Download N Engl J Med

ICDs for Heart Failure
Derek T. Connelly
President - Heart Rhythm UK
Consultant Cardiologist - Glasgow Royal
Infirmary
September 2005
ICD Technology
Weight
Implant site
Leads
Implant time
Implant
mortality
Post-op stay
1989
250 g
Abdominal
Epicardial
4 hours
4-6%
2004
80 g
Pectoral
Endocardial
40 mins
< 1%
7-10 days
1 day
ICD Technology
1989
2004
Battery life
2 years
7-9 years
Pacing
None
DDDR, + LV
Tachy detection
Rate
Tachy Rx
Shock
Rate, onset,
stability,
atrial rate
morphology
Shock, pacing
Diagnostics
Limited
Extensive
ICD Trials:
“Secondary prevention”
Randomised Trials of ICD Therapy
“Secondary prevention” - patients who
have had sustained VT or VF



Antiarrhythmics versus Implantable
Defibrillator (AVID) - 1997
Cardiac Arrest Study Hamburg (CASH) 2000
Canadian Implantable Defibrillator Study
(CIDS) - 2000
Antiarrhythmics Versus Implantable
Defibrillator (AVID)



6000 patients screened, 1016 randomised
Mean age 65, 79% male, mean LVEF 31%
Inclusion arrhythmia:
• Ventricular fibrillation
• Ventricular tachycardia with syncope
• Symptomatic VT with LVEF <40%

45%
21%
34%
ICD in 507, Antiarrhythmic drugs in 509
N Engl J Med 1997; 337: 1576-83
N Engl J Med 1997; 337: 1576-83
AVID subgroups
N Engl J Med 1997; 337: 1576-83
Meta-analysis - ICD v Amiodarone
S J Connolly, Eur Heart J 2000; 21:2071-8
Meta-analysis - ICD v Amiodarone
S J Connolly, Eur Heart J 2000; 21:2071-8
ICD Trials:
“Primary prevention”
Randomised Trials of ICD Therapy
“Primary prevention” - patients who
have not yet had VT or VF, but are
thought to be at high risk





Multicenter Automatic Defibrillator
Implantation Trial (MADIT) -1996
Multicenter UnSustained Tachycardia Trial
(MUSTT) - 1999
MADIT 2 – 2002
COMPANION – 2004
SCD-HeFT - 2004
Studies of Non-Sustained VT
in pts with CAD, poor LV, inducible sustained VT

Multicenter Automatic Defibrillator
Implantation Trial (MADIT)
• Hypothesis that survival with ICD is better
than with antiarrhythmic drugs when VT
cannot be suppressed by IV procainamide

Multicenter UnSustained Tachycardia Trial
(MUSTT)
• Hypothesis that survival with EP guided Rx
(with ICD for drug failures) is better than
controls
Multicenter Automatic Defibrillator
Implantation Trial (MADIT)



Post - MI patients with asymptomatic
non-sustained VT and LVEF < 35%;
age 25 - 80
Sustained VT reproducibly inducible
at EPS and not suppressible with IV
procainamide
Randomised to antiarrhythmic drugs
or ICD
Moss et al N Engl J Med 1996; 335: 2933-40
MADIT - Results
Moss et al N Engl J Med 1996; 335: 2933-40
MUSTT Protocol
Baseline EPS + SAECG
EPS -ve
No AA drugs
EPS +ve
EP Guided Rx
No AA drugs
Drug responders
Non-responders
F/U on drug
ICD
MUSTT Results

2202 pts with NSVT studied, 767
inducible, 704 pts randomised
• 351 EP guided Rx, 353 no antiarrhythmic Rx
• 40% on b-blockers, 75% on ACE inhibitors

158 pts (45%) on antiarrhythmic drugs
• Class I 26%, amio 10%, sotlol 9%

161 pts (46%) had ICD
Buxton et al N Engl J Med 1999; 341: 1882-90
MUSTT Results

5 year mortality 24% in pts with
ICD, 55% in those without
(p<0.001)
• antiarrhythmic drugs had no effect on
mortality

Relative risk of total mortality in ICD
treated patients was 0.40 (95% CI
0.27-0.59)
Buxton et al N Engl J Med 1999; 341: 1882-90
MUSTT - Results
Buxton et al. N Engl J Med 1999 ;341:1882-90
UK ICD Guidelines

‘Secondary Prevention’:
• Cardiac arrest due to VT or VF
• Spontaneous sustained VT with syncope
or significant haemodynamic
compromise
• Sustained VT with poor ejection fraction
(<35%), NYHA Class > 3
www.nice.org.uk September 2000
UK ICD Guidelines

‘Primary Prevention’:
• Previous MI and all of the following:



Non-sustained VT on 24 hour ECG
monitoring
Inducible VT on electrophysiological testing
LV ejection fraction < 35%, NYHA Class > 3
• A familial condition with a high risk of
sudden death, e.g. Long QT, HOCM,
Brugada syndrome, ARVD, repaired
tetralogy of Fallot
www.nice.org.uk September 2000
NICE ICD Guidelines
Additional Recommendations

Protocols for the implantation of ICDs
should be developed, to include:
•
•
•
•
early referral of appropriate patients
rapid decision making and implantation
conscious sedation rather than GA
rehabilitative approach to after-care, including
psychological preparation for living with ICD
• early discharge
• efficient and comprehensive follow-up
ICD Trials: Why is the benefit greater in
“Primary Prevention” studies?

In AVID, CASH and CIDS, the main entry
criterion was ventricular arrhythmia
• Some patients had preserved LV function
• Mortality reduction with ICD 28% overall
• Mortality reduction 34% in patients with LVEF
< 35%

In MADIT and MUSTT, the main entry
criterion was poor LV function
• LVEF <35% in MADIT, <40% in MUSTT
• Mortality reduction with ICD 54 - 60%
• Heterogeneity in antiarrhythmic drug use
Who benefits most from ICDs?
1990’s


Patients at highest
risk of sudden death
are those with
ventricular
arrhythmias
(spontaneous or
induced)
The ICD is a
treatment for
ventricular
arrhythmias
2000’s


Patients at highest
risk of sudden death
are those with heart
failure due to poor
LV systolic function
The ICD is a
treatment for
heart failure
MADIT-2





Post MI, LVEF < 30%
ICD or control
Post - randomisation: non-invasive
markers, EP study
Primary end-point total mortality;
secondary: QOL, cost
Target enrolment 1200 patients
Klein et al Am J Cardiol 1999; 83: 91D-97D
MADIT-2


Study terminated November 20, 2001
1232 patients randomised
• 742 defibrillator, 490 conventional




Mean follow-up 20 months (range 6 days 53 months
105 deaths in ICD group (14.2%)
97 deaths in conventional group (19.8%)
31% reduction in risk of death with ICD
Moss et al New Engl J Med 2002; 346: 877-883
MADIT-2
Concomitant therapies





ACE inhibitors used in 70%
b blockers used in 70%
Statins used in 68%
57% had previously had CABG
44% had previously had PTCA
• MADIT-2 targeted patients who were
considered suitable for CABG / PTCA
• Benefit of ICD is over & above benefit
from revascularisation
MADIT II Results
Moss et al New Engl J Med 2002; 346: 877-883
MADIT-2
Subgroup analyses and additional tests


Heart rate variability (several
parameters), signal averaged ECG not useful
EP study performed in those with
ICD
• If EP +ve, more likely to get VT
• If EP -ve, more likely to get VF !
• Overall limited usefulness

QRS width - powerful predictor of
benefit from ICD
MADIT II - Subgroup analysis
Moss et al New Engl J Med 2002; 346: 877-883
COMPANION Results
Bristow et al New Engl J Med 2004; 350: 2140
COMPANION Results
Bristow et al New Engl J Med 2004; 350: 2140
COMPANION Subgroups
Bristow et al New Engl J Med 2004; 350: 2140
Companion Study

Biventricular pacing (+ ICD)
• Improves quality of life
• Improves 6-minute walk time
• Reduces need for hospitalisation for
heart failure
• Improves NYHA functional class
MIRACLE ICD Study
Efficacy of antitachycardia pacing
• 88% from RV (336 episodes)
• 95% from LV (658 episodes)
Sudden Cardiac Death in Heart
Failure Trial (SCD-HeFT)



2500 patients with symptomatic heart
failure (NYHA 2-3) and LV ejection fraction
< 35%
50% ischaemic, 50% idiopathic DCM
Randomised to
• No antiarrhythmic therapy
• Amiodarone
• ICD


5 year follow-up
Results presented March 2004
Hypothesis and Primary
Endpoint

To determine, by intention-to-treat
analysis, if amiodarone or a
conservatively programmed shockonly ICD reduces all-cause mortality
compared to placebo* in patients
with either ischemic or non-ischemic
NYHA Class II and III CHF and EF <
35%.
* Double-blind for drug therapy
Baseline Enrollment
Characteristics

Age
60.1 yrs (51.7, 68.5)
median (25th, 75th percentiles)

Female
23%

Minorities
23%

Heart rate
73 bpm (63, 84)

Blood pressure

• Systolic
118 mmHg (106, 130)
• Diastolic
70 mmHg (62, 80)
Weight
190 lbs (164, 219)
Baseline Enrollment
Characteristics












CHF duration
LV EF
NYHA II, III
Ischemic, non-ischemic
6 minute walk
Diabetes
CABG and/or Perc. Revasc.
H/O Hypertension
H/O Hyperlipidemia
H/O AF
H/O NSVT
ECG QRS duration ms
24.5 mo (8.1, 59.4)
25.0 (20.0, 30.0
70%, 30%
52%, 48%
1130 ft (840, 1360)
30%
37%
56%
53%
15%
23%
112 ms (96, 140), 41% > 120
Background Medications
Baseline
Last follow-up
85%
72%
ACE Inhibitor or ARB 96%
87%
Beta-blocker
69%
78%
Spironolactone
19%
31%
Loop diuretics
82%
80%
Aspirin
56%
55%
Statin
38%
47%
ACE Inhibitor
Median follow-up 45.5 months
Mortality by Intention-to-Treat
0.4
• Median follow-up: 45.5 mo (34.8, 55.2)
• Vital status known on 100% of 2,521 patients
36.1%
7.2%/year
Mortality
0.3
0.2
Amiodarone
0.1
ICD Therapy
Placebo
0
0
6
12
18
24
30
36
Months of follow-up
42
48
54
60
Mortality by Intention-to-Treat
0.4
HR
1.06
Amiodarone vs. Placebo
97.5% Cl
0.86, 1.30
P-Value
0.529
Mortality
0.3
0.2
Amiodarone
0.1
ICD Therapy
Placebo
0
0
6
12
18
24
30
36
Months of follow-up
42
48
54
60
Amiodarone vs. Placebo
Hazard Ratios
Patient Group
All Patients
NYHA Class
Class II
Class III
CHF Etiology Ischemic
Non-Ischemic
N
HR
97.5% Cl
1692
1.06
0.86, 1.30
1195
497
0.85
1.44
0.65, 1.11
1.05, 1.97
879
813
1.05
1.07
0.81, 1.36
0.76, 1.51
0.5
1
2
4
Additional Subgroups:
Amiodarone vs. Placebo
Patient Group
N
HR
97.5% Cl
Gender
Female
Male
398
1294
1.17
1.04
0.72, 1.90
0.83, 1.30
LVEF
<30%
> 30%
1407
285
1.04
1.24
0.84, 1.29
0.66, 2.31
Age
< 65
> 65
1119
573
1.00
1.13
0.76, 1.32
0.83, 1.52
QRS Duration
< 120 ms
> 120 ms
999
692
1.06
1.05
0.80, 1.41
0.78, 1.41
Race
White
1292
Non-White 400
1.06
1.08
0.84, 1.34
0.71, 1.62
Enrolling Country U.S.
Non-U.S.
1534
158
1.07
0.98
0.86, 1.32
0.52, 1.84
Beta Blocker
Yes
No
1162
530
1.10
0.98
0.85, 1.42
0.69, 1.38
Diabetes
Yes
No
514
1178
1.20
1.00
0.87, 1.65
0.77, 1.30
0.5
1
2
4
Mortality by Intention-to-Treat
0.4
Amiodarone vs. Placebo
ICD Therapy vs. Placebo
0.3
Mortality
HR
1.06
0.77
97.5% Cl
0.86, 1.30
0.62, 0.96
P-Value
0.529
0.007
0.2
Amiodarone
0.1
ICD Therapy
Placebo
0
0
6
12
18
24
30
36
Months of follow-up
42
48
54
60
ICD vs. Placebo
Hazard Ratios
Patient Group
All Patients
NYHA Class
Class II
Class III
CHF Etiology Ischemic
Non-Ischemic
N
HR
97.5% Cl
1676
0.77
0.62, 0.96
1160
516
0.54
1.16
0.40, 0.74
0.84, 1.61
884
792
0.79
0.73
0.60, 1.04
0.50, 1.04
0.25
0.5
1
2
Additional Subgroups:
ICD vs. Placebo
Patient Group
N
HR
97.5% Cl
Gender
Female
Male
382
1294
0.96
0.73
0.58, 1.61
0.57, 0.93
LVEF
<30%
> 30%
1390
285
0.73
1.08
0.57, 0.92
0.57, 2.07
Age
< 65
> 65
1098
578
0.68
0.86
0.50, 0.93
0.62, 1.18
QRS Duration
< 120 ms
> 120 ms
977
699
0.84
0.67
0.62, 1.14
0.49, 0.93
Race
White
1283
Non-White 393
0.78
0.75
0.61, 1.00
0.48, 1.17
Enrolling Country U.S.
Non-U.S.
1512
164
0.82
0.37
0.65, 1.04
0.17, 0.82
Beta Blocker
Yes
No
1157
519
0.68
0.92
0.51, 0.91
0.65, 1.30
Diabetes
Yes
No
524
1152
0.95
0.67
0.68, 1.33
0.50, 0.90
0.125
0.25 0.5
1
2
4
SCD-HeFT: Conclusions
In class II or III CHF patients with EF <
35% on good background drug therapy,
the mortality rate for placebo-controlled
patients is 7.2% per year over 5 years
 Simple, shock-only ICDs decrease
mortality by 23%
 Amiodarone, when used as a primary
preventive agent, does not improve
survival

SCD-HeFT – Cost-benefit analysis









Cost per life-year saved (US$)
LVEF < 30%
$33,509
LVEF > 30%
$29,275
Age > 65
$39,469
Age < 65
$29,164
QRS > 120 ms
$31,244
QRS < 120 ms
$34,821
Ischaemic
$33,603
Non-ischaemic
$32,170
DB Mark, AHA November 2004
CARE-HF: Background


Cardiac dyssynchrony is common in
patients with HF due to LVSD
CRT has been shown to be
haemodynamically effective in such
patients and to improve
• Symptoms
• Quality of life
• Exercise capacity

Effects of CRT on hospitalisation and
mortality remain uncertain
Aims


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
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 120149 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
CARE-HF: All-Cause Mortality
1.00
Event-free Survival
HR 0.64 (95% CI 0.48 to 0.85)
0.75
CRT
P = .0019
0.50
Medical
Therapy
0.25
0.00
Number at
risk
CRT
Medical
Therapy
0
409
404
500
376
365
351
321
1000
213
192
89
71
1500 Days
8
5
Symptoms & Quality of Life at
90 days
Outcome
NYHA class
MLWHF
score
Medical
Therapy
Mean
(SD)
2.7 (0.9)
40 (22)
CRT
Group
Mean
(SD)
Difference in
means (95%
CI; P value)
2.1 (1.0)
0.6
(0.4 to 0.7;
P < 0.0001)
31 (22)
-10
(-8 to -12;
P < 0.0001)
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
Conclusions

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
*http://content.nejm.org/
How do we improve quality of life in
patients with ICDs?



Patient preparation for life with ICD
Meticulous implant technique
Judicious programming
• Tachycardia detection- discrimination between VT and
SVT / AF
• Antitachycardia pacing


Optimal pharmacological therapy
Biventricular pacing if needed
• For resynchronisation and ATP
• Which patients need CRT with defibrillator, which
need CRT alone?

Rehabilitation
• Physical and psychological