Long-Term Outcome and Risks of Catheter Ablation for Atrial Fibrillation Carlo Pappone, MD, PhD, FACC EP Director, Villa Maria Hospital Group
How many times AF can increase mortality DO MORTALITY REALLY EXIST? 7 2,5 2 1,9 JACC 2006
AADS DO THEY WORK? Conversion: variable efficacy and safety in restoring SR AFib prophylaxis: at 1 year 50% of patients will remain sinus Safety: 2-6% at mid-to-long term Source: Revised Guidelines for AFib 2006 AHA/ESC/ACC/Hrbook
PIAF, RACE, STAF, AFFIRM, HOT CAFE Mortality equivalent or even worse with AAD Source: Revised Guidelines for AFib 2006 AHA/ESC/ACC/HR
RHYTHM VS. RATE ( 02) ABLATION VS. AAD ( 03)
2003 ABLATION? INVESTIGATIONAL
2010 WHAT IS CHANGED?
ATRIAL FIBRILLATION THE COMMON RATIONALE
BENEFIT OF THE INTERVENTION No. Pts F/u (mo.) Efficacy PAPPONE ablation drugs 12 12 87% 22% NATALE ablation drugs 12 12 87% 56% ablation drugs 12 12 64% 26% ablation drugs 12 12 89% 23% 1 2 FDA study 3 JAIS4 1 JACC 2006; 2 JAMA 2005; 3 submitted; 4 Circulation 2008
THE APAF STUDY JACC 2006
198 patients enrolled Randomization CPVA N=99 CPVA-F CPVA-A ADT N=99 CPVA-S Flecainide Amiodarone 1 month run-in phase after AAD start CARTO NavX CPVA 8 mm tip 4 mm cool tip Blanking period Follow-up Continuing AAD 1 month 12 months Sotalol
PATIENT CHARACTERISTICS CPVA (99) Control Group (99) P Age 55 ± 10 57 ± 10 0.24 Gender (M/F) 69 / 30 64 / 35 0.54 AF episode/year 52 ± 84 30 ± 56 0.05 Duration of AF (years) 6±4 6±6 0.81 LA diameter (mm) 40 ± 6 38 ± 6 0.25 Diabetes 5.1% 4% 1.00 Hypercholesterolemia 17% 21% 0.59 Hypertension 56% 57% 1.00 60 ± 8 61 ± 6 0.49 2% 3% 2% 2% 1% 1% 0.22 No of previously ineffective AADs 2±1 2±1 0.63 No of prior cardioversions 2 ±1 2±1 0.87 LV EF Structural heart disease Coronary artery disease Valvular heart disease Congenital heart disease THE APAF TRIAL
APAF - OUTCOMES
THE FIRST FDA STUDY MULTICENTER, RANDOMIZED Wilber, Pappone, submitted
THE FIRST FDA STUDY: CPVA VS. AAD AF Freedom Wilber, Pappone, submitted
43% REDO RATE 89% VS 23% Circulation, 2005
CPVA ON THE TOP OF AAD 66% vs. 9% 137 patients randomized to ablation and AAD (ablation group) AAD alone (control group)
UNMET NEEDS Short-term results of the APAF, CACAF, A4 and FDA studies suggest that AF ablation strategy warrants consideration in selected patients in whom ADT has already failed and maintenance of SR is desired. However, before translating the results of this study into clinical practice, longer follow-up studies are required.
THE APAF 2 STUDY 3-YEAR EXTENSION STUDY PRESENTED AT THE 2009 AHA SCIENTIFIC SESSIONS
APAF 2 - OBJECTIVE APAF2 is an extension study to evaluate long-term outcome of catheter ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation.
APAF 2 - METHODS APAF 2 study: After completion of 1-year follow-up period, patients were offered participation in a 3-year continuation phase and the follow-up was extended to June 2009.
APAF 2 METHODS Minimum follow-up 4 years Follow-up visits at 12, 18, 24, 30 and 36 months after randomization At each visit, 12-lead electrocardiogram (ECG), 48-h Holter monitoring, and transthoracic echocardiography Patients were provided with an event monitor to record their rhythm twice a week and whenever they experienced symptoms suggestive of AF
APAF 2 - ENDPOINTS Primary endpoint AF/AT freedom after a single procedure off AADs at 4y Secondary endpoints: Redo procedures Crossover AF progression Late complications QoL (SF-36)
STUDY FLOW Screened patients (n = 334) Inclusion criteria not met (n = 136) Enrolled patients with paroxysmal AF (n = 198) Randomization CPVA (n = 99) Recurrent AT/AF (n = 4) 2 after index and >1 AAD 2 after redo CPVA and >1 AAD Persistent/permanent AF (n = 1) After redo CPVA and 1 AAD trial Pappone, APAF 2 3 year Sinus rhythm (n = 95) 77 after index CPVA 18 after redo CPVA ADT (n = 99) Sinus rhythm (n = 62) 11 after 1 AAD 01 after >1 AAD 50 after switch to CPVA 11/26 of unablated patients progressed to chronic AF (42%) Recurrent AT/AF (n = 37) 26 after >1 AAD 11 after switch to CPVA 17 persistent AF after >1 AAD 11 permanent AF after >1 AAD
CPVA ARM CPVA (n = 99) Recurrent AT/AF (n = 4) 2 after index and >1 AAD 2 after redo CPVA and >1 AAD Persistent/permanent AF (n = 1) After redo CPVA and 1 AAD trial Sinus rhythm (n = 95) 77 after index CPVA 18 after redo CPVA
ADT ARM ADT (n = 99) Sinus rhythm (n = 62) 11 after 1 AAD 01 after >1 AAD 50 after switch to CPVA Recurrent AT/AF (n = 37) 26 after >1 AAD 11 after switch to CPVA 17 persistent AF after >1 AAD 11 permanent AF after >1 AAD
PRIMARY ENDPOINT 72% VS 12%
LONG-TERM ABLATION SUPERIORITY 1.0 log-rank p<0.001 Proportion of AF-free patients 0.9 CPVA 0.8 0.7 0.6 0.5 0.4 0.3 0.2 ADT 0.1 1y 0 0 3 6 9 2y 12 15 18 21 3y 24 Months of Follow-up 27 30 33 36
NEED FOR CROSS OVER DURING F/U The need for crossover increased over f/u
RESULTS AFTER CROSS OVER Crossover strikingly works on ADT failure
BASELINE CLINICAL CHARACTERISTICS OF CROSSOVER AND NON CROSSOVER PATIENTS No Crossover Crossover LA dilation and frequent AF predict ADT failure and need for ablation
COMPARISON OF CROSSOVER PATIENTS WITH AND WITHOUT AT/AF RECURRENCE LA dilation and frequent AF predict CPVA failure after cross over
APAF 2 PROGRESSION TO PERSISTENT & PERMANENT AF Persistent AF Ablation halt AF natural history to progress Permanent AF
PROGRESSION TO PERSISTENT AF Progression to persistent AF occurred in 17 ADT patients (mean age 54±10, 14 males) and just in one CPVA patient (59 y). Echo data ADT patients showed a marked increase in LA diameters (from 34 to 50 mm and from 38 to 47 ml, p<0.001). E/A ratio increased from 1.25 to 1.7 (p<0.001) LVEF remained unchanged (61% to 59%, p=0.26)
PROGRESSION TO PERMANENT AF Persistent AF became permanent AF in 11 of the 17 ADT patients (55 years, 8 males) after 2 AAD trials including amiodarone and multiple unsuccessful electrical cardioversions Echo data LA diameters (from 33.0±4.4 to 51.9±3.65 mm; p<0.001) LA volumes (from 39 to 48 ml, p<0.001) LVEF remained unchanged (61% to 60%, p=0.28)
APAF 2 AF PROGRESSION The only patient in the CPVA group who progressed to persistent and then to permanent AF was a 59-year old man with previous myocardial infarction and metabolic syndrome Echo data: LA diameter (from 59 to 65 mm) EF 40% remained unchanged
APAF 2 SILENT AF RECURRENCES Silent AF recurrences occurred in many patients on long-term ADT and only in a minority of those who underwent catheter ablation (40% vs 5%)
APAF 2 LATE COMPLICATIONS CPVA No late complications were observed either after index/redo procedures or crossover to ablation ADT 33 patients experienced serious intolerable adverse events requiring crossover to ablation Severe bradycardia (12 pts) Amiodarone-induced thyroid dysfunction (15 patients) Amiodarone-induced acute hepatitis (1 pt) Hypotensive wide QRS tachycardia (5 patients) after flecainide and amiodarone.
APAF 2 HOSPITALIZATIONS CPVA Hospitalization (2 patients) after an unsuccessful redo procedure for cardioversion ADT Multiple hospitalizations for recurrent paroxysmal (35 patients) or persistent AF (17 patients) for cardioversion and for an acute pulmonary edema (4 patients with persistent AF, diabetes and hypertension).
APAF 2 QUALITY OF LIFE BASELINE RFA (n=99) AADs (n=99) Physical functioning 68 (68-68) 75 (62-75) Role physical 65 (62-75) Bodily pain FOLLOW-UP p-value RFA (n=99) AADs (n=99) p-value 0.006 80 (75-80)* 62 (50-70)* <0.001 75 (62-75) 0.261 78 (75-80)* 62 (50-75)* <0.001 70 (70-75) 75 (62-75) 0.005 80 (75-80)* 50 (50-75)* <0.001 General health 62 (50-75) 70 (50-75) 0.126 80 (75-80)* 62 (50-75)** <0.001 Vitality 75 (75-75) 75 (70-75) 0.568 75 (75-80)* 75 (50-75)* <0.001 Social Functioning 60 (55-60) 60 (59-65) 0.034 75 (75-75)* 50 (50-75) <0.001 Role emotional 75 (75-75) 75 (75-75) 0.454 75 (75-80)* 62 (50-75)* <0.001 Mental health 63 (63-63) 62 (50-75) 0.063 80 (75-80)* 50 (50-50)* <0.001 Despite AAD patients showed better QoL at baseline, all physical and mental scales were in favor of RFA at the final assessment
APAF 2 - LIMITATIONS Catheter ablation was performed in a single highly specialized center with extensive experience in catheter ablation of AF The majority of ablated patients were relatively young without structural heart diseases. Therefore, these results cannot be generalized or applied to all AF patient populations Despite these limitations, we believe that the reported results challenge the notion that multiple antiarrhythmic drugs, as single drugs or in combination, should be used life-long in patients with a long history of PAF
APAF 2 CONCLUSIONS Catheter ablation maintains over years its striking superiority over ADT in terms of efficacy, morbidity and QoL. Patients on long-term ADT are more likely to progress to persistent/permanent AF than ablated patients These findings justify the early deployment of catheter ablation in patients with symptomatic PAF
PERMANENT AF STEPS BEYOND PULMONARY VEIN ABLATION STEPS 1. CPVA 2. ENDO CS 3. SEPTUM 4. LAA 5. EPI CS 6. RIGHT ATRIUM 7. CFE
PERMANENT AF SHORT- MID-TERM RESULTS No. Pts F/u (mo.) Efficacy ORAL PAPPONE CAFE3 CPVA4 12 12 33% 74% HAISSAGU ERRE1 ablation 12 87% PAPPONE4 Biatrial Ablation 36 87% JCE 2007 Circulation 2007 3 NEJM 2006 4 Submitted 1 2
BENEFIT OF THE INTERVENTION Consensus has been reached about ablation efficacy in selected patients Pappone, NEJM 2006
THE STEPWISE STRATEGY Goal: organization of a chaotic AF into a single mappable AT or SR (RF cardioversion) Method: progressive substrate ablation to de-complex AF tailored in individual patient
PERMANENT AF CLINICAL OUTCOME 100 90 80 70 60 50 40 30 20 10 0 % R S Biatrial Group CPVA Group 1 7 13 19 F/U months 25 31 Submitted
COMPLICATIONS WHAT S MATTER? Acute complications rate approaching AF intrinsic morbidity/mortality can nullify any mid- to long-term benefit
SAFETY IN AN EXPERIENCED CENTER (N=19029) Death 0 (0%) Pericardial effusion 20 (0.23%) Stroke 1 (0.011%) TIA 4 (0.05%) Tamponade 7 (0.08%) Atrial-esophageal fistula 1 (0.012%) PV stenosis 0 (0%) Incisional LA tachycardia 601 (6.99%) Transient ERAF 1166 (17%) * Overall complication rate including post CPVA LA AT 7.30% Major complication rate 0.38% over 8,682 AFib patients treated with CPVA or CPVA-M* Minor complication preventable with the CPVA-M *
INCIDENCE OF DEATH ACCORDING TO TYPE OF COMPLICATION. Complication death / overall events Incidence no. % - Tamponade 7/331 2.3 - Atrio-esophageal fistula 2/4 50.0 - Massive pneumonia 2/2 100.0 - Peripheral embolism - Stroke 3/59 5.1 - Myocardial infarction 1/3 33.3 - Torsade de pointes 1/1 100.0 - Septicemia (3 weeks after procedure) 1/3 33.3 - Sudden respiratory arrest 1/1 100.0 - Acute pulmonary vein occlusion of both lateral veins 1/6 16.7 - Internal bleeding 3/21 14.3 - Anaphylaxis 1/6 16.7 - Acute respiratory distress syndrome 1/1 100.0 - Esophageal perforation from intra-operative TEE probe 1/1 100.0of R. Cappato Courtesy
SUMMARY STANDARDIZATION OF THERAPY Pulmonary Vein Ablation has become the stadard of care
You can die of ablation (1/1000) Survey 2 0.05 to 0.1% peri-procedure risk 0.3% risk for disabling stroke
Matter of patients, of course
Success rate Complication rate Safety and Efficacy 100 COMPLICATIONS OF CATHETER ABLATION 90 UNIVERSITY OF MILAN (N=19029) + 80 70 + 60 % + Matter of experience, also 50 40 Pericardial effusion and tamponade Atrial Tachy 30 + 20-10 + - - 0 1996 1997 1998 1999 2000 Year LA maze Ostial CPVA 2001 2002 2003 2004 Irrigated Junctional CPVA catheter CPVA-M 2005 Vagal Denervation
COMPLICATIONS ABLATION GUIDELINES Be aware of what risk you are incurring to Train also in complication detection and management
SUCCESS IS NOT THE SAME ANYWHERE
AF Freedom High enrolling, 98% FDA STUDY Low enrolling, 48% Wilber, Pappone, submitted
CONCLUSIONS AF is associated with an excess mortality which can t be lowered with AAD Catheter ablation is superior to AAD after 1 year, results are maintained longterm (3 YEARS) High complication rate can impair any longterm benefit With both depending from learning curve
To bridge the gap between promise and practice appropriately powered randomized controlled MORTALITY trials will be needed (CABANA NEEDED)
AF OTHER THINKING
AF OTHER THINKING
IF WE ALL AGREE, THE SCIENTIFIC PROGRESS WILL NEVER MOVE FORWARD