Trial e crt

E-Day 19 Settembre 2015

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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%

19902010

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.

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


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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%


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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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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


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



Bristow et al N Eng J Med 2004; 350: 2140


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CRT: nascita ed evoluzione• Scompenso Cardiaco: patologia cardiovascolare tra le più disabilitanti,

mortali e costose



• 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 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


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CRT: nascita ed evoluzione• Scompenso Cardiaco: patologia cardiovascolare tra le più disabilitanti,

mortali e costose



• 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 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


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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/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


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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;143:1085-91N=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


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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 meccanica2) Frazione d’eiezione del ventricolo sinistro3) 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

2005Mounting evidence


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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


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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-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.


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PATH-CHFChronic VO2 AT

0.5

0.75

1


VO2

AT (l

/min

)

0.76+0.21

0.91+0.31

N=18P=0.018

Impr

ovem

ent



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PATH-CHFChronic six-minute walk distances

300

350

400

450

500


six-m

inut

e w

alk

(m)

357+101

446+74

N=25P<0.001

Impr

ovem

ent



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PATH-CHFChronic NYHA

1

2

3

4


NYH

A fu

nctio

nal c

lass 3.05+0.16

1.90+0.76

N=29P<0.001

Impr

ovem

ent



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PATH-CHFChronic quality of life

10

20

30

40

50

60


Qua

lity

of li

fe (p

oint

s)

49+23

20+22

N=28P<0.001

Impr

ovem

ent



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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-IVLVEDD > 60 mm

QRS > 150 msSix-minute walk < 450 meters

EF < 35%


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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


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Quality of life scoresMUSTIC


• 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


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 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)


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)


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


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 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


Secondary Efficacy ResultsSecondary Efficacy Results


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



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


CRT Improves Metabolic ExerciseCRT Improves Metabolic Exercise

Change in MR Jet AreaChange in MR Jet Area

-4-4-3-3-2-2-1-10011



cmcm22

P<0.001P<0.001 P=0.009P=0.009

Change in LVEDDChange in LVEDD

-6-6

-4-4

-2-2

00

22



mmmm P<0.001P<0.001

Absolute Change in LVEFAbsolute Change in LVEF

-2-2

00

22

44

66

88



%%

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

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


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


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


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:


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)


Time to Death or Worsening Heart FailureTime to Death or Worsening Heart FailureRequiring HospitalizationRequiring Hospitalization


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• 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


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


542-12-#68

COMPANION: Secondary EndpointCOMPANION: Secondary EndpointAll 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 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



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



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


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


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


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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


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 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.


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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


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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


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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


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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


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QUESTIONI APERTE• Pazienti con classe NYHA II• CRT-P vs CRT-D


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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


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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


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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


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QUESTIONI APERTE• Pazienti con classe NYHA II• CRT-P vs CRT-D• Percentuali Responders


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CRT Responder

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


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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.


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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%


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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.


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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


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Direzioni future della CRT


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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


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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

Documents

Trial e crt