EMPHASIS Heart Failure Study Group. Eplerenone in patients with systolic heart failure and mild symptoms

Article (PDF Available)inNew England Journal of Medicine 364(1):11-21 · November 2010with40 Reads
DOI: 10.1056/NEJMoa1009492 · Source: PubMed
Abstract
Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms. In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001). Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).

Figures

n engl j med 364;1 nejm.org january 6, 2011
11
The new england
journal
of medicine
established in 1812
january 6, 2011
vol. 364 no. 1
Eplerenone in Patients with Systolic Heart Failure
and Mild Symptoms
Faiez Zannad, M.D., Ph.D., John J.V. McMurray, M.D., Henry Krum, M.B., Ph.D., Dirk J. van Veldhuisen, M.D., Ph.D.,
Karl Swedberg, M.D., Ph.D., Harry Shi, M.S., John Vincent, M.B., Ph.D., Stuart J. Pocock, Ph.D.,
and Bertram Pitt, M.D., for the EMPHASIS-HF Study Group*
A B S TR AC T
From INSERM, Centre d’Investigation
Clinique 9501 and Unité 961, Centre Hos-
pitalier Universitaire, and the Department
of Cardiology, Nancy University, Nancy,
France (F.Z.); the British Heart Founda-
tion Cardiovascular Research Centre,
University of Glasgow, Glasgow, United
Kingdom (J.J.V.M.); the Department of
Epidemiology and Preventive Medicine,
Centre of Cardiovascular Research and
Education in Therapeutics, Monash Uni-
versity, Melbourne, VIC, Australia (H.K.);
the Department of Cardiology, Thorax
Center, University Medical Center, Gron-
ingen, the Netherlands (D.J.V.); the De-
partment of Emergency and Cardiovas-
cular Medicine, Sahlgrenska Academy,
University of Gothenburg, Gothenburg,
Sweden (K.S.); Pfizer, New York (H.S.,
J.V.); the Department of Medical Statis-
tics, London School of Hygiene and Trop-
ical Medicine, London (S.J.P.); and Uni-
versity of Michigan School of Medicine,
Ann Arbor (B.P.). Address reprint re-
quests to Dr. Zannad at the Clinical Inves-
tigation Center, INSERM, Institut Lorrain
du Coeur et des Vaisseaux, F-54500, Van-
doeuvre-lès-Nancy, Nancy, France, or at
f.zannad@chu-nancy.fr.
*Members of the Eplerenone in Mild Pa-
tients Hospitalization and Survival Study
in Heart Failure (EMPHASIS-HF) study
group are listed in the Supplementary
Appendix, available at NEJM.org.
This article (10.1056/NEJMoa1009492)
was published on November 14, 2010,
and updated on December 1, 2010, at
NEJM.org.
N Engl J Med 2011;364:11-21.
Copyright © 2010 Massachusetts Medical Society.
BACKGROUND
Mineralocorticoid antagonists improve survival among patients with chronic, se-
vere systolic heart failure and heart failure after myocardial infarction. We evalu-
ated the effects of eplerenone in patients with chronic systolic heart failure and
mild symptoms.
METHODS
In this randomized, double-blind trial, we randomly assigned 2737 patients with
New York Heart Association class II heart failure and an ejection fraction of no
more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to
recommended therapy. The primary outcome was a composite of death from car-
diovascular causes or hospitalization for heart failure.
RESULTS
The trial was stopped prematurely, according to prespecified rules, after a median
follow-up period of 21 months. The primary outcome occurred in 18.3% of patients
in the eplerenone group as compared with 25.9% in the placebo group (hazard ra-
tio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of
patients receiving eplerenone and 15.5% of those receiving placebo died (hazard
ratio, 0.76; 95% CI, 0.62 to 0.93; P = 0.008); 10.8% and 13.5%, respectively, died of
cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P = 0.01). Hospital-
izations for heart failure and for any cause were also reduced with eplerenone. A
serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients
in the eplerenone group and 7.2% of those in the placebo group (P<0.001).
CONCLUSIONS
Eplerenone, as compared with placebo, reduced both the risk of death and the risk
of hospitalization among patients with systolic heart failure and mild symptoms.
(Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.)
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
T h e
n e w e n g l a n d j o u r n a l
o f
m e d i c i n e
n engl j med 364;1 nejm.org january 6, 2011
12
T
he activation of mineralocorti-
coid receptors by aldosterone and cortisol
has deleterious effects in patients with car-
diovascular disease.
1
In the placebo-controlled
Randomized Aldactone Evaluation Study (RALES),
2
adding the mineralocorticoid-receptor antagonist
spironolactone to recommended therapy in pa-
tients with systolic heart failure and moderate-
to-severe symptoms (i.e., New York Heart Associa-
tion [NYHA] functional class III or IV symptoms)
decreased the rate of death from any cause and
the risk of hospitalization for cardiovascular rea-
sons. In the Eplerenone Post–Acute Myocardial In-
farction Heart Failure Efficacy and Survival Study
(EPHESUS),
3
the selective mineralocorticoid-
receptor antagonist eplerenone, added to recom-
mended medical therapy, reduced the rates of
death from any cause and hospitalization for car-
diovascular reasons among patients with acute
myocardial infarction complicated by left ven-
tricular systolic dysfunction and heart failure.
Consequently, current guidelines recommend the
use of a mineralocorticoid-receptor antagonist in
these patients.
4,5
The aim of our Eplerenone in Mild Patients
Hospitalization and Survival Study in Heart Fail-
ure (EMPHASIS-HF) was to investigate the effects
of eplerenone, added to evidence-based therapy,
on clinical outcomes in patients with systolic
heart failure and mild symptoms (i.e., NYHA
functional class II symptoms).
6
M e t hod s
Study Oversight
The executive steering committee (see the Sup-
plementary Appendix, available with the full text
of this article at NEJM.org) designed and oversaw
the conduct of the trial and data analysis in col-
laboration with representatives of the study spon-
sor (Pfizer). The trial was monitored by an inde-
pendent data and safety monitoring committee.
Data were collected, managed, and analyzed by
the sponsor according to a predefined statistical
analysis plan, and the analyses were replicated by
an independent academic statistician. The manu-
script was prepared by an academic writing group,
whose members had unrestricted access to the
data, and was subsequently revised by all the
authors. All the authors made the decision to sub-
mit the manuscript for publication and assume
responsibility for the accuracy and completeness
of the data and analyses.
Study Patients
The design of the EMPHASIS-HF trial has been
published in detail,
6
and the trial protocol and
statistical analysis plan are available at NEJM.org.
The trial was approved by each center’s ethics
committee. All patients provided written informed
consent.
Eligibility criteria were as follows: an age of
at least 55 years, NYHA functional class II symp-
toms, an ejection fraction of no more than 30%
(or, if >30 to 35%, a QRS duration of >130 msec
on electrocardiography), and treatment with an
angiotensin-converting–enzyme (ACE) inhibitor,
an angiotensin-receptor blocker (ARB), or both
and a beta-blocker (unless contraindicated) at the
recommended dose or maximal tolerated dose.
Randomization was to occur within 6 months
after hospitalization for a cardiovascular reason.
Patients who had not been hospitalized for a car-
diovascular reason within 6 months before the
screening visit could be enrolled if the plasma
level of B-type natriuretic peptide (BNP) was at
least 250 pg per milliliter or if the plasma level
of N-terminal pro-BNP was at least 500 pg per
milliliter in men and 750 pg per milliliter in
women.
Key exclusion criteria were acute myocardial
infarction, NYHA class III or IV heart failure, a
serum potassium level exceeding 5.0 mmol per
liter, an estimated glomerular filtration rate
(GFR) of less than 30 ml per minute per 1.73 m
2
of body-surface area, a need for a potassium-
sparing diuretic, and any other clinically signifi-
cant, coexisting condition.
Study Procedures
We used a computerized randomization system
involving concealed study-group assignments to
randomly assign patients to receive eplerenone
(Inspra, Pfizer) or matching placebo. Eplerenone
was started at a dose of 25 mg once daily and was
increased after 4 weeks to 50 mg once daily (or
started at 25 mg on alternate days, and increased
to 25 mg daily, if the estimated GFR was 30 to
49 ml per minute per 1.73 m
2
), provided the se-
rum potassium level was no more than 5.0 mmol
per liter.
Thereafter, investigators evaluated patients
every 4 months and were instructed to decrease
the dose of the study drug if the serum potas-
sium level was 5.5 to 5.9 mmol per liter and to
withhold the study drug if the serum potassium
level was 6.0 mmol per liter or more. Potassium
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
Epler enone in Patients wi th He a rt Failure
n engl j med 364;1 nejm.org january 6, 2011
13
was to be remeasured within 72 hours after the
dose reduction or study-drug withdrawal, and the
study drug was to be restarted only if the level
was below 5.0 mmol per liter.
Study Outcomes
The primary outcome was a composite of death
from cardiovascular causes or a first hospital-
ization for heart failure. The prespecified adjudi-
cated secondary outcomes were hospitalization
for heart failure or death from any cause, death
from any cause, death from cardiovascular causes,
hospitalization for any reason, and hospitaliza-
tion for heart failure, among others (listed in
Table 2). Adjudication of the outcomes was car-
ried out by an independent committee (see the
Supplementary Appendix) according to prespec-
ified criteria.
Statistical Analysis
The initial assumptions were that, with 2584 pa-
tients and an annual event rate of 18% in the
placebo group (based on data from a subgroup
analysis of the Candesartan in Heart Failure: As-
sessment of Reduction in Mortality and Morbid-
ity–Added trial [CHARM-Added; ClinicalTrials
.gov number, NCT00634309]),
7
our trial would
require 813 patients with a primary outcome oc-
curring within 48 months to achieve 80% power
to detect an 18% relative reduction in the risk of
the primary outcome in the eplerenone group as
compared with the placebo group (with a two-
sided alpha of 0.05). Because the overall blinded
event rate was lower than expected, the sample
size was increased to 3100 patients, according to
a protocol amendment adopted in June 2009.
The data and safety monitoring committee’s
charter specified interim analyses of the primary
outcome after approximately 271 and 542 events
had occurred, with a statistical stopping guide-
line for an overwhelming benefit (two-sided
P<0.001 in favor of eplerenone). On May 6, 2010,
after the second interim analysis, the data and
safety monitoring committee reported to the
executive committee chairs that the prespecified
stopping boundary for an overwhelming benefit
had been crossed. The full executive committee
was informed, decided to stop the trial, and
notified the sponsor of this decision on May 9,
2010. Operationally, May 25, 2010, was chosen
as the trial cutoff date for all efficacy and safety
analyses reported here.
Comparability of baseline characteristics be-
tween the two study groups was assessed by
means of a two-sample t-test, for continuous vari-
ables, or Fisher’s exact test, for categorical vari-
ables. The analyses of the adjudicated primary
and secondary outcomes were conducted on data
from all patients who had undergone randomiza-
tion, according to the intention-to-treat princi-
ple, with the use of Kaplan–Meier estimates and
Cox proportional-hazards models. Hazard ratios,
95% confidence intervals, and P values were cal-
culated with the use of models adjusted for the
following prespecified baseline prognostic fac-
tors: age, estimated GFR, ejection fraction, body-
mass index, hemoglobin value, heart rate, systolic
blood pressure, diabetes mellitus, history of hy-
pertension, previous myocardial infarction, atrial
fibrillation, and left bundle-branch block or QRS
duration greater than 130 msec. Sensitivity analy-
ses were also performed, by means of unadjust-
ed Cox models.
The consistency of the treatment effect was
assessed among 20 prespecified subgroups. The
effect in each subgroup was analyzed with the
use of a Cox proportional-hazards model, with-
out adjustment for covariates. The treatment-by-
subgroup interaction was evaluated by means of a
Cox proportional-hazards model with terms for
treatment, subgroup, and their interaction.
The number of patients who would need to be
treated to prevent one primary-outcome event
from occurring was determined according to the
method of Altman and Andersen.
8
Post hoc com-
parisons between the two groups of the total
number of hospitalizations for any reason and
for heart failure were performed with the use of
a t-test, assuming a Poisson distribution. Serious
adverse events, anticipated adverse events, and
adverse events leading to permanent study-drug
withdrawal were tabulated according to random-
ized group assignment and analyzed by means
of Fisher’s exact test.
R e s u lt s
Study Patients
From March 30, 2006, through May 25, 2010, we
recruited 2737 patients at 278 centers in 29 coun-
tries. Of these patients, 1364 were randomly as-
signed to eplerenone and 1373 to placebo. The
two groups were balanced with respect to base-
line characteristics, and all the patients were re-
ceiving recommended pharmacologic therapy for
systolic heart failure (Table 1).
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
T h e
n e w e n g l a n d j o u r n a l
o f
m e d i c i n e
n engl j med 364;1 nejm.org january 6, 2011
14
A total of 45 patients (3.3%) in the eplerenone
group and 51 patients (3.7%) in the placebo
group were enrolled on the basis of a QRS dura-
tion that was greater than 130 msec (with an
ejection fraction >30 to 35%); 195 patients (14.3%)
in the eplerenone group and 190 patients (13.8%)
in the placebo group were enrolled on the basis
of the BNP or N-terminal pro-BNP criterion (with
no hospitalization for cardiovascular reasons
within the 180 days before screening). Half the
patients reported having had a myocardial in-
farction, but all cases of infarction had occurred
more than 30 days before the screening visit.
Study-Drug Administration and Follow-Up
Eight patients (four in each study group) did not
start the study medication and were not included
in the safety analysis. After completion of the
dose-adjustment phase, at 5 months, 60.2% of
patients who had been assigned to receive eplere-
none were taking the higher dose (50 mg daily);
the corresponding proportion in the placebo
Table 1. Baseline Characteristics of the Patients, According to Study Group.*
Characteristic
Eplerenone
(N = 1364)
Placebo
(N = 1373)
Age — yr 68.7±7.7 68.6±7.6
Female sex — no. (%) 309 (22.7) 301 (21.9)
Race — no. (%)†
White 1127 (82.6) 1141 (83.1)
Black 37 (2.7) 30 (2.2)
Asian 158 (11.6) 158 (11.5)
Other 42 (3.1) 44 (3.2)
Heart rate — beats/min 72±12 72±13
Blood pressure — mm Hg
Systolic 124±17 124±17
Diastolic 75±10 75±10
Left ventricular ejection fraction — % 26.2±4.6 26.1±4.7
QRS duration — msec 121±45 122±44
QRS duration >130 msec in nonpaced baseline ECG — no./total no. (%) 298/1157 (25.8) 307/1143 (26.9)
Body-mass index‡ 27.5±4.9 27.5±4.9
Principal cause of heart failure — no. (%)
Ischemic heart disease 951 (69.7) 935 (68.1)
Nonischemic heart disease 410 (30.1) 436 (31.8)
Unknown 3 (0.2) 2 (0.1)
Duration of heart failure — yr 4.8±5.9 4.6±5.5
Medical history — no. (%)
Hospitalization for heart failure 714 (52.3) 726 (52.9)
Hypertension 910 (66.7) 909 (66.2)
Angina pectoris 590 (43.3) 599 (43.6)
Myocardial infarction 686 (50.3) 695 (50.6)
PCI 300 (22.0) 296 (21.6)
CABG 256 (18.8) 260 (18.9)
Atrial fibrillation or flutter 409 (30.0) 435 (31.7)
Left bundle-branch block in nonpaced baseline ECG 304/1171 (26.0) 318/1162 (27.4)
Diabetes mellitus 459 (33.7) 400 (29.1)
Stroke 136 (10.0) 126 (9.2)
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
Epler enone in Patients wi th He a rt Failure
n engl j med 364;1 nejm.org january 6, 2011
15
group was 65.3%. Among the patients taking the
study drug at 5 months, the mean (±SD) doses in
the eplerenone and placebo groups, respectively,
were 39.1±13.8 mg and 40.8±12.9 mg.
At the trial cutoff date, the study drug had
been discontinued in 222 patients (16.3%) receiv-
ing eplerenone and 228 patients (16.6%) receiving
placebo. Among these patients, the median time
from randomization to the last dose was 533 days
for eplerenone and 494 days for placebo.
At the trial cutoff date, 17 patients (1.2%) in
the eplerenone group and 15 patients (1.1%) in
the placebo group were lost to follow-up. If con-
tact could not be made at the trial cutoff date,
the data were censored in the analysis at the
time of the last contact. The median duration of
follow-up among all patients was 21 months,
with 4783 patient-years of follow-up.
Study Outcomes
Death from cardiovascular causes or hospitaliza-
tion for heart failure (the primary outcome) oc-
curred in 249 patients (18.3%) in the eplerenone
group and 356 patients (25.9%) in the placebo
group (Fig. 1A and Table 2). The hazard ratio for
the primary outcome in the eplerenone group, as
compared with the placebo group, was 0.63 (95%
confidence interval [CI], 0.54 to 0.74; P<0.001). The
effect of eplerenone on this outcome was consistent
in an unadjusted analysis (hazard ratio, 0.66; 95%
CI, 0.56 to 0.78; P<0.001) (Table 2). It was also con-
sistent across all prespecified subgroups (Fig. 2).
Death from any cause or hospitalization for
heart failure occurred in 270 patients (19.8%) in
the eplerenone group as compared with 376 pa-
tients (27.4%) in the placebo group (hazard ratio,
0.65; 95% CI, 0.55 to 0.76; P<0.001) (Table 2). A
Table 1. (Continued.)
Characteristic
Eplerenone
(N = 1364)
Placebo
(N = 1373)
Hemoglobin — g/dl 13.8±1.6 13.8±1.6
Serum creatinine — mg/dl 1.14±0.30 1.16±0.31
Estimated GFR — ml/min/1.73 m
2
of body-surface area 71.2±21.9 70.4±21.7
Estimated GFR rate <60 ml/min/1.73 m
2
no. (%) 439 (32.2) 473 (34.5)
Serum potassium — mmol/liter 4.3±0.4 4.3±0.4
Device therapy — no. (%)
Implantable cardioverter–defibrillator 178 (13.0) 184 (13.4)
Cardiac-resynchronization therapy 38 (2.8) 22 (1.6)
Implantable cardioverter–defibrillator with cardiac resynchronization 74 (5.4) 99 (7.2)
Medication at randomization visit — no. (%)
Diuretic 1150 (84.3) 1176 (85.7)
ACE inhibitor 1068 (78.3) 1055 (76.8)
ARB 261 (19.1) 266 (19.4)
ACE inhibitor, ARB, or both 1282 (94.0) 1275 (92.9)
Beta-blocker 1181 (86.6) 1193 (86.9)
Digitalis glycosides 363 (26.6) 377 (27.5)
Antiarrhythmic drug 196 (14.4) 192 (14.0)
Antithrombotic drug (antiplatelet or oral anticoagulant) 1205 (88.3) 1214 (88.4)
Lipid-lowering agent 857 (62.8) 856 (62.3)
* Plus–minus values are means ±SD. Percentages may not total 100 because of rounding. None of the characteristics
differed significantly (P<0.05) between the two groups, except for diabetes mellitus (P = 0.01) and cardiac-resynchroni-
zation therapy (P = 0.04). To convert the values for creatinine to micromoles per liter, multiply by 88.4. ACE denotes
angiotensin-converting enzyme, ARB angiotensin-receptor blocker, CABG coronary-artery bypass grafting, ECG electro-
cardiography, GFR glomerular filtration rate, and PCI percutaneous coronary intervention.
Race was reported by the investigators.
The body-mass index is the weight in kilograms divided by the square of the height in meters.
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
T h e
n e w e n g l a n d j o u r n a l
o f
m e d i c i n e
n engl j med 364;1 nejm.org january 6, 2011
16
total of 171 patients (12.5%) in the eplerenone
group and 213 patients (15.5%) in the placebo
group died (hazard ratio, 0.76; 95% CI, 0.62 to
0.93; P = 0.008) (Fig. 1B and Table 2). A total of
147 deaths (10.8%) in the eplerenone group and
185 (13.5%) in the placebo group were attributed
to cardiovascular causes (hazard ratio, 0.76; 95%
CI, 0.61 to 0.94; P = 0.01) (Table 2).
In the eplerenone group, 408 patients (29.9%)
were hospitalized for any reason, as compared
with 491 (35.8%) patients in the placebo group
(hazard ratio, 0.77; 95% CI, 0.67 to 0.88; P<0.001)
(Fig. 1C and Table 2). Of the patients receiving
eplerenone, 164 (12.0%) were hospitalized for
heart failure, as compared with 253 patients
(18.4%) receiving placebo (hazard ratio, 0.58;
95% CI, 0.47 to 0.70; P<0.001) (Fig. 1D and Table
2). The total number of hospitalizations (includ-
Hospitalization for Heart Failure or Death
from Cardiovascular Causes (%)
100
60
40
30
10
50
20
0
0 1 2 3
Years since Randomization
C
A
Hazard ratio, 0.63 (95% CI, 0.540.74)
P<0.001
Hazard ratio, 0.76 (95% CI, 0.620.93)
P=0.008
Hazard ratio, 0.77 (95% CI, 0.670.88)
P<0.001
Hazard ratio, 0.58 (95% CI, 0.470.70)
P<0.001
No. at Risk
Placebo
Eplerenone
1373
1364
848
925
512
562
199
232
Placebo
Eplerenone
Hospitalization for Any Reason (%)
100
60
40
30
10
50
20
0
0 1 2 3
Years since Randomization
No. at Risk
Placebo
Eplerenone
1373
1364
742
795
403
451
146
179
Placebo
Eplerenone
Death from Any Cause (%)
100
60
40
30
10
50
20
0
0 1 2 3
Years since Randomization
D
B
No. at Risk
Placebo
Eplerenone
1373
1364
947
972
587
625
242
269
Placebo
Eplerenone
Hospitalization for Heart Failure (%)
100
60
40
30
10
50
20
0
0 1 2 3
Years since Randomization
No. at Risk
Placebo
Eplerenone
1373
1364
848
925
512
562
199
232
Placebo
Eplerenone
Figure 1. Cumulative KaplanMeier Estimates of Rates of the Primary Outcome and Other Outcomes, According to Study Group.
The hazard ratios for eplerenone versus placebo are shown for hospitalization for heart failure or death from cardiovascular causes (the
primary outcome) (Panel A), death from any cause (Panel B), hospitalization for any reason (Panel C), and hospitalization for heart fail-
ure (Panel D).
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
Epler enone in Patients wi th He a rt Failure
n engl j med 364;1 nejm.org january 6, 2011
17
ing second and subsequent hospitalizations) was
also lower in the eplerenone group (750, vs. 961
in the placebo group, for a 24% reduction;
P<0.001), as were the total numbers of hospital-
izations for cardiovascular reasons (509 vs. 699,
for a 29% reduction; P<0.001) and hospitaliza-
tions for heart failure (273 vs. 429, for a 38%
reduction; P<0.001). Findings for all other pre-
specified adjudicated secondary outcomes and
other outcomes are summarized in Table 2, in
which all the results are adjusted for prespeci-
fied baseline variables.
The estimated number of patients who would
need to be treated to prevent one primary out-
come from occurring, per year of follow-up, was
19 (95% CI, 15 to 27), and the estimated number
needed to treat to postpone one death, per year
of follow-up, was 51 (95% CI, 32 to 180).
Safety
During the course of the study, 188 patients
(13.8%) receiving eplerenone and 222 patients
(16.2%) receiving placebo discontinued the study
drug because of an adverse event (P = 0.09). Rel-
evant adverse events are summarized in Table 3.
At 1 month, the mean change in serum cre-
atinine level from baseline was 0.15±0.35 mg per
deciliter (13.3±30.9 µmol per liter) in the eplere-
none group, as compared with 0.00.29 mg per
deciliter (6.2±25.6 µmol per liter) in the placebo
Table 2. Primary Outcome, Component Events, and Key Secondary Outcomes.*
Outcome
Eplerenone
(N = 1364)
Placebo
(N = 1373)
Adjusted
Hazard Ratio
(95% CI)
Adjusted
P Value
Unadjusted
Hazard Ratio
(95% CI)
Unadjusted
P Value
no. of patients (%)
Primary outcome: death from cardiovascular
causes or hospitalization for heart failure
249 (18.3) 356 (25.9) 0.63 (0.54–0.74) <0.001 0.66 (0.56–0.78) <0.001
Prespecified adjudicated secondary outcomes
Death from any cause or hospitalization for
heart failure
270 (19.8) 376 (27.4) 0.65 (0.55–0.76) <0.001 0.68 (0.58–0.79) <0.001
Death from any cause 171 (12.5) 213 (15.5) 0.76 (0.62–0.93) 0.008 0.78 (0.64–0.95) 0.01
Death from cardiovascular causes 147 (10.8) 185 (13.5) 0.76 (0.61–0.94) 0.01 0.77 (0.62–0.96) 0.02
Hospitalization for any reason 408 (29.9) 491(35.8) 0.77 (0.67–0.88) <0.001 0.78 (0.69–0.89) <0.001
Hospitalization for heart failure 164 (12.0) 253 (18.4) 0.58 (0.47–0.70) <0.001 0.61 (0.50–0.75) <0.001
Hospitalization for cardiovascular causes 304 (22.3) 399 (29.1) 0.69 (0.60–0.81) <0.001 0.72 (0.62–0.83) <0.001
Fatal or nonfatal myocardial infarction 45 (3.3) 33 (2.4) 1.32 (0.84–2.06) 0.23 1.34 (0.86–2.10) 0.20
Death from any cause or hospitalization for
any reason
462 (33.9) 569 (41.4) 0.75 (0.66–0.85) <0.001 0.76 (0.68–0.86) <0.001
Death from heart failure or hospitalization for
heart failure
170 (12.5) 262 (19.1) 0.58 (0.48–0.70) <0.001 0.61 (0.51–0.74) <0.001
Fatal or nonfatal stroke 21 (1.5) 26 (1.9) 0.79 (0.44–1.41) 0.42 0.78 (0.44–1.39) 0.40
Implantation of a cardioverter–defibrillator 61 (4.5) 59 (4.3) 0.99 (0.69–1.42) 0.98 1.01 (0.71–1.45) 0.95
Implantation of a cardiac-resynchronization
device
33 (2.4) 41 (3.0) 0.77 (0.49–1.22) 0.27 0.78 (0.49–1.23) 0.28
Hospitalization for worsening renal function† 9 (0.7) 8 (0.6) 0.97 (0.37–2.58) 0.95 1.09 (0.42–2.82) 0.86
Hospitalization for hyperkalemia† 4 (0.3) 3 (0.2) 1.15 (0.25–5.31) 0.85 1.31 (0.29–5.87) 0.72
Other outcomes‡
Sudden cardiac death 60 (4.4) 76 (5.5) 0.76 (0.54–1.07) 0.12 0.77 (0.55–1.08) 0.12
Death from worsening heart failure 45 (3.3) 61 (4.4) 0.68 (0.46–1.00) 0.05 0.71 (0.48–1.04) 0.08
* Adjusted results were adjusted for prespecified baseline characteristics (see the Statistical Analysis section). CI denotes confidence interval.
No death was attributed to hospitalization for worsening renal function or hyperkalemia.
“Other outcomes” were secondary outcomes that were adjudicated but not prespecified.
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
T h e
n e w e n g l a n d j o u r n a l
o f
m e d i c i n e
n engl j med 364;1 nejm.org january 6, 2011
18
group. At the trial cutoff date, the serum cre-
atinine level had increased from baseline by
0.09±0.37 mg per deciliter (8.32.7 µmol per
liter) and 0.04±0.40 (3.5±35.4 µmol per liter),
respectively.
At 1 month, the mean change in potassium
level from baseline was 0.16±0.51 mmol per liter
in the eplerenone group, as compared with
0.04±1.16 mmol per liter in the placebo group
(P = 0.001). At the trial cutoff date, potassium lev-
els had increased from baseline by 0.16±0.56 and
0.05±0.53 mmol per liter, respectively (P<0.001
for both comparisons). A serum potassium level
above 5.5 mmol per liter was reported in 158 of
1336 patients (11.8%) in the eplerenone group
and 96 of 1340 patients (7.2%) in the placebo
group (P<0.001). A serum potassium level above
6.0 mmol per liter occurred in 33 of 1336 patients
(2.5%) in the eplerenone group and 25 of 1340
patients (1.9%) in the placebo group (P = 0.29). A
serum potassium level below 4.0 mmol per liter
was reported in 519 of 1336 patients (38.8%) in
the eplerenone group and 648 of 1340 patients
(48.4%) in the placebo group (P<0.001). A serum
potassium level below 3.5 mmol per liter was re-
ported in 100 of 1336 patients (7.5%) in the eplere-
none group and 148 of 1340 patients (11.0%) in
the placebo group (P = 0.002).
Systolic blood pressure decreased during the
study period to a greater degree in the eplere-
none group, with a mean overall reduction of
2.5±17.9 mm Hg, than in the placebo group, with
a reduction of 0.17.2 mm Hg (P = 0.001). There
were no other clinically significant differences
between the two groups with respect to labora-
tory variables, reported adverse events, or adverse
events leading to permanent withdrawal of the
study drug.
Dis c us s ion
We evaluated the effect of adding eplerenone to
recommended treatment for systolic heart failure
in patients with mild symptoms (NYHA function-
al class II symptoms). The rate of the primary
outcome, a composite of death from cardiovas-
cular causes or hospitalization for heart failure,
was 18.3% in the eplerenone group versus 25.9%
in the placebo group. This effect of eplerenone
was consistent across all prespecified subgroups.
With eplerenone, there was also a reduction in
both the rate of death from any cause and the
rate of hospitalization for any reason.
The mechanisms by which mineralocorticoid-
receptor antagonists such as eplerenone provide
cardiovascular protection in patients with heart
failure are not completely understood. Activation
of the mineralocorticoid receptor by both aldo-
sterone and cortisol plays an important role in
the pathophysiology of heart failure,
1,9
and min-
eralocorticoid receptors are overexpressed in the
failing heart.
10,11
Despite therapy with ACE in-
hibitors, ARBs, and beta-blockers, patients with
even mild heart failure may have persistently
elevated plasma aldosterone and cortisol lev-
els.
12-17
Mineralocorticoid receptors are not
blocked by these treatments.
Activation of the mineralocorticoid receptor
has been shown to promote cardiac fibrosis in
experimental models.
18
In patients with heart
failure,
19
as well as in patients after myocardial
infarction, the use of mineralocorticoid-receptor
antagonists decreases extracellular-matrix turn-
over, as assessed by measuring serum levels
of collagen biomarkers.
20,21
Experimental and
clinical studies suggest that mineralocorticoid-
receptor antagonists favorably affect several other
important mechanisms known to have a role in
the progression of heart failure.
1,15,22,23
In our study, as anticipated, there was an in-
creased incidence of hyperkalemia among pa-
tients receiving eplerenone. This finding under-
scores the need to measure serum potassium
levels serially and to adjust the dose of eplere-
none accordingly. We attempted to minimize
the risk of hyperkalemia by excluding patients
with a baseline serum potassium level above
5.0 mmol per liter and a baseline estimated GFR
below 30 ml per minute per 1.73 m
2
.
Figure 2 (facing page). Hazard Ratios for Hospitalization
for Heart Failure or Death from Cardiovascular Causes
(the Primary Outcome) with Eplerenone versus Placebo,
According to Prespecified Subgroups.
The subgroups are based on baseline demographic
and clinical characteristics. The size of the square cor-
responds to the number of patients with an event. Data
are missing for some patients in some subgroups. ACE
denotes angiotensin-converting enzyme, ARB angio-
tensin-receptor blocker, BNP B-type natriuretic peptide,
CRT cardiac-resynchronization therapy, GFR glomeru-
lar filtration rate, ICD implantable cardioverter–defi-
brillator, and LVEF left ventricular ejection fraction.
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
Epler enone in Patients wi th He a rt Failure
n engl j med 364;1 nejm.org january 6, 2011
19
0.50.2 1.0 2.0
Placebo BetterEplerenone Better
Overall
Sex
Female
Male
Age
<65 yr
≥65 yr
Age
<75 yr
≥75 yr
Region
Asia, Middle East, or Africa
Eastern Europe
North or South America
Western Europe or Australia
Systolic blood pressure
Below median
At or above median
Pulse pressure
Below median
At or above median
Heart rate
Below median
At or above median
Estimated GFR
<60 ml/min/1.73 m
2
≥60 ml/min/1.73 m
2
Primary diagnosis
Ischemic heart failure
Nonischemic heart failure
Beta-blocker, ACE inhibitor, and ARB use
at randomization visit
No
Yes
Beta-blocker use at randomization visit
No
Yes
ACE inhibitor or ARB use at randomization visit
No
Yes
LVEF
<30%
≥30%
History of atrial fibrillation
No
Yes
History of diabetes
No
Yes
History of hypertension
No
Yes
Prior CRT or ICD procedure or both
No
Yes
QRS in nonpaced ECG
≤130 msec
>130 msec
Left bundle-branch block present in nonpaced ECG
No
Yes
Enrollment criterion
Hospitalization ≤180 days before screening
Met BNP or pro-BNP criterion
Hazard Ratio (95% CI)No. of PatientsSubgroup
P Value for
Interaction
2737
610
2127
883
1854
2080
657
380
911
346
1100
1352
1384
1272
1464
1340
1383
912
1821
1886
846
2652
85
363
2374
180
2557
1912
819
1891
844
1877
859
917
1819
2264
473
1695
605
1711
622
2282
385
0.36
0.37
1.00
0.46
0.65
0.75
0.79
0.50
0.73
0.50
0.07
0.68
0.89
0.59
0.10
0.69
0.15
0.51
0.45
0.39
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
T h e
n e w e n g l a n d j o u r n a l
o f
m e d i c i n e
n engl j med 364;1 nejm.org january 6, 2011
20
Re f e renc e s
In contrast, the risk of hypokalemia was
significantly reduced among patients receiving
eplerenone. This is important because a serum
potassium level below 4.0 mmol per liter has
been associated with an increased risk of death
from any cause among patients with systolic
heart failure.
22
Our study has some limitations. Our results
may not be applicable to all patients with mild
symptoms, because to be eligible for the study,
patients had to have additional factors known
to increase cardiovascular risk, including an age
over 55 years, in most cases an ejection fraction
of no more than 30%, and a recent hospitaliza-
tion for a cardiovascular reason. Use of an im-
plantable cardioverter–defibrillator was relative-
ly infrequent, but this finding is similar to those
in recent registries and trials.
24,25
The early stop-
ping of the trial may have resulted in overesti-
mation of the magnitude of the treatment ef-
fect,
26
but the results are consistent with those
seen in RALES.
2
In conclusion, our study showed that, as com-
pared with placebo, eplerenone added to recom-
mended therapy for systolic heart failure in pa-
tients with mild symptoms was associated with
a reduction in the rate of death from a cardio-
vascular cause or hospitalization for heart fail-
ure. Similar reductions were seen in rates of
death from any cause, death from cardiovascular
causes, hospitalization for any reason, and hos-
pitalization for heart failure.
Supported by Pfizer.
Dr. Zannad reports receiving fees for serving on the board of
Boston Scientific, consulting fees from Novartis, Takeda, Astra-
Zeneca, Boehringer Ingelheim, GE Healthcare, Relypsa, Servier,
Boston Scientific, Bayer, Johnson & Johnson, and Resmed, and
speaker’s fees from Pfizer and AstraZeneca and that his institu-
tion receives grant support from BG Medicine and Roche Diag-
nostics on his behalf. Dr. McMurray reports receiving grant
support from the Eugene Braunwald Endowment for the Ad-
vancement of Cardiovascular Discovery and Care. Dr. Krum re-
ports receiving travel reimbursements from Pfizer. Mr. Shi and
Dr. Vincent report being employees of Pfizer and receiving stock
options and travel reimbursements from Pfizer. Dr. Pocock re-
ports receiving consulting fees from Servier, Amgen, AstraZen-
eca, and Novartis and that his institution receives grants from
Servier and AstraZeneca on his behalf. Dr. Pitt reports receiving
fees for serving on the board of Novartis, consulting fees from
Takeda, AstraZeneca, Boehringer Ingelheim, GE Healthcare,
Relypsa, BG Medicine, Nile Therapeutics, Merck, Forest Labora-
tories, and Novartis, grant support from Forest Laboratories and
Novartis, and stock options from Relypsa, BG Medicine, Nile
Therapeutics, and Aurasenc and that his institution receives
grant support from Forest Laboratories on his behalf and he and
his institution receive grant support from Bayer. No other poten-
tial conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
This article is dedicated to the memory of Dr. Helmut Drexler,
who was a member of the EMPHASIS-HF Executive Committee.
Table 3. Selected Investigator-Reported Adverse Events and Those Leading to Permanent Withdrawal of the Study Drug,
According to Study Group.*
Event Adverse Event
Adverse Event Leading to Study-Drug
Withdrawal
Eplerenone
(N = 1360)
Placebo
(N = 1369) P Value
Eplerenone
(N = 1360)
Placebo
(N = 1369) P Value
no. of patients (%) no. of patients (%)
All events 979 (72.0) 1007 (73.6) 0.37 188 (13.8) 222 (16.2) 0.09
Hyperkalemia 109 (8.0) 50 (3.7) <0.001 15 (1.1) 12 (0.9) 0.57
Hypokalemia 16 (1.2) 30 (2.2) 0.05 0 3 (0.2) 0.25
Renal failure 38 (2.8) 41 (3.0) 0.82 4 (0.3) 6 (0.4) 0.75
Hypotension 46 (3.4) 37 (2.7) 0.32 0 3 (0.2) 0.25
Gynecomastia or other breast
disorders
10 (0.7) 14 (1.0) 0.54 2 (0.1) 2 (0.1) 1.00
* Patients who had received at least one dose of the study drug were included in the safety analysis. P values were calcu-
lated on the basis of the number of patients.
1. Funder JW. Reconsidering the roles of
the mineralocorticoid receptor. Hyper-
tension 2009;53:286-90.
2. Pitt B, Zannad F, Remme WJ, et al.
The effect of spironolactone on morbidity
and mortality in patients with severe heart
failure. N Engl J Med 1999;341:709-17.
3. Pitt B, Remme W, Zannad F, et al.
Eplerenone, a selective aldosterone blocker,
in patients with left ventricular dysfunc-
tion after myocardial infarction. N Engl J
Med 2003;348:1309-21. [Erratum, N Engl
J Med 2003;348:2271.]
4. Dickstein K, Cohen-Solal A, Filippa-
tos G, et al. ESC guidelines for the diag-
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
Epler enone in Patients wi th He a rt Failure
n engl j med 364;1 nejm.org january 6, 2011
21
nosis and treatment of acute and chronic
heart failure 2008: the Task Force for the
diagnosis and treatment of acute and
chronic heart failure 2008 of the Europe-
an Society of Cardiology: developed in col-
laboration with the Heart Failure Associa-
tion of the ESC (HFA) and endorsed by the
European Society of Intensive Care Medi-
cine (ESICM). Eur J Heart Fail 2008;10:933-
89. [Errata, Eur J Heart Fail 2009;11:110,
2010;12:416.]
5. Hunt SA, Abraham WT, Chin MH, et
al. 2009 Focused update incorporated
into the ACC/AHA 2005 guidelines for the
diagnosis and management of heart fail-
ure in adults: a report of the American
College of Cardiology Foundation/Ameri-
can Heart Association Task Force on Prac-
tice Guidelines developed in collabora-
tion with the International Society for
Heart and Lung Transplantation. J Am
Coll Cardiol 2009;53(15):e1-e90. [Erra-
tum, J Am Coll Cardiol 2009;54:2464.]
6. Zannad F, McMurray JJ, Drexler H, et
al. Rationale and design of the Eplerenone
in Mild Patients Hospitalization And Sur-
vIval Study in Heart Failure (EMPHASIS-
HF). Eur J Heart Fail 2010;12:617-22.
7. McMurray JJ, Ostergren J, Swedberg
K, et al. Effects of candesartan in patients
with chronic heart failure and reduced
left-ventricular systolic function taking an-
giotensin-converting-enzyme inhibitors:
the CHARM-Added trial. Lancet 2003;362:
767-71.
8. Altman DG, Andersen PK. Calculat-
ing the number needed to treat for trials
where the outcome is time to an event.
BMJ 1999;319:1492-5.
9. Rocha R, Rudolph AE, Frierdich GE,
et al. Aldosterone induces a vascular in-
flammatory phenotype in the rat heart.
Am J Physiol Heart Circ Physiol 2002;
283:H1802-H1810.
10. Silvestre JS, Heymes C, Oubénaïssa A,
et al. Activation of cardiac aldosterone
production in rat myocardial infarction:
effect of angiotensin II receptor blockade
and role in cardiac fibrosis. Circulation
1999;99:2694-701.
11. Delcayre C, Swynghedauw B. Molecu-
lar mechanisms of myocardial remodel-
ing: the role of aldosterone. J Mol Cell
Cardiol 2002;34:1577-84.
12. Struthers AD. The clinical implica-
tions of aldosterone escape in congestive
heart failure. Eur J Heart Fail 2004;6:539-
45.
13. Fung JW, Yu CM, Yip G, et al. Effect of
beta blockade (carvedilol or metoprolol)
on activation of the renin-angiotensin-
aldosterone system and natriuretic pep-
tides in chronic heart failure. Am J Car-
diol 2003;92:406-10.
14. McKelvie RS, Yusuf S, Pericak D, et al.
Comparison of candesartan, enalapril, and
their combination in congestive heart fail-
ure: Randomized Evaluation of Strategies
for Left Ventricular Dysfunction (RESOLVD)
pilot study. Circulation 1999;100:1056-64.
15. Boccanelli A, Mureddu GF, Cacciatore
G, et al. Anti-remodelling effect of canre-
none in patients with mild chronic heart
failure (AREA IN-CHF study): final re-
sults. Eur J Heart Fail 2009;11:68-76.
16. Cohn JN, Anand IS, Latini R, Masson
S, Chiang YT, Glazer R. Sustained reduc-
tion of aldosterone in response to the an-
giotensin receptor blocker valsartan in
patients with chronic heart failure: re-
sults from the Valsartan Heart Failure
Trial. Circulation 2003;108:1306-9.
17. Fullerton MJ, Funder JW. Aldosterone
and cardiac fibrosis: in vitro studies. Car-
diovasc Res 1994;28:1863-7.
18. Weber KT. Aldosterone and spirono-
lactone in heart failure. N Engl J Med
1999;341:753-5.
19. Zannad F, Alla F, Dousset B, Perez A,
Pitt B. Limitation of excessive extracellu-
lar matrix turnover may contribute to sur-
vival benefit of spironolactone therapy in
patients with congestive heart failure: in-
sights from the Randomized Aldactone
Evaluation Study (RALES). Circulation
2000;102:2700-6.
20. Hayashi M, Tsutamoto T, Wada A, et al.
Immediate administration of mineralo-
corticoid receptor antagonist spironolac-
tone prevents post-infarct left ventricular
remodeling associated with suppression
of a marker of myocardial collagen syn-
thesis in patients with first anterior acute
myocardial infarction. Circulation 2003;
107:2559-65.
21. Iraqi W, Rossignol P, Angioi M, et al.
Extracellular cardiac matrix biomarkers
in patients with acute myocardial infarc-
tion complicated by left ventricular dys-
function and heart failure: insights from
the Eplerenone Post-Acute Myocardial In-
farction Heart Failure Efficacy and Sur-
vival Study (EPHESUS) study. Circulation
2009;119:2471-9.
22. Ahmed A, Zannad F, Love TE, et al.
A propensity-matched study of the asso-
ciation of low serum potassium levels and
mortality in chronic heart failure. Eur
Heart J 2007;28:1334-43.
23. Tsutamoto T, Wada A, Maeda K, et al.
Effect of spironolactone on plasma brain
natriuretic peptide and left ventricular re-
modeling in patients with congestive heart
failure. J Am Coll Cardiol 2001;37:1228-
33.
24. van Veldhuisen DJ, Maass AH, Priori
SG, et al. Implementation of device thera-
py (cardiac resynchronization therapy and
implantable cardioverter defibrillator) for
patients with heart failure in Europe:
changes from 2004 to 2008. Eur J Heart
Fail 2009;11:1143-51.
25. Swedberg K, Komajda M, Böhm M, et
al. Ivabradine and outcomes in chronic
heart failure (SHIFT): a randomised place-
bo-controlled study. Lancet 2010;376:875-
85.
26. Pocock SJ. When (not) to stop a clini-
cal trial for benefit. JAMA 2005;294:2228-
30.
Copyright © 2010 Massachusetts Medical Society.
The New England Journal of Medicine
Downloaded from nejm.org by OMAR DARWISH on February 11, 2011. For personal use only. No other uses without permission.
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
    • "After the pioneer studies by Pitt et al. [5][6][7], aldosterone antagonists started to be evaluated in different cardiac aggression models, which showed that they prevent or attenuate left ventricular (LV) structural, functional, and molecular changes [8][9][10][11] . In clinical settings, aldosterone blockers reduced mortality and hospitalizations in patients with systolic heart failure of any cause [5,7], and in patients with systolic dysfunction after myocardial infarction [6]. Therefore, aldosterone blockade is now recommended for symptomatic systolic heart failure patients [12]. "
    [Show abstract] [Hide abstract] ABSTRACT: Methods: Three days after inducing AS, weaning rats were randomized to receive spironolactone (AS-SPR, 20mg/kg/day) or no drug (AS) for 18weeks, and compared with sham-operated rats. Myocardial function was studied in isolated left ventricular (LV) papillary muscles. Statistical analyses: ANOVA or Kruskal-Wallis tests. Results: Echocardiogram showed that LV diastolic (Sham 8.73±0.57; AS 8.30±1.10; AS-SPR 9.19±1.15mm) and systolic (Sham 4.57±0.67; AS 3.61±1.49; AS-SPR 4.62±1.48mm) diameters, left atrial diameter (Sham 5.80±0.44; AS 7.15±1.22; AS-SPR 8.02±1.17mm), and LV mass were higher in AS-SPR than AS. Posterior wall shortening velocity (Sham 38.5±3.8; AS 35.6±5.6; AS-SPR 31.1±3.8mm/s) was lower in AS-SPR than Sham and AS; E/A ratio was higher in AS-SPR than Sham. Developed tension was lower in AS and AS-SPR than Sham. Time to peak tension was higher in AS-SPR than Sham and AS after post-rest contraction. Right ventricle weight was higher in AS-SPR than AS, suggesting more severe heart failure in AS-SPR than AS. Interstitial collagen fractional area and myocardial hydroxyproline concentration were higher in AS than Sham. Metalloproteinase-2 and -9 activity, evaluated by zymography, did not differ between groups. Conclusion: Early spironolactone administration causes further hypertrophy in cardiac chambers, and left ventricular dilation and dysfunction in rats with AS-induced chronic pressure overload.
    Full-text · Article · Aug 2016
    • "Our experience of designing and running the study raises important points for the choice of endpoints in future device studies with populations not already indicated for devices. Today, the commonly used endpoint for HF trials is the combination of HF hospitalization and mortality [20] or the combination of HF hospitalization and CV mor- tality [32] . In a population with decreasing event rates due to improvements in HF and other cardiovascular medication and invasive treatments it may prove extremely hard to calculate an accurate event rate in a long term RCT study. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: The benefits of CRT for symptomatic heart failure (HF) patients with a wide QRS and reduced left ventricular ejection fraction (LVEF ≤35%), are well established .Post-hoc subgroup analyses suggest that CRT benefit may extend to patients with LVEF >35%. Methods: The MIRACLE EF was a prospective, randomized, controlled, double-blinded study to evaluate CRT-P in NYHA II-III HF patients with LBBB and with LVEF of 36%-50% and no previous pacing or ICD. The primary endpoint was a composite of time to first HF event or death. All patients were implanted with a CRT-P and randomized 2:1 to CRT-P ON or CRT-P OFF groups. The minimum follow up time was 24months. Results: The MIRACLE EF study was stopped for enrollment futility after 13months and enrolling only 44 patients. The main difficulties in recruiting patients were lack of eligible patients, previous ICD implants, and the reluctance of institutions, patients or physicians to enroll in the study which included a potential 5year CRT OFF period. Conclusion: Despite a careful design, identification and randomization of eligible patients were challenging and a trial to assess morbidity and mortality trial was not feasible. The MIRACLE EF experience illustrates the difficulties of designing a scientifically robust but feasible study to assess potential new indications for implantable devices. Smaller randomized studies with surrogate endpoints may therefore be more reasonable, although the potential impact of such studies on clinical practice, guidelines, and reimbursement remain to be determined.
    Full-text · Article · Sep 2015
    • "Clinical trials conducted by the Randomized Aldactone Evaluation Study (5) and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (6) have demonstrated that the receptor antagonists of aldosterone may significantly reduce cardiovascular-associated mortality in patients with severe heart failure. Recent studies have also shown that the receptor antagonists of mineralocorticoids may improve the survival of patients with systolic heart failure or mild to severe symptoms of heart failure (7–9). Clinical data have indicated that angiotensin-converting enzyme inhibitors are an effective therapeutic strategy for the treatment of heart failure to inhibit aldosterone and improve cardiac remodeling. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of the present study was to investigate the effects of spironolactone and losartan on the early healing stage of acute myocardial infarction (AMI) in rats. An AMI rat model was established and the rats were randomly divided into four groups: AMI (n=12), AMI + spironolactone (AMI + S; n=12), AMI + losartan (AMI + L; n=12) and AMI + spironolactone combined with losartan (AMI + S + L; n=12). Sham-operated rats served as a control group (n=12). The expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in the non-infarcted myocardium surrounding the AMI area were determined using immunohistochemistry. In addition, the capillary density in the non-infarcted myocardium surrounding the AMI area was detected. The capillary densities around the infarcted area in the AMI and treatment groups at day 7 and 14 following AMI surgery were significantly higher compared with the sham-operated rats. Compared with the AMI group, the capillary densities around the infarcted area and the ratio of MMPs/TIMP-1 were increased in the treatment groups following AMI surgery; however, the increased ratio of MMPs/TIMP-1 was reduced at day 14 following AMI surgery. Therefore, these results indicated that spironolactone and losartan may promote the formation of collateral circulation in the non-infarcted tissue surrounding the infarcted area by regulating the production of MMPs.
    Full-text · Article · Sep 2014
Show more

Supplementary resources