or absent drug-drug and drug-food interactions

More “user-friendly” than Warfarin

Alternative to warfarin in patients with AF

Treatment Limitations

Clopidogrel+ASA > Effective vs. ASA alone but < Warfarin (ACTIVE-W study)

Idraparinux s.c. once weekly

> Effective vs. Warfarin but >> risk of bleeding (AMADEUS Study)

Oral Ximelagatran = Warfarin for efficacy and safety but hepatotoxicity (SPORTIF Studies)

Targets of different antithrombotic drugs

Indirect inhibition Direct inhibition(block the face of coagulation propagation)

FondaparinuxIdraparinux

AT III

Enoxaparin

AT III

UFH

AT III

Xa

IIIII

Apixaban

Bivalirudin

Dabigatran

-

-

-

RivaroxabanOtapixabanEdoxaban

--

-Thrombin inhibitors(prevent fibrin formation andblock throbin mediiated activationof other anticoagulant factors)

Apixaban

.

ROCKETAHA 11/10

Rivaroxaban

RE-LYRELYABLE

Dabigatran

2009 2010 2011

AVERROES estimated

completion April 2010

ARISTOTLEEstimated completion

November 2010

Atrial Fibrillation Phase 3 Study Timelines

ENGAGE-AF TIMI 48

Edoxaban

Oral Factor Xa inhibitors

Parenteral Factor Xa inhibitors(modified idraparinux)

New oral direct thrombin inhibitors(other than ximelagatran)

NEW PERSPECTIVES

Antithrombotic Prophylaxis in AF

Rivaroxaban Bayer Phase III

Apixaban Bristol-Myers Squibb Phase III

Edoxaban Daiichi Sankyo Phase III

YM 150 Astellas Pharma Planned

LY 517717 Lilly Planned

PRT 054021 Portola Planned

New Oral Direct FXa Inhibitors Under Investigation for Stroke Prevention in Atrial Fibrillation

ROCKET AF Trial

Rivaroxaban

Primary Endpoint: Stroke or non-CNS systemic embolismStatistics: non-inferiority, >95% power, 2.3% warfarin event

rate

Atrial Fibrillation

RandomizeDouble blind / Double Dummy

(n ~ 14,000)

Risk Factors• CHF • Hypertension • Age ≥ 75 • Diabetes

OR• Stroke, TIA, or Systemic embolus

At least 2 required

Monthly monitoring and adherence to standard of care guidelines

20 mg daily15 mg for Cr Cl 30-49

Warfarin

INR target - 2.5 (2.0-3.0 inclusive)

Primary Efficacy OutcomeStroke and non-CNS Embolism

Event Rates are per 100 patient-yearsBased on Protocol Compliant on Treatment Population

No. at risk:Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: <0.001

Days from Randomization

Cum

ulat

ive

even

t rat

e (%

)

Rivaroxaban

Rivaroxaban WarfarinEvent Rate 1.71 2.16

Rivaroxaban Warfarin Event Rate

Event Rate

HR(95% CI) P-value

On TreatmentN= 14,143

1.70 2.15 0.79 (0.65,0.95) 0.015

ITTN= 14,171 2.12 2.42 0.88

(0.74,1.03) 0.117

Rivaroxabanbetter

Warfarinbetter

Primary Efficacy OutcomeStroke and non-CNS Embolism

Event Rates are per 100 patient-yearsBased on Safety on Treatment or Intention-to-Treat thru Site Notification populations

Key Secondary Efficacy OutcomesRivaroxaban Warfarin

Event Rate Event Rate HR (95% CI) P-value

Vascular Death, Stroke, Embolism 3.11 3.63 0.86 (0.74, 0.99) 0.034

Stroke Type Hemorrhagic Ischemic Unknown Type

0.261.340.06

0.441.420.10

0.59 (0.37, 0.93)0.94 (0.75, 1.17)0.65 (0.25, 1.67)

0.0240.5810.366

Non-CNS Embolism 0.04 0.19 0.23 (0.09, 0.61) 0.003

Myocardial Infarction 0.91 1.12 0.81 (0.63, 1.06) 0.121

All Cause Mortality Vascular Non-vascular Unknown Cause

1.871.530.190.15

2.211.710.300.20

0.85 (0.70, 1.02)0.89 (0.73, 1.10)0.63 (0.36, 1.08)0.75 (0.40, 1.41)

0.0730.2890.0940.370

Event Rates are per 100 patient-yearsBased on Safety on Treatment Population

Rivaroxaban Warfarin

Event Rate or N (Rate)

Event Rate or N (Rate)

HR (95% CI) P-value

Major >2 g/dL Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death

3.602.771.650.820.24

3.452.261.321.180.48

1.04 (0.90, 1.20)1.22 (1.03, 1.44)1.25 (1.01, 1.55)0.69 (0.53, 0.91)0.50 (0.31, 0.79)

0.5760.0190.0440.0070.003

Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019

Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060

Intraventricular 2 (0.02) 4 (0.04)

Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051

Subarachnoid 4 (0.04) 1 (0.01)

Event Rates are per 100 patient-yearsBased on Safety on Treatment Population

Primary Safety Outcomes

Summary

Efficacy: Rivaroxaban was non-inferior to warfarin for prevention of

stroke and non-CNS embolism. Rivaroxaban was superior to warfarin while patients were

taking study drug. By intention-to-treat, rivaroxaban was non-inferior to

warfarin but did not achieve superiority. Safety:

Similar rates of bleeding and adverse events. Less ICH and fatal bleeding with rivaroxaban.

Conclusion: Rivaroxaban is a proven alternative to warfarin for

moderate or high risk patients with AF.

ARISTOTLE

APIXABAN Phase 3 Clinical Trial vs Warfarin to Prevent Stroke or Embolism in AF Pts

AF = atrial fibrillation; INR = international normalized ratio.National Institutes of Health Clinical Trials.gov.

www.clinicaltrials.gov/ct2/show/NCT00412984?term=apixaban&rank=4. Accessed January 16, 2008.

Apixaban 2.5 mg bid or 5 mg bid

Warfarin 2 mg qd, target INR 2.0-3.0

Primary outcome measures: Time to first occurrence of confirmed stroke or systemic embolismTime to major bleeding in treatment or follow-up

Patient characteristics

Ran

dom

izat

ion

≈ 1.8 years

• Aged 18 years

• Atrial fibrillation

1 additional risk factor for stroke

N=15,000

ENGAGE-AF-TIMI 48(Study for Evaluation of DU-176b (Edoxaban) vs Warfarin in Subjects with AF)

Low Exposure StrategyDU-176b 30 mg QD

(n=5500)

Active ControlWarfarin(n=5500)

High Exposure StrategyDU-176b 60 mg QD

(n=5500)

1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38)2º EP = Stroke or SEE or All-Cause MortalitySafety EP’s = Major Bleeding, Hepatic Function

AF on ECG < 12 mosIntended oral A/CCHADS2 Score > 2

RRandomization Strata:1. CHADS2 2-3 vs 4-62. Drug clearance

Median Duration of Followup 24 months

n~16,500

Patients with atrial fibrillation +

an indication for anticoagulation

IdrabiotaparinuxSubcutaneous, 3 mg once weekly

for 7 weeks, then adjusted based on age and renal function

Warfarin(INR 2.0–3.0)

R

BOREALIS-AF: Trial design

Primary outcome measures Efficacy: all stroke and systemic embolism Safety: clinically relevant bleeding

Ongoing

Double-blind

# CHADS2 ≥ 2

3-6

mon

ths

obse

rvat

iona

l per

iod

Anti-Thrombotic Prophylaxis in AF

Oral Factor Xa inhibitors

Parenteral Factor Xa inhibitors(modified idraparinux)

New oral direct thrombin inhibitors(other than ximelagatran)

NEW PERSPECTIVES

RE-LY® – study designAtrial fibrillation with ≥ 1 risk factor

Absence of contraindications

R

Warfarin1 mg, 3 mg, 5 mg

(INR 2.0-3.0)N=6000

Dabigatran etexilate 110 mg bid

N=6000

Dabigatran etexilate 150 mg bid

N=6000

Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin

Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up

Ezekowitz MD, et al. Am Heart J 2009;157:805-10.Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

RE-LY® – outcome measures

Primary efficacy endpoint

Secondary efficacy endpoints

Safety criteria include

All stroke (ischaemic + haemorrhagic) and systemic embolism

All stroke (ischaemic + haemorrhagic)

Systemic embolismAll death

Bleeding events (major and minor)

Pulmonary embolismAcute MIVascular death (incl.

deaths from bleeding)

Intracranial haemorrhage

Cerebral haemorrhage

Subdural haematomaSubarachnoid

haemorrhageElevations in liver

enzymes or hepatic dysfunction

Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

RE-LY Study: Time to first stroke / SSE

RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superiorConnolly SJ., et al. NEJM published online on Aug 30th 2009.

DOI 10.1056/NEJMoa0905561

0.01

0.02

0.03

0.05

0.04

Cum

ulat

ive

haza

rd r

ates

RR 0.91(95% CI: 0.74–1.11)p<0.001 (NI)p=0.34 (Sup)

RR 0.66(95% CI: 0.53–0.82)p<0.001 (NI)p<0.001 (Sup)

Years0 0.5 1.0 1.5 2.0 2.5

0.00

WarfarinDabigatran etexilate 110 mgDabigatran etexilate 150 mg

RRR34%

RE-LY Study: Hemorrhagic stroke

RR 0.26 (95% CI: 0.14–0.49)p<0.001 (sup)

RR 0.31 (95% CI: 0.17–0.56)p<0.001 (sup)

Num

ber o

f eve

nts

6,015 6,076 6,022

14 12

45

0

10

20

30

40

50

D110 mg BID D150 mg BID Warfarin

0.10%

0.38%

RRR69%

RRR74%

0.12%

RE-LY® – summary results

150 mg dose v. warfarin Statistically significant reduction in stroke/systemic embolism Statistically significant reduction in hemorrhagic stroke Statistically significant reduction in vascular mortality Comparable rates of major bleeding rates Significant reduction in total bleeds, life threatening bleeds and intracranial bleeds

110 mg dose versus warfarin Comparable rates of stroke/systemic embolism Statistically significant reduction in hemorrhagic stroke Statistically significant reduction in major bleeding rates Significant reduction in total bleeds, life threatening bleeds and intracranial bleeds

Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

Bleeding Risk Assessment in AF:

HAS-BLED Bleeding Risk ScoreClinical

Characteristic* Points Awarded

H Hypertension 1

A Abnormal renal and liver function (1 point each )

1 or 2

S Stroke 1B Bleeding 1L Labile INRS 1E Elderly 1D Drugs or alcohol 1 or 2

Maximum 9 points

Letter

Ideal candidates for the use of Dabigatran among

patients with AF

Warfarin-naïve

Hard to maintain the therapeutic range

Previous bleeding complication with Warfarin

Multiple medications (high risk of interactions)

Open issues in the RE-LY study

Short follow-up (safety requires longer observations)

Small but significant excess of MI in high dose of Dabigatran

vs. Warfarin

The risk/benefit of combining Warfarin with antiplatelet agents

(only 20% of study patients)

Safety and efficacy in patients with renal failure

(<30 ml/min excluded from study)

No known antidote or reversal agent for Dabigatran

Dabigatran: FDA approval

FDA advisory panel in September voted 9-0 to recommend that dabigatran be approved

FDA approved October 20,2010

Doses approved: 150 mg twice daily

75 mg twice daily (severe renal impairment)

Canadian Cardiovascular Guidelines for AF

Based on its safety and efficacy profile, dabigatran is preferred over warfarin. Overall, the 150 mg dose of dabigatran is preferred over the 110 mg dose.

For patients at low risk of stroke (CHADS2 score=1), treatment should include either warfarin or dabigatran. However, based on individual risk/benefit considerations, aspirin is a resonable alternative.

For patients at moderate to high risk of stroke (CHADS2 >2), treatment should include either warfarin or dabigatran

October 26,2010

How can we make a strong recommendation

from one trial?

That single trial includes more patients than all the trials with warfarin combined (18.000 patients)

Comprehensive Management of AF Should Addressits Multiple Impacts

In addition to stroke prevention and reduction of AF burden*, successful management of AF should also aim at further reducing

hospitalisations as well as CV morbidity and mortality

Prevention of

thrombo-embolism

Reduction of AF burden*↑ QoL↓ Symptoms

Reduction in the risk

of CV events and

hospitalisations

Reductionin

mortality

Current Treatment Strategies for AF

Rhythm control

Rate control

Prevention of thromboembolism

The Aim of Rhythm Control is to RestoreSinus Rhythm and Maintain it

Restore sinus rhythm Maintain sinus rhythm

Successful rhythm control has physiological advantages over rate control:

Produces better control of symptoms than rate controlCan also improve left ventricular function and exercise capacity, even compared to AF patients with controlled ventricular rate

Lip et al. Lancet 2007;370:604 -18

Anti-arrhythmic drugs (AADs)

Electrical cardioversion

Structural Differences Between Dronedarone and Amiodarone

Zimetbaum PJ, et al. N Engl J Med 2009;360(18):1811-13.

Schafer JA, et al. Cardiovasc Ther 2010

Dronedarone AmiodaroneBioavailability Increased to 15% with

food50%

Volume of Distribution ~12L/kg ~60L/kgProtein Binding >98% ~96%Metabolism Primarily CYP3A4 CYP3A4 and CYP2D6

Elimination half life ~13-19h ~58 daysExcretion Feces: 84%

Renal: 6%Hepatically

Dose Adjustment in Renal Impairment?

None None

Dose Adjustment in Hepatic Impairment?

Moderate: NoneSevere: Contraindicated

Limited data. Monitoring recommended

Dronedarone has Multiple Properties

Extensive anti-arrhythmic efficacy at atrial and ventricular level1, 2

Rate controlling effects1

Vasodilatory effects2

Anti-adrenergic effects3

Blood pressure lowering properties4

1 Gautier P, et al. J Cardiovasc Pharmacol. 2003;41(2):191-202. 2 Hodeige D, et al. European Journal of Pharmacology 1995;279:25-32.

3 Guiraudou P, et al. European Journal of Pharmacology 2004;496:119-127.4 Hohnloser SH et al. N Engl J Med 2009;360:668-78.

Multaq [package insert]. Bridgewater, NJ: Sanofi Aventis; 2009

• Dronedarone increases serum creatinine levels~0.1 mg/dl increaseInhibits tubular secretion of creatinineNo effect on GFRRapid onset, plateaus after 7 days, reversible upon drug discontinuation

Dronedarone – Warnings

DAFNEDronedarone 400mg bid Significantly

Prolonged Time to First AF Recurrence

Touboul P, et al. Eur Heart J. 2003;24:1481-7.

0 30 60 90 120 150 180Days0.0

0.1

0.20.30.40.50.60.70.80.91.0

Prop

ortio

n of

pat

ient

s in

sin

us rh

ythm

0 30 60 90 120 150 180

PlaceboDR 800mgDR 1200mgDR 1600mg

55% RRR800mg vsplacebo (p=0.001)

Patients with persistent AF were randomly allocated to 800, 1200, 1600 mg daily doses of dronedarone or placebo. The main analysis was conducted on 199/270 patients, who

entered the maintenance phase following pharmacological cardioversion or, if unsuccessful, DC cardioversion.

EURIDIS and ADONISObjective

EURIDIS and ADONIS investigated whether dronedarone is superior to placebo on top of standard therapy* for maintaining sinus rhythm after electrical, pharmacologic, or spontaneous conversion from atrial fibrillation or atrial flutter

Singh BN, et al. N Engl J Med. 2007;357:987-99.

* Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonists and/or digoxin) and/or anti-

thrombotic therapy (oral anticoagulation and/or long-term antiplatelet therapy) and/or other cardiovascular therapy such as ACE inhibitors and statins

Hohnloser, M.D., for the EURIDIS and ADONIS Investigators, NEJM 2007

828 patients at least 21 years of age with at least one episode of atrial fibrillation in the preceding 3 months, in sinus rhythm for at least 1 hour before randomization. receiving dronedarone 400 mg twice daily and 409 receiving placebo FU 12 months

Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter

1000 patients who were hospitalized with symptomatic heart failure and severe LV systolic dysfunction randomized to receive 400 mg of dronedarone twice a day or placebo. The primary end point was the composite of death from any cause or hospitalization for heart failure

Conclusions: In patients with severe heart failure and left ventricular systolic dysfunction, treatment with dronedarone was associated with increased early mortality related to the worsening of heart failure.

HR in the dronedarone group, 1.38; 95% CI,0.92 to 2.09; p = 0.12

HR in the dronedarone group, 2.13; 95% CI, 1.07 to 4.25; p = 0.03

N Engl J Med 2008

ANDROMEDA

0

10

20

30

40

Primaryendpoint

Firsthospitalization for CV causes

%

p<0.001

p<0.001

DronedaronePlacebo

p<0.001

p=0.18p=0.03

p=0.01

Firsthospitalization

for AF

Death fromany cause

Death fromCV

causes

Death fromcardiac

arrhythmias

Hohnloser et al for the ATHENA Investigators, N Engl J Med 2009

ATHENA-Results

“Conclusions—In this post hoc analysis, a reduction in stroke was observed in patients with atrial fibrillation who were receiving usual care, which included antithrombotic therapy and heart rate control, who were randomized to dronedarone. Further studies to investigate the effect of dronedarone and other antiarrhythmic agents on stroke are indicated” Connolly et al, Circulation 2009

Analysis of Stroke in ATHENA:A Placebo-Controlled Double-Blind, Parallel-Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients With Atrial Fibrillation / Atrial Flutter

Five hundred and four amiodarone-naıve patients were randomized to receive dronedarone 400 mg bid (n = 249) or amiodarone 600 mg qd for 28 days then 200 mg qd (n = 255) for at least 6 months.

Primary composite endpoint was recurrence of AF (including unsuccessful electrical cardioversion, no spontaneous conversion and no electrical cardioversion) or premature study discontinuation.

Main safety endpoint (MSE) was occurrence of thyroid-, hepatic-, pulmonary-, neurologic-, skin-, eye-, or gastrointestinal-specific events, or premature study drug discontinuation following an adverse event.

J Cardiovasc Electrophysiol, Vol. 21, pp. 597-605, June 2010

A Short-Term, Randomized, Double-Blind, Parallel-Group Study to Evaluate the Efficacy and Safety of Dronedarone

versus Amiodarone in Patients with Persistent Atrial Fibrillation:

The DIONYSOS Study

§ Primary composite endpoint: Time to first AF Recurrence or Premature Drug Discontinuation at 12 months

DIONYSOS-RESULTS


0.0%10.0%20.0%30.0%40.0%50.0%60.0%70.0%80.0%

Composite 1 Endpoint

First Recurrence Premature Drug D/C

Amiodarone Dronedarone

55.3%

* 73.9%

42.0%

63.5%

13.3% 10.4%

o


§ Primary Safety Endpoint: First occurrence of a thyroid, hepatic, pulmonary, neurologic, skin, ocular, or GI related event, or any adverse event requiring drug discontinuation

“Conclusion: In this short-term study, dronedarone was less effective than amiodarone in decreasing AF recurrence, but had a better safety profile, specifically with regard to thyroid and neurologic events and a lack of interaction with oral anticoagulants.”

Adverse Event Dronedarone Amiodarone P ValuePrimary SafetyEndpoint

33.9% 44.5% p=0.13

GI 13.3% 7.1%Thyroid 1.2% 7.8% p<0.001Neurologic 1.2% 9.4% p<0.001

Ocular and hepatic events were similar between groups.No cases of pulmonary fibrosis in either group.

ADVERSE EVENT

Piccini et al, J Am Coll Cardiol 2009

- a systematic overview of all randomized controlled trials in which the authors evaluated dronedarone or amiodarone for the prevention of AF. The effect of amiodarone versus dronedarone was summarized by the use of indirect comparison meta-analysis and normal logistic meta-regression models.


Comparative Efficacy of Dronedarone and Amiodarone for the Maintenance of Sinus Rhythm in Patients with

Atrial Fibrillation

”…A normal logistic regression model incorporating all trial evidence found amiodarone superior to dronedarone (OR: 0.49; 95% CI: 0.37 to 0.63; p 0.001) for the prevention of recurrent AF. In contrast, these models also found a trend toward greater all-cause mortality (OR: 1.61; 95% CI: 0.97 to 2.68; p 0.066) and greater overall adverse events requiring drug discontinuation with amiodarone versus dronedarone (OR: 1.81; 95% CI: 1.33 to 2.46; p 0.001).

”Conclusion: Dronedarone is less effective than amiodarone for the maintenance of sinus rhythm, but has fewer adverse effects. For every 1,000 patients treated with dronedarone instead of amiodarone, we estimate approximately 228 more recurrences of AF in exchange for 9.6 fewer deaths and 62 fewer adverse events requiring discontinuation of drug.”


Comparative Efficacy of Dronedarone and Amiodarone for the Maintenance of Sinus Rhythm

in Patients with Atrial Fibrillation

• Indicated to reduce the risk of CV hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL). Dose: 400mg po BID• Patients:

In sinus rhythm or who will be cardioverted Recent episode of AF/AFL CV risk factors

Age > 70yrsHypertensionDiabetesPrior CVALeft Atrial Diameter > 55 mm EF < 40%

Dronedarone: FDA Approval: July 2009

Potential Role for Amiodarone and Dronedarone in AF

*Dronedarone as a reasonable alternative for patients intolerant of first-line treatment. Adapted from Singh et al, JACC 2010

Conclusions

Dronedarone exhibits both rhythm and rate control properties and has been proven to significantly prolong time to AF recurrence and decrease ventricular rate

Dronedarone demonstrates a low risk of pro-arrhythmia, cardiac and extra-cardiac toxicity, with favourable tolerability

However, ANDROMEDA results preclude its use in patients with unstable heart failure, such as patients with Class IV heart failure or recent hospitalization for decompensation of heart failure

Dronedarone is easy-to-use because of its fixed-dosing regimen, outpatient initiation and minimal monitoring requirements

Dronedarone is the only anti-arrhythmic drug proven to reduce CV hospitalisation or mortality in AF patients, excluding those with unstable heart failure, whilst also prolonging time to AF recurrence and providing rate control - all achieved with a favourable safety profile

Warfarin, Aspirin, or Both after MI (WARIS)

Distribution of Separate Events According to Treatment Group*

*CI denotes confidence interval, and NS not significant†The rate ratio is for aspirin plus warfarin as compared with aspirin‡The rate ratio is for warfarin as compared with aspirin

Event

Thromboembolic stroke

Death

Reinfarction

No. of events

Aspirin(n=1206)

Aspirin PlusWarfarin(n=1208)

Warfarin(n=1216)

Rate Ratio(95% CI) P Value

17

69

96

17

90117

32

92 95

0.74 (0.55-0.98)‡

0.56 (0.41-0.78)†

0.52(0.28-0.98)†

0.52(0.28-0.97)‡ .03

.82

.03

.03

<.001

A Phase II RE-DEEM OverviewRandomized, double-blind, placebo-controlled, dose escalation

studyST elevation or non-ST elevation ACS with

≥1 additional risk factor for CV complications, on aspirin & clopidogrel at randomization

Placebo BIDN=373

Dabigatran50 mg BID

N=372

Dabigatran75 mg BID

N=371

Dabigatran110 mg BID

N=411

Dabigatran150 mg BID

N=351

Randomization within 14 days

Study treatment for 6 months

Primary outcome: Major * + clinically relevant minor bleedsSecondary (efficacy): Coagulation activity (D-dimer)

Clinical endpoints (death, MI, stroke)

RE-DEEMPrimary Outcome - Bleeding

ITT= Intention to treat;OT=On treatment (within 3 days before the event)

00

11

22

33

44

55

66

77

88

%%

ITTITT OOTT

Clinically relevant minorClinically relevant minor99

Major (ISTHMajor (ISTH))

OOTT

OTOT OOTT

ITTITT ITTITTITTITT

7

P<.001 linear trendP<.001 linear trendN=1861N=1861

Dabigatran 110Dabigatran 110PlaceboPlacebo DabigatranDabigatran 75 75DabigatranDabigatran 5050

722

Dabigatran 150Dabigatran 150

33

OOTT

ITTITT

22

109

23 23

6688

1514

44 44

2324

APPRAISEISTH Major or

CR Minor BleedingDual Antiplatelet Group

RE-DEEMISTH Major or

CR Minor BleedingDual Antiplatelet

ATLASTIMI Major + Minor

+ Req Medical AttentionDual Antiplatelet Group

12%

10%

8%

6%

4%

2%

0% Placebo Apixaban Placebo D50 D75 D110 D150 Placebo Rivaroxaban 2.5 BID 5 BID 2.5 BID 5 BID

RE-DEEMClinical Endpoint- Secondary Outcome

Composite of CV Death, Nonfatal MI, Stroke

9 6884425

9

5

4

3

2

0

8

7

6

1

89

4

3

4

2 98

8 8

8 87

4

ITTITT OOTT

OOTT

OTOT OOTT

ITTITT ITTITTITTITT OOTT

ITTITT

1 1%

Placebo Dabigatran 50 Dabigatran 75 Dabigatran 110 Dabigatran 150

Stroke

Nonfatal MI

CV death

Consequences of AF

Hospitalizations:Most common arrhythmia requiring hospitalization2-3 risk for hospitalization

Thromboembolism:Stroke: 4.5x riskMicroemboli: reduced cognitive functionProthrombotic state

Reduced QoL:Palpitations, dyspnea, fatigue, exercise tolerance

Mortality:2x risk independent of comorbid CV diseaseSudden death in heart failure and HCM

Impaired Hemodynamics:Loss of atrial kickIrregular ventricular contractionsHeart failureTachycardia-induced cardiomyopathy

Sinus Rhythm Strategy:Who Are Appropriate Candidates?

Highly symptomatic with AFFirst episodeReversible causeYoung ageSymptomatic despite rate controlRate-related cardiomyopathyLV dysfunction / CHFDiastolic dysfunction with symptomsHCM or aortic stenosisPrior embolic stroke or TIA

New Pharmacologic Agents for AF

Multi-ion channel blockers:

DronedaroneBudiodarone

Atrial-selective AADs:

I Kur -, Ito and I KACh - blockerAtrial-selective Na channel blockerHistamine (5-HT4) receptor antagonist

Other ion channel blockersOther mechanismsUpstream therapies:

StatinsACEI / ARBOmega -3 fatty acidsAnti-inflammatory drugs

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