2006 orvieto, workshop interattivo. la terapia elettrica dello scompenso cardiaco

““ Cardiac Resynchronization Therapy ”Cardiac Resynchronization Therapy ”
Stefano Nardi, MD
AZIENDA OSPEDALIERA SANTA MARIA TERNIAZIENDA OSPEDALIERA SANTA MARIA TERNI
DIPARTIMENTO CARDIOTORACOVASCOLAREDIPARTIMENTO CARDIOTORACOVASCOLARE
UNITA’ OPERATIVA DI ARITMOLOGIA CARDIACAUNITA’ OPERATIVA DI ARITMOLOGIA CARDIACA
LABORATORIO DI ELETTROFISIOLOGIA ED ELETTROSTIMOLAZIONELABORATORIO DI ELETTROFISIOLOGIA ED ELETTROSTIMOLAZIONE

NYHA CLASS
Annualsurvival(%)
Hospitalizations/year
100
75
50
25
0
I II III IV
1
10
Survival
Hospitalization
.1
Hospitalization / NYHA-class
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy

Quality of Life
for HF patients Overall perception of health
36
45
55
48
48
52
56
58
70
Heart Failure NYHA Class IV
Heart Failure NYHA Class III
Heart Failure NYHA Class II
Chronic Bronchitis
Valve disease symptomatic
AF symptomatic
Angina
Depression
General population
Hobbs FDR, et al. Eur Heart J 2002

Sinus
node
AV
node
Bundle
branch or
diffuse block
Delayed conduction
• Delayed AV sequence
• Mitral regurgitation
• Decreased filling time
Delayed Ventricular ActivationDelayed Ventricular Activation
What is abnormal in the HF pts?What is abnormal in the HF pts?

SinusSinus
nodenode
AVAV
nodenode
BundleBundle
branch orbranch or
diffuse blockdiffuse block
Delayed conductionDelayed conduction
• Abnormal RV-LV
sequence
• Abnormal LV activation
sequence
• Segmentary dyskinesia
• Aggravation of mitral
regurgitation
• Disynchrony of RV and
LV filling flows
Dyssynchrony Ventricular ContractionDyssynchrony Ventricular Contraction
What is abnormal in the HF pts?What is abnormal in the HF pts?

• Reduced LVEF remains the single most
important risk factor for overall mortality
and SCD.1
• Increased risk is measurable at EF above
30%, but an EF ≤30% is the single most
powerful independent predictor for SCD.2
1
Prior SG, Aliot E, Blonstrom-Lundqvist C, et al. Task Force on Sudden Cardiac Death of the European Society of
Cardiology. Eur Heart J, Vol. 22; 16; August 2001.
2
Myerburg RJ, Castellanos A. Cardiac Arrest and Sudden Cardiac Death, in Braunwald E, Zipes DP, Libby P, Heart
Disease, A textbook of Cardiovascular Medicine. 6th
ed. 2001. W.B. Saunders, Co., p. 895.
Relationship of SCDRelationship of SCD
and LV Dysfunctionand LV Dysfunction

Which is the prognostic value
of QRS width ?
• VEST study analysis
• NYHA Class II – IV pz
• 3,654 ECGs digitally
scanned
• Age, creatinine, LVEF,
heart rate, and QRS
duration found to be
independent predictors
of mortality
• Relative risk of widest
QRS group 5x greater
than narrowest
60%
70%
80%
90%
100%
0 60 120 180 240 300 360
Days in Trial
CumulativeSurvival
QRS
Duration
(msec)
<90
90-120
120-170
170-220
>220
Adapted from Gottipaty et al. JACC
1999; 33(2):145A (abstract 847-4)

CHF Population
6.5 Mio
NYHA III + IV (30 - 35%)
1.95 Mio
Wide QRS (10 - 30%)
Resynchronization Rx
Target Population:
195’000
650’000
Incidence = 580’000 (9.0%)
Mortality = 300’000 (4.6%)
CHF Population in EuropeCHF Population in Europe

• WHO?
 Which criteria ?
• WHEN?
 Which NYHA class ?
• WHERE?
 RV+LV / LV ?
• WHY?
 Symptoms / Mortality ?
KEY QUESTIONSKEY QUESTIONS

• Optimizes AV contraction sequence
• Reduces pre-systolic mitral regurgitation
• Improves atrial preloading of the ventricle
• Increases filling time
Mechanism IMechanism I
Atrio-Ventricular SynchronyAtrio-Ventricular Synchrony
What does pacing changeWhat does pacing change??

OAVD Restores AV Synchrony
PP RR
INTRINSICINTRINSIC
AorticAortic
pressurepressure
LVLV
pressurepressure
PPPP
PeakPeak
atrial systoleatrial systole
Start ofStart of
LV systoleLV systole
Diastolic
Mitral
Regurgitation
Maximum
Effective Preload
PP VV
PACEDPACED
PPPP
SynchronizedSynchronized
LV and atrialLV and atrial
systolessystoles
Auricchio et al, PACE 1998

• Optimizes ventricular activation
• Increases pumping effectiveness
• Reduces regional wall stress (WMSI)
• Decreases mitral regurgitation
• Resynchronizes ventricular filling flows
• Decreases filling pressures
Mechanism IIMechanism II
Ventricular CoordinationVentricular Coordination
What does pacing changeWhat does pacing change??

LV Lead Implant
Historical Evolution
• Thoracic epicardial LV lead - 1994 1
• RV lead adapted for transvenous LV implant - 1996 2
• CS lead adapted for transvenous LV implant -1997 3
• Special designed transvenous LV lead - 1998 4
• Guiding catheter sheath for LV lead delivery -1998 5
1. Bakker et al. PACE 1994; 2. Cazeau et al. PACE 1996;
3.Daubert et al. PACE 1997; 4. Gras et al. PACE 1998
5. Lurie et al. Circulation 1998

Blanc et al., Circulation 199723 pts mean ± SD
90
100
110
120
130
140
150
SYSTOLICSYSTOLIC
Blood PressureBlood Pressure
RVARVA LV BVRVORVOBASBAS
mmHgmmHg
p<.01 p<.03
0
10
20
30
40
Pulmonary CapillaryPulmonary Capillary
Wedge PressureWedge Pressure
RVARVA LV BVBVRVORVOBASBAS
p<.01 p<.01
Acute studies

Kass et al,Kass et al,
Circulation 99Circulation 99
IntrinsicIntrinsic
PacedPaced
00 100100 200200 300300
00
4040
8080
120120
RV SeptumRV Septum
00 100100 200200 300300
00
4040
8080
120120
BiventricularBiventricular
00 100100 200200 300300
00
4040
8080
120120
RV ApexRV Apex
00 100100 200200 300300
00
4040
8080
120120
LV FreewallLV Freewall
LV VolumeLV Volume (mL)(mL)
LVPressureLVPressure
(mmHg)(mmHg)
LVPressureLVPressure
(mmHg)(mmHg)
LV VolumeLV Volume (mL)(mL)
Acute studies

Auricchio et al., NASPE ‘99
PATH-CHF:
Inclusion Criteria (42 pts)
• Dilated cardiomyopathy of any etiology
• NYHA Class III (> 6 months) or NYHA IV
• Optimal individual drug therapy
• QRS duration >120 msec
• PR Interval >150 msec
• Sinus rate > 55 bpm
• No conventional pacemaker indication
PATHCHF

4 weeks
4 weeks
One Year
4 weeks
Acute Testing at Implant
Randomization Prior to Discharge
Pre-OP Evaluation
Best Unichamber Biventricular
No Pace No Pace
Biventricular Best Unichamber
Best Chronic Pacing Mode
FlexStim
PATH CHF:
Study Design PATHCHF

MUSTIC
• Dilated cardiomyopathy of any etiology
• NYHA Class III
• Optimal individual drug therapy
• LBBB and QRS duration >150 msec
• LVEF<35% and LVEDD>60mm
• 6-MWT<450m
• SR & no conventional pacemaker indication

Results Active
pacing
Inactive
pacing
p
6-min w (m) 399 ± 100 326 ± 134 .0001
QOL score 29.6 ± 21.3 43.2 ± 22.8 .0002
VO2 (ml/min/Kg) 16.2 ± 4.7 15 ± 4.9 0.02
S.Cazeau et al NEJM 2001;344:873-80S.Cazeau et al NEJM 2001;344:873-80
MUSTIC
Results (67 pts)

Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk
10
15
20
25
30
35
40
*
* †
*
*
*
†
†
Mitralregurgitation(%)
MR area
Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk
100
125
150
175
200
225
*
*
*
*
†
* *
*
†
Leftventricularvolume(mL)
*
LVESV and LVEDV
LV Reverse Remodeling
Pacing No pacing
N = 25
MUSTIC Results (67 pts)

MIRACLE
• Moderate or severe HF (NYHA III-IV)
• Stable optimal HF medical therapy regimen for >1mo
Diuretics (93-94%)
ACE-I or ARB (90-93%) if tollerated
β-blocker (55-62%) at stable regimen for>3 months
• QRS duration ≥150 msec
• LVEF ≤35% or LVEDD ≥55mm (echo measure)
• Sinus rate > 55 bpm
• 6 MWT <450m
Abraham WT, Fisher WG, Smith AL, et al.
N Engl J Med 2002;346:1845-1853

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 (cm 2
)
7.2 ± 4.9
7.6 ± 6.4
Baseline (%)Baseline (%)
22 ± 6
22 ± 6
Paired median change from baseline at 6 months
Cardiac Function and Structure
MIRACLE

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
Metabolic Exercise
MIRACLE
Abraham WT, Fisher WG, Smith AL, et al.
N Engl J Med 2002;346:1845-1853

VO2(ml/min/mVO2(ml/min/m22
))
DODO22 (ml/min/m(ml/min/m22
))
OO22ERER
Critical DOCritical DO22
DISOXIADISOXIA
Critical VOCritical VO22
VOVO22 = DO= DO22 XX OO22ERER
NormalNormal
Myocardial Oxidative Metabolism

Effects on Cardiac Function
and Oxidative Stress
0,14
0,16
0,18
0,20
0,22
0,24
500 600 700 800 900
dP/ dtmax (mm/ Hg/ s)
MVO2/HR(RelativeUnits)
Dobutamin
LV Pacing
P< 0.05
Nelson et al. Circulation 2000
Myocardial Oxidative
Metabolism
0
0,02
0,04
0,06
LV RV
kmono(min-1
)
p=
0.86
p=
0.62
n=8
Myocardial Efficiency
Work Metabolic Index
0
2
4
6
8
10
12
mmHG·L·m-2
Baseline CRT
p =0.024
Ukkonen et al. Circulation 2003
n=7

Control 225 214 204 197 191 179 70
CRT 228 218 213 209 204 201 99
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
EventFreeEventFreeSurvivalSurvival(%)(%)
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 HF requiring Hospitalization
MIRACLE

Survival
80%
85%
90%
95%
100%
0 1 2 3 4 5 6
Months Since Randomization
%ofPatientsSurviving
Control n=402 CRT n=415
P=0.42
W.T. Abraham for MIRACLE and MIRACLE ICD Investigators
MIRACLE and MIRACLE ICD Trials

QOL & Functional Capacity
6 Months in Moderate to Severe HF
-20
-15
-10
-5
0
P<0.001 P=0.02 P=0.017P<0.001
QoL Score
(MLWHF)
Avg. Change
0%
20%
40%
60%
80%
MIRACLE MUSTIC SR MIRACLE ICD Contak CD
P<0.001 P=0.006P=0.007
Data sources:
MIRACLE: Circulation 2003;107:1985-90 MUSTIC SR: NEJM 2001;344:873-80
MIRACLE ICD:JAMA 2003;289:2685-94 CONTAK CD: JACC 2003;2003;42:1454-59
 Control CRT
NYHA Class
Proportion
Changing 1
or more
Classes
Improve. ↓
Not
Reported

Exercise Capacity
6 Months in Moderate to
Severe HF
-20
0
20
40
60 P<0.001 P=0.36 P=0.029
P<0.001
6 Min Walk
Avg. Change
(m)
00
0
1
2
3
MIRACLE MUSTIC SR MIRACLE ICD Contak CD
P<0.001
P=0.029
P=0.04
P=0.003
Data sources:
MIRACLE: Circulation 2003;107:1985-90 MUSTIC SR: NEJM 2001;344:873-80
MIRACLE ICD:JAMA 2003;289:2685-94 CONTAK CD: JACC 2003;2003;42:1454-59
 Control  CRT
Peak VO2
Avg. Change
(mL/kg/min)

Mortality/Morbidity
from Published Randomized, Controlled
Trials Risk reduction with CRT
Study
(n random.) FU
Mor-
tality &
Hosp.
Mortal.
& HF
Hosp.
Mor-
tality
HF
Mort.
HF
Hosp.
MIRACLE
(n=453)
6 Mo NR 39%* 27% NR 50%*
MIRACLE ICD
(n=369)
6 Mo 2% 0% 0% NR NR
Contak CD
(n=490)
3-6 Mo NR NR 30% NR 18%
Meta-analysis
(n=1634)
3-6 Mo NR NR 23% 51%* 29%*
* P < 0.05

CRT Does Not Promote
Ventricular Arrhythmias
• Analyzed 1,044 patients
with ICDs from 2 trials:
– CONTAK CD
– MIRACLE ICD
• Odds ratio (CI):
0.92 (0.67 – 1.27)
Patients with VT or
VF during Follow-up
17,2%
18,4%
No CRT CRT
Proportion
Bradley DJ, et al. JAMA 2003

Baseline
ex CPX
Implant
Attempt
Successful
Implant
Control
ICD
CRT
CRT + ICD
Pre-discharge
Randomization
6 Month
Follow-up
6 Month
Follow-up
CRT
Double
Blinded
Stable
Medical
Therapy
≤ 1
week
• Class NYHA II
• Intent to treat analyses
• Comparison between groups
• Core labs: metabolic exercise,
echocardiography, and
neurohormone data
CRT
Long term follow up
every 6 months
CPX
MIRACLE ICD II

210 Class II 429 Class III/IV
98 Completed 6M FU 82 Completed 6M FU
2 Death 2
1 Missed 6M FU 1
101 Control (ICD+OPT) 85 CRT (CRT+ICD+OPT)
639 Enrolled and Implant Attempted
19 Unsuccessful 191 (91%) Successful
186 Randomized
5 not randomized
- 1 death
- 4 LV lead dislodge.
MIRACLE ICD II

Left Ventricular End
Systolic Diameter
200
250
300
350
400
cm3
Base 6 Mo
P=0.01
Reverse Remodeling in Class II CHF
Left Ventricular End
Diastolic Diameter
200
250
300
350
400
cm3
Base 6 Mo
P=0.04
Left Ventricular
Ejection Fraction
20
22
24
26
28
30
%
Base 6 Mo
P=0.02
• Control (n=85) ♦ CRT (n=69)
MIRACLE ICD II

Related Risks
Com plicat ions ( 1)
4,8
3,7
1,5
1,0
1,8
0,3
10,6
10,0
2,3
2,4
1,7
0,3
0 5 10 15
Unsucess. Implant
LV Lead
Coronary Sinus
Infection
30 day mortality
Procedure death
Percent of Pat ient s
MIRACLE+CONTAK
CD+MIRACLE ICD
InSync III/Attain
4193
Reduced Procedure Time w it h
I ncreased Experience (2)
60
120
180
240
300
Up t o first
5
Next 6 t o
10
Next 11
more
Cent er-based experience
ImplantTime(minutes)
P < 0.001
Study Period Attempts
Primary
LV Lead
MIRACLE 11/98 – 12/00 591 Attain 2187
CONTAK CD 2/98 – 12/00 517 EasyTrak
MIRACLE ICD 10/99 – 8/01 636 Attain 4189
INSYNC III 11/00 – 6/02 334 Attain 4193
1. Greenberg, et al.
PACE 2003;26(4p2):
952 (Abstract 93)
2. Unpublished data.
Medtronic. Inc.

Cumulative Enrollment in C.R.T.Cumulative Enrollment in C.R.T.
Randomized TrialsRandomized Trials
0
1000
2000
3000
4000
1999 2001 2003 2005
Results Presented
CumulativePatients
PATH CHF
MUSTIC SR
MUSTIC AF
MIRACLE
CONTAK CD
MIRACLE ICD
PATH CHF II
COMPANION
MIRACLE ICD II
CARE HF
•• Actual ProjectedActual ProjectedDOUG SMITHDOUG SMITH

0
5000
10000
15000
Baseline Post-implant
Intensive care
Cardiology
Others
Patient Cost Baseline: 12,784 Euro
Patient Cost (Implant included): 12,362 Euro
Patient Cost Post-implant: 1,680 Euro
Hospital costs per patient
Cost Effectiveness
Analysis of Biventricular
Pacing in HF
Curnis A 2001

Relative Cost of CRT
Cost per patient
$0$20$40$60
CRT+ I CD
CRT
Hip/ knee replace
PTCA
CABG
Dialysis
$ t housands
Total Annual Expenditures
$0 $5 $10 $15 $20
$ Billions
Doug Smith:
Doug Smith:

Weight of Evidence: CRT
• More than 4000 patients evaluated in
randomized controlled trials
• Consistent improvement in QOL, functional
status, and exercise capacity
• Strong evidence for reverse remodeling
– ↓ LV volumes and dimensions
↑ LV ejection fraction
– ↓ Mitral regurgitation Courtesy of Dr. Bill Abraham

Reduced Mortality
in Heart Failure
ACE-I & Beta Blockade
Reduce Mortality
11,5%
15,6%
12,4%
7,8%
0%
4%
8%
12%
16%
SOLVD-T MERIT-HF
+ CIBIS II
1YearMortality
Placebo Treatment
Further Reduction
with CRT + ICD
for Higher Risk Patients
CHF
Mortality
Sudden
Cardiac
Death
CRT
ICD

• CRT in NYHA class II ?
• Which implication in pts with
unstable Haemodinamic profile ?
• CRT in chronic Atrial Fibrillation ?
• CRT in Right Bundle Branch Block ?
• QRS<120ms or QTc dispersion ?
• “Up-grading” in RVA pacing ?
Actual Key QuestionsActual Key Questions

Creating Realistic
patients expectations
• Approximately two-third of patients should experience improvement
(responders vs. non-responders)
• A relevant percentage of patients (25-30%) may not experience
(immediate) improvement

• Have patients set their own goals of what they
would like to do following CRT:
Grocery shopping, Decreasing Lasix dose
Walking to the mailbox without stopping, Lying flat to sleep
• Encourage them to be part of the group that
responds to their therapy
Creating Realistic
patients expectations

2006 orvieto, workshop interattivo. la terapia elettrica dello scompenso cardiaco

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