Erwan DONAL Cardiologie

Nancy, Vendredi 18 septembre 2015
"Insuffisance cardiaque à fraction d'éjection
ventriculaire gauche préservée : on avance !"
Erwan DONAL
Cardiologie – CHU RENNES
erwan.donal@chu-rennes.fr
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Diagnosis of Heart Failure
Poor specificity and poor sensitivity
2
ESC HF guideliens 2012
By 2030, >8 million people in
the United States (1 in every 33) will have HF
Circ Heart Fail. 2013;6:606-619 3
HFREF
Heart Failure:
2-3% of population,
HFPEF
10-20% of elderly
AHA Statistics, Go Circ 2014
Bimodal distribution of EF
OPTIMIZE-HF, Fonarow JACC 2007
4
Supine pulmonary arterial wedge pressure (PAWP) by average E/e′ ratio
groups using the recommended cut off of 13.
5
Mário Santos et al. Circ Heart Fail. 2015;8:749-7
KaRen. Patients Characteristics
Main baseline clinical
characteristics
N /%
Age
Gender (females)
Hypertension
Prior Heart failure
Prior Stroke
Coronary artery disease
Prior AMI
Valvular heart disease
Diabetes
Renal dysfunction
Anemia
COPD
At admission for
acute HF
539
77±9
303 (56%)
419 (78%)
216 (40%)
56 (10%)
158 (29%)
77 (15%)
74 (14%)
161 (30%)
146 (27%)
202 (37%)
73 (14%)
Donal et al 6
ACVD 2014
HFPEF characteristics: Big differences by study design
Approximate
Baseline and
Outcome data from
Different HFPEF
settings
OPTIMIZE
-HF
HFPEF
OPTIMIZE
-HF
HFREF
Fonarow JACC
2007, Patel
JACC HF 2013
Fonarow JACC
2007
Owan /
Bhatia
KaRen
HFPEF
NEJM 2006
Lund EJHF
2014
Swedish
Heart
Failure
Registry
HFPEF
Swedish
Heart
Failure
Registry
HFREF
Lund JAMA
2012, 2014
Lund JAMA
2012, 2014
HFPEF
trials
BASELINE risk factors and severity and ? Presence of HF
Age
75
70
74-75
79
76
72
67-75
Women, %
62
38
56-65
56
47
29
40-61
Hypertension %
76
66
55-63
78
60
46
65-89
CAD %
38
54
35-53
33
35
43
24-44
DM %
43
39
32-33
30
25
25
20-28
AF %
33
28
32-41
65
57
47
17-29
18
25
27
23
Lung disease %
Obesity %
SBP
129
119
156
148
132
124
130-140
Creatinine
114
124
141
GFR 61
GFR 63
GFR 69
88-97
NT-proBNP
2448
2000
3000
320-1000
Hb
120
130
134
132-140
82
80
80
44-75
13
20
20
5-6%
32
40
45
10%
Diuretic use %
73
77
OUTCOMES
1-yr mortality
30
1-yr mort or HF hosp
40
22-29
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Heart Failure Preserved EF:
prognosis
Preserved
LVEF
Depressed
LVEF
P-value
In-hospital mortality
2.9%
3.9%
<0.0001
Post-discharge mortality (60-90
days)
9.5%
9.8%
0.459
Rehospitalization at 60–90 days
29.2%
29.9%
0.591
Post-discharge mortality or
rehospitalization at 60–90 days
35.3%
36.1%
0.436
Event in OPTIMIZE-HF




 5-year survival : 35% after a HF hospitalization
 QoL poor ~end-stage renal disease
Care of patients with HFpEF can be frustrating
Diagnosis is not straightforward
Comorbidities are common
Treatment still an Enigma
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Fonarow et al. JACC 2007
MAGGIC-Meta-analyis: Mortality
for patients with HF-PEF and HFREF , adjusted for age, gender, aetiology of
KaRen Data
heart failure, hypertension, diabetes, atrial
fibrillation.
Time to 1-st hospitalization or allcause of death
Mean follow-up time = 28 months
Primary outcome event :
177 patients (42.9%)
- 61 death (14.8%)
- 116 HF-hospit (28.1%)
Donal et al . EJHF 2015
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Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) Eur Heart J 2012;33:1750-1757
The incidence of hospitalizations for HF
and deaths in KaRen was high and E/e′
predicted adverse clinical outcomes
E/e’ with a cut-off = 13
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Donal et al EJHF 2015
the primary outcome: time to all-cause mortality or first heart
failure hospitalization
Lund, Donal et al EJHF 2014
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the secondary outcome: time to all-cause mortality
Lund, Donal et al EJHF 2014
12
Readmission rate
Mortality rate
21 397 very elderly veterans with a first HF hospitalization during the study period. Thirty-day
mortality decreased from 14% to 7% (both P<0.001) and 1-year mortality decreased from 49% to
27% (P<0.001).
Circ Heart Fail. 2011;4:301-307 13
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HFPEF Treatment - failed
CHARM-Preserved:
CV death or HF hospitalization
Yusuf, Lancet 2003
PEP-CHF:
Death or HF hospitalization
Cleland, EHJ 2006
Why?
• Difficult definition
• Difficult diagnosis
• Heterogeneous
(some patients did not have HF)
Solution:
• Phenotyping =
Characterize HFPEF
patients
• Match treatment to
phenotype
• Match endpoint to
phenotype and treatment
I-PRESERVE:
Death or CV hospitalization
Massie, NEJM 2008
TOPCAT:
Death or HF Hospitalization
Pitt NEJM 2014, Pfeffer Circ 2014
HFpEF: Treatment?
“No treatment has yet been
shown, convincingly, to reduce
morbidity and mortality in
patients with HFpEF.”
Diuretics – Best BP control
ESC HF Guidelines; EJHF 2008 17
ESC HF Guidelines EHJ 2012
Meta-analysis
No negative trends
in any outcome
There is no significant effect on mortality (relative risk: 0.99;
95% confidence interval [CI]: 0.92 to 1.06) in randomized
controlled trials , and the results appear homogeneous...
Effects of Treatment on Exercise Tolerance, Cardiac Function, and Mortality in
Heart Failure With Preserved Ejection Fraction : A Meta-Analysis
Holland DL et al. JACC 2011. 57(16): 1676 - 1686 18
Effect of treatment on mortality in observational studies
There appears to be a favorable effect on mortality but with a
great heterogeneity and a much greater heterogeneity than among
the RCTs
Effects of Treatment on Exercise Tolerance, Cardiac Function, and Mortality in
Heart Failure With Preserved Ejection Fraction : A Meta-Analysis
Holland DL et al. JACC 2011. 57(16): 1676 - 1686 19
Only 183 patients drawn from 6 trials
There appears to be a significant effect on exercise capacity
(weighted difference 51.47; 95% CI: 27.29 to 75.65) in RCTs, and the
results appear homogeneous.
Effects of Treatment on Exercise Tolerance, Cardiac Function, and Mortality in
Heart Failure With Preserved Ejection Fraction : A Meta-Analysis
Holland DL et al. JACC 2011. 57(16): 1676 - 1686
20
Lack of Improvement in resting diastolic function despite significant improvements in
exercise capacity
Treatment Effect on Diastolic Function in RCTs
There is no significant effect on diastolic function
(E/A ratio [weighted difference −0.01; 95% CI: −0.03 to 0.02]) in RCTs
Effects of Treatment on Exercise Tolerance, Cardiac Function, and Mortality in
Heart Failure With Preserved Ejection Fraction : A Meta-Analysis
Holland DL et al. JACC 2011. 57(16): 1676 - 1686
21
Why have prior clinical trials of
HFpEF failed?
 Heterogeneity
(syndrome, not a specific disease
process)
 Exercise induced diastolic
dysfunction
 Chronic volume overload
 Associated RF failure of
pulmonary hypertension
 What’s the objective?
Shah . JACC 2013;62:1339
Kitzman. JACC 2011; 57: 1687
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Conclusions
A principle for futur studies in HFpEF:
“Add Life to the remaining years than to add years to the remaining
life”
Diastolic dysfunction is probably not the main or the only
abnormality to which HFpEF treatment should be
targeted
Need for objective criteria for HFpEF
Need for homogeneous samples
>> great expectations in the upcoming treatments
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Based on a comparison of 2 key trials, LIFE and I-PRESERVE, the
poor outcomes in patients with HF-PEF may not be explained by LVH
or other comorbidities. (Campbell et al JAm Coll Cardiol 2012;60:2349–56)
►2 things that most clearly differentiate patients with HF-PEF from
those with hypertension :
 the clinical syndrome of heart failure
(and often previous hospital admission with heart failure)
 and elevated natriuretic peptide levels.
Phenotyping by phenomapping Shah Heart Failure Clinics 2014, Circulation 2014
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