Comorbitities in CRT
A.CURNIS
University of Brescia Iitaly
Hheart Failure &Co.
Napoli 2013
The birth of CRT … in Europe, 15 years ago
Since then … many major improvements …
then Guidelines 30% nonresponders
ESC/EHRA guidelines
•NYHA III-IV
•QRS > 120 ms
•LVEF < 35%
•HF optimal medical therapy
Class I/A
•NYHA III-IV, LVEF<35%
•Indication to permanent pacing
Class IIa/C
•NYHA III-IV, LVEF<35%
•Permanent AF
•Indication to AVN ablation
Class IIa/C
Other potential candidates to CRT
(ongoing trials)
•NYHA I-II
•QRS < 120 ms
•HF & AF
•Upgrade from antibrady-pacing
Soft End-Points
Hard End-Points
(QOL, VO2, 6min WT)
(Mortality, Hospitalization reduction)
*Commentary of “Current practice of CRT in the real world: insights from the European
CRT survey”; EHJ August 2009
Research programs in CRT today
New pts groups?
PTS’
SELECTION
CRT to “prevent HF”
Reduction of
NON-responder rate
IMPLANT
TECHNIQ.
Implant procedure
Success Rate
Reduction of
NON-responders rate
CRT Optimization
Patients’
Follow-up
Reduction of
NON-responders rate
Remote management
of HF pts
ESC HF Guidelines 2012: CRT Summary
Sinus Rhythm
Permanent AF
Need for Pacing
NYHA III/IV(amb.)
NYHA II
NYHA III/IV(amb.)
NYHA III/IV
NYHA II
EF ≤ 35%
EF ≤ 30%
EF ≤ 35%
EF ≤ 35%
EF≤35%
QRS ≥ 120ms
any QRS
any QRS
LBBB
NonLBBB
LBBB
NonLBBB
Slow V rate or
Post AVN ablation
or 60bpm at rest &
QRS ≥
120ms
QRS ≥
150ms
QRS ≥
130ms
QRS ≥
150ms
Class
IA
Class
IIa A
Class
IA
Class
IIa A
Class
IIb C
Class
IIa C
Class
IIb C
CRT-P
CRT-D
CRT-P
CRT-D
Preferably
Preferably
CRT-D
CRT-D
CRT-P
CRT-D
CRT-P
CRT-D
CRT-P
CRT-D
Eur Heart J. 2012
90bpm on ex.
All patients under Optimal Pharmacological Therapy & life expectancy > 1 year
Most common reasons for Non-Response
3.
47% inadequate device programming
32% suboptimal medical treatment
32% arrhythmias
4.
21% inappropriate lead position
5.
9% lack of baseline dyssynchrony
1.
2.
3.
4.
CRT Delivery
Suboptimal Drug Therapy
Arrhythmias
Lead Position
1.
2.
5. Patient Selection
Insights from a Cardiac Resynchronization Optimization Clinic as Part of a Heart Failure
Disease Management Program; Mullens et. All. JACC Vol.53, No.9, 2009
Echo in heart failure :
What is mandatory in the report ?
• LV size and systolic function (low dose dobutamine)
• Mitral regurgitation
• LV diastolic function
• Pulmonary artery pressure
• RV function
• Inter- and Intra-ventricular asynchrony
• Coro-angio
LV Lead Position in CRT
Higher response when pacing
the latest site of contraction1
1
Lower response when pacing
areas of scar2
Ypenburg et al J Am Coll Cardiol.2009;53(6):483-490
et al Circulation 2006;113(7):969-976.
2Bleeker
Progression of Heart Failure
Stage A
Stage B
Stage C
Stage D
At high risk but
without structural
disease or
symptoms
Structural
heart disease
but without HF
symptoms
Structural heart
disease with
prior or current
HF symptoms
Refractory
HF requiring
specialized
Interventions
Patients with
- Hypertension
Structural
- CAD
heart
- Diabetes
disease
- Obesity
-Metabolic syndrome
OR
- using cardiotoxins
- with familial Hx of DCM
Patients with
- previous MI
- LV systolic
dysfunction,
- asymptomatic
valve disease
Patients with
Development
of symptoms
of HF
- known
structural heart
disease
- shortness of
breath, fatigue,
reduced ex.
tolerance
Refractory
symptoms of
HF at rest
Patients with
marked
symptoms at
rest despite
maximal
medical
therapy
ACC/AHA Guidelines, JACC 2001; 38:2092
The Cascade of Advanced Heart Failure
Ageing of the population
Better CV treatment
↑ HF prevalence
Use of neurohumoral antagonists
↑ survival / ≈ symptoms
↑ Indication / Use of ICDs
↓↓↓ Sudden death
↑ pts. With end-stage HF
Severe symptoms / Poor
QOL / high mortality
Aims of treatment in Advanced HF
Quality of life
Prognosis
End of life
Treatment of Advanced HF
↓ Symptoms
Diuretics
Vasodilators
Inotropes…
Haemodynamic support:
Relief of congestion
↑ peripheral perfusion
Failure
↑ short-term survival
↓ arrhythmias
↓ myocardial damage
↑ renal function
Neurohormonal
antagonists, CRT …
↑ Long-term survival
↓ neurohormonal activation
↑ renal function
↓ myocardial damage
Patient stable
Ultrafiltration,
devices, …
Co-morbidities Causing Abnormalities of the
Laboratory Exams in the Patients with Heart
Failure
• Ischemia  Necrosis
• Diabetes
• Anemia
• Renal insufficiency
• Hypercholesterolemia
• Hyperuricemia
Prevention of Heart Failure: The Next Target
• Hypertension
• Coronary artery disease
– Hypercholesterolemia  Statins
– Neurohumoral blockade (ACEi /  -blockade)
– Revascularization / Antiplatelet agents
• Diabetes
– Glycemic control
– BP control
• Albuminuria
• Renal disease
• Obesity
• Metabolic Syndrome
Effect of the aging population on the prevalence of
heart failure in the U.S.
9
Population (1.000.000s)
8
7
6
5
4
3
2
1
0
1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050
(data from Phase I of the National Health and Nutrition Examination Survey III 1980
and US Bureau of the Census Data and Projections in Bristow MR Management of
HF in Braunwald’s Heart Disease)
Hypertensive Patients Are at Increased Risk for
Cardiovascular Events. Framingham Study
Heart failure
Population attributable risk (%)
Biennial Age-Adjusted Rate per 1000
Men
16
13.9
14
39%
12
10
8
6.3
6
4
Women
3.5
2.1
2
0
Men
Normotensive
Women
59%
Hypertensive
Kannel WB JAMA 1996;275(24):1571-1576
Levy et al., JAMA 1996; 275:1557
Hypertension
Non HBP
Risk of Death in the Patients with LVD with Recurrent Myocardial
Infarction (MI) or Unstable Angina (SOLVD Trials)
Myocardial infarction
Unstable Angina
70
60
30
MI
% Event
% Event
50
40
30
20
20
Angina
10
No MI
10
No Angina
P<0.001
0
P<0.001
0
0
6
12
18
24
Months
30
36
42
0
6
12
18
24
30
36
Months
Yusuf et al., Lancet 1992;340:1173
42
Severity of the Residual Stenosis of the InfarctRelated Artery and LV Dilatation After Acute MI
End-Diastolic Volume
(mL/m2)
120
End-Systolic Volume
(mL/m2)
70
110
*
100
*
90
*
*
60
†
Ejection Fraction
(%)
50
45
†
40
50
80
35
40
70
*
30
60
30
25
50
40
20
0
6
Months
Total occlusion
12
20
0
6
Months
Lesion diameter > 1.5 mm
12
0
6
12
Months
Lesion diameter < 1.5 mm
Leung et al. JACC 1992;20:307
Prevention of Heart Failure: The Next Target
• Hypertension
• Coronary artery disease
– Hypercholesterolemia  Statins
– Neurohumoral blockade (ACEi /  -blockade)
– Revascularization / Antiplatelet agents
• Diabetes
– Glycemic control
– BP control
• Albuminuria
• Renal disease
• Obesity
• Metabolic Syndrome
Diabetes as a Risk Factor for Heart Failure
Incidence
Risk of developing HF in diabetes (Framingham, JAMA 1979)
• 4 fold increase in young diabetic males (< 65 years)
• 8 fold increase in young diabetic females (< 65 years)
Prevalence
Proportion of Patients with Diabetes
23%
CONSENSUS
SOLVD
25%
V-HeFT II
20%
ATLAS
20%
NETWORK
10%
RESOLVD
27%
0%
10%
20%
30%
Proportion of diabetic patients (%)
40%
50%
Rate per 1000 pt. Per year
Glycemic Control and Heart Failure Among 48
858 Adult Patients with Diabetes
Incidence of HF Hospitalization or
10
Death
9.2
9
8
7
6
5
4
3
2
1
0
8.3
5.8
6.3
4.5
<7
7 to <8
8 to <9
Hb A 1c
9 to <10
> 10
Each 1% increase in HbA1C is associated with a 8% increase in the risk of heart failure
Iribarren et al., Circulation 2001; 103:2668
Diabetes Mellitus as a Predictor of Mortality:
SOLVD Trials
All-cause mortality
Treatment trial
Placebo
35
Enalapril
30
CV mortality
33
% of patients
30
Total
Prevention trial
Placebo
23
20
21
20
18
15
5
Total
0,5
27
10
Enalapril
0
25
29
1
1,5
2
2,5
3
0
Placebo Enalapril Placebo Enalapril
Relative risk (95% CI)
Non diabetic
Diabetic
Schindler et al., Am J Cardiol 1996; 77:1017
Prognostic Impact of Diabetes Mellitus
According to the Etiology of Heart Failure
SOLVD Treatment
SOLVD Prevention
1
EVENT-FREE SURVIVAL
1
0.9
P<0.0001
0.9
0.8
0.8
0.7
0.7
0.6
0.6
Ischemic nondiabetics (n=3086)
Nonischemic (n=562)
Ischemic diabetics (n=575)
0.5
0.4
0
365
730
DAYS
1095
1460
P<0.0001
Ischemic
nondiabetics (n=1392)
Nonischemic (n=642)
Ischemic diabetics (n=534)
0.5
0.4
0
365
730
1095
1460
DAYS
Dries et al., J Am Coll Cardiol 2001; 38:421
Anemia is Associated with Increased Mortality in HF:
Single-center study in 1061 patients
60
1
Hb>14.8
0.8
Hb 13.7-14.8
Hb 12.3-13.6
0.6
40
30
20
10
Hb < 12.3
P=0.00001
% mortality
0
0.4
0
2
4
6
Months
8
10
12
<1
11 1.0
.0
-1
12 1.9
.0
-1
12 2.5
.6
-1
13 3.1
.2
-1
13 3.6
.7
-1
14 4.1
.2
-1
14 4.5
.6
-1
15 5.1
.2
-1
5.
8
>1
5.
8
% survival
50
Hemoglobin Deciles
Horwich, Fonarow, Hamilton et al., JACC 2002;39:1780
Hemodilution Is Common in Patients With
Advanced Heart Failure
Dilutional
Normal Hct
True anemia
Anemic
P<0.05
P=0.08
Androne et al., Circulation. 2003;107:226
Anemia is related with Maximal Functional Capacity
and Rehospitalization rate in the Patients with
Heart Failure
Rehospitalization-free
survival
Peak VO2
1.2
30
25
20
15
10
5
0 9
R = 0.50
P < 0.01
Fraction of patients, %
Peak VO2, mL/kg/min
35
Hb < 12.5
Hb > 12.5
1.0
0.8
0.6
P < 0.05
0.4
0.2
0.0
10 11 12 13 14 15 16 17 18
Hemoglobin, Gm/dL
0
200
Time, days
L Dei Cas et al., 2003
400
Impact of Comorbidities in Patients with Chronic
Kidney Disease
5 years follow-up of 27 998 patients with estimated GFR < 60 mL/min per 1.73 m2
14
13.1
11.5
% of subjects
12
10.4
10
7.4
8
6.2
6
6
5.2
4
1.8
2
0
CAD
baseline
CAD Δ in
prevalence
Control
CHF
Baseline
CHF Δ in
prevalence
Chronic Kidney Disease
Keith et al., Arch Intern Med 2004; 164:659
Impact of Proteinuria and Chronic Kidney Disease
in the Incidence of Heart Failure
5 years follow-up of 27 998 patients with estimated GFR < 60 mL/min per 1.73 m2
25
19.4
% of subjects
20
15
12.6
12.5
10.7
10
5.8
5.4
3.9
5
1.4
0
GFR 60-89
No proteinuria
Stage 2
Baseline
Stage 3
Stage 4
Change
Keith et al., Arch Intern Med 2004; 164:659
Obesity and the Risk of Heart Failure:
Framingham Study (5881 subjects; 14 ys FU)
Men
Obesity Class
2 (35-39.9)
Obesity class
1 (30-34.9)
Overweight
Women
Obesity class
3 (>40)
Obesity Class
2 (35-39.9)
Obesity class
1 (30-34.9)
Overweight
0
5
10
15
Risk ratio (95% CI)
Kenchaiah et al. New Engl J Med 2002; 347:305
Continuous Relationship Between Total Cholesterol and
5-years Rates of Death or Urgent Transplantation
Horwich, Hamilton, Maclellan, Fonarow. J Cardiac Fail 2002; 8:216
Rate of In-Hospital from Hyperkalemia
(per 1000 patients)
Rate of In-Hospital Death Associated with Hyperkalemia among
Patients Recently Hospitalized for Heart Failure Who Were Receiving
ACE Inhibitors
2.5 –
Online release
Of RALES
2.0 –
1.5 –
1.0 –
0.5 –
0.0 –
1994
1995
1996
1997
1998
1999
2000
2001
Study Year
Juurlink, D. N. et al. N Engl J Med 2004;351:543-551
Outcome of patients hospitalized for HF
Mortality
Study (Acronym)
Year
No.
Days of
hosp
Cleland et al.
(EuroHF)
2003
11,327
11+8
In-hosp, %
FU %
Rehosp
,%
3 ms: 13
3 ms:
35.6
In-hospital2003mortality:
2,127
11 4-9%
5.6
6 ms: 15.5
44.6
Lee
et al. (EFFECT)
2003
4,031
… 9-15%
8.9
1 y: 32.9
…
6-months
mortality:
Rudiger et al.,
2005
312
11.5
8
6 ms: 18
6-months 2005
rehospitalizations,
30-45%
Adams (ADHERE)
107,362
4
4
…
…
Di Lenarda et al.
(TEMISTOCLE)
O’Connor et al.
(IMPACT)
2005
567
8+7
OPTIMIZE-HF
2005
48,612
4
4
Goldberg et al.,
2005
2,604
4
5.1
Italian survey
2006
2,807
9
7.3
Zannad, (EFICA)
2006
581
15
Ms = months
2 ms: 8.5
2 mts:
25.7
6 ms: 9
30
6 ms:12.8
38.1
1 y: 46.5
Predictors of subsequent CV mortality or HF
hospitalisations in patients with Acute HF:
Results of multivariable analysis in 318 patients
Diabetes
SBP at discharge
<115 mmHg
Anemia at admission
∆ s-creatinine >0.30
Furosemide dose >50
mg/d
Restrictive LV filling
at discharge
0
1
2
3
4
Odds ratio (95% CI)
Decreased ←
→ Increased
L Dei Cas, 2006
The last six months of life for patients with congestive heart
failure: data from SUPPORT: 539/1404 patients died < 1 year
100
% of patients
80
71
68
59
60
40
41
45
43
30
37
40
32
29
20
0
in ain nea
od ess iety etite tion iting nce ion
a
o
p
P e
a
m ssn Anx pp
n e n f us
sp
m
p
i
r
i
y
t
o
t
D Low ple
ve
/v con Co
f a ns
e
a
o
S
s
ee
Co use y in
s
Sl
Lo
Na inar
Ur
Levenson JW, et al. J Am Geriatr Soc 2000;48:S101-9.
Towards new paradigms to better select patients?
Auricchio A, Prinzen FW.
Circulation Journal 2011;75:521-7
Identify NON-Responders (and potential reasons) is relevant…
n = 75 CRT-D pts referred to the HF lab
due to NON-response to CRT
… these are the reasons for a
suboptimal response to CRT
Mullens W & al, JACC 2009
Conclusions
• Better patient selection and better Non-responders management:
the main clinical topics to be targeted (Comorbidity)
• CRT optimization (device optimization, optimal lead position, new implant options..) to
improve therapy efficacy: the technical improvements to be explored
• Refine Diagnostic capacity of CRT devices: the clinical usefulness to
be empowered
• CRT patient follow-up (with remote monitoring) to early identify acute
HF events: the new management challenge
Comparison of Healthcare Costs
ICD Costs are Minimal Compared to Other
Healthcare Spending in Europe
160
150.00
Annual Cost in € Billion
140
120
100
80
64.00
60
46.00
40
20
0
0.49
1.07
2.12
2.70
ICD
Pacemakers
CABG*
PTCA*
* Includes only Fr, De, It, UK
Healthcare Inefficiencies
Cost of
1
Administration* in hospital
inappropriate
2
operations
care & adverse
drug usage*1
Source: 1Datamonitor report: E-healthcare opportunities The risks and rewards 1999, 2 Mckinsey Health Europe Ma
Comparison of Healthcare Costs
350.0
294
Annual Cost in Billions
300.0
250.0
200.0
$11.6 B—estimated
amount due to miscoding,
insufficient documentation,
etc. in Medicare
Healthcare
Administratio
n1
(HCFA 2000 Financial Report)
150.0
100
100.0
50.0
2
0.0
ICD*
8
9
9
30
PTCA† CABG+ Statins‡
*Medtronic estimations (total number of implants x $30,000).
Economic impact
†Morgan Stanley Dean Witter Research Report, 2001 / CMS reimbursement data.
+AHA 2002 / Cowper, et al; American Heart Journal. 143;(1):130–9.
of over‡ Pharmacy Times, “Top 200 drugs of 2000”; 2001.
prescribing
^ National Institute of Health, Antimicrobial Resistance, NIAID Fact Sheet.
^^ U.S. General Accounting Office 2001.
antibiotics^
1 Woolhandler S, et al. Costs of Healthcare Administration in the United States and Canada. N Engl J Med 344, 2003; 349: 768-75.
Lost dollars from
healthcare fraud,
abuse and
waste^^
Final Considarations
Clinical Randomized Study
exclusion Criteria
• Guidelines
• Comorbiditys
• Life perspective
• Clinical experience
Inclusion Criteria