1. John D. Hummel, MD Ohio State University Medical Center Ross Heart Hospital Columbus, Ohio Management of Atrial Fibrillation in 2010

2. Learning Objectives Understand the risk factors for atrial fibrillation. Understand the guidelines for anticoagulation and where there is latitude for physician decision making. Be able to determine when patients should be evaluated for curative ablation.

3. Atrial Fibrillation Easily recognized. Seems to bother healthcare workers as much as patients. Who’s Problem? Internists cardiologists EP.

4. Go A, et al. JAMA. 2001;285:2370-2375. Projected Number of Adults With AF in the US: 1995 to 2050.

5. Atrial Fibrillation: Costs to the Health Care System 35% of arrhythmia hospitalizations Average hospital stay = 5 days Mean cost of hospitalization = $18,800 Does not include: Costs of outpatient cardioversions Costs of drugs/side effects/monitoring Costs of AF-induced strokes Estimated US cost burden 15.7 billion ALOT!!

6. Paroxysmal (Self-terminating) First Detected Permanent Classification of Atrial Fibrillation ACC/AHA/ESC Guidelines Persistent (Not self-terminating)

7. DIAGNOSTIC WORKUP Identify Causes and Risk Factors Minimum Evaluation History and physical – BP, CV dz Electrocardiogram – WPW, LVH, MI Echocardiogram – LVH, LAE, EF, Valve Dz Labs – TSH, Renal fxn, LFTs (Clearance,ETOH) [D-dimer, ESR] Additional Testing ETT – CAD, Exercise induced SVT / AF Holter / Event Monitor – Confirm AF and Sxs TEE – LA clot [CXR] EPS – SVT triggered AF AHA / ACC / ECS Guidelines 2006

8. 20 – 15 – 10 – 5 – 0 – Years Cumulative Frequency of AF (%) OSA Gami, et al. JACC 2007;49:565-71 Cumulative frequency curves for incident atrial fibrillation (AF) for subjects < 65 years of age with and without obstructive sleep apnea (OSA) during an average 4.7 years of follow-up. p = 0.002 0123456789101112131415 Number at Risk OSA No OSA 844 2,209 709 1,902 569 1,616 478 1,317 397 1,037 333 848 273 641 214 502 173 393 134 296 110 217 94 195 70 130 46 94 29 69 8 28 Incidence of AF Based on Presence or Absence of OSA No OSA

9. Goals of Therapy 1.Relieve symptoms 2.Prevent Stroke 3.Prevent Heart Failure

10. Maintenance of SR Pharmacologic Stroke prevention Nonpharmacologic Class IA Class IC Class III  -blocker Catheter ablation Surgery (MAZE) Pacing Pharmacologic Warfarin Thrombin inhibitor Heparin Aspirin Nonpharmacologic Removal / isolation LA appendage Rate control Pharmacologic Ca 2+ blockers  -blockers Digitalis Amiodarone Nonpharmacologic Ablate and pace Prevent remodeling ACE-I ARB AF: TREATMENT OPTIONS Adapted from Prystowsky, Am J Cardiol. 2000;85:3D-11D.

11. Risk Factors for Thromboembolism in AF High-Risk FactorsRecommended Therapy Previous CVA / TIA / EmbolismHigh-risk factor or > 2 Mitral Stenosismoderate-risk factors Prosthetic heart valveCoumadin INR 2-3 Moderate-Risk Factors(mechanical valve INR > 2.5) Age > 75 yrs HTN1 moderate-risk factor CHFASA or Coumadin DM EF < 35%No risk factors Weaker-Risk FactorsASA 81-325mg daily Female CAD Thyrotoxicosis Age 65 – 74 yrs AHA / ACC / ECS Guidelines 2006

12. D-Dimer Prediction of Risk Evaluate whether elevated D-dimer levels can predict thromboembolic and cardiovascular events in patients with atrial fibrillation during oral anticoagulant therapy. Single-center, prospective, study of 269 pts with atrial fibrillation treated with warfarin D-dimer levels were measured End points were thromboembolic events and combined cardiovascular events (thromboembolic events, cerebral hemorrhage, myocardial infarction, cardiovascular death). RESULTS: D-dimer levels were elevated (> or =0.5 microg/ml) in 63 (23%) patients. During an average follow-up period of 756 +/- 221 days: 1. 10 (1.8%/year) thromboembolic events (8 ischemic strokes, 1 transient ischemic attack, and 1 peripheral embolism 2. 27 (4.8%/year) combined cardiovascular events (10 thromboembolisms, 9 deaths from heart failure, 3 sudden deaths, 2 myocardial infarctions, and 3 cerebral hemorrhages) Patients with elevated D-dimer levels experienced higher thromboembolic and combined cardiovascular events. Sadanaga T, et. AL; J Am Coll Cardiol. 2010 May 18;55(20):2225-3.

13. Dabigatran vs. Warfarin Noninferiority trial randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive: 1. Fixed doses of dabigatran — 110 mg or 150 mg twice daily in a blinded fashion 2. Adjusted-dose warfarin in an unblinded fashion The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. Results Primary outcome 1.69% per year in the warfarin group 1.53% per year in the group that received 110 mg of dabigatran (P<0.001 for noninferiority) 1.11% per year in the group that received 150 mg of dabigatran ( P<0.001 for superiority) Major bleeding 3.36% per year in the warfarin group 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). Hemorrhagic stroke 0.38% per year in the warfarin group 0.12% per year with 110 mg of dabigatran (P<0.001) 0.10% per year with 150 mg of dabigatran (P<0.001). Mortality rate 4.13% per year in the warfarin group 3.75% per year with 110 mg of dabigatran (P=0.13) 3.64% per year with 150 mg of dabigatran (P=0.051). Conclusions Dabigatran 110 mg had rates of stroke and systemic embolism similar to warfarin with less major hemorrhage. Dabigatran 150 mg had lower rates of stroke and systemic embolism but similar rates of major hemorrhage. Stuart J. Connolly and the RE-LY Steering Committee and Investigators NEJM Sept 17, 2009, No. 12, Vol 361: 1139-1151

14. AF THERAPY ANTITHROMBOTIC RX RHYTHM CONTROL RATE CONTROL OR ? AND

15. The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833. AFFIRM Trial: Rate vs Rhythm Control Management Strategy Trial Design –5-year, randomized, parallel-group study comparing rate control vs. AARx attempt at NSR –Primary endpoint: overall mortality Patient population –4060 patients with AF and risk factors for stroke –Minimal symptoms –Mean Age = 69 yo –Hx of hypertension: 70.8% –CAD: 38.2% –Enlarged LA: 64.7% –Depressed EF: 26.0%

16. AFFIRM: All-Cause Mortality Rate N: Rhythm N: 2027 2033 1925 1932 1825 1807 1328 1316 774 780 236 255 0 5 10 15 20 25 30 01 2 3 4 5 Mortality, % Rate Rhythm p=0.078 unadjusted Time (years) p=0.068 adjusted The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

17. RateRhythm Ischemic stroke 77 (5.5%)* 80 (7.1%)* INR < 2.027 (35%)17 (21%) Not taking warfarin 25 (32%)44 (55%) * p=0.79 The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833. AFFIRM: Adverse Events

18. 100 – 80 – 60 – 40 – 20 – 0 – Time (years) Percent With AF Recurrence Rate Control Raitt, et al. Am H J 2006 0123456 N, Events (%) Rate control: Rhythm control: 563, 3 (0) 729, 2 (0) 167, 383 (69) 344, 356 (50) 98, 440 (80) 250, 422 (60) 42, 472 (87) 143, 470 (69) 10, 481 (92) 73, 494 (75) 2, 484 (95) 18, 503 (79) Time to first recurrence of AF. Time 0 is the day of randomization Rhythm Control Log rank statistic = 58.62 p < 0.0001

19. Implications AFFIRM has demonstrated that rate control is an acceptable primary therapy in a selected high-risk subgroup of AF patients with minimal symptoms Continuous anticoagulation seems warranted in all patients with risk factors for stroke –Asymptomatic recurrences

20. Atrial fibrillation: Why Control Rate? Rate control – the problem: Increased rates – more symptomatic, greater hemodynamic impact. Persistent increased rates – tachycardia induced cardiomyopathy Rate control – the goal: PAF – control symptomatic tachycardia Chronic afib – mean 24hr HR < 80-90 bpm (?)

21. RACE II Hypothesis: Lenient rate control is not inferior to strict rate control for preventing cardiovascular morbidity and mortality in pts with permanent AFib Randomly assigned 614 patients with permanent AF to: –lenient rate-control strategy (resting heart rate <110 beats per minute) –strict rate-control strategy (resting heart rate <80 beats per minute and heart rate during moderate exercise <110 beats per minute). Primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. The duration of follow-up was at least 2 years, with a maximum of 3 years. Results: Primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group. (90% confidence interval, –7.6 to 3.5; P<0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets 97.7% vs. 67.0% in the strict-control group; P<0.001 with fewer total visits (75 vs. 684]; P<0.001). The frequencies of symptoms and adverse events were similar in the two groups. Conclusions: In patients with permanent atrial fibrillation, lenient rate control is as effective as strict rate control and is easier to achieve. Van Gelder, et.al, for the RACE II Investigators NEJM April 15, 2010, No. 15, Vol 362: 1363-1373

22. Atrial fibrillation Rate control – Drug Therapy: Digoxin – controls resting rate, OK in CHF patients. Beta, Ca+2 blockers – controls resting and exercise rates. Best therapy – combination of beta blocker and digoxin. Even in the best of circumstances pacing support is sometimes required Goal: Chronic afib – mean 24hr HR < 80-90 bpm (?)

23. Rate control plus anticoagulation preferred Rhythm control preferred No or lesser AF symptoms Longer AF Hx More SHD Toxicity Risk Elderly Greater risk of proarrhythmia Greater AF symptoms Symptoms despite rate control Younger age No or lesser SHD Rx option of class IC AAD In anticoagulation candidates, continue anticoagulation indefinitely APPROACHES TO AF THERAPY

24. Atrial Fibrillation Duration of AF is the best predictor of recurrent AF after cardioversion Dittrich HC. Am J Cardiol. 1989;63:193-197. < 3 Months 3 - 12 Months > 12 Months 100 80 60 40 20 0 Initial One month post-CV Six months post-CV *P = <0.02 Patients in sinus rhythm (%) Length of time in AF prior to cardioversion *

25. Class IA Quinidine Procainamide Disopyramide Class IC Propafenone Propafenone SR Flecainide Class III Sotalol Amiodarone Dofetilide Miller and Zipes. In: Braunwald, et al (eds). Heart Disease. 6th ed. 2001. Procainamide, disopyramide, and amiodarone are not FDA-approved for treatment of AF. Rhythm Control for AF: Commonly Used Oral Antiarrhythmic Drugs

26. AF Efficacy: Maintaining NSR > 6 Months

27. ORGAN TOXICITY Examples: –Lupus, agranulocytosis, thrombocytopenia, optic neuritis, pulmonary fibrosis, hepatitis, etc. Negligible: –Dofetilide, flecainide, propafenone, sotalol, dronedarone Acceptable: –Azimilide, disopyramide High: –Amiodarone, procainamide, quinidine

28. Drug-Induced Proarrhythmia - Torsades

29. Factors Which Influence Ventricular Proarrhythmia Risk Hypokalemia, hypomagnesemia Long QT at baseline CHF / Decreased EF / Ventricular hypertrophy Bradycardia Female gender Reduced drug metabolism or clearance Amiodarone and Dronedarone has lowest risk (drondedarone cannot be started if baseline QTc>/=500)

30. AARx Choice Heart diseaseAntiarrhythmic NoneIC or Dronedarone Vagal afibDisopyramide HTNIC (if no sig. LVH) then dronedarone CADSotalol CHF/SubstantialAmiodarone LVH

31. Prevention of atrial fibrillation by Renin- Angiotensin system inhibition Schneider MP, et. Al. J Am Coll Cardiol. 2010 May 25;55(21):2299-307 Meta analysis of published clinical trial data on the effects of renin-angiotensin system (RAS) inhibition for the prevention of atrial fibrillation A total of 23 randomized controlled trials with 87,048 patients were analyzed. In primary prevention: 6 trials in hypertension, 2 trials in myocardial infarction, and 3 trials in heart failure were included. In secondary prevention: 8 trials after cardioversion and 4 trials assessing the medical prevention of recurrence were included. Overall, RAS inhibition reduced the odds ratio for AF by 33% (p < 0.00001), but there was substantial heterogeneity among trials. In primary prevention: RAS inhibition was effective in patients with heart failure and those with hypertension and left ventricular hypertrophy but not in post-myocardial infarction patients overall. In secondary prevention: RAS inhibition was often administered in addition to antiarrhythmic drugs, including amiodarone, further reducing the odds for AF recurrence after cardioversion by 45% (p = 0.01) and in patients on medical therapy by 63% (p <0.00001). RAS inhibition is an emerging treatment for the primary and secondary prevention of AF

32. Alternatives to Drug therapy “Non-Pharmacologic Therapy”  Coumadin – LAA closure (Watchman)  Rate Control – AVN RFA + PCMK  AARx – Adjunctive AFL RFA  AARX – Curative Afib RFA

33. WATCHMAN ® LAA Filter System

34. Complete AVN ablation

35. Pacemaker Placement

36. AVN RF ablation

37. Objective Benefits of AV nodal Ablation Rodriguez LM. Am J Cardiol. 1993;72:1137-1141. A Left ventricular ejection fraction (%) B Left ventricular end systolic diameter (mm) 70 60 50 40 30 20 BeforeAfter LVEF (%) mean 54 + 7 p < 0.001 mean 43 + 8 55 50 45 35 30 20 BeforeAfter LVESD (mm) mean 34 + 5 p < 0.003 mean 40 + 5 40 25

38. Complete AVN Ablation Advantages: 100% efficacy 85% symptomatic improvement Improved EF (LV remodeling) Eliminates need for rate control drugs Disadvantages: Pacemaker dependant Good Candidates: Tachy / Brady Syndrome PCMK in Place – CHF with BiV device Medication refractory / intolerant Elderly

39. 60 F with PAF treated with Rythmol Presented with recurrent tachycardia

40. Atrial Flutter Circuit

42. Atrial Flutter Ablation

43. Atrial Flutter RFA

44. Atrial Flutter Ablation Approximately 15% of AF patients treated with an AA will develop AFL Advantages: 95% efficacy ≈ 80% arrhythmia control if AARx continued As primary Rx: RFA more effective than AARx Disadvantages: Invasive Good Candidates: Typical AFL (IVC / TV isthmus) Primary AFL or AARx related AFL

45. Focal Origin of Atrial Fibrillation Hassaiguerre M, NEJM, 1998 94% of AF triggers from Pulmonary Veins “90 – 95% of all AF is initiated by PV ectopy” RALA CS FO SVC IVC Pulmonary Veins 17 31 611

46. 74 yo medically refractory AF, Echo – Normal AA Rx - Verapamil, Rythmol, Betapace, Norpace I II III V1 RSPV dist RSPV prox LIPV RA *

47. Lasso Catheter

48. Circular Mapping & Ablation Catheter in Right Superior Pulmonary Vein

49. Atrial Fibrillation Ablation Atrial Shell and Cardiac MRI

50. 45 yo F with medically refractory Highly Symptomatic PAF

51. 45 yo F with Medically Refractory PAF CT Scan / Carto Images – PA View

52. 45 yo with PAF Conversion of AF to NSR, LSPV with AF Lasso LSPV CS Abl

53. Current State of Curative Catheter-Based RFA Procedural Success & Complications Total Patients > 1300 (65% PAF) Expected success @ 1yr –≈ 70% after first procedure –≈ 80% after second procedure Complications ≈ 1 to 3% –Tamponade – 0.6% –Pulmonary vein stenosis – 0.6% –TIA / CVA – 0.5% –Esophageal-LA fistula - 0 –Groin Bleeding / Hematoma (Last 200 pts complications < 1%)

54. Atrial Fibrillation: Ablation vs Drug Rx. Ablation 80% success PV stenosis AE fistula TIA/CVA Drug Rx. 50% success Proarrhythmia End Organ Toxicity No Free Lunch PV stenosis AE fistula Torsades

55. Current State of Curative Catheter-Based RFA Who is a good candidate? Symptomatic / Frequent AF Limited Heart Dz EF > 35% LA < 5.5cm No MS / Rheumatic Dz Younger Patients No LA thrombus or Hx of CVA Medically Refractory / Intolerant (Ablation now second line therapy)

56. Atrial Fibrillation New Technology Coming Your Patients Way at Ohio State University Stereotaxis – Magnetic Catheter Navigation Ablation Frontiers Cryoablation Balloon Endosense

57. A-Fib vs. EP Labs

58. AF TREATMENT GOALS AF is rarely life-threatening and is typically recurrent Treatment goals in symptomatic pts –  frequency of recurrences –  duration of recurrences –  severity of recurrences Minimize risk of tachycardia induced cardiomyopathy Safety is primary concern