PLEASE TAKE A MOMENT TO COMPLETE THE PRE-TEST

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2 PLEASE TAKE A MOMENT TO COMPLETE THE PRE-TEST

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4 Atrial Fibrillation Affects 2 to 5 million US patients 1% of population Associated with older age and chronic heart disease, especially HF Comorbidities AF complicates management of comorbidity and vice versa Increases risk of stroke, HF, and death 71,000 patients die per year from complications of AF or atrial flutter (AFL) Most common arrhythmia requiring hospitalization 416,000 hospital discharges per year Most common arrhythmia DRG discharge dx Fuster V, et al. Circulation. 2006;114: Thom T, et al. Circulation. 2006;113:e85-e151. Feinberg WM, et al. Arch Intern Med. 1995;155: Waktare JE, et al. Am J Cardiol. 1998;81:3C-15C. Benjamin EJ, et al. Circulation. 1998;98: Wang TJ, et al. Circulation. 2003;107: Miyasaka Y, et al. Circulation. 2006;114:

5 Clinical Impact of AF Death (2x increased risk) Increased risk of cardiovascular hospitalization (2-3x) Thromboembolism/Stroke (4.5 increased risk) Reduced quality of life secondary to symptoms and exercise intolerance Hemodynamic impairment and tachycardia-induced cardiomyopathy Krahn AD, et al al. Am J Med. 1995;98: Benjamin EJ, et al. Circulation. 1998;98:

6 Projection for Prevalence of Atrial Fibrillation: 5.6 Million by 2050 Projected number of adults with atrial fibrillation in the United States between 1995 and 2050 Adults with atrial fibrillation in millions Upper and lower curves represent the upper and lower scenarios based on sensitivity analyses Years Go AS et al. JAMA. 2001;285:

7 Increasing Hospitalizations for AF (National Hospital Discharge Survey) Prevalence per 10,000 Persons Principal Diagnosis of AF Year Per 10,000 Persons Any Diagnosis of AF Year Age (y) Wattigney WA, et al. Circulation. 2003;108:

8 Hospitalization Costs in AF Medicare Patients Study With AF (n = 13,558) Without AF (n = 13,195) Nominal Costs ($) * * Men Women Men Women Men Women yr Follow-up * Significantly different from patients with AF at P < Wolf PA, et al. Arch Intern Med. 1998;158:

9 Atrial Fibrillation Adversely Affects Quality of Life (QoL) Dorian P et al. J Am Coll Cardiol. 2000;36:

10 Interplay of AFib and HF: The Vicious Cycle Interstitial fibrosis Triggered activity Heterogeneous conduction Altered atrial refractoriness Volume + pressure overload AFib HF Loss of atrial contraction Rapid ventricular rate Energy depletion Remodeling Ischemia Abnormal Ca 2+ handling R-R variability Maisel WH, et al. Am J Cardiol. 2003;91(suppl):2D-8D.

11 Stroke and Atrial Fibrillation Atrial fibrillation increases the risk of ischemic stroke by a factor of 5 13,559 patients studied with nonvalvular atrial fibrillation 596 experienced ischemic strokes 42% - no treatment 27% - on aspirin 32% - on warfarin Among patients with nonvalvular AF, anticoagulation that results in an INR of 2.0 or greater reduces not only the frequency of ischemic stroke but also its severity and the risk of death from stroke. These findings provide further evidence against the use of lower INR target levels in patients with atrial fibrillation. Hylek EM, et al. NEJM 2003; 349:

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15 Classifying AF

16 Patterns of Atrial Fibrillation First detected Paroxysmal (self-terminating) Persistent (not self-terminating) Permanent (accepted) Fuster V, et al. J Am Coll Cardiol 2006;48:854.

17 Causes of atrial fibrillation Structural heart disease Hypertension Coronary artery disease Mitral valvular disease Cardiomyopathy (dilated, hypertrophic, restrictive) Congenital heart disease (especially ASD) Pericarditis (acute, constrictive, post cardiac surgery) Wolff-Parkinson-White syndrome Non-structural heart disease Pulmonary disease (COPD, pneumonia, embolus) Thyrotoxicosis Acute ethanol ingestion holiday heart syndrome Methylxanthine (theophylline, caffeine) Systemic illness (sepsis, malignancy, electrolyte disturbances) Lone atrial fibrillation

18 Atrial Fibrillation: After Open-Heart Surgery Atrial fibrillation following open-heart surgery: Incidence 20% to 50% (mean incidence 30%) Peak incidence day 2; gradually declines through day 5 Increased postoperative morbidity Prolonged hospital stay and the most common cause of re-admission Di Domenico, RJ et al. Ann Thorac Surg. 2005; 79: Fuster V, et al. Circulation. 2006;114:

19 AFib Causes Several Types of Remodeling Over Time That Have Adverse Physiologic Consequences Electrophysiologic changes Shortening of atrial refractory periods 1 Loss of normal adaptation of atrial refractoriness to heart rate 2 Contractile changes Reduced atrial contractility 3 Structural changes Left atrium and LA appendage enlargement 4 Decrease in cardiac output 5 Histologic changes 3 1. Prystowsky EN, et al. Circulation. 1996;93: ; 2. Hobbs WJC, et al. Circulation. 2000;101: ; 3. Thijssen VLJL, et al. Cardiovasc Pathol. 2000;9:17-28; 4. Sanfilippo AJ, et al. Circulation. 1990;82: ; 5. Fuster V, et al. J Am Coll Cardiol. 2001;38:

20 Remodeling in AF: Different Time Domains AF begets AF Prolonged duration of subsequent episodes of AF Shorter periods between events Lower likelihood of maintaining NSR Atrial refractoriness shortens markedly during first 24 hours of AF Atrial dimensions increase over time with AF (part of an atrial myopathy) Adapted from Wijffels MC et al. Circulation. 1995:92:

21 Progression of AFib Natural history of AFib is characterized by gradual worsening over time 1 Disease progression can have devastating consequences Electrical and structural damage to the atrial myocardium that can predispose individuals to clinical consequences such as stroke and death 2-4 Paroxysmal AFib may become persistent, and both paroxysmal AFib and persistent AFib may become permanent 1 Therefore, treatment of AFib may halt disease progression and improve outcomes 1,5 Retrospective analyses suggest that if an effective method of maintaining sinus rhythm with fewer adverse events were available, survival might be improved 6 1. Fuster V, et al. Circulation. 2006;114:e257-e354; 2. Savelieva I, et al. Pacing Clin Electrophysiol. 2000;23: ; 3. Arch Intern Med. 1994;154: ; 4. Stewart S, et al. Am J Med. 2002;113: ; 5. Hohnloser S, et al. J Cardiovasc Electrophysiol. 2008;19:69-73; 6. The AFFIRM Investigators. Circulation. 2004;109:

22 Risk Stratification in AF Stroke Risk Factors High-Risk Factors Mitral stenosis Prosthetic heart valve History of stroke or TIA Moderate-Risk Factors Age >75 years Hypertension Diabetes mellitus Heart failure or LV function Less Validated Risk Factors Age years Coronary artery disease Female gender Thyrotoxicosis Dubious Factors Duration of AF Pattern of AF (persistent vs. paroxysmal) Left atrial diameter Singer DE, et al. Chest 2004;126:429S. Fang MC, et al. Circulation 2005; 112: 1687.

23 CHADS 2 Risk Stratification Scheme Risk Factors Score C Recent congestive heart failure 1 H Hypertension 1 A Age 75 years 1 D Diabetes mellitus 1 S 2 History of stroke or transient ischemic attack 2 Rockson SG, et al. J Am Coll Cardiol. 2004;43:

24 Risk Stratification and Anticoagulation Stroke Reduction with Warfarin Instead of Aspirin EAFT Study Group. Lancet 1993; 324:1255. Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31:1622.

25 Newly Discovered AF Pharmacological Management Newly Discovered AF Paroxysmal Persistent No therapy needed, unless severe symptoms (eg, hypotension, HF, angina pectoris) Anticoagulation, as needed Accept permanent AF Anticoagulation and rate control, as needed Rate control and anticoagulation, as needed Consider antiarrhythmic drug therapy Cardioversion Long-term drug prevention unnecessary Fuster V, et al. J Am Coll Cardiol 2006;48:854.

26 Antithrombotic Therapy for Atrial Fibrillation ACC/AHA/ESC Guidelines 2006 RISK CATEGORY No risk factors CHADS 2 = 0 One moderate risk factor CHADS 2 = 1 Any high risk factor or >1 moderate risk factor CHADS 2 >2 or Mitral stenosis Prosthetic valve RECOMMENDED THERAPY Aspirin, mg qd Aspirin, mg/d or Warfarin (INR , target 2.5) Warfarin (INR , target 2.5) Warfarin (INR , target 3.0 Fuster V, et al. Eur Heart J 2006;27:1979.

27 56 year old male with out Past Med History complaint of palpitation past two weeks. EKG shows AFIB. Treatment of choice is; Cardioversion Start coumadin and cardioversion in 4 weeks Start bete blocker ASA and amiodorone Start verapamil

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30 Watchman Device The Watchman (Atritech) is a device that closes off the left atrial appendage (LAA) to minimize the risk of stroke. It is one of several techniques for closing off the left atrial appendage as an alternative to Coumadin or warfarin other techniques include removing or clamping off the left atrial appendage during surgery.

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33 Managing AF

34 Agents for Chemical Cardioversion IV Procainamide class Ia fast Na+ channel, alpha blocking may cause hypotension efficacy ~60%, hypotension ~8% IV Amiodarone class III, action potential duration, hypotension 11%, phlebitis 16%, QT negligible efficacy 62% 1 hr, 93% 24 hr

35 Agents for Chemical Cardioversion IV Ibutilide Class III K + channel blockade hypotension 8% QT prolongation 20% BBB 22% 3% torsades Efficacy 61-69% IV Vernakalant New agent not yet in US Mixed Na + and K + blocker with K +(dur) preference Selectively prolongs atrial refractory periods No effects on ventricular refractoriness or QT Efficacy 62% in 11 min

36 Chronic Pharmacologic Rate Control in Atrial Fibrillation Digoxin oral ddose mg once daily Calcium Channel Blockers: - Verapamil: mg daily - Diltiazem: mg daily Beta Blockers: - Metrapolol: mg twice daily -Atenolol: mg daily

37 Antiarrhythmic Drugs to Suppress Atrial Fibrillation Class I Drugs IA (vagally mediated AF) - Disopyramide IC (avoid in pts with CAD, LVH, CM) - Flecanide mg bid - Propafenone mg tid or bid Class III Drugs - Sotalol mg bid (avoid in sever CHF) - Dofetilide - Amiodarone mg daily (drug of choice pts with CHF) - Dronidarone 400mg bid

38 Summary of Major Trials Comparing Rhythm Strategy and Rate Strategy Trial Name Primary Endpoint Pts. Reaching Primary End point [n/n (%)] Rate Rhythm P value Total Deaths n (rate/rhythm) CV Deaths Non- CV Deaths Strok e AFFIRM 1,2 All-cause mortality 310/ 2027 (25.9) 356/ 2033 (26.7) (310/356) 130/ /169 28/28 RACE 3 Composite: CV death, CHF, severe bleeding, pacemaker implantation, thromboembolic events, severe adverse events from AADs 44/256 (17.2) 60/ 266 (22.6) /18 N/A N/A PIAF 4 Symptom improvement 76/125 (60.8) 70/127 (55.1) /1 N/A N/A STAF 5 Composite: overall mortality, cerebrovascular complications, CPR, embolic events 10/100 (10.0) 9/100 (9.0) (8/4) 8/3 0/1 1/5 AF-CHF 6 Death from CV causes 175 (25.0) 182 (27.0) (228/217) 175/182 53/35 11/9 1. The AFFIRM Investigators. N Engl J Med 2002;347: ; 2. Steinberg JS et al. Circulation. 2004;109: ; 3. Van Gelder IC, et al. N Engl J Med. 2002;347: ; 4. Hohnloser SH, et al. Lancet. 2000;356: ; 5. Carlsson J, et al. J Am Coll Cardiol. 2003;41: ; 6. Roy D, et al. N Engl J Med. 2008;358:

39 Rate Control vs. Rhythm Control AFFIRM Trial Randomized multicenter trial of rate control vs. rhythm control 4060 patients (mean [+/-SD] age, 69.7+/-9.0 years) 70.8 percent had a history of hypertension 38.2 percent had coronary artery disease The primary end point was overall mortality. A comparison of rate control and rhythm control in patients with atrial fibrillation The AFFIRM writing group N Engl J Med Dec 5;347(23):

40 The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) 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:

41 72 year old male with CAD, HTN, DM Recently diaagnsed with Atrial Fib. By routine physical exam. Totally asymptomatic, currently on Ace Inhibitor, beta blocker and ASA. Appropiate management. Rate control and anticoagulation Start coumadin and cardioversion in 4 weeks Start amiodorone Start sotolal Cardiac Cath

42 RAte Control Efficacy in Permanent Atrial Fibrillation RACE II Hypothesis: Lenient rate control is not inferior to strict rate control in patients with permanent AF in terms of cardiovascular morbidity and mortality 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. Primary study endpoint: A composite of CV mortality, HF hospitalization, stroke, systemic emboli, bleeding and life-threatening arrhythmic events. Primary outcome was similar in lenient and strict control arms (12.9% vs. 14.9%) 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 Van Gelder IC, et al. N Engl J Med 2010;Mar 15:[Epub]

43 RecordAF Registry The RecordAF Registry was established to trace the influence of the physician s choice of a rate versus rhythm control strategy for consecutive patients with first onset or recent recurrent atrial fibrillation. Real-life International, observational, prospective, longitudinal cohort study from 2007 to Evaluate management and clinical outcomes in recently diagnosed AF patients over 1 year.

44 1 st Primary Endpoint Therapeutic Success at 1 year Therapeutic Success Rhythm control n=2879 % Rate control n=2292 % p-value Therapeutic success p<0.001 Control of AF No change in strategy between baseline and 1 year No clinical outcome between baseline and 1 year

45 2 nd Primary Endpoint Clinical Outcomes at 1 year Clinical Events Rhythm control n=2879 % Rate control n=2292 % Any clinical event p- value = 0.35 CV death 1 3 Stroke or TIA 2 3 Myocardial infarction 1 1 Hospitalization or prolongation of hospitalization for arrhythmia or pro-arrhythmia 11 7 Hospitalization or prolongation of hospitalization for other CV events or interventions: 7 9 Congestive heart failure 2 5 Unstable angina 1 2 Other 4 4 Hospitalization or prolongation of hospitalization for major complications of ablative procedure 1 1 Hospitalization for CV event Yes 17 17

46 RecordAF Registry - Conclusions Rhythm control was preferred in cardiology settings (55%) AF progressed more rapidly to a permanent status at 1 year with rate control (54%) than with rhythm control (13%) Therapeutic success was achieved more frequently in patients treated by rhythm control (60% vs. 47%), driven by 81% in SR in the rhythm control group and 74% at HR target of 80 bpm at 1 year in the rate control group The high occurrence of CV clinical events was dependent on co-morbidity rather than the choice of strategy In real life, the better success of AF management with rhythm control did not translate into better outcomes These results confirm and complement results from previous controlled randomized trials

47 Antiarrhythmic Drug Therapy

48 A Trial with dronedarone to prevent Hospitalization or death in patients with Atrial fibrillation/flutter ATHENA Tested the hypothesis that dronedarone, a multichannel blocking antiarrhthymic drug would prolong time to first cardiovascular hospitalization or death in moderate- to high-risk patients with AF Prospective, multicenter placebo controlled, minimum follow-up of 1 year Unique primary endpoint: Time to first CV hospitalization or all-cause mortality Secondary endpoint All cause mortality Cardiovascular death Cardiovascular hospitalization >500 international centers 4628 patients randomized Largest antiarrhythmic drug trial in patients with AF ever conducted ClinicalTrials.gov Identifier: NCT Hohnloser SH. J Cardiovasc Electrophysiol. 2008;19: Hohnloser SH, et al. NEJM 2009;360:

49 ATHENA Primary Outcome Time to first cardiovascular hospitalization or death Cummulative Incidence (%) Patients at risk Placebo Dronedarone HR=0.76 P< Placebo Dronedarone Months Mean follow-up 21 ± 5 months Hohnloser SH, et al. NEJM 2009;360:

50 ATHENA Cardiovascular Hospitalization Cummulative Incidence (%) Patients at risk Placebo Dronedarone HR=0.75 HR=0.74 P< Placebo Dronedarone Months Mean follow-up 21 ± 5 months Hohnloser SH, et al. NEJM 2009;360:

51 ATHENA Non-fatal Outcomes Outcome Placebo (N=2327) Dronedarone (N=2301) Hazard Ratio (95% CI) P-value Primary outcome ;0.84 <0.001 First hospitalization for Cardiovascular reasons ;0.82 <0.001 Atrial fibrillation ;0.72 <0.001 Congestive heart failure ; Acute coronary syndrome ; Syncope ; Ventricular arrhythmia or non-fatal cardiac arrest ;

52 ANtiarrhythmic Trial with DROnedarone in Moderate to severe CHF Evaluating morbidity DecreAse (ANDROMEDA) Not designed as an AF trial Outcome trial in high-risk, severe HF population Stopped early Jan 2003 (n = 626/1000) - increased HF mortality dronedarone group (24 vs 10 placebo) HR, 1.38; 95% CI, All patients had recent episode of decompensated HF, all Class III or IV All had ejection fraction <.35 ClinicalTrials.gov Identifier: NCT

53 ANDROMEDA: Mortality Results at Time of DSMB Recommendation At risk PBO DRO Køber L et al. N Engl J Med Jun 19; 358(25):

54 Efficacy Trials: Adjudicated First Recurrence of AF/AFL Cumulative incidence EURIDIS Hazard ratio, 0.78 (95% CI, ) P = 0.01 Cumulative incidence ADONIS Hazard ratio, 0.73 (95% CI, ) P = Time (days) Placebo Time (days) Dronedarone 400 mg BID Copyright 2007 Massachusetts Medical Society. All rights reserved. Singh B, et al. N Engl J Med. 2007;357:

55 Outpatient Treatment of Recent-onset Atrial Fibrillation with the Pill-in-the-Pocket Approach 268 consecutive patients with recent-onset (< 48 hours) A. Fib with mean heart rate > 70/min and systolic BP > 100mmHg Patients treated in emergency room or cardiology ward Some exclusions: Preexcitation; BB block; IHD; DCM; HCM; History of HF; prev AF > 7 days duration Single oral AA drug dose: Flecainide 300mg (>70kg); 200mg (<70kg) Propafenone 600mg (>70kg); 450mg (<70kg) 58 (22%) patients excluded because of treatment failures or side effects (n=14) hypotension (n=4); symptomatic bradycardia (n=3); transient A Fl (n=7) Conclusions: In a selected, risk-stratified population of patients with recurrent atrial fibrillation, pill-in-the-pocket treatment is feasible and safe, with a high rate of compliance by patients, a low rate of adverse events, and a marked reduction in emergency room visits and hospital admissions Alboni P et al. N Engl J Med 2004; 351:

56 Treatment of Chronic AF Nonpharmacologic Alternatives Radiofrequency ablation ablation of the AV junction ablation creating linear lesions in the atria May challenge impression rate control and rhythm control are equivalent Surgical approaches the corridor procedure isolating the sinus and AV nodes from the remaining right and left atria the maze procedure dividing the left and right atria by multiple surgical incisions

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62 Complications of AF Ablation Cariac Tamponade Pulmonary Vein Stenosis Esophageal Injury/Atrio-esophageal Fistula Phrenic Nerve Injury Thromboembolism Air Embolism Post-procedural Arrhythmias Vascular Complications Acute Coronary Artery Occlusion Periesophageal Vagal Injury

63 Maintain SR in Patients with Recurrent Paroxysmal or Persistent AF Maintenance of sinus rhythm No (or minimal) Hypertension CAD HF Flecainide Propafenone Sotalol Substantial LVH No Yes Dofetilide Sotalol Amiodarone Dofetilide Amiodarone Dofetilide Catheter ablation Amiodarone Flecainide Propafenone Sotalol Catheter ablation Amiodarone Catheter ablation Amiodarone Dofetilide Catheter ablation Fuster V, et al. ACC/AHA/ESC Practice Guidelines. J Am Coll Cardiol. 2006;48:

64 Summary AF is the most common arrhythmia encountered in clinical practice It affects 1 % of the US population (2 to 5 million) Associated with older age and chronic heart disease, especially HF AF complicates management of comorbidity and vice versa Increases risk of stroke, HF, and death 71,000 patients die per year from complications of AF or atrial flutter (AFL)

65 PLEASE TAKE A MOMENT TO COMPLETE THE POST-TEST & EVALUATION

66 Cryoballoon Ablation of Pulmonary Veins for Paroxysmal Atrial Fibrillation First Results of the North American Arctic Front STOP-AF Pivotal Trial Primary Effectiveness Hypothesis: Cryoballoon ablation would have significantly greater treatment success at 12 months than drug therapy Co-Primary Safety Hypotheses Cryoablation Major AF Event (MAFE) rate would be non-inferior to drug and Cryoablation Procedure Event (CPE) rate would be < 14.8% 1º Study Outcome Measures Effectiveness: freedom from chronic treatment failure No detectable AF (non-blanked period) No use of nonstudy drugs No AF interventions Packer et al., ACC Atlanta, March 15, 2010

67 STOP AF Treatment Success By Analysis Method

68 Comparison of Antiarrhythmic Drug Therapy and Radiofrequency Catheter Ablation in Patients With Paroxysmal Atrial Fibrillation (Thermocool AF) A prospective, multicenter, randomized (2:1), unblinded, Bayesian-designed study conducted at 19 hospitals of 167 patients who did not respond to at least 1 antiarrhythmic drug and who experienced at least 3 AF episodes within 6 months before randomization. Enrollment occurred between October 25, 2004, and October 11, 2007, with the last follow-up on January 19, At the end of the 9-month effectiveness evaluation period, 66% of patients in the catheter ablation group remained free from protocol-defined treatment failure compared with 16% of patients treated with ADT. The hazard ratio of catheter ablation to ADT was 0.30 (95% confidence interval, ; P <.001). Major 30-day treatment-related adverse events occurred in 5 of 57 patients (8.8%) treated with ADT and 5 of 103 patients (4.9%) treated with catheter ablation. Mean quality of life scores improved significantly in patients treated by catheter ablation compared with ADT at 3 months; improvement was maintained during the course of the study. Wilber DJ, et al. JAMA 2010;303:

69 Kaplan-Meier Curves of Time to Protocol-Defined Treatment Failure, Recurrence of Symptomatic Atrial Arrhythmia, and Recurrence of Any Atrial Arrhythmia by Treatment Group Wilber, D. J. et al. JAMA 2010;303: Wilber, D. J. et al. JAMA 2010;303:

70 Design of the CABANA Pilot Study Inclusion Criteria ³2 paroxysmal AF episodes (³1 hour) over 4 mos or >1 persistent AF episode (>1 week) ³65 yr of age, or <65 yr with ³1 risk factors Hypertension Diabetes Heart failure Prior CVA or TIA LA size >5.0 cm (Vol In ³40 cc/m2) EF 35 % Eligible for ablation and ³2 rhythm control and/or ³3 rate control drugs CABANA Pilot Study; ACC 2010

71 QuickTime and a decompressor are needed to see this picture. CABANA Pilot Study Treatment CABANA Pilot Study; ACC 2010

72 QuickTime and a decompressor are needed to see this picture. CABANA Pilot Study Cross-Overs and Redo Therapy Drug Rx n=31 Ablation Rx n=29 30 n=8 28% n=6 21% Pt (%) n=4 13%* 0 Crossover to Abl AA Rx Re-ablation *2 failed Ic; 2 failed IIIs CABANA Pilot Study; ACC 2010