John D. Hummel, MDProfessor of internal Medicine

Director, Cardiac Electrophysiology ResearchRoss Heart Hospital , Ohio State University

Columbus, Ohio

Atrial Fibrillation When to Ablate, When to Medicate

Atrial Fibrillation

Easily recognized.Seems to bother healthcare workers as much as patients.

Who’s Problem? Internists cardiologists EP.

Thromboembolism• Stroke: 4.5 ↑risk

• Microemboli: ↓cognitive function

• Prothrombotic state

Mortality• 2 ↑risk independent of comorbid CV disease

• Sudden death in HF and HCMHospitalizations

• Most common arrhythmia requiring hospitalization

• 2-3 ↑risk for hospitalization

Impaired hemodynamics• Loss of atrial kick

• Irregular ventricular contractions

• Heart failure• Tachycardia-induced

cardiomyopathy

• ↓Quality of life• Palpitations, dyspnea,

fatigue, ↓exercise tolerance

Van Gelder IC et al. Europace. 2006;8:943-9; Narayan SM et al. Lancet. 1997;350:943-50. Wattigney WA et al. Circulation. 2003;108:711-6. Wyse DG et al. Circulation. 2004;109:3089-95.

• AF is an enormous contributor to the growing cost of medical care• Estimated US cost burden:

15.7 billion

The Consequences of AF

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.

DIAGNOSTIC WORKUPIdentify 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

Incidence of AF Based on the Severity of OSA and ObesityCumulative frequency of incident atrial fibrillation (AF) during an average 4.7

years

Gami, et al. JACC 2007;49:565-71

The Problem

de Vos CB et al. J Am Coll Cardiol. 2010;55:725-31.

Heart failure 2Age 1TIA/stroke 2COPD 1HTN 1

Incidence of AF Progression

Goals of Therapy

1. Relieve symptoms

2. Prevent Stroke

3. Prevent Heart Failure

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 < 0.0005)

• No Difference in Risk with Paroxysmal vs Persistent AF

P < 0.0005

Dulli DA et al. Neuroepidemiology. 2003;22:118-23.

Risk Factors for Thromboembolism in AFCHADS2 Score

High-Risk Factors= 2 pointsPrevious CVA / TIA / EmbolismMitral StenosisProsthetic heart valve

Moderate-Risk Factors= 1 pointAge > 75 yrsHTNCHF / EF < 35% DM

Weaker-Risk Factors= no points but add weightFemaleCADThyrotoxicosisAge 65 – 74 yrs

AHA / ACC / ECS Guidelines 2006

Stroke Risk in AF: ACP/AAFP Guidelines

CHADS2*score

Adjusted stroke rate†

(95% CI)CHADS2

risk level

0 1.9 (1.2–3.0) Low ASA

12.8 (2.0–3.8) Low

ASA / Warfarin

2 4.0 (3.1–5.1) Moderate

Warfarin

3 5.9 (4.6–7.3) Moderate

4 8.5 (6.3–11.1) High

5 12.5 (8.2–17.5) High

6 18.2 (10.5–27.4) High

*CHF, hypertension, age ≥75, diabetes, stroke or TIA; †Expected rate of stroke per 100 patient-yearsSnow V et al. Ann Intern Med. 2003;139:1009-17.

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;31:2369-429.

Atrial FibrillationAtrial FibrillationAnticoagulationAnticoagulation

Drug Dabigatran Rivaroxaban Apixaban Betrixaban Edoxaban

Mechanismof 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

CYP3A4 substrate

and P-glycoprotein

inhibitor

Usman MH et al. Curr Treat Options Cardiovasc Med. 2008;10:388-97. Piccini JP et al. Curr Opin Cardiol. 2010;25:312-20.

Notsubstratefor major

CYPs

Novel Oral Anticoagulants

ACTIVE-A, ACTIVE-W Trials

ACTIVE-A: N = 7554Median follow-up 3.6 yrs

ACTIVE-W: N = 6706; Warfarin superior to clopidogrel + ASA;

Trial stopped early*

Clopidogrel + Aspirin AspirinWarfarin

6

4

0

2

Ou

tco

me

/ yea

r (%

)

StrokeVascularevent

Majorbleeding

5

3

1

P = 0.0003

P = 0.001 P = 0.53

8

6

4

0

2

StrokeVascularevent

Majorbleeding

7

5

3

1

P = 0.01

P < 0.001

P < 0.001

ACTIVE Investigators. N Engl J Med. 2009;360:2066-78. ACTIVE Investigators. Lancet. 2006;367:1903-12.*Due to clear evidence of superiority of oral

anticoagulation therapy

AF THERAPY

ANTITHROMBOTIC RX

RHYTHMCONTROL

RATECONTROL

OR ?

AND

The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

AFFIRM Trial: Rate vs Rhythm ControlManagement 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%

AFFIRM: All-Cause Mortality

Rate N:

Rhythm N:

2027

2033

1925

1932

1825

1807

1328

1316

774

780

236

255

0

5

10

15

20

25

30

0 1 2 3 4 5

Mo

rtal

ity,

%

Rate

Rhythm

p=0.078 unadjusted

Time (years)

p=0.068 adjusted

The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

100 –

80 –

60 –

40 –

20 –

0 –

Time (years)

PercentWith AF

Recurrence

Rate Control

Raitt, et al. Am H J 2006

0 1 2 3 4 5 6

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)

Recurrence of AF in Affirm

Rhythm Control

Log rank statistic = 58.62

p < 0.0001

Risk of Death in Affirm: Is Sinus Rhythm the Goal?

*HR <1.00: Decreased risk of death, HR >1.00: Increased risk of death

AFFIRM Investigators. Circulation. 2004;109:1509-13.

AFFIRM: Selected time-dependent covariates associated with survival

Sinus rhythm <0.00010.53 0.39–0.72

Warfarin <0.00010.50 0.37–0.69

Digoxin 0.00071.42 1.09–1.86

Antiarrhythmic 0.00051.49 1.11–2.01

Covariate PHazard ratio* 99% CI

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

Van Gelder, et.al, for the RACE II Investigators NEJM April 15, 2010, No. 15, Vol 362: 1363-1373

If lenient rate control: check serial echo for declining LV functionIf lenient rate control: check serial echo for declining LV function

Rate control plusanticoagulation preferred

Rhythm controlpreferred

• No AF symptoms• Long AF Hx• More SHD• Toxicity Risk• Greater risk of

proarrhythmia• 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

APPROACHES TO AF THERAPY

Problems with Meds• Proarrhythmia:

– 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.

ACCF/AHA/HRS 2011 Guidelines Update Treatment of Atrial Fibrillation

*Knight BP. HRS Practical Rate and Rhythm Management of Atrial Fibrillation. Updated January 2010. Available at: http://www.hrsonline.org/ClinicalGuidance/upload/2010_rate-rhythm_guide1.pdf

“In some patients, especially young individuals with very

symptomatic AF, ablation may be preferred over years of drug

therapy.”*

Maintenance of Sinus RhythmMaintenance of Sinus Rhythm

DronedaroneFlecainide

PropafenoneSotalol

DronedaroneFlecainide

PropafenoneSotalol

CatheterAblation

CatheterAblation

AmiodaroneAmiodarone

CatheterAblation

AmiodaroneDofetilide

CatheterAblation

CatheterAblation

AmiodaroneDofetilide

Substantial LVH

No Yes

DofetilideDronedarone

Sotalol

AmiodaroneDofetilide

No (or Minimal)Heart Disease

HypertensionCoronary Artery

DiseaseHeart Failure

Prevention of atrial fibrillation by Renin-Angiotensin system inhibition

Schneider MP, et. Al. J Am Coll Cardiol. 2010 May 25;55(21):2299-307

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 < 0.00001), 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 <0.00001).

RAS inhibition is an emerging treatment for the primary and secondary prevention of AF

Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of

Standard Therapy (PALLAS)

Source: http://www.fda.gov/Drugs/DrugSafety/ucm264059.htm

  Dronedarone Placebo N = 1572 N = 1577

Hazard P n (%) n (%)

ratio value

CV death, myocardial infarction, 32 (2) 14 (0.9) 2.3 0.009

stroke, systemic embolism*

Death, unplanned CV hospitalization* 118 (7.5) 81 (5.1) 1.5 0.006

Death 16 (1) 7 (0.4) 2.3 0.065

Myocardial infarction 3 (0.2) 3 (0.2) 1.0 1

Stroke 17 (1.1) 7 (0.4) 2.4 0.047

Heart Failure hospitalization 34 (2.2) 15 (1) 2.3 0.008

COMET: Effect of Amiodarone on All-cause Mortality

COMET = Carvedilol or Metoprolol European Trial

Torp-Pedersen C et al. J Card Failure. 2007;13:340-5.

N = 3029 with chronic HF randomized to carvedilol or metoprolol Median follow-up 58 months

Drug Therapy for Prevention of Recurrent Atrial Fibrillation

Roy D et al. N Engl J Med. 2000;342:913-20.

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

Wilber DJ et al. JAMA. 2010;303:333-40.

66%

16%

Alternatives to Drug therapy“Non-Pharmacologic Therapy”

Coumadin – LAA closure (Watchman)

Rate Control – AVN RFA + PCMK

AARx – Adjunctive AFL RFA

AARX – Curative Afib RFA

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

Watchman Device

Watchman Device

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

Pacemaker PlacementPacemaker Placement

AVN RF ablation

Complete AVN Ablation Advantages:

100% efficacy85% symptomatic improvementImproved EF (LV remodeling)Eliminates need for rate control drugs

Disadvantages:Pacemaker dependantRisk of LV dysfunction with RV pacing

Some pts still have sx’s

Good Candidates:Tachy / Brady SyndromePCMK in Place – CHF with BiV deviceMedication refractory / intolerantElderly

Atrial Flutter RFA

Atrial Flutter Circuit

Atrial Flutter Ablation Approximately 15% of AF patients treated with an AA will develop

AFL

Advantages:98% efficacyAs primary Rx: RFA more effective than AARxIncreases the success of medical therapy

Disadvantages: Invasive

Good Candidates:Typical AFL (IVC / TV isthmus)AARx related AFL

Focal Origin of Atrial Fibrillation

Hassaiguerre M, NEJM, 1998

• 94% of AF triggers from Pulmonary Veins

• “90 – 95% of all AF is initiated by PV ectopy”

RA LA

CS

FO

SVC

IVC

Pulmonary Veins

17 31

6 11

74 yo medically refractory AF, Echo – Normal AA Rx - Verapamil, Rythmol, Betapace, Norpace

IIIIII

V1RSPV

distRSPV

prox

LIPV

RA

*

Lasso Catheter

Atrial Fibrillation AblationAtrial Shell and Cardiac MRI

Properties of Cryoablation

• Removes heat from the tissue• Leads with a wave of hypothermia• Ablates at the point of balloon contact

Hypothermic Zone

Ablation Zone (sub-zero)

45 yo with PAFConversion of AF to NSR, LSPV with AF

Lasso

LSPV

CS

Abl

A-Fib vs. EP Labs

Current State of CurativeCatheter-Based Ablation at OSU

Procedural Success & Complications• Total Patients > 2000 (65% Persistent AF)

average procedure 3 hours (2-5)• Expected success @ 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%)

RSPV

RIPV

Phased Rf Catheter PositioningIn Antrum of Right PVs

II

Pair 1

Pair 2

Pair 3

Pair 4

Pair 5

Pre

II

Pair 1

Pair 2

Pair 3

Pair 4

Pair 5

Post

LIPV RF Ablation

Mitigation of Ablation Risk• Tamponade: Force sensing catheters

• Esophageal-Atrial Fistula: Esophageal sensors, Cryoballoon

• CVA/Groin Hematoma: Uninterrupted Warfarin

• Phrenic nerve Palsy: Phrenic Mapping

FIRM MAPFIRM MAPAnimal Rotors/DriversAnimal Rotors/Drivers Human RotorsHuman Rotors

Current State of CurativeCatheter-Based RFA Who is a good candidate?

Symptomatic / Frequent AFLimited Heart Dz

LA < 5.5cmNo MS / Rheumatic Dz

Younger PatientsMedically Refractory / Intolerant

(Ablation now second line therapy)

Atrial Fibrillation: Ablation vs Drug Rx.Ablation70% successPV stenosisAE fistula TIA/CVA

Drug Rx.40% successProarrhythmiaEnd Organ Toxicity

No Free Lunch

PV stenosis

AE fistula

Torsades

Current State of CurativeCatheter-Based RFA Who is a good candidate?

Symptomatic / Frequent AFLimited Heart Dz

LA < 5.5cmNo MS / Rheumatic Dz

Younger PatientsMedically Refractory / Intolerant

(Ablation now second line therapy)

Singh SN et al. J Am Coll Cardiol. 2006;48:721-30.

Sinus rhythm

Atrial fibrillation

0

10

20

30

40

50

60

70

80

90

100

P = 0.01P = 0.02

8 weeks 1 year

Incr

ease

in d

ura

tio

n (

mea

n)

SAFE-T: Sinus Rhythm vs AF – Increase in Maximal Exercise Duration

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)

Statins in Prevention of AF (1st Episode or AF Recurrence)

Fauchier L et al. J Am Coll Cardiol. 2008;51:828-35.

Favors treatment

Favors control

Odds ratio (random); 95% CI

0.1 0.2 0.5 1 2 5 10

Study Statin Controlor subcategory n/N n/M

MIRACL 93/1539 96/1548

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) 1775 1782

Total events: 165 (Statin), 221 (Control)

Not assessed in this meta-analysis: Degree of LDL-C; Statin dose

Test for heterogeneity: Chi2 = 29.47, df = 5 (P < 0.0001), I2 = 83.0%Test for overall effect: Z = 2.35 (P = 0.02)

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

AFFIRMFunctional 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;46:1891-9.

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;31:2369-429.

Mortality: AF vs Sinus Rhythm

0

10

20

30

40

50

60

70

V-HeFT(Carson)

Mahoney SOLVD(Dries)

Middlekauff Crijns

AF SRP = NS

P = NS

P 0.001

P = 0.001

P = 0.04

n=795

n=234n=6517

n=390

n=427

Carson PE et al. Circulation. 1993;87(suppl VI):VI-102-VI-110; Dries DL et al. J Am Coll Cardiol. 1998;32:695-703; Crijns HJ et al. Eur Heart J. 2000;21:1238-45; Middlekauff HR

et al. Circulation. 1991;84:40-8; Mahoney P et al. Am J Cardiol. 1999;83:1544-7.

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: 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: http://www.fda.gov/Drugs/DrugSafety/ucm264059.htm

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: http://www.fda.gov/Drugs/DrugSafety/ucm264059.htm

DIAMOND – Evidence for Survival Benefit of Sinus Rhythm

Pedersen OD et al.Circulation. 2001;104:292-6.

Survival rates of patients treated with dofetilide or placebo by SR conversion status

Survival rates of patients treated with dofetilide or placebo by SR conversion status

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

Pro

bab

ilit

y o

f su

rviv

alP

rob

abil

ity

of

surv

ival Dofetilide groupDofetilide group

00 66 1212 1818 2424 3030 3636 4242 4848

SRSR

Not SRNot SR

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0.00.0

Pro

bab

ilit

y o

f su

rviv

alP

rob

abil

ity

of

surv

ival

Placebo groupPlacebo group

00Time (months)Time (months)

66 1212 1818 2424 3030 3636 4242 4848

Jais P. et al. Circulation. 2008;118:2498-505.

Catheter Ablation vs Antiarrhythmic Drugs for AF: Early Studies

Pappone C et al. J Am Coll Cardiol. 2006;48:2340-7.

The A4 StudyThe APAF Study

Early studies limited by small study populations, variable entry criteria and definitions of success, and were conducted in single or limited number of centers

Dabigatran vs. WarfarinNoninferiority 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 group1.53% 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 group2.71% 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 stroke0.38% per year in the warfarin group0.12% 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 group3.75% 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: 1139-1151

PABA-CHF: Study DesignProspective, randomized, controlled trial

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;359:1778-85.

N = 81 with symptomatic, drug-resistant AF; LVEF ≤40%; NYHA Class II or III HF

Primary outcome: Composite of ejection fraction, 6-minute walk distance, and Minnesota Living with Heart Failure score at 6 months

Pulmonary-vein isolation(n = 41)

Atrioventricular-node ablation with biventricular pacing (n = 40)

Randomized trial of NYHA Class II or III CHF & EF <40% to PVI or AVN + BiV

Khan MN et al. N Engl J Med. 2008;359:1778-85.

PABA-CHF: Composite Primary Endpoints at 6 Months

Months

AVN + BiV

6-Minute walk

Dis

tan

ce

(m

)

3 60

360

340

320

300

280

260

0

PVI

P < 0.001

MLHF score*

Sc

ore

*

Months0 6

100

80

60

40

20

0

P < 0.001

PVI AVN + BiV

AVN + BiVEje

ctio

n f

ract

ion

(%

)

P < 0.001

Ejection fraction

Months

3 60

37

35

33

31

29

27

25

0

PVI

*↓Score = ↑QoL

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