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Relevant financial relationship(s) with industry
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Off Label Usage
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Overview
• Mechanisms of AF
• AF as a syndrome, not a disease
• The role of ablation
• The role of medical therapy, AADs
• Anticoagulation
Atrial Fibrillation
• Chaotic rhythm in atria, variably conducted to ventricles - irregular rate
• Common - up to 6 million in US • Increasing prevalence due to increased longevity (like HF)
Understanding of AF changed over time…
1947 Scherf D et al. Proc Soc Exp Bio 1962 Moe G et al. Arch Int Pharm Ther
Focal Multiple Wavelet
Whatever the mechanism, MAZE works..
• Multiple incision lines, including around PVs
• Up to 30% in need for PPM postop
The Pulmonary Veins..
Haissaguerre M et al. NEJM 1998 Sep 3;339(10):659-66
However, AF begets AF • The longer you are in AF, the more likely to stay in it
Dittrich HC et al. Am J Cario 1989;63:193-197
However, AF begets AF
Wijffels MC et al. Circulation 1995 Oct 1:92(7):1954-68
• There must be something changing in the substrate as well
Atrial Remodelling Electrical Remodelling • Shortening of atrial AP duration
• Shortening of action potential duration
• Decrease in Ica(L)
Structural Remodelling
• Fibrosis
Bosch et al. CV Res. 1999 Oct;44(1):121-31.
Nademanee K et al. J Cardiology 2010; 55; 1-12
Autonomic Input
AF duration
Scherf and Moe are both correct
Trigger/ initiation
Substrate/ maintenance
Paroxysmal
Permanent
Persistent
Ablation
LA ablation - PV isolation AV node ablation - PPM implant “Ablate and Pace”
Left Atrial Ablation
PV isolation (PVI)
Ablating Focal Triggers - Parosxysmal Substrate Modification - Persistent
Ablating rotors – CFAE Mapping
Linear ablation lesions
LA Ablation -The Harsh Reality
• Only Class 1 indication for LA ablation is paroxysmal patients breaking through Class 1 or III AAD.
• For persistent AF, ablation of identified focal triggers IIa, all other substrate modification techniques (CFAE, lines) IIb.
Calkins et al. Heart Rhythm 2017
HRS/EHRA/ECAS 2017 AF Guidelines
STAR AF II
Verma et al. N Engl J Med 2015; 372:1812-1822
Ablation complications – PV Stenosis
Antral PV ablation - WACA
PV isolation (PVI) Wide area circumferential ablation (WACA)
Atrio-esophageal Fistula
Phrenic nerve injury
Cryoballoon
Kuck et al. N Engl J Med 2016; 374:2235-2245
Fire and Ice Study
Kuck et al. N Engl J Med 2016; 374:2235-2245
CMAP
Dubuc et al.Heart Rhythm. 2011;8(7):1068-1071
“Antiarrhythmics”
Class I / III
agents
Catheter ablation
Pacing
Implantable atrial defibrillator
Surgery maze
Pharmacologic Non- pharmacologic Pharmacologic
•Ca2+ blockers
•-blockers
•Digitalis
Non- pharmacologic
•AVN ablation and pace
Pharmacologic treatment of AF
Rhythm Control Rate
control
Q: A dialysis dependent 64 year old patient with EF35% has symptomatic atrial fibrillation
The antiarrhythmic drug of choice would be:
1. Dofetililde
2. Sotalol
3. Amiodarone
4. Dronedarone
Q: A dialysis dependent 64 year old patient with EF35% has symptomatic atrial fibrillation
The antiarrhythmic drug of choice would be:
1. Dofetililde
2. Sotalol
3. Amiodarone
4. Dronedarone
Flecainide (and, by association, propafenone) ↑↑ mortality in patients with CAD: Cardiac Arrhythmia
Suppression Trial (CAST)
NEJM, 1989
0 100 200 300 400 500
Survival (%)
Days after randomization
100
95
90
85
0
Placebo (n=725)
Encainide or flecainide (n=730)
P=0.0006
Class I agents Contraindicated with
“structural” heart disease / CAD
0.0
0.2
0.4
0.6
0.8
1.0
0 12 24 36
Safety of Dofetilide in Patients with Congestive Heart Failure, Left Ventricular Dysfunction and prior MI
Torp-Pederson: N Eng J Med 341:857, 1999
No. at risk
Dofetilide
Placebo
Probability survival
Months
Placebo
Dofetilide
762 564 214 6
759 536 199 1
No Increase in
Mortality
No
Flecainide Propafenone
Sotalol Amiodarone, Dronedarone
dofetilide
Yes
Amiodarone
Renal Failure
Heart disease?
CHF?
Amiodarone, dofetilide
CAD?
Sotalol
Amiodarone, Dronedarone
dofetilide
Drug Choices: Rhythm control in Atrial Fibrillation
No
Flecainide Propafenone
Sotalol Amiodarone, Dronedarone
dofetilide
Yes
Amiodarone
Renal Failure
Heart disease?
CHF?
Amiodarone, dofetilide
CAD?
Sotalol
Amiodarone, Dronedarone
dofetilide
AVOID Flecainide
Propafenone Caution with
Sotalol Dofetilide
Drug Choices: Rhythm control in Atrial Fibrillation
Is ablation better than drug? Primary Endpoint (Death, Disabling Stroke, Serious Bleeding, or Cardiac Arrest) (ITT)
Packer, DL et al. JAMA. March 15 2019
Estimates of All-Cause Mortality Risk (ITT)
Is ablation better than drug?
Packer, DL et al. JAMA. March 15 2019
All-Cause Mortality or Cardiovascular Hospitalization (ITT)
Is ablation better than drug?
Packer, DL et al. JAMA. March 15 2019
Recurrent Atrial Fibrillation After Blanking by Intention-to-Treat Analysis
Is ablation better than drug?
Packer, DL et al. JAMA. March 15 2019
CABANA Trial – Key points
• AF ablation reduces AF Burden significantly more than medical management
• AF ablation reduces hospitalization significantly more than medical management
• No difference in all cause mortality or combined endpoint by intention to treat analysis
• Significant crossover in both arms – on treatment effect showed significant mortality benefit and decrease in combined endpoint
AF-CHF Trial
Roy D et al: N Engl J Med. 2008;358(25):2667
Ablation in Heart Failure
Catheter Ablation in CHF
ARC-CHF PABA-CHF CAMTAF
Jones DG et al. JACC 2013;61(18):1894
Khan M et al. N Engl J Med 2008;359:1778-85
Hunter RJ Circ Arrhythm Electrophysiol. 2014;7(1):31
n=52 n=81 n=50
Ablation in Heart Failure
Ablation in Heart Failure
Marrouche et al. NEJM 2018 378(5):417-427
CASTLE-AF Death or hospitalization for worsening HF
Ablation in Heart Failure CASTLE-AF All cause mortality
Marrouche et al. NEJM 2018 378(5):417-427
Ablation in Heart Failure CASTLE-AF Freedom from heart failure hospitalization
Marrouche et al. NEJM 2018 378(5):417-427
Better than ablation..?
Pathak et al. JACC May 2015
70% AF free at one year without ablation 90% AF free at 5 years with ablation
What is the intervention?
• 1. Amiodarone therapy
• 2. Dronedarone therapy
• 3. Weight loss
• 4. CPAP for sleep apnea
>10% weight loss if BMI>27
70% AF free at one year without ablation 90% AF free at 5 years with ablation
LEGACY-AF
Pathak et al. JACC May 2015
Anticoagulation in AF
0 points: 0.2% per year
1 point : 0.6% per year
2 points: 2.2% per year
3 points: 3.2% per year
4 points: 4.8% per year
5 points: 7.2% per year
6 points: 9.7% per year
7 points: 11.2% per year
8 points: 10.8% per year
9 points: 12.2% per year
Risk of ischemic stroke
CHA2DS2-VASc acronym
Score
Congestive HF 1
Hypertension 1
Age ≥75 years 2
Diabetes mellitus 1
Stroke/TIA/TE 2
Vascular disease (prior MI, PAD, or aortic plaque)
1
Age 65 to 74 years 1
Sex category (ie, female sex)
1
Maximum score 9
Anticoagulation in AF
Letter Clinical characteristic* Points HAS-BLED score
(total points) Bleeds per 100 patient-years¶
H Hypertension (ie, uncontrolled blood pressure)
1 0 1.13
A Abnormal renal and liver function (1 point each)
1 or 2 1 1.02
S Stroke 1 2 1.88
B Bleeding tendency or predisposition
1 3 3.74
L Labile INRs (for patients taking warfarin)
1 4 8.70
E Elderly (age greater than 65 years)
1 5 to 9 Insufficient data
D Drugs (concomittant aspirin or NSAIDs) or alcohol abuse (1 point each)
1 or 2
Maximum 9
points
Anticoagulation in AF
• Warfarin was historically standard therapy • 3 meta-analyses – compared to warfarin NOACs are associated with:
•A significant reduction in stroke/systemic embolism (OR 0.85) and major bleeding (OR 0.86) •A significant and marked relative reduction in hemorrhagic stroke (RR 0.48) and a significant reduction in all-cause mortality (RR 0.88) •Trend toward reduced major bleeding with the NOAC agents (RR 0.86).
Dentali F et al. Circulation. 2012;126(20):2381 Adam SS et al. Ann Intern Med. 2012;157(11):796 Nitaios et al. Stroke. 2012 Dec;43(12):3298-304.
Focused Update of the AHA/ACC/HRS Atrial Fibrillation Guidelines
• NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) are recommended over warfarin in NOAC-eligible patients with AF (except moderate-to-severe mitral stenosis or mechanical heart valve)
• Idarucizumab (I) or Andexanet alfa (IIa) for urgent reversal
• Watchman device (IIb) if AC necessary but high risk of bleeding
• Catheter ablation for AF may have mortality benefit in selected patients with heart failure
• For overweight and obese patients with AF, weight loss, combined with risk factor modification, is recommended
January CT et al. JACC 2019, in press
Conclusions
• Role of left atrial ablation for AF is primarily for symptomatic patients with paroxysmal AF
• Ablation may decrease AF burden and hospitalization more than AAD, but no mortality advantage (CABANA)
• Ablation may provide mortality benefit in some heart failure patients (CASTLE-AF)
• NOACs now favoured over Warfarin with exception of mechanical valves or mitral stenosis
