AF 2011: Therapeutic Update

Gerald V. Naccarelli M.D.

Research support:

Boston-Scientific, sanofi-aventis, Boehringer-Ingelheim, Glaxo-Smith-Kline, Astellas

Consultant:

Glaxo-Smith-Kline, Boston-Scientific, Medtronic, Pfizer, sanofi-aventis, Xention, Gilead, Novartis, Astra Zeneca, Boehringer-Ingelheim, Merck, Bristol Myers Squibb, Otsuka , Blue Ash Therapeutics, St. Jude’s, Cordis Webster, Ortho-McNeill, Daiichi-Sankyo

Projected Number of Patients with AF by 2050

16 14 12 10 8 6 4 2 MarketScan and Thomson Reuters Medicare Databases, 2009

2.08

Olmsted County Data, 2006

(assuming a continued increase in AF incidence)

Olmsted County Data, 2006

(assuming no further increase in AF incidence)

ATRIA Study Data, 2000

11.7

10.2

8.9

7.7

9.4

5.9

6.7

8.4

5.1

6.8

7.5

6.1

5.1

3.03

5.6

2.94

3.33

3.80

4.34

2.26

2.44

2.66

13.1

10.3

4.78

14.3

11.1

5.16

15.2

11.7

5.42

0 1990 1995 2000 2005 2010 2015 2020 Year 2025 2030 2035 2040 2045

15.9

12.1

7.56

5.61

2050 ATRIA = Anticoagulation and Risk Factors in Atrial Fibrillation.

Go AS, et al. JAMA. 2001;285(18):2370-2375. Miyasaka Y, et al. Circulation. 2006;114:119-125. Naccarelli GV, et al. Am J Cardiol. 2009;104(11):1534-1539.

AF: Prevalence of Common Co-morbidities

Naccarelli GV, et al. Am J Cardiol 2009; 104:1534-1539



The Consequences of AF

Thromboembolism

Stroke: 4.5

  increased risk Microemboli: reduced cognitive function  Prothrombotic state  

Mortality

2  increased risk independent of comorbid CV disease Sudden death in HF and HCM

Hospitalizations

 Most common arrhythmia  requiring hospitalization 2-3  increased risk for hospitalization 

Impaired Hemodynamics

 Loss of atrial kick Irregular ventricular contractions  HF  Tachycardia-induced cardiomyopathy

Reduced QoL

 Palpitations, dyspnea, fatigue, reduced exercise tolerance • AF is an enormous contributor to the growing cost of medical care HCM=hypertrophic cardiomyopathy; QoL=quality-of-life.

Van Gelder IC, et al.

Europace

. 2006;8:943-949; Narayan SM, et al.

Lancet.

1997;350:943-950; Wattigney WA, et al.

Circulation

. 2003;108:711-716; Wyse DG, et al.

Circulation

. 2004;109:3089-3095; Favale S, et al.

PACE

. 2003;26:637-639.

What Are the Goals of AF Therapy?

• Improve survival • Reduce sequelae – Stroke

, systemic emboli, heart failure

• Reduce hospitalizations • Improve symptoms • Improve QoL • Restore atrial function/reverse the remodeling process • Minimize adverse effects of therapies employed

QoL = quality of life.

Cost Increases With Each AF Recurrence, Mainly Driven by Hospital Costs

12,000 10,000 FRACTAL Registry —Annual Costs of AF-Related Medical Care

P

<.05

$10,312

P

<.05

8,000 $6,331 6,000 Hospital costs 4,000 $3,385 2,000 $2,372 Outpatient costs Drug costs 0 Permanent AF (n=34) 0 (n=620) 1-2 (n=286) Documented Recurrences ≥3 (n=33) Reynolds MR et al.

J Cardiovasc Electrophysiol

. 2007;18:628-633 .

AF: CV Hospitalization Implications

• AF accounts for more hospitalizations than any other arrhythmia 1 – 1/3 of hospitalizations for cardiac arrhythmia 2 • During the past 20 years hospital admissions for AF have increased by 66% 2 • Except cardioversion, hospitalization is motivated by the severity of an AF episode or an AF-related complication such as a cardiovascular event 3 • Hospitalization is an important negative determinant of QoL in patients with AF 4 • 50 to 70% of the cost of AF management is driven by in-patient care 5 •

Direct cost of AF in USA: $6.65 billion annually

Adapted from A.J. Camm. 1. Bialy D, et al. J Am Coll Cardiol 1992;19:41A. 2. ACC/AHA/ESC 2006 guidelines Eur Heart J 2006;27:1979 126. 6. Bajpai A, et al.

US Cardiovascular Disease

. 2007:14-17.

–2030. 3. Stewart S, et al. Eur Heart J 2001;22:693-701. 4. Dorian P, et al. Circ Arrhythmia Electrophysiol 2009;218-224. 5. Le Heuzey J.Y.et al. Am. Heart J. 2004; 47 : 121-

Guideline-Based AF Treatment Options

Rate control Maintenance of SR Stroke prevention •

Pharmacologic

• CCBs  -blockers • Digitalis • Amiodarone • Dronedarone

Nonpharmacologic

• Ablate and pace Pharmacologic Class IA Class IC Class III  -blockers Nonpharmacologic Catheter ablation Pacing Surgery Implantable devices

AF and Stroke

• • AF increases stroke risk 4- to 5-fold Stroke is the most common and devastating complication of AF – Incidence of all-cause stroke in patients with AF is 5% • • AF is an independent risk factor for stroke – Approximately 15% of all strokes in the United States caused by AF – Risk for stroke increases with age • Stroke risk persists even in asymptomatic AF Stroke risk persists in patients with a “high-risk” profile despite a strategy of rhythm control (AFFIRM study, RACE study)

10 8 6 4 2 0 Annual Stroke Rate (%) Permanent AF Intermittent AF Low Risk Moderate Risk High Risk RACE II = Rate Control Efficacy in Permanent Atrial Fibrillation.

Fuster V, et al. J Am Coll Cardiol. 2006;48(4):e149-e246. Kannel WB, et al. Med Clin North Am. 2008;92(1):17-42. Page RL, et al. Circulation. 2003;107(8):1141-1145. Hart RG, et al. J Am Coll Cardiol. 2000; 35(1):183-187. Dulli DA, et al. Neuroepidemiology. 2003;22(2):118-123.

Risk Factor C

ardiac failure

H

TN

A

ge ≥75 y

D

iabetes

S

troke

Total Score

Stroke Risk Stratification in AF

CHADS 2 CHA 2 DS 2 -VASc Score

1 1 1 1 2

Risk Factor C

ardiac failure

H

TN

A

ge ≥75 y

D

iabetes

S

troke

V

asc dz (MI, PAD, aortic ath)

A

ge 65-74 y

Annual Risk of Stroke (%) S

ex

c

ategory (female)

Score

1 1 2 1 2 1 1 1 0 1 2 3 4 5 6 1.9

2.8

4.0

5.9

8.5

12.5

18.2

20 15 10 5 0 Relationship between CHA 2 stroke DS 2 -VASc score and annual risk of 9.8

6.7

2.2 3.2

4.0

0 1.3

9.6

6.7

15.2

0 1 2 3 4 5 6 7 CHA 2 DS 2 -VASc Score 8 9 Lip GY, Halperin JL.

Am J Med

. 2010;123(6):484-488.

HAS-BLED Bleeding Risk Score

ESC AF Guidelines EHJ 2010

Approach to Thrombo-prophylaxis in AF

ESC AF Guidelines EHJ 2010

Efficacy of Warfarin

Compared With Control in 5 Studies 62% to 67% RRR with warfarin vs placebo No. of Events Patient Years Risk Reduction, %

AFASAK BAATAF CAFA SPAF SPINAF Combined 27 15 14 23 29 108 811 922 478 508 972 3691

100 50 Warfarin Better 0 -50 Warfarin Worse -100 Atrial Fibrillation Investigators.

Arch Intern Med.

1994;154(13):1449-1457.

Antiplatelet Therapy in AF

ACTIVE-W:

6706 randomized patients;

trial stopped

6 5 4 3 2 1 0

P

= .0003

Vascular Event Clopidogrel + ASA Warfarin

P

= .001

Stroke

P

= .53

Major Bleeding 3 2 5 4 6 7 8 ACTIVE-A:

7554 randomized patients; median follow-up of 3.6 years

P

= .01

Clopidogrel + ASA ASA

P

<.001

1 0 Vascular Event

P

<.001

Stroke Major Bleeding ACTIVE = AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events.

ACTIVE Investigators. Lancet. 2006;367:1903-1912. ACTIVE Investigators. N Engl J Med. 2009;360(20):2066-2078.

Potential Advantages of New Oral Anticoagulants

• Oral administration • Rapid onset of action -- eliminates 2 AC regimen • • • Predictable effect with fixed or weight-based dosing -- no monitoring • Less food/drug interactions • Short half- life: ease of reversal/ no bridging • More convenient -- potentially leading to greater use • More cost effective − No routine monitoring − Fewer ADEs requiring ER visits and hospitalizations Possible superior efficacy -- demonstrated for dabigatran Possible superior safety -- demonstrated for dabigatran

Characteristics of New Oral Anticoagulants

1,2

Drug Dabigatran Rivaroxaban Apixaban Betrixaban Edoxaban Mechanism of action Half-life Regimen Thrombin inhibitor 14-17 h BID Peak to trough Renal excretion of absorbed drug ~7x ~80% Potential for drug interactions FXa inhibitor 5-9 h QD, BID 12x (QD) 36-45% FXa inhibitor 12 h BID 3-5x 25-30% FXa inhibitor 19-24 h QD ~3x ~15% P-glycoprotein inhibitor CYP3A4 substrate and P-glycoprotein inhibitor CYP3A4 substrate and P-glycoprotein inhibitor Not substrate for major CYPs FXa inhibitor 6-12 h QD ~3x 35% CYP3A4 substrate and P-glycoprotein inhibitor

1. Usman MH, et al.

Curr Treat Cardiovasc Med.

2008;10(5):388-397.

2. Piccini JP, et al.

Curr Opin Cardiol.

2010;25(4):312-320.

Dabigatran

• Dabigatran etexilate is a pro-drug that undergoes metabolism to dabigatran which is a competitive inhibitor of thrombin that binds clot-bound and free thrombin with high affinity and specificity and also inhibits thrombin-induced platelet aggregation • Bioavailability 6.5%; low protein binding • No known food or CYP450 drug interactions • No need for INR monitoring • Hepatotoxicity <1% • Half-life: 8 hours after single dose and 14-17 hours after multiple doses • BID dosing • 80% renal excreted Usman MH, et al.

Curr Treat Cardiovasc Med.

2008;10(5):388-397

Design of the RE-LY ® Trial

• • • • •

Study Parameters

Open label, noninferiority, intent-to-treat trial Blinded adjudication of outcome events 50% patients VKA naïve* Primary outcome: incidence of stroke (ischemic and hemorrhagic) and systemic embolism in patients with non-valvular atrial fibrillation Primary safety outcome: incidence of major bleeds † Warfarin (INR 2.0-3.0) N= 6022 Patient Flow Randomized N= 18,113 Blinded to dose Dabigatran 110 mg twice daily N= 6015 Dabigatran 150 mg twice daily N= 6076 Avg CHADS score 2.2, with 32% CHADS 3 or higher Minimum 1-year follow-up, maximum 3 years, median of 2 years of follow-up. INR: international normalized ratio; VKA: vitamin K antagonist.

*Total lifetime exposure of < 2 months.

† Major bleeds fulfilled one or more of the following criteria: bleeding associated with a reduction in hemoglobin of at least 2 grams per deciliter or leading to a transfusion of at least 2 units of blood, or symptomatic bleeding in a critical area or organ. A life-threatening bleed met one or more of the following criteria: fatal, symptomatic intracranial bleed, reduction in hemoglobin of at least 5 grams per deciliter, transfusion of at least 4 units of blood, associated with hypotension requiring the use of intravenous inotropic agents, or necessitating surgical intervention, Intracranial hemorrhage included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.

Connolly SJ, Ezekowitz MD et al.

N Engl J Med

. 2009;361:1139-1151.

Stroke Prevention in AF

Dabigatran Etexilate vs Warfarin (RE-LY)

4.0

3.5

1.5

1.0

0.5

3.0

2.5

2.0

*

P<.001

†

P<.001

P = .003

P<.001

P<.001

Dabigatran 110 mg Dabigatran 150 mg Warfarin INR 2.0-3.0 Avg TTR: 67%

Dabigatran 110 mg is not FDA approved for this indication; for informational purposes only

P<.048

0.0

Stroke/Systemic Embolism Major Bleed Intracranial Hemorrhage MI *Noninferiority; † Superiority MI = myocardial infarction; RE-LY = Randomized Evaluation of Long-term Anticoagulation Therapy. Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.

Dabigatran: DC Cardioversion Dabigatran 110 mg

N (Pts/CV)

409/647 Dabigatran 150 mg 415/672 Warfarin 431/664

CVA/SEE

5 (0.8%) 2 (0.3%) 4 (0.6%)

Nagarakanti R, et al. Circulation 2011:123:131-136

ROCKET AF Trial: Rivaroxaban

1,2 Treatment period 12-32 months Rivaroxaban 20 mg once daily Nonvalvular AF, history of stroke, TIA, or embolism, or at least 2 of the following: heart failure, hypertension, age  75 y, or diabetes mellitus R N =14,264 Rivaroxaban 15 mg once daily (CrCL 30-49 mL/min at entry) Warfarin target INR, 2.5 (INR range, 2.0-3.0) • • • • • • Day 1 Day 30 after last dose In AF patients with a moderate to high risk of stroke, does rivaroxaban reduce the risk of major vascular events compared with warfarin? 1 0 study end point: composite of all-cause stroke and non-CNS systemic embolism 2 1 0 0 end points: composite of transient ischemic attack, all-cause death, vascular death, and MI safety end point: composite of major and clinically relevant nonmajor bleeding events Randomization completed in June 2009; follow-up completed 2010 Follow-up: up to 4 years (until 405 primary outcome events have been observed) 1. ROCKET AF Study Investigators.

Am Heart J.

2. ClinicalTrials.gov identifier: NCT00403767.

2010;159(3):340-347.e1.

ROCKET AF: Primary Efficacy Outcome Stroke and non-CNS Embolism

On Treatment

N= 14,143

ITT

N= 14,171 Rivaroxaban* Warfarin Event Rate Event Rate 1.70

2.15

HR (95% CI) 0.79 (0.65,0.95) P-value 0.015

2.12

2.42

0.88 (0.74,1.03) 0.117

TTR 57.8% Rivaroxaban better Warfarin better Avg CHADS score 3.7

*Rivaroxaban is not FDA approved.

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

ROCKET AF: Key Secondary Efficacy Outcomes

Vascular Death, Stroke, Embolism Stroke Type Hemorrhagic Ischemic Unknown Type Non-CNS Embolism Myocardial Infarction All Cause Mortality Vascular Non-vascular Unknown Cause Event Rates are per 100 patient-years Based on Intention-to-Treat Population Rivaroxaban Event Rate 4.51

0.26

1.62

0.15

0.16

1.02

4.52

2.91

1.15

0.46

Warfarin Event Rate 4.81

0.44

1.64

0.14

0.21

1.11

4.91

3.11

1.22

0.57

HR (95% CI) 0.94 (0.84, 1.05) 0.58 (0.38, 0.89) 0.99 (0.82, 1.20

1.05 (0.55, 2.01) 0.74 (0.42, 1.32

0.91 (0.72, 1.16) 0.92 (0.82, 1.03) 0.94 (0.81, 1.08) 0.94 (0.75, 1.18) 0.80 (0.57, 1.12) P-value 0.265

0.012

0.916

0.871

0.308

0.464

0.152

0.350

0.611

0.195

ROCKET AF Compared With RE-LY

N VKA naive Design Treatment Regimen Primary outcome Secondary outcome ROCKET AF 1

14,171 37% Randomized, double-blind, double-dummy study Rivaroxaban 1 dose (with dose adaptation for moderate renal impairment) Once daily Efficacy: Composite of all-cause stroke and non-CNS systemic embolism Safety: Composite of major and clinically relevant nonmajor bleeding events

RE-LY 2

18,000 50% PROBE design Dabigatran 2 doses Twice daily Efficacy: Incidence of stroke (including hemorrhagic) and systemic embolism Safety: Major bleeding events Each category of bleeding events, and adverse events Composite of TIA, all-cause death, vascular death, and MI Incidence of stroke (including hemorrhagic), systemic embolism, all death, pulmonary embolism, MI, TIA, vascular deaths (including deaths from bleeding), and hospitalizations

1. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347. 2. Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.

ROCKET AF Compared With RE-LY

TTR (median) CHADS2 (mean) Previous TIA/CVA Primary outcome HR ROCKET AF 1

58% 3.7

55% 0.79

Hem CVA rate Ischemic CVA: HR Major Bleeding rate

0.24

0.99

3.6%

RE-LY 2

67% 2.1

20% 0.66 (150 dose) 0.24 (150 dose) 0.75 (150 dose) 3.3% (150 dose)

1. ROCKET AF Study Investigators. Am Heart J. 2010;159(3):340-347. 2. Connolly SJ, et al. N Engl J Med. 2009;361(12):1139-1151.

AVERROES Trial 1,2

Unsuitable for warfarin therapy N= 5600 E ASA (81-324 mg daily; up to 36 mo/end of study) R Double-blind Apixaban (5 mg twice daily; 2.5 mg in selected patients a ; up to 36 mo/end of study) a At least 2 of: age  80 y, weight  60 kg, or serum Cr  1.5 mg/dL • • • • • • Is apixaban more effective than ASA in preventing stroke and systemic embolism in moderate to high-risk (stroke; at least 1 risk factor) AF patients?

1 0 efficacy end point: confirmed ischemic or hemorrhagic stroke or systemic embolism 2 0 study end points: as above, including MI or vascular death 1 0 safety end point: major bleeding Study period: until 226 primary outcome events have been observed In June 2010, BMS-Pfizer announced that the study had been stopped early because a predefined interim analysis revealed clear evidence of a clinically important reduction in stroke and systemic embolism. Results presented at ESC 2010, Stockholm, Sweden.

AVERROES, Apixaban Versus ASA to Reduce the Risk Of Stroke.

1. Eikelboom JW, et al.

Am Heart J.

2010;159(3):348-353.e1.

2. ClinicalTrials.gov identifier: NCT00496769. http://www.theheart.org/article/1087291.do

.

AVERROES: Stroke or Systemic Embolic Event

RR=0.45

95% CI, 0.32-0.62

P<.001

ASA Apixaban*

*Apixaban is not FDA approved.

0

No. at Risk ASA 2791 Apix 2809

3

2720 2761

6

2541 2567

9 12 Months

2124 1541 2127 1523

18 21

626 617 329 353

Connolly S., et al N Engl J Med 2011

AVERROES: Major Bleeding

RR=1.13

95% CI, 0.74-1.75

P=.57

Apixaban

ASA

0 3 6

No. at Risk ASA 2791 2744 2572 Apix 2809 2763 2567

Connolly S, et al. N Engl J Med 2011 9 12 Months

2152 1570 1521

18 21

642 622 340 357

ARISTOTLE Trial: Apixaban 1,2

Warfarin INR, 2.0-3.0

AF or atrial flutter 18,206 randomized E R Double-blind Apixaban (5 mg twice daily; 2.5 mg twice daily in selected patients a ) a At least 2 of: age  80 y, weight  60 kg, or serum Cr  1.5 mg/dL • • • • • Is apixaban noninferior to standard therapy (warfarin) in preventing stroke and systemic embolism in moderate- to high-risk (stroke; at least 1 risk factor) AF patients?

1 0 efficacy end point: confirmed ischemic or hemorrhagic stroke, or systemic embolism 2 0 efficacy end points: composite of confirmed ischemic or hemorrhagic stroke, systemic embolism, and all-cause death 1 0 safety end point: time to first occurrence of confirmed major bleeding Treatment period: up to 4 years (until 448 primary outcome events have been observed — >90% power to demonstrate noninferiority); – Stratified by warfarin naïve status 1. Lopes RD, et al.

Am Heart J.

2010;159(3):331-339.

2. ClinicalTrials.gov identifier: NCT00412984.

ENGAGE AF –TIMI 48: Edoxaban

AF >20,000 pts E Warfarin INR, 2.0-3.0

3 treatment arms R Double-blind Edoxaban (60 mg vs 30 mg qd) • • • • Is edoxaban noninferior to standard therapy (warfarin) in preventing stroke and systemic embolism in moderate- to high-risk (CHADS 2 score ≥2) AF patients?

1 0 efficacy end point: composite primary end point of stroke and systemic embolic events 2 0 efficacy end points: composite clinical outcome of stroke, systemic embolic events, and all-cause mortality; also major bleeding events Treatment period: up to 2 years ClinicalTrials.gov identifier NCT00781391 .

Anticoagulation in AF

•

Anticoagulation

is needed in patients at increased thromboembolic risk –

CHADS 2 :

Age ≥75 years, prior CVA/TIA, diabetes, HTN, LV dysfunction

. Highest risk: RHD

–

Anticoagulation

usually should be continued chronically • Drugs, herbals, diet, genetic patterns, generics must all be considered

in choosing and during anticoagulation

• Warfarin has been more effective than ASA in all comparative studies, without excess risk;

dabigatran 150 mg bid is superior to warfarin

• Anticoagulation is necessary prior to cardioversion of nontransient (>48 hours) AF • New oral direct thrombin inhibitors and factor Xa drugs may replace warfarin in the future for

many/most

patients with AF

CVA = cerebrovascular accident; LV = left ventricular; RHD = rheumatic heart disease.

Fuster V, et al. J Am Coll Cardiol. 2006;48(4):e149-e246.

Connolly SJ, et al.

N Engl J Med

. 2009;361(12):1139-1151 .

Canadian Cardiovascular Society Recommendations

Favors Rate Control Favors Rhythm Control Persistent AF Less Symptomatic >65 years of age Hypertension No History of Congestive Heart Failure Paroxysmal AF Newly Detected AF More Symptomatic < 65 years of age No Hypertension Congestive Heart Failure clearly exacerbated by AF Previous Antiarrhythmic Drug Failure No Previous Antiarrhythmic Drug Failure

Canadian Cardiovascular Society AF Guidelines. http://www.ccsguidelineprograms.ca/index.php. Accessed January 25, 2011.

Dronedarone

• • Amiodarone-like compound lacking the iodine moiety Similar electrophysiologic properties to amiodarone – Low propensity to cause TDP • • • 13 to 30-hour T ½ , but administered as bid regimen Food effect (2x-3x increase in levels) • Extensive first-pass hepatic metabolism through CYP4503A4 system – Only 15% bioavailability – Elevates serum creatinine 10% to 15% without a change in glomerular filtration rate • Drug interactions similar to amiodarone, except no significant interaction with warfarin No evidence of thyroid or pulmonary toxicity but rare cases of serious hepatotoxicity

Hynes BJ, et al. Future Cardiol. 2005;1(2):135-144.

Clinical Profiles for Amiodarone and Dronedarone

Iodine moiety T ½ Blocks I Kr ; I Ks ; B 1 ; I Ca ; I to ; I Na Dosing Food effect CYP4503A4 metabolism Inhibits tubular secretion of creatinine Increase QT but low TDP Efficacy in suppressing AF

Amiodarone Yes 53 days Yes Daily after loading Yes No Yes Yes 65%

Efficacy in suppressing ventricular tachyarrhythmias

Yes

Decreases CV hospitalization

No

Warfarin interaction Pulmonary/thyroid toxicity Safety concerns in CHF

Yes Yes SCD-HEFT NYHA III Dronedarone

No 14-30 hours Yes bid with meals Yes Yes Yes Yes 50% Not well studied Yes No No ANDROMEDA

SCD-HEFT = Sudden Cardiac Death in Heart Failure Trial.

Wolbrette DL, et al. Vasc Health Risk Manag. 2010;(6):517-523.

ATHENA: Primary Endpoint (CV Hospitalization or Death)

4628 patients with paroxysmal or persistent AF were randomized if they met the following: ≥75 years of age with or without additional risk factors or ≥70 years of age and ≥1 risk factor (HTN, diabetes, prior stroke/TIA, LA diameter ≥50 mm, LVEF ≤0.40)

50 40 Placebo Dronedarone 24% reduction in relative risk 30 20 10 HR = 0.76

P<.001

0 0 6 12 18 24 30 Months ATHENA = A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation. Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678.

ATHENA: Primary and Secondary Endpoints

Outcome Placebo (N = 2327) Primary Endpoint

First CV hospitalization or death First CV hospitalization First hospitalization for AF

Secondary Endpoints 917 (39.4%) 859 (36.9%) 510 (21.9%)

Death from any cause Death from non-CV causes Death from CV causes Cardiac nonarrhythmic death

139 (6.0%) 49 (2.1%) 90 (3.9%) 18 (0.8%)

Cardiac arrhythmic death Any CV hospitalization or death

48 (2.1%) 1668 (71.7%) Dronedarone (N = 2301) 734 (31.9%) 675 (29.3%) 335 (14.6%) 116 (5.0%) 53 (2.3%) 63 (2.7%) 17 (0.7%) 26 (1.1%) 1253 (54.5%) HR 0.76

0.74

0.63

0.84

1.10

0.71

0.95

0.55

0.76

95% CI

0.69-0.84

0.67-0.82 0.55-0.72

0.66-1.08

0.74-1.62

0.51-0.98

0.49-1.85

0.34-0.88

0.68-0.84

P

Value <.001

<.001

<.001

.18

.65

.03 .89

.01

<.001

In a post-hoc analysis, dronedarone was also associated with a 34% reduction in relative risk of stroke, HR 0.66 (95% CI 0.46-0.96),

P

= .027.

Adapted from Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678. Connolly SJ, et al. Circulation. 2009;120(13):1174-1180.

1 2 3 4 5

ATHENA: Stroke Incidence

Post-Hoc Analysis

HR=0.66

p

=0.027

Placebo Dronedarone

Mean follow-up 21 ± 5 months

0 0 2327 2301 6 2275 2266 12 2220 2223 18 1598 1572 24 618 608 30

Months

6 4 Placebo Dronedarone Connolly SJ, et al. Circulation. 2009;120(13):1174-1180

CV Outcome Benefits: Amiodarone and Dronedarone in Large AF Trials

Amiodarone use Total mortality CV mortality Hospitalization* Stroke AFFIRM

63% of patients

P

= .08

NA

P

<.001

AF-CHF

82% of patients

ATHENA

None

P

= .06

P P P

= .03

<.001

= .027

*Limited interpretation; hospitalization was not reported in the same way in ATHENA, AFFIRM, and AF-CHF trials. NA = not applicable. Wyse DG, et al. N Engl J Med. 2002;347(23):1825-1833. Roy D, et al. N Engl J Med. 2008;358(25):2667 2677. Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678. Torp-Pedersen C, et al. Circulation. 2008;118:S828. Connolly SJ, et al. Circulation. 2009;120(13):1174-1180.

ATHENA Post-Hoc Analysis Risk of unplanned CV hospitalization or death in "permanent" AF patients

50 Placebo on top of standard therapy DR 400mg bid on top of standard therapy 40 30

26%

reduction in relative risk 20 10 Patients at risk:

Placebo DR 400mg bid

0 0

295 178

6

244 160

12

224 150

HR=0.74

p

=0.096

Patients with AF/AFL at each ECG recording were classified as having "permanent AF" Months 18 24 30

151 110 60 47 0 1

Mean follow-up 21 ± 5 months. Page R, et al.

AHA Scientific Sessions

2008.

Page R, et al.

Circulation.

2008;118:S_827.

Any unplanned hospitalisation (i.e., admission with an overnight stay in the hospital) was classified by the investigator as a hospitalisation due to either CV or non-CV causes

Patients with permanent AF and additional risk factors* Event-Driven N~10800 R

PALLAS

Study Design

Dronedarone 400 mg BID

On top of Standard of Care

Placebo BID

•

Co-primary Endpoints

•• Composite endpoint of first stroke, systemic arterial embolism, myocardial infarction or cardiovascular death •• Composite endpoint of first unplanned cardiovascular hospitalization or death from any cause *Patients aged 65 years or older with at least one of the following risk factors or combination of risk factors: Coronary artery disease Prior stroke Symptomatic heart failure Left ventricular ejection fraction less than or equal to 0.40

Peripheral arterial occlusive disease Aged 75 years or older with both hypertension and diabetes mellitus

ANDROMEDA: Study Primary Endpoint and Results

•

Primary endpoint

– The primary composite endpoint was all-cause mortality or hospitalization for HF vs placebo •

Results

Number of patients who died

Relative risk (relative to placebo)

95% CI

P

value

Analysis Up to Study Discontinuation Placebo (n = 317)

12

Dronedarone 800 mg/day (n = 310)

25

2.13

1.07, 4.25

.03

Køber L, et al. N Engl J Med. 2008;358(25):2678-2687.

Dronedarone Safety Profile

• Safety profile of dronedarone has been established in >6700 patients – Low risk of extracardiac toxicities (<0.1%) (thyroid, pulmonary, dermatologic) – Low risk of proarrhythmia (<0.1%) – Most frequently reported adverse events • Gastrointestinal effects (24% vs 21% for placebo) • General disorders and administration site conditions (16% vs 15% for placebo) • Serum creatinine increase without indications of renal toxicity (4% vs 1% for placebo) •

Rare cases of serious hepatotoxicity were reported in 2010 within 6 months of beginning therapy, two required transplantation Tschuppert Y, et al. Br J Clin Pharmacol. 2007;64:785-791. US Food and Drug Administration (FDA). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ CardiovascularandRenalDrugsAdvisoryCommittee/UCM136957.pdf. Accessed July 9, 2010.

Dronedarone Indication

• Approved by the FDA in July 2009 to – Reduce the risk of CV hospitalization in patients with paroxysmal or persistent AF or AFL, with a recent episode of AF/AFL, and 1 or more associated CV risk factors • • • • • Age >70 HTN Diabetes Prior CVA LA diameter ≥50 mm or LVEF <40% – Treat patients who are in SR, or who will be cardioverted • Contraindicated in class IV HF or lesser HF with recent decompensation

FDA = US Food and Drug Administration; AFL = atrial flutter.

Multaq [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2009.

Efficacy of AADs in AF Trials

100 80 Amiodarone Dronedarone Sotalol Class IC Placebo 60 40 20 0 CTAF SAFE-T AFFIRM DAFNE* EURIDIS* ADONIS EURIDIS/ DIONYSOS ADONIS Pooled † *At 6 months; † Mean follow-up 7 months. CTAF = Canadian Trial of Atrial Fibrillation; SAFE-T = Sotalol Amiodarone Atrial Fibrillation Efficacy Trial; DAFNE = Dronedarone Atrial Fibrillation Study after Electrical Cardioversion; EURIDIS = European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm; ADONIS = American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter for the Maintenance of Sinus Rhythm; DIONYSOS = Randomized, Double-blind Trial to Evaluate the Efficacy and Safety of Dronedarone vs Amiodarone for at Least 6 Months for the Maintenance of Sinus Rhythm in Patients with AF. Courtesy of G Naccarelli, MD. Roy D, et al. Am J Cardiol. 1997;80:464-468. Singh BN, et al. N Engl J Med. 2005;352(18):1861-1872. AFFIRM Investigators. J Am Coll Cardiol. 2003;42:20-29. Touboul P, et al. Eur Heart J. 2003;24:1481-1487. Singh BN, et al. N Engl J Med. 2007;357(10):987-999. Le Heuzey JY, et al. J Cardiovasc Electrophysiol. 2010;21:597-605.

2011 ACCF/AHA/HRS Guidelines:

Antiarrhythmic Approaches to Maintain SR in Patients with Recurrent PAF or Persistent AF*

Maintenance of SR No (or minimal) heart disease HTN CAD HF Dronedarone Flecainide Propafenone Sotalol Amiodarone Dofetilide Catheter ablation No Dronedarone Flecainide Propafenone Sotalol Substantial LVH Dofetilide Dronedrone Sotalol Yes Amiodarone Amiodarone Catheter ablation Amiodarone Dofetilide Catheter ablation A Safety-Driven Approach Amiodarone Dofetilide Catheter ablation Catheter ablation 2010 ESC Guidelines – Dronedarone recommended for patients with LVH and stable NYHA I/II CHF *Within each box, drugs are listed alphabetically and not in order of suggested use. HTN = hypertension; CAD = coronary artery disease; HF = heart failure; CHF = congestive heart failure.

Wann LS, et al. Circulation. Published online Dec 20, 2010. Camm AJ, et al. Eur Heart J. Published online August 29, 2010.

Outpatient vs Inpatient Initiation of Antiarrhythmics for AF

IA* IC* Sotalol Dofetilide Dronedarone Amiodarone Hospital In AF Outpatient

X X

†

X X X X

Hospital In NSR Outpatient

X X X X

†

X

‡

X X

*After rate control; † No SHD or sinus node/conduction abnormalities; ‡ No risk factors for TDP (QT <450 ms, normal electrolytes).

TDP = Torsades de pointes.

Fuster V, et al. Circulation. 2006;114:e257-e354. Multaq [package insert]. Bridgewater, NJ: sanofi aventis U.S. LLC; 2009.

Possible “Upstream” Treatments and Mechanisms for AF Prevention

ACE-Is/ARBs Statins Glucocorticoids Physical activity Omega-3 fatty acids



Inflammation



Oxidative stress



RAAS activity Endothelial function



Autonomic nervous system activity Plaque stability



Atrial remodeling Stabilize LA endocardium



AF

To date, large prospective trials have not confirmed benefit of upstream therapies in suppressing AF

RAAS = renin-angiotensin-aldosterone system.

Courtesy of CJ Pepine, MD.

Fish Oil/n-3 PUFA for Prevention of AF

• • Prospective cohort of 4815 adults with 12-year follow-up – People who consumed tuna or other broiled/baked fish 1-4 times/week had 28% lower risk of AF (

P

= .005) compared to <1 time/month Randomized controlled trial of 160 patients treated pre- and post-bypass surgery (2 g PUFA/day)

35 30 25 20 15 10 5 AF Post-CABG

P

= .013

P

PUFA Control

= .017

0 Post-Op AF (%) Hospital Days (n) PUFA = polyunsaturated fatty acid; CABG = coronary artery bypass graft.

Mozaffarian D, et al. Circulation. 2004;110(4):368-373. Calo L, et al. J Am Coll Cardiol. 2005;45(10): 1723-1728.

OM 8: Primary Endpoint: Time to First Recurrence of Symptomatic AF/Flutter (PAF)

PLA: 129/269 (48%) P-OM3: 135/258 (52%) HR: 1.15

CI: (0.90, 1.46) P value: 0.263

Analysis based on Cox model: log (HR)=treatment+region+ACE/ARB+Statin

Kowey PR, et al. JAMA 2010;302(21):2363-2372

ACE-Is and ARBs Reduce the Risk of AF

• Meta-analysis: 11 studies (N = 56,308) • 4 in HF, 3 in HTN, 2 in patients following cardioversion for AF, and 2 in patients after MI

RR (95% CI) ACE-Is ARBs Total

ACE-Is and ARBs reduced the RR of AF by 28% (

P

= .0002) Reduction in AF was similar with ACE-Is (28%,

P

= .01) and ARBs (29%,

P

= .00002) Effect was most pronounced in HF and only significant in HTN when associated with LVH

0.0

0.5

Favors Treatment 1.0

1.5

Favors Control 2.0

RR = relative risk. Healey JS, et al. J Am Coll Cardiol. 2005;45(11):1832-1839.

GISSI-AF

Study Results: Probability of First Recurrence of AF

0.6

Placebo 0.5

Valsartan 0.4

0.3

0.2

0.1

Valsartan: 371/722 (51.4%) Placebo: 375/720 (52.1%) Adjusted HR 0.97

96% CI 0.83-1.14

P

= .73

Log-rank test

P

= .829

0 0 1 2 3 4 5 6 7 8 9 10 Time since Randomization (months) 11 12 Patients at Risk Valsartan Placebo

722 720 586 589 524 520 491 484 465 454 445 435 423 407 398 387 383 377 368 359 356 344 343 334 260 254

The GISSI-AF Investigators. N Engl J Med. 2009;360:1606-1617.

Triggers of AF: Focal Firing and Interplay with Reentrant Rotors

RA LA SVC

17

PVs

31

Fossa Ovalis

6 11

IVC CS Septum CS = coronary sinus; RA = right atrium.

Haissaguerre M, et al. N Engl J Med. 1998;339(10):659-666. Calkins H, et al. Heart Rhythm. 2007;4(6): 816-861.

Anatomy of PVs

SVC Extension of muscular fibers into PV LSPV Ganglia noted in yellow LIPV RSPV LSPV LIPV RIPV IVC SVC Common locations of PV (purple) and common sites of origin of non-PV triggers (black) LSPV LIPV RSPV LSPV RIPV IVC

Calkins H, et al. Heart Rhythm. 2007;4(6):816-861.

LIPV SVC Large and small RSPV reentrant wavelets that RIPV IVC play a role in initiating and sustaining AF SVC RSPV of anatomic and arrhythmic RIPV Composite mechanisms of AF IVC

Common Lesions Performed in AF Ablation

A.

Circumferential ablation around left and right PV antra

A.

SVC

B.

SVC RSPV RSPV LSPV LSPV

B.

and

C.

Additional linear lesion sets for the roof, mitral isthmus, carinae, SVC, and cavotricuspid isthmus LIPV

C.

RIPV IVC SVC RSPV LIPV

D.

RIPV IVC SVC RSPV LSPV LSPV

D.

Targeting fractionated electrograms and/or ganglionic plexi LIPV RIPV IVC LIPV RIPV IVC

SVC = superior vena cava; PV = pulmonary vein; LSPV = left superior pulmonary vein; RSPV = right superior pulmonary artery; LIPV = left inferior pulmonary vein; RIPV = right inferior pulmonary vein; IVC = inferior vena cava.

Calkins H, et al. Heart Rhythm. 2007;4(6):816-861.

Success Rates with Ablation: Worldwide Survey

Success without AADs Success with AADs Overall Success 100 90 40 30 20 10 80 70 60 50 0 0-3 4-6 7-9 10-12 13-18 Range of Follow-Up (months) 19-24 >24

Additional recent studies suggest 5 yr success rates are <50%; LA size and function may not normalize despite control of the arrhythmia, and new MRI detected embolic CNS lesions occur in >10% of subjects

Cappato R, et al. Circulation. 2005;111:1100-1105.

Jeevanantham et al. AJC 2010; 105:1317-26

* Ouyang et al. Circuation 2010;122:2368-77 ** Weerasooriya et al. JACC 2011 *** Gaita F, et al. Circulation 2010; 122:1667-73 **** Schwarz et al. Heart Rhythm 2010; 7:1761-67

Risks of AF Ablation: The Second International AF Ablation Registry

Type of Complication

Death Tamponade Pneumo/hemo thorax Sepsis, abscesses, or endocarditis Permanent diaphragmatic paralysis Femoral pseudoaneurysm/AV fistula Valve damage/requiring surgery Atrium-esophageal fistulae Stroke/TIA PV stenoses requiring intervention TOTAL

Number of Patients

25 215 19 2 28 152/88 11/7 3 37/115 49 741

Rate (%)

0.15

1.31

0.11

0.01

0.17

0.93/0.54

0.07

0.02

0.23/9.71

0.29

4.54

Iatrogenic atrial flutter occurred in 8.3% of patients Heart Rhythm Society. Lessons from the Second International Ablation Registry Update. http://www.hrsonline.org/education/selfstudy/webcasts/af/ablationregistry/. Accessed February 2010.

Additional Ablation Data

•

Longer term success (5 yr):

–

With a single procedure, sinus rhythm has been maintained at 5 yrs in just under 46.6% of pts in 1 study and just 29% in another* **

•

Recently appreciated additional embolic events:

–

Gaita et al *** studied 232 consecutive patients with PAF or persistent AF who underwent ablation (PVI +/- additional lesions). Standard anticoagulation was employed. All pts underwent preprocedural and postablation cerebral MRIs.

•

A periprocedural symptomatic CVA occurred in 1 pt (0.4%). Postablation MRIs,

however, were positive for new lesions in 33 pts (14%).

–

Schwarz et al **** studied 23 pts in a similar study.

•

14.3% had new ischemic lesions on post-procedure imaging, and, compared to 23 controls, the ablation pts showed neuropsychological decline

* Ouyang et al. Circuation 2010;122:2368-77 ** Weerasooriya et al. JACC 2011 *** Gaita F, et al. Circulation 2010; 122:1667-73 **** Schwarz et al. Heart Rhythm 2010; 7:1761-67

Additional Ablation Data Cont’d

•

Atrial size and function post ablation:

–

17 studies enrolling 869 pts provided adequate data on LA size and function after RFA.

–

Compared to pre-ablation values, there were significant decreases in LA diameter and volumes at post-ablation follow up.

–

Decreases remained significant in those without AF recurrence but not in those with recurrent AF.

–

Compared to pre-ablation values, however, there were no improvements in LA EF or LA active emptying fraction, and LA size did not routinely decrease to normal.

•

LAEF and LA emptying remained unchanged in pts without AF recurrence but decreased further in those with recurrent AF.

Jeevanantham et al. AJC 2010; 105:1317-26

PVI Is Superior to AVN Ablation/CRT in CHF Patients with Drug-Refractory AF

Ejection Fraction 6-Minute Walk 37 35 33 31 29 27 25 0

P

= .03

P

<.001

360 340 320 300 280 260 0

P

= .003

P

<.001

0 3 Months 6 0 3 Months 6 Minnesota Living with HF Questionnaire 100

P

<.001

80 60 40 20 0 0 6 Months PVI AVN Ablation + BiV PVI = pulmonary vein isolation; CRT = cardiac resynchronization therapy; BiV = biventricular pacing.

Khan MN, et al. N Engl J Med. 2008;359(17):1778-1785.

Indications for Catheter AF Ablation

• Symptomatic AF refractory or intolerant to at least 1 class I or III AAD • Selected symptomatic patients with HF and/or reduced ejection fraction • As an alternative to device implantation to support AAD therapy in bradycardic patients • Presence of an LA thrombus is a contraindication to catheter ablation of AF •

Discontinuation of anticoagulation is not an indication for ablation

Calkins H, et al. Heart Rhythm. 2007;4(6):816-861.

Circ.AHAjournals.org Dec 20, 2010

LAA Device for AF

PROTECT-AF Study

• 707 patients with nonvalvular AF randomized to LAA device + 45 days of warfarin vs warfarin vs warfarin alone • Primary efficacy end point of stroke, CV death, or systemic embolism was 3.0% (1.9-4.5) with device and 4.9% (2.8-7.1) with warfarin; [RR 0.62, 95% CI (0.35 1.25)] • Primary safety end point of excessive bleeding, serious pericardial effusion, device embolization, or procedure-related stroke was 7.4% with device and 4.4% with warfarin; [RR 1.69, 95% CI (1.01 3.19)]

AF: atrial fibrillation; CV: cardiovascular; INR: international normalized ratio; LAA: left atrial appendage.

Holmes DR, et al. Lancet. 2009;374:534-542.

AF Trial Endpoints

• Symptoms • QoL • Recurrence of AF • LV function • Exercise tolerance • • • • • Major adverse cardiac events All hospitalizations CV hospitalizations CV, all-cause mortality Thromboembolism

Outcome Parameters for Trials in AF

Recommendations from a consensus conference organized by the German AF Competence NETwork (AFNET) and the EHRA

EHRA = European Heart Rhythm Association.

Kirchof P, et al. Europace. 2007;9(11):1006-1023.

Ongoing Ablation Trials

CABANA: Catheter Ablation vs AAD for AF – NIH/industry-cooperative, 5-year study to investigate if mortality is improved with ablation compared to drug therapy (rate or rhythm control) CASTLE-AF: Catheter Ablation vs Standard Conventional Treatment in Patients with LV Dysfunction and AF – Time to first event of death or hospitalization for HF

NIH = National Institutes of Health.

Calkins H, et al. Heart Rhythm. 2007;4(6):816-861. Marrouche NF, et al. Pacing Clin Electrophysiol. 2009;32(8):987-994.

New Goals of AF Management

• 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 hospitalizations and costs, 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 hospitalizations and costs Reduction in mortality *Total percentage of time a patient has AF as determined by the number and duration of AF episodes.

Wolf PA, et al. Stroke. 1991;22:983-988. Singh SN, et al. J Am Coll Cardiol. 2006;48:721-730. Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(Suppl 2):S7-S10. Hohnloser S, et al. J Cardiovasc Electrophysiol. 2008;19:69-73. Camm AJ, et al. Eur Heart J Suppl. 2008;10(Suppl H):H55-H78.

Summary

• AF is a common disease that is increasing in prevalence • For any patient with AF, decisions need to be made regarding antithrombotic therapy, rate control, and/or rhythm control • Guidelines provide recommendations for the management of patients with AF • Anticoagulation is essential in AF patients with risk markers, regardless of any restoration of SR • New agents and procedures may provide antiarrhythmic and antithrombotic options with improved outcomes for managing AF