2006 orvieto, workshop interattivo. la terapia elettrica dello scompenso cardiaco
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Transcript of 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 CARDIOTORACOVASCOLARE DIPARTIMENTO CARDIOTORACOVASCOLARE
UNITA’ OPERATIVA DI ARITMOLOGIA CARDIACA UNITA’ OPERATIVA DI ARITMOLOGIA CARDIACA LABORATORIO DI ELETTROFISIOLOGIA ED ELETTROSTIMOLAZIONE LABORATORIO DI ELETTROFISIOLOGIA ED ELETTROSTIMOLAZIONE
NYHA CLASS
Ann
ual s
urvi
val (
%)
Hos
pita
lizat
ions
/ y
ear
100
75
50
25
0I II III IV
1
10Survival
Hospitalization
.1
Hospitalization / NYHA-class
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Quality of Life for HF patients Overall perception of health
3645
554848
525658
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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Sinusnode
AVnode
Bundlebranch 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?Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
SinusSinusnodenode
AVAVnodenode
BundleBundlebranch 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?Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
• 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
1Prior 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 SCD Relationship of SCD and LV Dysfunctionand LV Dysfunction
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
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 360Days in Trial
Cu
mu
lati
ve S
urv
ival
QRS Duration (msec)
<9090-120
120-170170-220
>220
Adapted from Gottipaty et al. JACC 1999; 33(2):145A (abstract 847-4)
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
• WHO? Which criteria ?
• WHEN? Which NYHA class ?
• WHERE? RV+LV / LV ?
• WHY? Symptoms / Mortality ?
KEY QUESTIONSKEY QUESTIONSCardiac Resynchronization TherapyCardiac Resynchronization Therapy
• Optimizes AV contraction sequence• Reduces pre-systolic mitral regurgitation• Improves atrial preloading of the ventricle• Increases filling time
Mechanism IMechanism IAtrio-Ventricular SynchronyAtrio-Ventricular Synchrony
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
What does pacing changeWhat does pacing change??
OAVD Restores AV Synchrony
PP RR
INTRINSICINTRINSICAorticAortic
pressurepressure
LVLVpressurepressure
PPPP
PeakPeakatrial systoleatrial systole
Start ofStart ofLV systoleLV systole
DiastolicMitral
Regurgitation
MaximumEffective Preload
PP VV
PACEDPACEDPPPP
SynchronizedSynchronizedLV and atrialLV and atrial
systolessystoles
Auricchio et al, PACE 1998
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
• Optimizes ventricular activation
• Increases pumping effectiveness
• Reduces regional wall stress (WMSI)• Decreases mitral regurgitation• Resynchronizes ventricular filling flows• Decreases filling pressures
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Mechanism IIMechanism IIVentricular 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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Blanc et al., Circulation 199723 pts mean ± SD
90
100
110
120
130
140
150
SYSTOLIC SYSTOLIC Blood PressureBlood Pressure
RVARVA LV BVRVORVOBASBAS
mm
Hg
mm
Hg
p<.01 p<.03
0
10
20
30
40
Pulmonary Capillary Pulmonary Capillary Wedge PressureWedge Pressure
RVARVA LV BVBVRVORVOBASBAS
p<.01 p<.01
Acute studies
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Kass et al, Kass et al, Circulation 99Circulation 99
IntrinsicIntrinsicPacedPaced
00 100100 200200 30030000
4040
8080
120120RV SeptumRV Septum
00 100100 200200 30030000
4040
8080
120120BiventricularBiventricular
00 100100 200200 30030000
4040
8080
120120RV ApexRV Apex
00 100100 200200 30030000
4040
8080
120120LV FreewallLV Freewall
LV Volume LV Volume (mL)(mL)
LV P
ress
ure
LV P
ress
ure
(mm
Hg)
(mm
Hg)
LV P
ress
ure
LV P
ress
ure
(mm
Hg)
(mm
Hg)
LV Volume LV Volume (mL)(mL)
Acute studies
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
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
PATH CHF
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
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 PATH CHF
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
MUSTIC Inclusion Criteria (67 pts)
• 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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Results Active pacing
Inactivepacing
p
6-min w (m) 399 ± 100 326 ± 134 .0001QOL score 29.6 ± 21.3 43.2 ± 22.8 .0002VO2 (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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
MUSTIC Results (67 pts)
Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk10
15
20
25
30
35
40
*
* †
*
*
*
†
†
Mitr
al r
egur
gita
tion
(%)
MR area
Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk
100
125
150
175
200
225
**
*
*
†
* *
*
†
Left
ven
tric
ular
vol
ume
(mL) *
LVESV and LVEDVLV Reverse Remodeling
Pacing No pacing
N = 25
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
MUSTIC Results (67 pts)
MIRACLE Inclusion Criteria (571 pts)
• 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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
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
-4-4-3-3-2-2-1-10011
ControlControl(n=118)(n=118)
CRTCRT(n=116)(n=116)
cmcm22
P<0.001P<0.001 P=0.009P=0.009
Change in LVEDDChange in LVEDD
-6-6
-4-4
-2-2
00
22
ControlControl(n=118)(n=118)
CRTCRT(n=116)(n=116)
mmmm P<0.001P<0.001
Absolute Change in LVEFAbsolute Change in LVEF
-2-2
00
22
44
66
88
ControlControl(n=146)(n=146)
CRTCRT(n=155)(n=155)
%%
Baseline (mm)Baseline (mm)69 ± 10
70 ± 10Baseline (cmBaseline (cm 2)
7.2 ± 4.9
7.6 ± 6.4Baseline (%)Baseline (%)
22 ± 6
22 ± 6
Paired median change from baseline at 6 months
Cardiac Function and Structure
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
MIRACLE
Improvement in Peak VOImprovement in Peak VO22
-0.5-0.5
0.00.0
0.50.5
1.01.0
1.51.52.02.0
ControlControl(n=145)(n=145)
CRTCRT(n=158)(n=158)
ml/
kg/m
inm
l/kg
/min
P=0.009P=0.009
Improvement in Improvement in Total Exercise TimeTotal Exercise Time
00
3030
6060
9090
120120
ControlControl(n=146)(n=146)
CRTCRT(n=159)(n=159)
seco
nds
seco
nds
P=0.001P=0.001
Baseline Baseline (ml/kg/min)(ml/kg/min)
13.7 ± 3.8
14.0 ± 3.5
BaselineBaseline (secondsseconds)
462 ± 217
484 ± 209
Metabolic Exercise
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
MIRACLE
Abraham WT, Fisher WG, Smith AL, et al. N Engl J Med 2002;346:1845-1853
VO2
(ml/
min
/mVO
2 (m
l/m
in/m
22 ))
DODO22 (ml/min/m (ml/min/m22))
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
OO22ERER
Critical DOCritical DO2 2
DISOXIADISOXIA
Critical VOCritical VO22
VOVO22 = DO= DO2 2 X X 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/ dt max ( mm/ Hg/ s)
MVO
2/HR
(Rel
ative
Unit
s) Dobutamin
LV Pacing
P< 0.05
Nelson et al. Circulation 2000
Myocardial Oxidative Metabolism
0
0,02
0,04
0,06
LV RV
k mon
o(min
-1)
p=0.86
p=0.62
n=8
Myocardial Efficiency Work Metabolic Index
0
2
4
6
8
10
12
mm
HG
·L·m
-2
Baseline CRT
p =0.024
Ukkonen et al. Circulation 2003
n=7
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Control 225 214 204 197 191 179 70CRT 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
Eve
nt
Fre
eE
ven
t F
ree
Su
rviv
al
Su
rviv
al (
%)
(%
)
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 HF requiring Hospitalization
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
MIRACLE
Survival
80%
85%
90%
95%
100%
0 1 2 3 4 5 6
Months Since Randomization
% o
f P
atie
nts
Su
rviv
ing
Control n=402 CRT n=415
P=0.42
W.T. Abraham for MIRACLE and MIRACLE ICD Investigators
Cardiac Resynchronization TherapyCardiac Resynchronization TherapyMIRACLE and MIRACLE ICD Trials
QOL & Functional Capacity 6 Months in Moderate to Severe HF
-20-15-10-50
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;344:873-80MIRACLE ICD:JAMA 2003;289:2685-94 CONTAK CD: JACC 2003;2003;42:1454-59
Control CRT
NYHA ClassProportionChanging 1
or more Classes
Improve. ↓
Not Reported
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Exercise Capacity 6 Months in Moderate to Severe HF
-20
0
20
40
60 P<0.001 P=0.36 P=0.029P<0.001
6 Min WalkAvg. Change
(m)
000
1
2
3
MIRACLE MUSTIC SR MIRACLE ICD Contak CD
P<0.001
P=0.029
P=0.04P=0.003
Data sources:MIRACLE: Circulation 2003;107:1985-90 MUSTIC SR: NEJM 2001;344:873-80MIRACLE ICD:JAMA 2003;289:2685-94 CONTAK CD: JACC 2003;2003;42:1454-59
Control CRT
Peak VO2
Avg. Change (mL/kg/min)
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
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
Prop
orti
on
Bradley DJ, et al. JAMA 2003
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Baseline ex CPX
ImplantAttempt
SuccessfulImplant
ControlICD
CRTCRT + ICD
Pre-dischargeRandomization
6 Month Follow-up
6 Month Follow-up
CRT
DoubleBlinded
StableMedicalTherapy
≤ 1week
• 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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
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.
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
MIRACLE ICD II
Left Ventricular End Systolic Diameter
200
250
300
350
400cm3
Base 6 Mo
P=0.01
Reverse Remodeling in Class II CHF
Left Ventricular End Diastolic Diameter
200
250
300
350
400cm3
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)
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
MIRACLE ICD II
Cardiac Resynchronization TherapyCardiac Resynchronization TherapyRelated Risks
Complicat 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+CONTAKCD+MIRACLE ICD
InSync III/Attain4193
Reduced Procedure Time w it h I ncreased Exper ience (2)
60
120
180
240
300
Up t o f ir st5
Next 6 t o10
Next 11more
Cent er-based exper ienceIm
plan
t Ti
me
(min
utes
) P < 0.001
Study Period AttemptsPrimary 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 2005Result s Present ed
Cum
ulat
ive
Patie
nts
PATH CHF
MUSTIC SR
MUSTIC AFMIRACLE
CONTAK CD
MIRACLE ICD
PATH CHF II
COMPANION
MIRACLE ICD II
CARE HF
• • Actual � ProjectedActual � ProjectedDOUG SMITHDOUG SMITH
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
0
5000
10000
15000
Baseline Post-implant
Intensive careCardiologyOthers
Patient Cost Baseline: 12,784 Euro Patient Cost (Implant included): 12,362 EuroPatient Cost Post-implant: 1,680 Euro
Hospital costs per patient
Cost EffectivenessAnalysis of Biventricular Pacing in HF
Curnis A 2001
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Relative Cost of CRTCost per pat ient
$0$20$40$60
CRT+ I CD
CRT
Hip/ knee replace
PTCA
CABG
Dialysis
$ t housands
Total Annual Expenditures
$0 $5 $10 $15 $20
$ BillionsDoug Smith:
Doug Smith:
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
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
1 Ye
ar M
orta
lity
Placebo Treatment
Further Reduction with CRT + ICD
for Higher Risk PatientsCHF
Mortality
SuddenCardiac Death
CRT
ICD
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
• 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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
• 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
Cardiac Resynchronization TherapyCardiac Resynchronization Therapy
Creating Realistic patients expectations