Luca Bontempi Fibrillazione Atriale e Scompenso Cardiaco : La terapia di resincronizzazione può prevenire o cardiovertire la fibrillazione atriale Luca Bontempi Cattedra e Divisione di Cardiologia Università degli Studi – Spedali Civili Brescia

Scompenso come causa di FA Heart Failure Atrial fibrillation Atrial dilatation and stretch  atrial pressure and/or volume Sympathetic activation Neurohormonal activation 2

FA come causa di Scompenso Atrial fibrillation  Cardiac output Loss of atrial systole fast ventricular rate Irregular ventricular rhythm 3

Correlation Between AF and HF Severity Irina Savelieva and A. John Camm. Europace 2004 4

FA /DEVICE Ogni paziente portatore di pacemaker, defibrillatore o dispositivo di resincronizzazione (CRT-P o CRT-D) è probabile che abbia o sviluppi FA è necessario poter trattare le COMORBIDITA’ della FA in pz già indicati alla terapia con un dispositivo impiantabile Bradiaritmia Scompenso Tachiaritmia FA Sino al 20% dei pazienti soffrono di aritmie atriali all’impianto di un pace maker1 Sino al 50% dei pazienti scompensati soffrono di FA3 Sino al 30% dei pazienti soffrono di aritmie atriali all’impianto di un ICD2 Importante parlarne perche è una patologia che interessa in diversa misura i nostri pazienti 1 - HCIA Hospital Discharge Data, 1992, and Medtronic Device Registration System. 2 - Schmitt C, Montero M, Melichercik J. Significance of supraventricular tachyarrhythmias in patients with implanted pacing cardioverter defibrillators.Pacing Clin Electrophysiol. 1994;17(1):295-302. 3 - Maisel W, Stevenson L. Atrial fibrillation in heart failure: epidemiology, pathophysiology and rationale for therapy, Am J Cardiol. 2003; 91(Suppl 6A):2D-8D.

Electro-mechanical decoupling: Factors that make up the heart dissynchrony Electrical QRS wide LBBB Mechanical Dissynchrony Atrio-ventricular intra- ventricular inter-ventricular Atrio- ventricular Intra- ventricular Mechanical dysynchrony may be a consequence of the electrical disturbance. The electrical disturbance has been associated with increased risk of mortality and poor left ventricular hemodynamic function. The hypothesis is that if a correction of some of the electrical disturbance is made, then a correction in some of the mechanical dyssynchrony will also result. The implication is a move toward ‘direct’ correction of the ‘coordination’ of the mechanical dysynchrony. Toussaint’s study confirms this hypothesis. Using radionuclide angiography in 92 HF patients compared with 35 age-mathced control subjects, they were ale to correlate increases in QRS to impairment of intra- and inter-ventricular synchrony. Inter- ventricular Toussaint J-F, et al. PACE 2002;25:178-182 Cazeau, et al. PACE 2003; 26[Pt. II]: 137–143

Randomized Controlled Trials on CRT Study (n randomized) NYHA QRS Sinus ICD? Status Results MIRACLE (453) III, IV 130 Normal No Published + MUSTIC SR (58) III 150 MUSTIC AF (43) 200* AF PATH CHF (41) 120 MIRACLE ICD (369) Yes CONTAK CD (490) II-IV In Press + ¶ COMPANION (1520) Presented PATH CHF II (89) Both MIRACLE ICD II (186) II CARE HF (814) Enrolled On Top of Optimal Drug Therapy CRT Improves: NYHA Class, Quality of life score, Exercise Capacity: 6 MW, Peak VO2 LV function: EF, MR Reverse remodeling: LVEDV Hospitalization Main purpose: Show that a large number of patients have been studied in completed and ongoing randomized controlled studies of CRT. Use in conjunction with next slide. Key messages: Nearly 3000 patients have been enrolled in randomized controlled clinical trials presented to date. All studies have used a wide QRS in the presence of moderate to severe, systolic, dilated cardiomyopathy as inclusion criteria. Most included patients with normal sinus, and without a primary indication fro an ICD. All studies have reported favorable outcomes. LVEF  35% for all trials * RV paced QRS ¶ Primary endpoint not met; key secondary endpoints reached 7

Clinical Evidence: CRT Reduces Mortality & Hosp. On Top of Optimal Drug Therapy Further Reduction with CRT + ICD for Higher Risk Patients HF Mortality Sudden Cardiac Death CRT ICD STUDY TREATMENT FOLLOW-UP MORTALITY + HOSPITALIZ. MORTALITY Single Trials CARE-HF (n=813) CRT-P 29.4 mths ↓ 37% ↓ 36% 36.4 mths (ext) ↓ 40% COMPANION (n=1520) 12 mths ↓ 19% ↓ 24% (n.s.) CRT-D ↓ 20% Meta-Analysis McAlister (n=3216; 9 trials) CRT- P & D 1-12 mths HF Hospitaliz. ↓ 32% (n.s.) ↓ 21% Freemantle (n=3380; 8 trials) 3-29.4 mths HF Hospitaliz. ↓ 45% ↓ 28% Abdulla (n=2514;8 trials) 1-29.4 mths HF Hospitaliz. ↓ 40% Rivero-Ayerza (n=2371; 5 trials) ↓ 29% McAlister, F. A. et. al. Ann Intern Med 2004;141:381-390 Abdulla J. et al.; Cardiology 2006;106:249–255 Freemantle N et al.; Eur J Heart Fail. 2006 Jun;8(4):433-40 Rivero-Ayerza M. et al.; Eur Heart J. 2006 Sep 11; [Epub ahead of print]

MADIT-CRT – Results Primary Endpoint (2) 34% reduction in the risk of all-cause mortality or first HF event Benefit driven by 41% reduction in the risk of heart failure events Similar benefit for ischemic and non-ischemic patient Cox Analysis HR p-value 0.66 0.001 0.67 0.003 0.62 0.01 favors CRT-D favors ICD Death or Heart Failure 0.59 < 0.001 0.58 0.01 HF only The MADIT-CRT trial set out to determine whether CRT-D or ICD-alone was best at reducing all-cause mortality or heart-failure, whichever came first, in mildly symptomatic patients. The results clearly demonstrate a significant 34% relative reduction in the risk of all-cause mortality or heart failure for CRT-D compared with ICD-alone (p = 0.001). What’s more, this benefit is driven by a 41% reduction in risk of heart failure events (p < 0.001). The benefit was similar for both ischemic and non-ischemic patients. Reduction in heart failure events did not result in a reduction in overall mortality, possibly because of the expected low annual mortality rate of 3% in each treatment group due to the fact that patients were NYHA class I or II. 1.00 0.99 1.06 0.80 0.87 0.68 Death at any time Non-ischemic patients Ischemic patients All patients 0.2 0.4 0.6 0.8 1 2 Adjusted Hazard Ratio Moss AJ, Hall WJ, Cannom DS, et al. [serial online]. NEJM. Sept 2009. In press. 9

CRT/FA Tuttavia, la percentuale di tutti gli impianti CRT eseguiti in pazienti con FA permanente è stata stimata in circa il 20 – 25% * Auricchio A, Metra M, Gasparini M et al, Am J Cardiol 2007; 99: 232 – 238)

20% of Patients with Heart Failure Develop AF within 4 Years Unadjusted cumulative incidence of first AF after Heart Failure - Framingham Study Development of AF was associated with increased mortality: hazard ratio of 1.6 (95% CI, 1.2 to 2.1) in men and 2.7 (95% CI, 2.0 to 3.6) in women. Wang, T. J. et al. Circulation 2003;107:2920-2925

FA in HF Dries et al. J Am Coll Cardiol. 1998 Sep;32(3):695-703 Analisi retrospettiva del SOLVD Dries et al. J Am Coll Cardiol. 1998 Sep;32(3):695-703

CRT e FA La maggior parte dei pazienti inclusi nei grandi trial sulla CRT erano in ritmo sinusale In alcuni di questi trial, l’FA era un criterio di esclusione: I pazienti in FA non possono “beneficiare della componente atriale della resincronizzazione” L’FA può causare una cattura ventricolare non soddisfacente (sottostimata da complessi di fusione)

FA e CRT Isonga comunque ricordare che è difficile valutare gli effetti di crt e fa e vicevers a x…

COME AGISCE LA CRT SU PREVENZIONE/ RIDUZIONE EVENTI FA 15

“Reverse remodeling” Miocardio atriale CRT e FA CRT potrebbe prevenire o ridurre FA in quanto: Aumenta la performance emodinamica ventricolare Riduce l’insufficienza mitralica Riduce l’attivazione del sistema RAA e del sistema nervoso simpatico “Reverse remodeling” Miocardio atriale Modificazioni strutturali Alterazioni elettriche

CRT ED FA: COSA SAPPIAMO Studio Pz FU mesi Criteri di selezione Disegno e scopi Principali risultati MUSTIC (JACC 2002) 75 12 NYHA III, QRS > 150 ms, FE < 35% Comparativo longitudinale: RS vs FA RS = FA Leon et al 20 > 6 NYHA III – IV, FE < 35% Preg. abl e pacing RV Longitudinale osservazionale: Basale e dopo CRT + MUSTIC AF (EHJ 2002) 59 6 NYHA III, FE ridotta Bassa Fc Singolo cieco, controllato, randomizzato: Biv pacing vs RV pacing Biv > RV Garrigue et al (Heart 2002) 13 = NYHA III, FE molto ridotta, QRS > 140 ms Singolo cieco, randomizzato, cross – over: ablate and pace Biv vs LV Biv = LV Puggioni et al JACC 2004 44 Acuto FA permanente, CHF Comparazione RV vs LV dopo ablate and pace LV > RV Molhoek et al (AJC 2004) 60 Fino a 24 NYHA III – IV, FE < 35%, QRS > 120 ms Comparativo: Biv in FA o RS

Effects of CRT on left atrial appendage function Changes in LAA areas in patients with DCM before and after CRT. LAAAmax, LAAAmin: left atrial appendage maximal and minimal areas, respectively. * P<0.05 vs. baseline. Vural et al., Int Journal Cardiol, 2005 18

Effects of CRT on left atrial appendage function Changes in LAA active emptying and filling velocities in patientswith DCM before and after CRT. * P < 0.05 vs. baseline. Vural et al., Int Journal Cardiol, 2005 19

Improved Atrial Function After CRT RESPONDER NON- RESPONDER BASELINE 3 MONTHS F.U In a responder, left atrial strain at ventricular end-systole (s), early diastole (e) as well as after atrial contraction (a) was increased when compared with baseline (A) and 3 months after cardiac resynchronization therapy (B). On the other hand, the nonresponder showed no improvement of atrial strain between baseline (C) and 3-month follow-up (D). Yu et al. JACC 2007 20

Improved Atrial Function After CRT The use of CRT improved LA and RA contractile function. The increase of atrial strain throughout the cardiac cycle is likely reflecting the improvement of atrial compliance. These changes lead to LA reverse remodeling with reduction of LA size before and after atrial systole. Yu et al. JACC 2007 21

Effetti CRT su FA Alcuni studi hanno dimostrato una riduzione di fa dopo crt The present study compared the incidence of AF in 36 consecutive patients with chronic heart failure receiving CRT with its incidence in controls matched for age, gender, and left ventricular ejection fraction but not receiving CRT. The findings suggest that patients with CRT had a significantly lower incidence of AF than controls. Further studies to establish the role of CRT in preventing AF and its mechanisms are warranted. 36 pts CRT had a significantly lower incidence of AF than controls FUNG JW al. AJCardiol 2005; 96:728–731

Effetti CRT su FA post-hoc CARE-HF analysis: analisi post-hoc care-hf: Nessun effetto della crt su fa dopo 2,5 anni e la nuova insoregnza di fa non ha ridotto impatto crt su mortwslità, ospedaslizzazione e sintomi There was no difference in the time until first onset of AF between groups. Mortality was higher in patients who developed AF, but AF was not a predictor in the multivariable model (hazard ratio 1.17; 95% confidence interval, 0.82 to 1.67; P=0.37). In patients with new-onset AF, CRT significantly reduced the risk for all-cause mortality and all other predefined end points and improved ejection fraction and symptoms (no interaction between AF and CRT; all P>0.2). CONCLUSIONS: Although CRT did not reduce the incidence of AF, CRT improved the outcome regardless of whether AF developed. was no difference in the time until first onset of AF between groups Hoppe UC et al. Circulation 2006; 114:18–25.

Burden of AF after CRT Adelstein et Saba, Am J Cardiol 2007 We sought to determine whether the extent of RA pacing influences the incidence of AF after CRT Compared to atrial sensing, atrial pacing is associated with a 2-fold increased risk of post-CRT AF. Prospective comparison of DDD and VDD pacing modes in CRT is warranted. Freedom from AF over time in patient without a history of AF before implant. Controls vs composite of patients undergoing CRT. The latter have a significant longer time to AF first-episode. Adelstein et Saba, Am J Cardiol 2007 24

AF burden in the post-implant period after CRT Eighty-four patients with drug-refractory CHF in NYHA-class II-IV received a CRT device. The response to CRT was assessed by determining NYHA class at baseline and at 3 months follow-up. Atrial fibrillation (AF) burden (defined as time of AF per day) was continuously measured by the device. A significant gradual reduction of AF burden (from 9.88 +/- 12.61 to 4.20 +/- 9.24 [hours/day]) and number of patients experiencing AF episodes (from 26 to 13) were observed during CRT. Diagnostic features for long-term monitoring of physiological variables provide useful information on the state and course of AF and may improve disease management. (2) AF burden reduces over time during the first 3 months after CRT implantation. Number of patients with AF episodes in the first 3 months of CRT by duration of AF episodes Hügl et al., J Cardiovasc Electrophysiol 2006 25

Sinus Rhythm Resumption Independent predictors: QRS < 150 ms baseline EDD 65 mm LA diameter 50 mm ablated AVJ In this large cohort, one in every 10 patients with HF and permanent AF treated with CRT spontaneously reverted to SR during follow-up, usually soon after implant. Independent predictors of this phenomenon were found to be post-CRT QRS 150 ms, baseline EDD 65 mm, LA diameter 50 mm, and ablated AVJ. Additional prospective clinical studies are needed to, on one hand, substantiate these findings and, on the other hand, to improve our understanding of CRT effects on atrial structure and function. 26

Effetti FA su CRT prospective observational study of 263 consecutive patients suuvival Questi sono i dati di un registro prosepettico che hanno evidenziato un analogo benefcio della crt in riduzione di moratlità ed eventi tra pz in rs e fa In this prospective observational study of 263 consecutive patients, CRT was performed in 96 patients (37%) with chronic AF and 167 patients (63%) with sinus rhythm (SR). Echocardiographic and clinical parameters were evaluated at baseline and 3 and 12 months. Reverse left ventricular (LV) remodeling is defined as LV end-systolic volume decrease > or =10%. Hospitalization rates for heart failure in the year before and after implantation were compared. Baseline characteristics between patients with and without AF were similar, but the AF group had smaller LV end-systolic and end-diastolic volumes and larger left atrial dimensions. New York Heart Association class, 6-minute walking distance, quality-of-life score, LV ejection fraction, and mitral regurgitation improved significantly at 3 and 12 months in both groups, and the changes were similar. Reverse LV remodeling after 3 and 12 months was 74% and 82% (AF group) versus 77% and 83%, respectively (SR group, p = 0.79). After 1 year, cardioversion had occurred in 25% of patients with AF. In the year after implantation, significant decreases in hospitalizations for heart failure in both groups (84% and 90%) were documented. Long-term mortality was almost equal in both groups. In conclusion, this large-scale study shows that the benefit of CRT in patients with chronic AF and heart failure is similar to that in patients with SR. Patients with chronic AF and heart failure should be considered candidates for CRT. The benefit of CRT in pts with chronic AF and HF is similar to that in patients with SR Delnoy P et al. Am J Cardiol 2007; 99:1252-1257

Effetti FA su CRT 60 pts :30 had SR/ 30 AF –CRT-P D’altra parte, è stata evidenziata in alcuni studi una riduzione del numero di responders nei pazienti in FA we evaluated the clinical response and long-term survival rate of CRT in patients who had heart failure and chronic AF, and the results were compared with those in patients who had sinus rhythm and who underwent CRT. Sixty patients who had end-stage heart failure (30 had sinus rhythm and 30 had chronic AF), New York Heart Association classes III to IV, left ventricular ejection fraction <35%, QRS interval >120 ms, and a left bundle branch block received a biventricular pacemaker. New York Heart Association class, Minnesota Quality of Life score, and 6-minute walking distance were evaluated at baseline and after 6 months of CRT. Long-term follow-up was </=2 years. New York Heart Association class, Minnesota Quality of Life score, and 6-minute walking distance improved significantly in the 2 groups after 6 months of CRT. The number of nonresponders was greater among patients who had AF. Nevertheless, the long-term survival rate was comparable between patients who had sinus rhythm and those who had AF. Patients who had AF demonstrated comparable benefit from CRT as those who had sinus rhythm. Molhoek SG et al. Am J Cardiol 2004; 94:1506–1509.

“CHF patients in permanent AF do not respond as well to CRT as patients in sinus rhythm.”

PERCHE’ DOVREBBE FUNZIONARE MENO ? Per ottenere percentuali elevate di pacing biventricolare, dovremmo stimolare a frequenze cardiache elevate, con effetti deleteri sulla funzione diastolica Durante le fasi di attività fisica, riduzione della stimolazione Battiti di fusione o “pseudofusione”

Aim : determinate the appropriate biventricular pacing target in pts whith heart failure

Survival free from HF hospitalization and all-cause mortality in all patients

Survival free from HF hospitalization and all-cause mortality in all patients No history of AF History of AF

RUOLO DELL’ABLAZIONE DEL NODO AV EFFETTO CRT EFFETTO ABL-NAV Resincr. INTERventricolare Resincr. INTRAventricolare Regolarizzazione del ritmo Controllo completo dellaFc Resincronia AV CERTEZZA DI STIMOLAZIONE CRT “PURA” AL 100%

Ablazione nodo AV: pro… Altro proble,a_ CRT OTTIMALE

…e contro Creazione di PM-dipendenza ( una metanalisi ha riportato in questi pazienti una mortalità improvvisa del 2%)* Possibilità di ripristino del ritmo sinusale durante il follow-up *J Am Coll Cardiol, 2002; 40:105-110

Anche in questo caso ci sono controversie: questo dice che è meglio ma non tutti sono d’accordo

Responder = Riduzione ≥ 10% LVESV

Studio osservazionale longitudinale EFFETTO DI ABLATE AND PACE BIV SULLA SOPRAVVIVENZA A LUNGO TERMINE IN PZ CON HF Studio osservazionale longitudinale 4 centri europei ad alto volume (Rozzano, Brescia, Magdeburgo, Bad Oeynhausen) Pazienti arruolati consecutivamente tra l’agosto 1995 e l’agosto 2004 1285 pazienti con FE ≤ 35%, QRS ≥ 120 ms, NYHA ≥ II, CHF e terapia medica ottimizzata Gasparini M, Auricchio A, Curnis A et a., Circulation (Suppl.) 2006; 114: II - 717

Analisi condotta su 243 pazienti con FA permanente EFFETTO DI ABLATE AND PACE BIV SULLA SOPRAVVIVENZA A LUNGO TERMINE IN PZ CON HF Analisi condotta su 243 pazienti con FA permanente 118 ablazione del nodo AV 125 farmaci + algoritmo VRR Gasparini M, Auricchio A, Curnis A et a., Circulation (Suppl.) 2006; 114: II - 717

RS (1042) FA (243) p Età 63.4 ± 10.0 66.2 ± 9.0 < 0.001 Maschi 75% EFFETTO DI ABLATE AND PACE BIV SULLA SOPRAVVIVENZA A LUNGO TERMINE IN PZ CON HF RS (1042) FA (243) p Età 63.4 ± 10.0 66.2 ± 9.0 < 0.001 Maschi 75% 82% 0.02 CAD 48% 40% 0.032 NYHA III – IV (%) 94% 97% NS QRS (ms) 170 ± 28 161 ± 32 FE (%) 24 ± 7 26 ± 8 0.005 CRT – D (%) 58% 49 % 0.006 Farmaci cronotropi negativi (%) 85% 99% < 0.0001 Gasparini M, Auricchio A, Curnis A et a., Circulation (Suppl.) 2006; 114: II - 717

EFFETTO DI ABLATE AND PACE BIV SULLA SOPRAVVIVENZA A LUNGO TERMINE IN PZ CON HF Gasparini M, Auricchio A, Curnis A et a., Circulation (Suppl.) 2006; 114: II - 717

EFFETTO DI ABLATE AND PACE BIV SULLA SOPRAVVIVENZA A LUNGO TERMINE IN PZ CON HF Gasparini M, Auricchio A, Curnis A et a., Circulation (Suppl.) 2006; 114: II - 717

EFFETTO DI ABLATE AND PACE BIV SULLA SOPRAVVIVENZA A LUNGO TERMINE IN PZ CON HF Gasparini M, Auricchio A, Curnis A et a., Circulation (Suppl.) 2006; 114: II - 717

Conclusioni CRT può essere efficace nel: Rimodellamento atriale Miglioramento della funzione atriale Riduzione del numero di episodi di fa

Conclusioni Ad oggi, non esistono dati certi sul ruolo della CRT nei con FA Dati preliminari sembrano tuttavia indicare un beneficio della CRT in questi pazienti L’FA non sembra diminuire i benefici della CRT ma un controllo della frequenza è essenziale La sicurezza e il beneficio dell’ablazione del nodo AV rimangono da determinare (Modulazione) Approccio ablativo “curativo” nell’FA parossistica o persistente di pazienti con scompenso cardiaco: Isolamento delle vene polmonari : ???

ISCHEMIC2/NON-ISCHEMIC ESC HF Guidelines - 2010 Focused Update of ESC Guidelines on Device Therapy in Heart Failure. Patient selection for CRT device therapy1 1. All patients on OPT, reasonable expectation of survival with good functional status for > 1 year 2. MI > 40 days Class of recommendation & Level of evidence NYHA II LVEF ≤ 35% QRS ≥ 150 ms CRT-D IA ISCHEMIC2/NON-ISCHEMIC NYHA III LVEF ≤ 35% QRS ≥ 120 ms CRT IA NYHA IV This flow chart summarizes the latest 2010 focused update of ESC guidelines on device therapy in heart failure. Indication for AV nodal ablation NYHA III/IV Permanent AF LVEF ≤ 35% QRS ≥ 130 ms CRT IIa B 2010 Focused Update of ESC guidelines on device therapy in Heart Failure, K.Dickstein et al., European Heart Journal doi:10.1093/eurheartj/ehq337 47

NAZEM AKOUM, et al. Vol. pp. 1-7 Clinical Implication The results of this study have an important impact on clinical decision making both for the AF patient and the physician managing the arrhythmia. For the patient, expectations for the outcomes of the ablation procedure can be satisfactorily estimated and the patient can then weigh the risks of undergoing the ablation procedure against the benefits of maintaining sinus rhythm. For the ablationist, quantification of fibrosis/SRM can be used to counsel the patients better about the expected outcomes of catheter ablation. Moreover, the operator can plan the procedure better with the knowledge that patients with advanced fibrosis/SRM will have a better outcome with a more extensive ablation rather than a PV isolation. A series of left atrial MRI 3D reconstructions displayed in the RAO and PA projections illustrating areas of fibrosis (bright green) across the 4 stages of fibrosis. Utah stage 1: <5% fibrosis, Utah stage 2: 5–20% fibrosis, Utah stage 3: 20–25% fibrosis, Utah stage 4: >35% fibrosis. Distribution of paroxysmal and persistent atrial fibrillation across the 4 stages of fibrosis. Note that each stage is a heterogeneous mix of both AF phenotypes with more predominant persistent AF in advanced stages.