Atrial FibrillationThe Last Big Hurdle in Treating SVT

Esam Baryun, MD, FACC, FHRS

Ever Felt Like This?

AF: an age related condition

Go et al JAMA 2001;285:2370-2375

AF: a growing problem

Go et al JAMA 2001;285:2370-2375

Doubling of patients with Doubling of patients with AF from 1995 to 2030AF from 1995 to 2030

Risk Factors

– Clinical:• Non-modifiable: Age, Sex, Ethnicity, Genetic• Modifiable: Htn, DM, CAD, Obesity, OSA, Tob

– Subclinical: • LVH, Systolic/Diastolic dysfunction, LA size/function• BNP, CRP

Obesity and AF Risk

Adjusted HR 1.5 with obesity, attributable to increased LA size

Wang et al, JAMA 2004; 292:2471

Causes of AF• Anything that damages or stretches the atria:

– Htn, Aging

– Obstructive Sleep Apnea, Pulm Dz

– Ischemia, CHF, Myocarditis, Valvular Dz (MS, MR), CABG

– Thyrotoxicosis, Ethanol (Holiday Heart)

– Obesity BMI>30

– Accessory Pathway

– Genetics

Classifications of AF• 1. Paroxysmal: “self terminating”

– Episodes of AF <7days.

• 2. Persistent– Episodes of AF >7days

• 3. Permanent – Rhythm control failed

• 4. “Lone”– Describes any of the classifications above that occur in individuals

without structural cardiac or pulmonary disease.

NORMAL RHYTHM AF MORE AF ADVERSE OUTCOMES

• Once AF begins, there are multiple adverse outcomes and therefore prevention is imperative.

• There are currently several potentially modifiable risk factors for AF that may provide strategies for population based interventions.

AF begets AF• Electrical Remodeling: Reversible

– Tachy Cellular Ca load Decrease ARP and WCL– Triggered Activity

• Structural Remodeling: Not reversible– Fibrous tissue deposition Local conduction abnormality Reentry– This is sufficient for AF maintenance– Preventable but not reversible– Irreversibility may necessitate early intervention

• AF is a moving target: if SR maintenance is the intention, earlier intervention may be particularly effective and important.

Pts Converted to SR in 3 Mo of Onset Are More Likely to Remain in SR Dittrich HC et al. Am J Cardiol. 1989;63:193-197

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>12-month duration of atrial fibrillation prior to cardioversion

The longer we wait to control rhythm the harder it is to regain SR

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AF causes Histologic Remodeling of Atria as Early as 4 Months

Enlarged atrial cells

Severe myolysis

Glycogen accumulation

Sinus Rhythm AF

Reduction in Connexin

40 expression

Gap JunctionsIn heart cells the signal to contract is passed efficiently through gap junctions

Stroke and AF• Framingham data: 4-5 fold increased risk

• Risk may be higher if silent multi-infarction cognitive impairment included

• Chronic AF and paroxysmal AF carry same risk

• Stroke associated with AF: more severe with higher mortality

• Coumadin only prevents 65% of strokes.

Prevention of AF• AF Genetics (Chromosome 4q25)

• Predictors (Who is at higher risk?)– Sex, Age, BMI, Syst BP, PR interval, Murmur– LA size, LV wall thickness

• Risk Prediction Models may help identify patients for primary prevention.– www.framinghamheartstudy.org/risk/index.html

AF Genetics

• Wolff described three brothers with AF in 1943.

• Increasing evidence of a heritable component of lone AF.

• Presence of AF in 1st degree relatives was associated with an increased risk of developing AF.

• Positive F/H of AF in 1/3 of pts with lone AF indicating that familial AF is more common than previously recognized.

Having at least 1 affected parent approximately doubled the risk of predicted AF

Fox…Benjamin JAMA 2004;291:2851

Therapeutic Options

Management• Medical therapy

– Rate control: AVN blockers– Rhythm control: Anti-arrhythmics– CVA prevention:

• Warfarin• New antithrombotics• LAA occlusion vs resection.

– PROTECT-AF (Watchman)

• Ablation– Catheter Ablation:

• AF ablation: PVAI, Substrate modification• AVN ablation and PPM

– Surgical Ablation

Other Anticoagulants

• Xa inhibitor– Apixaban

• ARISTOTLE: Apixaban vs Warfarin• AVERROES: Apixaban vs ASA in pts who can’t take coumadin

– Rivaroxaban – RECORD (Canada, Europe 9/08)

• Direct Thrombin Inhibitors:– Dabigatran – PETRO phase III, RE-LY Study

• Very few drug-drug interaction (PPIs). No antidote.• 110mg same CVA but less hge• 150mg less CVA but same hge

– Ximelagatran – SPORTIF – as good as Warfarin but not FDA approved due to Liver Toxicities

Dabigatran• Direct Thrombin Inhibitor• Approved by the FDA in October 19, 2010 for prevention of CVA in AF• Dose:

– 150 mg twice daily– If severe renal impairment (CrCl 15-30): 75 mg twice daily (dose Not studied in RELY!!)

• No specific antidote. – Due to its short duration of effect drug discontinuation is usually sufficient to reverse

any excessive anticoagulant activity. – In life-threatening bleeding: recombinant activated factor VII and prothrombin complex

concentrates can be considered.

Anti-arrhythmic Choice

New Antiarrhythmic Drugs• Dronedarone

– Similar to Amiodarone but less lipophilic, no iodine, & half life 24hr.

– No significant organ toxicities

• Ranolazine (Na channel blocker)– Alters the trans-cellular late Na current, indirectly prevents the

Ca overload, inhibits triggered activity– Approved as anti-anginal.

• Vernakalant (K channel blocker)– Atria selective– Accepted for review by the FDA

Rate Control vs Rhythm Control

• AFFIRM (AF f/u Investigation of Rhythm Management) , NEJM 2002

• RACE (Rate Control vs. cardioversion for persistent AF) – NEJM 2002

• PIAF (Pharmacologic Intervention in Atrial Fibrillation) – Lancet 2000

• STAF (Strategies of Treatment of Atrial Fibrillation) – JACC 2003

• HOT CAFÉ ( How to Treat Chronic Atrial Fibrillation) – Chest 2004

Rate Control vs Rhythm Control

• Favor attempts to maintain SR:– First or infrequent episodes of persistent AF– Young active patient– Significant symptoms– Difficult rate control– Contraindication to long term warfarin

• Favor rate control:– Asymptomatic sedentary elderly patient– Contraindication to anti-arrhythmics or ablation

AFFIRM TRIAL4060 patients

Persistent AFAge >65, Mean 70Other risk factors for stroke

Patients with contraindications for anticoagulant therapy were excluded

Primary endpoint: all-cause mortality. Mean 3.5 years follow up.

For rhythm control group anticoagulant encouraged but could be discontinued

AFFIRM TRIAL• No difference in

mortality

• Similar incidenceof stroke: 1% per year in each group

• Most strokes occurred in pts off warfarin or subtherapeutic INR

AFFIRM Investigators NEJM 2002;347:1825-33

WHAT AFFIRM DOES NOT TELL US

• Optimal management for:– Pts with mod-severe disabling AF symptoms– Younger pts with paroxysmal AF

• Outcome if better tools to maintain sinus rhythm were available

• Long-term implications of rate vs rhythm control (mean duration of follow-up only 3.5 years)

What DOES AFFIRM tell us?

• Do not stop coumadin in rhythm control pts.

• Elderly pts with asymptomatic persistent AF are less likely to benefit from antiarrhythmics.

• Unfortunately we don’t have good antiarrhythmic agents.

Limitations of the AFFIRM Study

• May not be applicable to all pts with AF. Results cannot be generalized to :– Younger patients– Pts without other RF for stroke– Paroxysmal AF

• Pts with severe symptoms might have been considered unsuitable for a rate control strategy and may not have been enrolled (Selection Bias).

• In the rhythm control group, continuous anticoagulation was encouraged but could be stopped at the physician’s discretion if SR had been maintained for at least 4-12 weeks

– Most strokes occurred in pts in whom warfarin was stopped or were sub-therapeutic

• Average follow-up was only 3.5 years and treatment of AF is a life-long process

• A large proportion of pts in the rate control arm remained in SR. Does not reflect typical outcome in pts with AF treated with rate control.

Rhythm Control

• In theory converting someone to NSR should:– Improve cardiac hemodynamics– Prevent LV dysfunction– Maintain proper cardiac output– Reduce risk of thromboembolism -> reduce risk of

death

AF Adversely Affects Qaulity of Life Dorian P et al. J Am Coll Cardiol. 2000;36:1303-1309

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General health Physicalfunction

Social function Mental health

Atrial fibrillation

Post myocardialinfarction

Controls

Clinical Trials Showed the Survival Advantage of Sinus Rhythm

• STAF: The Strategies for Treatment of AF study– SR maintained in 30% of rhythm control patients– Mortality:

• 2.5% per year in the rhythm control group• 4.9% per year in rate control group• Result was NOT statistically significant

• Framingham Heart Study cohort• CHF-STAT• SOLVD• DIAMOND

AF increases mortality

• Framingham Heart Study cohort : Follow-up of the original– AF was associated with a 1.5- to 1.9-fold mortality risk after

adjustment for preexisting cardiovascular conditions

• SOLVD: Studies of LV Dysfunction Prevention and Treatment Trial– retrospective analysis– Evaluated whether AF in pts with low EF was associated with higher

mortality.– AF pts had greater:

• All-cause mortality (34% vs 23%, P < 0.001)

SR Decreases Mortality

• DIAMOND: The Danish Investigations of Arrhythmia and Mortality ON Dofetilide study

– 3028 pts with severe CHF or recent MI– Presence of SR was associated with a significant reduction in mortality (RR

0.44, 95% CI, 0.30-0.64, P < 0.0001)

• CHF-STAT : The CHF Survival Trial of Antiarrhythmic Therapy– AF pts who converted to SR (n=16) had a lower mortality rate (P = 0.04) than

those who did not (n=35)

• AFFIRM Study Post Hoc Analyses: SR is a Predictor of Survival– SR was associated with a lower risk of death (47% reduction)– Anticoagulant use associated with a decreased risk of death (50% reduction)

Sustaining Sinus Rhythm Is Associated With Decreased Mortality

47%44%

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The AFFIRM Investigators. Circulation. 2004;109:1509-1513;Circulation. 2001;104:292-296; Lancet. 2006;367:262-272.

CAN SINUS RHYTHM IMPROVE SURVIVAL?

Predictors of Mortality in AFFIRM

Epstein et al, Circulation 2004;109:1509

CABANA TrialAblation Vs Anti-Arrhythmic Drug Therapy for AF

• Designed to test the hypothesis that the treatment strategy of Afib ablation will be superior to current therapy with either rate control or rhythm control drugs for reducing total mortality.

• 3000 Pts randomized to Ablation or Pharmacologic Therapy

• CABANA Trial will disclose:– The role of medical and non-pharmacologic therapies for AF– Establish the cost and impact of therapy on quality of life– Determine if AF is a modifiable risk factor for increased mortality.

• Advantages: – adequate rate control without drugs– regularizes ventricular rate

• Disadvantages– requires permanent pacemaker– fibrillation continues: anticoagulation needed– risk of torsade de pointes early after sudden rate decrease– risk of hemodynamic deterioration from RV pacing

AVN ablation and Pacemaker Implantation

GN Kay et al Ablate and Pace J Intervent Card Electrophy 1998Brignole et al Circulation 1998. Geelen P, et al. VF and sudden death after AVJ ablation. PACE 1997;20:343–8.Jordaens L, et al. Sudden death and long term survival . Eur J Card EP 1993;21:102–9.Gasparini M, et al. Long-term follow-up after AV ablation…PACE 2000;23:1925–9.Ozcan C, et al. Long-term survival. NEJM 2001;344: 1043–51.

Haissguerre et al. NEJM1998;339:659-66

A New Idea Came Along

Mechanistic Approach to AF Ablation- Some Simplifications

• AF is predominantly driven by the LA.

• AF is predominantly driven by 2 mechanisms:– I. Focal Rapid Firing from the PVs (Paroxysmal

AF).– II. Multiple Reentry Circuits around anatomical

obstacles (Chronic AFIB).

Ectopic Foci

Haissguerre et al. NEJM1998;339:659-66Haissguerre et al. NEJM1998;339:659-66 Chen Circ1999;100:1879-86Chen Circ1999;100:1879-86

AF ablation

Pulmonary Vein Antral Isolation

Pulmonary Vein Isolation

Haïssaguerre, M. et al., Circulation. 2000;102:2463–2465.

Going…Going… Going…Going… Gone !Gone !

Peter Cheung

Instead of targeting ectopies, PV potentials are targeted

Lt Inferior Pulmonary Vein

Side-by-Side GeometryElectroanatomic Map & 3-D CT: Cranial View

ESI Nav-X 3-D Geometry 3-D CT via CardEP

(Cranial View)

LA Roof

Esophagus

Left PVsRight PVs

LAA

AF ablation

• How is procedure performed?– Out pt, 3-5hr, moderate-heavy sedation– Discharged home next am– Coumadin mandatory 6-8 weeks after– Four vein sheaths:

• 2 RFV (Lasso, Ablation)• LFV (ICE)• RIJ (Duo-deca)

Visualization: Intracardiac Ultrasound

• Facilitate trans-septal access to LA• Visual guidance of catheters at PV ostium• Direct visualization of:

– PV ostial size– Anatomic abnormalities– Pericardial effusion– Thrombus

Left Atrial Mapping and Catheter AblationVisualization: Intracardiac Ultrasound

Transeptal Access to LATranseptal Access to LA

Tenting of theintra-atrialseptum duringtranseptalcatheterization

AcuNav 10 Fr Phased Array Diagnostic Ultrasound Catheter (by Acuson)

Left Atrial Mapping and Catheter AblationVisualization : Intracardiac Ultrasound

Optimizing Catheter Placement at PV OsOptimizing Catheter Placement at PV Os

Trans-septal Puncture with LA entry

Intracardiac Echo

Tenting of Interatrial septum Esophagus posterior to LA

Lasso on Lt Inf PV

Lasso on Lt Sup PV

So why ablate?

• Our best drugs are:– Only moderately effective (30-50%)– Have side effects/toxicities

• Many patients despite adequate rate control remain symptomatic in AF

• Sustaining SR may be associated with decreased mortality

AF ablationPappone, JACC, 2003

Risks vs Benefits

Potential benefits • Symptomatic benefit

• No need for AADs

• Thromboembolic benefit

• Mortality benefit?

Potential harm• Stroke

• LA flutters

• Tamponade

• TE fistula

• PV stenosis

Post Ablation Care• Early AF recurrence (not uncommon)

– 20-50% of patients– More than half will resolve within 3 mos– Antiarrhythmic drugs usually continued for first 2-6 months

• Atrial tachycardias post ablation

• Anticoagulation– High risk of CVA in first month post RFA

• Redo procedures in 20% of pts (after 3 mo)

AF case 1• 67y old female, school teacher• Recurrent symptomatic AF with RVR

– Admitted to hospital several times, twice in 10/08– Tachypalpitations several times a week

• Failed amiodarone and sotalol• AFib RFA 11/08• Post RFA:

– One AF episode 2 days after ablation (blanking period)– No tachypalpitations since then– A 2 wk MCOT 2 & 6 months later shows no AF– Off amiodarone and coumadin

MCOT 2mo after ablatioin

AF case 2

• Middle age female, Nurse• Paroxysmal AF with RVR, once/1-2months• Failed anti-arrhythmics• A fib ablation in 12/08• Follow up:

– No episodes since ablation– MCOT 2/16-2/24 showed 0% AF– Tikosyn was stopped four months after ablation

Case 3

• 50y old female• Frequent tachypalpitations, with significant

symptoms• Propafenone helped a little

– Dose increased but still significantly symptomatic– Palpitations occur if one dose is delayed 2hr– Max dose of AA caused metallic taste

Baseline MCOT

Higher dose only decreased episodes

Propafenone 225mg Propafenone 150mg

• A fib ablation 3/09• Follow up:

– No more palpitations immediately after ablation– 2 month:

• No palpitations even when misses AA dose• Feels great and more energetic

– 3 months:• Propafenone was discontinued three months after ablation• Repeat MCOT showed no AF

Case 4

• 51y old man with symptomatic persistent AF• On amiodarone for >6 mo• Amiodarone stopped given his age, and 2 mo

later started on tikosyn• AF ablation 3/09

MCOT 2 months post RFA

Remains AF free 5 months after

Case 5

• 66y old female• Persistent symptomatic AF for >1 year• Failed multiple AA therapy• Success rate with ablation less than

paroxysmal AF

AF Ablation on 5.28.09AF burden decreased gradually weeks after PVAI

Case 660 y old man with persistent AF. Amiodarone started 7.28.09.

DC CV 9.3.09. AF ablation 11.16.09.

Case 765y old man failed two anti-arrhythmics

AF ablation in 5.09

MCOT 4 months laterPropafenone was discontinued

Conclusion

• These advances may yet tip the balance back in favor of a rhythm control strategy.

• RFA of the PVs has been successful in long-term maintenance of SR, representing a curative strategy that eliminated the need for pharmacotherapy for AF in drug-refractory patients.