3-4 aprile
Santa Margherita Ligure
tigullio cardiologia
2014
Quando l’evidenza dai trial è insufficiente:
il grande anziano
ICD e CRT nel grande anziano: come regolarsi ?
S. Fumagalli, Firenze
SOD Cardiologia e Medicina Geriatrica, AOU Careggi e
Università di Firenze
Heart Disease and Stroke Statistics—2012 Update
Prevalence of HF
Incidence of HF
National Health and Nutrition
Examination Survey
Framingham Heart Study
Per 1000 Person Years
Percent of Population
A Report From the American Heart Association
Men
Speranza di vita alla nascita (2011)
Uomini – 79.4 anni
Donne – 84.5 anni
Speranza di vita a 65 anni (2011)
Uomini – 18.4 anni ! 83.4 anni
Donne – 21.9 anni ! 86.9 anni
20-39
40-59
http://demo.istat.it/altridati/indicatori/2011/Tab_5.pdf
60-79
Age (years)
>80
65-74
Roger VL, 2012
75-84
Age (years)
>85
! Despite the compelling findings from several CRT trials,
it must be recognized that patients enrolled in these
studies were highly selected
! Specifically, few patients >75 were enrolled …
! Thus, RCT
evidence
for
efficacy
of
CRT
in
patients
Età media dei principali trial sugli ICD
>75 years
is lacking
as previously noted,
MADIT
(1996) –and,
63 anni
extrapolation
of data–from
trials in much younger
MUSTT (1999)
66 anni
patientsMADIT
to theIIvery
elderly
may not be justified due to
(2002)
– 64 anni
age-related
alterations
both
the risks (higher) and
DEFINITE
(2004) in
– 58
anni
benefits
(potentially
lower)
in older patients
SCD-HeFT
(2005)
– 60 anni
2011
Al-Khatib SM, 2013
Clinical characteristics of the patients enrolled in the
InSync / InSync ICD Italian Registry, by age groups
N=1787
Age (years)
Men (%)
COPD (%)
Diabetes (%)
Renal failure (%)
>2 diseases (%)
Age Groups (years)
<65
65-74
>75
(N=571)
(N=740)
(N=476)
P
57 ± 7
84
5
8
3
2
70 ± 3
81
7
9
8
4
78 ± 3
76
6
6
4
3
/
0.003
0.088
0.312
0.001
0.099
39
70 ± 10
60 ± 12
26 ± 8
167 ± 33
1.6 ± 1.4
50
69 ± 9
58 ± 10
26 ± 7
165 ± 31
1.6 ± 1.5
50
68 ± 9
57 ± 11
27 ± 8
162 ± 32
1.7 ± 1.4
<0.001
0.015
0.016
0.123
0.136
0.256
Permanent AF (%)
11
18
21
<0.001
Diuretics (%)
Nitrates (%)
III Class AAD (%)
87
17
34
89
23
38
88
46
34
0.415
0.001
0.312
CAD (%)
LVEDD (mm)
LVESD (mm)
EF (%)
QRS length (ms)
Hospitalizations (n)
CAD: coronary artery disease; Hospitalizations: CHF hospitalizations
in the previous 12 months; AAD: anti-arrhythmic drugs
Fumagalli S,
2011
CRT-induced changes of left ventricular (LV) diameters
during the follow-up, by age group
The results of the InSync / InSync ICD Italian Registry
LV diameters (mm)
75
70
End-diastolic
70
69
68
**
65
End-systolic
60
60
58
57
55
50
Fumagalli S,
2011
Age groups (years)
<65 65 – 74 >75
**: p<0.001 vs. Baseline
Baseline
**
**
**
**
**
**
**
**
** 54
53
**
** 51
6 months
Follow-up
66
66
64
12 months
CRT-induced changes of LV ejection fraction during
the follow-up, by age group
The results of the InSync / InSync ICD Italian Registry
45
LV ejection fraction
(%)
35
25
27
26
26
**
**
**
**
**
**
37
34
34
**: p<0.001 vs. Baseline
Age groups (years)
<65 65 – 74 >75
15
Baseline
6 months
Follow-up
12 months
Fumagalli S,
2011
Clinical predictors of prognosis in CRT patients
in the InSync / InSync ICD Italian Registry
The results of the multivariate Cox model
HR (95% CI)
p Value
1
/
65-74 years
1.17 (0.80-1.69)
NS
>75 years
1.57 (1.06-2.35)
0.026
Men
1.38 (0.90-2.12)
NS
Renal failure
1.29 (0.75-2.22)
NS
Coronary artery disease
1.18 (0.87-1.60)
NS
LVEF, per Δ %
0.96 (0.94-0.98)
<0.001
Permanent AF
1.63 (1.16-2.30)
0.005
ACE-I / Anti-AII
0.72 (0.52-0.98)
0.038
β-blockers
0.49 (0.35-0.67)
<0.001
CRT responder
0.37 (0.27-0.51)
<0.001
Age <65 years
Fumagalli S, 2011
Ruwald AC, 2014
Risk of Heart Failure / Death Comparing CRT-D to ICD in LBBB Patients With
and Without History of intermittent atrial tachyarrhythmias (TA)
Probability of HF/death
History of intermittent atrial
tachyarrhythmia (N=140)
No History of intermittent atrial
tachyarrhythmia (N=1101)
HR=0.50, 95%CI=0.27-0.93,
p=0.028
0.5
0.4
HR=0.46, 95%CI=0.36-0.59,
p<0.001
ICD
0.3
ICD
CRT-D
0.2
CRT-D
0.1
0.0
Biv. Pacing >92%: 95%
0
1
2
3
Biv. Pacing >92%: 90%
4
0
1
2
3
Follow-up (years)
Age: 67 years*; Women: 19%*
CRT-D: 51%*; LVEF: 28%;
Antiarrhythmics: 39%*
*: p<0.05 vs. No Hx of Atrial TA
Age: 61 years; Women: 32%
CRT-D: 61%*; LVEF: 29%;
Antiarrhythmics: 3%*
4
Improvements in exercise capacity in patients with moderate-to-severe
heart failure by CRT. A review of the results of clinical trials
60
6 Min Walk Test
(Change, m)
40
P<0.001
P=0.001
P=NS
P=0.029
20
0
-20
Peak VO2
(Change,
mL/min)
3
2
P=0.029
P<0.001
P=0.003
P=0.04
1
0
MIRACLE
(N, NYHA Class)
CRT
N=453, III-IV
Control
MUSTIC SR MIRACLE ICD CONTAK CD
N=58, III
N=369, III-IV
N=227, II-IV
Linde C et al,
2012
Patient self-reported global assessment and rate
of death during follow-up
% of Patients
81%
Much
better
A little
better
No
change
A little
worse
Much
worse
Dead
Bogale N et al., 2012
Survival of octogenarians undergoing CRT compared
with the age- and gender-matched general population
Age: 83 years; CRT-D: 86.3%;
LVEF: 25% (N=95)
Survival (%)
6m–
4.2%
1y–
10.5%
2y–
All-cause mortality in octogenarians
with advanced HF is only
21.1%
y–
modestly worse compared to the 3.6
general
octogenarian population.
49.4%
Therefore, … CRT should not be withheld based on age alone
Years
Percentages express
FU mortality
Rickard J, 2014
!
P=0.002
0,41
0,4
0,2
Mortalità annuale (%)
Morte Improvvisa / Mortalità Totale
The Amiodarone Trialists MetAnalysis - N = 6252, Follow-up: 16.8 mesi
20
0,6
Mortalità totale
15
11,7
10
5
Morte improvvisa
4,8
0
0
<50
<50
51-60 61-70 71-80 >80
Gruppi di età (anni)
51-60 61-70 71-80
>80
Gruppi di età (anni)
Mortalità
Totale
Improvvisa
Krahn AD et al, 2004
Age-related effects on mortality of the implantable cardioverter
defibrillator. An analysis of the Italian Clinical Service® Project
database!
Caratteristiche cliniche, per gruppi di età!
23.9%!
Risultati dell’analisi univariata di Cox!
N = 6311
Età (anni)
Gruppi di età (anni)
<65
65-74
>75
(n=2470)
(n=2331)
(n=1510)
55±9
70±3
78±3
P
/
Uomini (%)
83.2
82.0
81.8
NS
Aritmie ventricolari (%)
43.0
42.9
44.2
NS
Fibrillazione atriale (%)
8.1
12.6
18.3
<0.001
Ipertensione (%)
45.0
59.0
60.5
<0.001
Ricoveri (%)
49.5
50.9
49.7
NS
LVEDV (mL)
218±88
202±75
183±67
<0.001
Frazione di eiezione (%)
29±10
29±8
29±8
NS
I-II
III-IV
Amiodarone (%)
54.6
45.5
43.6
44.3
55.7
49.3
40.6
59.5
49.0
0.001
CRT (%)
62.4
70.7
67.8
<0.001
NYHA (%)
0.004
Aritmie ventricolari: aritmie ventricolari complesse; LVEDV: volume telediastolico
del ventricolo sinistro; NYHA: classe NYHA; CRT: terapia di resincronizzazione
cardiaca!
Fumagalli S, Marchionni N,
Padeletti L, 2014!
Age-related effects on mortality of the implantable cardioverter
defibrillator. An analysis of the Italian Clinical Service® Project database
Fattori clinici correlati alla mortalità
Risultati del modello multivariato di Cox
#
Mortalità
"
1.65
#22.6%
Gruppi di età (Δ·gruppo)
P<0.001
Aritmie v. (Si vs. No)
P<0.001
BPCO (Si vs. No)
P<0.001
CAD (Si vs. No)
P=0.001
Diabete (Si vs. No)
P=0.013
IRC (Si vs. No)
P<0.001
Frazione di eiezione (Δ·%)
P<0.001
Aritmie v. : aritmie ventricolari
complesse; CAD: malattia coronarica;
IRC: insufficienza renale cronica
HR (95% CI)
Fumagalli S, Marchionni N,
Padeletti L, 2014!
Age-related effects on mortality of the implantable cardioverter
defibrillator. An analysis of the Italian Clinical Service® Project
database
Fattori clinici correlati alla mortalità per gruppi di età
Risultati del modello multivariato di Cox
<65 anni
HR
Età (Δ·anno)
CAD (Si vs. No)
p
/
2.55 <0.001
65-74 anni
>75 anni
HR
p
HR
p
1.07
0.018
1.09
0.006
1.68
0.002
/
IRC (Si vs. No)
/
2.38 <0.001
/
Aritmie V. (Si vs. No)
/
1.42
/
FA (Si vs. No)
FE (Δ·%)
NYHA (III-IV vs. I-II)
2.05
0.017
/
2.10
0.037
/
0.95 <0.001
0.001
/
/
/
/
CAD: malattia coronarica; IRC: insufficienza renale cronica; Aritmie V.: aritmie ventricolari
complesse; FA: fibrillazione atriale; FE: frazione di eiezione del VS
Fumagalli S, Marchionni N,
Padeletti L, 2014!
Temporal Trends in Quality of Care among ICD
Recipients: Insights from the NCDR®
Overall trends in quality of care metrics in the ICD Registry – N=367,153
Adverse events
(%)
P<0.001
CRT (%)
P<0.001
69
P<0.01
Age (years)
OMT (%)
P<0.001
67,7
67
OMT: optimal medical Tx
ACE-i/ARB & β-blockers
67,5
67,1
CRT: CRT among eligible
patients
66,9
The ICD Registry is an initiative
of the ACCF and the HRS
65
2006-7 2007-8 2008-9 2009-10
Dodson JA, 2014
Correlation among optimal medical therapy (OMT) and cardiac resynchronization
therapy (CRT), for hospitals performing >50 procedures per year – N=367,153
100
CRT (%)
80
60
40
R=0.17 - P<0.001
20
0
20
CRT: CRT among eligible patients
OMT: optimal medical Tx
ACE-i/ARB & β-blockers
40
60
80
100
OMT (%)
The ICD Registry is an initiative
of the ACCF and the HRS
Dodson JA, 2014
Outcome after device implantation in chronic heart
failure is dependent on concomitant medical
treatment
C. Adlbrecht , M. Hu¨lsmann
, M. Gwechenberger
, G. Strunk , C. endpoint
Khazen , F. Wiesbauer
, M. Elhenicky free
,
Kaplan–Meier
estimates
of primary
- survival
of cardiac
S. Neuhold , T. Binder , G. Maurer , I. M. Lang and R. Pacher
Medical University of Vienna,
Vienna, Austria,
University of Economics
and Business,
Vienna,in
Austria
hospitalization
- (left)
andVienna
all-cause
death
(right),
patients with and without OMT
*
*
*
*
*
*
*
*
†
*
*
*
*
†
All-cause death or cardiac
All-cause death
Background Device implantation in chronic heart failure (CHF) for cardiac resynchronization therapy (CRT) with
hospitalization
or without implantable cardioverter
⁄ defibrillator (ICD) is an established treatment option for symptomatic
ABSTRACT
patients under medical baseline therapy. Although recommended, the need for optimization of medical therapy
was never proven. As in ‘the real world’, medical therapy is not always up-titrated to the desirable dosages; this
provides the opportunity to evaluate the impact of optimizing medical therapy in patients who had received a
device therapy with proven effectiveness.
1.0
Optimized MT
N=1/56 (1.8%)
Optimized MT
N=14/56 (25%)
Event-free survival
Materials and methods This observational cohort study retrospectively assessed the ‘real life’-effect of CRT
compared with that of CRT ⁄ ICD therapy and the impact of concomitant pharmacotherapy on outcome. Outcome
of patients with guideline recommended renin–angiotensin system inhibitor and ß-blocker dosages was compared with that of patients who failed to reach the desired dosages. Mean follow-up for the 205 CHF (95 CRT
and 110 CRT ⁄ ICD) patients was 16Æ8 ± 12Æ4 months.
0.8
Results In the total study cohort, 83 (41%) reached the combined primary endpoint of all-cause death or cardiac
hospitalization [CRT group: 25 (26%), CRT ⁄ ICD group: 58 (52Æ7%), P < 0Æ001]. Multiple cox regression analysis
revealed non-optimized medical therapy at follow-up [HR = 2Æ080 (1Æ166–3Æ710), P = 0Æ013] and CRT ⁄ ICD vs.
CRT [HR = 2Æ504 (1Æ550–4Æ045), P < 0Æ001] as significant predictors of the primary endpoint.
0.6
Non Optimized MT
N=26/148 (17.6%)
Conclusion Our data stress the importance of professional monitoring and titration of pharmacotherapy not
only in medically treated CHF patients but also in patients under device therapy by a heart failure unit or a specialized cardiologist.
Non Optimized MT
N=68/148 (45.9%)
0.4Cardiac resynchronization, device therapy, heart failure, medical therapy, outcome.
Keywords
Eur J Clin Invest 2009; 39 (12): 1073–1081
P=0.002
0.2
HR=2.08, 95%CI=1.17-3.71,
CRT – N=95
CRT-D – N=110
p=0.013
rates of sudden cardiac death were reported for CRT ⁄ ICD
Device implantation in chronic heart failure (CHF) for
0.0
compared with that for CRT; however, this did not transcardiac resynchronization
therapy (CRT) with or without
late into significant improvements of total mortality [3].
implantable cardioverter ⁄ defibrillator (ICD) is an established
10patients20
30
40 included
50 in randomized0trials were
10under optimal
20
Patients
treatment option for0symptomatic
under medical
Introduction
baseline therapy [1]. The Comparison of Medical Therapy,
Pacing, and Defibrillation in Heart Failure (COMPANION)
study demonstrated comparable outcomes for CRT and
CRT ⁄ ICD combination devices, with a further reduction of
mortality in the combination therapy group compared with
that in the group undergoing medical therapy alone [2]. In
Follow-up (months)
medical baseline therapy before implantation and
medications were adjusted as appropriate at the scheduled
follow-up visits; this was suggested to be one plausible
explanation for the low mortality rates [1].
Recently published data from the Multicenter Automatic
Defibrillator Trail (MADIT) II demonstrated the importance of
Age – OMT: 62 vs. Non OMT: 67 years, p=0.003;
LVEF: OMT: 28 vs. Non OMT: 27%, P=NS
30
40
50
OMT: Optimized Medical Therapy
Adlbrecht C,
Eur J Clin Invest 2009
Age-related effects on mortality of the implantable cardioverter
defibrillator. An analysis of the Italian Clinical Service® Project
database!
Terapia farmacologica, per gruppi di età!
P<0.014!
P<0.001!
P=0.072!
ACE-I: ACE-inibitori; Anti-ATII:
antagonisti dell’angiotensina II!
Fumagalli S, Marchionni N,
Padeletti L, 2014!
Number of Implants
Number with Early Mortality
Annual ICD implantation rates and incidence of early mortality
(N=1062; implant years: 1997-2007)
Implantation year
Early Mortality: death < 1year after ICD implant
Bhavnani SP,
2013
Charlson Comorbidity Index: prevalence in the study cohorts (left) and
associated risk of early mortality (right)
Days to
death
P<0.001
221
Number of Implants
CCI 0 – Ref.
0.97
2.38
153
4.30
4.81
5.14
All patients
N=1062
Early Mortality No Early Mortality
N=110
N=110
Early Mortality (EM): death < 1year after ICD
implant; CCI: Charlson Comorbidity Index
*: P<0.05 for the comparison between the EM and no EM
groups
181
0.5
9
1
3
6
HR Early Mortality
Follow-up: 3.1 years
Mortality: 35% (EM: 10%)
156
137
129
15
Bhavnani SP,
2013
N=294; Age: 59 years; Men: 72%
Secondary prevention: 28%: Implantation: 2008-2012!
Patients (%)
Before
implantation
Decreased
life
expectancy
The only predictor of a favorable attitude toward device
During the
dying
deactivation at end of life:
process
«A worthy avoidance of shocks during dying»,
Batteryp<0.0001!
replacement
Yes
No
Knowledge about
deactivation
Yes
No
In favor of
deactivation
When the physician should discuss the
issue of deactivation with patients?
Pedersen SS, 2013
!
!
Location of death in 125 ICD patients
ICD as a secondary prevention: 82%
Age: 74+9 years
ICD implanted: 2.6 years
CRT-D: 35%
Kinch Westerdahl A, 2014
!
Mechanisms of death in 125 ICD patients
Cardiac causes (N=74, 59%)
!
Kinch Westerdahl A, 2014
Non Cardiac causes (N=51, 41%)
!
Kinch Westerdahl A, 2014
Terapy for VT / VF : 32%
Patients with electrical storm: 24%!
DNR patients: 52% (65/125)
ICD “on”: 65% (42/65)
Treated patients: 24% (10/42)!
Shocks received
24-h before death (N)
Episodes of VT / VF
24-h before death (N)
!
2013
Key points
•  The incidence of SCD increases with age owing to increasing prevalence
of CHD and CHF among elderly individuals
•  Elderly patients are more likely to have PEA or asystole at the time of
SCD and are less likely to survive a cardiac arrest
•  The mortality benefit and cost-effectiveness of primary prevention ICD
therapy in elderly patients is dependent on competing mortality risks
•  CRT has demonstrated mortality and HRQL benefits across age groups
•  A substantial and growing proportion of primary prevention ICD and CRT
devices are being implanted in elderly patients, and additional outcomes
data in this growing population are needed
In lieu of randomized trial data, long-term outcome data from registries
will be required to evaluate both the clinical effectiveness and costeffectiveness of ICD and CRT in the elderly population
Age-specific ICD implantation rates per 100,000 of population in
the Western Australian population (N=1593/2010113, 1995-2009)
14.91
63.5 years
Implantation Rate / 100.000
Rate: 0.83
Mean age: 58.7
65-74
>75
55-64
45-54
20-44
Year
Bradshaw PJ et al.
Am Heart J 2013
N=1812 - Age: 72±11
Men: 72%
Follow-up: 10.7% months
Event Free Probability
1.0
0.9
Q4-100% N=362
P<.001 vs Q1
Q3-98-99% N=509
0.8
P=.0004 vs Q1
Q2-93-97% N=474
P=.0013 vs Q1
0.7
Q1-0-92% N=467
Death & HF hospitalization by percentage
of biventricular pacing (quartiles)
Q2-Q4 vs Q1 – HR=0.56, p<0.00001
0.6
0.5
0
2
4
6
8
10
12
Months post Implant
Koplan BA, J Am Coll Cardiol, 2009
Age-related effects on mortality of the implantable cardioverter
defibrillator. An analysis of the Italian Clinical Service® Project
database
Mortalità per MADIT II Score e per gruppi di età
HR=1.47
P<0.001
MADIT II
Score
HR=1.31
P<0.001
HR=1.10
P=0.331
Fumagalli S, Marchionni N,
Padeletti L, 2014!
Age-related effects on mortality of the implantable cardioverter
defibrillator. An analysis of the Italian Clinical Service® Project
database!
Principali patologie associate, per gruppi di età!
P<0.001!
P<0.001!
P<0.001!
Fumagalli S, Marchionni N,
Padeletti L, 2014!
P<0.001!
BPCO: broncopneumopatia cronicoostruttiva; CAD: malattia coronarica;
IRC: insufficienza reale cronica!