Υπέρταση, Κολπική μαρμαρυγή και νέα αντιθρομβωτικά φάρμακα by Cardio Asklepeion

New Generation of Anticoagulant Drugs In Cardiovascular Diseases

Athanasios J. Manolis

Director of Cardiology Dept, Asklepeion General Hospital, Athens Greece.

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

4.5 million

2.3 million 0

* EU 2001, US 2006, both cited in 2006 guidelines 1. Go AS et al. JAMA 2001;285:2370-2375 2. Fuster V et al. J Am Coll Cardiol 2006;38:1231-1265

Risk Factor for the Development of AF

Age adjusted odds ratio

38-year follow-up of the Framingham study 4 3 2 1 0

Cigarettes

Diabetes ECG LVH Hypertension

Risk factors

BMI

Alcohol

AF Increases Risk Along the Cardiovascular Continuum

Remodelling

Ventricular dilation

Heart failure

Atherosclerosis and LVH

Risk factors (diabetes, hypertension)

Atrial Fibrillation1,2

End-stage microvascular and heart disease

Death

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

ESH/ESC Guidelines and Search for Subclinical Organ Damage 2003 2003 GLs GLs

LVH (Echo) CA thickening / plaques MA

↑ SCr (> 1.4-1.5 mg/dl) EKG †

Routine

2007 2007 GLs GLs

12/12/12 03.28 p. 11760 M

Recommended

↑ SCr (> 1.4-1.5 mg/dl) ↓ eCrCl / GFR MA EKG †

Search for multiorgan OD OD assessed before and during T

LVH (Echo) Concentric LVH LA enlargement CA thickening / plaques Ankle/Brachial ratio Arterial stiffening (PWV)*

* Depending on availability / also shown by high SBP / low DBP

What is Atrial Fibrillation?

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

Atrial Fibrillation

Sinus node

Abnormal electrical pathways Normal electrical pathways

Multiple co-existing wavelets cause rapid and irregular atrial activity (400-600 bpm) Veenhuyzen et al. CMAJ sept 28, 2004;171(7)

The Conclusive Sign of AF is the Absence of P Waves on an ECG On the ECG, rapid oscillations, or fibrillatory waves that vary in amplitude, shape, and timing, replace consistent P waves There is an irregular ventricular response that is rapid when conduction is intact

Sinus Rhythm R

R-R Interval

P Q

P wave

Atrial Fibrillation

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

AF is a Progressive Disease

Relative Importance

AF Duration

Trigger dependent (Initiation)

Substrate dependent (Maintenance)

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

Over Time AF Causes Atrial Remodelling  Contractile remodelling  Electrical remodelling -

Shortening of atrial refractory periods Occurs rapidly (within several days) and contributes to the increased stability of AF

Shortened refractory period

 Structural remodelling -

-80 mV

Reduced atrial contractility Sets the stage for thrombus formation May lead to atrial dilation further altering electrophysiologic properties Occurs rapidly

Histologic changes Left atrium and left atrial appendage enlargement Decrease in cardiac output Occurs after a period of weeks to months

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

Cardiac Output Decreases and the Risk of Thromboembolism Increases

 Atrial stasis

Loss of atrial contraction (atrial systole)

 Loss of atrial systole compromises ventricular filling  Ventricle only ejects its contents

Rapid and irregular ventricular rate

 Coronary flow is diastolic  Diastole shortens due to tachycardia

 Risk of thromboembolism  Mainly in the left atrial appendage  Decrease in ventricular filling: about 20%  Decrease in cardiac output

 Oxygen consumption increases  Supply decreases

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

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 occurs in a patient with AF2 Ischemic stroke associated with AF is typically more severe than stroke due to other etiologies3 Stroke risk persists even in asymptomatic AF4 1. Wolf et al. Stroke 1991;22:983-988 2. Fuster V et al. Circulation 2006;114:e257-e354 3. Dulli DA et al. Neuroepidemiology 2003;22:118-123 4. Page RL et al. Circulation 2003;107:1141-1145

AF Increases the Risk of Stroke Recurrence and Post-Stroke Mortality Framingham

1-year stroke recurrence

AF patients

Non-AF patients

23%

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

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

Rate control Rhythm control

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

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)

Event rate (%PY)

3 2.52 2.26 2

1.77

1.52

1.47

1.47 1.06

1.06 1

SPORTIF III-V Ximelagatran Q1Q2Q3Q4

Warfarin Q1Q2Q3Q4 Lip G. et al., Eur Heart J 2007

AF Increases Risk Along the Cardiovascular Continuum

Remodelling

Ventricular dilation

Heart failure

Atherosclerosis and LVH

Risk factors (diabetes, hypertension)

Atrial Fibrillation1,2

End-stage microvascular and heart disease

Death

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

Meta-analysis: Inhibition of renin-angiotensin system prevents new-onset atrial fibrillation 95% CI

Lower Limit

Upper Limit

% Weight

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

GISSI-3

0.92

0.83

1.01

TRACE

0.52

0.31

0.87

Pooled RR

0.73

0.43

1.26

Val-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

Hypertension trials

Post-myocardial infarction trials

Heart failure trials

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/ enlargement

Reduced ECG–LVH

Vascular remodeling

Inhibited atherosclerosis formation Reduced carotid artery hypertrophy Reduced gluteal artery hypertrophy

Endothelial dysfunction

Improved endothelial function

Prothrombotic state

Inhibition of platelet aggregation Reduced proaggregatory factors

Anti-thrombotic Therapy is Essential for Reducing 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 Age >75 years Hypertension Diabetes mellitus

2 points 1 point 1 point 1 point

CHADS2 Stroke Risk Stratification Scheme For Patients With Nonvalvular AF Risk Factors

Score

Recent congestive heart failure

Hypertension

Age ≥ 75 y

Diabetes mellitus

History of stroke or transient ischemic attack

Stroke Rate %

18.2

12.5

10 5

1.9

2.8

4.0

5.9

Relationship between CHADS2 score and annual risk of stroke

8.5

0 0

CHADS2 Score

Stroke Risk Assessment in AF: CHA2DS2-VASC* Stroke Risk Factors

Score

Congestive heart failure / LV dysfunction

Hypertension

Age ≥75 yrs

Diabetes mellitus

Stroke / TIA / TE

Vascular disease

(prior MI, PAD, or aortic plaque) Age 65-74

Sex category (i.e., female sex)

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

Effect of VKA compared to placebo Stroke

Death

67%

26%

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

Oral VKAs Advantages of warfarin

Disadvantages of warfarin

 Used for more than 60 years

 Requires frequent monitoring to keep in therapeutic range

 Well studied  Fairly effective if INR kept in therapeutic range  Well-known and defined drug and food interactions

 Multiple medication adjustments often required  Significant interactions with multiple medications and foods  Patient reluctance

 Relatively inexpensive  Easy to reverse

 Bad reputation among healthcare providers

Underuse of oral anticoagulants in AF: A Systematic Review Underuse of oral anticoagulants for high-risk atrial fibrillation patients was found in most of the 54 studies (19982008) 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%.

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

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 Clopidogrel+ASA

Limitations > 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)

Fondaparinux Idraparinux AT III

Enoxaparin

Apixaban Rivaroxaban Otapixaban Edoxaban

AT III UFH AT III

II III

Thrombin inhibitors (prevent fibrin formation and block throbin mediiated activation of other anticoagulant factors)

Bivalirudin Dabigatran

Atrial Fibrillation Phase 3 Study Timelines Dabigatran

Rivaroxaban

Edoxaban

RE-LY RELYABLE

ROCKET AHA 11/10

ENGAGE-AF TIMI 48

2009

2010

2011

AVERROES estimated completion April 2010

ARISTOTLE Estimated completion November 2010

Apixaban .

Antithrombotic Prophylaxis in AF NEW PERSPECTIVES  Oral Factor Xa inhibitors  Parenteral Factor Xa inhibitors (modified idraparinux)  New oral direct thrombin inhibitors (other than ximelagatran)

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

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

ROCKET AF Trial Atrial Fibrillation

Rivaroxaban

Randomize Double blind / Double Dummy (n ~ 14,000)

Risk Factors • CHF At least 2 • Hypertension required • Age ≥ 75 • Diabetes OR • Stroke, TIA, or Systemic embolus

Warfarin

INR target - 2.5 (2.0-3.0 inclusive)

20 mg daily 15 mg for Cr Cl 30-49

Monthly monitoring and adherence to standard of care guidelines

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

Primary Efficacy Outcome Stroke and non-CNS Embolism Cumulative event rate (%)

6 5

Rivaroxaban

Warfarin

1.71

2.16

Event Rate

Warfarin

Rivaroxaban

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

P-value Non-Inferiority: <0.001

1 0

No. at risk: Rivaroxaban 6958 Warfarin 7004

120

240

360

480

600

720

840

Days from Randomization 6211 6327

5786 5911

5468 5542

4406 4461

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

3407 3478

2472 2539

1496 1538

634 655

960

Primary Efficacy Outcome

Stroke and non-CNS Embolism Rivaroxaban

Warfarin

Event Rate

HR (95% CI)

P-value

On Treatment

1.70

2.15

0.79 (0.65,0.95)

0.015

ITT

2.12

2.42

0.88 (0.74,1.03)

0.117

N= 14,143

N= 14,171

Rivaroxaban better

Warfarin better

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

Key Secondary Efficacy Outcomes Rivaroxaban

Warfarin

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

0.26 1.34 0.06

0.44 1.42 0.10

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

0.024 0.581 0.366

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

1.87 1.53 0.19 0.15

2.21 1.71 0.30 0.20

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

0.073 0.289 0.094 0.370

Event Rates are per 100 patient-years Based on Safety on Treatment Population

Primary Safety Outcomes Rivaroxaban

Warfarin

Event Rate or N (Rate)

HR (95% CI)

P-value

3.60 2.77 1.65 0.82 0.24

3.45 2.26 1.32 1.18 0.48

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)

0.576 0.019 0.044 0.007 0.003

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)

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

Event Rates are per 100 patient-years Based on Safety on Treatment Population

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.

APIXABAN Phase 3 Clinical Trial vs Warfarin to Prevent Stroke or Embolism in AF Pts ARISTOTLE ≈ 1.8 years

Patient characteristics

• Atrial fibrillation ∀≥1 additional risk factor for stroke

Apixaban 2.5 mg bid or 5 mg bid

N=15,000

noi t azi mo dna R

• Aged ≥18 years

Warfarin 2 mg qd, target INR 2.0-3.0

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

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

n~16,500

AF on ECG < 12 mos Intended oral A/C CHADS2 Score > 2

R Low Exposure Strategy DU-176b 30 mg QD (n=5500)

Randomization Strata: 1. CHADS2 2-3 vs 4-6 2. Drug clearance

High Exposure Strategy DU-176b 60 mg QD (n=5500)

Median Duration of Followup 24 months 1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38) 2º EP = Stroke or SEE or All-Cause Mortality Safety EP’s = Major Bleeding, Hepatic Function

Active Control Warfarin (n=5500)

BOREALIS-AF: Trial design Double-blind Ongoing

# CHADS2 ≥ 2

Idrabiotaparinux Subcutaneous, 3 mg once weekly for 7 weeks, then adjusted based on age and renal function

Primary outcome measures 

Efficacy: all stroke and systemic embolism



Safety: clinically relevant bleeding

3-6 months observational period

Patients with atrial fibrillation + an indication for anticoagulation

Warfarin (INR 2.0–3.0)

Anti-Thrombotic Prophylaxis in AF NEW PERSPECTIVES  Oral Factor Xa inhibitors  Parenteral Factor Xa inhibitors (modified idraparinux)  New oral direct thrombin inhibitors (other than ximelagatran)

RE-LY® – study design Atrial fibrillation with ≥ 1 risk factor Absence of contraindications

R Warfarin 1 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

 All stroke (ischaemic + haemorrhagic) and systemic embolism

 All stroke (ischaemic + haemorrhagic)  Systemic embolism  All death Pulmonary embolism Acute MI Vascular death (incl. deaths from bleeding)

Safety criteria include  Bleeding events (major and minor)  Intracranial haemorrhage  Cerebral haemorrhage  Subdural haematoma  Subarachnoid haemorrhage  Elevations 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 0.91 (95% CI: 0.74–1.11) p<0.001 (NI) p=0.34 (Sup)

Cumulative hazard rates

0.05 0.04

RRR 34%

Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg

0.03

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

0.02

0.01

0.00 0

0.5

1.0

1.5

2.0

2.5

Years RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior Connolly SJ., et al. NEJM published online on Aug 30th 2009. DOI 10.1056/NEJMoa0905561

RE-LY Study: Hemorrhagic stroke RR 0.31 (95% CI: 0.17–0.56) p<0.001 (sup)

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

RRR 74%

RRR 69%

0.38%

st nev ef o r eb mu N

20 10

0.12%

0.10%

0 D110 mg BID

D150 mg BID

Warfarin

6,015

6,076

6,022

RE-LY® – summary results  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  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

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

Bleeding Risk Assessment in AF: HAS-BLED Bleeding Risk Score Letter

Clinical Characteristic*

Points Awarded

Hypertension

Abnormal renal and liver function (1 point each )

Stroke

Bleeding

Labile INRS

Elderly

Drugs or alcohol

1 or 2

1 or 2 Maximum 9 points

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 Address its 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 thromboembolism

Reduction of AF burden* ↑ QoL ↓ Symptoms

Reduction in the risk of CV events and hospitalisations

Reduction in mortality

Current Treatment Strategies for AF

Prevention of thromboembolism

Rate control Rhythm control

The Aim of Rhythm Control is to Restore Sinus Rhythm and Maintain it

Restore sinus rhythm

Maintain sinus rhythm

Anti-arrhythmic drugs (AADs) Electrical cardioversion

Successful rhythm control has physiological advantages over rate control: Produces better control of symptoms than rate control Can 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

Structural Differences Between Dronedarone and Amiodarone

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

Dronedarone

Amiodarone

Bioavailability

Increased to 15% with food

50%

Volume of Distribution

~12L/kg

~60L/kg

Protein Binding

>98%

~96%

Metabolism

Primarily CYP3A4

CYP3A4 and CYP2D6

Elimination half life

~13-19h

~58 days

Excretion

Feces: 84% Renal: 6%

Hepatically

Dose Adjustment in Renal Impairment?

None

Dose Adjustment in Hepatic Impairment?

Moderate: None Limited data. Severe: Contraindicated Monitoring recommended

Schafer JA, et al. Cardiovasc Ther 2010

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.

Dronedarone – Warnings

• Dronedarone increases serum creatinine levels ~0.1 mg/dl increase Inhibits tubular secretion of creatinine No effect on GFR Rapid onset, plateaus after 7 days, reversible upon drug discontinuation

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

DAFNE Dronedarone 400mg bid Significantly Prolonged Time to First AF Recurrence

Proportion of patients in sinus rhythm

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. 1.0 Placebo DR 800mg DR 1200mg DR 1600mg

0.9 0.8 0.7

55% RRR 800mg vs placebo (p=0.001)

0.6 0.5 0.4 0.3 0.2 0.1 0.0 0

120

150

180

Days

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

EURIDIS and ADONIS Objective  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

* Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonists and/or digoxin) and/or antithrombotic therapy (oral anticoagulation and/or long-term antiplatelet therapy) and/or other cardiovascular therapy such as ACE inhibitors and statins

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

Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter  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

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

ANDROMEDA 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

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

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. N Engl J Med 2008

ATHENA-Results 40

p<0.001 p<0.001

Dronedarone

Placebo p<0.001

10 p=0.18 p=0.03 p=0.01

0 Primary endpoint

First hospitalization for CV causes

First hospitalization for AF

Death from any cause

Death from CV causes

Death from cardiac arrhythmias

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

“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

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 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

DIONYSOS-RESULTS Amiodarone 80.0% 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0%

Dronedarone

* 73.9% 63.5% 55.3% 42.0%

13.3%

Composite 1 Endpoint

First Recurrence

10.4%

Premature Drug D/C

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

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

ADVERSE EVENT Adverse Event

Dronedarone

Amiodarone

P Value

Primary Safety Endpoint GI

33.9%

44.5%

p=0.13

13.3%

7.1%

Thyroid

1.2%

7.8%

p<0.001

Neurologic

1.2%

9.4%

p<0.001

Ocular and hepatic events were similar between groups. No cases of pulmonary fibrosis in either group. § 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.” J Cardiovasc Electrophysiol, Vol. 21, pp. 597-605, June 2010

Comparative Efficacy of Dronedarone and Amiodarone for the Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation - 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.

Piccini et et al, al, JJ Am Am Coll Piccini Coll Cardiol Cardiol2009 2009

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.” Piccini et al, J Am Coll Cardiol 2009

Dronedarone: FDA Approval: July 2009 • 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 > 70yrs Hypertension Diabetes Prior CVA Left Atrial Diameter > 55 mm  EF < 40%

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* Event

Aspirin (n=1206)

Warfarin (n=1216)

Aspirin Plus Warfarin (n=1208)

Rate Ratio P Value (95% CI)

No. of events

Reinfarction

117

Thromboembolic stroke

Death

*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

0.56 (0.41-0.78)†

<.001

0.74 (0.55-0.98)‡

.03

0.52(0.28-0.98)†

.03

0.52(0.28-0.97)‡

.03

.82

A Phase II RE-DEEM Overview Randomized, double-blind, placebo-controlled, dose escalation study ST elevation or non-ST elevation ACS with ≥1 additional risk factor for CV complications, on aspirin & clopidogrel at randomization

Randomization within 14 days

Placebo BID N=373

Dabigatran 50 mg BID N=372

Dabigatran 75 mg BID N=371

Dabigatran 110 mg BID N=411

Dabigatran 150 mg BID N=351

Study treatment for 6 months

Primary outcome: Secondary (efficacy):

Major * + clinically relevant minor bleeds Coagulation activity (D-dimer) Clinical endpoints (death, MI, stroke)

RE-DEEM Primary Outcome - Bleeding ITT= Intention to treat; OT=On treatment (within 3 days before the event) 9

Clinically relevant minor

Major (ISTH) P<.001 linear trend N=1861

O T

ITT

4 3 2

1 0

10 7

2 ITT

Placebo

O T

15 9

14 8

ITT

O T

Dabigatran 50

ITT

Dabigatran 75

ITT

Dabigatran 110

O T

Dabigatran 150

APPRAISE

RE-DEEM

ISTH Major or CR Minor Bleeding Dual Antiplatelet Group

ISTH Major or CR Minor Bleeding Dual Antiplatelet

ATLAS TIMI Major + Minor + Req Medical Attention Dual Antiplatelet Group

12%

10%

0% Placebo

Apixaban 2.5 BID 5 BID

Placebo D50 D75 D110 D150

Placebo

Rivaroxaban 2.5 BID 5 BID

RE-DEEM Clinical Endpoint- Secondary Outcome Composite of CV Death, Nonfatal MI, Stroke 9

Stroke

Nonfatal MI

CV death 1

5 4 3 3

1 8

8 7 8

O T

Placebo

ITT

O T

5 ITT

0 ITT

ITT

2 O T

ITT

O T

Dabigatran 50 Dabigatran 75 Dabigatran 110 Dabigatran 150

Consequences of AF

Hospitalizations: Most common arrhythmia requiring hospitalization 2-3 risk for hospitalization

Mortality: 2x risk independent of comorbid CV disease Sudden death in heart failure and HCM

Thromboembolism: Stroke: 4.5x risk Microemboli: reduced cognitive function Prothrombotic state

Reduced QoL: Palpitations, dyspnea, fatigue, exercise tolerance

Impaired Hemodynamics: Loss of atrial kick Irregular ventricular contractions Heart failure Tachycardia-induced cardiomyopathy

Sinus Rhythm Strategy: Who Are Appropriate Candidates?  Highly

symptomatic with AF

First episode Reversible cause Young age Symptomatic despite rate control Rate-related cardiomyopathy LV dysfunction / CHF Diastolic dysfunction with symptoms HCM or aortic stenosis Prior embolic stroke or TIA

New Pharmacologic Agents for AF Multi-ion channel blockers: Dronedarone Budiodarone

Atrial-selective AADs: I Kur -, Ito and I KACh blocker Atrial-selective Na channel blocker Histamine (5-HT4) receptor antagonist

Other ion channel blockers Other mechanisms Upstream therapies: Statins ACEI / ARB Omega -3 fatty acids Anti-inflammatory drugs