Trial e crt

E-Day 19 Settembre 2015
GiuseppeArena
DirettoreU.O.CUTIC–CardiologiaUSL1MassaCarrara
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

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CRT: nascita ed evoluzione
• Scompenso Cardiaco: patologia cardiovascolare in aumento
tra le più disabilitanti, mortali e costose

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2%2%
2.7%2.7%
4.9%4.9%
1990
2010
2030
Kelly DT, Circulation 1997
PREVALENZA CRESCENTE

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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.
100100
9090
8080
7070
6060
5050
4040
3030
2020
1010
00
Probabilityofsurvival,%
Men (n = 237)
Women (n = 230)
Time after CHF diagnosis, years
00 22 44 66 88 1010
80% of men and 70% of
women who have CHF will
die within 8 years.2
80% of men and 70% of
women who have CHF will
die within 8 years.2

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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%+50%

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• 1 su 3 pazienti con SC: contrazione ventricolare dissincrona

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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

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• 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

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• Scompenso Cardiaco: patologia cardiovascolare tra le più disabilitanti, mortali e costose
• 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

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• Scompenso Cardiaco: patologia cardiovascolare tra le più disabilitanti,
mortali e costose
• 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

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 54 aa. CMPD e CHF refrattario
PR 200 ms
BBS (QRS 200 ms)
Blocco interatriale (90 ms dx-sn)
Four Chamber Pacing in Dilated Cardiomyopathy
S. 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

GiuseppeArena
• Scompenso Cardiaco: patologia cardiovascolare tra le più disabilitanti,
mortali e costose
• 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

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Domanda:
• Quali possono essere allo stato attuale gli obiettivi nell’ambito
della CRT:
1) aumentare il rate dei pazienti responder alla terapia CRT
2) estendere il trattamento a pazienti che potrebbero
beneficiare della terapia CRT 
3) ridurre le possibili controindicazioni alla terapia CRT
4) selezionare con maggiore accuratezza i pazienti candidati

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Prevalence of Ventricular
Dyssynchrony in Heart Failure
Left Bundle Branch Block More Prevalent
with Impaired LV Systolic Function
38%
24%
8%
Moderate/Severe
HF (2)
Impaired LVSF
(1)
Preserved LVSF
(1)
1. Masoudi, et al. JACC 2003;41:217-23
2. Aaronson, et al. Circ 1997;95:2660-7

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Elements of Cardiac Dyssynchrony
Atrio-
ventricular
Inter-
ventricular
Intra-
ventricular
Cazeau, et al. PACE 2003; 26[Pt. II]: 137–143

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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

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Deleterious Effects of Ventricular
Dyssynchrony on Survival
Long Term--45 Months
34%
49%
QRS <
120 ms
QRS >
120 ms
Iuliano et al. AHJ 2002;143:1085-91
N=669
P < 0.001
Moderate Term--1 Year
11%
16%
QRS <
120 ms
QRS >
120 ms
P < 0.001
Baldasseroni S, et al. Am Heart J 2002;143:398-405
N=5,517

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Cardiac Resynchronization Therapy
Jaffe LM, Morin DP Cardiac Resynchronization Therapy: History, Present Status, and Future Directions.The Ochsner Journal 2014; 14:596-607

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Domanda:
• Quale può essere il marker di dissincronia validato per
qualificare i pazienti candidati alla CRT:
1) Dissincronia meccanica
2) Frazione d’eiezione del ventricolo sinistro
3) Durata QRS 
4) Percentuale di stimolazione del ventricolo destro

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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

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Cumulative Enrollment in Cardiac Resynchronization
Randomized Trials

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Heart Failure Trial Progression
Symptoms/quality of life
Measures of disease progression
Transvenous system
Pilot
Mortality and morbidity
1996
2005
Mounting evidence

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Early Trials
Feasibility and safety
Relief of symptoms
Trials with hard end-points
Mortality
Morbidity
Path-CHF
MUSTIC
MIRACLE
Companion
CARE-HF
Heart Failure Trial Progression

Multicenter controlled randomized crossover trial
AIM of the STUDY
Evaluation 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-CHF
Study Design
Inclusion Criteria
NYHA III/IV
Sinus Rhythm
QRS width > 120 msec
PR >150 msec
42 pts
randomized

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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.

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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.

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PATH-CHF
Chronic peak VO2
0.5
0.75
1
1.25
1.5
Pre-implant 12 months
PeakVO2(l/min)
0.97+0.26
1.19+0.34
N=14
P=0.019
Improvement
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.

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PATH-CHF
Chronic VO2 AT
0.5
0.75
1
VO2AT(l/min)
0.76+0.21
0.91+0.31
N=18
P=0.018
Improvement

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PATH-CHF
Chronic six-minute walk distances
300
350
400
450
500
six-minutewalk(m)
357+101
446+74
N=25
P<0.001
Improvement

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PATH-CHF
Chronic NYHA
1
2
3
4
NYHAfunctionalclass
3.05+0.16
1.90+0.76
N=29
P<0.001
Improvement

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PATH-CHF
Chronic quality of life
10
20
30
40
50
60
Qualityoflife(points)
49+23
20+22
N=28
P<0.001
Improvement

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PATH-CHF
P=0.003

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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

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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-IV
LVEDD > 60 mm
QRS > 150 ms
Six-minute walk < 450 meters
EF < 35%

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Six-minute walk distances
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.
• 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

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Quality of life scores
MUSTIC
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)

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MUSTIC
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%

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Domanda:
• Quale maggiore aspetto critico presentavano i primi studi?
1) Periodo di follow-up breve
2) Disomogeneità della popolazione in esame
3) Terapia farmacologica non ottimizzata
4) 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 theHayes, 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;346:1845-18532002;346:1845-1853
MIRACLE Trial ResultsMIRACLE Trial Results
Cardiac ResynchronizationCardiac Resynchronization
in Chronic Heart Failurein Chronic Heart Failure

• Moderate or severe heart failureModerate or severe heart failure
– NYHA Functional Class III or IVNYHA Functional Class III or IV
• QRS durationQRS duration ≥≥ 130 msec130 msec
• LVEFLVEF ≤≤ 35%35%
• LVEDDLVEDD ≥≥ 55 millimeters (echo measure)55 millimeters (echo measure)
• 6 minute walk distance6 minute walk distance ≤≤ 450 meters450 meters
• Stable optimal HF medical regimenStable optimal HF medical regimen
forfor ≥≥ 1 month1 month
– ACE-I or ARB, if toleratedACE-I or ARB, if tolerated
– β-blocker - stable regimenβ-blocker - stable regimen
forfor ≥≥ 3 months3 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;346:1845-18532002;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 FailureDeath or Worsening Heart Failure (Safety)(Safety)
– # Days Spent in Hospital# Days Spent in Hospital (Health Care Utilization)(Health Care Utilization)

Signed ConsentSigned Consent
(N=571)(N=571)
UnsuccessfulUnsuccessful
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-Month6-Month
ProtocolProtocol
(N=453)(N=453)
3-Month Protocol3-Month Protocol
(N=71)(N=71)
EnrollmentEnrollment

Completed 6-MonthCompleted 6-Month
Follow-upFollow-up
(n = 201)(n = 201)
Completed 6-MonthCompleted 6-Month
Follow-upFollow-up
(n = 215)(n = 215)
1616 DeathDeath 1212
22 Heart transplantHeart transplant 00
11 Infection/explantInfection/explant 11
55 Missed 6M FUMissed 6M FU 00
ControlControl
(n = 225)(n = 225)
CRTCRT
(n = 228)(n = 228)
RandomizedRandomized
6-Month Protocol6-Month Protocol
(n = 453)(n = 453)
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 66
Follow-up Period (Month)Follow-up Period (Month)
MetersMeters
11
* Paired median change* Paired median change
Error bars are 95% CI.Error bars are 95% CI.
P=0.004P=0.004
P=0.003P=0.003
P=0.005P=0.005
Baseline (meters)Baseline (meters)
291 ± 101
305 ± 85
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
* Paired median change* Paired median change
Change from Baseline*Change from Baseline*
00
55
1010
1515
2020
2525
00 33 66
Follow-up Period (Month)Follow-up Period (Month)
ScoreImprovement(points)ScoreImprovement(points)
11
P=0.001P=0.001
P<0.001P<0.001
P<0.001P<0.001
CRTCRT
ControlControl

CRT Improves NYHA Functional ClassCRT Improves NYHA Functional Class
00
2020
4040
6060
8080
100100
120120
NumberofPatientsNumberofPatients
Improved 2 orImproved 2 or
more classesmore classes
Improved 1Improved 1
classclass
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

Secondary Efficacy ResultsSecondary Efficacy Results

Paired median change at 6 months from baseline.Paired median change at 6 months from baseline.
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/kg/minml/kg/min
P=0.009P=0.009
Improvement inImprovement in
Total Exercise TimeTotal Exercise Time
00
3030
6060
9090
120120
ControlControl
(n=146)(n=146)
CRTCRT
(n=159)(n=159)
secondsseconds
P=0.001P=0.001
BaselineBaseline
(ml/kg/min)(ml/kg/min)
13.7 ± 3.8
14.0 ± 3.5
BaselineBaseline
(secondsseconds)
462 ± 217
484 ± 209
CRT Improves Metabolic ExerciseCRT Improves Metabolic Exercise

Change in MR Jet AreaChange in MR Jet Area
-4-4
-3-3
-2-2
-1-1
00
11
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.
CRT Improves Cardiac Function and StructureCRT Improves Cardiac Function and Structure

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
ProportionProportion
Control N=225Control N=225 CRT N=228CRT N=228
P < 0.001P < 0.001
Chi-square test

Safety and Health Care UtilizationSafety and Health Care Utilization
EndpointsEndpoints

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 22
Relative 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
CRT (n=228)CRT (n=228)
Control (n=225)Control (n=225)
Adverse Clinical EventsAdverse Clinical Events
During Double-blind PeriodDuring Double-blind Period

83
363
↓↓ 77%77%
ControlControl
n=34n=34
CRTCRT
n=18n=18
Adverse Clinical EventsAdverse Clinical Events
Total 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, andimproves 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 combinedmay have a favorable effect on combined
measures of morbidity and mortalitymeasures of morbidity and mortality
In NYHA Class III and IV systolic heart failureIn NYHA Class III and IV systolic heart failure
patients with intraventricular conduction delays,patients with intraventricular conduction delays,
cardiac resynchronization therapy:cardiac resynchronization therapy:
ConclusionsConclusions

ControlControl 225225 214214 204204 197197 191191 179179 7070
CRTCRT 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 66
Months After RandomizationMonths After Randomization
EventFreeSurvival(%)EventFreeSurvival(%)
CRTCRT
ControlControl
P = 0.033P = 0.033
Relative risk = 0.60;Relative risk = 0.60;
95% CI (0.37, 0.96)95% CI (0.37, 0.96)
Time to Death or Worsening Heart FailureTime to Death or Worsening Heart Failure
Requiring HospitalizationRequiring Hospitalization

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• Parallel, randomized
• OPT
1
• OPT
• CRT
+
2
• OPT
• CRT-D
+
2
Randomization
Study design
COMPANION
(COmparison of Medical Therapy, Pacing, ANd DefibrillatION
in Heart Failure)
N°pts planned: 2200
N°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

542-12-#67
COMPANION: Primary EndpointCOMPANION: Primary Endpoint
Composite of all-cause mortality or all-cause hospitalizationComposite of all-cause mortality or all-cause hospitalization

542-12-#68
COMPANION: Secondary EndpointCOMPANION: Secondary Endpoint
All Cause MortalityAll Cause Mortality

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

The CARE-HF Study
CArdiac REsynchronisation in Heart Failure
John GF Cleland - Kingston-upon-Hull. UK
Jean-Claude Daubert – Rennes. France
Erland Erdmann – Cologne. Germany
Nick Freemantle – Birmingham. UK
Daniel Gras – Nantes. France
Lukas Kappenberger – Lausanne. Switzerland
Werner Klein – Graz. Austria
Luigi 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 Therapy
768166273323409CRT
Number at risk
0 500 1000 1500
0.00
0.25
0.50
0.75
1.00
Event-freeSurvival
Days
Medical
Therapy

Primary Endpoint
768166273323409CRT
Number at risk
0 500 1000 1500
0.00
0.25
0.50
0.75
1.00
HR 0.63 (95% CI 0.51 to 0.77)
Event-freeSurvival
Days
P < .0001
CRT
Medical
Therapy

Primary Endpoint
768166273323409CRT
Number at risk
0 500 1000 1500
0.00
0.25
0.50
0.75
1.00
HR 0.63 (95% CI 0.51 to 0.77)
Event-freeSurvival
Days
P < .0001
CRT
Medical
TherapyNo statistical significant
heterogeneity in subgroups

All-Cause Mortality
889213351376409CRT
Number at risk
0 500 1000 1500
0.00
0.25
0.50
0.75
1.00
Event-freeSurvival
Days
Medical
Therapy

All-Cause Mortality
889213351376409CRT
Number at risk
0 500 1000 1500
0.00
0.25
0.50
0.75
1.00
Event-freeSurvival
Days
Medical
Therapy
HR 0.64 (95% CI 0.48 to 0.85)
P = .0019
CRT

GiuseppeArena
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
Circulation
Volume 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
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
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
MIRACLE ICD II

REsynchronization reVErses Remodeling in
Systolic left vEntricular dysfunction:
Results of the REVERSE Trial
Cecilia Linde, Stockholm, Sweden
William T. Abraham, Columbus, U.S
Michael R. Gold, Charleston, U.S.
Jean-Claude Daubert, Rennes, France
On Behalf of the REVERSE
Investigators 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 ON
Europe: 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 Randomized
U.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 Analysis
Proportion Worsened
Conventional Analysis
Distribution 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
LVESVi(ml/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 LWHF
P=0.26
6-Min Walk Test
P=0.26
NYHA
P=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
%ofPatientsHo
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 IIor non-ischemic NYHA class II
EFEF ≤≤0.300.30
QRSQRS >>130 msec130 msec
Sinus RhythmSinus Rhythm
Optimal pharmacologic therapy:Optimal pharmacologic therapy:
B-b (>3 mo.); ACE/ARB (>1 mo.);B-b (>3 mo.); ACE/ARB (>1 mo.);
statins in IHDstatins 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 3or 3rdrd
degreedegree
HBHB
BUN >70mg/dl or creatinineBUN >70mg/dl or creatinine
>3.0mg/dl>3.0mg/dl
RandomizationRandomization
N=1,820N=1,820
CRT-DCRT-D
N=1,089N=1,089
ICM NYHA I/II and NICM NYHA IIICM NYHA I/II and NICM NYHA II
EFEF << 0.300.30
QRSQRS >>0.13sec0.13sec
ICD onlyICD only
N=731N=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) PP
ValueValue
Heart failure or DeathHeart failure or Death 0.660.66 (0.52–0.84)(0.52–0.84) 0.0010.001
Heart failure onlyHeart failure only 0.590.59 (0.47–0.74)(0.47–0.74) <0.001<0.001
Death at any timeDeath at any time 1.001.00 (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 QRSEffects 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 ofCumulative Probability of Heart Failure (HF) Event or DeathHeart Failure (HF) Event or Death
by Treatment (CRT-D vs. ICD only) in patients with LBBB andby 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 ofCumulative Probability of Heart Failure (HF) Event or DeathHeart Failure (HF) Event or Death
by Treatment (CRT-D vs. ICD only) in patients with RBBB andby 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 ofCumulative Probability of DeathDeath by Treatment (CRT-D vs. ICDby Treatment (CRT-D vs. ICD
only) in patients with LBBB and Non-LBBB QRS Patternonly) in patients with LBBB and Non-LBBB QRS Pattern
in MADIT-CRT Patientsin MADIT-CRT Patients

Endpoint LBBB
n=1,281
Non-
LBBB
n=536
P value
for Inter-
action
Heart Failure Event HR 0.47 1.24
or 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 1.23
95% CI 0.31,0.54 0.76,1.68
P value <0.001 0.559 <0.001
Death HR 0.75 1.79
95% CI 0.49,1.16 0.90,3.57
P 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 ventricularhospitalizations for heart failure, ejection fraction, QRS>150, left ventricular
ejection fraction, left ventricular end-systolic volume.ejection fraction, left ventricular end-systolic volume.

Endpoint LBBB
n=1,281
Non-
LBBB
n=536
P value
for Inter-
action
VT/VF HR 0.67 1.11
95% CI 0.52,0.87 0.77,1.60
P value 0.002 0.574 0.028
VF HR 0.54 1.24
95% CI 0.33,0.87 0.58,2.66
P value 0.011 0.585 0.070
VT/VF/Death HR 0.69 1.21
95% CI 0.55,0.87 0.87,1.69
P 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 ventricularhospitalizations 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
LBBB
Non-LBBB
RBBB
IVCD
Hazard Ratios for Primary and Secondary EndpointsHazard 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 andHazard Ratios for Primary Endpoint by QRS Morphology and
Duration by GenderDuration by Gender
MalesMales FemalesFemales
nn HRHR P valueP value nn HRHR P valueP value
QRS DurationQRS Duration
<140 ms<140 ms 240240 1.691.69 0.0630.063 6161 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 6161 0.330.33 0.1000.100
QRS MorphologyQRS Morphology
LBBB*LBBB* 887887 0.560.56 <0.001<0.001 394394 0.250.25 <0.001<0.001
Non-LBBBNon-LBBB 477477 1.251.25 0.2730.273 5959 1.551.55 0.5160.516
RBBBRBBB 210210 0.940.94 0.8410.841 1818 NANA
IVCDIVCD 267267 1.491.49 0.1330.133 4141 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
LBBB
Non-LBBB
Mean Change in EchocardiographicMean Change in Echocardiographic
Parameters from Enrollment to 12 months inParameters from Enrollment to 12 months in
CRT-D PatientsCRT-D Patients
**
**
**
* p<0.001 when comparing* p<0.001 when comparing
LBBB and Non-LBBBLBBB 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 andHeart failure patients with NYHA class I or II and
ejection fractionejection fraction ≤30% who present with LBBB≤30% who present with LBBB
derive substantial benefit from CRT-D: reductionderive substantial benefit from CRT-D: reduction
in heart failure progression and reduction in thein 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 inNo evidence of CRT-D benefit was observed in
patients with Non-LBBB QRS pattern: RBBB orpatients 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 wasBeneficial effect of CRT-D in LBBB patients was
observed in all studied subjects: males andobserved in all studied subjects: males and
females, ischemic and non-ischemic, QRS>150 andfemales, ischemic and non-ischemic, QRS>150 and
QRS<150 ms.QRS<150 ms.

GiuseppeArena
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
COMPANION
CARE-HF
MADIT CRT

GiuseppeArena
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

GiuseppeArena
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

GiuseppeArena
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-HF
2.COMPANION
3.MADIT-CRT 
4.RAFT

GiuseppeArena
QUESTIONI APERTE
• CRT-P vs CRT-D

GiuseppeArena
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

GiuseppeArena
CRT-P vs. CRT-D
Considerazioni:
1.Recupero della EF > 35% dopo 6-12 mesi di CRT
2.Maggiori rischi device-related per la CRT-D (longevità inferiore,
complicanze leads) e costi
3.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%)

GiuseppeArena
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

GiuseppeArena
QUESTIONI APERTE
• CRT-P vs CRT-D
• Percentuali Responders

GiuseppeArena
CRT Responder
Brignole M. et al., 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J. 2013; 34, 2281–2329

GiuseppeArena
CRT Responder
Barsheshet 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.

GiuseppeArena
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% 

GiuseppeArena
QUESTIONI APERTE
• 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.

GiuseppeArena
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

GiuseppeArena
Direzioni future della CRT

GiuseppeArena
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

GiuseppeArena
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

Trial e crt

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