Terapia di resincronizzazione nello scompenso cardiaco

Giovedì 2 Dicembre 2010 Simposio NUOVE TECNOLOGIE IN CARDIOLOGIA GERIATRICA Terapia di resincronizzazione nello scompenso cardiaco Stefano Fumagalli Unità di Cura Intensiva - SOD Cardiologia e Medicina Geriatrica AOU Careggi e Università di Firenze

LVEF: 25%; NYHA III / IV 29.4 months Patients Free of Death from Any Cause (%) HR=0.64-95%CI=0.48-0.85 p<0.002 20% 30% Cardiac resynchronization (N=409, Age: 67 years) Medical Therapy (N=404, Age: 66 years) Days Cleland JGF et al., 2005

CRT-P / CRT-D is recommended to reduce MORBIDITY & MORTALITY CRT, preferentially by CRT-D, is recommended to reduce MORBIDITY or to prevent disease PROGRESSION CRT-P / CRT-D SHOULD be considered to reduce MORBIDITY Patient Population NYHA function Class III / IV LVEF <35%, QRS >120 ms, SR Optimal Medical Therapy (Class IV pts ambulatory) NYHA function Class II LVEF <35%, QRS >150 ms, SR Optimal Medical Therapy NYHA function Class III / IV LVEF <35%, QRS >130 ms, AF Pacemaker dependency induced by AV nodal ablation Slow ventricular rate and frequent pacing Class I A I A IIa B IIa C Dickstein K et al., 2010

ICD-CRT (N=894) Age: 66 yrs; Males: 84.8%; LVEF: 22.6%; NYHA II: 79.2% ICD (N=904) Age: 66 yrs; Males: 81.0%; LVEF: 22.6%; NYHA II: 80.8% Death or Hospitalization for HF Death Probability of Event-free Survival HR=0.75 95%CI=0.64-0.87; p<0.001 ICD-CRT N=297 (33.2%) ICD N=364 (40.3%) Probability of Survival HR=0.75 95%CI=0.62-0.91; p=0.003 ICD-CRT N=186 (20.8%) ICD N=236 (26.1%) Years of Follow-up Years of Follow-up Mean Follow-up: 40±20 months Tang ASL for the RAFT Investigators, 2010

Admissions (N) CRT-D ICD CRT-P PREMIER s Perspective Comparative Database (2004-2005) N=26887 - Mean Age=70 years Age >80 years N=4694 (17.5%) 19-79 (N=22193) 80-85 (N=3702) Age-groups >85 (N=992) Swindle JP, Arch Intern Med, 2010

Length of Stay in Hospital by Age and Comorbidity in CRT-D Patients 19-79 years P<0.001 Length of Stay (Median, days) 80-85 years >85 years P=0.09 P<0.001 0 1-2 >3 Charlson Comorbidity Index Swindle JP, Arch Intern Med, 2010

P=0.03 P<0.001 Complications - Frequency (%) Mortality (%) 19-79 (N=14456) 80-85 (N=2583) >85 (N=765) Age-groups Swindle JP, Arch Intern Med, 2010 19-79 (N=14456) 80-85 (N=2583) Age-groups >85 (N=765)

Percentage mortality (%) 25 20 15 10 5 P=NS 17% 1 year 10% >70 years N=68 <70 years N=102 Age: 66±11 yrs N=170 Patients at risk 0 0 180 360 540 720 Follow-up (days) 70 159 123 87 67 Bleeker GB, 2005

Caratteristiche cliniche della popolazione del Registro Italiano InSync / InSync ICD, per gruppi di età <65 (N=571) Gruppi di età (anni) 65-74 (N=740) >75 (N=476) P Età (anni) 57 ± 7 70 ± 3 78 ± 3 / Uomini (%) 84 81 76 0.003 BPCO (%) 5 7 6 0.088 Diabete (%) 8 9 6 0.312 IRC (%) 3 8 4 0.001 >2 patologie (%) 2 4 3 0.099 CAD (%) 39 50 50 <0.001 LVEDD (mm) 70 ± 10 69 ± 9 68 ± 9 0.015 LVESD (mm) 60 ± 12 58 ± 10 57 ± 11 0.016 FE (%) 26 ± 8 26 ± 7 27 ± 8 0.123 Durata QRS (ms) 167 ± 33 165 ± 31 162 ± 32 0.136 Ricoveri (n) 1.6 ± 1.4 1.6 ± 1.5 1.7 ± 1.4 0.256 FA permanente (%) 11 18 21 <0.001 Diuretici (%) 87 89 88 0.415 Nitrati (%) 17 23 46 0.001 AA Classe III (%) 34 38 34 0.312 IRC: insufficienza renale cronica; CAD: cardiopatia ischemica; Ricoveri: ricoveri per CHF nei 12 mesi precedenti; AA: antiaritmici Fumagalli S. EHJ, 2009

Terapia con β-bloccanti e ACE-inibitori o sartani, per gruppo di età. I risultati del Registro Italiano InSync / InSync ICD Uso di ACE-I e anti-atii (%) 80 60 40 20 79 71 70 P=0.001 Uso di β bloccanti (%) 75 60 45 30 15 60 45 P <0.001 37 0 <65 65 74 >75 Gruppi di età (anni) 0 <65 65 74 >75 Gruppi di età (anni) Fumagalli S. EHJ, 2009

Variazioni dei diametri e della frazione di eiezione del ventricolo sinistro (VS) con CRT durante il follow-up, per gruppo di età. I risultati del Registro Italiano InSync / InSync ICD Diametri VS (mm) Telediastolico 70 69 68 Telesistolico 60 58 57 ** ** ** ** ** ** 66 66 64 ** ** 54 ** ** 53 ** ** 51 Base 6 mesi 12 mesi Follow-up (%) Fumagalli S. EHJ, 2009 FE VS 27 26 26 ** ** ** **: p<0.001 vs. Base Gruppi di età (anni) <65 65 74 >75 Base 6 mesi 12 mesi Follow-up ** ** ** 37 34 34

Classe NYHA in condizioni di base e durante il follow-up, per gruppo di età. I risultati del Registro Italiano InSync / InSync ICD 4 P = NS <65 anni p per trend <0.001 65 74 anni p per trend <0.001 >75 anni p per trend <0.001 *: p<0.001 vs. Base Classe NYHA 3 2 1 2.9 3 3 * * * * * * 1.9 2 2 2 2.1 2.2 0 <65 65 74 >75 <65 65 74 >75 <65 65 74 >75 Base 6 mesi 12 mesi Fumagalli S. EHJ, 2009

Responder alla CRT ed utilizzo della CRT-D, per gruppo di età. I risultati del Registro Italiano InSync / InSync ICD 100 Responder alla CRT: volume telesistolico VS >10% a 6 mesi 80 CRT-D - CRT + ICD Responder alla CRT (%) 80 60 40 20 P = NS 58 60 62 Utilizzo CRT-D (%) 60 40 20 48 43 P <0.001 29 0 <65 65 74 >75 Gruppi di età 0 <65 65 74 >75 Gruppi di età Fumagalli S. EHJ, 2009

Responder alla CRT ed utilizzo della CRT-D, per gruppo di età. I risultati del Registro Italiano InSync / InSync ICD 100 Responder alla CRT: volume telesistolico VS >10% a 6 mesi 80 CRT-D - CRT + ICD Responder alla CRT (%) 80 60 40 20 P = NS 58 60 62 Utilizzo CRT-D (%) 60 40 20 48 43 P <0.001 CRT-D HR=0.94 29 95%CI=0.70-1.25; p=0.664 0 <65 65 74 >75 Gruppi di età 0 <65 65 74 >75 Gruppi di età Fumagalli S. EHJ, 2009

Sopravvivenza durante il follow-up, per risposta alla CRT & gruppo di età. I risultati del Registro Italiano InSync / InSync ICD Sopravvivenza 1.0 0.8 0.6 0.4 <65 anni 0.2 p=0.003 Σ -10.5% 0.0 0 500 1000 1500 2000 Follow-up (giorni) P<0.001 65-74 anni Σ -11.6% 0 500 1000 1500 2000 Follow-up (giorni) Sopravvivenza 1.0 0.8 0.6 0.4 >75 years 0.2 P<0.001 Σ -13.6% 0.0 0 500 1000 1500 2000 Follow-up (giorni) Responder alla CRT Non Responder alla CRT Responder alla CRT: riduzione del volume telesistolico del VS >10% nella valutazione a 6 mesi Fumagalli S. EHJ, 2009

Variabili cliniche correlate alla prognosi durante CRT nel Registro Italiano InSync / InSync ICD. Risultati del modello di Cox HR (95% CI) p Value Età <65 anni 1 / 65-74 anni 1.17 (0.80-1.69) NS >75 anni 1.57 (1.06-2.35) 0.026 Uomini 1.38 (0.90-2.12) NS Insufficienza renale 1.29 (0.75-2.22) NS Cardiopatia ischemica 1.18 (0.87-1.60) NS FE VS, per % 0.96 (0.94-0.98) <0.001 FA permanente 1.63 (1.16-2.30) 0.005 ACE-I / ARB 0.72 (0.52-0.98) 0.038 β-bloccanti 0.49 (0.35-0.67) <0.001 Responder CRT 0.37 (0.27-0.51) <0.001 Fumagalli S. EHJ, 2009

Younger patients N=3232 ICD Trials Relevant to the Current Practice ICD Better HR (95% CI) Medical Therapy Better DEFINITE, 2004 MADIT-II, 2002 SCD-HeFT, 2005 OVERALL HR=0.65 (0.50-0-83), p<0.001 ICD Trials that Enrolled Early After Acute MI DINAMIT, 2004 IRIS, 2009 OVERALL HR=0.72 (0.58-0-89), p=0.003 Santangeli P, Di Biase L, 2010

Younger patients N=3232 ICD Trials Relevant to the Current Practice DEFINITE, 2004 MADIT-II, 2002 SCD-HeFT, 2005 OVERALL ICD Better HR (95% CI) Medical Therapy Better HR=0.65 (0.50-0-83), p<0.001 ICD Trials that Enrolled Early After Acute MI DINAMIT, 2004 IRIS, 2009 OVERALL HR=0.72 (0.58-0-89), p=0.003 ICD Trials Relevant to the Current Practice DEFINITE, 2004* MADIT-II, 2002 * * SCD-HeFT, 2005 * OVERALL Elderly patients N=2551 HR=0.81 (0.62-1.05), p=0.11 ICD Trials that Enrolled Early After Acute MI DINAMIT, 2004 * * IRIS, 2009 * OVERALL HR=0.97 (0.78-1.19), p=0.075 */** = >65 / >60 yrs old 0.5 1 2 Santangeli P, Di Biase L, 2010

The Advancement in ICD Therapy (ACT) Registry N=4566 P=0.05 vs 18-39 yrs P=0.05 vs 18-39 yrs Sudden Cardiac Death 2-year Mortality (%) Non Sudden Cardiac Death Non Cardiac Death 18-39 40-49 50-59 60-69 70-79 >80 Age-groups Epstein AE, Heart Rhythm, 2009

Delnoy PPHM, Am Heart J, 2008 1-year Length of Stay for CHF (days) P=0.003 P<0.001 6-Min Walking Test Distance (m) ** * Age <75 years * *: p<0.01 vs. Baseline **: p<0.01 vs. >75 years * Age >75 years B 1-yr FU <75 (N=159) B 1-yr FU >75 (N=107) B 3-Mo 1-Yr 2-Yr Study period

Age: 68±8 yrs (range: 56-84) N=21 EF: B=30% - 3m=39%, p<0.01 6-mWT : B=351 m - 3m=381 m, p<0.05 90 Physical Function Pain Index General Health Perception Vitality Score P<0.01 Social Function Role- Physical Function Role- Emotional Function Mental Health Index 80 70 SF-36 (score) 60 50 40 30 B: baseline 3m: 3 months 20 10 0 B3m B3m B3m B3m B3m B3m B3m B3m Hoth KF, Clin Interv Aging, 2008

Age: 68±8 yrs (range: 56-84) N=21 EF: B=30% - 3m=39%, p<0.01 6-mWT : B=351 m - 3m=381 m, p<0.05 90 Physical Function P<0.01 Pain Index General Health Perception Vitality Score P<0.01 Social Function Role- Physical Function Role- Emotional Function Mental Health Index 80 70 SF-36 (score) 60 50 40 30 B: baseline 3m: 3 months 20 10 0 B3m B3m B3m B3m B3m B3m B3m B3m Hoth KF, Clin Interv Aging, 2008

Adjusted mean Total Brain Volume (%) 80.1 80.0 79.9 79.8 79.7 79.6 79.5 79.4 79.3 Age: 61±9 yrs - Female: 54% N=501 N=502 N=501-0.36 - p=0.04-0.35 - p=0.04 <2.54 2.54-2.92 >2.92 Cardiac Index (L min m 2 ) Tertiles Brain MRI (% of cranial volume) Total brain volume: 79.66% White matter hyperintensity: 0.09% Jefferson AL, Circulation, 2010

Patients - Age: 68 yrs; LVEF: 29%; QRS: 152 ms Controls - Age: 66 yrs; LVEF: 32%; QRS: 110 ms Responders 6-month reduction >15% of LV end-systolic volume Mean velocity (cm/s) 60 50 40 Cerebral blood flow P<0.001 vs Baseline Baseline Follow-up 6-months Responders* (N=16) Controls (N=14) Non-responders (N=16) (score) 40 30 20 10 Baseline MLHFQ P=0.005 vs Baseline Non-responders Responders Follow-up 6-months Cerebral blood flow - Transcranial Doppler of the right middle cerebral artery MLHF Minnesota Living with Heart Failure Questionnaire */ : p<0.01 / p<0.05 vs Controls & Non-responders Van Bommel RJ, 2010

Dixit NK, Clin Cardiol, 2010 Age: 55±12 N=20 Baseline (B) EF: 17% 3-month EF: 30% Attention Digit Span Speed of Processing Digit Symbol Executive Function TMT Part B Language COWA Age & Education Converted T-scores 70 P=0.015 60 50 40 30 20 10 0 56 B 62 3-month 47 B P<0.001 55 3-month 47 B P=NS 49 3-month 47 B P=0.004 51 3-month

Estimates from individual patient data from the CARE-HF & the COMPANION trials Quality adjusted life years (QALYs) 9 8 7 6 5 4 3 2 1 0 55 8.54 7.42 4.72 6.86 7.72 4.39 6.06 6.75 4.08 CRT + ICD (CRT-D) CRT Medical Therapy (MT) 5.25 5.78 3.62 Starting Age (years) 4.38 60 65 70 75 4.73 3.16 Incremental Cost per QALY ( ) 80000 60000 40000 20000 0 Yao G, Eur Heart J, 2007 47909 42701 36777 15805 55 CRT-D vs. CRT CRT-D vs. MT CRT vs. MT 7139 16427 7243 7538 55578 7666 73299 22490 19450 18017 60 65 70 75 Starting Age (years) 7982

Conclusioni La CRT determina il miglioramento della geometria e della funzione del VS in pazienti di tutte le età I benefici della CRT sono apprezzabili anche in termini di capacità funzionale e qualità della vita L aumento della perfusione cerebrale, indotto dalla CRT, potrebbe rallentare il deterioramento cognitivo dei pazienti di età avanzata con scompenso cardiaco L undertreatment farmacologico costituisce un problema reale, soprattutto nei più anziani L uso della CRT in età avanzata è vantaggioso anche in termini economici Sono necessari studi clinici per confermare questi risultati ottenuti da registri di ampie proporzioni

Primary source of data: The Healthcare Cost and Utilization Project Nationwide Inpatient Samples (by the Agency for Healthcare Research and Quality) CRT-D Cardiac Device Implantation US National Estimates (N) CRT-P AICD 1997 1998 1999 2000 2001 2002 2003 2004 Years Zhan C, J Gen Intern Med, 2008

40 Left-BB/non-CAD Left-BB/CAD Right-BB/non-CAD Right-BB/CAD HR=1.99 95%CI=1.75-2.26 41.9 2.5 2 Medicare ICD Registry (2005-6) Mean Follow-up: 40 months Age: 73 years - N=14946 1.75 Mortality (%) 30 20 10 22.4 3-year Mortality (HR) 1.5 1 0.5 0.97 1.23 0 1-year Bilchick KC, Circulation, 2010 2-year 3-year 50-59 60-69 70-79 >80 Age (years)

Predictors of non-response to cardiac resynchronization therapy Age: 62±11; Age >65 yrs: 36 (41%) Men: 55 (63%) LVEF: 24% - (N=87) Age >65 years QRS <120 ms LVDD >74 mm MR jet area >10 cm 2 OR=4.83 OR=4.62 OR=13.80 0.749 0.004 0.020 0.038 NYHA IV 0.128 Renal dysfunction 0.391 Left atrium >47 mm 0.473 Diabetes 0.758 LVDD: left ventricular end-diastolic diameter MR: mitral regurgitation 01 5 10 15 20 OR Antonio N, J Interv Card Electrophysiol, 2010

Predictors of non-response to cardiac resynchronization therapy Age: 62±11; Age >65 yrs: 36 (41%) Men: 55 (63%) LVEF: 24% - (N=87) Age >65 years QRS <120 ms LVDD >74 mm MR jet area >10 cm 2 OR=0.79 OR=4.83 OR=4.62 OR=13.80 0.749 0.004 0.020 0.038 NYHA IV 0.128 Renal dysfunction 0.391 Left atrium >47 mm 0.473 Diabetes 0.758 LVDD: left ventricular end-diastolic diameter MR: mitral regurgitation 01 5 10 15 20 OR Antonio N, J Interv Card Electrophysiol, 2010

1.0 N=1812 - Age: 72±11 Men: 72% Follow-up: 10.7% months Event Free Probability 0.9 0.8 0.7 0.6 Death & HF hospitalization by percentage of biventricular pacing (quartiles) Q2-Q4 vs Q1 HR=0.56, p<0.00001 Q4-100% N=362 P<.001 vs Q1 Q3-98-99% N=509 P=.0004 vs Q1 Q2-93-97% N=474 P=.0013 vs Q1 Q1-0-92% N=467 0.5 0 2 4 6 8 10 Months post Implant 12 Koplan BA, J Am Coll Cardiol, 2009

Epstein AE, Heart Rhythm, 2009 The Advancement in ICD Therapy (ACT) Registry N=4566 November 2004 March 2006 P=0.05 P=0.03 ICD CRT-D Implantations (%) 2-year Mortality (%) (N) 18-39 (120) 40-49 (394) 50-59 (918) 60-69 (1260) Age-groups 70-79 (1326) >80 (548) 18-39 40-49 50-59 60-69 70-79 >80 Age-groups