cardiac resynchronization therapy for heart failure patient selection and clinical outcomes edited...
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Cardiac Resynchronization Therapy for Heart Failure
Patient Selection and Clinical Outcomes
Edited by A kharazi M.Dcardiac electrophysiologist
Heart Failure (HF) Definition
A complex clinical syndrome in which the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return.
Etiology of Heart Failure
What causes heart failure?• The loss of a critical quantity of functioning
myocardial cells after injury to the heart due to:– Ischemic Heart Disease – Hypertension – Idiopathic Cardiomyopathy– Infections (e.g., viral myocarditis, Chagas’ disease)– Toxins (e.g., alcohol or cytotoxic drugs) – Valvular Disease – Prolonged Arrhythmias
Prevalence of HF by Age and Gender
United States: 1988-94
0
2
4
6
8
10
Percent of Population
20-24 25-34 35-44 45-54 55-64 65-74 75+
Males
Females
Source: NHANES III (1988-94), CDC/NCHS and the American Heart AssociationSource: NHANES III (1988-94), CDC/NCHS and the American Heart Association
New York Heart Association Functional Classification
Class I: No symptoms with ordinary activity
Class II: Slight limitation of physical activity. Rest comfortable but ordinary physical activity results in fatigue,
palpitation, dyspnea, or angina
Class III: Marked limitation of physical activity. Comfortable at
rest, but less than ordinary physical activity results in
fatigue, palpitation, dyspnea, or anginal pain
Class IV: Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may
be present even at rest
Poor 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
Adjusted SF 36 means
Hobbs FDR, et al. Eur Heart J 2002;23:1867-1876
Doug Smith:Doug Smith:
MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). intervention trial in congestive heart failure (MERIT-HF). LANCET. LANCET. 1999;353:2001-07.1999;353:2001-07.
Severity of Heart FailureModes of Death
12%12%
24%24%
64%64%
CHFCHF
OtherOther
SuddenSuddenDeathDeath
n = 103n = 103
NYHA IINYHA II
26%26%
15%15%
59%59%
CHFCHF
OtherOther
SuddenSuddenDeathDeath
n = 103n = 103
NYHA IIINYHA III
56%56%
11%11%
33%33%
CHFCHF
OtherOther
SuddenSuddenDeathDeath
n = 27n = 27
NYHA IVNYHA IV
Volume Volume OverloadOverload
Pressure Pressure OverloadOverload
Loss of Loss of MyocardiumMyocardium
Impaired Impaired ContractilityContractility
LV DysfunctionLV DysfunctionEF < 40%EF < 40%
Cardiac Cardiac OutputOutput
Hypoperfusion Hypoperfusion
End Systolic Volume End Systolic Volume
End Diastolic Volume End Diastolic Volume
Pulmonary Congestion Pulmonary Congestion
Left Ventricular Dysfunction
Treatment Approach for the Patient with Heart Failure
Stage AStage A
At high risk, no At high risk, no structural diseasestructural disease
Stage BStage B
Structural heart Structural heart disease, disease,
asymptomaticasymptomatic
Stage DStage D
Refractory HF Refractory HF requiring requiring
specialized specialized interventionsinterventions
TherapyTherapy
• Treat HypertensionTreat Hypertension
• Treat lipid Treat lipid disordersdisorders
• Encourage regular Encourage regular exerciseexercise
• Discourage alcohol Discourage alcohol intakeintake
• ACE inhibitionACE inhibition
TherapyTherapy
• All measures All measures under stage Aunder stage A
• ACE inhibitors in ACE inhibitors in appropriate appropriate patientspatients
• Beta-blockers in Beta-blockers in appropriate appropriate patientspatients
TherapyTherapy
• All measures All measures under stage Aunder stage A
Drugs:Drugs:
• DiureticsDiuretics
• ACE inhibitorsACE inhibitors
• Beta-blockersBeta-blockers
• DigitalisDigitalis
• Dietary salt Dietary salt restrictionrestriction
TherapyTherapy
• All measures All measures under stages A,B, under stages A,B, and Cand C
• Mechanical assist Mechanical assist devicesdevices
• Heart Heart transplantationtransplantation
• Continuous (not Continuous (not intermittent) IV intermittent) IV inotropic infusions inotropic infusions for palliationfor palliation
• Hospice careHospice care
Stage CStage C
Structural heart Structural heart disease with disease with prior/current prior/current
symptoms of HFsymptoms of HF
Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001Chronic Heart Failure in the Adult, 2001
Diuretics, ACE Inhibitors
Reduce the number of sacks on the wagon
ß-Blockers
Limit the donkey’s speed, thus saving energy
Digitalis Compounds
Like the carrot placed in front of the donkey
Ventricular Dysynchrony
• Abnormal ventricular conduction resulting in a mechanical delay– Wide QRS (IVCD); typically LBBB morphology– Poor systolic function– Impaired diastolic function
ECG depicting interventricular conduction delayECG depicting interventricular conduction delay
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
Elements of Cardiac Dyssynchrony
Atrio-ventricular
Inter-ventricular
Intra-ventricular
Cazeau, et al. PACE 2003; 26[Pt. II]: 137–143
Intra-ventricular DyssynchronySeptal-Posterior Wall Motion Delay
• Difference in times from peak excursions of the septum and of the posterior wall at the papillary muscle level
• SPWMD 130 ms predicted response (LVEDVi) to CRT in study of 25 pts with QRS 140 ms1 From parasternal short-axis
view at papillary muscle level
1. Pitzalis M, et al. JACC 2002;40:1615-1622
septum
Posteriorwall
Parasternal Long-axis View Shown
Animation – Ventricular Dysynchrony
Click to Start/StopClick to Start/Stop
11 Tavazzi L. Eur Heart J 2000;21:1211-1214. Tavazzi L. Eur Heart J 2000;21:1211-1214.22 Shenkman et al. Shenkman et al. CirculationCirculation 2000; 102(18):Suppl II, abstract 2293. 2000; 102(18):Suppl II, abstract 2293.
Etiology of Ventricular Dysynchrony
• What Causes Ventricular Dysynchrony?1
– Inter- or intraventricular conduction delays usually manifested as left bundle branch block
– Regional wall motion abnormalities with increased workload and stress—compromising ventricular mechanics
– Disruption of myocardial collagen matrix impairing electrical conduction and mechanical efficiency
• Estimated that 15% of all HF patients have ventricular dysynchrony2
Clinical Consequences of Ventricular Dysynchrony
• Abnormal interventricular septal wall motion1
• Reduced dP/dt3
• Reduced diastolic filling time1,2
• Prolonged MR duration1,2
11 Grines CL, Bashore TM, Boudoulas H, et al. Grines CL, Bashore TM, Boudoulas H, et al. CirculationCirculation 1989;79:845-853. 1989;79:845-853. 2 2 Xiao, HB, Lee CH, Gibson DG. Xiao, HB, Lee CH, Gibson DG. Br Heart J Br Heart J 1991;66:443-447.1991;66:443-447. 33 Xiao HB, Brecker SJD, Gibson DG. Xiao HB, Brecker SJD, Gibson DG. Br Heart J Br Heart J 1992;68:403-407.1992;68:403-407.
Click to Start/StopClick to Start/Stop
Deleterious Effects of VentricularDyssynchrony 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
Cardiac Resynchronization Therapy
• The therapeutic intent of atrial-synchronized, biventricular pacing is to restore ventricular synchrony
• Complements drug therapy
Cardiac Resynchronization Therapy
Goals
• Improve hemodynamics
• Improve Quality of Life
Cardiac Resynchronization Therapy
• Cardiac resynchronization, in association with an optimized AV delay, improves hemodynamic performance by forcing the left ventricle to complete contraction and begin relaxation earlier, allowing an increase in ventricular filling time.
• Coordinate activation of the ventricles and septum.
ECG depicting cardiac resynchronizationECG depicting cardiac resynchronization
ECG depicting IVCDECG depicting IVCD
Cardiac Resynchronization Therapy
Increase the donkey’s (heart) efficiency
Achieving Cardiac Resynchronization
Goal: Atrial synchronous biventricular pacing
Transvenous approach for left ventricular lead via coronary sinus
Back-up epicardial approach
Doug Smith:Doug Smith:
Right AtrialLead
Right VentricularLead
Left VentricularLead
• Transvenous Approach– Standard pacing leads in RA and RV– Specially designed left heart lead placed in a left ventricular
cardiac vein via the coronary sinus
Achieving Cardiac ResynchronizationMechanical Goal: Pace Right and Left Ventricles
Cardiac Resynchronization SystemCardiac Resynchronization System
Proposed Mechanisms of Cardiac Resynchronization
• Improved Contraction Pattern
• AV Interval Optimization
Click to Start/StopClick to Start/Stop
0.14
0.16
0.18
0.20
0.22
0.24
500 600 700 800 900 1000
dP/dtmax (mmHg/s)
MV
O2/
HR
(R
elat
ive
Uni
ts)
LV Pacing
Dobutamine
Nelson et al. Nelson et al. CirculationCirculation 2000;102:3053-3059. 2000;102:3053-3059.
CRT Improves Cardiac Function at Diminished Energy Cost
p< 0.05
CRT Improves Cardiac Function at 6 Months in Moderate to Severe Heart Failure
0
2
4
6
P<0.001
P=0.12
P=0.029
LVEFAvg. Change(Absolute %)
-3
-2
-1
0
MIRACLE MIRACLE ICD Contak CD
P<0.001
P=0.58
Data sources: MIRACLE: Circulation 2003;107:1985-1990MIRACLE ICD:JAMA 2003;289:2685-2694Contak CD: J Am Coll Cardiol 2003;2003;42:1454-1459
Control CRT
MR Jet AreaAvg. Change
(cm2) Not Reported
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) *
LV End Systolic and Diastolic Volumes
LV Reverse Remodeling after CRT
Pacing No pacing
N = 25Yu CM, et al, Circulation 2002;105:438-445
Mortality/Morbidity Comparison
Risk reduction with CRT or CRT + ICD
Study (n random.)
Follow-up
Treat-ment
Mor-tality
& Hosp.
Mortal. & HF Hosp.
Mor-tality
HF Mort.
HF Hosp.
MIRACLE1
(n=453)6 M CRT 39% 27% 50%
JAMA meta-analysis2 (n=1634)*
3-6M CRT 23% 51% 29%
P < 0.05
* Includes MIRACLE
Date Sources: 1. Abraham WT, et al. N Engl J Med 2002;346:1845-53 2. Bradley DJ, et al. JAMA 2003;289:730-740
CRT 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 changeError bars are 95% CI.
P=0.004P=0.004
P=0.003P=0.003P=0.005P=0.005
Baseline (meters)Baseline (meters)
291 ± 101
305 ± 85
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
CRTCRT
ControlControl
CRT Improves Patients’ Quality of Life
Minnesota Living with Heart Failure QuestionnaireMinnesota Living with Heart Failure Questionnaire
Baseline (score)Baseline (score)
59 ± 21
59 ± 20
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
* Paired median changeError 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)
Sco
re I
mp
rove
men
t (p
oin
ts)
Sco
re I
mp
rove
men
t (p
oin
ts)
11
P=0.001P=0.001P<0.001P<0.001P<0.001P<0.001
CRTCRT
ControlControl
CRT Improves NYHA Functional Class
00
2020
4040
6060
8080
100100
120120
Nu
mb
er o
f P
atie
nts
Nu
mb
er o
f P
atie
nts
Improved 2 orImproved 2 ormore classesmore classes
Improved 1Improved 1classclass
No ChangeNo Change WorsenedWorsened
ControlControl CRTCRT
6%6%
32%32%
59%59%
4%4%
16%16%
52%52%
30%30%
2%2%
P<0.001P<0.001
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
CRT Improves Exercise Capacity in Moderate to Severe Heart Failure
-20
0
20
40
60 P<0.001 P=0.36 P=0.029
P<0.0016 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;107:1985-90MUSTIC SR: NEJM 2001;344:873-80MIRACLE ICD:JAMA 2003;289:2685-94Contak CD: J Am Coll Cardiol 2003;2003;42:1454-59
Control CRT
Peak VO2
Avg. Change (mL/kg/min)
Optimizing VV Delay Based on Aortic VTI
• Obtain Pulsed Wave Doppler of LVOT with several different sequential ventricular paced intervals
• Select the setting yielding the largest VTI as the optimal paced interval
• CSA is assumed constant, therefore optimal delay is based on VTI alone
LV first by 4 ms
LV first by 20 ms
RV first by 40 ms
Relative Cost of CRT
Cost per patient
$0$20$40$60
CRT+ICD
CRT
Hip/ knee replace
PTCA
CABG
Dialysis
$ thousands
Total Annual Expenditures
$0 $5 $10 $15 $20
$ Billions
Doug Smith:Doug Smith:
CRT: Moderate to severe systolic heart failure with wide QRS
Jessup M, Brozena S. Medical Progress--Heart Failure. N Eng J Med 2003; 348: 2007-2018. Copyright 2002 Massachusetts Medical Society. All rights reserved.
Patient Indications
CRT device:
– Moderate to severe HF (NYHA Class III/IV) patients
– Symptomatic despite optimal, medical therapy
– QRS 130 msec
– LVEF 35%
CRT plus ICD:
– Same as above with ICD indication
Cardiac Resynchronization Therapy
– is safe and well tolerated
– improves quality of life, functional class, and exercise capacity
– Improves cardiac function and structure
– improves heart failure composite response
– may have a favorable effect on combined measures of morbidity and mortality
In NYHA Class III and IV systolic heart failure In NYHA Class III and IV systolic heart failure patients with intraventricular conduction delays, patients with intraventricular conduction delays, cardiac resynchronization therapy:cardiac resynchronization therapy:
Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853
Conclusions
Summary
• Large number of patients studied in RCTs• Concordant proof that CRT improves
quality of life, exercise capacity, functional capacity– Improvements persist through 1 year
• CRT reduces the risk of mortality and heart failure due to worsening HF
• CRT + ICD reduces risk of mortality• CRT improves cardiac function and
structure