1. AFib Management and the Role of Catheter Ablation

2. Slide Kit Structure Section I. AFib Overview Section II. Clinical Management of AFib Section III. Catheter Ablation for the Treatment of AFib

3. Section I: AFib Overview

4. Atrial fibrillation Atrial fibrillation (AFib) is a common disease that causes the upper chambers of the heart (atria) to beat rapidly and in an uncontrolled manner (fibrillation). Uncoordinated, rapid beating of the atria affects the flow of blood through the heart, causing an irregular pulse and sometimes a sensation of fluttering in the chest.

5. Classification of AFib Subtypes ParoxysmalSpontaneous termination usually < 7 days and most often < 48 hours PersistentDoes not interrupt spontaneously and needs therapeutic intervention for termination (either pharmacological or electrical cardioversion) PermanentAFib in which cardioversion is attempted but unsuccessful, or successful but immediately relapses, or a form of AFib for which a decision was taken not to attempt cardioversion Levy S, et al. Europace (2003) 5: 119

6. Prevalence of AFib General population-based prevalence 0.95% Go AS, et al. JAMA (2001) 285: 2370 ATRIA study 2.5% Olmsted County study Miyasaka Y, et al. Circulation (2006) 114: 119

7. Prevalence of AFib in the General Population in USA and EU USA 2.8 million7.4 million EU 4.3 million11.4 million ATRIAOlmsted (  300 million inhabitants) (  456 million inhabitants of 25 member states)

8. Prevalence of AFib Olmsted County study Projected number of persons with AF (millions) 2000 Year 2005201020152020203020252035204020452050 0 16 14 10 6 2 12 8 5.1 15.9 15.2 14.3 13.1 11.7 10.2 8.9 7.7 5.9 6.7 4 5.1 12.1 11.7 11.1 10.3 9.4 8.4 7.5 6.8 5.6 6.1 Miyasaka Y, et al. Circulation (2006) 114: 119

9. Men 0.49 % Women0.28 % Ratio men to women = 1.86 Incidence of AFib in the General Population – Gender Differences Observational period: 20 years Olmsted County study Miyasaka Y, et al. Circulation (2006) 114: 119

10. Principal Reasons for Increasing Incidence and Prevalence of AFib 1. The population is aging rapidly, increasing the pool of people most at risk of developing AFib 2. Survival from underlying conditions closely associated with AFib, such as hypertension, coronary heart disease and heart failure, is also increasing 3. According to the Olmsted County study, the increase is also related to the increasing population 4. These figures may also be significantly under- estimated because they do not take into account asymptomatic AFib (25% of cases in Olmsted survey) Miyasaka Y, et al. Circulation (2006) 114: 119 Steinberg JS, et al. Heart (2004) 90: 239

11. General health 54 ± 2178 ± 17* Physical functioning 68 ± 2788 ± 19* Role physical 47 ± 4289 ± 28* Vitality 47 ± 2171 ± 14* Mental health 68 ± 1881 ± 11* Role emotional 65 ± 4192 ± 25* Social functioning 71 ± 2892 ± 14* Bodily pain69 ± 1977 ± 15* AFib patients (n=152) Healthy controls (n=47) SF-36 scale * p<0.001 AFib has an Impact on All Aspects of QoL SF-36 quality of life scores in AFib patients and healthy subjects Dorian P, et al. J Am Coll Cardiol (2000) 36: 1303

12. Risk Factors for AFib Diagnosed heart failure29.2% Hypertension49.3% Diabetes mellitus17.1% Previous coronary heart disease34.6% Characteristic (n=17,974) Baseline characteristics of 17,974 adults with diagnosed AFib, July 1, 1996-December 31, 1997 Go AS, et al. JAMA (2001) 285: 2370 ATRIA study

13. AFib is Responsible for 15-20% of all Strokes – AFib is responsible for a 5-fold increase in the risk of ischaemic stroke Wolf PA, et al. Stroke (1991) 22: 983 Go AS, et al. JAMA (2001) 285: 2370 Friberg J, et al. Am J Cardiol (2004) 94: 889 12 0 2 8 4 415324153 Cumulative stroke incidence (%) Women AFib+ Women AFib- Men AFib+ Men AFib- Years of follow-up

14. Increased Risk of Cardiovascular Events Stewart S, et al. Am J Med (2002) 113: 359 At least one CV event (%) AFibNo AFib 0 20 40 80 100 45 60 66 AFibNo AFib 27 89 MenWomen Death or hospitalization in individuals with CV event(s) after 20 years

15. 80 60 40 20 0 Mortality Associated with AFib 201098764153 Framingham Heart Study, n=5209 Benjamin EJ, et al. Circulation (1998) 98: 946 Follow-up (y) Mortality during follow-up (%) Men AFib+ Women AFib+ Men AFib- Women AFib-

16. Total health care expenditure (£ million) Incremental AFib Healthcare Costs UK costs for AFib in 1995 vs. 2000 Stewart S, et al. Heart (2004) 90: 286 7006005004003002001000 Cost of stroke admission  warfarin use 10%  admission 10%  community- based care Base cost of AF in 2000 Cost of heart failure admission +50% +5.1% +7.4% +5.6% +48% Base cost of associated conditions and procedures Incremental cost of AFib Other costs Base cost of AFib 1995: Direct cost of AFib in the UK between £244 and £531 million (0.6–1.2% of overall health care expenditure) 2000: £459 million direct cost – double that in 1995 (0.9–2.4% of NHS expenditure)

17. 23% 9% 8% 2% 6% 52% Hospitalizations Drugs Consultations Further investigations Paramedical procedures Loss of work Major Costs in Treatment of AFib Le Heuzey JY, et al. Am Heart J (2004) 147:121 COCAF Study

18. Cost of AFib (Europe) 4507 consecutive patients with AFib/flutter admitted to ER enrolled in FIRE study ( 1.5% of all ER admissions ) 61.9% of AFib/flutter patients were hospitalized ( 3.3% of all hospitalizations ) Mean hospital stay 7+6 days FIRE study Santini M, et al. Ital Heart J (2004) 5: 205

19. The Burden of AFib AFib is responsible for significant economic and healthcare costs – Hospitalization costs – Drug treatment – Treatment of AFib-associated co-morbidities and complications The health and economic impact will increase with the increasing prevalence and incidence of AFib AFib, owing to its epidemiology, morbidity, and mortality, represents a significant health problem with important social and economic implications that needs greater attention and allocation of more resources

20. Section II: Clinical Management of AFib

21. Restore and maintain sinus rhythm whenever possible Prevent thromboembolic events In order to: –Reduce symptoms and improve QoL –Minimize impact of AFib on cardiac performance –Reduce risk of stroke –Minimize cardiac remodelling Primary Therapeutic Aims in AFib ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation J Am Coll Cardiol (2006) 48: 854

22. Treatment Options for AFib Cardioversion Pharmacological Electrical Drugs to prevent AFib Antiarrhythmic drugs Non-antiarrhythmic drugs Drugs to control ventricular rate Drugs to reduce thromboembolic risk Non-pharmacological options Electrical devices (implantable pacemaker and defibrillator) AV node ablation and pacemaker implantation (ablate & pace) Catheter ablation Surgery (Maze, mini-Maze)

23. Recurrence Following Cardioversion: AFFIRM Study Raitt MN, et al. Am Heart J (2006) 151: 390 AFFIRM: most recurrences occur within 2 months of cardioversion Time (years) Patients with AF Recurrence (%) 0 20 40 60 80 100 0123456 Log rank statistic = 58.62 p<0.0001 Rate control:563, 3 (0)167, 383 (69)96, 440 (80)42, 472 (87)10, 481 (92)2, 484 (95) Rhythm control:729, 2 (0)344, 356 (50)250, 422 (60)143, 470 (69)73, 494 (75)18, 503 (79) N, Events (%) Rate control Rhythm control Treatment Arm

24. Patients without AFib (%) Roy D, et al. N Engl J Med (2000) 342: 913 Amiodarone to Prevent Recurrence of AFib Follow-up (days) 0100200300400500600 p<0.001 Sotalol Propafenone Amiodarone 0 20 40 60 80 100 CTAF Study: mean follow-up 16 months

25. Even with the most effective AAD, such as amiodarone, long-term efficacy is low ~50% or less at 1 year Effectiveness of Current AADs

26. SurgeryElectrophysiologicalDevices Pacemaker (single or dual chamber) Internal atrial defibrillators Catheter ablation AV node ablation Non-Pharmacological Treatment Options for AFib Maze procedure Modified Maze (mini-Maze) ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation J Am Coll Cardiol (2006) 48: 854 Pacemakers not curative and must be worn for life Surgical procedures may be effective but are not a practical solution for the millions of sufferers of AFib Catheter ablation is potentially curative

27. Management of AFib - Summary Current antiarrhythmic drug therapies are not highly effective in maintaining sinus rhythm and generally have poor outcomes – high recurrence rates – adverse effects and high discontinuation rate A potentially curative therapy for AFib is desirable

28. Section III: Catheter Ablation for the Treatment of AFib

29. Catheter Ablation Uses a series of long, thin wires (catheters) that are inserted through an artery or a vein and then guided through to the heart. One of the catheters is then used to localise the source of the abnormal electrical signals and another then delivers high energy waves that neutralise (ablate) abnormal areas. Using catheters to reach the heart is a common approach to treat a range of heart conditions and is much less invasive than surgical treatments.

30. Maze reproduction Schwarz 1994 Right atrial linear lesions Haïssaguerre 1994 Right and left atrial linear lesions Haïssaguerre 1996 PV foci ablation Jaïs / Haïssaguerre 1997/8 Ostial PV isolation Haïssaguerre 2000 Circumferential PV ablation Pappone 2000 Ablation of non-PV foci Lin 2003 Antral PV ablation Maroucche / Natale 2004 Double Lasso technique Ouyang / Kuck 2004 CFAE sites ablation Nademanee 2004 Ostial or circumferential or antral PV ablation plus extra lines (mitral isthmus, posterior wall, roof) Jaïs / Hocini 2004/5 Circumferential PV ablation with vagal denervation Pappone 2004 TechniquePublication date Landmarks in Catheter Ablation Techniques

31. 1998: Ablation of PV Foci Pivotal study identifying the pulmonary veins as a major source of ectopic electrical activity Radiofrequency ablation of ectopic foci was associated with a 62% success rate (absence of recurrence at 8  6m follow-up) Spontaneous Initiation of Atrial Fibrillation by Ectopic Beats Originating in the Pulmonary Veins Haïssaguerre, M, Jaïs, P, Shah, DC, et al. N Engl J Med (1998) 339: 659

32. Trigger - Ectopic Foci PV & non-PV Foci Ablation, PV Isolation Autonomic Nervous System AFib CFAEs Ablation Linear Lesions (e.g. mitral isthmus, roof) Substrate - Atrial tissue A Combination of Techniques may now be used Depending on the Type of AFib Vagal Denervation (parasympathetic ganglia ablation)

33. Cardiac Imaging Techniques Electroanatomical mapping – C ARTO ™ / C ARTO M ERGE ™ Fluoroscopy Angiography Intracardiac echography Cardiac spiral CT Cardiac MRI

34. C ARTO ™ System 3D-electroanatomic maps (C ARTO ™) showing ablation points encircling PVs – Localization of catheter to within 1 mm – Increase safety margin during ablation

35. LLPV LUPV RUPV RLPV RMPV AC LA PV Antrum Isolation Guided by C ARTO M ERGE ™ Image Integration Software Module Courtesy of Professor Antonio Raviele, Mestre, Italy

36. Catheter Visualization under Fluoroscopic Guidance L ASSO ® Ablation catheter LAO RAO

37. Efficacy and Safety of Catheter Ablation

38. Linear44375%26%33%55% Focal50881%35%54%71% Isolation2,18783%36%62%75% Circumferential (all) 15,45568%37%64%74% Circumferential (LACA, WACA) 2,44965%37%59%72% Circumferential (PVAI) 11,13268%42%67%76% Substrate ablation (CFAE) 55951%49%75%87% TOTAL23,62661%55%63%75% Patients Paroxysmal AF 6-month cure 6-months OK Ablation method SHD Fisher JD, et al. PACE (2006) 29: 523 Meta-analysis of Catheter Ablation Cure (by each author’s criteria) means no further AFib 6 months after the procedure in the absence of AAD. OK means improvement (fewer episodes, no episodes with previously ineffective AAD). SHD indicates structural heart disease.

39. Worldwide Survey on Efficacy and Safety of Catheter Ablation for AFib Total success rate: 76% Of 8745 patients: – 27.3% required 1 procedure – 52.0% asymptomatic without drugs – 23.9% asymptomatic with an AAD within <1 yr Outcome may vary between centres Cappato R, et al. Circulation (2005) 111: 1100

40. Improved Survival with Ablation vs Drug Treatment Pappone C, et al. J Am Coll Cardiol (2003) 42: 185 Days of follow-up 100 0 80 60 1080 Ablation Group Medical Group 90 70 0180360540900720 One-sample log-rank test Obs=36, Exp=31, Z=0.597, p=0.55 10800180360540900720 One-sample log-rank test Obs=79, Exp=341, Z=7.07, p<0.001 Survival probability (%) Expected Observed 589 ablated patients compared with 582 on AADs

41. More AFib-free Patients with Catheter Ablation vs Drug Treatment Pappone C, et al. J Am Coll Cardiol (2003) 42: 185 AFib-free survival probability (%) Ablation Medical No. at risk 0 100 80 60 40 20 Follow-up (days) 282135217 20797141 0300200100 589479507 582354456 379 277 Ablation Group Medical Group

42. Randomised Clinical Trials of Catheter Ablation RF ablation vs AAD as first-line treatment for AFib Wazni OM et al. JAMA (2005) 293: 2634-2640 Catheter ablation in drug-refractory AFib Stabile G et al. Eur Heart J (2006) 27: 216-221 Circumferential PV ablation for chronic AFib Oral H et al. N Engl J Med (2006) 354: 934-941

43. Wazni OM, et al. JAMA (2005) 293: 2634 AFib.free survival 0 1.0 0.8 0.6 0.4 0.2 Follow-up (days) 0300200100 PVI Group Antiarrhythmic Drug Group Patients randomised to receive ablation (n=33) or AADs (n=37): AFib-free Survival RF Ablation vs Antiarrhythmic Drugs as First-line Therapy

44. Catheter Ablation vs. AADs Alone in Drug-refractory AFib Stabile G, et al. Eur Heart J (2006) 27: 216 AFib-free survival (%) 0 100 80 60 40 20 Months 0129511108764321 Ablation Group Medical Group AADs plus ablation (n=68) or AADs alone (n=69): 1 year follow-up

45. Randomized Controlled Trial of Amiodarone + Cardioversion + Catheter Ablation Oral H, et al. N Engl J Med (2006) 354: 9 Sinus rhythm (%) 12 0 20 60 100 80 40 Months 1110987654321 Circumferential pulmonary-vein ablation Control Amiodarone & cardioversion (n=69) vs. amiodarone & cardioversion plus PV ablation (n=77)

46. Catheter Ablation is Successful in the Long Term Oral H, et al. J Am Coll Cardiol (2002) 40: 100 1.0 0.8 0.4 0 012108642 Months after PV isolation Freedom from Recurrent AFib 0.6 0.2 No ERAF ERAF

47. Transient ischaemic attack40.40 - 3 Permanent stroke10.10 - 1 Severe PV stenosis (>70%, symptomatic) 30.30 - 3 Moderate PV stenosis (40-70%, asymptomatic) 131.30 - 5 Tamponade / perforation50.50 - 3 Severe vascular access complication 30.30 - 4 Events (n) Range in studies (%) Rate (%) Complication Complications Reported by Leading Centres Major complications with pulmonary vein ablation in 1039 patients (6 series) Verma A & Natale A Circulation (2005) 112: 1214

48. Cost Effectiveness Analyses of Catheter Ablation

49. 118 patients with symptomatic, drug-refractory AFib 32 weeks 1.52 ± 0.71 ablation procedures Catheter ablationPharmacological treatment Catheter Ablation May Be More Cost- effective than Pharmacological Therapy Weerasooriya R, et al. Pacing Clin Electrophysiol (2003) 26: 292 €4715 followed by €445/year €1590/year After 5 years, the cost of RF ablation was below that of medical management and further diverged thereafter

50. Clinical visits per year7.4 (2.5)1.1 (0.6) Emergency room visits per year1.7 (0.9)0.03 (0.17) Hospitalization days per year1.6 (0.8)0 (0) Healthcare costs per year$1920 (889)$87 (68) No ablationCatheter ablation Differences in Hospital Visits and Costs with and without Catheter Ablation Goldberg A, et al. J Interv Card Electrophysiol (2003) 8: 59 Although the initial cost of ablation is high, after ablation, utilization of healthcare resources is significantly reduced

51. Catheter Ablation Cost-Effective in Patients at High Risk of Stroke Chan DP, et al. J Am Coll Cardiol (2006) 47: 2513 Model to compare the cost-effectiveness of left atrial catheter ablation (LACA), amiodarone, and rate control therapy in the management of AFib The use of LACA may be cost-effective in patients with AFib at moderate risk for stroke This model did not find it to be cost-effective in low-risk patients. Conclusions Cost-effective in patients at moderate or high risk of stroke

52. Current Guidelines and Summary

53. Current ACC/AHA/ESC Guidelines Recurrent Paroxysmal AF Minimal or no symptoms Disabling symptoms in AF Anticoagulation and rate control as needed No drug for prevention of AF AAD therapy AF ablation if AAD treatment fails ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation J Am Coll Cardiol (2006) 48: 854

54. Recent Commentary Verma A & Natale A Circulation (2005) 112: 1214 “Current therapies, especially AAM, not only are ineffective but also pose a threat to patient QoL and even longevity. In the hands of experienced operators, AF ablation is an effective, safe, and established treatment for AF that offers an excellent chance for a lasting cure … unlike other therapies, ablation tackles AF at its electrophysiological origin.” Why Ablation for AFib might be Considered First- Line Therapy for Some Patients

55. Summary of catheter ablation (I) Catheter ablation for AFib has undergone significant methodological and technical revolution since its initial appearance two decades ago Discovery that PVs are a major source of ectopic triggers was pivotal in determining efficacy of procedure Significant technological advances in catheters and imaging are further improving the efficiency of catheter ablation 3D reconstructions of actual left atrial PV anatomy using CT, MRI, or intracardiac echography enables ever more accurate placement of lesions

56. Summary of catheter ablation High success rate Improves survival, cardiac function and freedom from recurrence New data from RCTs confirm benefits Safe, with a risk comparable to other low-risk, routine interventions Cost effective compared to standard pharmacological therapy, at least in patients at moderate thromboembolic risk