atrial fibrillation management and treatment

1. Atrial Fibrillation: 2014
Emerging Concepts
New Treatment Paradigms
John Hakim, MD, FACC

2. Atrial Fibrillation Talk Goals
Describe etiology of Atrial fibrillation
Treatment Goals for Atrial Fibrillation
–
–
Novel Anticoagulants
Rate Control/ Rhythm Control
Advances in Therapy for Atrial
fibrillation

4. The hallmark of AF is chaotic atrial impulses leading to irregularly
irregular ventricular contraction, usually with incessant tachycardia

7. OVERVIEW
Atrial fibrillation is a progressive disease
Atrial fibrillation has hemodynamic and myocardial
consequences (i.e., reduced cardiac output and heart failure)
There is significant morbidity and mortality consequences
-increased hospitalizations
-reduced quality of life
-increased risk of thromboembolism and stroke (accounts for 75,000
strokes per year in the United States alone)
-decreased survival (AF is associated with increased mortality, but
whether it is the cause or an innocent bystander
is not well established)1-8
Atrial fibrillation is a treatable disorder, especially with early
intervention
What’s new in atrial fibrillation treatment
1
Benjamim EJ, et al. Impact of AF on the risk of death: The Framinham Heart Study. Circulation. 1998; 98: 946-52.
2
Gajewski J, et al. Mortality in an insured population with AF. JAMA. 1981; 245: 1540-44.
3
Krahn AD, et al. The natural history of AF. Am J Med. 1995; 98: 476-84.
4
Flegel KM, et al. Risk of stroke in non-rheumatic AF. Lancet. 1987; 1: 526-9.
5
Kulbertus HE, et al. AF in elderly, ambulatory patients. AF; 1982: 148-57.
6
Lake FR, et al. AF and mortality in an elderly population. Aus N Z J Med. 1989; 19: 321-6.
7
Kannel WB, et al. Epidemiologic features of chronic AF: the Framingham Study. NEJM 1982; 306: 1018-22.
8
Kitchin AH, et al. Longitudinal survey of ischemic heart disease in randomly selected older population. Br Heart J 1977; 39: 889-93.

8. Classification and Patterns of AF
Paroxysmal: terminates spontaneously, typically
duration is <7 days (most<24 hours). May be recurrent.
Persistent: medication or electrical intervention is
required to restore sinus rhythm; does not self-terminate.
Typically lasts > 7 days. May be recurrent.
Permanent: sinus rhythm cannot be restored or
maintained despite intervention.
* Evaluate for thrombotic risk each of these situations.*

9. Causes of Atrial Fibrillation
Hypertension
Heart attacks/ CAD
Valvular Heart Disease
Congenital heart defects
Hyperthyroid or other metabolic
imbalance
Exposure to stimulants such as
medications, caffeine or tobacco, or to
alcohol (holiday heart)
Sick sinus syndrome — improper
functioning of the heart's natural
pacemaker
Emphysema or other lung diseases
CABG/ Previous heart surgery
Viral infections /Pericarditis
Stress due to pneumonia, surgery or
other illnesses (Catecholamine)
Pulmonary Embolus
Pneumonia
Sleep Apnea
Pericarditis
Lone A fib (younger people)
Left ventricular Hypertrophy
Cardiomyopathy
CHF –Systolic or Diastolic
Idiopathic – mostly in younger people –
Lone Atrial Fib
Familial Predisposition.
Glucocorticoids
Electrolyte abnormalities (especially Low
Mg+2)
Atrial fibrosis from Sarcoid, collegen
vascular disease, infiltrating diseases

10. Risk Factors for AF: Diabetes
AF is 44% more prevalent and 38% more likely to develop when
diabetes was present in an adult population
Prevalence and incidence of AF in 17,372 patients with diabetes and in
the same amount of age- and sex-matched controls without type 2
diabetes included in a Kaiser Permanente diabetes registry. The
researchers followed patients without AF for the comparison of AF
incidence while controlling for known risk factors.
Prevalence for AF was significantly higher among patients with
diabetes compared with those without (3.6% vs. 2.5%; P<.0001).
Over 7.2 years, patients with diabetes without AF at baseline
developed AF at an age- and sex-adjusted rate of 9.1 per 1,000 personyears vs. 6.6 per 1,000 person-years for patients without diabetes.
Diabetes was associated with a 26% increased risk for AF among
women after adjusting for other risk factors (HR=1.26; 95% CI, 1.081.46). Diabetes was not a statistically significant risk factor among men.
Men had a higher prevalence of AF in all age groups regardless of
diabetes

18. HAS BLED SCORE

19. HAS BLED score
Hypertension History(Uncontrolled, >160 mmHg systolic)
Renal DiseaseDialysis, transplant, Cr >2.6 mg/dL or >200 µmol/L
Liver Disease: Cirrhosis, Bilirubin >2x Normal, AST/ALT/AP >3x
Normal
Stroke History
Prior Major Bleeding or Predisposition to Bleeding
Labile INR(Unstable/high INRs), Time in Therapeutic Range <60%
Age > 65
Medication Usage Predisposing to Bleeding(Antiplatelet agents,
NSAIDs)
Alcohol Usage History≥ 8 drinks/week
Risk was 0.9% in one validation study and 1.13 bleeds per 100 patientyears in another validation study.

21. Original Article
Effect of Clopidogrel Added to Aspirin in Patients
with Atrial Fibrillation --- ACTIVE TRIAL
• A randomized trial enrolled 7554 patients with AF who were at
increased risk of stroke but not candidates for vitamin K
antagonists
• Participants were assigned to aspirin or aspirin plus clopidogrel
• At a median of 3.6 years, the risk of major vascular events
decreased significantly with clopidogrel, primarily because of
reduced risk of stroke
• The risk of major bleeding increased significantly with
clopidogrel
N Engl J Med Volume 360(20):2066-2078
May 14, 2009

22. Cumulative Incidence of Trial Outcomes, According to Treatment Group
The ACTIVE Investigators. N Engl J Med 2009;360:2066-2078

23. The ACTIVE Investigators
In patients with atrial fibrillation for
whom vitamin K–antagonist therapy
was unsuitable, the addition of
clopidogrel to aspirin reduced the risk
of major vascular events, especially
stroke, and increased the risk of major
hemorrhage.

24. Change to 2011 Afib guidelines

25. Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism,
According to Treatment Group
Connolly SJ et al. N Engl J Med 2009;361:1139-1151

26. Dabigatran versus Warfarin in Patients with
Atrial Fibrillation (NEJM 9/7/2009)
In patients with AF, dabigatran given at a dose of 110
mg was associated with rates of stroke and systemic
embolism that were similar to those associated with
warfarin, as well as lower rates of major hemorrhage.
Dabigatran administered at a dose of 150 mg, as
compared with warfarin, was associated with lower
rates of stroke and systemic embolism but similar
rates of major hemorrhage

27. Primary Outcome
Stroke (ischemic or hemorrhagic) or systemic embolism
P (non-inferiority)<0.001
21% RRR
Apixaban 212 patients, 1.27% per year
Warfarin 265 patients, 1.60% per year
HR 0.79 (95% CI, 0.66–0.95); P (superiority)=0.011
No. at Risk
Apixaban
Warfarin
9120
9081
8726
8620
8440
8301
6051
5972
3464
3405
1754
1768

28. Major Bleeding
ISTH definition
31% RRR
Apixaban 327 patients, 2.13% per year
Warfarin 462 patients, 3.09% per year
HR 0.69 (95% CI, 0.60–0.80); P<0.001
No. at Risk
Apixaban
Warfarin
9088
9052
8103
7910
7564
7335
5365
5196
3048
2956
1515
1491

34. Stroke and Bleeding in Atrial Fibrillation with Chronic Kidney Disease
Jonas Bjerring Olesen, M.D., et al
N Engl J Med 2012; 367:625-635August 16, 2012
• Chronic kidney disease was associated with an increased risk of
stroke or systemic thromboembolism and bleeding among
patients with atrial fibrillation.
• Warfarin treatment was associated with a decreased risk of stroke
or systemic thromboembolism among patients with chronic
kidney disease, whereas warfarin and aspirin were associated
with an increased risk of bleeding.

35. Novel Anticoagulants in
Renal failure.
ELIQUIS (apixaban) (25% URINE /Renal 75% Hepatic metabolism:
The dosing adjustment for moderate renal impairment is described above The recommended dose for patients with end-stage renal disease
(ESRD) maintained on hemodialysis is 5 mg twice daily. Reduce dose to 2.5 mg twice daily if one of the following patient characteristics (age
≥80 years or body weight ≤60 kg) is present.
In Apixaban ( Eliquis) if two of the following present reduce the dose to 2.5 bid. ( Creatinine >1.5, age ≥80 years or body weight ≤60 kg)
Pradaxa For patients with creatinine
clearance (CrCl) >30 mL/min, the
recommended dose of PRADAXA is
150 mg taken orally, twice daily. For
patients with severe renal
impairment (CrCl 15-30 mL/min), the
recommended dose of PRADAXA is 75
mg twice daily [see Use in Specific

36. Novel Anticoagulants in
Renal failure.
Apixaban (ELIQUIS) (25% Renal 75% Hepatic metabolism)
In Apixaban ( Eliquis) if two of the following present reduce the dose to 2.5 bid. ( Creatinine
>1.5, age ≥80 years or body weight ≤60 kg)
The recommended dose for patients with end-stage renal disease (ESRD) maintained on
hemo dialysis is 5 mg twice daily. Reduce dose to 2.5 mg twice daily if one of the following
patient characteristics (age ≥80 years or body weight ≤60 kg) is present.
Xarelto ( 51% Renal 49% hepatic metabolism)
Patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily
resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in
patients with better renal function administered XARELTO 20 mg once daily. ( Patients
with Cr Cl <30 ml/min not studied).
Dabigantran (Pradaxa) (80% renal cleared)
For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of
PRADAXA is 150 mg taken orally, twice daily. For patients with severe renal impairment
(CrCl 15-30 mL/min), the recommended dose of PRADAXA is 75 mg twice daily . Dosing
recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.

37. Rate versus Rhythm control
Benefits of rhythm control include: decreased
hospitalizations, improved cardiac function, improved
exercise tolerance, and improvement in quality of life
Consequences of failure to maintain sinus rhythm: Atrial
remodeling and permanent atrial fibrillation
The goals of anti-arrhythmic therapy to maintain normal
sinus rhythm should be:
1. To reduce the frequency, severity, and duration of AF
2.
effects
to a degree acceptable to the patient
To do so with the lowest likelihood of adverse

39. If clinicians do not try to maintain normal sinus rhythm in the present, it becomes
more difficult over time. Patients converted to normal sinus rhythm within 3
months have a 69% chance of remaining in sinus rhythm at 6 months compared to
only 27% if they are allowed to remain in AF for > 12 months.2
Dittrich HC, et al. Am J Cardiol 1989; 63: 193-7.
2

40. Therapeutic Goals in the Treatment of AF
•Prevent Stroke/TE
•Prevention of CHF
•Relief of symptoms
•Improved quality of life
•Reduction in cost of care
to medical system

42. Atrial Fibrillation: A Unifying
Theory
Focal triggering initiation
Multiple wavelets for AF maintenance
Parasympathetic effects on atrial substrate
Varying importance among population of lone,
vagally-mediated, PAF, persistent , and
permanent atrial fibrillation.

43. Electrophysiologic mechanisms of AF
AUTONOMIC INFLUENCE
PV AND LA TRIGGERS
WAVELETS AND ROTORS
FOCAL TRIGGERS LEADING
TO INITIATION OF REENTRY
AND WAVELETS

44. Substrate Evolution Hints at a PatientTailored approach
-The role of pulmonary veins in
the perpetuation and initiation
of paroxysmal AF have been
demonstrated;
hence
the
effectiveness of pulmonary vein
isolation techniques in this
cohort of patients.
-As atrial fibrillation progresses
to persistent and permanent,
the role of “muscle, scar, and
fibrosis”, that is structural
disease,
becomes
more
prominent, hence a hybrid
approach is more effective both
targeting the substrate and the
triggers
Fisher JD, et al. PACE 2006; 29: 523.
Wyse DG, Gersh BJ. Circ 2004; 109: 3089.

45. A Comparison of Rate
Control and Rhythm Control
in Patients with Atrial
Fibrillation
The Atrial Fibrillation Follow-up
Investigation of Rhythm Management
(AFFIRM) Investigators
NEJM 347:1825-1833 December 5, 2002

46. AFFIRM Trial
There are two approaches to the treatment of AF: one
is cardioversion and treatment with antiarrhythmic drugs to
maintain sinus rhythm, and the other is the use of rate-controlling
drugs, allowing AF to persist. In both approaches, the use of
anticoagulant drugs is recommended.
AFFIRM was a randomized, multicenter comparison of
these two treatment strategies in patients with AF and a high risk
of stroke or death. The primary end point was overall mortality.
Results A total of 4060 patients (mean [±SD] age, 69.7±9.0
years) were enrolled in the study; 70.8 percent had a history of
hypertension, and 38.2 percent had coronary artery disease. Of
the 3311 patients with echocardiograms, the left atrium was
enlarged in 64.7 percent and left ventricular function was
depressed in 26.0 percentgroup of high-risk patients.

47. Cumulative Mortality from Any Cause in the Rhythm-Control Group and the Rate-Control Group
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. N
Engl J Med 2002;347:1825-1833

48. Hazard Ratios for Death in Prespecified Subgroups
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. N
Engl J Med 2002;347:1825-1833

49. Result of AFFIRM Trial
. There were 356 deaths among the patients assigned to rhythmcontrol therapy and 310 deaths among those assigned to ratecontrol therapy (mortality at five years, 23.8 percent and 21.3
percent, respectively; hazard ratio, 1.15 [95 percent confidence
interval, 0.99 to 1.34]; P=0.08). More patients in the rhythm-control
group than in the rate-control group were hospitalized, and there
were more adverse drug effects in the rhythm-control group as well.
In both groups, the majority of strokes occurred after warfarin had
been stopped or when the international normalized ratio was
subtherapeutic.
Conclusions Management of AF with the rhythm-
control strategy offers no survival advantage over
the rate-control strategy, and there are potential
advantages, such as a lower risk of adverse drug effects, with the
rate-control strategy. Anticoagulation should be continued in this
(NEJM 2002)

51. Which Strategy is Better in
Heart Failure Patients?
Rhythm Control versus Rate Control for Atrial
Fibrillation and Heart Failure Trial
NEJM 358:2667-2677 June 19, 2008

52. Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure
(AF- CHF TRIAL)
NEJM 2008; 358: 2667-2677
Common practice is to restore and maintain sinus rhythm in patients
with AF and heart failure. This approach is based in part on data
indicating that AF is a predictor of death in patients with heart failure
and suggesting that the suppression of AF may favorably affect the
outcome.
Methods A multicenter, randomized trial comparing the maintenance
of sinus rhythm (rhythm control) with control of the ventricular rate
(rate control) in patients with EF 35% or less, symptoms of
congestive heart failure, and a history of AF. The primary outcome
was the time to death from cardiovascular causes. as compared with a
rate-control strategy

53. RESULTS of AF CHF
Results A total of 1376 patients were enrolled (682 in the rhythmcontrol group and 694 in the rate-control group) and were
followed for a mean of 37 months. Of these patients, 182 (27%)
in the rhythm-control group died from cardiovascular causes, as
compared with 175 (25%) in the rate-control group (hazard ratio
in the rhythm-control group, 1.06; 95% confidence interval, 0.86
to 1.30; P=0.59 by the log-rank test).
Secondary outcomes also did not differ significantly between the two treatment
strategies:
– All-cause death: 32% and 33%, P = 0.73
– Stroke: 3% and 4%, P = 0.32
– Worsening heart failure: 28% and 31%, P = 0.17
– Composite of CV death, stroke, worsening heart failure: 43% and 46%, P =
0.20
There were also no significant differences favoring either strategy
in any predefined subgroup.

54. AF CHF results
Conclusions In patients with AF and
congestive heart failure, a routine
strategy of rhythm control does not
reduce the rate of cardiovascular death.
Comment: The investigators caution
that, "Our results cannot be generalized
to patients with heart failure and
preserved left ventricular function.“
NEJM 358:2667-2677 June 19, 2008

56. Why hasn’t rhythm control
worked in trials?
Drugs used in trials don’t guarantee rhythm control
Toxicity of Anti arrythmic drugs contribute to lack of
benefit of rhythm control groups.
AF may be a marker of poor prognosis, in which the
primary problem is poor ventricular function,
neurohormonal activation, or inflammation, with no
independent effect of atrial fibrillation on outcome.

57. IF Drugs Don’t work, Will
Ablation?
AF Ablation
– eliminates confounding contributions of low
efficacy and high toxicity associated with
antiarrhythmic drug therapy
– may better determine the desirability of
maintaining sinus rhythm in patients with atrial
fibrillation.
– Clinical Trials are in progress comparing catheter
ablation of atrial fibrillation to conventional
antiarrhythmic drug therapy.
– AF Ablation has yet to be proven to be better than
rate control.

58. Rate versus Rhythm Control

61. Digoxin
Described by William Withering, 1785 to treat rapid heart rate
and CHF
decreases conduction of electrical impulses through the
AV node, making it a commonly used antiarrhythmic agent in
controlling the heart rate during atrial fibrillation or atrial
flutter.
An increase of force of contraction via inhibition of the Na +/K+
ATPase pump

62. Quinidine- OLD school
seen as too dangerous now
A stereoisomer of quinine initially derived from the bark of the
cinchona tree has been used for decades for AF. Chinchona is
an evergreen native to the mountainous areas of Central and
South America. Quinine is the base flavor in most bitters and
contributes the bitter essence to tonic water.
Discovered by a Danish Merchant seaman with AF who took
quinine for malaria prophylaxis during trips to India. He noted
his pulse was regular while in India but irregular at home.
Chichonism describes tinnitus and hearing loss with quinidine
excess.
Quinidine can cause thrombocytopenia, granulomatous
hepatitis, myasthenia gravis, and torsades de pointes and for
that reason is not used much today. Torsades can occur after
the first dose.

63. Drugs used for atrial fib
Flecanide
Dofetilide
Propafenone
Sotolol
Amiodarone
Dronedarone

69. What is the Future of A Fib
Advances in Anticoagulation
New Drugs: Substantial resources are
being invested in the development of
new drugs that promise to be more
efficacious and safer for use in patients
with atrial fibrillation
Advances in Ablation

71. Things that Havent worked
in Atrial Fib
Dronedarone: a novel antiarrhythmic drug with
electrophysiological properties that are similar to those of
amiodarone, but it does not contain iodine and thus does not
cause iodine-related adverse reactions. In patients with severe
heart failure and left ventricular systolic dysfunction, treatment
with dronedarone was associated with increased early mortality
related to the worsening of heart failure NEJM358: 2725-2727
June 19, 2008
Atrial Defibrillators – Convert the Atrial Fib, but not tolerated
by patients.

73. Amiodarone side effects
Skin
toxicity
Cataracts
Lung fibrosis
Liver damage
Hypo/hyperthyroid

75. Indications for Catheter ablation of
Atrial fibrillation

76. Left Atrial Circumferential Ablation
VOM
(1) PV isolation for trigger initiation of AF
(2) Ablation of areas of potential reentry rotors/wavelets
(3) Transect the vein of Marshall
(4) Vagal denervation altering electrophysiologic substrate

79. Atrial Fibrillation Talk Goals
Describe etiology of Atrial fibrillation
Treatmemt Goals for Atrial Fibrillation
–
–
Novel Anticoagulants
Rate Control/ Rhythm Control
Advances in Therapy for Atrial
fibrillation

81. Questions
Goals were to discuss– Etiology of Atrial fib
– Treatment of Atrial fib
Anticoagulation
Anti arrhythmic therapy
– Advances in therapy

82. Balloon Catheter Technology in AF
Ablation
HIFU (Highfrequency
Ultrasound) :
noncontact technique
with tissue heating
Cryoablation:
tissue
contact and freezing
Laser (infrared):
tissue contact and heating

83. Catheter ablation
*Ablation strategies
target the PVs and or
PV antrum.
*Complete electrical
isolation should be the
goal.

84. Image Integration and Image-Guided
Mapping and Ablation
3-Dimensional Electroanatomical Mapping (EAM)
systems are used to construct image of the left atrium
This image is merged into a LA CT or MRI scan
Using intracardiac ultrasound, the antrum of the
pulmonary veins can be reliably determined
The location and delivery of radiofrequency energy
can be monitored and tracked with the 3-D EAM
system

85. Common Lesion Sets used in AF
Ablation

89. ICE IMAGES

91. NON-PULMONARY VEIN TRIGGERS OF
AFIB