Download AFFIRM Trial

A Fib begets A fib
An Overview of AF and Treatment Strategies
Jad Skaf, MD
11/12/15
Southern Regional AHEC adheres to ACCME Essential Areas and Policies regarding
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content have disclosed and there are no unresolved conflicts prior to this program.
The following presenters and panelists (and their family
members) have no relevant financial disclosures to make:
Jad Georges Skaf, MD
There will not be discussion of any off-label, experimental, or
investigational use of drugs or devices in this presentation
This program is not being supported by any commercial funding.
Background

Atrial fibrillation is the most prevalent cardiac
arrhythmia

It affects 1% to 2% of the general population with an
important increase in incidence with age (10% after
age 75)

AF has multiple adverse clinical implications

The loss of atrial systole and the irregular, fast heart
rate contribute to symptoms such as palpitations and
reduced exercise tolerance and also predispose to
the development of intracardiac thrombus and
systemic thromboembolism
Background
 AF
can also cause tachycardia-mediated
cardiomyopathy or worsening of preexisting
heart failure
 Moreover,
AF is known to increase the mortality
risk 1.5- to 2-fold and the risk for stroke 5-fold
Cost
CLASSIFICATION
Symptoms
~60% of
patients with
AF are
asymptomatic
initially.
Mechanisms
ANTICOAGULATION
Class I
LOE C
In patients with AF, antithrombotic therapy should be individualized
based on shared decision making after discussion of the absolute
and relative risks of stroke and bleeding and the patient’s values
and preferences
Class I
LOE B
In patients with nonvalvular AF, the CHA2DS2-VASc score is
recommended for assessment of stroke risk
CHA2DS2-VAsc
WARFARIN - ASA
Class IIa
LOE B
For patients with nonvalvular AF with a CHA2DS2-VASc score of 2 or
greater and who have end-stage chronic kidney disease (CKD)
(creatinine clearance < 15 mL/min) or are on hemodialysis, it is
reasonable to prescribe warfarin (INR 2.0 to 3.0) for oral
anticoagulation
Class I
LOE B
For patients with AF who have mechanical heart valves, warfarin is
recommended, and the target international normalized ratio (INR)
intensity (2.0 to 3.0 or 2.5 to 3.5) should be based on the type and
location of the prosthesis
Class IIb
LOE C
For patients with nonvalvular AF and a CHA2DS2-VASc score of 1,
no antithrombotic therapy or treatment with an oral anticoagulant
or aspirin may be considered.
MANAGEMENT
RATE vs. RHYTHM
The decision to adopt a rhythm or rate control strategy is often
dictated by the
1) presence of symptoms associated with atrial fibrillation and/or
2) presence of diminutions in left ventricular systolic function thought
secondary to the arrhythmia.
MANAGEMENT
RATE vs. RHYTHM
What do we know?
Framingham study,
10 year follow-up
5209 patients
AF is BAD
Benjamin EJ, Wolf PA, D'Agostino RB, et al. Circulation 1998; 98:946.
MANAGEMENT
RATE vs. RHYTHM
Rate Control
Which Patients?
AFFIRM Trial
AFFIRM
Baseline Characteristics





4060 patients
Age = 69.7 ± 9.0 yrs
39% female
> 2 days of AF in 69%
CHF class > II in 9%
Wyse DG, N Engl J Med. 2002;347(23):1825
AFFIRM Trial
Wyse DG, N Engl J Med. 2002;347(23):1825
AFFIRM Trial
Wyse DG, N Engl J Med. 2002;347(23):1825
AFFIRM Trial
Wyse DG, N Engl J Med. 2002;347(23):1825
RACE Trial
Rate Control versus Electrical Cardioversion for Persistent Atrial
Fibrillation (RACE) Trial (n=522)
Van Gelder, I. et al. N Engl J Med 2002;347:1834-1840
Are we done?
Is rate control the answer?
LIMITATIONS 1
LIMITATIONS of Trials: AGE
Guideline Statement
- The mean ages in AFFIRM and RACE were 70
and 68 years, respectively.
-The RACE and AFFIRM trials did not address AF in
younger, symptomatic patients with little underlying
heart disease, in whom restoration of sinus rhythm by
cardioversion antiarrhythmic drugs or nonpharmacological interventions still must be
considered a useful therapeutic approach.
One may conclude from these studies that rate
control is a reasonable strategy in elderly patients
with minimal symptoms related to AF.
ACC/AHA/ESC Guidelines 2014
LIMITATIONS 2
LIMITATIONS of Trials: SYMPTOMS
Approximately one-half of patients in AFFIRM
who had a detailed history had symptomatic
episodes of AF that occurred less often than
once per month.
Such patients would be expected to derive little
symptomatic benefit from rhythm control, and
the results may not directly apply to patients with
frequent episodes of symptomatic AF
LIMITATIONS 3
LIMITATIONS of Trials: ANTICOAGULATION
Both trials allowed for cessation of anticoagulant
therapy four weeks after documentation of SR,
leading to a higher rate of stroke.
It has been postulated that continued
anticoagulation might have led to a lower
mortality in the rhythm control group
LIMITATIONS 4
LIMITATIONS of Trials: DRUGS
The use of antiarrhythmic drugs in AFFIRM was
associated with a significant increase in mortality
(HR 1.49), which was due to non-cardiovascular
causes, while the presence of SR was associated
with a significant reduction in mortality (HR 0.53).
A similar benefit from being in sinus rhythm
(relative risk 0.44) was noted in the DIAMOND trial
that compared dofetilide to placebo in patients
with reduced left ventricular systolic function
LIMITATIONS
LIMITATIONS of Trials: DRUGS
One interpretation of these data is that
maintenance of SR might be beneficial if there
were a safer and more effective approach than
current antiarrhythmic drugs:
The AFFIRM and RACE data were largely
gathered before catheter ablation was common.
The potential impact of this procedure (versus
chronic antiarrhythmic therapy) remains
incompletely explored
NEW TRIALS
CABANA
The Catheter Ablation versus Antiarrhythmic
Drug Therapy for Atrial Fibrillation trial is
being done to compare drug therapy
with catheter ablation in patients with
atrial fibrillation. This study will help to
decide which treatment approach is best
and if under certain circumstances, one
therapy is preferred over the other
treatment.
NEW TRIALS
CABANA
Estimated Enrollment: 2200 patients
Study Start Date: August 2009
Estimated Study Completion Date: June 2018
Estimated Primary Completion Date: December 2017
(Final data collection date for primary outcome measure)
https://clinicaltrials.gov/ct2/show/NCT00911508
Anti-Arrhythmics
ABLATION
% Patients Free of
Symptomatic AF
100
80
Ablation…
60
Amiodarone*
40
Propafenone**
Sotalol**
Hx of Two Failed Drugs***
20
2
* Roy et al NEJM, 2000
**Antman et.al., JACC 1990
***Crijns et. al., AJC 1991
4
6
Months
8
10
12
ABLATION Guidelines
Paroxysmal AF
Class I
LOE A
PAROXYSMAL REFRACTORY
AF catheter ablation is useful for symptomatic paroxysmal
AF refractory or intolerant to at least 1 class I or III antiarrhythmic
medication when a rhythm-control strategy is desired
Class IIa
LOE B
PAROXYSMAL INITIAL
In patients with recurrent symptomatic paroxysmal AF, catheter
ablation is a reasonable initial rhythm-control strategy before
therapeutic trials of antiarrhythmic drug therapy, after weighing the
risks and outcomes of drug and ablation therapy
ACC/AHA/ESC Guidelines 2014
ABLATION Guidelines
Persistent AF
Class IIb
LOE B
PERSISTENT REFRACTORY
AF catheter ablation may be considered for symptomatic
long-standing (>12 months) persistent AF refractory or intolerant
to at least 1 class I or III antiarrhythmic medication when a rhythmcontrol strategy is desired
Class IIb
LOE C
PERSISTENT INITIAL
AF catheter ablation may be considered before initiation of
antiarrhythmic drug therapy with a class I or III antiarrhythmic
medication for symptomatic persistent AF when a rhythm-control
strategy is desired.
ACC/AHA/ESC Guidelines 2014
Does not work in AF
Hypothesis
 Atrial
fibrillation itself causes progressive
electrophysiological and/or structural changes
to the atria, which promote the initiation or
perpetuation of atrial fibrillation


Electrical Remodeling
Mechanical Remodeling
Diagram showing the localization of the 27 chronically implanted electrodes on the atria.
Wijffels M C et al. Circulation. 1995;92:1954-1968
Copyright © American Heart Association, Inc. All rights reserved.
Prolongation of the duration of episodes of electrically induced atrial fibrillation (AF) after
maintaining AF for respectively 24 hours and 2 weeks.
Wijffels M C et al. Circulation. 1995;92:1954-1968
Copyright © American Heart Association, Inc. All rights reserved.
Prolongation of the duration of episodes of electrically induced atrial fibrillation (AF) after
maintaining AF for respectively 24 hours and 2 weeks.
Wijffels M C et al. Circulation. 1995;92:1954-1968
Copyright © American Heart Association, Inc. All rights reserved.
AF Begets AF
AF causes changes in atrial electrophysiology
that promote AF maintenance
Wijffels Circulation 1995; 92: 1954-68
Clinical implications
 Shortening
of the atrial refractory might explain
the diminished success rate of chemical and
electrical cardioversion in patients with longlasting atrial fibrillation
 Study
implicates that the best prevention of
atrial fibrillation is to terminate the arrhythmia as
soon as possible, thus interrupting the
electrophysiological sequelae which will lead to
chronic atrial fibrillation
Mechanisms

Interplay of Trigger and Substrate

Induction of AF requires an initiating trigger
(usually the pulmonary veins ~80% of times)

Perpetuation occurs because triggering activity is
sustained or because of the presence of a susceptible
atrial substrate

Premature atrial ectopy has been shown to be the most
frequent trigger for AF
Precipitants
 Observations
in patients with dual chamber
pacemakers revealed that 48% of AF episodes
were triggered by premature atrial beats, 33%
were preceded by bradycardia, and 17% were
sudden in onset
 Also,
continuous cardiac monitoring in
postoperative patients demonstrated that
supraventricular premature beats induced AF in
72% to 100% of cases
AF Sustenance
TRIGGERS
Development of AF requires trigger + susceptible substrate
APD
Goal of ablation:
Eliminate triggers
and/or
alter substrate
(may also interrupt
innervation from
autonomic ganglia)
PV Isolation
ABLATION
RadioFrequency Ablation – RFA
Vs.
Cryoablation
RFA
RadioFrequency Ablation – RFA
Vs.
Cryoablation
TRIGGERS
PV Origin for Triggers for Initiating Atrial
Fibrillation ~ 80 –90% of Triggers
Preferential inputs or
“breakthroughs”
enable non-circumferential
disconnection
myocardial
sleeves
Focal
Ablation
PV
Isolation
TRIGGERS
MRA of LA
Success ~ 70-80% paroxysmal
~ 50-70% persistent
Multiple
Foci from
Multiple
Veins
PVI
CRYO
CRYO
CRYO
Contrast injected to verify pulmonary vein
ostium occlusion and full contact
CRYO
Complications of RF ablation:
 Systemic
embolism/CVA (1-2%)
 PV stenosis < 1-3%
 Pericardial effusion/cardiac tamponade
(1%)
 Proarrhythmia (intra-atrial reentry
tachycardia/left atrial flutter)
 Atrial-esophageal fistula (very rare)
 Need for multiple procedures (10 to 30%) to
achieve clinical efficacy
Complications of Cryo-ablation
 Systemic
embolism/CVA (1-2%)
 PV stenosis < 1-3%
 Pericardial effusion/cardiac tamponade
(1%)
 PN palsy 1-3%
 Atrial-esophageal fistula (very rare)
 Need for multiple procedures (10 to > 30%)
to achieve clinical efficacy
end
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