Atrial Fibrillation: Emerging Atrial Fibrillation: Emerging ConceptsConcepts

New Treatment Paradigms

John Hakim, MD, FACC

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

OVERVIEWOVERVIEW Atrial fibrillation is a progressive diseaseAtrial fibrillation is a progressive disease Atrial fibrillation has hemodynamic and myocardial consequences Atrial fibrillation has hemodynamic and myocardial consequences

(i.e., reduced cardiac output and heart failure)(i.e., reduced cardiac output and heart failure) There is significant morbidity and mortality consequencesThere is significant morbidity and mortality consequences --increased hospitalizationsincreased hospitalizations --reduced quality of lifereduced quality of life -increased risk of thromboembolism and stroke-increased risk of thromboembolism and stroke (accounts for (accounts for

75,00075,000 strokes per year in the United States alone)strokes per year in the United States alone) --decreased survivaldecreased survival (AF is associated with increased mortality, but (AF is associated with increased mortality, but whether it is the cause or an innocent whether it is the cause or an innocent

bystanderbystander is not well established)is not well established)1-81-8

Atrial fibrillation can be a treatable disorder, especially with early Atrial fibrillation can be a treatable disorder, especially with early interventionintervention

What’s new in atrial fibrillation treatmen.tWhat’s new in atrial fibrillation treatmen.t

1Benjamim EJ, et al. Impact of AF on the risk of death: The Framinham Heart Study. Circulation. 1998; 98: 946-52.

2Gajewski J, et al. Mortality in an insured population with AF. JAMA. 1981; 245: 1540-44.

3Krahn AD, et al. The natural history of AF. Am J Med. 1995; 98: 476-84.

4Flegel KM, et al. Risk of stroke in non-rheumatic AF. Lancet. 1987; 1: 526-9.

5Kulbertus HE, et al. AF in elderly, ambulatory patients. AF; 1982: 148-57.

6Lake FR, et al. AF and mortality in an elderly population. Aus N Z J Med. 1989; 19: 321-6.

7Kannel WB, et al. Epidemiologic features of chronic AF: the Framingham Study. NEJM 1982; 306: 1018-22.

8Kitchin AH, et al. Longitudinal survey of ischemic heart disease in randomly selected older population. Br Heart J 1977; 39: 889-93.

Classification and Patterns Classification and Patterns of AFof AF ParoxysmalParoxysmal: terminates spontaneously, : terminates spontaneously,

typically duration is <7 days (most<24 hours). typically duration is <7 days (most<24 hours). May be recurrent. May be recurrent.

PersistentPersistent: medication or electrical : medication or electrical intervention is required to restore sinus intervention is required to restore sinus rhythm; does not self-terminate. Typically rhythm; does not self-terminate. Typically lasts > 7 days. May be recurrent.lasts > 7 days. May be recurrent.

PermanentPermanent: sinus rhythm cannot be restored : sinus rhythm cannot be restored or maintained despite interventionor maintained despite intervention

*** Evaluate for thrombotic risk each of these *** Evaluate for thrombotic risk each of these situations.*****situations.*****

Causes of Atrial Causes of Atrial FibrillationFibrillation

HypertensionHypertension Heart attacks/ CADHeart attacks/ CAD Valvular Heart DiseaseValvular Heart Disease Congenital heart defects Congenital heart defects Hyperthyroid or other metabolic Hyperthyroid or other metabolic

imbalance imbalance Exposure to stimulants such as Exposure to stimulants such as

medications, caffeine or tobacco, or medications, caffeine or tobacco, or to alcohol (holliday heart)to alcohol (holliday heart)

Sick sinus syndrome — improper Sick sinus syndrome — improper functioning of the heart's natural functioning of the heart's natural pacemaker pacemaker

Emphysema or other lung diseases Emphysema or other lung diseases CABG/ Previous heart surgery CABG/ Previous heart surgery Viral infections /PericarditisViral infections /Pericarditis Stress due to pneumonia, surgery or Stress due to pneumonia, surgery or

other illnesses (Cathecholamines)other illnesses (Cathecholamines)

Pulmonary EmbolusPulmonary Embolus PneumoniaPneumonia Sleep ApneaSleep Apnea PericarditisPericarditis Lone A fib (younger people)Lone A fib (younger people) Left ventricular HypertrophyLeft ventricular Hypertrophy CardiomyopathyCardiomyopathy CHF –Systolic or DiastolicCHF –Systolic or Diastolic Idiopathic – mostly in younger Idiopathic – mostly in younger

people – Lone Atrial Fibpeople – Lone Atrial Fib Familial Predisposition.Familial Predisposition. glucocorticoidsglucocorticoids

Risk Factors for AF: Risk Factors for AF: DiabetesDiabetes AF was 44% more prevalent and 38% more likely to develop when AF was 44% more prevalent and 38% more likely to develop when

diabetes was present in an adult population diabetes was present in an adult population Prevalence and incidence of AF in 17,372 patients with diabetes and in 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 the same amount of age- and sex-matched controls without type 2 diabetes included in a Kaiser Permanente diabetes registry. The diabetes included in a Kaiser Permanente diabetes registry. The researchers followed patients without AF for the comparison of AF researchers followed patients without AF for the comparison of AF incidence while controlling for known risk factors. incidence while controlling for known risk factors.

Prevalence for AF was significantly higher among patients with Prevalence for AF was significantly higher among patients with diabetes compared with those without (3.6% vs. 2.5%; diabetes compared with those without (3.6% vs. 2.5%; PP<.0001). <.0001).

Over 7.2 years, patients with diabetes without AF at baseline 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 person-developed AF at an age- and sex-adjusted rate of 9.1 per 1,000 person-years vs. 6.6 per 1,000 person-years for patients without diabetes. years vs. 6.6 per 1,000 person-years for patients without diabetes.

Diabetes was associated with a 26% increased risk for AF among Diabetes was associated with a 26% increased risk for AF among women after adjusting for other risk factors (HR=1.26; 95% CI, 1.08-women after adjusting for other risk factors (HR=1.26; 95% CI, 1.08-1.46). Diabetes was not a statistically significant risk factor among 1.46). Diabetes was not a statistically significant risk factor among men. men.

Men had a higher prevalence of AF in all age groups regardless of Men had a higher prevalence of AF in all age groups regardless of diabetesdiabetes

Original Article Effect of Clopidogrel Added to Aspirin in Patients

with Atrial Fibrillation --- ACTIVE TRIAL

N Engl J Med Volume 360(20):2066-2078 May 14, 2009

• 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

Cumulative Incidence of Trial Outcomes, According to Treatment Group

The ACTIVE Investigators. N Engl J Med 2009;360:2066-2078

The ACTIVE Investigators The ACTIVE Investigators

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

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

Dabigatran versus Warfarin in Dabigatran versus Warfarin in Patients with Atrial Fibrillation (NEJM Patients with Atrial Fibrillation (NEJM

9/7/2009)9/7/2009) In patients with AF, dabigatranIn patients with AF, dabigatran given at a dose given at a dose

of 110 mg was associated with rates of strokeof 110 mg was associated with rates of stroke

and systemic embolism that were similar to and systemic embolism that were similar to those associatedthose associated with warfarin, as well as with warfarin, as well as lower rates of major hemorrhage. Dabigatranlower rates of major hemorrhage. Dabigatran

administered at a dose of 150 mg, as administered at a dose of 150 mg, as compared with warfarin,compared with warfarin, was associated with was associated with lower rates of stroke and systemic embolismlower rates of stroke and systemic embolism

but similar rates of major hemorrhagebut similar rates of major hemorrhage

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

2Dittrich HC, et al. Am J Cardiol 1989; 63: 193-7.

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

Atrial Fibrillation: A Unifying Atrial Fibrillation: A Unifying TheoryTheory

Focal triggering initiationFocal triggering initiation

Multiple wavelets for AF maintenanceMultiple wavelets for AF maintenance

Parasympathetic effects on atrial substrateParasympathetic effects on atrial substrate

Varying importance among population of lone, vagally-Varying importance among population of lone, vagally-mediated, PAF, persistent , and permanent atrial mediated, PAF, persistent , and permanent atrial fibrillation.fibrillation.

Electrophysiologic mechanisms Electrophysiologic mechanisms of AFof AF

AUTONOMIC INFLUENCE WAVELETS AND ROTORS

PV AND LA TRIGGERSFOCAL TRIGGERS LEADING TO INITIATION OF REENTRY AND WAVELETS

Substrate Evolution Hints at a Substrate Evolution Hints at a Patient-Tailored approachPatient-Tailored 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.

Benefits of rhythm control include: decreased Benefits of rhythm control include: decreased hospitalizations, improved cardiac function, hospitalizations, improved cardiac function, improved exercise tolerance, and improvement in improved exercise tolerance, and improvement in quality of lifequality of life

Consequences of failure to maintain sinus rhythm: Consequences of failure to maintain sinus rhythm: atrial remodeling and permanent atrial fibrillationatrial remodeling and permanent atrial fibrillation

The goals of antiarrhythmic therapy to maintain The goals of antiarrhythmic therapy to maintain normal sinus rhythm should be: normal sinus rhythm should be:

1. To reduce the frequency, severity, and 1. To reduce the frequency, severity, and duration of AF duration of AF

to a degree acceptable to the patientto a degree acceptable to the patient

2. To do so with the lowest likelihood of 2. To do so with the lowest likelihood of adverse effectsadverse effects

Rate versus Rhythm controlRate versus Rhythm control

So the Question in So the Question in atrial fibrillation, which atrial fibrillation, which is better: rate control is better: rate control

or rhythm control?or rhythm control?

First answered in 2002First answered in 2002

          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 347:1825-1833

December 5, 2002

                                                                                                                                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.

AFFIRM Trial

The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. N Engl J Med 2002;347:1825-1833

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

Hazard Ratios for Death in Prespecified Subgroups

Result of AFFIRM TrialResult of AFFIRM Trial. There were 356 deaths among the patients assigned to rhythm-control therapy and 310 deaths among those assigned to rate-control 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)

Which Strategy is Which Strategy is Better in Heart Failure Better in Heart Failure

Patients?Patients?

Rhythm Control versus Rate Control Rhythm Control versus Rate Control for Atrial Fibrillation and Heart for Atrial Fibrillation and Heart

Failure Trial Failure Trial

NEJM 358:2667-2677 NEJM 358:2667-2677 June 19, 2008

Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Rhythm Control versus Rate Control for Atrial Fibrillation and Heart FailureFailure

(AF- CHF TRIAL)(AF- CHF TRIAL) NEJM 2008; 358: 2667-2677 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

RESULTS of AF CHFRESULTS of AF CHF

ResultsResults A total of 1376 patients were enrolled (682 in the rhythm- A total of 1376 patients were enrolled (682 in the rhythm-controlcontrol group and 694 in the rate-control group) and were group and 694 in the rate-control group) and were followed forfollowed for a mean of 37 months. Of these patients, 182 (27%) a mean of 37 months. Of these patients, 182 (27%) in the rhythm-controlin the rhythm-control group died from cardiovascular causes, as group died from cardiovascular causes, as compared with 175compared with 175 (25%) in the rate-control group (hazard ratio (25%) in the rate-control group (hazard ratio in the rhythm-controlin the rhythm-control group, 1.06; 95% confidence interval, 0.86 group, 1.06; 95% confidence interval, 0.86 to 1.30; P=0.59 byto 1.30; P=0.59 by the log-rank test). the log-rank test).

Secondary outcomes also did not differ significantly between the two treatment Secondary outcomes also did not differ significantly between the two treatment strategies: strategies: – All-cause death: 32% and 33%, P = 0.73 All-cause death: 32% and 33%, P = 0.73 – Stroke: 3% and 4%, P = 0.32 Stroke: 3% and 4%, P = 0.32 – Worsening heart failure: 28% and 31%, P = 0.17 Worsening heart failure: 28% and 31%, P = 0.17 – Composite of CV death, stroke, worsening heart failure: 43% and 46%, P = Composite of CV death, stroke, worsening heart failure: 43% and 46%, P =

0.20 0.20

There were also no significantThere were also no significant differences favoring either strategy in differences favoring either strategy in any predefined subgroup.any predefined subgroup.

AF CHF resultsAF CHF results

ConclusionsConclusions In patients with AF and In patients with AF and congestivecongestive heart failure, a routine heart failure, a routine strategy of rhythm control does notstrategy of rhythm control does not

reduce the rate of cardiovascular reduce the rate of cardiovascular death.death.

Comment: Comment: The investigators caution that, "Our The investigators caution that, "Our results cannot be generalized to patients with results cannot be generalized to patients with heart failure and preserved left ventricular heart failure and preserved left ventricular function.“function.“

NEJM 358:2667-2677 NEJM 358:2667-2677 June 19, 2008

Why hasn’t rhythm Why hasn’t rhythm control worked in control worked in

trials?trials? Drugs used in trials don’t guarantee rhythm Drugs used in trials don’t guarantee rhythm

controlcontrol Toxicity of Anti arrythmic drugs contribute to Toxicity of Anti arrythmic drugs contribute to

lack of benefit of rhythm control groups.lack of benefit of rhythm control groups. AF may be a marker of poor prognosis, in AF may be a marker of poor prognosis, in

whichwhich the primary problem is poor ventricular the primary problem is poor ventricular function, neurohormonalfunction, neurohormonal activation, or activation, or inflammation, with no independent effect of inflammation, with no independent effect of atrialatrial fibrillation on outcome.fibrillation on outcome.

IF Drugs Don’t work, IF Drugs Don’t work, Will Ablation?Will Ablation?

AF Ablation AF Ablation – eliminates confoundingeliminates confounding contributions of low contributions of low

efficacy and high toxicity associated withefficacy and high toxicity associated with

antiarrhythmic drug therapyantiarrhythmic drug therapy– may better determine the desirabilitymay better determine the desirability of of

maintaining sinus rhythm in patients with atrial maintaining sinus rhythm in patients with atrial fibrillation.fibrillation.

– Clinical Trials are in progress comparing catheter Clinical Trials are in progress comparing catheter ablation of atrialablation of atrial fibrillation to conventional fibrillation to conventional antiarrhythmic drugantiarrhythmic drug therapy.therapy.

– AF Ablation has yet to be proven to be better than AF Ablation has yet to be proven to be better than rate control.rate control.

Rate versus Rhythm ControlRate versus Rhythm Control

DigoxinDigoxin

Described by WilliamDescribed by William Withering, 1785 to treat rapid Withering, 1785 to treat rapid heart rate and CHFheart rate and CHF

decreases conduction of decreases conduction of electrical impulses through the through the AV node, making it a commonly used , making it a commonly used antiarrhythmic agent in controlling the in controlling the heart rate during during atrial fibrillation or or atrial flutter. .

An increase of An increase of force of of contraction via inhibition of the via inhibition of the NaNa++/K/K++ ATPase pump ATPase pump

Quinidine- OLD schoolQuinidine- OLD schoolseen as too dangerous seen as too dangerous

nownow A stereoisomer of quinine initially derived from the bark of the A stereoisomer of quinine initially derived from the bark of the

cinchona tree has been used for decades for AF.  Chinchona is an cinchona tree has been used for decades for AF.  Chinchona is an evergreen native to the mountainous areas of Central and South evergreen native to the mountainous areas of Central and South America. Quinine is the base flavor in most bitters and contributes America. Quinine is the base flavor in most bitters and contributes the bitter essence to tonic water.the bitter essence to tonic water.

Discovered by a Danish Merchant seaman with AF who took quinine Discovered by a Danish Merchant seaman with AF who took quinine for malaria prophylaxis during trips to India.  He noted his pulse was for malaria prophylaxis during trips to India.  He noted his pulse was regular while in India but irregular at home. regular while in India but irregular at home.

Chichonism describes tinnitus and hearing loss with quinidine Chichonism describes tinnitus and hearing loss with quinidine excess. excess. 

Quinidine can cause thrombocytopenia, granulomatous hepatitis, Quinidine can cause thrombocytopenia, granulomatous hepatitis, myasthenia gravis, and torsades de pointes and for that reason is myasthenia gravis, and torsades de pointes and for that reason is not used much today. Torsades can occur after the first dose.not used much today. Torsades can occur after the first dose.

Drugs used for atrial fibDrugs used for atrial fib

Flecanide Flecanide DofetilideDofetilide PropafenonePropafenone SotololSotolol AmiodaroneAmiodarone

What is the Future of A What is the Future of A FibFib

Advances in AnticoagulationAdvances in Anticoagulation New Drugs: Substantial resources New Drugs: Substantial resources

are being invested in the are being invested in the developmentdevelopment of new drugs that of new drugs that promise to be more efficacious and promise to be more efficacious and safer forsafer for use in patients with atrial use in patients with atrial fibrillationfibrillation

Advances in AblationAdvances in Ablation

Things that Havent Things that Havent worked in Atrial Fibworked in Atrial Fib

DronedaroneDronedarone: a novel antiarrhythmic drug with : a novel antiarrhythmic drug with electrophysiologicalelectrophysiological properties that are similar to those properties that are similar to those of amiodarone, but it doesof amiodarone, but it does not contain iodine and thus not contain iodine and thus does not cause iodine-related adversedoes not cause iodine-related adverse reactions. In reactions. In patients with severe heart failure and left ventricularpatients with severe heart failure and left ventricular

systolic dysfunction, treatment with dronedarone was systolic dysfunction, treatment with dronedarone was associatedassociated with increased early mortality related to the with increased early mortality related to the worsening of heartworsening of heart failure NEJM358: 2725-2727failure NEJM358: 2725-2727 June 19, June 19, 2008 2008

Atrial Defibrillators – Convert the Atrial Fib, but not Atrial Defibrillators – Convert the Atrial Fib, but not tolerated by patients.tolerated by patients.

Indications for Catheter ablation Indications for Catheter ablation of Atrial fibrillationof Atrial fibrillation

Left Atrial Circumferential Ablation

(1) PV isolation for trigger initiation of AF

(2) Ablation of areas of potential reentry rotors/wavelets

(4) Vagal denervation altering electrophysiologic substrate

(3) Transect the vein of Marshall

VOM

HIFU HIFU (High-(High-frequency frequency Ultrasound) : Ultrasound) : noncontact technique noncontact technique with tissue heatingwith tissue heating

CryoablationCryoablation: : tissue contact and tissue contact and freezingfreezing

LaserLaser (infrared): (infrared): tissue contact and tissue contact and heatingheating

Balloon Catheter Technology in Balloon Catheter Technology in AF AblationAF Ablation

Catheter ablationCatheter ablation

*Ablation strategies target the PVs and or PV antrum.

*Complete electrical isolation should be the goal.

Image Integration and Image-Image Integration and Image-Guided Mapping and AblationGuided Mapping and Ablation

3-Dimensional Electroanatomical Mapping 3-Dimensional Electroanatomical Mapping (EAM) systems are used to construct image of (EAM) systems are used to construct image of the left atriumthe left atrium

This image is merged into a LA CT or MRI scanThis image is merged into a LA CT or MRI scan Using intracardiac ultrasound, the antrum of Using intracardiac ultrasound, the antrum of

the pulmonary veins can be reliably the pulmonary veins can be reliably determineddetermined

The location and delivery of radiofrequency The location and delivery of radiofrequency energy can be monitored and tracked with the energy can be monitored and tracked with the 3-D EAM system3-D EAM system

Common Lesion Sets used in AF Common Lesion Sets used in AF AblationAblation

ICE IMAGES

NON-PULMONARY VEIN TRIGGERS OF AFIB