Fibrillazione Atriale e Scompenso Cardiaco: Controllo della Frequenza o del Ritmo? Dott. Gaetano M. De Ferrari Dipartimento di Cardiologia, IRCCS Policlinico San Matteo, Pavia

Disclosures Membro di Steering Committee Trial Internazionali per Merck, Boston Scientific, BioControl Lecture fees per Merck Pregressi grant di ricerca clinica e Coordinatore Italiano Trial per Sanofi-Aventis, Cardiome, BioControl

La Fibrillazione atriale é un Predittore Indipendente nei Pazienti con Scompenso Cardiaco ?

Sopravvivenza ad 1 Anno: confronto in 390 pz con scompenso grave 52% vs 71% p = 0.0013 pz in ritmo sinusale n = 315 pz in fibrillazione atriale n = 75 10 20 30 40 50 (sett) Middlekauff Circulation 1991; 84: 40

Heart Failure and Atrial Fibrillation Impact on Mortality n = 391 pts 20 40 60 80 100 Survival (%) pts in AF, n = 93 120 240 360 480 600 (days) p = 0.09 720 pts in SR, n = 298 Stevenson J Am Coll Cardiol 1996; 28: 1458

Prognostic Significance of AF in Patients With Heart Failure Anter E, et al. Circulation 2009;119;2516-25

Impatto sulla Mortalità confronto in 409 pz con scompenso grave 100 47% vs 60%, p = 0.04 80 pz in ritmo sinusale n = 325 60 40 Non è ancora completamente noto l’effetto della comparsa o della presenza della fibrillazione atriale in questa popolazione. In questo studio condotto dal gruppo olandese i pazienti con fa hanno una peggiore prognosi rispetto ai pz in RS. Quando però si analizza la sopravv ad una analisi multivariata con fe, età ecc, tale differenza in sopravvivenza perde di significatività 20 pz in fibrillazione atriale n = 84 1 2 3 4 (anni) Crijns Eur Heart J 2000; 21: 1238 7

AF and mortality Odds Ratio (95% CI) Follow up= 3.4 yrs N°= 409 AF= 84 0.5 1.0 1.5 Odds Ratio (95% CI) Follow up= 3.4 yrs Crijns HJ et al. Eur Heart J 2000

AF and mortality Odds Ratio (95% CI) Follow up= 3.4 yrs OR corrected for age, EF, AP, NYHA Class and renal function Odds Ratio (95% CI) 1.0 0.5 1.5 p=NS Follow up= 3.4 yrs Crijns HJ et al. Eur Heart J 2000

Perché la Fibrillazione Atriale Spesso Risulta un Predittore NON Indipendente ? Punto di Vista Personale

Quality of Life Scores SF-36 score 73 pts Paroxysmal AF P <0.05 Van Der Berg Euro Heart J 2001

Dati del Registro (3513 pazienti) 12

Dati del Registro (3513 pazienti)

Prevalence of Advanced NYHA Class on the Basis of LVEF 51% 68% 35% 54% 27% 52% 14% 38% 43% 18% Prevalence of NYHA III & IV LVEF Sinus Rhythm AF 14

Prevalence of Advanced NYHA Class on the Basis of Age Sinus Rhythm AF 10 20 30 40 50 60 < 60 60-68 69-76 77 + 22% 27% 32% 44% 48% 49% 56% Prevalence of NYHA III & IV Age 15

Controllo del Ritmo o della Frequenza nella Popolazione Generale: Il Padre di Tutti gli Studi: AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management

AFFIRM Inclusion Criteria Atrial Fibrillation Follow-up Investigation of Rhythm Management AFFIRM Inclusion Criteria Atrial fibrillation  6 hrs over past 6 mos Qualifying episode within 12 wks and  6 mos in duration  1 risk factor for stroke/death Age  65 HTN DM CHF Prior TIA/CVA/or systemic embolus LA  50 mm LV shortening fraction < 25% LVEF < 40%

AFFIRM: Total Mortality Atrial Fibrillation Follow-up Investigation of Rhythm Management AFFIRM: Total Mortality Years 5 4 3 2 1 15 20 25 30 10 Cumulative Mortality (%) Rhythm control Rate control p = 0.08 Total pts: 4060 No of DEATHS number (percent) Rhythm control: 80 (4) 175 (9) 257 (12) 314 (18) 352 (24) Rate control: 78 (4) 148 (7) 210 (11) 275 (16) 306 (21) Wyse DG, et al. N Eng J Med 2002;347(23):1825-33 18

Change of Treatment Strategy AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management Change of Treatment Strategy 50 (37.5 %) inability to mantain SR drug intolerance 40 30 Rhythm control Change (%) 20 p<0.0001 Rate control 10 (14.9%) uncontrolled symptoms congestive heart failure 1 2 3 4 5 Time (Years) Rhythm N: 2033 1627 1427 953 507 152 Rate N: 2027 1781 1652 1188 664 205

Warfarin Use AFFIRM Time % Using Warfarin At Follow-Up Visit Rate N: Atrial Fibrillation Follow-up Investigation of Rhythm Management Warfarin Use % Using Warfarin At Follow-Up Visit Time Rate N: 2027 1942 1934 1852 1726 1229 735 248 Rhythm N: 2033 1950 1933 1851 1718 1241 737 268

AFFIRM: Adverse Events Atrial Fibrillation Follow-up Investigation of Rhythm Management AFFIRM: Adverse Events RATE CONTROL RHYTHM CONTROL p-value Death 306 (27%) 356 (28%) 0.058 TdP VT 2 (0.2%) 13 (0.8%) 0.004 Sustained VT/VF Arrest 24 (1.7%) 18 (1.2%) 0.355 Bradycardic Cardiac Arrest 2 (0.1%) Hospitalization after baseline 1218 (70%) 1375 (78%) <0.001 Ischemic Stroke* 79 (5.7%) 84 (7.3%) 0.680 *78% of RHYTHM CONTROL and 68% of RATE CONTROL pts with ischemic stroke were off warfarin or had PT/INR <2.0

The Benefit of Sinus Rhythm in Reducing Mortality in the General Population Only sinus rhythm and warfarin use associated with improved survival in AFFIRM Hazard Ratio SR AFFIRM p<0.0001 Warfarin use p<0.0001 Digoxin use p=0.0007 The benefit of sinus rhythm in reducing mortality AAD use conferred minimal benefit in the rhythm vs rate control trials. However, those patients who converted and/or remained in sinus rhythm – across treatment arms – for the duration of the study saw significant clinical benefit. Overall mortality at five years was 23.8% in the rhythm-control group vs 21.3% in the rate-control group (HR 1.15 [95% CI 0.99-1.34]; p=0.08). Patients in sinus rhythm at the end of the study (across treatment arms) had a 47% mortality risk reduction compared to those who were in AF (p<0.0001). In addition, a separate sub-analysis shown that mean NYHA Functional Class score was significantly better at each visit in patients in sinus rhythm. Corley SD, et al. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation 2004;109(12):1509-13. Chung MK, et al. Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Functional Status Substudy. J Am Coll Cardiol 2005;46(10):1891-9. AAD use p=0.0005 Heart failure p<0.0001 Stroke/TIA p<0.0001 0.5 1 1.5 2 2.5 Corley SD, et al. Circulation 2004;109:1509-13 22

Comma 22 AFFIRM Chi é in ritmo sinusale muore di meno. Chi assume antiaritmici allo scopo di essere in ritmo sinusale e morire di meno, muore di più.

AFFIRM: Cause-specific Mortality Sub-analysis of AFFIRM assessed causes of death within rhythm and rate control groups p=0.07 Difference in total deaths driven by pulmonary and cancer events p=0.0008 p=0.95 AFFIRM: Cause-specific mortality The only significant difference was in non-CV deaths (greater in the rhythm-control arm), which were due to pulmonary and cancer-related deaths. Non-fatal pulmonary complications requiring drug discontinuation were also more common in the rhythm-control group. Despite the association of class Ic/III AADs with torsades de pointe, there was no difference in CV deaths between study arms. Steinberg JS, et al. Analysis of cause-specific mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study. Circulation 2004;109(16):1973-80. p=0.82 p=0.34 Steinberg JS, et al. Circulation 2004;109:1973-80 26

AFFIRM: Total Mortality Wyse DG, et al. N Eng J Med 2002;347(23):1825-33

Quindi nei Pazienti con Scompenso la Strategia di Rhythm Control Potrebbe Essere Benefica?

Popolazione 50 pazienti, 48 uomini e 2 donne età media 57 ± 8 anni CMD: idiopatica in 32 pz (64%) postischemica in 18 pz (36%) classe NYHA media: 2.7 ± 0.5 (moda 3) durata FA media 31 m (range 1 m - 9 a) tentativo inefficace di CVE: 100% dei pz Abbiamo studiato…. 29

Risultati a Lungo Termine Curva di sopravvivenza libera da recidiva di FA 100 persistenza RS 69% ad 1 anno (IC 95%: 53-85%) persistenza RS (%) I pazienti sono stati seguiti con un follow up medio di 1 anno follow-up (mesi) 30

Risultati a Lungo Termine Miglioramento funzionale nella popolazione totale basale 1 mese p < 0,005 10 20 30 40 6 mesi 4 p < 0,005 12 mesi 3 2 1 Classe NYHA FE (%)

Risultati a Lungo Termine Miglioramento funzionale nella popolazione in RS basale p < 0,005 1 mese 10 20 30 40 4 6 mesi p < 0,005 12 mesi 3 2 1 Classe NYHA FE (%)

Atrial Fibrillation and Congestive Heart Failure Trial (AF-CHF)

Baseline Characteristics of the Patients - 1 Roy D, et al. N Engl J Med 2008;358:2667-77

Baseline Characteristics of the Patients - 2 Roy D, et al. N Engl J Med 2008;358:2667-77

Medical Therapy at 12 Months Roy D, et al. N Engl J Med 2008;358:2667-77

Prevalence of Atrial Fibrillation at Each Follow-up Visit and Between Visits Roy D, et al. N Engl J Med 2008;358:2667-77

Kaplan–Meier Estimates of Death from Cardiovascular Causes (Primary Outcome) Roy D, et al. N Engl J Med 2008;358:2667-77

Kaplan–Meier Estimates of Secondary Outcomes Roy D, et al. N Engl J Med 2008;358:2667-77

E se Utilizzassimo un Antiaritmico Meno Tossico dell’Amiodarone ?

ATHENA: Patients in NYHA II/III Hohnloser SH, et al. Eur Heart J 2010;31:1717-21

E se Utilizzassimo l’Ablazione invece che un Antiaritmico?

Baseline Characteristics of the Patients Khan MN, et al. N Engl J Med 2008;359:1778-85

Freedom from Atrial Fibrillation in Patients Undergoing Pulmonary-Vein Isolation with or without Antiarrhythmic Drugs Khan MN, et al. N Engl J Med 2008;359:1778-85

Composite Primary End Point Khan MN, et al. N Engl J Med 2008;359:1778-85

Dubbi Personali Un paziente in FA con FC media di 80 b/min e un QRS di 90 ms e’ un buon candidato ad Ablate and Pace? La tolleranza da sforzo di un pazienti con ritmo da PM non dipende molto dalla programmazione della funzione RR ?

Possibili Conclusioni Alla luce dei dati disponibli la strategia di controllo della frequenza rimane la opzione primaria per la maggior parte dei pazienti con scompenso cardiaco e risposta ventricolare controllata La terapia medica ottimale compresa la TAO ha un ruolo importante Pazienti “sintomatici per FA” e con risposta ventricolare non controllata sono candidati a strategia di controllo del ritmo farmacologica o ablativa Il beneficio del ritmo sinusale potrebbe essere maggiore in pazienti con PLVEF (e pattern restrittivo?)

Improvement in LVEF and in LVESD after Ablation in Patients with Congestive Heart Failure 58 pz, 74% FA permanente, durata FA media 80 mesi EF < 45%, DCM 55% CAD 21% Prospettico/matched Hsu L-F, et al. N Engl J Med 2004;351:2373-83

Indipendentemente da: CARDIOPATIA ASSOCIATA CONTROLLO FC pre presenza di tachimiopatia pre Hsu L-F, et al. N Engl J Med 2004;351:2373-83

CHARM: AF Development During the Course of the Study by Treatment Group 8 7 p < .05 6 6.74% 5 5.55% % 4 3 2 1 Placebo Candesartan OR (95% CI) = 0.81 (0.66 - 1.0) Ducharme A, et al. Am Heart J 2006;152:86-92

CHARM: AF Development in the 3 Component Trials P heterogenity = 0.57 Odds ratio (95% CI) P value Alternative 0.686 (0.470-1.002) Added 0.856 (0.617-1.187) Preserved 0.894 (0.618-1.295) 2 low EF trials 0.779 (0.608-0.997) .0472 Overall 0.812 (0.662-0.998) .0476 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Odds ratio (95% CI) Ducharme A, et al. Am Heart J 2006;152:86-92

Val-HeFT: Predictors of AF Occurrence 0.63 Study treatment (valsartan vs placebo) 1.51 Age (70 vs <70 years) 1.53 Gender (males vs females) 2.28 BNP (97 vs 97 pg/mL) 0.5 1 1.5 2 2.5 3 Hazard ratios for AF occurrence Maggioni AP, et al. Am Heart J 2005;149:548-57

Improvement in LV Function After AF Ablation Tondo C, et al. PACE 2006;29:962-70

Murdock DK, et al. J AFIB 2010;2:705-710

Circulation 1998; 98: 2574-2579 60 60

AFFIRM: Drug Treatment Wyse DG, et al. N Eng J Med 2002;347(23):1825-33

AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management Secondary Endpoint: Death, Disabling Stroke or Anoxic Encephalopathy, Major Bleed, or Cardiac Arrest Rhythm control p = 0.283 Rate control Time (Years) Rhythm N: 2033 1895 1746 1259 719 231 Rate N: 2027 1889 1760 1264 722 208

Heart Failure And Atrial Fibrillation Impact on Mortality 100 80 Converted pts n = 16 n = 35 60 Survival (%) 40 p = 0.04 Non converted pts 20 n = 667 pts, 103 (15%) with AF 10 20 30 40 50 (wks) CHF-STAT (Amio vs Plac) Circulation 1998; 98: 2574

ATHENA: Patients in NYHA II/III Hohnloser SH, et al. Eur Heart J 2010;31:1717-21