Nouveautés dans le traitement de l`Insuffisance cardiaque chronique:

Nouveautés dans le traitement de l`Insuffisance cardiaque chronique:

Nouveautés dans le traitement de l’Insuffisance cardiaque chronique: Richard Isnard Hôpital Pi=é-­‐Salpêtrière Université Paris 6 CHRONIC MALADAPTATIVE Braunwald, JACC Heart Failure 2013 Event-free probability
1·0
0·8
0·6
0·4
Sudden death or resuscitated arrest
or hospital admission for
any reason
ARA2 versus IEC Hospital admissions
Any reason
Heart failure
659 (41·8%) 638 (40·5%) 1·04 (0·9
270 (17·1%) 293 (18·6%) 0·92 (0·7
*95·7% CI for total mortality, 95% CI for other endpoints, including com
Table 2: Endpoint results
Insuffisance cardiaque p=0·08
Chronique à FE basse Infarctus avec FE basse ou insuffisance cardiaque Probability of survival
Event-free probability
Event-free probability
Endpoint rate (%)
group, irrespective of whether they continued on
Patients lost to follow-up were censored at the
ARTICLES
contact.
0
ARTICLES
We analysed the primary endpoint of death from a
25
time
to event.
The hazard rate, CI, and test for
Losartan
All-cause mortality or hospital admission
1·0 All-cause mortality
Captoprill
Endpoint between treatments
Losartan
Captopril
Hazardson Cox’s
p regres
were based
1·0
(n=1578)
(n=1574)
ratio
(CI)*
(terms
included in the model: treatment group, g
20
All-cause mortality
(primary
endpoint)
0·8
region, and
stratification level based on !-bloc
0·8
Total mortality
280 (17·7%) 250 (15·9%) 1·13 (0·95–1·35) 0·16
randomisation).
Similar
used for all ti
15
Sudden death
130 (8·2%)
101 methods
(6·4%) 1·30were
(1·00–1·69)
0·6
0·6
Progressiveoutcome
heart failure variables.
46 (2·9%) For53combined
(3·4%) 0·88 outcome
(0·59–1·30) variables
Myocardial infarction
31 (2·0%)
28 (1·8%) 1·11 (0·66–1·85)
the
used.
We included geographical r
10 first event18was
Stroke
(1·1%)
11 (0·7%) 1·65 (0·78–3·49)
0·4
0·4
Losartan
model to account
for any
potential
differences in mo
Other cardiovascular
5 (0·3%)
6 (0·4%)
0·84 (0·26–2·76)
Captopril
Non-cardiovascular
50 (3·2%)analyses
51 (3·2%)of 0·99
the(0·67–1·47)
primary endpoin
5Several interim
0·2
0·2
Sudden death
or
142
(9·0%) done
115
(7·3%)
0·08
mortality)
were
byrisk1·25
the(0·98–1·60)
independent
d
p=0·16
Relative
1·13
resuscitated
cardiac
arrest
(95%
CI
0·99–1·28)
p=0·069
p=0·18
0
monitoring
committee during the trial. An O’Br
0
0
Combined total
mortality
752
(47·7%)
707 (44·9%)
1·07 (0·97–1·19)
type0 stopping
boundary
as a 0·18
guideli
6
12
18 was24used 30
36
or hospital admission
for
Sudden
death
or
resuscitated
arrest
0
100
200
300
400
500
600
700any reason recommendation to stop the study early beca
1·0
Number at risk
21
overwhelming
mortality.
The commit
2744
2504 effect
2432 on
2390
2344
2301
1285
Losartan
Hospital
admissions
Follow-up (days)
consider
of observing
significant
2733 futility
2534
2463
2374
2329 treatmen
1309
Any reason
659 (41·8%)
6382423
(40·5%) a
1·04
(0·94–1·16)
0·45
Captoprill
0·8
Figure 2: Endpoint results
Heart failure reason to stop
270 (17·1%)
293 (18·6%)
(0·78–1·08)
the study.
To 0·92
maintain
the 0·32
overall
Figure
4:
Kaplan-Meier
curve
for
primary
endpoint
(all-cause
0·6
*95·7% CI forlevel
total mortality,
95%the
CI forcritical
other endpoints,
including
at 5%,
p value
forcomponents.
the primary end
mortality)
admissions for heart failure; NYHA functional classification;
Table
2: Endpoint
results
final analysis was adjusted to 0·043 (two-sided) an
0·4 of life; discontinuation of treatment for worsening heart
quality
are were
reported.
Otherbut
outcome
were as
There
significant
differences
ELITE Lancet OPTIMAAL, Linconsistent
ancet variables
2003 failure, intolerance,
and2, cough;
and2000
multiple occurrences of
significance
level
of 5%,
to the
protocol.
group,
irrespective
whether
theytoaccording
continued
on
treatment.
among
countriesof with
respect
overall mortality
and to
0·2
myocardial infarction or
multiple admissions for heart failure,
Patients
lost to follow-up
were losartan
censoredand
at the
time ofThese
last
p=0·08
the treatment
effects with
captopril.
cardiovascular
reasons, or any reason.
contact.
0
findings require further investigation. Table 4 presents
0·2
Associa=on IEC – ARA2 Insuffisance cardiaque Chronique à FE basse VAL-­‐HEFT, NEJM 2001 Infarctus avec FE basse ou insuffisance cardiaque VALIANT, NEJM 2003 Associa=on an=aldostérone-­‐ IEC Insuffisance cardiaque chronique grave avec FE basse RALES, NEJM 1999
Infarctus avec FE basse ou insuffisance cardiaque EPHESUS, NEJM 2003
Zannad, N Engl J Med 2010 Emphasis Main Results Zannad, N Engl J Med 2010 Natriure=c pep=des: a success story secretion granules
x 4700
x 82 000
Rats atrial myocytes (PY Hatt)
Sciences, Vol. 28, pp. 89-94
ted in the U.S.A.
Life Sciences, Vol. 28, pp. 89-94
Printed in the U.S.A.
Vol. 28, No.
Pergamon Press
Pergamon Press
I, 1981
A RAPID AND POTENT NATRIURETIC RESPONSETO INTRAVENOUS INJECTION OF
MYOCARDIAL EXTRACT IN RATS
experiment at 1.2 m l / h rATRIAL
.
20 min urine c o l l e c t i o n s
ined inA.theJ.middle
of
de Bold,
H. B. Borenstein, A. T. Veress, H. Sonnenberg
0.3 - 0.4A gRAPID
of e i tAND
h e r POTENT NATRIURETIC RESPONSETO INTRAVENOUS INJECTION OF
4 min. The constant
ATRIAL MYOCARDIAL EXTRACT IN RATS
Pathology,
Queen's U n i v e r s i t y , Kingston, Ont. and
ine c o l l eDept.
c t i o n s of
were
nning with
theA.of
f r aJ.c Physiology,
t i de
o n Bold, H. B.U nBorenstein,
Dept.
i v e r s i t y ofA. Toronto,
Ont.
T. Veress, Toronto,
H. Sonnenberg
collections.
Solutions
(Received in final form October 21, 1980)
e time of bioassay.
Dept. of Pathology, Queen's University, Kingston, Ont. and
e same procedures as
of Physiology, U nSummary
i v e r s i t y of Toronto, Toronto, Ont.
into i d e n t i c a l lDept.
y
v e h i c l e . Eleven rats (Received in final form October 21, 1980)
in 3 d iSupernatants
f f e r e n t batches, of a t r i a l or v e n t r i c u l a r myocardial homogenates
d were
with vinjected
e h i c l e aloneintravenously into Summary
anaesthetized non-diuretic rats.
Impact Factor = 2.53
Extract derived
from aof
t r i aa tl r i amuscle
rapid, more
than 30Supernatants
l or v e ncaused
t r i c u l a r a myocardial
homogenates
were
injected
intravenously
into anaesthetized
rats.
foldwereincrease
of
and chloride
excretions,non-diuretic
while urine
ions
measured
by sodium
Extract
t r i a l muscleexcretion
caused a rapid,
more than
30urine volumes
volume
rose were
l Oderived
- f o l d , from
and apotassium
doubled.
No such
of sodium
urine
nechanges
by l i q u fold
i dwere
s cincrease
i n tobserved
ila f t e r and
i n j chloride
e c t i o n excretions,
of v e n t r i c uwhile
l a r tissue
rose l O - f o l d ,
e l e c t r o l y t evolume
excretions
and potassium excretion doubled.
No such
Vasoconstric8on Réten8on sel Réten8on eau DECOMPENSE Sympathique Angiotensine 2 Aldostérone Endothéline AVP … INSUFFISANCE CARDIAQUE Vasodilata8on Diurèse natriurèse COMPENSE ANP BNP Prostacycline Bradykinine Adrénomédulline … Voies de dégrada=on des pep=des natriuré=ques PARADIGM-­‐HF new england
journal of medicine
The
established in 1812
september 11, 2014
vol. 371
no. 11
Angiotensin–Neprilysin Inhibition versus Enalapril
in Heart Failure
John J.V. McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H., Jianjian Gong, Ph.D.,
Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean L. Rouleau, M.D., Victor C. Shi, M.D.,
Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., and Michael R. Zile, M.D.,
for the PARADIGM-HF Investigators and Committees*
A BS T R AC T
Background
We compared the angiotensin receptor–neprilysin inhibitor LCZ696 with enalapril
in patients who had heart failure with a reduced ejection fraction. In previous stud-
From the British Heart Foundation (BHF)
Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
(J.J.V.M.); the Department of Clinical Sci-
64
J.J.V. McMurray et a
Figure 1 PARADIGM-HF study schema.
Table 1 Minimum required pre-study daily doses of
ommonly prescribed angiotensin-converting enzyme
nhibitors and angiotensin receptor blockers
to enalapril 10 mg b.i.d. might not be tolerated (e.g. because o
hypotension, renal dysfunction, and/or hyperkalaemia). Thes
patients were up-titrated to enalapril 10 mg b.i.d. after 1–
weeks. Patients tolerating enalapril 10 mg b.i.d. as defined by th
10,513 Patients entered enalapril run-in phase
(median duration, 15 days; IQR, 14–21)
1102 Discontinued study
591 (5.6%) Had adverse event
66 (0.6%) Had abnormal laboratory
or other test result
171 (1.6%) Withdrew consent
138 (1.3%) Had protocol deviation,
had administrative problem, or
were lost to follow-up
49 (0.5%) Died
87 (0.8%) Had other reasons
9419 Entered LCZ696 run-in phase
(median duration, 29 days; IQR, 26–35)
977 Discontinued study
547 (5.8%) Had adverse event
58 (0.6%) Had abnormal laboratory
or other test result
100 (1.1%) Withdrew consent
146 (1.6%) Had protocol deviation,
had administrative problem, or
were lost to follow-up
47 (0.5%) Died
79 (0.8%) Had other reasons
8442 Underwent randomization
43 Were excluded
6 Did not undergo valid randomization
37 Were from four sites prematurely
closed because of major GCP violations
4187 Were assigned to receive LCZ696
4176 Had known final vital status
11 Had unknown final vital status
4212 Were assigned to receive enalapril
4203 Had known final vital status
9 Had unknown final vital status
Table
1.
Characteristics
Patients
Race
group — of
no.the
(%)†
Tableor
1.ethnic
Characteristics
of
the
Patients at
at Baseline.*
Baseline.*
White
2763
(66.0)
LCZ696
LCZ696
(N
4187)
213
(N ==(5.1)
4187)
63.8±11.5
759
(18.1)
63.8±11.5
2781
(66.0)
Enalapril
Enalapril
(N
== 4212)
215
(5.1)
(N
4212)
63.8±11.3
750 (17.8)
63.8±11.3
452
879
(21.0)
879 (10.8)
(21.0)
466
953
(22.6)
953 (11.1)
(22.6)
North
White
White America
Latin
Black
BlackAmerica
310 (7.4)
2763
(66.0)
2763
(66.0)
713
213
(5.1)
213 (17.0)
(5.1)
292 (6.9)
2781
(66.0)
2781
(66.0)
720
215
(5.1)
215 (17.1)
(5.1)
Western
Asian
Asian Europe and other‡
Central
Other Europe
1026
759
(18.1)
759 (24.5)
(18.1)
1393
452 (33.3)
(10.8)
1025
750
(17.8)
750 (24.3)
(17.8)
1433
466 (34.0)
(11.1)
Asia–Pacific
Region
— no. (%)
Systolic
blood
pressure — mm Hg
North
America
745 (17.8)
742 (17.6)
122±15
310
(7.4)
72±12
713
(17.0)
121±15
292
(6.9)
73±12
720
(17.1)
28.1±5.5
1026
(24.5)
1.13±0.3
1393
(33.3)
28.2±5.5
1025
(24.3)
1.12±0.3
1433
(34.0)
745 (17.8)
2506
(59.9)
122±15
742 (17.6)
2530
(60.1)
121±15
29.6±6.1
72±12
25528.1±5.5
(155–474)
29.4±6.3
73±12
25128.2±5.5
(153–465)
16311.13±0.3
(885–3154)
15941.12±0.3
(886–3305)
2506 (59.9)
(59.9)
2506
180 (4.3)
29.6±6.1
2530 (60.1)
(60.1)
2530
209 (5.0)
29.4±6.3
Characteristic
Black
Characteristic
Age
—
AgeAsian
— yr
yr
Other
Female
sex
Female
sex —
— no.
no. (%)
(%)
Region
no. (%)
Race
ethnic
group
Race or
or—
ethnic
group —
— no.
no. (%)†
(%)†
Heart
rateAmerica
— beats/min
Latin
Body-mass
Westernindex§
Europe and other‡
Serum
creatinine
Central
Europe— mg/dl
Clinical
features of heart failure
Asia–Pacific
Ischemic
no. (%)
Systolic
bloodcardiomyopathy
pressure — mm—Hg
Leftrate
ventricular
ejection fraction — %
Heart
— beats/min
Median index§
B-type natriuretic peptide (IQR) — pg/ml
Body-mass
Median
N-terminal
pro–B-type natriuretic peptide (IQR)
Serum
creatinine
— mg/dl
— pg/ml
Clinical features of heart failure
NYHA functional class — no. (%)¶
Ischemic cardiomyopathy
cardiomyopathy —
— no.
no. (%)
(%)
Ischemic
I
Left ventricular ejection fraction — %
Left ventricular
ejectionoffraction
— %at Baseline.*
Table
1. Characteristics
the Patients
29.6±6.1
29.4±6.3
Median B-type natriuretic peptide (IQR) — pg/ml
255 (155–474)
LCZ696
1631(N
(885–3154)
= 4187)
251 (153–465)
Enalapril
1594(N(886–3305)
= 4212)
Median N-terminal pro–B-type natriuretic peptide (IQR)
Characteristic
— pg/ml
Age — yr
NYHA functional class — no. (%)¶
Female sex — no. (%)
I
Race or ethnic group — no. (%)†
II
White
III
Black
IV
Asian
Missing data
Other
Medical history — no. (%)
Region — no. (%)
Hypertension
North America
Diabetes
Latin America
63.8±11.5
63.8±11.3
879 (21.0)
180 (4.3)
953 (22.6)
209 (5.0)
2998 (71.6)
2763 (66.0)
969 (23.1)
213 (5.1)
33 (0.8)
759 (18.1)
7 (0.2)
452 (10.8)
2921 (69.3)
2781 (66.0)
1049 (24.9)
215 (5.1)
27 (0.6)
750 (17.8)
6 (0.1)
466 (11.1)
2969 (70.9)
310 (7.4)
1451
713(34.7)
(17.0)
2971 (70.5)
292 (6.9)
1456
720 (34.6)
(17.1)
Atrial
fibrillation
Western
Europe and other‡
Hospitalization
for heart failure
Central Europe
1517
1026(36.2)
(24.5)
2607
1393(62.3)
(33.3)
1574
1025 (37.4)
(24.3)
2667
1433 (63.3)
(34.0)
Myocardial
infarction
Asia–Pacific
Stroke blood pressure — mm Hg
Systolic
1818
745(43.4)
(17.8)
355122±15
(8.5)
1816
742 (43.1)
(17.6)
370
(8.8)
121±15
Pretrial
use
ACE inhibitor∥
Heart
rate
—of
beats/min
Pretrial useindex§
of ARB∥
Body-mass
326672±12
(78.0)
929
(22.2)
28.1±5.5
3266
(77.5)
73±12
963
(22.9)
28.2±5.5
Serum creatinine — mg/dl
1.13±0.3
1.12±0.3
Clinical features of heart failure
Ischemic cardiomyopathy — no. (%)
n engl j med
nejm.org
2506 (59.9)
2530 (60.1)
Table 1. (Continued.)
LCZ696
(N = 4187)
Enalapril
(N = 4212)
Diuretic
3363 (80.3)
3375 (80.1)
Digitalis
1223 (29.2)
1316 (31.2)
Beta-blocker
3899 (93.1)
3912 (92.9)
Mineralocorticoid antagonist
2271 (54.2)
2400 (57.0)
Implantable cardioverter–defibrillator
623 (14.9)
620 (14.7)
Cardiac resynchronization therapy
292 (7.0)
282 (6.7)
Characteristic
Treatments at randomization — no. (%)
Plus–minus values are means ±SD. There were no significant differences between the two groups except for the use of
digitalis (P = 0.04) and mineralocorticoid-receptor antagonists (P = 0.01), with values not adjusted for multiple testing.
Percentages may not total 100 because of rounding. More details about the baseline characteristics are provided in
Section 3 in the Supplementary Appendix. To convert the values for creatinine to micromoles per liter, multiply by 88.4.
IQR denotes interquartile range.
Arrêt de l’étude après un suivi de 27 mois A Primary End Point
B Death from Cardiovascular Causes
1.0
Hazard ratio, 0.80 (95% CI, 0.73–0.87)
P<0.001
Cumulative Probability
Cumulative Probability
1.0
0.6
0.5
0.4
Enalapril
0.3
LCZ696
0.2
0.1
0.0
Hazard ratio, 0.80 (95% CI, 0.71–0.89)
P<0.001
0.6
0.5
0.4
0.3
Enalapril
0.2
LCZ696
0.1
0
180
360
540
720
900
1080
0.0
1260
0
180
Days since Randomization
3922
3883
1.0
3663
3579
3018
2922
2257
2123
1544
1488
896
853
249
236
900
1080
1260
0.5
0.4
0.3
Enalapril
0.2
0.1
360
3891
3860
3282
3231
2478
2410
1716
1726
1005
994
280
279
540
720
900
1080
Hazard ratio, 0.84 (95% CI, 0.76–0.93)
P<0.001
0.6
0.5
0.4
0.3
Enalapril
0.2
LCZ696
0.1
LCZ696
180
4056
4051
1.0
Hazard ratio, 0.79 (95% CI, 0.71–0.89)
P<0.001
0
4187
4212
D Death from Any Cause
0.6
0.0
LCZ696
Enalapril
Cumulative Probability
Cumulative Probability
720
No. at Risk
4187
4212
C Hospitalization for Heart Failure
0.0
1260
0
180
Days since Randomization
360
540
720
900
1080
1260
1005
994
280
279
Days since Randomization
No. at Risk
LCZ696
Enalapril
540
Days since Randomization
No. at Risk
LCZ696
Enalapril
360
No. at Risk
4187
4212
3922
3883
3663
3579
3018
2922
2257
2123
1544
1488
896
853
249
236
LCZ696
Enalapril
4187
4212
4056
4051
3891
3860
3282
3231
2478
2410
1716
1726
Packer
et alet al Angiotensin
Neprilysin
Inhibition
in Heart
Failure
Packer
Angiotensin
Neprilysin
Inhibition
in Heart
Failure 5
1.0
0.5
0.0
Total number of hospitalisa=ons 1.5Hazard ratio 0.60 (0.38-0.94)
60
Cumulative Number of Hospitalizations
for Heart Failure per 100 Patients
Cumulative Number of Hospitalizations
for Heart Failure per 100 Patients
1.5
K-M Estimate of Cumulative Rate
K-M Estimate of Cumulative Rate
Time to 1st hosp (30 days) Hazard ratio 0.60 (0.38-0.94)
P = 0.027
P = 0.027
Enalapril
Enalapril
(n=4212)
(n=4212)
1.0
40
0.5
8
(n=4187)
(n=4187)
0
0.0 00
0
Patients at Risk
Patients at Risk
LCZ696
4187
4187
EnalaprilLCZ6964212
Enalapril
4212
10
20
10
20
Days After Randomization
Days After Randomization
4174
4192
4174
4192
4153
4166
4153
4166
30
4140
4143
Rate ratio 0.77 (0.67-0.89)
Rate
0.77 (0.67-0.89)
P <ratio
0.001
P < 0.001
40
Enalapril
Enalapril
(n=4212)
(n=4212)
16
16
20
20
LCZ696
LCZ696
0.0
60
30
4140
4143
LCZ696
LCZ696
(n=4187)
(n=4187)
8
0.0 00
0
180
360 540 720
900 1080 1260 1440
0
180
360 540 720
900 1080 1260 1440
Patients at Risk
Patients at Risk
4054
LCZ696
4187
4187
Enalapril LCZ6964212
4049
Enalapril
4212
Days After Randomization
Days After Randomization
3885
4054
3857
4049
3276
3885
3228
3857
2472
3276
2408
3228
1710
2472
1724
2408
1001
1710
993
1724
279
1001
278
993
12
27917
278
12
17
Figure 2. Cumulative number of hospitalizations for heart failure
Figure 2. Cumulative number of hospitalizations for heart failur
Figure 1. Kaplan–Meier curve for the time to first hospitalization
and LCZ696 groups per 100 patients. Shown is
Figure 1. Kaplan–Meier curve for the time to first hospitalization in theinenalapril
the enalapril and LCZ696 groups per 100 patients. Shown is
for heart failure during first 30 days after randomization,
the cumulative number of hospitalizations for heart failure in the
for heart failure during first 30 days after randomization,
the cumulative number of hospitalizations for heart failure in th
according to study group. Shown is the Kaplan–Meier estimate of
groups per 100 patients, ignoring death as an informative
according to study group. Shown is the Kaplan–Meier estimate of 2 study
2 study groups per 100 patients, ignoring death as an informat
the cumulative probability of a first hospitalization for heart failure
dropout,
with the rate ratio calculated by using the negative
the cumulative probability of a first hospitalization for heart failure
dropout, with the rate ratio calculated by using the negative
during the first 30 days after randomization. The analysis at Packer, Cbinomial
regression
model.
ircula=on 2014 during the first 30 days after randomization. The analysis at
binomial regression
model.
30 days was prespecified and also represented the earliest time
30 days was prespecified and also represented the earliest time
point, at which the difference between the LCZ696 and enalapril
6
January 6, 2015
Circulation
A
N-terminal pro-BNP
pg/ml
2500
Troponin T
ng/L
25
P< 0.0001
P< 0.0001
P< 0.0001
P< 0.0001
2000
20
1500
15
1000
10
500
5
0
ENL LCZ
Entry Run-in
B
pg/ml
4 wk
8 mo
0
ENL LCZ
Entry Run-in
Double-blind
B-type Natriuretic Peptide
ng/L
4 wk
8 mo
Double-blind
Urinary
Cyclic
GMP 2014 Packer, Circula=on wh
cat
in
tria
O
bio
exp
cyc
wit
GM
enh
of
pat
NT
pon
Th
ure
Primary End Point
Subgroup
LCZ696
Hazard Ratio
(95% CI)
Enalapril
Death from Cardiovascular Causes
P value for
interaction
Hazard ratio
(95% CI)
P value for
interaction
no.
All patients
Age
<65 yr
≥65 yr
Age
<75 yr
≥75 yr
Sex
Male
Female
Race
White
Black
Asian
Native American
Other
Region
North America
Latin America
Western Europe and other
Central Europe
Asia–Pacific
NYHA class
I or II
III or IV
Estimated GFR
<60 ml/min/1.73 m2
≥60 ml/min/1.73 m2
Diabetes
No
Yes
Systolic blood pressure
≤Median
>Median
Ejection fraction
≤Median
>Median
Ejection fraction
≤35%
>35%
Atrial fibrillation
No
Yes
NT-proBNP
≤Median
>Median
Hypertension
No
Yes
Prior use of ACE inhibitor
No
Yes
Prior use of aldosterone antagonist
No
Yes
Prior hospitalization for heart failure
No
Yes
Time since diagnosis of heart failure
≤1 yr
>1 to 5 yr
>5 yr
4187
4212
2111
2076
2168
2044
3403
784
3433
779
3308
879
3259
953
2763
213
759
84
368
2781
215
750
88
378
310
713
1026
1393
745
292
720
1025
1433
742
3178
1002
3130
1076
1541
2646
1520
2692
2736
1451
2756
1456
2298
1889
2299
1913
2239
1948
2275
1936
3715
472
3722
489
2670
1517
2638
1574
2079
2103
2116
2087
1218
2969
1241
2971
921
3266
946
3266
1916
2271
1812
2400
1580
2607
1545
2667
1275
1621
1291
1248
1611
1353
0.3
0.5
0.7
0.9
LCZ696 Better
1.1
1.3
0.47
0.70
0.32
0.62
0.63
0.92
0.58
0.88
0.37
0.81
0.03
0.76
0.91
0.73
0.40
0.05
0.87
0.62
0.71
0.80
0.36
0.36
0.25
1.00
0.16
0.33
0.87
0.14
0.09
0.06
0.10
0.32
0.10
0.19
0.27
0.21
1.5
Enalapril Better
1.7
0.3
0.5
0.7
0.9
LCZ696 Better
1.1
1.3
1.5
Enalapril Better
1.7
Table 3. Adverse Events during Randomized Treatment.*
Event
LCZ696
(N = 4187)
Enalapril
(N = 4212)
P Value
no. (%)
Hypotension
Symptomatic
588 (14.0)
388 (9.2)
<0.001
Symptomatic with systolic blood pressure <90 mm Hg
112 (2.7)
59 (1.4)
<0.001
≥2.5 mg/dl
139 (3.3)
188 (4.5)
0.007
≥3.0 mg/dl
63 (1.5)
83 (2.0)
0.10
>5.5 mmol/liter
674 (16.1)
727 (17.3)
0.15
>6.0 mmol/liter
181 (4.3)
236 (5.6)
0.007
474 (11.3)
601 (14.3)
<0.001
10 (0.2)
5 (0.1)
0.19
Use of catecholamines or glucocorticoids without
hospitalization
6 (0.1)
4 (0.1)
0.52
Hospitalization without airway compromise
3 (0.1)
1 (<0.1)
0.31
Airway compromise
0
0
—
Elevated serum creatinine
Elevated serum potassium
Cough
Angioedema†
No treatment or use of antihistamines only
Rôle de la fréquence cardiaque divided the placebo and ivabradine groups by quintil
heart-rate distribution in the placebo group at base
Heart rate as a risk factor in CHF 50
p<0·0001
40
30
20
≥87 bpm
80 to <87 bpm
75 to <80 bpm
72 to <75 bpm
70 to <72 bpm
10
0
0
mber at risk
≥87 bpm 682
6
12
18
534
441
351
24
30
Boehm, 185
Lancet 2010 66
Patients with first hospital admission
Patients with primary composite endpoint (%)
A
Swedberg, Lancet 2010 Décès ou Hosp IC
Hosp IC
Swedberg, Lancet 2010 Archives of Cardiovascular Disease (2014) 107, 563—571
Available online at
ScienceDirect
www.sciencedirect.com
GUIDELINES
Diagnosis and treatment of iron deficiency
in patients with heart failure: Expert
position paper from French cardiologists
Diagnostic et traitement de la carence martiale chez les patients
insuffisants cardiaques : le point de vue d’experts cardiologues
français
Alain Cohen-Solal a,∗, Christophe Leclercq b,
Alexandre Mebazaa c, Pascal De Groote d,
Thibaud Damy e, Richard Isnard f, Michel Galinier g
with baseline NYHA
class III (P < 0.01)
Randomized
placebo-controlled
studies
Toblli et al. (2007)
[7]
40
Iron deficiency
and anaemia
NYHA class
II—IV;
ejection
fraction ≤ 35%
Iron sucrose
6 months
Okonko et al. (2008)
(FERRIC-HF study)
[6]
35
Iron deficiency
with and
without
anaemia
NYHA class
II—III
Iron sucrose
(928 ± 219 mg)
18 weeks
Anker et al. (2009)
(FAIR-HF study) [4]
459
Iron deficiency
with or
without
anaemia
NYHA class
II—III
Ferric car24 weeks
boxymaltose
(1850 ± 433 mg)
Reduction in
NT-proBNP (P < 0.01)
and CRP (P < 0.01);
improvement in
LVEF, NYHA
functional class,
exercise capacity,
renal function and
quality of life (all
P < 0.01)
Increase in pVO2 /kg
(P = 0.01);
improvement in
NYHA functional
class (P = 0.007) and
patient global
assessment
(P = 0.002)
Improvement in
patient global
assessment and
NYHA functional
class (primary
criteria; P < 0.001);
improvement in
6-minute walk
distance and quality
of life (P < 0.001);
similar effect in
patients with or
without anaemia
European Heart Journal (2015) 36, 657–668
doi:10.1093/eurheartj/ehu385
ESC HOT LINE
Heart failure/cardiomyopathy
Beneficial effects of long-term intravenous iron
therapy with ferric carboxymaltose in patients with
symptomatic heart failure and iron deficiency†
Piotr Ponikowski 1,2*, Dirk J. van Veldhuisen 3, Josep Comin-Colet 4, Georg Ertl 5,6,
Michel Komajda7, Viacheslav Mareev8, Theresa McDonagh9, Alexander Parkhomenko10,
Luigi Tavazzi11, Victoria Levesque12, Claudio Mori12, Bernard Roubert12,
Gerasimos Filippatos13, Frank Ruschitzka14, and Stefan D. Anker15, for the
CONFIRM-HF Investigators
1
Department of Heart Diseases, Medical University, Wroclaw, Poland; 2Department of Cardiology, Center for Heart Diseases, Clinical Military Hospital, Weigla 5 53-114, Wroclaw, Poland;
Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 4Heart Diseases Biomedical Research Group, IMIM (Hospital del
Mar Medical Research Institute), Barcelona, Spain; 5Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany; 6Comprehensive Heart Failure Center,
University of Würzburg, Würzburg, Germany; 7CHU Pitié-Salpêtrière, Institut de Cardiologie, Paris, France; 8Lomonosov Moscow State University, Moscow, Russia; 9Department of
Cardiology, King’s College Hospital, Denmark Hill, London SE5 9RS, UK; 10Ukranian Strazhesko Institute of Cardiology, 5, Narodnoko Opolchenia St, Kiev 03151, Ukraine; 11Maria Cecilia
Hospital, GVM Care&Research—E.S. Health Science Foundation, Cotignola, Italy; 12Vifor Pharma, Glattbrugg, Switzerland; 13Athens University Hospital Attikon, Athens, Greece;
14
Department of Cardiology, University Hospital Zurich, Switzerland; and 15Department of Innovative Clinical Trials, University Medical Centre Göttingen, Göttingen, Germany
3
Received 5 August 2014; revised 16 August 2014; accepted 21 August 2014; online publish-ahead-of-print 31 August 2014
This paper was guest edited by Prof. Karl Swedberg, Sahlgrenska University Hospital/Östra (karl.swedberg@hjl.gu.se).
See page 645 for the editorial comment on this article (doi:10.1093/eurheartj/ehu392)
Aim
The aim of this study was to evaluate the benefits and safety of long-term i.v. iron therapy in iron-deficient patients with
heart failure (HF).
.....................................................................................................................................................................................
Methods
CONFIRM-HF was a multi-centre, double-blind, placebo-controlled trial that enrolled 304 ambulatory symptomatic
Downloaded from by guest on April 7, 2015
Ferri=ne < 100 ng/ml ou si entre 100 et 300 ng/ml, satura=on transferrine < 20 % Downloaded from by guest on April 7, 2015
Figure 2 Patient Global Assessment and NYHA Functional Class over Time (full-analysis set). The data presented are odds ratios for patient
Ponikowsky, Eur Heart J 2015 global assessment (A) and NYHA functional class (B) for the ferric carboxymaltose group when compared with the placebo, of being in a better
category of patient global assessment (A) and NYHA functional class (B). In those panels, the P-values are for the comparison between the two
Ponikowsky, Eur Heart J 2015 Ponikowsky, Eur Heart J 2015 570
A. Cohen-Solal et
Figure 1. Assessment of iron variables and treatment of iron deficiency in chronic heart failure. ESC: European Society of Cardiolo
HF: heart failure; IV: intravenous; NYHA: New York Heart Association; OMS: Organización Mundial de la Salud (World Health Organizatio
Les échecs dans l’IC à FE basse • 
• 
• 
• 
• 
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• 
Les inotropes (Essen=al, Atomic) Les vasodilatateurs purs: flosequinan (Profile) Inhibiteurs de la rénine (aliskiren) (Astronaut) Omapatrilat (Overture) Les an=-­‐endothélines: bosentan (Reach) Les an= TNF (recover, renaissance) Les sta=nes (corona) L’EPO (Red-­‐HF) MITRACLIP Procedural Overview
f the MV
re—no
ss
ositioning
ptimize
surgical
ss
h of stay
surgery
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Information contained herein is for presentation for Europe, Middle East and Africa ONLY
014 REV F
4
Procedural Overview
© 2014 Abbott. All rights reserved. 9-EH-4-2405-01 06-2014 REV F
Information contained herein is for presentation for Europe, Middle East and Africa ONLY
5
IC à FE préservée Estimated Cumulative Proportion of Pati
Who Died from Cardiovascular Caus
0.80
95% CI, 0.49 to 0.87; P = 0.003) (see Table S5A in
0.20
outcome
0.75
the Supplementary Appendix for the primary
0.70
Death from cardiovascular outcome
160and
(9.3)its components
2.8according to176
(10.2)
3.1
0.900.15
(0.73–1.12)
0.35 Placebo
ran0.65
causes
domization stratum). As compared with patients
0.60
Aborted cardiac arrest
3 (0.2)
0.05 patients in the
5 (0.3)
0.09
0.600.10
(0.14–2.50)
0.48
0.55
in the hospitalization
stratum,
Spironolactone
0.50
Hospitalization for heart failure
206 (12.0)
3.8 less likely to
245be
(14.2)
4.6
0.83 (0.69–0.99)
0.04
BNP stratum
were older; were
0.05
0.45
dditional secondary outcomes current smokers; had higher baseline creatinine
0.40
levels, 252
lower
potassium levels,
esti0.35
0.00
Death from any cause
(14.6)
4.2 and lower 274
(15.9)
4.6
0.91
(0.77–1.08)
0.29
0 1512
24
36
48
60
72
established
in
1812
april
10,
2014
vol. 370 no.
0.30
mated
GFRs;
and
were
less
likely
to
be
enrolled
Hospitalization for any reason
766 (44.5)
18.8
792 (46.0)
20.0
0.94 (0.85–1.04)
0.25
0.25
at sites in Russia or Georgia (Table S5B in the
(95% CI, 0.73–1.12)0.98
0.20
Myocardial infarction
65 (3.8)
1.2
64 (3.7)
1.1 Hazard ratio,
1.000.90
(0.71–1.42)
Supplementary Appendix).
P=0.35 by log-rank test
0.15
Stroke
1.0 marked regional
60 (3.5)
1.1
0.94 (0.65–1.35)
0.73
Post 57
hoc(3.3)
analysis indicated
0.10
0.05
differences
in Marc
eventA.rates
(Table
in the
SuppleBertram
Pitt, M.D.,
Pfeffer,
M.D.,S6Ph.D.,
Susan
F. Assmann, Ph.D., Robin Boineau, M.D., Inder S. Anand, M.D.,
ome participants had more than one component of the primary outcome and are included once for
0.00the primary outcome and once for
mentary
Appendix).
In Nadine
the Americas
Brian Claggett,
Ph.D.,
Clausell,(the
M.D.,United
Ph.D., Akshay S. Desai, M.D.,
Diaz, M.D.,
0 M.P.H.,
12 Rafael24
36
48
60
72
ach component they had.
Jerome
L. Fleg,
M.D., Ivan
Gordeev,
M.D.,
Ph.D., Brian
Harty,
M.A., John F. Heitner, M.D., Christopher T. Kenwood,
M.S.,
States,
Canada,
Brazil,
and
Argentina),
the
priMonths
hown are unadjusted hazard ratios calculated with the use of Cox proportional-hazards models.
Eldrin
F. Lewis,
M.D.,occurred
M.P.H., Eileen
O’Meara,
M.D.,
M.D., Tamaz Shaburishvili, M.D., Ph.D.,
mary
outcome
in 242
patients
inJeffrey
the L. Probstfield,
at Risk
Sanjiv J. Shah,
M.D.,(27.3%)
Scott D.and
Solomon,
M.D., Nancy K.No.
Sweitzer,
M.D., Ph.D., Song Yang, Ph.D.,
spironolactone
group
280 patients
Spironolactone 1722
1582
1258
956
667
359
58
and Sonja M. McKinlay, Ph.D., for thePlacebo
TOPCAT Investigators*
1723
1571
1257
934
655
365
59
in the placebo group (31.8%). In Russia and
dence rates and the adjusted models are shown
Georgia, the primary outcome occurred in 78
1.00
BT S4 in the Supplementary Appendix.
0.30
A BS Tin
R AC
Table
patients in the spironolactone group (9.3%) and
0.95
1.00
0.30
cardiovascular
causes occurred in
71 patients in the placebo group (8.4%). How- Death from0.95
0.90
Background
0.25
Placebo
160 patients in0.90
the spironolactone
group (9.3%)
ever, the prespecified test for interaction be0.85
0.25
of Michigan School
Mineralocorticoid-receptor antagonists improve the prognosis for patients0.85
with From the University
tween
region
and
study
group
was
not
signifiMedicine,
Ann Arborgroup
(B.P.); the Cardio0.80
and 176 patients
in ofthe
placebo
(10.2%),
heart
0.80 ef- vascular Division, Brigham and Women’s
0.20failure and a reduced left ventricular ejection fraction. We evaluated the
0.20
cant
(P
=
0.12)
(Fig.
S3
in
the
Supplementary
0.75
Spironolactone
fects of spironolactone in patients with heart failure and awith
preserved
left ventricular
Placebo
0.75
a hazard
ratio
ofHospital,
0.90Boston
(95%(M.A.P.,
CI, 0.73
to 1.12;
B.C., A.S.D.,
Appendix).
0.70
E.F.L., S.D.S.); New England Research Instiejection
fraction.
0.70
new england
journal of medicine
The
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
P = 0.35 by the0.65
log-rank
test)
2A).
Aborted
0.15 (Fig.
tutes, Watertown,
MA (S.F.A.,
B.H., C.T.K.,
S.M.M.); National Heart, Lung, and Blood
Spironolactone
0.60
cardiac arrest occurred
in 3 patients in the spirSecondary
Outcomes
Institute, Bethesda, MD (R.B., J.L.F., S.Y.);
In this
randomized,
double-blind trial, we assigned 3445 patients with symptomatic
0.10
0.55
0.10
Veterans
Affairs
Medical
Center
and
Unigroup
and 5 patients in the
There
differences
heart
failurewere
and ano
leftsignificant
ventricular ejection
fractionbetween
of 45%onolactone
or more to receive
either(0.2%)
0.50
versity of Minnesota, Minneapolis (I.S.A.);
study groups
in45
time
to death
from any
cause or
spironolactone
(15 to
mg daily)
or placebo.
The primary
outcome was
a composite
Hospital
de0.05
Clinicas de
Portothe
Alegre,log-rank
Porto
0.45
placebo
group
(0.3%)
(P =
0.48
by
of 0.05
death
cardiovascular
aborted(Table
cardiac2 arrest,
or hospitalization
0.40for Alegre, Brazil (N.C.); Estudios Clinicos
first from
hospitalization
forcauses,
any reason
and
test). Hospitalization
for heart
failure
occurred
in
Latinoamerica,
Rosario,
Argentina
(R.D.);
0.35
the Fig.
management
of S4
heart
failure.
0.00 National Research Med3, and Fig.
in the
Supplementary Appendix).
Pirogov Russian
0
12group
36
48
60
72
206 patients in0.30
the spironolactone
ical University, Moscow
(I.G.);24
New(12.0%)
York
0.00
Results
Causes of death were generally similar between
0.25
Methodist
Hospital,
Brooklyn
(J.F.H.);
0mean12follow-up
24
363.3 years,
48
60 primary
72
and occurred
245 patients
in Montreal
theratio,
placebo
(14.2%),
0.83Institute,
(95%group
CI,
0.69–0.99)
With
of
outcome
in 320
Heart
Montreal
(E.O.);
thea two
groups (Table
S7 in thetheSupplementary
0.20 of Hazard
P=0.04
by log-rank
test
University
of
Washington
Medical
Cen1722
patients
in
the
spironolactone
group
(18.6%)
and
351
of
1723
patients
in
0.15
with a hazard ratio
ofter,0.83
(95% CI, 0.69 to
0.99;
Appendix). The frequency of hospitalization for
Seattle (J.L.P.); Diagnostic Services
0.10
the any
placebo
group
(20.4%)
(hazard
ratio,
0.89;
95%
confidence
interval
[CI],
0.77
Clinic,
Tbilisi,
Georgia
(T.S.);
Northwestreason (including recurrent hospitalization)
P = 0.04 by the0.05
log-rank
test) (Fig. 2B). Approxito 1.04; P = 0.14). Of the components of the primary outcome, only hospitalization
ern University, Chicago (S.J.S.); and the
did not differ significantly according to study
0.00
University
of Wisconsin, Madison (N.K.S.).
two thirds
of first
primary-outcome
events
for heart failure had a significantly lower incidence in mately
the spironolactone
group
Hazard
ratio,
0.89 (95% CI, 0.77–1.04)
0
12 reprint 24
60
72
Address
requests to36
Dr. Pfeffer48
at
group
(36.8
hospitalizations
per[12.0%]
100 personthan
in theP=0.14
placebo
group
(206
patients
vs.
245
patients
[14.2%];
hazard
were
hospitalizations
for
heart
failure.
In
an
the Cardiovascular
Division,
Brigham
by
log-rank
test
Months
years
theCI,spironolactone
groupNeither
and 36.3
ratio,
0.83;in95%
0.69 to 0.99, P = 0.04).
total per
deaths nor hospitalizations and Women’s Hospital, 75 Francis St.,
analysis
of with
totalspirhospitalizations
Boston, MA 02115, or at(including
mpfeffer@rics reperson-years
in the
No. at Risk
for 100
any24reason
were
reduced
by spironolactone.
36 significantly
48 placebo
60 group,
72P = 0.71). Treatment
.bwh.harvard.edu.
Spironolactone
1502
1167 failure
869
613 the330
53
peat
for heart
over
onolactone
was associated
with increased
serumincreatinine
levelshospitalizations)
and a doubling1722
of
There were
no significant
differences
rates of
0.15
Methods
0
12
Estimated Cumulative Proportion of Patients
Hospitalized for Heart Failure
Estimated Cumulative Proportion of Patients
with Primary End Point
Spironolactone for Heart Failure with Preserved Ejection Fraction
6
Circulation
Varia=ons régionales January 6, 2015
P<0.001) than in Russia/Georgia (0.08 mmol/L; P<0.001; interaction P<0.001), and the average magnitude of the increase in
creatinine associated with spironolactone relative to placebo was
greater in the Americas (0.10 mg/dL; P<0.001) than in Russia/
Georgia (0.02 mmol/L; P=0.002; interaction P<0.001). These
3 differences in magnitude of treatment response similarly persisted in adjusted models using these serial measurements.
Discussion
This post hoc analysis was based on the observation of an unusually large difference in the placebo event rates between the sites
conducting TOPCAT in the 4 countries in the Americas compared with those in Russia and Georgia.14 In addition to the
marked differences in prognosis, this regional analysis revealed
many additional important dissimilarities in patient characteristics; the potassium, creatinine, and blood pressure responses to
spironolactone; and reports of adherence to study medications.
Regional differences have complicated the interpretations of
other randomized trials in cardiovascular medicine.1–7,20–22 The
prior observed pattern of fewer events in patients from Eastern
Europe2,5,7 may have been amplified in TOPCAT because Russia
and Georgia contributed 49% of the total enrollment. However,
the observed difference between regions in TOPCAT is striking
in magnitude, exceeding that anticipated by variations in practice
patterns; indeed, it is the marked difference in the placebo groups
that distinguishes this from many previous reports of regional
variation. This observed difference in population risk profiles
obfuscates our ability to unite the results from these 2 disparate
regions to draw conclusions about the results of the overall study.
Autres effets Pfeffer et al
Regional Variation in TOPCAT
7
Americas is equally puzzling. In models adjusting for baseline
factors known to influence potassium and creatinine responses
to spironolactone (including age, estimated glomerular filtration rate, diabetes mellitus, and angiotensin-converting enzyme
inhibitor/angiotensin receptor blocker use), these important
differences between geographic regions persisted.16–19 These
unexplained regional differences in the renal and electrolyte
responses to spironolactone are an additional confounder of the
TOPCAT results from the Russia/Georgia cohort. On the other
hand, within each treatment group, the percentage of subjects
discontinuing study treatment as a result of breast tenderness
or gynecomastia was similar between the 2 regions.
There is a marked disparity in the number of randomized
trial--based recommendations for patients with symptomatic
heart failure according to ejection fraction because patients
with reduced ejection fraction (generally <40%) have been the
focus of most of the major randomized, controlled trials.41,42 In
sharp contrast, for those with preserved ejection fraction, there
have been only 3 major randomized, placebo-controlled, clinical outcome trials, including TOPCAT, specifically addressing
this large segment of the symptomatic heart failure population,
and in each, the primary outcome was not found to be improved
by the investigational therapy.14,36,37 This lack of randomized,
controlled, clinical trial evidence for effectiveness is reflected
in the guidelines, which offer little direction for this substantial
and expanding proportion of patients with heart failure, aside
from empirical treatment of underlying comorbidities.41–44 As
a result, prognosis has been improving for those with reduced
but not for those with preserved ejection fraction.45,46
This lack of evidence-based guidelines for treatment of heart
failure with preserved ejection fraction continues to be perpetu-
4
Circulation
January 6, 2015
Table 2. Reported Study Drug Use at Month 8 Visit
Americas,
Russia/Georgia,
P,
Month 8
n (%)
n (%)
TreatmentReported
Spironolactone Placebo Spironolactone Placebo
Region
Daily
(n=866)
(n=846)
(n=823)
(n=830) Interaction
Dose, mg
0
212 (24.5)
160 (18.9)
59 (7.2)
61 (7.3)
15
194 (22.4)
105 (12.4)
83 (10.1)
38 (4.6)
30
319 (36.8)
386 (45.6)
570 (69.3)
597 (71.9)
45
141 (16.3)
195 (23.0)
111 (13.5)
134 (16.1)
21.7
25.9
28.4
29.5
Average
dose, mg
0.001