trial e crt
TRANSCRIPT
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Trial e CRT: uno sguardo critico al passato,
un occhio al presente e cosa ci riserva il futuro
Dott. Giuseppe Arena
Direttore U.O.C. UTIC-Cardiologia USL 1 Massa Carrara
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT: nascita ed evoluzione• Scompenso Cardiaco: patologia cardiovascolare in aumento
tra le più disabilitanti, mortali e costose
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT: nascita ed evoluzione• Scompenso Cardiaco: patologia cardiovascolare in aumento
tra le più disabilitanti, mortali e costose
2%2%2.7%2.7%
4.9%4.9%
19902010
2030
Kelly DT, Circulation 1997
PREVALENZA CRESCENTE
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT: nascita ed evoluzione• Scompenso Cardiaco: patologia cardiovascolare in aumento
tra le più disabilitanti, mortali e costose
2%2%2.7%2.7%
4.9%4.9%
1990
2010
2030
1. Framingham Heart Study (1948 – 1988) in Atlas of Heart Diseases.2. American Heart Association. Heart Disease and Stroke Statistics—2003 Update. Dallas, Tex.
100100909080807070606050504040303020201010
00
Prob
abili
ty o
f sur
viva
l, %
Men (n = 237)Women (n = 230)
Time after CHF diagnosis, years00 22 44 66 88 1010
80% of men and 70% of women who have CHF will
die within 8 years.2
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Numero di Ricoveri per Scompenso Cardiaco negli Ospedali Italiani: DRG 127
0,000
40,000
80,000
120,000
160,000
200,000
1996 1997 1998 1999 2000 2001 2002 2003
127.043
190.340
Dati del Ministero della Salute
177.276+50%
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT: nascita ed evoluzione• Scompenso Cardiaco: patologia cardiovascolare in aumento
tra le più disabilitanti, mortali e costose
• 1 su 3 pazienti con SC: contrazione ventricolare dissincrona
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Curry CW, et al. Mechanical dyssynchrony in dilated cardiomyopathy with intraventricular conduction delay as depicted by 3D tagged magnetic resonance imaging.
Normal Dilated Cardiomyopathy
Abnormal local wall motion & strain
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT: nascita ed evoluzione• Scompenso Cardiaco: patologia cardiovascolare tra le più
disabilitanti, mortali e costose
• 1 paziente con HF su 3: contrazione ventricolare dissincrona
• Ottimizzazione della terapia farmacologica: buoni risultati ma ancora elevato tasso di mortalità e bassa qualità della vita
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT: nascita ed evoluzione• Scompenso Cardiaco: patologia cardiovascolare tra le più disabilitanti, mortali e costose
• 1 paziente con HF su 3: contrazione ventricolare dissincrona
• Ottimizzazione della terapia farmacologica: buoni risultati ma ancora elevato tasso di mortalità e bassa qualità della vita
Bristow et al N Eng J Med 2004; 350: 2140
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT: nascita ed evoluzione• Scompenso Cardiaco: patologia cardiovascolare tra le più disabilitanti,
mortali e costose
• 1 paziente con HF su 3: contrazione ventricolare dissincrona
• Ottimizzazione della terapia farmacologica: buoni risultati ma ancora elevato tasso di mortalità e bassa qualità della vita
• 1994: primo impianto di sistema di stimolazione biventricolare
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
54 aa. CMPD e CHF refrattario
PR 200 ms
BBS (QRS 200 ms)
Blocco interatriale (90 ms dx-sn)
Four Chamber Pacing in Dilated CardiomyopathyS. Cazeau, P. Ritter, S. Bakdach, A. Lazarus, M. Limousin, L. Henao, O. Mundler, J.C. Daubert, J. Mugica
Pace Clin Electrophysiol 1994;17(Pt II):1974-1079c
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT: nascita ed evoluzione• Scompenso Cardiaco: patologia cardiovascolare tra le più disabilitanti,
mortali e costose
• 1 paziente con HF su 3: contrazione ventricolare dissincrona
• Ottimizzazione della terapia farmacologica: buoni risultati ma ancora elevato tasso di mortalità e bassa qualità della vita
• 1994: primo impianto di sistema di stimolazione biventricolare
• 20 anni dopo: sviluppo tecnologico della CRT, messa a punto e miglioramento delle linee guida sulla CRT, ampliamento delle indicazioni CRT in pazienti HF
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Domanda:• Quali possono essere allo stato attuale gli obiettivi nell’ambito
della CRT:
1) aumentare il rate dei pazienti responder alla terapia CRT2) estendere il trattamento a pazienti che potrebbero
beneficiare della terapia CRT 3) ridurre le possibili controindicazioni alla terapia CRT4) selezionare con maggiore accuratezza i pazienti candidati
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Prevalence of Ventricular Dyssynchrony in Heart Failure
Left Bundle Branch Block More Prevalent with Impaired LV Systolic Function
38%
24%
8%
Moderate/SevereHF (2)
Impaired LVSF(1)
Preserved LVSF(1)
1. Masoudi, et al. JACC 2003;41:217-232. Aaronson, et al. Circ 1997;95:2660-7
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Elements of Cardiac Dyssynchrony
Atrio-ventricular
Inter-ventricular
Intra-ventricular
Cazeau, et al. PACE 2003; 26[Pt. II]: 137–143
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Deleterious Effects of Ventricular Dyssynchrony on Cardiac Function
Reduced diastolic filling time 1
+ Weakened contractility 2
+ Protracted mitral regurgitation 2
+ Post systolic regional contraction 3
= Diminished stroke volume
1. Grines CL, et al Circulation 1989;79: 845-853 2. Xiao HB, et al Br Heart J 1991;66: 443-447 3. Søgaard P, et al. J Am Coll Cardiol 2002;40:723–730
Courtesy of Ole-A. Breithardt, MD
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Deleterious Effects of Ventricular Dyssynchrony on Survival
Long Term--45 Months
34%
49%
QRS < 120 ms
QRS > 120 ms
Iuliano et al. AHJ 2002;143:1085-91N=669
P < 0.001Moderate Term--1 Year
11%
16%
QRS < 120 ms
QRS > 120 ms
P < 0.001
Baldasseroni S, et al. Am Heart J 2002;143:398-405N=5,517
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Cardiac Resynchronization Therapy
Jaffe LM, Morin DP Cardiac Resynchronization Therapy: History, Present Status, and Future Directions.The Ochsner Journal 2014; 14:596-607
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Domanda:
• Quale può essere il marker di dissincronia validato per qualificare i pazienti candidati alla CRT:
1) Dissincronia meccanica2) Frazione d’eiezione del ventricolo sinistro3) Durata QRS 4) Percentuale di stimolazione del ventricolo destro
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Domanda:• Quali possono essere stati i maggiori criteri di inclusione dei
pazienti nei primi trials sulla resincronizzazione cardiaca:
1) Classe NYHA II e III, ritmo sinusale, QRS ≥ 120 ms 2) QRS ≥ 120 ms, LVEF ≤ 25 %3) Terapia farmacologica ottimizzata, NYHA III e IV, QRS ≥ 120
ms, LVEF ≤ 35% 4) Ritmo sinusale, QRS ≥ 120 ms, terapia farmacologica in atto
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Cumulative Enrollment in Cardiac Resynchronization Randomized Trials
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Heart Failure Trial Progression
Symptoms/quality of life
Measures of disease progression
Transvenous system
Pilot
Mortality and morbidity
1996
2005Mounting evidence
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Early TrialsFeasibility and safetyRelief of symptoms
Trials with hard end-pointsMortalityMorbidity
Path-CHFMUSTICMIRACLE
CompanionCARE-HF
Heart Failure Trial Progression
Multicenter controlled randomized crossover trial
AIM of the STUDYEvaluation of CRT compared to best single chamber pacing (acutely tested) and no pacing
Pacing Therapy for Congestive Heart Failure
Acute hemodynamic testing
Randomization 1:1
CRT
Best chronic mode
4 weeks
8 weeks
One year
No CRT
Implant
Best unichamber
Best unichamber
No CRT
CRT12 weeks
PATH-CHFStudy Design
Inclusion CriteriaNYHA III/IVSinus RhythmQRS width > 120 msecPR >150 msec
42 ptsrandomized
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
PATH-CHF
• Primary endpoints– Peak VO2– VO2 uptake at anaerobic threshold– Six-minute walk distance
• Secondary endpoints– Minnesota Living with Heart Failure score– NYHA class– Hospitalization– Improvement in prognostic and hemodynamic parameters
Endpoints
Aurricchio A, Stellbrink C, Sack S, et al. The pacing therapies for congestive heart failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol. 1999;83:130D-135D.
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
PATH-CHF
Aurricchio A, Stellbrink C, Sack S, et al. The pacing therapies for congestive heart failure (PATH-CHF) study: rationale, design, and endpoints of a prospective randomized multicenter study. Am J Cardiol. 1999;83:130D-135D.
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
PATH-CHFChronic peak VO2
0.5
0.75
1
1.25
1.5
Pre-implant 12 months
Peak
VO
2 (l/
min
)
0.97+0.26
1.19+0.34
N=14P=0.019
Impr
ovem
ent
Aurricchio A, Stellbrink C, Sack S, et al. Long-term benefit as a result of pacing resynchronization in congestive heart failure: results of the Path-CHF trial. Circulation. 2000;102(suppl II):II-693. Abstract 3352.
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
PATH-CHFChronic VO2 AT
0.5
0.75
1
Pre-implant 12 months
VO2
AT (l
/min
)
0.76+0.21
0.91+0.31
N=18P=0.018
Impr
ovem
ent
Aurricchio A, Stellbrink C, Sack S, et al. Long-term benefit as a result of pacing resynchronization in congestive heart failure: results of the Path-CHF trial. Circulation. 2000;102(suppl II):II-693. Abstract 3352.
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
PATH-CHFChronic six-minute walk distances
300
350
400
450
500
Pre-implant 12 months
six-m
inut
e w
alk
(m)
357+101
446+74
N=25P<0.001
Impr
ovem
ent
Aurricchio A, Stellbrink C, Sack S, et al. Long-term benefit as a result of pacing resynchronization in congestive heart failure: results of the Path-CHF trial. Circulation. 2000;102(suppl II):II-693. Abstract 3352.
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
PATH-CHFChronic NYHA
1
2
3
4
Pre-implant 12 months
NYH
A fu
nctio
nal c
lass 3.05+0.16
1.90+0.76
N=29P<0.001
Impr
ovem
ent
Aurricchio A, Stellbrink C, Sack S, et al. Long-term benefit as a result of pacing resynchronization in congestive heart failure: results of the Path-CHF trial. Circulation. 2000;102(suppl II):II-693. Abstract 3352.
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
PATH-CHFChronic quality of life
10
20
30
40
50
60
Pre-implant 12 months
Qua
lity
of li
fe (p
oint
s)
49+23
20+22
N=28P<0.001
Impr
ovem
ent
Aurricchio A, Stellbrink C, Sack S, et al. Long-term benefit as a result of pacing resynchronization in congestive heart failure: results of the Path-CHF trial. Circulation. 2000;102(suppl II):II-693. Abstract 3352.
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
PATH-CHF
Aurricchio A, Stellbrink C, Sack S, et al. Long-term benefit as a result of pacing resynchronization in congestive heart failure: results of the Path-CHF trial. Circulation. 2000;102(suppl II):II-693. Abstract 3352.
P=0.003
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
MUSTIC
• 137 patients across 17 centers in Europe• Designed to evaluate the safety and clinical
efficacy of multi-site biventricular pacing in patients with severe CHF, chronic LV dysfunction and a wide QRS complex
• Resulted in improvement in exercise tolerance and decrease in hospitalization rates during biventricular phase
Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction Delay. N Engl J Med. 2001;344:12:873-80.
Multi-Site Stimulation in Cardiomyopathy
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
MUSTIC
1 year follow-up
1 month
2 weeks
3 months
3 months CRT on
CRT off
CRT off
CRT on
Implant success
Randomization
NYHA class III-IVLVEDD > 60 mm
QRS > 150 msSix-minute walk < 450 meters
EF < 35%
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Six-minute walk distancesMUSTIC
Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344:12:873-80.
• During the active phase (pacing turned on), the mean distance walked in six minutes was 23% longer (P < 0.001) than during the inactive phase
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Quality of life scoresMUSTIC
Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344:12:873-80.
• Minnesota Living with Heart Failure scores decreased by a mean of 32% (P < 0.001) with active pacing (pacing is on)
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
MUSTIC
Cazeau S, Leclercq C, Lavergne T, et al. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med. 2001;344:12:873-80.
6 min walking test + 23% p=0.0001 Peak VO2 +8% p=0.015 QoL Minnesota - 30% p=0.0002 Reduced Hospitalization Patient’s preference
CRT 86%
no pacing 4% p=0.001
no preference 10% 6 months mortality 5%
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Domanda:• Quale maggiore aspetto critico presentavano i primi studi?
1) Periodo di follow-up breve2) Disomogeneità della popolazione in esame3) Terapia farmacologica non ottimizzata4) Sottodimensionamento della popolazione
William T. Abraham, M.D., Westby G. Fisher, M.D., Andrew L. Smith, M.D., William T. Abraham, M.D., Westby G. Fisher, M.D., Andrew L. Smith, M.D., David B. Delurgio, M.D., Angel R. Leon, M.D., Evan Loh, M.D., Dusan Z. David B. Delurgio, M.D., Angel R. Leon, M.D., Evan Loh, M.D., Dusan Z.
Kocovic, M.D., Milton Packer, M.D., Alfredo L. Clavell, M.D., David L. Kocovic, M.D., Milton Packer, M.D., Alfredo L. Clavell, M.D., David L. Hayes, M.D., Myrvin Ellestad, M.D., and John Messenger, M.D., for the Hayes, M.D., Myrvin Ellestad, M.D., and John Messenger, M.D., for the
MIRACLE Study GroupMIRACLE Study Group
N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
MIRACLE Trial ResultsMIRACLE Trial Results Cardiac Resynchronization Cardiac Resynchronization
in Chronic Heart Failurein Chronic Heart Failure
• Moderate or severe heart failureModerate or severe heart failure– NYHA Functional Class III or IV NYHA Functional Class III or IV
• QRS duration QRS duration 130 msec 130 msec• LVEF LVEF 35% 35%• LVEDD LVEDD 55 millimeters (echo measure) 55 millimeters (echo measure)• 6 minute walk distance 6 minute walk distance 450 meters 450 meters• Stable optimal HF medical regimen Stable optimal HF medical regimen
for for 1 month 1 month– ACE-I or ARB, if toleratedACE-I or ARB, if tolerated– β-blocker - stable regimen β-blocker - stable regimen
for for 3 months 3 months Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
Study PopulationStudy Population
Study EndpointsStudy Endpoints
• Primary Efficacy:Primary Efficacy:– NYHA Functional ClassNYHA Functional Class
– Quality of life (Minnesota Living with Heart Failure)Quality of life (Minnesota Living with Heart Failure)
– 6-minute Walk Distance6-minute Walk Distance
• Secondary Efficacy Included:Secondary Efficacy Included:– Peak VOPeak VO22, Exercise Time, LVEF, LVEDD, MR, QRS , Exercise Time, LVEF, LVEDD, MR, QRS
Duration, Clinical Composite ResponseDuration, Clinical Composite Response
• Other Protocol Specified Endpoints:Other Protocol Specified Endpoints:– Death or Worsening Heart Failure Death or Worsening Heart Failure (Safety)(Safety)
– # Days Spent in Hospital # Days Spent in Hospital (Health Care Utilization)(Health Care Utilization)
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
Signed ConsentSigned Consent(N=571)(N=571)
Unsuccessful Unsuccessful ImplantsImplants(N=43)(N=43)
RandomizedRandomized(N=524)(N=524)
Not RandomizedNot Randomized(N=4)(N=4)
Implant SuccessImplant Success(N=528) 92%(N=528) 92%
6-Month 6-Month ProtocolProtocol(N=453)(N=453)
3-Month Protocol3-Month Protocol(N=71)(N=71)
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
EnrollmentEnrollment
Completed 6-MonthCompleted 6-MonthFollow-upFollow-up(n = 201)(n = 201)
Completed 6-MonthCompleted 6-MonthFollow-upFollow-up(n = 215)(n = 215)
1616 DeathDeath 121222 Heart transplantHeart transplant 0011 Infection/explantInfection/explant 1155 Missed 6M FUMissed 6M FU 00
Control Control (n = 225)(n = 225)
CRT CRT (n = 228)(n = 228)
Randomized Randomized 6-Month Protocol6-Month Protocol
(n = 453)(n = 453)
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
Enrollment and Follow-upEnrollment and Follow-up
CRT Improves Submaximal ExerciseCRT Improves Submaximal Exercise
Distance Walked in 6 MinutesDistance Walked in 6 Minutes Change from Baseline*Change from Baseline*
00
1010
2020
3030
4040
5050
6060
00 33 66Follow-up Period (Month)Follow-up Period (Month)
Met
ers
Met
ers
11* Paired median change* Paired median changeError bars are 95% CI.Error bars are 95% CI.
P=0.004P=0.004P=0.003P=0.003
P=0.005P=0.005
Baseline (meters)Baseline (meters)
291 ± 101
305 ± 85
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
CRTCRT
ControlControl
CRT Improves Patients’ Quality of LifeCRT Improves Patients’ Quality of Life
Minnesota Living with Heart Failure QuestionnaireMinnesota Living with Heart Failure Questionnaire
Baseline (score)Baseline (score)
59 ± 21
59 ± 20
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
* Paired median change* Paired median changeError bars are 95% CI.Error bars are 95% CI.
Change from Baseline*Change from Baseline*
00
55
1010
1515
2020
2525
00 33 66Follow-up Period (Month)Follow-up Period (Month)
Scor
e Im
prov
emen
t (po
ints
)Sc
ore
Impr
ovem
ent (
poin
ts)
11
P=0.001P=0.001P<0.001P<0.001P<0.001P<0.001
CRTCRT
ControlControl
CRT Improves NYHA Functional ClassCRT Improves NYHA Functional Class
00
2020
4040
6060
8080
100100
120120
Num
ber o
f Pat
ient
sN
umbe
r of P
atie
nts
Improved 2 orImproved 2 ormore classesmore classes
Improved 1Improved 1classclass
No ChangeNo Change WorsenedWorsened
ControlControl CRTCRT
6%6%
32%32%
59%59%
4%4%16%16%
52%52%
30%30%
2%2%
P<0.001P<0.001
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
Secondary Efficacy ResultsSecondary Efficacy Results
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
Paired median change at 6 months from baseline. Paired median change at 6 months from baseline. Error bars are 95% CI.Error bars are 95% CI.
Improvement in Peak VOImprovement in Peak VO22
-0.5-0.5
0.00.0
0.50.5
1.01.0
1.51.5
2.02.0
ControlControl(n=145)(n=145)
CRTCRT(n=158)(n=158)
ml/k
g/m
inm
l/kg/
min
P=0.009P=0.009
Improvement in Improvement in Total Exercise TimeTotal Exercise Time
00
3030
6060
9090
120120
ControlControl(n=146)(n=146)
CRTCRT(n=159)(n=159)
seco
nds
seco
nds
P=0.001P=0.001
Baseline Baseline (ml/kg/min)(ml/kg/min)
13.7 ± 3.8
14.0 ± 3.5
BaselineBaseline (secondsseconds)
462 ± 217
484 ± 209
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
CRT Improves Metabolic ExerciseCRT Improves Metabolic Exercise
Change in MR Jet AreaChange in MR Jet Area
-4-4-3-3-2-2-1-10011
ControlControl(n=118)(n=118)
CRTCRT(n=116)(n=116)
cmcm22
P<0.001P<0.001 P=0.009P=0.009
Change in LVEDDChange in LVEDD
-6-6
-4-4
-2-2
00
22
ControlControl(n=118)(n=118)
CRTCRT(n=116)(n=116)
mmmm P<0.001P<0.001
Absolute Change in LVEFAbsolute Change in LVEF
-2-2
00
22
44
66
88
ControlControl(n=146)(n=146)
CRTCRT(n=155)(n=155)
%%
Baseline (mm)Baseline (mm)
69 ± 10
70 ± 10
Baseline (cmBaseline (cm2)
7.2 ± 4.9
7.6 ± 6.4
Baseline (%)Baseline (%)
22 ± 6
22 ± 6
Paired median change from baseline at 6 months. Error bars are 95% CI.Paired median change from baseline at 6 months. Error bars are 95% CI.
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
CRT Improves Cardiac Function and StructureCRT Improves Cardiac Function and Structure
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
Effect of CRT on Composite ResponseEffect of CRT on Composite Response
39%39%34%34%
27%27%
67%67%
17%17% 16%16%0%0%
20%20%
40%40%
60%60%
ImprovedImproved No ChangeNo Change WorsenedWorsened
Pro
porti
onP
ropo
rtion
Control N=225Control N=225 CRT N=228CRT N=228
P < 0.001P < 0.001
Chi-square test
Safety and Health Care Utilization Safety and Health Care Utilization EndpointsEndpoints
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
HF IV medHF IV med
HF hospitalizationHF hospitalization
Death/HF hosp/HF IVDeath/HF hosp/HF IV
Death/HF hospitaliz.Death/HF hospitaliz.
Death—all causeDeath—all cause
00 11 22Relative RiskRelative Risk
0.50.5 1.51.5
Favors CRTFavors CRT Favors ControlFavors Control
P=0.40P=0.40
P=0.03P=0.03
P=0.02P=0.02
P=0.02P=0.02
P<0.01P<0.01
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
CRT (n=228)CRT (n=228)Control (n=225)Control (n=225)
Adverse Clinical EventsAdverse Clinical EventsDuring Double-blind PeriodDuring Double-blind Period
83
363
77%77%
ControlControln=34n=34
CRTCRTn=18n=18
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
Adverse Clinical EventsAdverse Clinical EventsTotal Days Hospitalized for Heart FailureTotal Days Hospitalized for Heart Failure
– is safe and well toleratedis safe and well tolerated– improves quality of life, functional class, and improves quality of life, functional class, and
exercise capacityexercise capacity– Improves cardiac function and structureImproves cardiac function and structure– improves heart failure composite responseimproves heart failure composite response– may have a favorable effect on combined may have a favorable effect on combined
measures of morbidity and mortalitymeasures of morbidity and mortality
In NYHA Class III and IV systolic heart failure In NYHA Class III and IV systolic heart failure patients with intraventricular conduction delays, patients with intraventricular conduction delays, cardiac resynchronization therapy:cardiac resynchronization therapy:
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
ConclusionsConclusions
ControlControl 225225 214214 204204 197197 191191 179179 7070CRTCRT 228228 218218 213213 209209 204204 201201 9999
Patients At RiskPatients At Risk
70%70%
75%75%
80%80%
85%85%
90%90%
95%95%
100%100%
00 11 22 33 44 55 66Months After RandomizationMonths After Randomization
Eve
nt F
ree
Sur
viva
l (%
)E
vent
Fre
e S
urvi
val (
%)
CRTCRT
ControlControlP = 0.033P = 0.033Relative risk = 0.60; Relative risk = 0.60; 95% CI (0.37, 0.96)95% CI (0.37, 0.96)
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
Time to Death or Worsening Heart FailureTime to Death or Worsening Heart FailureRequiring HospitalizationRequiring Hospitalization
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
• Parallel, randomized
• OPT1
• OPT• CRT
+2
• OPT• CRT-D +
2
Randomization
Study design
COMPANION(COmparison of Medical Therapy, Pacing, ANd DefibrillatION
in Heart Failure)
N°pts planned: 2200N°pts enrolled: 1520
542-12-#65
COMPANION: Endpoints (1)COMPANION: Endpoints (1)
• Primary Endpoint– Composite of time to first all-cause mortality
or all-cause hospitalization analyzed from randomized
• Hospital emergency or outpatient (unscheduled administration of IV inotropes or vasoactive drugs for more than 4 hours were considered a hospitalization primary endpoint)
HFSA Late-Breaker Sept 24, 2003
542-12-#66
COMPANION: Endpoints (2)COMPANION: Endpoints (2)
• Highest order secondary endpoint:– All-Cause Mortality
• Other outcomes analyzed: – Combined mortality or CV, heart failure
hospitalizations
HFSA Late-Breaker Sept 24, 2003
542-12-#67
COMPANION: Primary EndpointCOMPANION: Primary Endpoint Composite of all-cause mortality or all-cause hospitalization Composite of all-cause mortality or all-cause hospitalization
HFSA Late-Breaker Sept 24, 2003
542-12-#68
COMPANION: Secondary EndpointCOMPANION: Secondary EndpointAll Cause MortalityAll Cause Mortality
HFSA Late-Breaker Sept 24, 2003
542-12-#69
COMPANION: ConclusionsCOMPANION: Conclusions
When added to optimal pharmacological therapy in patients with moderate-severe LV dysfunction, NYHA Class III or IV symptoms and QRS lengthening• CRT or CRT-D reduces mortality + hospitalization• CRT-D reduces mortality
– 2/3 of the effect size can be attributed to CRT
HFSA Late-Breaker Sept 24, 2003
The CARE-HF StudyCArdiac REsynchronisation in Heart Failure
John GF Cleland - Kingston-upon-Hull. UKJean-Claude Daubert – Rennes. FranceErland Erdmann – Cologne. GermanyNick Freemantle – Birmingham. UK
Daniel Gras – Nantes. FranceLukas Kappenberger – Lausanne. Switzerland
Werner Klein – Graz. AustriaLuigi Tavazzi – Pavia. Italy
on behalf of the CARE-HF Study Investigators
Main Inclusion & Exclusion Criteria• Heart failure for at least 6 weeks requiring loop diuretics• Currently in NYHA class III/IV• A high standard of pharmacological therapy
• LV systolic dysfunction and dilation– EF 35%; EDD 30mm/height in metres
• QRS 120 ms– Dyssynchrony confirmed by echo if QRS 120-149 ms
• Aortic pre-ejection delay >140ms• Interventricular mechanical delay >40 ms• Delayed activation of postero-lateral LV wall
• Patients with AF or requiring pacing excluded
N° pts enrolled: 813
Primary & Principal Secondary Endpoints
Primary composite endpoint• All-cause mortality or unplanned hosp. for a major
CVS event (time to first event analysis)– Hospitalisations adjudicated by a blinded EP committee
Principal secondary endpoint• All-cause mortality
Primary Endpoint(All-cause Mortality or Unplanned Hosp. for Major CVS Event)
348118232292404Medical Therapy768166273323409CRT
Number at risk 0 500 1000 15000.00
0.25
0.50
0.75
1.00
Eve
nt-f
ree
Surv
ival
Days
Medical Therapy
Primary Endpoint(All-cause Mortality or Unplanned Hosp. for Major CVS Event)
348118232292404Medical Therapy768166273323409CRT
Number at risk 0 500 1000 15000.00
0.25
0.50
0.75
1.00HR 0.63 (95% CI 0.51 to 0.77)
Eve
nt-f
ree
Surv
ival
Days
P < .0001CRT
Medical Therapy
Primary Endpoint(All-cause Mortality or Unplanned Hosp. for Major CVS Event)
348118232292404Medical Therapy768166273323409CRT
Number at risk 0 500 1000 15000.00
0.25
0.50
0.75
1.00HR 0.63 (95% CI 0.51 to 0.77)
Eve
nt-f
ree
Surv
ival
Days
P < .0001CRT
Medical TherapyNo statistical significant
heterogeneity in subgroups
All-Cause Mortality
571192321365404Medical Therapy889213351376409CRT
Number at risk 0 500 1000 15000.00
0.25
0.50
0.75
1.00
Eve
nt-f
ree
Surv
ival
Days
Medical Therapy
All-Cause Mortality
571192321365404Medical Therapy889213351376409CRT
Number at risk 0 500 1000 15000.00
0.25
0.50
0.75
1.00
Eve
nt-f
ree
Surv
ival
Days
Medical Therapy
HR 0.64 (95% CI 0.48 to 0.85)
P = .0019CRT
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
QUESTIONI APERTE• Pazienti con classe NYHA II
Effects of Cardiac Resynchronization on Disease Progression in Patients With Left Ventricular Systolic
Dysfunction, an Indication for an Implantable Cardioverter-Defibrillator, and Mildly Symptomatic
Chronic Heart Failure
by William T. Abraham, James B. Young, Angel R. León, Stuart Adler, Alan J. Bank, Shelley A. Hall, Randy Lieberman, L. Bing Liem, John B. O’Connell, John S.
Schroeder, and Kevin R. Wheelan
CirculationVolume 110(18):2864-2868
November 2, 2004
Copyright © American Heart Association, Inc. All rights reserved.
MIRACLE ICD II
Effects of Cardiac Resynchronization on Disease Progression in Patients With Left Ventricular Systolic
Dysfunction, an Indication for an Implantable Cardioverter-Defibrillator, and Mildly Symptomatic
Chronic Heart Failure
by William T. Abraham, James B. Young, Angel R. León, Stuart Adler, Alan J. Bank, Shelley A. Hall, Randy Lieberman, L. Bing Liem, John B. O’Connell, John S.
Schroeder, and Kevin R. Wheelan
Copyright © American Heart Association, Inc. All rights reserved.
MIRACLE ICD II
Patients eligible for enrollment:• mildly symptomatic (NYHA class II) chronic heart failure• LV ejection fraction ≤35%• LV end diastolic dimension ≥55 mm• QRS interval ≥130 ms,• an indication for an ICD
Patients were then randomly assigned to either optimal medical treatment with active CRT and active ICD therapy (CRT group) or optimal medical treatment and active ICD therapy only (control group)
…. 186 implanted patients were randomized (control group, n101; CRT group, n85)
Figure 1. Change in LV volumes and LVEF after 6 months of CRT or no pacing.
William T. Abraham et al. Circulation. 2004;110:2864-2868
Copyright © American Heart Association, Inc. All rights reserved.
MIRACLE ICD II
Figure 2. Effect of CRT on composite clinical response at 6 months.
William T. Abraham et al. Circulation. 2004;110:2864-2868
Copyright © American Heart Association, Inc. All rights reserved.
MIRACLE ICD II
REsynchronization reVErses Remodeling inSystolic left vEntricular dysfunction:
Results of the REVERSE Trial
Cecilia Linde, Stockholm, SwedenWilliam T. Abraham, Columbus, U.S
Michael R. Gold, Charleston, U.S.Jean-Claude Daubert, Rennes, France
On Behalf of the REVERSEInvestigators and Coordinators
• To determine the effects of CRT with or without an ICD on disease progression over 12 months in patients with asymptomatic and mildly symptomatic heart failure and ventricular dysynchrony
• Randomized, double-blind, parallel-controlled clinical trial
Purpose and DesignPurpose and Design
• NYHA Class II or I (previously symptomatic)
• QRS 120 ms; LVEF 40%; LVEDD 55 mm
• Optimal medical therapy (OMT)
• Without permanent cardiac pacing
• With or without an ICD indication
Inclusion CriteriaInclusion Criteria
Baseline Assessment
Successful CRT Implant
Randomized 1:2
CRT OFF(OMT ± ICD)
CRT ON(OMT ± ICD)
U.S., Canada: at 12 Months, all patients recommended CRT ONEurope: at 24 Months, all patients recommended CRT ON
1
2
12 Months
Study SchematicStudy Schematic
• Primary: HF Clinical Composite Response, comparing the proportion of patients worsened in CRT OFF vs. CRT ON groups
• Composite includes: all-cause mortality, HF hospitalizations, crossover due to worsening HF, NYHA class, and the patient global assessment assessed in double blind manner
• Prospectively Powered Secondary: Left Ventricular End Systolic Volume Index (LVESVi) comparing CRT OFF vs. CRT ON subjects
• LVESVi is assessed by two core labs (1 in Europe, 1 in U.S)
End PointsEnd Points
684 Enrolled (2004-2006)
642 Implant Attempts
610 Patients RandomizedU.S. 343 (56%); Europe 262 (43%); Canada 5 (<1%)
CRT OFF 191 Patients CRT ON 419 Patients
- 594/598 completed 12 month follow-up - 12 deaths (2%) - 0 lost to follow-up, 0 exits
-21 unsuccessful implant
621 Successful CRT Implants(97%)
-42 ineligible or withdrew
-11 exits after successful implant
Enrollment and RandomizationEnrollment and Randomization
40%54%
39%30%
16%21%
0%
20%
40%
60%
80%
100%
CRT OFF
CRT ON
Improved / Unchanged
Pre-Specified AnalysisProportion Worsened
Conventional AnalysisDistribution Worsened/Unchanged
/Improved
Worsened
Unchanged
Improved
P=0.004
Primary End Point: Primary End Point: Clinical Composite ResponseClinical Composite Response
79% 84%
16%21%
0%
20%
40%
60%
80%
100%
CRT OFF CRT ON
P=0.10
Worsened
70
75
80
85
90
95
100
105
110
115
Baseline 12 Months
LVES
Vi (m
l/m2 )
CRT OFF = -1.3
CRT ON = -18.4
P<0.0001
n=487
Powered Secondary End Point: LVESViPowered Secondary End Point: LVESVi (ml/m(ml/m22))
12 MonthsBaseline
LVEDVi (ml/m(ml/m22))P<0.0001
LVEF (%)P<0.0001
12 MonthsBaseline
CRT OFF ∆ = 0.6
CRT ON ∆ = 3.8
CRT OFF ∆ = -1.4
CRT ON∆ = -20.5
n=487
20
22
24
26
28
30
32
34
90
100
110
120
130
140
150
Other Remodeling ParametersOther Remodeling Parameters
360
370
380
390
400
410
420
430
440
Baseline 12 Mo
CRT OFF=18.7
CRT ON=12.7
15
17
19
21
23
25
27
29
31
33
35
Baseline 12 Mo
CRT OFF=-6.7
CRT ON=-8.4
MN LWHFP=0.26
6-Min Walk TestP=0.26
NYHAP=0.06
Other Secondary EndpointsOther Secondary Endpoints
32%
65%
57%
13% 11%
22%
0%
20%
40%
60%
80%
100%
CRT OFF CRT ON
Improved
Same
Worse
0%
5%
10%
15%
0 3 6 9 12% o
f Pat
ient
s H
ospi
taliz
ed fo
r HF
Number at Risk CRT OFF 191 187 181 176 119 CRT ON 419 415 411 409 251
P=0.03 Hazard Ratio=0.47
CRT OFF
CRT ON
Months Since Randomization
Time to First HF HospitalizationTime to First HF Hospitalization
REVERSE is the first large, randomized, double-blind study to show that CRT in asymptomatic and mildly symptomatic heart failure patients on optimal medical therapy:
• Reverses LV remodeling• Reduces the risk of heart failure hospitalization• May improve clinical outcome as assessed by the
clinical composite response measure
Note: FDA has not yet reviewed the clinical data to determine whether or not CRT systems are safe and effective in this patient population.
ConclusionConclusion
MADIT-CRTMADIT-CRTEntry Criteria:Entry Criteria: Ischemic NYHA I-IIIschemic NYHA I-II
or non-ischemic NYHA class II or non-ischemic NYHA class II EF EF ≤≤0.300.30 QRS QRS >>130 msec130 msec Sinus RhythmSinus Rhythm Optimal pharmacologic therapy: Optimal pharmacologic therapy:
B-b (>3 mo.); ACE/ARB (>1 mo.); statins in IHDB-b (>3 mo.); ACE/ARB (>1 mo.); statins in IHD
Exclusions:Exclusions: NYHA III-IV <90 days PTENYHA III-IV <90 days PTE Acute MI, CABG, PCI <3 monthsAcute MI, CABG, PCI <3 months Existing ICD or CRT deviceExisting ICD or CRT device AF; PRAF; PR>>250ms; 2250ms; 2ndnd or 3 or 3rdrd degree HB degree HB BUN >70mg/dl or creatinine >3.0mg/dlBUN >70mg/dl or creatinine >3.0mg/dl
RandomizationRandomizationN=1,820N=1,820
CRT-DCRT-DN=1,089 N=1,089
ICM NYHA I/II and NICM NYHA II ICM NYHA I/II and NICM NYHA II EF EF << 0.30 0.30
QRS QRS >>0.13sec0.13sec
ICD onlyICD onlyN=731 N=731
Kaplan-Meier Estimates of the Probability of Survival Free of Heart Failure
Moss AJ et al. N Engl J Med 2009;361:1329-1338
HRHR (95% CI) (95% CI) P P ValueValue
Heart failure or DeathHeart failure or Death 0.66 0.66 (0.52–0.84)(0.52–0.84) 0.0010.001
Heart failure onlyHeart failure only 0.59 0.59 (0.47–0.74) (0.47–0.74) <0.001<0.001
Death at any timeDeath at any time 1.00 1.00 (0.69–1.44) (0.69–1.44) 0.990.99
Hazard Ratio for CRT-D vs. ICD only in MADIT-Hazard Ratio for CRT-D vs. ICD only in MADIT-CRTCRT
Changes in Mean Echocardiographic Left Ventricular Volumes and Ejection Fraction between Baseline and 1-Year
Follow-up
Moss AJ et al. N Engl J Med 2009;361:1329-1338
Effects of CRT-D by QRS Effects of CRT-D by QRS Morphology in MADIT-CRTMorphology in MADIT-CRT
LBBB; 1281; 70%
RBBB; 228; 13%
IVCD; 306; 17%Non-Non-
LBBBLBBB
534, 30%534, 30%
Cumulative Probability of Cumulative Probability of Heart Failure (HF) Event or DeathHeart Failure (HF) Event or Death by Treatment (CRT-D vs. ICD only) in patients with LBBB and by Treatment (CRT-D vs. ICD only) in patients with LBBB and
Non-LBBB QRS Pattern in MADIT-CRT PatientsNon-LBBB QRS Pattern in MADIT-CRT Patients
LBBBLBBB Non-LBBBNon-LBBB
RBBBRBBB IVCDIVCD
Cumulative Probability of Cumulative Probability of Heart Failure (HF) Event or DeathHeart Failure (HF) Event or Death by Treatment (CRT-D vs. ICD only) in patients with RBBB and by Treatment (CRT-D vs. ICD only) in patients with RBBB and
IVCD QRS Pattern in MADIT-CRT PatientsIVCD QRS Pattern in MADIT-CRT Patients
LBBBLBBB Non-LBBBNon-LBBB
Cumulative Probability of Cumulative Probability of DeathDeath by Treatment (CRT-D vs. ICD by Treatment (CRT-D vs. ICD only) in patients with LBBB and Non-LBBB QRS Pattern only) in patients with LBBB and Non-LBBB QRS Pattern
in MADIT-CRT Patientsin MADIT-CRT Patients
Endpoint LBBBn=1,281
Non-LBBBn=536
P value for Inter-
actionHeart Failure Event HR 0.47 1.24or Death 95% CI 0.37,0.61 0.85,1.81
P value <0.001 0.257 <0.001
Heart Failure Event HR 0.41 1.2395% CI 0.31,0.54 0.76,1.68P value <0.001 0.559 <0.001
Death HR 0.75 1.7995% CI 0.49,1.16 0.90,3.57P value 0.196 0.097 0.037
Hazard Ratios for Clinical Endpoints by QRS MorphologyHazard Ratios for Clinical Endpoints by QRS Morphology
* The model adjusted for sex, ischemic or nonischemic cardiomyopathy, prior * The model adjusted for sex, ischemic or nonischemic cardiomyopathy, prior hospitalizations for heart failure, ejection fraction, QRS>150, left ventricular hospitalizations for heart failure, ejection fraction, QRS>150, left ventricular ejection fraction, left ventricular end-systolic volume. ejection fraction, left ventricular end-systolic volume.
Endpoint LBBBn=1,281
Non-LBBBn=536
P value for Inter-
actionVT/VF HR 0.67 1.11
95% CI 0.52,0.87 0.77,1.60P value 0.002 0.574 0.028
VF HR 0.54 1.2495% CI 0.33,0.87 0.58,2.66P value 0.011 0.585 0.070
VT/VF/Death HR 0.69 1.2195% CI 0.55,0.87 0.87,1.69P value 0.002 0.254 0.006
Hazard Ratios for Clinical Endpoints by QRS MorphologyHazard Ratios for Clinical Endpoints by QRS Morphology
* The model adjusted for sex, ischemic or nonischemic cardiomyopathy, prior * The model adjusted for sex, ischemic or nonischemic cardiomyopathy, prior hospitalizations for heart failure, ejection fraction, QRS>150, left ventricular hospitalizations for heart failure, ejection fraction, QRS>150, left ventricular ejection fraction, left ventricular end-systolic volume. ejection fraction, left ventricular end-systolic volume.
0,0
0,5
1,0
1,5
2,0
2,5
HF or Death HF Death VT/VF/Death VF/Death
LBBBNon-LBBBRBBBIVCD
Hazard Ratios for Primary and Secondary Endpoints Hazard Ratios for Primary and Secondary Endpoints by QRS Morphology in MADIT-CRTby QRS Morphology in MADIT-CRT
**p<0.05p<0.05
********
Hazard Ratios for Primary Endpoint by QRS Morphology and Hazard Ratios for Primary Endpoint by QRS Morphology and Duration by GenderDuration by Gender
MalesMales FemalesFemalesnn HR HR P valueP value nn HR HR P valueP value
QRS DurationQRS Duration <140 ms<140 ms 240240 1.691.69 0.0630.063 61 61 0.200.20 0.0080.008 140-159 ms140-159 ms 465465 0.770.77 0.1640.164 178178 0.310.31 0.0010.001 160-179 ms160-179 ms 417417 0.510.51 0.0030.003 153153 0.420.42 0.0360.036 ≥ ≥180 ms180 ms 242242 0.500.50 0.0190.019 61 61 0.330.33 0.1000.100
QRS MorphologyQRS Morphology LBBB*LBBB* 887887 0.56 0.56 <0.001<0.001 394394 0.25 0.25 <0.001<0.001 Non-LBBBNon-LBBB 477477 1.25 1.25 0.273 0.273 59 59 1.551.55 0.5160.516 RBBBRBBB 210210 0.94 0.94 0.841 0.841 18 18 NANA
IVCD IVCD 267267 1.49 1.49 0.133 0.133 41 41 1.311.31 0.7010.701
* p=0.006 for interaction comparing HR = 0.56 in males vs. HR = 0.25 in females* p=0.006 for interaction comparing HR = 0.56 in males vs. HR = 0.25 in females
-23
-35
12
-16
-26
9
-40
-30
-20
-10
0
10
20
LVEDV LVESV EF
LBBBNon-LBBB
Mean Change in Echocardiographic Mean Change in Echocardiographic Parameters from Enrollment to 12 months in Parameters from Enrollment to 12 months in
CRT-D PatientsCRT-D Patients
**
**
**
* p<0.001 when comparing * p<0.001 when comparing LBBB and Non-LBBB LBBB and Non-LBBB patientspatients(all changes within (all changes within subgroups were significant)subgroups were significant)
MADIT-CRT ConclusionsMADIT-CRT Conclusions
1.1. Heart failure patients with NYHA class I or II and Heart failure patients with NYHA class I or II and ejection fraction ejection fraction ≤30% who present with LBBB ≤30% who present with LBBB derive substantial benefit from CRT-D: reduction derive substantial benefit from CRT-D: reduction in heart failure progression and reduction in the in heart failure progression and reduction in the risk of ventricular tachyarrhythmias. risk of ventricular tachyarrhythmias.
2.2. No evidence of CRT-D benefit was observed in No evidence of CRT-D benefit was observed in patients with Non-LBBB QRS pattern: RBBB or patients with Non-LBBB QRS pattern: RBBB or IVCD regardless of their QRS duration. IVCD regardless of their QRS duration.
3.3. Beneficial effect of CRT-D in LBBB patients was Beneficial effect of CRT-D in LBBB patients was observed in all studied subjects: males and observed in all studied subjects: males and females, ischemic and non-ischemic, QRS>150 and females, ischemic and non-ischemic, QRS>150 and QRS<150 ms. QRS<150 ms.
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra Indicazioni CRT• Linee guida ESC CRT (2010)
Dickstein K. et al., 2010 Focused Update of ESC Guidelines on device therapy in heart failure. Eur Heart J. 2010; 31, 2677–2687
COMPANIONCARE-HF
MADIT CRT
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra Indicazioni CRT• Linee guida ESC CRT
(update 2013)
Brignole M. et al., 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J. 2013; 34, 2281–2329
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra Indicazioni CRT• Linee guida ESC CRT
(update 2015)
Priori S. et al., 2015 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death Eur Heart J. 2015
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Domanda
•Quale importante trial clinico sulla CRT ha permesso di identificare meglio i pazienti candidati e dal quale è nata la necessità di un aggiornamento delle linee guida?
1.CARE-HF2.COMPANION3.MADIT-CRT 4.RAFT
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
QUESTIONI APERTE• Pazienti con classe NYHA II• CRT-P vs CRT-D
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT-P vs. CRT-D• Argomento ancora molto dibattuto• EF compromessa → CRT + ICD• Scelta guidata spesso da fattori geografici,
economici, ...• Superiorità del CRT-D vs. CRT-P
– non sempre dimostrata– con differenze nei risultati non sempre statisticamente
significative– periodi di follow-up brevi
Exner D. et al., Contemporary and future trends in cardiac resynchronization therapy to enhance response. Heart Rhythm, Vol 9, No 8S, August Supplement 2012
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT-P vs. CRT-DConsiderazioni:
1.Recupero della EF > 35% dopo 6-12 mesi di CRT2.Maggiori rischi device-related per la CRT-D (longevità inferiore, complicanze leads) e costi3.Rischio di shock inappropriati: 13 ÷ 17% pz. (MADIT II, SCD-HeFT)4.Possibilità di considerare il downgrade da CRT-D a CRT-P in pazienti con EF normalizzata (> 50%)
Exner D. et al., Contemporary and future trends in cardiac resynchronization therapy to enhance response. Heart Rhythm, Vol 9, No 8S, August Supplement 2012
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra CRT-P vs. CRT-D
Martin H. Ruwald MH, Solomon SD, Foster E, et al. Left Ventricular Ejection Fraction Normalization in Cardiac Resynchronization Therapy and Risk of Ventricular Arrhythmias and Clinical Outcomes: Results from the MADIT-CRT Trial. Circ, 2014
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
QUESTIONI APERTE• Pazienti con classe NYHA II• CRT-P vs CRT-D• Percentuali Responders
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
CRT Responder
Brignole M. et al., 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J. 2013; 34, 2281–2329
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra CRT Responder
Exner D. et al., Contemporary and future trends in cardiac resynchronization therapy to enhance response. Heart Rhythm, Vol 9, No 8S, August Supplement 2012Barsheshet A, Goldenberg I, Moss AJ, et al. Response to preventive cardiac resynchronization therapy in patients with ischaemic and nonischaemic cardiomyopathy in MADIT-CRT. Eur Heart J 2011;32:1622–1630.
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra Domanda
•Quale percentuale di stimolazione biventricolare risulta efficace per la riduzione significativa del tasso di mortalità in pazienti con terapia CRT?
1.> 85%2.> 90% 3.> 95%4.> 98%
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
QUESTIONI APERTE• Pazienti con classe NYHA II• CRT-P vs CRT-D• Percentuali Responders• QRS stretto
From: Impact of QRS Duration on Clinical Event Reduction With Cardiac Resynchronization Therapy: Meta-analysis of Randomized Controlled Trials
Arch Intern Med. 2011;171(16):1454-1462. doi:10.1001/archinternmed.2011.247
Figure 4. Meta-regression analysis examining the impact of baseline QRS duration on the effect of cardiac resynchronization therapy (CRT) on composite clinical events. Each circle represents a QRS subgroup within a trial. The sizes of the circles are proportional to the sample size in each subgroup. The dashed line corresponds to a log risk ratio (RR) of 0 (ie, RR, 1.00), where there is no net benefit or harm. The further the circles are below the 0 line, the larger the clinical benefit for prevention of composite of adverse clinical events. There was a statistically significant relationship between the QRS duration at baseline and log RR (slope, −0.07 [95% confidence interval, −0.10 to −0.04]; z = −4.60) (P < .001). Accordingly, groups with QRS ranges below 150 milliseconds did not benefit from CRT (black circles, log risk ratio close to 0). Clinical benefit appeared when cases with QRS intervals of 150 milliseconds or greater were included (gray circles) and became more prominent with increasing QRS width (white circles). CARE-HF indicates Cardiac Resynchronization-Heart Failure; COMPANION, Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure; CRT, cardiac resynchronization therapy; MADIT-CRT, Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy; RAFT, Resynchronization-Defibrillation for Ambulatory Heart Failure Trial; REVERSE, Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction.
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra QRS stretto: EchoCRT
Ruschitzka F. et al., Cardiac-Resynchronization Therapy in Heart Failure with a Narrow QRS Complex, N Engl J Med 2013;369:1395-405
• CRT ON vs. CRT OFF (Control Group)- 809 pazienti con QRS stretto (QRS < 130 ms) - classe NYHA III o IV- EF ≤ 35%- dissincronia meccanica LV valutata con ecocardiografia- follow-up: 19 mesi
• CRT non riduce il tasso di mortalità o di ospedalizzazione per HF
• Possibilità che la CRT in tali pazienti incrementi la mortalità
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Direzioni future della CRT
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
Direzioni future della CRT• Trial CRT:
- rafforzare le conoscenze derivanti da precedenti trial
- sondare l’efficacia della CRT sugli aspetti meno investigati della patologia HF
- individuare sottogruppi di pazienti con criteri di inclusione non testati nei precedenti studi per verificare l’efficacia della CRT in questi pool
- dimostrare il reale beneficio delle nuove tecnologie dei device CRT per la riduzione della morbidità e mortalità della popolazione HF
E-Day 19 Settembre 2015
Gius
eppe
Are
naDi
rett
ore
U.O
.C U
TIC
– Ca
rdio
logi
a U
SL1
Mas
sa C
arra
ra
La ricerca futura...
• Criteri di aggiudicazione degli endpoint sempre più uniformi (es. definizione di ospedalizzazione)
• Metodi di raggiungimento, definizione e mantenimento della terapia farmacologica ottimizzata standardizzati
• Valutazione del rapporto costo-efficacia CRT• Identificazione dei pazienti super-responder• Ottimizzazione della programmazione dei device CRT, follow-up ambulatoriale
e remoto• Maggiore comprensione patofisiologica della dissincronopatia a livello
meccanico ed elettrico
Approccio multidisciplinare alla cura dei pazienti HF