Stuart Beldner, MD, FHRS
Assistant Professor NSLIJ Hofstra School of Med
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None
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“There’s no reason to panic. While it is true
that one of the crew members is ill, slightly ….”
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Absence of discrete P waves
Chaotic atrial activity
Ventricular rate irregularity
Mechanisms of AF. AF indicates atrial fibrillation; Ca++, ionized calcium; and RAAS, reninangiotensin-aldosterone system.
January C T et al. Circulation. 2014;130:e199-e267
Copyright © American Heart Association, Inc. All rights reserved.
Term
Definition
Paroxysmal AF
•AF that terminates spontaneously or with intervention
within 7 d of onset.
•Episodes may recur with variable frequency.
Persistent AF
•Continuous AF that is sustained >7 d.
Longstanding persistent
AF
•Continuous AF >12 mo in duration.
Permanent AF
•The term “permanent AF” is used when the patient
and clinician make a joint decision to stop further
attempts to restore and/or maintain sinus rhythm.
•Acceptance of AF represents a therapeutic attitude on
the part of the patient and clinician rather than an
inherent pathophysiological attribute of AF.
•Acceptance of AF may change as symptoms, efficacy
of therapeutic interventions, and patient and clinician
preferences evolve.
Nonvalvular AF
•AF in the absence of rheumatic mitral stenosis, a
mechanical or bioprosthetic heart valve, or mitral valve
repair.
Rate versus Rhythm Trials
HR (Rate vs
Rhythm
Control)
P
1.10
0.31
Trial
Year
n
Primary End
Point
PIAF3
2000
252
Improvement AF
symptoms
AFFIRM1
2002
4060
Overall mortality
0.87
0.08
RACE2
2002
522
Composite
0.73
0.11
205
Composite
1.98
>0.71
STAF4
2003
200
AF-CHF6
2008
1376
0.94
0.59
PABACHF15
Cardiovascular
mortality
2008
81
Composite
Multiple
<0.001
HOT CAFE5 2004
Composite
1.09
0.99

Trials such as AFFIRM and RACE, did NOT
prove that rate-controlled and anticoagulated
AF is as good as NSR.
◦ They show that a rhythm control strategy using an
ITT analysis, suggests equivalence in at least some
populations.
◦ These trials do NOT disprove that sinus rhythm
would be better than AF in regard to QOL if one
were to actually attain and maintain it with a safe
and effective therapy.
Patients in Sinus Rhythm, %
Rate Arm
Rhythm Arm
100
90
80
70
60
50
40
30
20
10
0
R
2 Mo 4 Mo 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr
Time
The AFFIRM Investigators. NEJM: 2002; 347: 18281833

5 fold increase in risk for stroke*
◦ AF strokes are usually more severe than nonAF
strokes


3 fold risk of heart failure **
2 fold risk of dementia*** and mortality
*
*Kannel et al. Am J of Coll.
1998
**Wang et al. Circu. 2003
*** Ott et al. Stroke 1997.
Time dependant, on treatment, Multivariate Analysis of Survival
1.06
1.56
1.57
1.56
1.78
1.70
0.74
1.36
0.50
1.42
0.53
1.49
HR (99%)
(1.05 – 1.08)
(1.20 – 2.04)
(1.18 – 2.09)
(1.17 – 2.07)
(1.25 – 2.53)
(1.24 – 2.33)
(0.55 – 0.98)
(1.03 – 1.80)
(0.37 – 0.69)
(1.09 – 1.86)
(0.39 – 0.72)
(1.11 – 2.01)
Factor
Age (per year)
CAD
CHF
Diabetes
Smoking
Stroke/TIA
Normal LVEF
Mitral Regurg
Warfarin
Digoxin
Sinus Rhythm
AA drug
0.
2
0.
4
0.
Better
6
0.
8
1.
0
1.
2
1.
Worse
4
1.
6
80
SF-36 Change in One Year
4
60
3
2
40
1
20
0
-1
NSR
AF
-2
0
-20
-3
-4
-40
-5
-6
Physical Fx
General
Health
Social Fx
Vitality
-60
HR Rest
Exercise
Duration
HR Peak
Singh BN, et al, NEJM 2005; 352:186172.
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Class I:
◦ Class IC: propafenone (also very weak β-blocker), flecainide
(no β-blockade effects)
 Sustained-release propafenone (Rythmol SR) and
flecainide are bid;
 Propafenone appears to be less proarrhythmic
◦ Class IA: disopyramide, quinidine, procainamide
 No longer included in the ACC/AHA/ESC algorithm
 Disopyramide may be useful in vagally induced AF

Class III:
◦
◦
◦
◦
Sotalol (class III plus β-blocker)
Dofetilide (pure class III)
Amiodarone (class III plus class I, II, IV); highly overused
Dronedarone (similar to amiodarone with different
pharmacokinetics and markedly reduced organ toxic potential)
Trial
Study Design
Dronedarone Effects
ERATO
Dronedarone vs placebo
Significant decrease in ventricular rates
(24-hr Holter and maximal exercise)
DAFNE
Dronedarone vs placebo
Efficacy vs placebo in time to first AF
recurrence with 400 mg bid dose
EURIDIS and
ADONIS
Dronedarone vs placebo in
1237 patients with AF/AFL
Significant and consistent reduction in
first recurrence of AF/AFL; comparable
safety vs placebo
ANDROMEDA
Dronedarone vs placebo in
627 patients with severe HF
Excess mortality risk vs placebo (n=25 vs
n=12; HR, 2.13; P=.03); trial stopped
early
DIONYSOS
Dronedarone vs amiodarone in
504 patients with persistent AF
Mixed observations
ATHENA
Dronedarone vs placebo in
4628 high-risk AF patients
PALLAS
Dronedarone vs placebo in
3236 patient with permanent AF
● Efficacy against AF
● Reduction in CV mortality and
hospitalization
● Reduction in additional end points
a 2.29-fold increase in the coprimary end
point of stroke, MI, embolism, or
cardiovascular death events, compared to
placebo, and led to a halt in a planned
10,800-patient international randomized trial
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Results show dronedarone significantly prolongs the time to AF
recurrence compared with placebo
No significant difference was found between placebo and
dronedarone in all-cause mortality
Dronedarone reduced CV mortality, CV hospitalizations, ACS,
arrhythmic deaths, and stroke
Adverse events occurring significantly more frequently with
dronedarone than with placebo included bradycardia, QTinterval prolongation, diarrhea, nausea, rash, and an increase in
the serum creatinine level
Total discontinuation rates for dronedarone and placebo were
identical, no pulmonary or thyroid toxicity was evident, and there
were no TDP/VF deaths in the “high-risk” AF population in
dronedarone-treated patients
Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678.
% Patients Free of
Symptomatic AF
Efficacy of Antiarrhythmic Drug Therapy for A Fib
Gold Standard for Judging Ablative Therapy
AFFIRM
TRIAL
–
Rhythm
Control
100
Arm
Overestimate AF
80
control
with drug (No Sxs)
Increased Mortality? (The prevalence of sinus rhythm in the rhythmcontrol group at follow-up was 82.4 percent, 73.3 percent, and 62.6 percent at one, three, and
60
AFFIRM
five years, respectively.)
RATE VS RHYTHM CONTROL
Amiodarone*
Sotalol**
Propafenone**
40
20
Hx of Two Failed Drugs***
Atrial Flutter
#
* Roy et al NEJM, 2000
**Antman et al, JACC 1990
***Crijns et al, AJC 1991
#Natale et al JACC 2001
2
4
6
Months
8
10
12

Ranalozine (Ranexa)
◦ Has a greater effect on the late sodium current (late
> peak) which should make it more effective in
ischemic patients.

Vernakalat
◦ Ikur Blocker
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Approved for the treatment of chronic
stable angina
An atrially effective compound,
substantially inhibiting peak Na+
current mainly in the atria and has
been shown to decrease the incidence
of atrial fibrillation in an in vitro
model.
MERLIN TIMI 361 (Metabolic Efficiency
with Ranolazine for Less Ischemia in
Non-ST Elevation Acute Coronary
Syndromes)
◦ 6,560 patients with prior chronic angina
◦ A neutral effect on overall mortality
◦ Suggested (P= 0.08) a 26% reduction in
new onset atrial fibrillation.
100
P= 0.08
75 (2.3%)
55 (1.7%)
50
0
Placebo
Ranolazine
 The incidence of significant arrhythmias
was screened with holter monitoring
JACC
2009;53:1510-6
Burashnikov A et al. JACC 2010

A Phase 2, Proof of Concept, Randomized, PlaceboControlled, Parallel Group Study to Evaluate the
Effect of Ranolazine and Dronedarone When Given
Alone and in Combination on Atrial Fibrillation
Burden in Subjects With Paroxysmal Atrial
Fibrillation
◦ Primary endpoint
 The effect of ranolazine and of low dose dronedarone when
given alone and in combination at different dose levels on
atrial fibrillation burden (AFB) over 12 weeks of treatment

the combination of ranolazine (Ranexa, Gilead Sciences)
and dronedarone (Multaq, Sanofi) appeared to lower the
burden of atrial fibrillation (AF) by >70% over three
months in 45% to 60% of patients with the paroxysmal
form of the arrhythmia
Kowey et al. Presented at HRS 2014
A 59-year-old woman is referred to you for management of
permanent atrial fibrillation that she has had for three years. The
referring physician reports that recently performed
echocardiography revealed normal findings. The patient's current
medications are dabigatran and metoprolol, 50 mg daily.
During your initial evaluation, the patient says she feels well and
has no symptoms. A 12-lead electrocardiogram shows a resting
heart rate of 100 beats per minute (bpm).
(A) Continue the current drug regimen and schedule follow-up evaluation
(B) Increase metoprolol dosage and obtain a 24-hour ambulatory
electrocardiographic recording; adjust metoprolol dosage to achieve a
heart rate of less than 70 bpm during rest and less than 120 bpm during
moderate exercise
(C) Increase metoprolol dosage and obtain a 24-hour ambulatory
electrocardiographic recording; adjust metoprolol dosage to achieve a
heart rate of less than 80 bpm during rest and less than 110 bpm during
moderate exercise
(D) Increase metoprolol dosage and obtain a 24-hour ambulatory
electrocardiographic recording; adjust metoprolol dosage to achieve a
heart rate of less than 80 bpm during rest and less than 130 bpm during
moderate exercise

2006 guidelines for AF recommended
◦ target heart rates of 60 to 80 bpm at rest and 90 to
115 bpm during moderate exercise

AFFIRM
◦ no higher than 80 bpm at rest and no higher than
110 bpm during a 6-minute walk test, and an
average heart rate no higher than 100 bpm over
18+ hours of Holter monitoring with no rates
>100% of maximal age-predicted heart rate, as well

RACE
◦ Resting heart rate < 100 bpm
Trial design: Patients with permanent AF were randomized to lenient (resting heart
rate [HR] <110 bpm) or strict rate control (resting HR <80 bpm). Patient follow-up
was 3 years.
(p = 0.001)*
%
(p = NS)
3
0
30
2
0
2
0



12.9
14.9
%
1
0
1
0
0
Results
Primary endpoint
* For noninferiority
Lenient
control
(n = 311)
Stroke ↓ with lenient control (1.6% vs.
3.9%, p< 0.05)
CHF (3.8% vs. 4.1%), CV death, PPM
implantation (0.8% vs. 1.4%) were similar
Conclusions
2.9
0
Primary outcome was similar in lenient
and strict control arms (12.9% vs. 14.9%)
3.9
CV mortality
Strict
control
(n = 303)
•Lenient rate control easier to achieve than
strict control, and noninferior for clinical
outcomes
•Most patients had lower CHADS2 score.
Safety and efficacy in patients with higher
CHADS2 score will need to be explored
•Needs to be tested in patients with
significant LV dysfunction
Van Gelder IC, et al. N Engl J Med 2010;Mar
15:[Epub]
CHADS2 Risk Criteria
Score
Prior stroke or TIA
2
Age > 75
1
Hypertension
1
Diabetes Mellitus
1
Heart Failure
1
Patients
Adjusted Stroke Risk
CHADS2 Score
120
1.9 (1.2 – 3.0)
0
468
2.8 (2.0 - 3.8)
1
528
4.0 (3.1 – 5.1)
2
337
8.5 (6.3-11.1)
3
65
12.5 (8.2-17.5)
4
5
18.2 (10.5-27.4
5
CHA 2 DS 2 -VASc
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Risk Factor
C ongestive heart failure/LV dysfunction
H ypertension
A ge > 75 y
D iabetes mellitus
S troke/TIA/TE
V ascular disease
A ge 65-74 y
S ex category (ie female gender)
Score
1
1
2
1
2
1
1
1
Summary of Recommendations for Risk-Based Antithrombotic Therapy.
January C T et al. Circulation. 2014;130:e199-e267
Copyright © American Heart Association, Inc. All rights reserved.
Primary Endpoint – stroke or systemic embolism
INR
D150
VKA (RELY)
Quartlie 1 1.10% 1.7% (HR= 0.61)
Rivaroxaban VKA (ROCKET AF) Apixaban VKA (ARISTOLE)
1.5
2 (HR= 0.48)
1.72
2.36 (HR= 0.73)
2
1.10% 2.2% (HR- 0.48)
1.5
2.6 (HR= 0.61)
1.61
1.72 (HR=0.94)
3
1.10% 1.4% (HR= 0.76)
1.5
2.6 (HR= 0.66)
0.86
1.35 (HR= 0.64)
4
1.30% 1.4% (HR= 0.88)
1.2
2.3 (HR= 0.58)
0.91
1.04 (HR= 0.88)
Major bleeding
INR
D150
VKA (RELY)
Quartlie 1 2.40% 3.3% (HR= 0.74)
Rivaroxaban* VKA (ROCKET AF)* Apixaban VKA (ARISTOLE)
11.3
14.12 (HR= 0.80)
1.44
2.89 (HR= 0.5)
2
3.20% 3.9% (HR= 0.84)
11.72
12.21 (HR= 0.81)
1.97
3.07 (HR= 0.64)
3
3.60% 3.2% (HR= 1.12)
15.1
14.88 (HR= 1.03)
2.61
3.06 (HR= 0.85)
4
3.20% 3% (HR= 1.08)
20.61
16.72 (HR= 1.25)
2.48
3.31 (HR=0.75)
* Event rate (100 pt years)


There is evidence from meta-analyses of
RCTs that home monitoring of VKA therapy
reduces thromboembolic events by 42%
compared with usual monitoring.
THIS IS SIMILAR TO THE 33% relative risk
reduction with dabigatran 150 mg Bid!!!

Dose adjusted VKA therapy + ASA is not
recommended in stable coronary artery
disease
◦ SPORTIF
 Associated with a nearly 2 fold increase in bleeding
with NO significant reduction in stroke or MI.
◦ RE-LY
 Major bleeding was twice as high in patients on aspirin
AND either dabigatran or wafarin


No increase in death
Nonfatal stroke
◦ CHADS2= 0
 2 fewer strokes/1000
◦ CHADS2= 1
 6 fewer strokes/1000
◦ CHADS2= 2
 11 fewer strokes/1000
◦ CHADS2= 3 – 6
 24 fewer strokes/1000

Nonfatal MI

Nonfatal Major Extracranial Bleed
◦ 21 fewer/1000
◦ 26 more bleeds/1000 (RR= 2.37)
CHEST February 2012
WOEST
Cumulative incidence of bleeding
Primary Endpoint: Total number of TIMI bleeding events
Triple therapy group
Double therapy group
50 %
44.9%
40 %
30 %
19.5%
20 %
p<0.001
10 %
HR=0.36 95%CI[0.26-0.50]
0%
0
30
60
90
120
180
270
365
159
226
140
208
Days
n at risk:
|
284 210 194 186 181
279 253 244 241 241
173
236
WOEST
Secondary Endpoint (Death, MI,TVR, Stroke, ST)
Triple therapy group
Double therapy group
Cumulative incidence
20 %
17.7%
15 %
11.3%
10 %
5%
p=0.025
HR=0.60 95%CI[0.38-0.94]
0%
0
30
60
90
120
180
270
365
242
258
223
234
Days
n at risk:
284 272 270 266 261
279 276 273 270 266
252
263

The primary purpose of this study is to
evaluate the safety for 2 different rivaroxaban
treatment strategies and one Vitamin K
Antagonist (VKA) treatment strategy utilizing
various combinations of dual antiplatelet
therapy (DAPT) or low-dose aspirin (ASA) or
clopidogrel (or prasugrel or ticagrelor).

Thank you