Transcript CARE-HF CArdiac REsynchronization in Heart Failure

CARE-HF
CArdiac REsynchronization
in Heart Failure
Clinical Study
Independent trial by Clinical Community
Sponsored by Medtronic
1
“Electromechanical Associations”
EP & HF Specialties Progressively More Entwined
Rogers JG & Cain ME
NEJM 2004;350:2193-95
• EP specialists
understand that:
– Drugs (ACEIs, BB, Aldo
Antagonists) have a
profound impact on HF
progression and
mortality
– Drugs (BB and Aldo
Antagonists)
significantly decrease
SCD
• HF specialists
understand that:
– 50% of HF patients die
from SCD
– ICD decreases mortality
– CRT decreases morbidity
and mortality
2
Prevalence and Prognosis of
Ventricular dyssynchrony
LBBB More Prevalent with
Impaired LV Systolic Function
Increased All-Cause Mortality with
Wide QRS at 45 Months (3)
P < 0.001
Preserved 8%
LVSF (1)
49%
34%
Impaired
LVSF (1)
Mod/Sev
HF (2)
24%
38%
QRS
< 120 ms
QRS
≥ 120 ms
3. Iuliano, et al. AHJ. 2002;143:1085-1091.
1. Masoudi, et al. JACC. 2003;41:217-223.
2. Aaronson, et al. Circulation. 1997;95:2660-2667.
3
Cardiac Resynchronization:
Proposed Mechanisms
Cardiac Resynchronization
Intraventricular
Synchrony
 dP/dt,  EF,  CO
( Pulse Pressure)
 LVESV
Atrioventricular
Synchrony
 MR
 LA
Pressure
 LV Diastolic
Filling
Interventricular
Synchrony
 RV Stroke
Volume
 LVEDV
Reverse Remodeling
Yu C-M, Chau E, Sanderson J, et al. Circulation 2002;105:438-445
4
Cumulative Benefit of ACE-I and Beta Blockers
INCIDENCE RATE /100 PERSON-YEARS OF FU
5.60%
6.00%
5.00%
NO BB
BB
P < 0.01
4.30%
4.00%
%
3.00%
1.80%
P < 0.05
1.30%
2.00%
1.00%
0.00%
Total Mortality
SCD
Exner DV et al. JACC; 1999; 33: 916-23
5
Total Mortality Benefit for an ICD Trial (AVID)
and a Statin Trial (WOSCOP)
AVID
WOSCOPS
100%
100.00%
90%
90.00%
80%
80.00%
70%
70.00%
60%
%
60.00%
50%
%
40%
50.00%
40.00%
4.1%
3.2%
30%
20%
25%
10%
30.00%
18%
20.00%
10.00%
0%
Drug
• 27%
ICD
Relative Risk Reduction
0.00%
Placebo
Statin
•22% Relative Risk Reduction
• 7% Absolute Risk Reduction
•0.9% Absolute Risk reduction
•18% Residual Risk
•3.2% Residual Risk
6
Residual Risk of SCD in Treatment Arms
of CHF-Beta Blocker Trials
156
160
145
Number of Deaths
140
Sudden Deaths
Total Deaths
120
100
79
80
60
48
40
20
12
22
0
CIBIS II (1999)
MERIT-HF (1999)
U.S. CARVEDILOL
(1996)
Sudden Death % of
Total Death
31%
54%
54%
No. Pts in Treatment Arm:
Average Follow Up:
n= 1327
16 months
n= 1990
12 months
n = 696
6.5 months
1.
CIBIS-II Investigators. Lancet 1999; 353: 9-13.
2.
MERIT-HF Study Group. Lancet. 1999; 353: 2001-07.
3. Packer, M, et al. N Engl J Med 1996: 334: 1349-55.
7
MADIT II: Hospitalization for Heart Failure
P= 0.009
% Pts. Hospitalized for HF
20.00%
19.9%
14.9%
18.00%
16.00%
14.00%
12.00%
10.00%
Conventional
ICD
8.00%
6.00%
4.00%
2.00%
0.00%
Moss AJ et al. NEJM 2002; 346: 877-83
8
Pharmacologic and Device Therapy Across the Continuum
Post-MI
LV dysfunction
Mild
CHF
Moderate
CHF
Severe
CHF
AIRE/SAVE
(ramipril/captopril)
SOLVD Treatment
(enalapril)
CONSENSUS
(enalapril)
CAPRICORN
(carvedilol)
US Carvedilol/MERIT
(carvedilol/metoprolol)
COPERNICUS
(carvedilol)
EPHESUS
(eplerenone)
CHARM/Val-HeFT
(candesartan/valsartan)
RALES
(spironolactone)
MADIT, MUSTT
(ICD)
SCD-HeFT, MADIT-II
(ICD)
MIRACLE, COMPANION,
MUSTIC (CRT +/- ICD)
CARE-HF
9
CRT Background
• CRT has been shown to be consistently
associated with:
–
–
–
–
–
–
Reductions in LV size and volume
Increased Stroke Volume
Increased Ejection Fraction
Reduced Mitral Regurgitation
Improved exercise capacity
Improved QOL and functional capacity
• Effects of CRT on hospitalisation and
mortality remain uncertain
10
CRT Improves Quality of Life and
NYHA Functional Class
Average Change in Score
(MLWHF)
NYHA: Proportion
Improving 1 or More Class
0
80%
-5
*
*
*
60%
-10
-15
40%
Control
RA
CL
EI
CD
*
20%
0%
MI
AK
CD
CO
NT
ST
IC
MU
RA
CL
E
MI
*
*
SR
*
-20
CRT
Abraham et al., 2003
* P < 0.05
MIRACLE CONTAK MIRACLE
CD
ICD
Control
CRT
11
CRT Improves Exercise Capacity
Average Change in Peak
VO2
Average Change in 6
Minute Walk Distance
*
*
3
*
ml/kg/min
m
60
40
20
0
-20
-40
*
*
2
*
*
1
0
Control
CRT
CD
MI
RA
C
LE
I
D
CO
NT
A
KC
R
MU
ST
IC
S
LE
MI
RA
C
I CD
LE
D
Control
MI
RA
C
NT
A
KC
R
CO
MU
ST
IC
S
MI
RA
C
LE
0
CRT
* P < 0.05
Abraham et al., 2003
12
CRT Benefits Sustained Through 2 Years
MIRACLE Study Program
Mean
distance
walked in
6 minutes
(m)
Mean
NYHA
Functional
Class
500
400
300
200
100
0
4
P<0.001
P<0.001
P<0.001
P=0.01
Baseline
Follow-up
Paired
Data
Displayed
P<0.001
P<0.001
P<0.001
P<0.001
P<0.001
P<0.001
P<0.001
P<0.001
6 (N=1124)
12 (N=693)
18 (N=320)
24 (N=68)
3
2
1
Mean
QoL
Score
100
80
60
40
20
0
Months of Active CRT
Abraham et al., AHA 2003
13
Comparison with Drug Trials: Digoxin,
ACE-I and Beta-blocker Therapies
Change from baseline in
CPX Duration
90
30
10
‡
5
60
†
*
0
seconds
meters
20
*
30
*
0
score
†
40
Change from baseline in
QoL (MLWHF) Score
Improvement
Change from baseline in 6
minute walk distance
0
-10
-20
Dig BB CRT
(1) (2) (6)
1 NEJM 1993;329:1-7 (RADIANCE)
2 Circulation 1996;94:2793-2799 (PRECISE)
3 JAMA 1988;259:539-544
-10
-15
‡
-20
Dig ACE CRT
(1)
(3)
(6)
Control
* P.05
‡
NS
-30
-30
-5
ACE
(4)
BB
(5)
CRT
(6)
Treatment
† P.01
‡ P.001
4 Am J Cardiol 1993;71:1106-1107 (SOLVD Treatment)
5 J Cardiac Failure 1997;3:173-179
6 NEJM 2002;346:1845-53 (MIRACLE)
14
Systematic Review
of 9 clinical trials
CRT reduces all-cause
mortality
by 21% (RR 0.79 [Ci 0.660.96]
NNTB 24
McAlister FA et al.
Ann Intern Med 2004; 141:381-90
CRT does not
significantly
reduce
all-cause mortality
Calvert M, Freemantle N and
Cleland JGF
Ann Intern Med 2005;
142 :305-7
15
Limitations of Previous Trials/Analyses or
Why Was CARE-HF Needed
• No individual clinical trial found a statistically
significant reduction in all-cause mortality
• 8/9 trials required successful device implantation
before pts. were randomly assigned to CRT on or
off [omission of implant failures (10%) and
procedural deaths (0.4%) and exposure of controls
to the effects of implanted device]
• CRT combined with ICD in some but not all
studies (difficult to isolate effect of CRT alone on
mortality)
16
Limitations of Previous Trials/Analyses or
Why Was CARE-HF Needed (cont’d)
• COMPANION had unbalanced 3-arm
design (OMT, CRT, CRT+ICD)
• Inclusion of all 3 arms of COMPANION in
meta-analyses inappropriately credits CRT
with the mortality reduction due to the ICD
17
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
18
CARE-HF
Intent
• To assess the effect on morbidity and mortality
of adding CRT to optimised pharmacological
therapy in patients with moderate and severe HF
due to LVSD complicated by cardiac
dyssynchrony
• To investigate the mechanisms underlying the
observed effect to identify markers predicting
success or failure of CRT
• To define long term effects and Health
Economics.
19
CARE-HF Committees
• Steering Committee (8)
• Data Safety and Monitoring Board (4)
•Ryden, Poole-Wilson, Wellens, Wedel
• Blinded Endpoint Adjudication
Committee (2)
•Uretsky, Thygesen
• Independent device-related adverse event assessor (1)
• (Bocker)
20
CARE-HF Communication
Steering
Committee
Sites
- Investigators
- Coordinators
FCM/
Monitors
DSMB
Core-labs
BRC
Quintiles
- SS&R
- DM
- CEVA
EPC
USA
Tolochenaz
21
CARE-HF
Study Overview
22
Primary & Main 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
Main Secondary Endpoint
• All-cause mortality
23
Statistical Methods
• Assumptions for Death or Unplanned CV
hospitalization
– Event rate in the control group: 40%
– Absolute reduction in risk: 5.7%
• 80% power with 300 primary outcome events
• Censoring data within first 10 post randomization
for Hospitalization endpoint. (No influence on
results when analyzed without 10 days)
24
Study Design
Patient screening- consent
Randomization
Optimal medical therapy
Follow-up (min 1.5 year)
Optimal medical therapy
& cardiac resynchronization
Follow-up (min 1.5 year)
Primary outcome
Secondary outcomes
Mechanistic & health economic outcomes
25
Intervention
• InSync® or InSync® III -> CRT-alone
• Atrial-based, biventricular stimulation
– RV: from apex using a standard pacing lead
– LV: from lateral or postero-lateral free wall via the
coronary sinus and veins using an Attain™ lead
• Echo guided optimization of AV delay
26
Main Inclusion 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
27
Main Inclusion Criteria (cont’d)
• QRS 120 ms
– Dyssynchrony confirmed by echo if
QRS = 120-149 ms
• Aortic pre-ejection delay >140ms
• Inter-ventricular mechanical delay >40 ms
• Delayed activation of postero-lateral LV wall
Main Exclusion Criteria
• Patients with chronic AF or requiring pacing excluded
28
Population – Baseline Characteristics
• 813 pts predominantly class III (94%)
• Mean age 65 (IQR 59-72)
– 34% aged > 70 years
– 27 % woman
•
•
•
•
•
38 % Ischaemic Heart Disease, 46% Dilated CM
Mean HR adequately controlled at 70 BPM
88% QRS > 150 msec.
Supine systolic BP : 117 (IQR 105-130)
94 % diuretic, 95 % Ace or ARB, 72 % b-Blocker,
56% Spironolactone
Baseline Characteristics of Patients Recruited into the CARE-HF Study; With Courtesy : JGF Cleland et al. Submitted to EJHF
29
Population – Baseline Characteristics (cont’d)
• LV EF 26%
• LVEDD 72 mm
• 2D and Doppler date suggest that few patients had
end-stage disease characterized by pulmonary
hypertension and right ventricular dysfunction
• Co-Morbidities:
– Diabetes 21%, history Atrial Arrhythmias 21%,
Pulmonary disease 19%, renal dysfunction 18%
Baseline Echo Cardiographic Characteristics of HF Patients enrolled in a large European Multicenter trial (Cardiac Resynchronization in Heart Failure) With
Courtesy : S. Ghio et al. Submitted to EJHF.
Baseline Characteristics of Patients Recruited into the CARE-HF Study; With Courtesy : JGF Cleland et al. Submitted to EJHF
30
Baseline Characteristics
Control
n = 404
CRT
n = 409
66 (59 to 72)
67 (60 to 73)
Male (%)
NYHA IV (%)
293 (73%)
27 (6.7%)
304 (74%)
23 (5.6%)
Ischaemic heart disease (%)
Treatment (%)
ACEIs / ARBs
142 (35%)
167 (41%)
383 (95%)
387 (95%)
Beta blockers
298 (73%)
288 (71%)
Furosemide Eq  80 mg/day
Digitalis
177 (44%)
181 (45%)
175 (43%)
165 (40%)
Spironolactone
238 (59%)
219 (54%)
Age [yr] - median (IQR)
31
Baseline Characteristics (cont’d)
Parameter
(median [IQR])
Control
n = 404
CRT
n = 409
Heart rate [bpm]
70 (61 to 78)
69 (60 to 78)
Systolic BP [mm Hg]
110 (100 to 125)
110 (100 to 125)
Diastolic BP [mm Hg]
70 (60 to 80)
70 (60 to 79)
160 (152 to 180)
160 (152 to 180)
50 (30 to 66)
25 (22 to 29)
49 (32 to 67)
25 (21 to 29)
117 (94 to 147)
121 (92 to 151)
23 (11 to 34)
61 (46 to 73)
1,806 (719 to 3,949)
21 (12 to 33)
60 (46 to 73)
1,920 (744 to 4,288)
QRS interval [ms]
IVMD [ms]
Ejection fraction
ESV index
MR [% of LA area]
GFR [mL min-1]
NT proBNP [pg mL-1]
32
MIRACLE, COMPANION, CARE-HF:
Similarities and Differences
MIRACLE
COMPANION
CARE-HF
C
CRT
C
CRT
CRT+ICD
C
CRT
Age (yrs.)
65
64
68
67
66
66
67
Ischemic
HD (%)
58
50
59
54
55
36
40
NYHA III
(%)
91
90
82
87
86
93
94
QRS
Duration
165
167
158
160
160
160
160
EF (%)
22
22
22
20
22
25
25
ACEI
90
93
87
89
90
95
95
BB
55
62
66
68
68
70
74
Spironolactone
-
-
55
53
55
59
54
F/U (mos.)
6
6
12
16
16
29
29
1 yr mortality (%)
(Control Arm )
19
12.6
33
CARE-HF vs. other CRT Trial Populations
• CARE-HF patients did not need a hospitalization within the year
preceding enrollment, as requested in the COMPANION trial.
• Diabetes co-morbidity in COMPANION was 40-45% vs. 21% in
CARE-HF. Ischaemic population 55-59 % vs. 38% in CARE-HF.
• One-year mortality in Control group : COMPANION 19% /
CARE-HF 12.6%.
• Average patient in CARE-HF appear to be less symptomatic than
in MIRACLE, as CARE-HF included over 94% NYHA Class III.
However, in CARE-HF >90% of patients had EF < 30 %.
• Since CRT proved effective in CARE-HF, this may provide
evidence of benefit in a broader symptomatic group than
previously studied.
Quote from Baseline Characteristics of Patients Recruited into the CARE-HF Study; With Courtesy : JGF Cleland et al. Submitted to EJHF
34
CARE-HF
Results
35
1-14 Patients/Center
>14 Patients/Center
Recruitment
•813 patients (Jan
2001 Mar 2003)
•82 centers in 12
countries
Austria, Belgium,
Denmark,
Finland, France,
Germany, Italy,
Netherlands,
Spain, Sweden,
Switzerland,
and UK
36
CRT Arm - Implantation
• 409 Patients Randomized to CRT Arm
– 1 Death
– 4 No implant attempt
• 404 Implant Attempts
– 390 pts CRT implanted
– 96% with 3 attempts, 86% at first attempt
• Time randomization to implant : 4 days [2,8]
• Implant success rate 96%
• Before activation of CRT therapy ->6 pts reached
primary objective
37
Conduct of the Study
• Follow-up time
– Minimum 18 month -> last patient Sep 2004
– Average (Mean) Follow up : 29.4 month accounting
• Cut-off data (30 Sept. 2004 – Randomization date)
– Maximum 44.7 months: 3years 8 months
• At completion (30th September 2004)
– <5% cross-over before primary endpoint
– Survival status ascertained on all patients
• 202/ 813 pts (25% reached secondary endpoint)
• 383/813 pts (45% reached primary endpoint)
• All Adverse Events were adjudicated into Major, Minor,
Planned hospitalization and for mode, cause, place
38
Primary Endpoint
(All-cause Mortality or Unplanned Hosp. for Major CVS Event)
Event-free Survival
1.00
0.75
0.50
Medical
Therapy
0.25
0.00
Number at risk
0
409
CRT
Medical Therapy 404
500
323
292
273
232
1000
166
118
68
48
1500 Days
7
3
39
Primary Endpoint
(All-cause Mortality or Unplanned Hosp. for Major CVS Event)
1.00
Event-free Survival
HR 0.63 (95% CI 0.51 to 0.77)
0.75
CRT : 159 pts (39%)
0.50
P < .0001
Medical : 224 pts
Therapy (55 %)
0.25
0.00
Number at risk
0
409
CRT
Medical Therapy 404
500
323
292
273
232
1000
166
118
68
48
1500 Days
7
3
40
All-Cause Mortality
Event-free Survival
1.00
0.75
0.50
Medical
Therapy
0.25
0.00
0
500
1000
1500 Days
Number at risk
409
CRT
Medical Therapy 404
376
365
351
321
213
192
89
71
8
5
41
All-Cause Mortality
1.00
Event-free Survival
HR 0.64 (95% CI 0.48 to 0.85)
0.75
CRT : 82pts (20%)
P = .0019
0.50
Medical 120 pts
Therapy (30%)
0.25
0.00
0
500
1000
1500 Days
Number at risk
409
CRT
Medical Therapy 404
376
365
351
321
213
192
89
71
8
5
42
Primary
Endpoint
Overall
Age
Low
High
Sex
Male)
Female
NYHA
Dilated
cardiomyopathy
III
IV
Absent
Present
Systolic BP
Low
High
NT-BNP
Low
High
Ejection fraction
Low
High
End systolic volume
Low
High
QRS
Low
High
IVMD
Low
High
Mitral regurgitation
Low
High
GFR
Low
High
Beta blockers
Absent
Present
Spironolactone
Absent
Present
Loop diuretics
Low
High
Digoxin
Absent
Present
0.2
0.5
1
2
43
Symptoms & Quality of Life at 90 days
Outcome
NYHA class
Medical
CRT
Difference in
Therapy
Group
means
Mean (SD) Mean (SD) (95% CI; P value)
2.7 (0.9)
2.1 (1.0)
MLWHF score 40.0 (21.7) 31.1 (21.6)
Euroqol EQ5D
0.626
(0.289)
0.700
(0.284)
0.6 (0.4 to 0.7;
P < 0.0001)
-10.1 (-8 to -12;
P < 0.0001)
0.076 (0.037 to
0.115;
P = 0.0001)
44
Mechanistic Outcomes
Outcome
Systolic BP (mm Hg)
Inter-ventricular
mechanical delay (ms)
Ejection fraction (%)
Left ventricular endsystolic volume (mL)
Mitral regurgitation (% of
LA Area)
NT Pro-BNP [pg mL-1]
Mean difference
at 3 mo*
+5.8
(P < 0.0001)
-21
(P < 0.0001)
+3.7
(P < 0.0001)
-18.2
(P < 0.0001)
-5.1
(P < 0.0001)
-225
(P = 0.36)
* Positive values indicate higher value with CRT compared to control
at 18 mo*
+6.3
(P < 0.0001)
-21
(P < 0.0001)
+6.9
(P < 0.0001)
-26.0
(P < 0.0001)
-4.2
(P = 0.003)
-1,122
(P = 0.0016)
45
Serious Adverse Events
SAE Groupings
Control
CRT
P value
Patients with Procedure or device related Adverse Event
(Assessed by Independent Expert)
Procedure related death
1
1
P = 0.99
Lead problems
6
27
P < 0.001
Coronary sinus dissection
0
12
P < 0.001
Pocket complications
1
9
P = 0.012
Patients with Other Serious Adverse Events (Investigator Reported)
Myocardial Isch & MI
84
70
P = 0.21
Worsening HF
263
191
P < 0.0001
Atrial arrhythmia
41
64
P = 0.02
Ventricular arrhythmia
54
58
P = 0.74
Respiratory infection
101
85
P = 0.15
AVB or bradycardia
27
17
P = 0.12
46
Cardiac Resynchronization Therapy:
Patient Selection February 2005
•  18 years of age
• NYHA Functional Class III or IV
despite stable/optimal drug regimen
• QRS duration  120-130 msec
• LVEF  35%; LVEDD  55
millimeters
• With or without indication for ICD
47
ICDs: Patient Selection February 2005
•  18 years of age
• NYHA Functional Class II or III despite
stable/optimal drug regimen
• LVEF  35%
• Ischemics must have “remote” MI
days)
(> 30
• Non-ischemics must have CHF of at least
3 (?9) months duration
48
Device Indications
• Stage C heart failure
• LVEF  35%
• Optimal medical
therapy
QRS
Duration
NYHA Functional Class
II
III
IV
1&
CRT
1
CRT
 120 ms ICD2
ICD2
< 120 ms
ICD2
ICD2
1. Abraham WT, Fisher WG, Smith AL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845-1853
2. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implanatble cardioverter-defibrillator for congestive heart failure. N Engl J
Med 2005;352:225-37
49
Remaining Questions About CRT
• Effects of CRT in pts. with EF ≤ 35%, but NYHA
class I or II ( MADIT-CRT, REVERSE)
• Effects of CRT in pts. with NYHA class IV HF
(< 5% of population in CRT trials)
• Effects of CRT in pts. with narrow QRS but
evidence of mechanical dyssynchrony
• Effects of CRT in pts. with atrial fibrillation
(excluded from CRT trials)
• Predictors of response to CRT (PROSPECT trial)
• Cost effectiveness of CRT
50
Conclusions
• Conclusive results from CARE-HF demonstrate that CRT
should be considered as part of routine therapy for patients
with moderate to severe HF due to LVSD with evidence
(ECG supported by Echo) of cardiac dyssynchrony to*:
– Improve cardiac function and efficiency
– Improve symptoms and QoL
– Reduce morbidity
– Prolong survival
• These benefits are in addition to those of pharmacological
therapy
• On-going promising research to solve remaining questions
about CRT
51
CARE-HF
Additional Resources
52
Additional Resources
Publications:
• Baseline:
The CARE-HF study: rationale, design and end-points Cleland JGF, Daubert
JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Klein W, Tavazzi L,
on behalf of The CARE-HF study Steering Committee and Investigators. Eur J
Heart Fail 2001;3:481-489.
• Results
The effect of cardiac resynchronization on morbidity and mortality in heart
failure. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D,
Kappenberger L, Tavazzi L; Cardiac Resynchronization-Heart Failure (CAREHF) Study Investigators. N Engl J Med. 2005;352:1539-49.
http://content.nejm.org/cgi/content/abstract/NEJMoa050
496
53
CARE-HF Results
Additional Information
54
Mechanistic Outcomes
At 18 months, compared to the control group, patients
randomized to CRT had:
•
•
•
•
•
•
Shorter Interventricular Mechanical delay
Higher LVEF (by about 7%)
Less mitral regurgitation
Lower ventricular volumes
Higher systolic blood pressure
Lower NT-pro-BNP
P < 0.0001
P < 0.0001
P = 0.003
P < 0.0001
P < 0.0001
P < 0.0016
55
CARE-HF Baseline QOL
Problem
Total #pts/ %
Moderate
Problem
Extreme
Problem
Any
Mobility
483 (64.6)
9 (1.2)
492 (65.8)
Self Care
168 (22.5)
8 (1.1)
176 (23.6)
Usual activities
455 (61.0)
111 (14.9)
566 (75.9)
Pain/Discomfort
449 (60.2)
56 (7.5)
505 (67.7)
Anxiety/Depress
ion
322 (43.1)
52 (7.0)
374 (50.1)
EQ-5D dimension
Calvert M et al. The impact of Chronic HF on Health Related QOL – CARE-HF baseline EJHF 2005;7(2) in press
56
Baseline EQ-5D : CARE-HF population
vs. Other Diseases
General population
0.86 (0.85, 0.87)
General population age 65-74
0.78 (0.76, 0.80)
CARE-HF
0.60 (0.58, 0.62)
Type II diabetes
0.77 (0.76, 0.78)
Mild motor neurone disease*
0.63 (0.49, 0.77)
Moderate motor neurone disease*
0.56 (0.43, 0.69)
Parkinson's disease
0.59 (0.54, 0.64)
Hospitalised after ischemic stroke
0.31 (0.24, 0.38)
3 month assessment post stroke
0.61 (0.55, 0.67)
Non-small Cell Lung Cancer
0.58 (0.51, 0.65)
0.0
0.2
0.4
0.6
0.8
1.0
Calvert M et al. The impact of Chronic HF on Health Related QOL – CARE-HF baseline EJHF 2005;7(2) in press
57
Investigators
Steering Committee – J.G.F. Cleland (Chairman), J-C. Daubert, E. Erdmann, D. Gras, L. Kappenberger, W. Klein, L.
Tavazzi;
Data and Safety Monitoring Committee – P.A. Poole-Wilson, L. Rydén (Chairman), H. Wedel, H.J.J. Wellens;
Endpoints Committee – B. Uretsky, K. Thygesen;
Independent Device Related Adverse Event Assessor – D. Böcker;
Study Management – M.M.H. Marijianowski;
Statistical Analysis Group – N. Freemantle, M.J. Calvert;
Pharmacovigilance and Data Management – Quintiles;
CARE-HF investigators – Austria – G. Christ, F. Fruhwald, R. Hofmann, A. Kypta, F. Leisch, R. Pacher, F. Rauscha;
Belgium – R. Tavernier; Denmark – P.E. Bloch Thomsen, S. Boesgaard, H. Eiskjær, G.T. Espersen, J. Haarbo, A.
Hagemann, E. Korup, M. Møller, P. Mortensen, P. Søgaard, T. Vesterlund; Finland – H. Huikuri, K.I. Niemelä, L.
Toivonen; France – F. Bauer, A. Cohen-Solal, C. Crocq, P. Djiane, J.L. Dubois-Rande, P. de Groote, Y. Juilliere, G.
Kirkorian, M. Komajda, T. Laperche, H. Le Marec, C. Leclercq, C. Tribouilloy; Germany – F. Er, E. Fleck, U.C. Hoppe,
F.X. Kleber, B. Maisch, J. Neuzner, C. Reithmann, T. Remp, C. Schmitt, C. Stahl, R.H. Strasser; Italy – M.C. Albanese, A.
Bartoloni, M. Bocchiardo, A. Capucci, A. Carboni, A. Circo, M. Disertori, R. del Medico, T. Forzani, M. Frigerio, A.
Gavazzi, M. Landolina, M. Lunati, S. Mangiameli, M. Piacenti, A. Pitì, P.A. Ravazzi, A. Raviele, M. Santini, A. Serio, G.P.
Trevi, M. Volterrani, M. Zardini; Netherlands – F.A.L.E. Bracke, C.C. de Cock, A. Meijer, R. Tukkie; Spain – J. Casares
Mediavilla, M. Concha, J.F. Delgado, A. González-García, R. Muñoz-Aguilera, J. Martínez Ferrer, F. Ridocci; Sweden – B.
Andren, J. Brandt, P. Blomström, M. Edner, K. Hellström, S. Jensen, F. Maru, S.J. Moller, F. Rönn, P. Smedgård, G.
Wikström; Switzerland – J. Fuhrer, G. Girod; UK – G.H. Broomes, S. Chalil, H. Dargie, W. Davies, A. Delaney, P. Elliott,
G.K. Goode, G. Haywood, G.C. Kaye, A.S. Kurbaan, R. Lane, T. Levy, F. Leyva, H. Marshall, S. Muhyaldeen, N. Nikitin,
M.J.D. Roberts, J.D. Skehan, W.D. Toff, D.J. Wright;
Corelabs – Echocardiography (Pavia, Italy) – C. Bassi, S. Ghio, E. Ghizzardi, G. Magrini, M. Pasotti, V. Pierota, E.
Tellaroli, A. Serio, L. Scelsi; Neuro-endocrine (Graz, Austria) – A. Fahrleitner, G. Leb, H. Wenisch; Therapy Delivery
(Kingston-upon-Hull, UK) – A. Bennett, M. Cooklin, J. Ghosh, S. Hurren, G.C. Kaye, N.K. Khan.
58
Supplemental Slides
59
CRT Background
60
Prevalence and Prognosis of
Ventricular dyssynchrony
• Cardiac dyssynchrony is common in patients
with HF due to LVSD. Approximately 15%
of all heart failure patients have an inter- or
intra-ventricular conduction delay
(QRS > 120 msec)1-2.
1
Havranek EP, Masoudi FA, Westfall KA, Wolfe P, Ordin DL, Krumholz HM. Spectrum of heart failure in older patients:
Results from the National Heart Failure Project. Am Heart J 2002;143:412-417
2
Shenkman HJ, McKinnon JE, Khandelwal AK, et al. Determinants of QRS Prolongation in a Generalized Heart Failure
Population: Findings from the Conquest Study [Abstract 2993]. Circulation 2000;102(18 Suppl II)
61
Achieving Cardiac Resynchronization
Goal: Atrial synchronous
biventricular pacing
Transvenous approach for left
ventricular lead via coronary sinus
Right Atrial
Lead
Back-up epicardial approach
Left Ventricular
Lead
Right Ventricular
Lead
62
CRT Studies: Over 90% NYHA III
Status at Enrollment
% enrolled
100
80
60
40
20
0
MIRACLE
InSync III
NYHA III
MUSTIC SR COMPANION
NYHA IV
63
Early Steps to Answer remaining
Questions about CRT
64
Roles of Echocardiography to Guide Cardiac
Resynchronization Therapy
Patient
Selection
LV & RV
Lead Positioning
Device Timing
Optimization
Intra-ventricular Dyssynchrony
Tissue Doppler Imaging
Velocity—6 segments
Strain rate—6 segments, same pt.
•
A standard deviation of 32.6 ms in differences in time to peak systolic
contraction (velocity) between 12 LV segments predicted response
(LVESV) to CRT in 30 pts. Yu CM et al. Am J Cardiol 2002;91:684–688
•
% of 6 basal LV segments with contraction after aortic valve closure
measured using strain rate* predicted change in LVEF with CRT in 20 pts.
Søgaard P, et al. JACC 2002;40:723–730
* Uses tissue velocity data to calculate regional deformation rates.
May be less influenced by translational motion or tethering.
One Study Assessed Whether Pacing at Site of Latest
Activation Had an Effect
• 31 nonischemic HF
patients with LBBB
• TDI used to assess basal
region of greatest delayed
activation
• Global improvement
versus baseline in
LVEDV, LVESV, LVEF,
NYHA class, 6 min walk
distance, LV filling time,
isovolumic contraction
time
Comparative changes in selected
parameters with CRT
Paced at most
delayed site?
Parameter
Yes
No
P-Value
-28.4
-9.2
0.04
LVEF (%)
+9
+2
0.04
6 min walk
distance (m)
+31
+8
0.19
LVESV (mL)
13 of 31 paced at most delayed site
18 of 31 paced at other site
Ansalone, et al. JACC 2002;39:489-99
CRT Device Optimization with Echo
Potential Targets
Stroke Volume
(Aortic VTI)
Trans-mitral
Flow
IntraVentricular
Synchrony
Should AV Delays be Optimized?
Optimal AV Delays Vary by Patient and by Target Optimization Measure
MIRACLE Study
% of Patients
80%
60%
40%
20%
0%
<80
80-120
>120
Optimal AV Delay
Predis N=353
6 Mo N=182
3 Mo N=288
Optimal AV delay (ms)
PATH-CHF Study
180
160
140
120
100
80
60
40
LV + dP/dt
Aortic PP
Optimization Target
Chronic study of biventricular pacing.
Optimal AV delay determined via
trans-mitral flow. Delurgio, et al. PACE
Acute study results of 27 patients with
biventricular pacing. Mean ± std. dev.
Pulse pressure (PP).
2001;24[pt 2]:651 [abstr. 452]
Auricchio, et al. Circulation 1999;99:2993-3001
Does Interventricular (VV) Delay Optimization
Make A Difference?
• Both studies:
• Rosanio, et al. Circ. 2003;108:IV-345
– N=22
– VV delay of 0 for first 2 months.
– Echo based optimization of VV
delay (OPT) at 2 months.
• Sogaard, et al. Circ. 2002;106:2078-84
– N=20
– Optimal VV delay based on TDI
– Acute data shown. After 3 mo.,
LVEF further improved to 38.6%.
(P<0.01)
30%
mean LVEF (%)
– Single center study of
consecutive patients with NYHA
III/IV HF, QRS > 130 ms;
– Trans-mitral flow optimized with
AV delay post implant
#
35%
#
*
*
Rosanio
Sogaard
25%
20%
15%
10%
5%
0%
Baseline
with AV OPT
VV OPT
* P<0.01 CRT with AV Opt versus Baseline
# P<0.01 VV Opt versus CRT with AV Opt
Do Wider QRS Respond Better to CRT?
• Positive Findings
– ↑ QOL and exercise
tolerance only if QRS >
150 msec. (Auricchio A. JACC
2003; 42: 2107)
– Longest QRS greatest
benefit (Bristow MR. NEJM
• Negative Findings
– Achilli’s Study: CRT
benefit (NYHA, 6 min
walk, QRS reduction)
equal in patients with
wide and narrow QRS
2004; 350: 2140)
– Average QRS in trials
showing CRT benefit
•
•
•
•
•
MIRACLE
MUSTIC
InSync ICD
Contak CD
COMPANION
166
176
165
158
160
– Conclusion: patient
selection for CRT
should be based on
evidence of mechanical
rather than electrical
dyssynchrony (Achilli C.
JACC 2003; 42: 2117-24)
71
Does Shortening of QRS Duration Indicate a Positive
Response to CRT?
• Positive Findings
– Positive response to CRT
related to electrical
resynchronization (Alonso
C. AJC 1999; 84: 1417-21)
– MIRACLE, InSync had
significant decline in
QRS duration
• Negative Findings
– Changes in QRS with
pacing did not predict CRT
efficacy (Kass DA.Circ. 1999;
99: 1567-73)
– Responders exhibit a
significant reduction in
QRS duration after CRT,
but individual responses
are highly variable and do
not permit adequate
selection of responders.
(Molhoek SG Pace, 2004; 27: 30813)
72
CRT – RBBB vs. LBBB
QRS
LBBB
Contak
Insync ICD
Miracle
MUSTIC
158
165
166
176
271 (54)
382 (69)
426 (80)
58 (87)
Bradley DJ JAMA 2003; 289: 733-40
Patients with RBBB benefit from CRT
if there is evidence of mechanical dyssynchrony
Bristow MR NEJM 2004: 350: 2140
Garrigue S. AJC; 2001; 88: 1436-41
Higgins JACC 2003; 42: 1454-1459
73
CRT and AF: All Trials Show Improvement
•MUSTIC
•Leclerq AJC 2000; 55: 1154
•Etienne AJC 1999; 83: 1138
PAVE Trial
PAVE: Changes in Peak VO2
P< 0.01
–
–
–
–
–
ml/kg/min
• Inclusion
Ablate and pace
RV vs BiV
NYHA I/II/III
Chronic AF > 1 mos
Walk < 450 meters in 6
minutes
RV (n=20)
BV (n=51)
6 weeks
6 months
Time Frame
PAVE: Changes in LVEF
47
• Endpoint
46
45
LVEF (%)
– 1° 6 minute walk
– 2 ° CPX V02
QOL
14.8
14.6
14.4
14.2
14
13.8
13.6
13.4
13.2
13
12.8
46.0
45.6
44.9
44
p=0.03
43
42
RV (n=67)
BV (n=76)
41
40.7
40
39
38
Pre-Implant
6 months
Time Frame
74
CRT: Decrease in VT ?
• Positive Findings
– Three studies show that
CRT is associated with
decreased ventricular
arrhythmias
(Higgins JACC 2000; 36: 842;
Walker S AJC 2000; 86:23133; Higgins JACC 2003; 42:
1454-1459)
• Negative Findings
– Epicardial LV leads
cause repolarization
abnormalities and
prolongation of QT
interval that may
trigger ventricular
arrhythmias
(Medina-Ravell VA Circ. 2003;
107: 740-46)
75