1. Atrial Fibrillation When to Ablate, When to Medicate
John D. Hummel, MD
Professor of internal Medicine
Director, Cardiac Electrophysiology Research
Ross Heart Hospital , Ohio State University
Columbus, Ohio

2. Atrial Fibrillation Easily recognized.
Seems to bother healthcare workers as much as patients.
Who’s Problem? Internists cardiologists EP.

3. The Consequences of AF Thromboembolism Impaired hemodynamics Mortality
Stroke: 4.5 ↑risk
Microemboli: ↓cognitive function
Prothrombotic state
Impaired hemodynamics
Loss of atrial kick
Irregular ventricular contractions
Heart failure
Tachycardia-induced cardiomyopathy
Mortality
2 ↑risk independent of comorbid CV disease
Sudden death in HF and HCM
Hospitalizations
Most common arrhythmia requiring hospitalization
2-3 ↑risk for hospitalization
AF is an enormous contributor to the growing cost of medical care
Estimated US cost burden: 15.7 billion
↓Quality of life
Palpitations, dyspnea, fatigue, ↓exercise tolerance
Van Gelder IC et al. Europace. 2006;8:943-9; Narayan SM et al. Lancet. 1997;350: Wattigney WA et al. Circulation. 2003;108: Wyse DG et al. Circulation. 2004;109:

4. Learning Objectives Review the risk factors for atrial fibrillation.
Understand the guidelines for anticoagulation and where there is latitude for physician decision making.
Be able to determine when patients should be evaluated for curative ablation versus treatment with medical therapy.

5. DIAGNOSTIC WORKUP Identify Causes and Risk Factors
Minimum Evaluation
History and physical – BP, CV dz, Sleep Apnea
Electrocardiogram – WPW, LVH, MI
Echocardiogram – LVH, LAE, EF, Valve Dz
Labs – TSH, Renal fxn, LFTs
Additional Testing
ETT – CAD, Exercise induced SVT / AF
Holter / Event Monitor – Confirm AF and Sxs
TEE – LA clot
EPS – SVT triggered AF
AHA / ACC / ECS Guidelines

6. Incidence of AF Based on the Severity of OSA and Obesity
Cumulative frequency of incident atrial fibrillation (AF) during an average 4.7 years
Gami, et al. JACC 2007;49:565-71

7. The Problem

8. Incidence of AF Progression
Heart failure 2
Age 1
TIA/stroke 2
COPD 1
HTN 1
de Vos CB et al. J Am Coll Cardiol. 2010;55:

9. Goals of Therapy
Relieve symptoms
Prevent Stroke
Prevent Heart Failure

10. Severity of Stroke with AF
N = 1061 admitted with acute ischemic stroke
20.2% had AF
Bedridden state
With AF 41.2%
Without AF 23.7%
Odds ratio for bedridden state following stroke due to AF = 2.23 (P < )
No Difference in Risk with Paroxysmal vs Persistent AF
P <
AF was present in 20.2% of acute ischemic stroke patients admitted between 1990 and Hypertension, ischemic heart disease, and other cardioembolic risks were significantly higher in patients with AF. The frequency of the bedridden state was markedly higher in patients with AF (41.2%) vs patients without AF (23.7%). AF was a strong independent predictor of severe ischemic stroke.
Dulli DA et al. Neuroepidemiology. 2003;22:

11. Risk Factors for Thromboembolism in AF CHADS2 Score
High-Risk Factors= 2 points
Previous CVA / TIA / Embolism
Mitral Stenosis
Prosthetic heart valve
Moderate-Risk Factors= 1 point
Age > 75 yrs
HTN
CHF / EF < 35% DM
Weaker-Risk Factors= no points but add weight
Female
CAD
Thyrotoxicosis
Age 65 – 74 yrs
AHA / ACC / ECS Guidelines 2006

12. Stroke Risk in AF: ACP/AAFP Guidelines
CHADS2* score
Adjusted stroke rate† (95% CI)
CHADS2 risk level
1.9 (1.2–3.0)
Low
ASA 1
2.8 (2.0–3.8)
ASA / Warfarin 2
4.0 (3.1–5.1)
Moderate
Warfarin 3
5.9 (4.6–7.3) 4
8.5 (6.3–11.1)
High 5
12.5 (8.2–17.5) 6
18.2 (10.5–27.4)
*CHF, hypertension, age ≥75, diabetes, stroke or TIA; †Expected rate of stroke per 100 patient-years
Snow V et al. Ann Intern Med. 2003;139:

13. Camm AJ et al. Eur Heart J. 2010;31:2369-429.
A score ≥3 indicates “high risk”, and some caution and regular review of the patient is needed following initiation of any anticoagulant
Camm AJ et al. Eur Heart J. 2010;31: 13

14. Atrial Fibrillation Anticoagulation

15. Novel Oral Anticoagulants
Drug
Dabigatran
Rivaroxaban
Apixaban
Betrixaban
Edoxaban
Mechanism of action
Thrombin inhibitor
Factor Xa inhibitor
Factor Xa inhibitor
Factor Xa inhibitor
Factor Xa inhibitor
T1/2
14-17 hours
5-9 hours
12 hours
19-24 hours
6-12 hours
Regimen
bid
qd, bid
bid qd qd
Peak to trough
~7x
12x (qd)
3x-5x
~3x
~3x
Renal excretion of absorbed drug
~80%
36%-45%
25%-30%
~15%
35%
Potential for drug interactions
P-glycoprotein inhibitor
CYP3A4 substrate and
P-glycoprotein inhibitor
CYP3A4 substrate and
P-glycoprotein inhibitor
Not substrate for major CYPs
CYP3A4 substrate and
P-glycoprotein inhibitor
Usman MH et al. Curr Treat Options Cardiovasc Med. 2008;10: Piccini JP et al. Curr Opin Cardiol. 2010;25:

16. ACTIVE-A, ACTIVE-W Trials
ACTIVE-W: N = 6706; Warfarin superior to clopidogrel + ASA; Trial stopped early*
ACTIVE-A: N = 7554
Median follow-up 3.6 yrs 8
P = 0.01 7 6
P = 6 5 5 4 4
P < 0.001
Outcome / year (%) 3
P = 0.001
P = 0.53 3
P < 0.001
ACTIVE = AF Clopidogrel Trial with Irbesartan for Prevention of Vascular Events 2 2 1 1
Vascular event
Stroke
Major bleeding
Vascular event
Stroke
Major bleeding
Warfarin
Clopidogrel + Aspirin
Aspirin
ACTIVE Investigators. N Engl J Med. 2009;360: ACTIVE Investigators. Lancet. 2006;367:
*Due to clear evidence of superiority of oral anticoagulation therapy

17. AF THERAPY
ANTITHROMBOTIC RX
RHYTHM
CONTROL
RATE
OR ?
AND

18. AFFIRM Trial: Rate vs Rhythm Control Management Strategy Trial
Design
5-year, randomized, rate control vs. AARx
Primary endpoint: overall mortality
Patient population
4060 patients with AF and risk factors for stroke
Minimal symptoms
Mean Age = 69 yo
Hx of hypertension: 70.8%
CAD: 38.2%
Enlarged LA: 64.7%
Depressed EF: 26.0%
The AFFIRM Investigators. N Engl J Med. 2002;347:

19. Atrial fibrillation: Why Control Rate?
Rate control – the problem:
Increased rates – more symptomatic, greater hemodynamic impact.
Persistent increased rates – tachycardia induced cardiomyopathy
Rate control – the goal:
PAF – control symptomatic tachycardia
Chronic afib – mean 24hr HR < bpm (?)
Beta, Ca+2 blockers – controls resting and exercise rates.
Digoxin – controls resting rate, OK in poor LVEF.

20. AFFIRM: All-Cause Mortality30
Rate
Rhythm 25 20
p=0.078 unadjusted 15
Mortality, %
p=0.068 adjusted 10 5 1 2 3 4 5
Time (years)
Rhythm N:
2033
1932
1807
1316
780
255
Rate N:
2027
1925
1825
1328
774
236
The AFFIRM Investigators. N Engl J Med. 2002;347:

21. Recurrence of AF in Affirm
100 –
80 –
60 –
40 –
20 –
0 –
Rate Control
Rhythm Control
Percent
With AF
Recurrence
Log rank statistic = 58.62
p < 1 2 3 4 5 6
Time (years)
N, Events (%)
Rate control:
Rhythm control:
563, 3 (0)
729, 2 (0)
167, 383 (69)
344, 356 (50)
98, 440 (80)
250, 422 (60)
42, 472 (87)
143, 470 (69)
10, 481 (92)
73, 494 (75)
2, 484 (95)
18, 503 (79)
Raitt, et al. Am H J 2006

22. Risk of Death in Affirm: Is Sinus Rhythm the Goal?
AFFIRM: Selected time-dependent covariates associated with survival
Sinus rhythm < –0.72
Warfarin < –0.69
Digoxin –1.86
Antiarrhythmic –2.01
Covariate P Hazard ratio* % CI
*HR <1.00: Decreased risk of death, HR >1.00: Increased risk of death
AFFIRM Investigators. Circulation. 2004;109: 22

23. If lenient rate control: check serial echo for declining LV function
RACE II
Hypothesis: Lenient rate control is not inferior to strict rate control
Randomly assigned 614 patients with permanent AF to:
lenient rate-control strategy (resting heart rate <110 beats per minute)
strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute).
Primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events.
No Differerence between Lenient and Strict Rate Control
If lenient rate control: check serial echo for declining LV function
Van Gelder, et.al, for the RACE II Investigators NEJM April 15, 2010, No. 15, Vol 362:

25. APPROACHES TO AF THERAPY
Rate control plus
anticoagulation preferred
No AF symptoms
Long AF Hx
More SHD
Toxicity Risk
Greater risk of
proarrhythmia
Rhythm control
preferred
Greater AF symptoms
AF compromising LV function
Symptoms despite rate control
Younger age
No or lesser SHD
Rx option of class IC AAD
In anticoagulation candidates, continue anticoagulation indefinitely

26. Problems with Meds Proarrhythmia: Organ Toxicity:
VT with Flecainide, Propafenone in LVH, CAD, Decreased EF
Torsades in Dronedarone, Sotalol, Dofetilide
Organ Toxicity:
Amiodarone, procainamide, quinidine
Organ Toxicity: Lupus, agranulocytosis, thrombocytopenia, optic neuritis, pulmonary fibrosis, hepatitis, etc.

27. ACCF/AHA/HRS 2011 Guidelines Update Treatment of Atrial Fibrillation
Maintenance of Sinus Rhythm
No (or Minimal) Heart Disease
Hypertension
Coronary Artery Disease
Heart Failure
Dronedarone Flecainide Propafenone Sotalol
Substantial LVH
Dofetilide Dronedarone Sotalol
Amiodarone Dofetilide No
Yes
Dronedarone Flecainide Propafenone Sotalol
Recommendations for Maintenance of Sinus Rhythm
Class I:
Catheter ablation performed in experienced centers* is useful in maintaining sinus rhythm in selected patients with significantly symptomatic, paroxysmal AF who have failed treatment with an antiarrhythmic drug and have normal or mildly dilated left atria, normal or mildly reduced LV function, and no severe pulmonary disease. (Level of Evidence: A) * An experienced center is defined as one performing more than 50 AF catheter ablation cases per year
Class IIa:
In patients with AF without structural or coronary heart disease, initiation of propafenone or flecainide can be beneficial on an outpatient basis in patients with paroxysmal AF who are in sinus rhythm at the time of drug initiation. (Level of Evidence: B)
Catheter ablation is reasonable to treat symptomatic persistent AF. (Level of Evidence: A)
Class IIb:
Catheter ablation may be reasonable to treat symptomatic paroxysmal AF in patients with significant left atrial dilatation or with significant LV dysfunction. (Level of Evidence: A)
Amiodarone
Amiodarone
Catheter Ablation
Catheter Ablation
Amiodarone Dofetilide
Catheter Ablation
“In some patients, especially young individuals with very symptomatic AF, ablation may be preferred over years of drug therapy.”*
Amiodarone Dofetilide
Catheter Ablation
Catheter Ablation
*Knight BP. HRS Practical Rate and Rhythm Management of Atrial Fibrillation. Updated January Available at:

29. Schneider MP, et. Al. J Am Coll Cardiol. 2010 May 25;55(21):2299-307
Prevention of atrial fibrillation by Renin-Angiotensin system inhibition
Meta analysis of published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation
A total of 23 randomized controlled trials with 87,048 patients were analyzed.
Overall, RAS inhibition reduced the odds ratio for AF by 33% (p < ), but there was substantial heterogeneity among trials.
In primary prevention:
RAS inhibition was effective in patients with heart failure and those with hypertension and left ventricular hypertrophy
In secondary prevention:
RAS inhibition in addition to antiarrhythmic drugs, including amiodarone, further reduced the odds for AF recurrence after cardioversion by 45% (p = 0.01) and in patients on medical therapy by 63% (p < ).
RAS inhibition is an emerging treatment for the primary and secondary prevention of AF
Schneider MP, et. Al. J Am Coll Cardiol May 25;55(21):

30. Source: http://www.fda.gov/Drugs/DrugSafety/ucm264059.htm
Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)
  Dronedarone Placebo N = N = Hazard P n (%) n (%) ratio value
CV death, myocardial infarction, (2) (0.9)
stroke, systemic embolism*
Death, unplanned CV hospitalization* (7.5) (5.1)
Death (1) (0.4)
Myocardial infarction (0.2) (0.2)
Stroke (1.1) (0.4)
Heart Failure hospitalization (2.2) (1)
Source: 30

31. COMET: Effect of Amiodarone on All-cause Mortality
N = 3029 with chronic HF randomized to carvedilol or metoprolol Median follow-up 58 months
COMET = Carvedilol or Metoprolol European Trial
Torp-Pedersen C et al. J Card Failure. 2007;13:340-5. 31

32. Drug Therapy for Prevention of Recurrent Atrial Fibrillation
Classic AF drug study
Roy D et al. N Engl J Med. 2000;342: 32

33. Randomized to catheter ablation (n = 106) or AAD (n = 61)
ThermoCool: Trial of Ablation vs. Alternative Antiarrhythmic Medication
N = 167 with paroxysmal AF
Randomized to catheter ablation (n = 106) or AAD (n = 61)
Single procedure
Mean age 55.7 yrs
33.5% women
66%
16%
Wilber DJ et al. JAMA. 2010;303:

34. Alternatives to Drug therapy “Non-Pharmacologic Therapy”
Coumadin – LAA closure (Watchman)
Rate Control – AVN RFA + PCMK
AARx – Adjunctive AFL RFA
AARX – Curative Afib RFA

35. Watchman Device
Copyright ©2010 American College of Cardiology Foundation. Restrictions may apply.

36. Post Surgical LAA Closure
50 pts. MV surgery and LAA ligation
TEE post op 30 pts, 6 days-13 yrs in 20 pts
Incomplete ligation in 18/50 (36%) of pts
No diff. b/w F/U TEE timing, Type of mitral surgery, operative approach, left atrial size or degree of MR.
SEC or thrombus in appendage in 9 of 18 (50%) patients with incomplete ligation
4 of these 18 (22%) patients had thromboembolic events.
Katz et. Al, JACC, 2000

37. Pacemaker Placement

38. AVN RF ablation

39. Complete AVN Ablation Advantages: 100% efficacy
85% symptomatic improvement
Improved EF (LV remodeling)
Eliminates need for rate control drugs
Disadvantages:
Pacemaker dependant
Risk of LV dysfunction with RV pacing
Some pts still have sx’s
Good Candidates:
Tachy / Brady Syndrome
PCMK in Place – CHF with BiV device
Medication refractory / intolerant
Elderly

40. Atrial Flutter RFA

41. Atrial Flutter Circuit

42. Atrial Flutter Ablation
Approximately 15% of AF patients treated with an AA will develop AFL
Advantages:
98% efficacy
As primary Rx: RFA more effective than AARx
Increases the success of medical therapy
Disadvantages: Invasive
Good Candidates:
Typical AFL (IVC / TV isthmus)
AARx related AFL

43. Focal Origin of Atrial Fibrillation Hassaiguerre M, NEJM, 1998RA LA
94% of AF triggers from Pulmonary Veins
“90 – 95% of all AF is initiated by PV ectopy”
SVC 17 31 FO
Pulmonary Veins 6 11
IVC CS

44. * 74 yo medically refractory AF, Echo – Normal
AA Rx - Verapamil, Rythmol, Betapace, Norpace I II
III V1
RSPV
dist
prox
LIPV RA *

45. Lasso Catheter

46. Atrial Fibrillation Ablation Atrial Shell and Cardiac MRI

47. Properties of Cryoablation
Hypothermic Zone
Ablation Zone (sub-zero)
Arctic Font uses cryo to create lesions. The properties of cryoablation are different than heat-based energy sources.
It enables physicians to create a circumferential, transmural lesion by removing heat from the tissue, leading with a wave of hypothermia, with the coldest temperatures contained within the ablation zone around the balloon. Maintaining contact with the tissue is important, since the balloon ablates at the point of tissue contact.
Removes heat from the tissue
Leads with a wave of hypothermia
Ablates at the point of balloon contact

48. 45 yo with PAF Conversion of AF to NSR, LSPV with AF
Abl
Lasso
LSPV CS

49. A-Fib vs. EP Labs

50. (Last 200 pts complications < 1.2%)
Current State of Curative Catheter-Based Ablation at OSU Procedural Success & Complications
Total Patients > 2000 (65% Persistent AF) average procedure 3 hours (2-5)
Expected 1yr
≈ 70% after first procedure
≈ 80% after second procedure
Complications ≈ 1 to 3%
Tamponade – 0.6%
Pulmonary vein stenosis – 0.6%
TIA / CVA – 0.5%
Esophageal-LA fistula - 0
Groin Bleeding / Hematoma
(Last 200 pts complications < 1.2%)

51. Phased Rf Catheter Positioning
In Antrum of Right PVs
RSPV
RIPV

52. LIPV RF Ablation Pre Post II Pair 5 Pair 4 Pair 3 Pair 2 Pair 1 II

53. Mitigation of Ablation Risk
Tamponade: Force sensing catheters
Esophageal-Atrial Fistula: Esophageal sensors, Cryoballoon
CVA/Groin Hematoma: Uninterrupted Warfarin
Phrenic nerve Palsy: Phrenic Mapping

54. Animal Rotors/Drivers
FIRM MAP
Animal Rotors/Drivers
Human Rotors

55. Current State of Curative Catheter-Based RFA Who is a good candidate?
Symptomatic / Frequent AF
Limited Heart Dz
LA < 5.5cm
No MS / Rheumatic Dz
Younger Patients
Medically Refractory / Intolerant
(Ablation now second line therapy)

56. Atrial Fibrillation: Ablation vs Drug Rx.
70% success
PV stenosis
AE fistula
TIA/CVA
Drug Rx.
40% success
Proarrhythmia
End Organ Toxicity
No Free Lunch
Torsades
AE fistula
PV stenosis

57. Current State of Curative Catheter-Based RFA Who is a good candidate?
Symptomatic / Frequent AF
Limited Heart Dz
LA < 5.5cm
No MS / Rheumatic Dz
Younger Patients
Medically Refractory / Intolerant
(Ablation now second line therapy)

59. SAFE-T: Sinus Rhythm vs AF – Increase in Maximal Exercise Duration
100
Sinus rhythm
Atrial fibrillation 90
P = 0.01
P = 0.02 80 70 60
Increase in duration (mean) 50 40 30 20 10
8 weeks
1 year
Singh SN et al. J Am Coll Cardiol. 2006;48:

60. Catheter Ablation vs. Surgical Ablation
2/3 patients failed catheter ablation, 1/3 HTN and LAE
Freedom from left atrial arrhythmia (30 seconds) without antiarrhythmic drugs after 12 months:
36.5% for CA
65.6% for SA (P=0.0022)
Safety end point of significant adverse events
16% for Catheter Ablation
35% for Surgical Ablation (P=0.027)

61. Statins in Prevention of AF (1st Episode or AF Recurrence)
Study Statin Control or subcategory n/N n/M
MIRACL 93/ /1548
Tveit 18/51 17/51
Dernellis 14/40 36/40
ARMYDA 3 35/101 56/99
Chello 2/20 5/20
Ozaydin 3/24 11/24
Total (95% CI)
Total events: 165 (Statin), 221 (Control)
Favors treatment
Favors control
These data are a meta-analysis of 6 randomized, controlled, parallel-design human trials examining the use of statins on the recurrence of AF in patients with paroxysmal or persistent AF or new-onset AF following cardiac surgery or acute coronary syndrome (ACS). Statin use was associated with a reduced risk of AF. This benefit appeared to be greater for the prevention of AF recurrence.
ARMYDA = Atorvastatin for Reduction of Myocardial Dysrhythmia after Cardiac Surgery
CI = confidence interval
df = degrees of freedom
LDL-C = low-density lipoprotein cholesterol
MIRACL = Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering
0.1
0.2
0.5 1 2 5 10
Odds ratio (random); 95% CI
Not assessed in this meta-analysis:
Degree of LDL-C; Statin dose
Test for heterogeneity: Chi2 = 29.47, df = 5 (P < ), I2 = 83.0%
Test for overall effect: Z = 2.35 (P = 0.02)
Fauchier L et al J Am Coll Cardiol. 2008;51:

62. AF TREATMENT GOALS
AF is rarely life-threatening and is typically recurrent
Treatment goals in symptomatic pts
 frequency of recurrences
 duration of recurrences
 severity of recurrences
Minimize risk of tachycardia induced cardiomyopathy
Safety is primary concern

63. AFFIRM Functional Status Substudy
Lower NYHA functional class in patients in sinus rhythm
6 min walk tests – 94 feet longer in Rhythm Control group (P = 0.049)
Chung MK et al. J Am Coll Cardiol. 2005;46: 63

66. Types of Atrial Fibrillation
First diagnosed AF
Categorized as 1st presentation, regardless of AF duration or presence/severity of AF symptoms
Paroxysmal AF
Self-terminating, usually 48 hours
Persistent AF
Lasts >7 days or requires termination by cardioversion
Long-standing persistent AF
Lasts ≥1 year
Permanent AF
Presence of arrhythmia is accepted by patient (and physician)
Camm AJ et al. Eur Heart J. 2010;31:

67. Mortality: AF vs Sinus Rhythm70 AF SR
P = 0.04
P = NS 60
P = 0.001 50
P  0.001 40
P = NS 30
Slide 17
To date, the results of trials in HF patients with AF have shown a small trend toward increased mortality compared with HF patients who are in SR, particularly in patients with advanced AF. While this trend cannot be viewed as definitive, clinicians should be aware of the potentially negative impact of AF on prognosis in HF patients. 20
n=795
n=427
n=390 10
n=6517
n=234
V-HeFT
(Carson)
Mahoney
SOLVD
(Dries)
Middlekauff
Crijns
Carson PE, Johnson GR, Dunkman WB, Fletcher RD, Farrell L, Cohn JN, for the V-HeFT VA Cooperative Studies Group. The influence of atrial fibrillation on prognosis in mild to moderate heart failure: the V-HeFT Studies. Circulation. 1993;87(suppl VI):VI-102-VI-110.
Dries DL, Exner DV, Gersh BJ, Domanski MJ, Waclawiw MA, Stevenson LW. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. J Am Coll Cardiol. 1998;32:
Crijns HJGM, Tjeerdsma G, de Kam PJ, et al. Prognostic value of the presence and development of atrial fibrillation in patients with advanced chronic heart failure. Eur Heart J. 2000; 21:
Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure: a study of 390 patients. Circulation. 1991;84:40-48.
Mahoney P, Kimmel S, DeNofrio D, Wahl P, Loh E. Prognostic significance of atrial fibrillation in patients at a tertiary medical center referred for heart transplantation because of severe heart failure. Am J Cardiol. 1999;83:
Carson PE et al. Circulation. 1993;87(suppl VI):VI-102-VI-110; Dries DL et al. J Am Coll Cardiol. 1998;32: ; Crijns HJ et al. Eur Heart J. 2000;21: ; Middlekauff HR et al. Circulation. 1991;84:40-8; Mahoney P et al. Am J Cardiol. 1999;83:

68. Source: http://www.fda.gov/Drugs/DrugSafety/ucm264059.htm
Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)
A randomized, double-blind, placebo controlled, parallel group trial for assessing the clinical benefit of dronedarone 400 mg bid on top of standard therapy in patients with permanent AF and additional risk factors
Eligible patients were ≥65 years, in permanent AF (defined by the presence of AF/atrial flutter for ≥6 months prior to randomization without plans to restore sinus rhythm), with ≥1 additional CV risk criterion
Source: 68

69. Source: http://www.fda.gov/Drugs/DrugSafety/ucm264059.htm
Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS)
Co-primary endpoints:
Major cardiovascular events (stroke, systemic arterial embolism, myocardial infarction or cardiovascular death), or
 Unplanned cardiovascular hospitalization or death from any cause
In July 2011, the data monitoring committee reviewed the preliminary data and concluded that there was a significant excess of CV events in the dronedarone group for both co-primary endpoints as well as other CV events. As a result, the PALLAS study was stopped. 
Source: 69

70. FDA Response Since PALLAS
"At this time, patients taking Multaq should talk to their healthcare professional about whether they should continue to take Multaq for non-permanent atrial fibrillation. Patients should not stop taking Multaq without talking to a healthcare professional. Healthcare professionals should not prescribe Multaq to patients with permanent atrial fibrillation." 
Source: 70

71. DIAMOND – Evidence for Survival Benefit of Sinus Rhythm
Survival rates of patients treated with dofetilide or placebo by SR conversion status
Dofetilide group
1.0 SR
0.8
Not SR
0.6
Probability of survival
0.4
0.2
0.0 6 12 18 24 30 36 42 48
1.0
Placebo group
0.8
0.6
Probability of survival
0.4
0.2
0.0 6 12 18 24 30 36 42 48
Time (months)
Pedersen OD et al.Circulation. 2001;104:292-6.

72. Catheter Ablation vs Antiarrhythmic Drugs for AF: Early Studies
The APAF Study
The A4 Study
Early AF studies with caveats
Jais P. et al. Circulation. 2008;118:
Pappone C et al. J Am Coll Cardiol. 2006;48:
Early studies limited by small study populations, variable entry criteria and definitions of success, and were conducted in single or limited number of centers

73. Dabigatran vs. Warfarin
Noninferiority trial randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive:
1. Fixed doses of dabigatran — 110 mg or 150 mg twice daily in a blinded fashion
2. Adjusted-dose warfarin in an unblinded fashion
The median duration of the follow-up period was 2.0 years.
The primary outcome was stroke or systemic embolism.
Results
Primary outcome
1.69% per year in the warfarin group
1.53% per year in the group that received 110 mg of dabigatran (P<0.001 for noninferiority)
1.11% per year in the group that received 150 mg of dabigatran ( P<0.001 for superiority)
Major bleeding
3.36% per year in the warfarin group
2.71% per year in the group receiving 110 mg of dabigatran (P=0.003)
3.11% per year in the group receiving 150 mg of dabigatran (P=0.31).
Hemorrhagic stroke
0.38% per year in the warfarin group
0.12% per year with 110 mg of dabigatran (P<0.001)
0.10% per year with 150 mg of dabigatran (P<0.001).
Mortality rate
4.13% per year in the warfarin group
3.75% per year with 110 mg of dabigatran (P=0.13)
3.64% per year with 150 mg of dabigatran (P=0.051).
Conclusions
Dabigatran 110 mg had rates of stroke and systemic embolism similar to warfarin with less major hemorrhage.
Dabigatran 150 mg had lower rates of stroke and systemic embolism but similar rates of major hemorrhage.
Stuart J. Connolly and the RE-LY Steering Committee and Investigators NEJM Sept 17, 2009, No. 12, Vol 361:

74. PABA-CHF: Study Design
Prospective, randomized, controlled trial
N = 81 with symptomatic, drug-resistant AF; LVEF ≤40%; NYHA Class II or III HF
Pulmonary-vein isolation
(n = 41)
Atrioventricular-node ablation with biventricular pacing (n = 40)
Primary outcome: Composite of ejection fraction, 6-minute walk distance, and Minnesota Living with Heart Failure score at 6 months
PABA-CHF = Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure
Khan MN et al. N Engl J Med. 2008;359:

75. PABA-CHF: Composite Primary Endpoints at 6 Months
Randomized trial of NYHA Class II or III CHF & EF <40% to PVI or AVN + BiV
360
6-Minute walk
PVI
AVN + BiV
340
PVI
Ejection fraction
320
P < 0.001
Distance (m) 37
300
PVI 35
280
AVN + BiV
260 33
P < 0.001 3
Ejection fraction (%) 6 31
Months 29
MLHF score*
100
P < 0.001 27
AVN + BiV 80 25 60
Score* 40 3 6 20
Months
Months 6
*↓Score = ↑QoL
Khan MN et al. N Engl J Med. 2008;359:

76. Wann LS et al. Circulation. 2011;8:157-76.