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Early Aldosterone Blockade in Acute Myocardial Infarction
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 67, NO. 16, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.02.033
Early Aldosterone Blockade in Acute Myocardial Infarction The ALBATROSS Randomized Clinical Trial Farzin Beygui, MD, PHD,a Guillaume Cayla, MD, PHD,b Vincent Roule, MD,a François Roubille, MD, PHD,c Nicolas Delarche, MD,d Johanne Silvain, MD, PHD,e Eric Van Belle, MD, PHD,f Loic Belle, MD,g Michel Galinier, MD,h Pascal Motreff, MD, PHD,i Luc Cornillet, MD, PHD,b Jean-Philippe Collet, MD, PHD,e Alain Furber, MD, PHD,j Patrick Goldstein, MD,k Patrick Ecollan, MD,l Damien Legallois, MD,a Alain Lebon, MD,a Hélène Rousseau, MSC,m Jacques Machecourt, MD,n Faiez Zannad, MD, PHD,o Eric Vicaut, MD, PHD,m Gilles Montalescot, MD, PHD,e on behalf of the ALBATROSS Investigators
ABSTRACT BACKGROUND Mineralocorticoid receptor antagonists (MRA) improve outcome in the setting of post–myocardial infarction (MI) heart failure (HF). OBJECTIVES The study sought to assess the benefit of an early MRA regimen in acute MI irrespective of the presence of HF or left ventricular (LV) dysfunction. METHODS We randomized 1,603 patients to receive an MRA regimen with a single intravenous bolus of potassium canrenoate (200 mg) followed by oral spironolactone (25 mg once daily) for 6 months in addition to standard therapy or standard therapy alone. The primary outcome of the study was the composite of death, resuscitated cardiac arrest, significant ventricular arrhythmia, indication for implantable defibrillator, or new or worsening HF at 6-month follow-up. Key secondary/safety outcomes included death and other individual components of the primary outcome and rates of hyperkalemia at 6 months. RESULTS The primary outcome occurred in 95 (11.8%) and 98 (12.2%) patients in the treatment and control groups, respectively (hazard ratio [HR]: 0.97; 95% confidence interval [CI]: 0.73 to 1.28). Death occurred in 11 (1.4%) and 17 (2.1%) patients in the treatment and control groups, respectively (HR: 0.65; 95% CI: 0.30 to 1.38). In a non–pre-specified exploratory analysis, the odds of death were reduced in the treatment group (3 [0.5%] vs. 15 [2.4%]; HR: 0.20; 95% CI: 0.06 to 0.70) in the subgroup of ST-segment elevation MI (n ¼ 1,229), but not in non–ST-segment elevation MI (p for interaction ¼ 0.01). Hyperkalemia >5.5 mmol/l–1 occurred in 3% and 0.2% of patients in the treatment and standard therapy groups, respectively (p < 0.0001). CONCLUSIONS The study failed to show the benefit of early MRA use in addition to standard therapy in patients admitted for MI. (Aldosterone Lethal effects Blockade in Acute myocardial infarction Treated with or without Reperfusion to improve Outcome and Survival at Six months follow-up; NCT01059136). (J Am Coll Cardiol 2016;67:1917–27) © 2016 by the American College of Cardiology Foundation.
From the aACTION Study Group, Service de Cardiologie, Centre Hospitalier Universitaire de Caen, Caen, France; bACTION Study Group, Service de Cardiologie, Centre Hospitalier Universitaire de Nimes, Nîmes, France; cService de Cardiologie, Centre HospiListen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
talier Universitaire de Montpellier, Montpellier, France; dService de Cardiologie, Centre Hospitalier de Pau, Pau, France; eACTION _ Study Group, Institut de Cardiologie (AP-HP), Centre Hospitalier Universitaire Pitié-Salpêtriere, Paris, France; fService de Cardiologie, Centre Hospitalier Universitaire de Lille, Lille, France; gService de Cardiologie, Centre Hospitalier d’Annecy, Annecy, France; hService de Cardiologie, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; iService de Cardiologie, Centre Hospitalier Universitaire de Clermont Ferrand, Clermont Ferrand, France; jService de Cardiologie, Centre Hospitalier Universitaire d’Angers, Angers, France; kService d’Accueil des Urgences et SAMU, Centre Hospitalier Universitaire de Lille, Lille, France; l
ACTION Study Group, SAMU, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France;
m
ACTION Study Group, Unite de
Recherche Clinique, Hôpital Lariboisière, Paris, France; nService de Cardiologie, Centre Hospitalier Universitaire de Grenoble, Grenoble, France; and oINSERM, CIC 1433 et Pôle de Cardiologie, Centre Hospitalier Universitaire de Nancy, Nancy, France. The trial was led by members of the nonprofit academic research organization ACTION, based at Pitié-Salpêtrière Hospital, Paris,
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JACC VOL. 67, NO. 16, 2016 APRIL 26, 2016:1917–27
Aldosterone Blockade in Myocardial Infarction
T
ABBREVIATIONS AND ACRONYMS CI = confidence interval HF = heart failure HR = hazard ratio
he mineralocorticoid receptor an-
MI in the prevention of LV remodeling (11,12) and life-
tagonists (MRA) spironolactone and
threatening arrhythmia (13,14).
eplerenone reduce mortality in the
Whether MRA use could improve clinical outcomes
setting of heart failure (HF) with reduced
of acute MI independent of the type of MI, reperfu-
ejection fraction (1,2). Eplerenone initiated
sion strategy, or the presence of LV dysfunction or HF
3 to 14 days after ST-segment elevation
is unknown.
IV = intravenous
myocardial infarction (STEMI) or non–ST-
MI = myocardial infarction
segment
infarction
Lethal effects Blocked in Acute MI Treated with or
elevation
myocardial
The objective of the ALBATROSS (Aldosterone
MRA = mineralocorticoid
(NSTEMI) complicated by left ventricular
without Reperfusion to improve Outcome and Sur-
receptor antagonists
(LV) dysfunction and HF is also associated
vival at Six months follow-up) trial was to investigate
NSTEMI = non–ST-segment
with a reduction of mortality (3). However,
the clinical effects of a rapid and prolonged MRA
there
regimen initiated early after the onset of any type
elevation myocardial infarction
STEMI = ST-segment elevation
is
limited
clinical
evidence
with
MRAs in myocardial infarctions (MI) inde-
myocardial infarction
of MI.
pendent of HF. The REMINDER (DoubleBlind,
Randomized,
Placebo-Controlled
Trial
METHODS
Evaluating The Safety And Efficacy Of Early Treatment With Eplerenone In Patients With Acute
STUDY DESIGN AND POPULATION. ALBATROSS is a
Myocardial Infarction) trial (4) showed that eplere-
multicenter, nationwide, randomized, open-labeled,
none used within the first 24 h of STEMI was safe
blinded endpoint, clinical trial. The study was
and effective on a composite outcome mainly driven
designed to assess the superiority of an MRA regimen
by the biological outcome of a lower plasma level of
initiated early after presentation for STEMI or
B-type natriuretic peptide.
high-risk NSTEMI plus standard therapy versus
SEE PAGE 1928
standard therapy alone (15). Patients were randomized as early as possible, including by pre-hospital
High aldosterone plasma levels early after STEMI
medical teams (ambulance) when possible, to allow
or NSTEMI are associated with mortality, sudden
rapid administration of the treatment. The coordi-
cardiac death, and HF (5–8). Experimental studies
nating center was the ACTION (Allies in Cardiovas-
have shown that early MRA administration after
cular Trials, Initiatives, and Organized Networks)
myocardial infarction (MI) could improve myocardial
Study Group at Pitié-Salpêtrière hospital. The study
healing (9) as well as both electrical and structural
design and protocol have been published previously
remodeling (10). Small-sized studies have also re-
(16). The hypotheses used for the study’s sample size
ported benefits of MRA therapy initiated early after
calculation are reported in the Online Appendix.
France (www.action-coeur.org). The study was sponsored by the Assistance Publique-Hôpitaux de Paris (AP-HP) and exclusively funded by public grants from the French Ministry of Health and the Foundation of the Institute of Cardiometabolism And Nutrition (ICAN). The funding organizations had no involvement in the design or conduct of the study, site selection, data collection, analysis of the results, or writing of the manuscript. Dr. Beygui has received research or educational grants to the institution from AstraZeneca, Bayer, Eli Lilly, Fédération Française de Cardiologie, Medtronic, Terumo, Biosensor, Pfizer, Sanofi, and Thermofischer; and consulting or lecture fees from AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, and Pfizer. Dr. Cayla has received lecture fees from AstraZeneca, Biotronik, Daiichi-Sankyo, Bayer, BMS, Eli Lilly, Novartis, Medtronic, MSD, Pfizer, and Sanofi. Dr. Silvain has received research grants to the institution from AstraZeneca, Brahms, Daiichi-Sankyo, Eli Lilly, Institute of Cardiometabolism (ICAN), INSERM, Fédération Française de Cardiologie, Fondation de France, Société Française de Cardiologie, and Sanofi; consulting fees from Actelion, AstraZeneca, Daiichi-Sankyo, Eli Lilly, and Sanofi; lecture fees from Algorythm, AstraZeneca, and Bristol-Myers Squibb; and travel fees from AstraZeneca, B. Braun, Bristol-Myers Squibb, and Pfizer. Dr. Collet has received research grant support, consulting fees, and speakers fees from AstraZeneca. Dr. Goldstein has received speakers fees and served on the Speakers Bureau for AstraZeneca, Boehringer Ingelheim, BMS Pfizer, and Bayer. Dr. Vicaut has received consulting fees from Pfizer, Novartis, BMS, Abbott Vascular, and Sorin; and his institution has received grant support from Eli Lilly. Dr. Montalescot has received research or educational grants to the institution from ADIR, Amgen, AstraZeneca, Bayer, Berlin Chimie AG, Boehringer Ingelheim, Bristol-Myers Squibb, Celladon, Daiichi-Sankyo, Eli Lilly, Fédération Française de Cardiologie, Gilead, ICAN, Janssen, Medtronic, MSD, Pfizer, Sanofi, and The Medicines Company; and consulting or lecture fees from Amgen, AstraZeneca, Bayer, Berlin Chimie AG, Boehringer Ingelheim, Bristol-Myers Squibb, Beth Israel Deaconess Medical, Brigham Women’s Hospital, Cardiovascular Research Foundation, CME Resources, Daiichi-Sankyo, Eli Lilly, Europa, Elsevier, Fondazione Anna Maria Sechi per il Cuore, Lead-Up, Menarini, MSD, Pfizer, Sanofi, The Medicines Company, TIMI Study Group, and WebMD. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received October 20, 2015; revised manuscript received February 12, 2016, accepted February 15, 2016.
Beygui et al.
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Aldosterone Blockade in Myocardial Infarction
The study was undertaken according to the Declaration of Helsinki and approved by the French
were to be treated by the most adapted therapy based on international guidelines.
National Institutional Ethical Review Board. Written
Patients assigned to the MRA regimen received a
informed consent was obtained from all patients
200 mg intravenous (IV) bolus of potassium canre-
before randomization.
noate as soon as possible. A first 25 mg oral dose of
To be eligible, patients had to have an ischemic
spironolactone was administered 12 to 24 h after the
symptom within 72 h before randomization and at least
IV injection, after control of plasma concentrations of
1 of the following indicators of MI: ST-segment eleva-
potassium and creatinine. The oral dose was not
tion in at least 2 contiguous leads; new or undated left
given if the first blood sample revealed a potassium
bundle branch block; Q waves in at least 2 contiguous
level >5.5 mmol/l–1 or a creatinine level >220 mmol/l –1 .
leads (not known to be old); troponin levels $3 times
Such
the upper limit of normal; and Thrombolysis In
intention-to-treat analysis.
Myocardial Infarction score $3 in the case of NSTEMI.
patients
Patients
were
were
nevertheless
followed
for
6
kept
in
months
the after
Key exclusion criteria included known hyperkalemia,
randomization and visits after hospital discharge
renal insufficiency, severe liver dysfunction, and car-
included measurements of LV ejection fraction. Spi-
diac arrest prior to randomization.
ronolactone was suspended during follow-up if
Eligible subjects were randomized in a 1:1 ratio to
plasma potassium concentrations were >5.5 mmol/l–1
receive either the MRA regimen added to standard
and/or plasma creatinine levels were >220 m mol/l–1
therapy or standard therapy alone. Randomization
on any blood sample whether protocol-specified
was
or
conducted
via
a
central
interactive
voice
not.
The
treatment
was
reintroduced
after
randomization system with stratification by center
normalization of potassium and creatinine levels if
using random sequences of block sizes. All subjects
the cause was considered reversible. The study
F I G U R E 1 Patient Enrollment and Follow-Up Flow Chart
1622 Patients enrolled
1616 Patients randomized
1 Patient was randomized twice
1615 patients were correctly randomized
15 patients were excluded : - 12 patients withdrew or had invalid consent 1603 included in the “intention-to-treat” analysis
801 were analyzed in the “standard treatment” arm
802 were analyzed in the “MRA regimen” arm
Patients were randomized to mineralocorticoid receptor antagonist (MRA) therapy or standard care.
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Beygui et al.
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Aldosterone Blockade in Myocardial Infarction
treatment was permanently discontinued if hyper-
(17) for implantable defibrillator, or new or worsening
kalemia >5.5 mmol/l –1 recurred after reintroduction
HF during 6-month follow-up.
of spironolactone, if any plasma potassium level was
Key secondary efficacy outcomes included each
>6 mmol/l–1 , or in case of clinical intolerance.
individual component of the primary outcome; the
STUDY OUTCOMES. The primary outcome was the
composite of death or resuscitated cardiac arrest; the
composite of death, resuscitated cardiac arrest, sig-
composite of death or new or worsening HF; death of
nificant ventricular arrhythmia, class IA indication
cardiovascular origin; recurrent MI; and urgent or unplanned revascularization, all at 6 months. Premature discontinuation of study treatment, acute renal failure, and hyperkalemia were closely
T A B L E 1 Patient Characteristics and Management
monitored. All outcomes were adjudicated in a Standard Treatment (n ¼ 801)
Age, yrs
58 (50.0–67.0)
Female
143 (17.9)
Body mass index, kg/m2
26.4 (24.0–29.7)
MRA Regimen (n ¼ 802)
58 (50.0–67.0)
blinded manner by an independent adjudication committee.
129 (16.1)
STATISTICAL ANALYSIS. We hypothesized that the
26.1 (23.8–28.9)
6-month rate of the primary endpoint would be 20%
Risk factors and medical history
in the standard therapy alone arm. With a sample size
Current smoking
414 (51.7)
377 (47.0)
Hypertension
352 (43.9)
335 (41.8)
Diabetes
126 (15.7)
128 (16.0)
Dyslipidemia
368 (45.9)
375 (46.8)
constant hazard ratio (HR) of 0.71 associated with the
of 793 per arm (for a total of approximately 1,600 subjects), a total event rate of 269 and an estimated
73 (9.1)
65 (8.1)
MRA regimen, using a bilateral equality of survival
Prior heart failure
5 (0.6)
9 (1.1)
log-rank test, the study would achieve an 80% power
Prior CABG
11 (1.4)
13 (1.6)
to detect a difference between a 0.853 proportion in
Prior PCI
86 (10.7)
74 (9.2)
1 group and a 0.800 proportion in the other group at
Prior stroke
18 (2.2)
24 (3.0)
Prior cancer
41 (5.1)
32 (4.0)
6 months with a p value of 0.049.
Prior MI
Presentation* STEMI
617 (77.0)
612 (76.3)
NSTEMI
183 (22.8)
186 (23.2)
The main efficacy analysis was based on all events that occurred in the intention-to-treat population defined as all randomized patients who signed an informed consent form. In case of consent with-
Killip class* I
732 (91.4)
750 (93.5)
II
52 (6.5)
39 (4.9)
III
6 (0.7)
9 (1.1)
IV
7 (0.9)
3 (0.4)
>I
65 (8.1)
Creatinine clearance, ml/min–1*
101.35 (77.26–121.14) –1
Potassium at admission, mmol/l Admission GRACE score
4.0 (3.7–4.3) 132 31
51 (6.4) 95.96 (75.39–119.66)
drawal, only data collected before withdrawal were used. The primary analysis based on all events corresponding to the primary outcome was carried out using a Kaplan-Meier survival analysis with a log-
4.0 (3.7–4.3)
rank test. All patients were censored at the time of
133 29
the last observation. A Cox survival model was used for the calculation of the HR presented with its
In-hospital medication Aspirin
796 (99.4)
797 (99.4)
2-sided 95% confidence interval (CI) for the primary
P2Y12 antagonist
796 (99.4)
797 (99.4)
endpoint and for the analysis of all secondary out-
Beta-blocker
744 (92.9)
750 (93.5)
comes at 6 months. Variables assessed at specific time
Statin
779 (97.3)
769 (95.9)
ACE inhibitor/ARB
718 (89.6)
702 (87.5)
72 (11.7)
64 (10.5)
270 (43.8)
268 (43.8)
Coronary angiography
792 (98.9)
793 (98.9)
compared between groups using chi-square or Fisher
PCI
727 (90.8)
720 (89.8)
exact tests where appropriate. Consistency of the
Primary PCI†
501 (81.2)
502 (82.0)
treatment effect was analyzed among 16 patient
23 (2.9)
26 (3.2)
50 (45–60)
50 (45–60)
Fibrinolysis† Glycoprotein IIb/IIIa inhibitor†
Left ventricular ejection fraction, %*
model with calculation of odds ratios and their 2-sided 95% CI. Safety analyses were performed on the per-protocol set. Rates of adverse events were
Interventional or surgical procedures
CABG
points were analyzed using a logistic regression
Values are median (interquartile range), n (%), or mean SD. *The information on the type of myocardial infarction and Killip class was missing in 5 patients. †In patients with STEMI in the standard therapy (n ¼ 617) and MRA regimen (n ¼ 612) groups. ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; CABG ¼ coronary artery bypass graft surgery; GRACE ¼ Global Registry of Acute Coronary Events; MI ¼ myocardial infarction; MRA ¼ mineralocorticoid receptor antagonist; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction.
subgroups. All tests had a 2-sided significance level of 5% and were performed using SAS software, version 9.3 (SAS Institute, Cary, North Carolina).
RESULTS Between February 2010 and January 2014, a total of 1,622 patients consented and were randomly assigned
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JACC VOL. 67, NO. 16, 2016 APRIL 26, 2016:1917–27
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Aldosterone Blockade in Myocardial Infarction
F I G U R E 2 Primary Outcome
1.0 Hazard ratio, 0.97 (95% CI 0.73-1.28) p = 0. 81
Primary End Point
0.8
0.20
0.15
0.6 0.10
0.4 0.05
0.2
0.00 0
50
100
150
200
Standard Therapy MRA regimen
0.0 0
50
100
150
200
Days Since Randomization
N at risk Standard Therapy 801
687
669
645
273
MRA Regimen
705
683
660
183
802
Per the Kaplan-Meier estimate, there was no difference between the arms in terms of the primary outcome, which was a composite of death, resuscitated cardiac arrest, significant ventricular arrhythmia, indication for implantable defibrillator, or new or worsening heart failure. CI ¼ confidence interval; MRA ¼ mineralocorticoid receptor antagonist.
to the MRA regimen plus standard therapy (n ¼ 802)
The results were consistent among all pre-specified
or standard therapy alone (n ¼ 801) (Figure 1). The
subgroups with respect to the primary outcome
groups were well balanced with respect to baseline
(Figure 4). The primary outcome was numerically
characteristics and treatment strategies (Table 1). The
lower with MRA therapy in the STEMI group (p for
standard of care included an invasive strategy with
interaction ¼ 0.08). Considering mortality, a signifi-
coronary angiography performed in 1,582 (98.7%) and
cant interaction (p ¼ 0.01) was found between the
percutaneous coronary intervention in 1,447 (90.3%)
treatment effect and type of MI (STEMI vs. NSTEMI)
of the patients. Three-quarters of the study population (n ¼ 1,229) presented with ongoing STEMI, of whom 1,003 (81.6%) underwent primary percuta-
T A B L E 2 Primary and Key Secondary Outcomes at 6-Month Follow-Up
Standard Therapy MRA Regimen (n ¼ 801) (n ¼ 802)
neous coronary intervention whereas 136 (11.1%) received fibrinolysis. HF at presentation was present in 116 (7.2%) patients. A total of 59 (3.7%) patients in
Primary composite outcome
the standard therapy alone group received an MRA
Components of primary outcome
(eplerenone in all) during follow-up based on physi-
Death
cian decision.
Resuscitated cardiac arrest
After a median follow-up of 188 days (interquartile range: 179 to 210 days), the primary outcome
Significant ventricular arrhythmia Indication for implantable defibrillator
p Value
0.81
95 (11.8)
17 (2.1)
11 (1.4)
0.65 (0.30–1.38)
0.26
2 (0.2)
0.66 (0.11–3.92)
0.64
3 (0.4) 48 (6)
45 (5.6)
0.94 (0.62–1.40)
0.75
6 (0.7)
5 (0.6)
0.82 (0.25–2.67)
0.74 0.85
45 (5.6)
47 (5.9)
1.04 (0.69–1.57)
Death or resuscitated cardiac arrest
19 (2.4)
13 (1.6)
0.68 (0.34–1.38)
0.28
(12.2%) patients in the MRA and standard therapy
Death or new or worsening HF
53 (6.6)
54 (6.7)
1.02 (0.70–1.49)
0.93
groups, respectively (HR: 0.97; 95% CI: 0.73 to 1.28).
Death of cardiovascular origin
14 (1.7)
9 (1.1)
0.64 (0.28–1.49)
0.30
Death from any cause (Figure 3A), as well as all other
Recurrent MI
8 (1)
5 (0.6)
0.62 (0.20–1.88)
0.39
components of the primary outcome (Table 2), did
Urgent or unplanned revascularization
1.10 (0.57–2.12)
0.77
(Figure 2, Table 2) occurred in 95 (11.8%) and 98
not differ between the 2 groups. All secondary outcomes occurred with comparable rates in the 2 groups (Table 2).
New or worsening HF
HR (95% CI)
0.97 (0.73–1.28)
98 (12.2)
17 (2.1)
19 (2.4)
Values are n (%). CI ¼ confidence interval; HF ¼ heart failure; HR ¼ hazard ratio; other abbreviations as in Table 1.
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Aldosterone Blockade in Myocardial Infarction
F I G U R E 3 Kaplan-Meier Estimates of Death
A
1.0 Hazard ratio, 0.65 (95% CI 0.30-1.38) p = 0. 26 0.8
0.05
Death
0.04
0.6 0.03
Standard Therapy
0.4
0.02
0.01
MRA regimen
0.2
0.00
0
50
100
150
200
0.0 0
50
100
150
200
Days Since Randomization
N at risks Standard Therapy 801
760
746
719
311
MRA Regimen
776
763
741
211
B
802
1.0 Hazard ratio, 0.20 (95% CI 0.06-0.69) p = 0. 0044 0.8
0.05
0.04
Death
1922
0.6
0.03
Standard Therapy 0.02
0.4 0.01
0.2
MRA regimen
0.00
0
50
100
150
200
0.0 0
50
100
150
200
Days Since Randomization N at risks Standard Therapy 617
587
579
556
236
MRA Regimen
595
587
571
162
612
Overall, there was no difference in death from any cause among all patients (A), but the MRA regimen significantly reduced mortality odds in patients with ST-segment elevation myocardial infarction (B). Abbreviations as in Figure 2.
(Figure 5). Compared to standard therapy alone, MRA
and the causes of death are reported in Table 3 and
use reduced the odds of death (3 [0.5%] vs. 15 [2.4%];
Online Table 1, respectively.
HR: 0.20; 95% CI: 0.06 to 0.70; p ¼ 0.0044) in the
There was a trend (HR: 1.37; 95% CI: 0.97 to 1.95;
STEMI subgroup (n ¼ 1,229), but not in the NSTEMI
p ¼ 0.075) towards higher rates of protocol-defined
subgroup (Figure 3B). The rates of the components of
acute
the primary endpoint in STEMI and NSTEMI groups
regimen. Hyperkalemia >5.5 mmol/l–1 occurred in 3%
renal
failure
associated
with
the
MRA
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Aldosterone Blockade in Myocardial Infarction
F I G U R E 4 Subgroup Analyses: Primary Outcome
Subgroups
Hazard ratio [95% confidence interval]
Primary Outcome
All patients Age >= 65 Age < 65 Women Men STEMI NSTEMI PCI No PCI ACE or ARB before randomization Neither ACE nor ARB before randomization ACE or ARB after randomization Neither ACE nor ARB after randomization BB after randomization No BB after randomization ACE/ARB and BB after randomization no ACE/ARB or no BB or neither after randomization Killip Class >= 2 Killip Class = 1 Pulsed blood pressure < 45mm Hg Pulsed blood pressure >= 45mm Hg Left ventricular ejection fraction < 40% Left ventricular ejection fraction >= 40% Admission creatinine clearance > 60ml/min Admission creatinine clearance <= 60ml/min Admission plasma potassium level <4 mmol/l Admission plasma potassium level >=4 mmol/l Diabetes No Diabetes Pre-hospital randomization In-hospital randomization BMI <= 25 BMI > 25
p for interaction
0.97 [ 0.73 , 1.28 ] 0.95 [ 0.62 , 1.47 ] 0.96 [ 0.66 , 1.40 ] 1.53 [ 0.78 , 2.98 ] 0.88 [ 0.64 , 1.20 ] 0.87 [ 0.64 , 1.18 ] 1.88 [ 0.84 , 4.21 ] 0.93 [ 0.69 , 1.25 ] 1.32 [ 0.53 , 3.29 ] 1.48 [ 0.89 , 2.46 ] 0.80 [ 0.57 , 1.13 ] 0.98 [ 0.71 , 1.33 ] 0.94 [ 0.46 , 1.90 ] 0.92 [ 0.68, 1.25 ] 1.57 [ 0.72 , 3.43 ] 0.93 [ 0.67 , 1.29 ] 1.10 [ 0.61 , 1.97 ] 0.78 [ 0.41 , 1.49 ] 1.06 [ 0.77 , 1.45 ] 0.77 [ 0.48 , 1.23 ] 1.10 [ 0.76 , 1.57 ] 0.71 [ 0.36 , 1.38 ] 0.98 [ 0.71 , 1.34 ] 0.92 [ 0.67 , 1.27 ] 1.08 [ 0.59 , 2.00 ] 0.86 [ 0.58 , 1.27 ] 1.15 [ 0.76 , 1.74 ] 0.94 [ 0.49 , 1.78 ] 0.97 [ 0.71 , 1.33 ] 1.91 [ 0.85 , 4.28 ] 0.87 [ 0.64 , 1.18 ] 1.15 [ 0.73 , 1.81 ] 0.82 [ 0.57 , 1.19 ]
0.00
1.00
2.00 3.00 Hazard Ratio
MRA better
4.00
0.97 0.14 0.08 0.46 0.05 0.93 0.21 0.63 0.40 0.24 0.40 0.64 0.31 0.92 0.08 0.26
5.00
Standard therapy Better
Results were consistent across pre-specified subgroups. ACE ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; BB ¼ betablocker; BMI ¼ body mass index; MRA ¼ mineralocorticoid receptor antagonist; NSTEMI ¼ non-ST-segment elevation myocardial infarction; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction.
F I G U R E 5 Subgroup Analyses: Mortality
Subgroups
Hazard ratio [95% confidence interval]
Death
All patients Age >= 65 Age < 65 Women Men STEMI NSTEMI PCI No PCI ACE or ARB before randomization Neither ACE nor ARB before randomization ACE or ARB after randomization Neither ACE nor ARB after randomization BB after randomization No BB after randomization ACE/ARB and BB after randomization no ACE/ARB or no BB or neither after randomization Killip Class >= 2 Killip Class = 1 Pulsed blood pressure < 45mm Hg Pulsed blood pressure >= 45mm Hg Left ventricular ejection fraction < 40% Left ventricular ejection fraction >= 40% Admission creatinine clearance > 60ml/min Admission creatinine clearance <= 60ml/min Admission plasma potassium level <4 mmol/l Admission plasma potassium level >=4 mmol/l Diabetes No Diabetes Pre-hospital randomization In-hospital randomization BMI <= 25 BMI > 25
0.65 [ 0.30 , 1.38 ] 0.68 [ 0.30 , 1.54 ] 0.34 [ 0.04 , 3.26 ] 0.73 [ 0.12 , 4.37 ] 0.63 [ 0.27 , 1.46 ] 0.20 [ 0.06 , 0.70 ] 3.47 [ 0.72 , 16.72 ] 0.50 [ 0.20 , 1.25 ] 1.95 [ 0.19 , 4.70 ] 0.83 [ 0.25 , 2.71 ] 0.55 [ 0.20 , 1.48 ] 0.47 [ 0.14 , 1.51 ] 0.94 [ 0.30 , 2.96 ] 0.72 [ 0.23 , 2.27 ] 0.75 [ 0.25 , 2.23 ] 0.63 [ 0.15 , 2.64 ] 0.67 [ 0.26 , 1.74 ] 0.71 [ 0.24 , 2.11 ] 0.73 [ 0.25 , 2.11 ] 0.96 [ 0.28 , 3.33 ] 0.56 [ 0.21 , 1.52 ] 0.62 [ 0.20 , 1.94 ] 0.63 [ 0.21 , 1.92 ] 0.88 [ 0.32 , 2.43 ] 0.45 [ 0.14 , 1.49 ] 0.70 [ 0.20 , 2.49 ] 0.67 [ 0.26 , 1.77 ] 1.33 [ 0.30 , 5.00 ] 0.50 [ 0.20 , 1.24 ] 1.33 [ 0.41 , 33.18 ] 0.50 [ 0.18 , 1.07 ] 0.55 [ 0.20 , 1.51 ] 0.74 [ 0.23 , 2.32 ]
0.00
1.00
2.00
3.00
4.00
5.00
Hazard Ratio MRA better
Standard therapy Better
The type of myocardial infarction in regard to ST-segment elevation significantly impacted mortality. Abbreviations as in Figure 4.
p for interaction
0.57 0.88 0.01 0.50 0.60 0.40 0.96 0.95 0.97 0.51 0.98 0.40 0.96 0.27 0.08 0.70
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Aldosterone Blockade in Myocardial Infarction
eplerenone was initiated 3 to 14 days after the onset
T A B L E 3 6-Month Outcomes: STEMI and NSTEMI Subgroups
of MI complicated by HF and reduced LV function.
STEMI
Primary composite outcome
NSTEMI
The benefit observed was apparently driven by the
Standard Therapy (n ¼ 617)
MRA Regimen (n ¼ 612)
Standard Therapy (n ¼ 183)
MRA Regimen (n ¼ 186)
89 (14.4)
77 (12.6)
9 (4.9)
17 (9.1)
15 (2.4)
3 (0.5)
2 (1.1)
7 (3.8)
outcomes (5–7). The recent REMINDER study also
3 (0.5)
1 (0.2)
0 (0)
1 (0.5)
reported encouraging results with eplerenone in low-
46 (7.5)
42 (6.9)
risk STEMI patients, although the benefit was
group of patients treated earlier (i.e., 3 to 7 days) (22). This finding is consistent with other studies reporting high aldosterone plasma levels early after MI (23,24) and the relationship of these levels with clinical
Components of primary outcome Death Resuscitated cardiac arrest Significant ventricular arrhythmia Indication for implantable defibrillator New or worsening HF
0 (0) 39 (6.3)
5 (0.8) 38 (6.2)
2 (1.1)
3 (1.6)
0 (0)
0 (0)
6 (3.3)
8 (4.3)
observed more on B-type natriuretic peptide levels than clinical outcomes (4). The ALBATROSS study recruited a broad popula-
Values are n (%). Abbreviations as in Tables 1 and 2.
tion of MI representing the general population hospitalized for this condition, rarely associated with concomitant HF or severe LV dysfunction. These pa-
and 0.2% of patients in the MRA and standard therapy alone groups, respectively (HR: 12.12; 95% CI: 2.87 to 51.29; p < 0.0001). The study medication was permanently discontinued in 106 patients (13.2%). The 2 groups were balanced with respect to other adverse events (data not shown) including endocrine and breast disorders which occurred in only 2 (0.25%) patients in the treatment group versus none in the standard therapy arm (p ¼ 0.5).
tients were enrolled early then received IV canrenoate for rapid mineralocorticoid receptor blockade and they had good adherence to spironolactone over 6 months. However, we were unable to show a benefit of early and sustained MRA therapy in this MI population, which cannot be compared to the much higher risk EPHESUS trial population. Although the STEMI population in our study was at much higher risk than the REMINDER (4) population, our finding of a potential mortality benefit in
DISCUSSION
the STEMI cohort must be interpreted with great
Despite a strong pre-clinical rationale and favorable
group at the time of randomization. However, the
clinical data from registries and small randomized
previously mentioned pre-clinical and clinical data,
studies, our randomized trial was unable to show a
as well as the strength of the association, support
benefit of an MRA regimen administered early in pa-
the plausibility of an MRA effect on mortality in the
tients presenting with acute MI, 92% of whom pre-
setting of STEMI, a more homogeneous patient
sented without HF (Central Illustration). Similarly, no
population with more acute and severe myocardial
significant difference was observed on rates of
ischemia
arrhythmia or HF over 6 months of follow-up.
NSTEMI patient groups have similar long-term out-
Intriguingly, there was a reduction of death in the
comes (15), their acute management is different with
group of patients with STEMI receiving the MRA
no need for either urgent reperfusion therapy or
regimen.
aggressive antithrombotic therapy in NSTEMI. Hence
caution in the absence of stratification for this sub-
than
NSTEMI.
Although
STEMI
and
Experimental studies have shown that the early
the early blunting of the previously reported early
use of MRA therapy after MI reduces LV expansion
biological effects of MR activation after acute co-
and extensive fibrosis (9) by antagonizing activation
ronary
of the mineralocorticoid receptor by aldosterone and
a favorable effect through the ‘un-triggering’ of
cortisol (18). The clinical benefit reported previously
neurohormonal activation and the subsequent post-
with MRA use in HF was consistent across groups
MI
defined by the ischemic or nonischemic origin of HF
more acute and enhanced processes in STEMI than
(1,2) and associated with a reduction of mortality in
NSTEMI.
artery
fibrosis
occlusion
and
(9,10,18),
remodeling,
may
which
lead
are
to
much
post-MI patients (3). Thus, the addition of MRAs to
The absence of effect on rates of ventricular
beta-blockers and angiotensin-converting enzyme
arrhythmia in our study is not in contradiction with a
inhibitors has been highly recommended (19–21) in
possible MRA effect on mortality as in both the Ran-
patients with HF and reduced LV function, irre-
domized
spective of the etiology of HF.
EPHESUS (3) trials, where mortality was reduced in
In the EPHESUS (Eplerenone Post-Acute MI Heart Failure
Efficacy
and
Survival
Study)
trial
(3),
Aldosterone
Evaluation
Study
(1)
and
association with MRA therapy despite the absence of any effect on ventricular arrhythmia. Furthermore,
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Aldosterone Blockade in Myocardial Infarction
CENTRAL ILLUSTRATION Aldosterone Blockade in MI: Mortality Outcomes
Beygui, F. et al. J Am Coll Cardiol. 2016;67(16):1917–27.
Although use of mineralocorticoid receptor antagonists (MRA) significantly reduced mortality in post–myocardial infarction (MI) patients with heart failure in the landmark randomized EPHESUS (Eplerenone Post-Acute MI Heart Failure Efficacy and Survival) study, mineralocorticoid receptor blockade did not decrease mortality compared to standard care in the ALBATROSS (Aldosterone Lethal effects Blocked in Acute MI Treated with or without Reperfusion to improve Outcome and Survival at Six months follow-up) trial in acute MI patients irrespective of the presence of heart failure (HF) or left ventricular dysfunction. CI ¼ confidence interval; HR ¼ hazard ratio; IV ¼ intravenous; Kþ ¼ potassium; NSTEMI ¼ non–ST-segment elevation myocardial infarction; RR ¼ relative risk; STEMI ¼ ST-segment elevation myocardial infarction.
ventricular arrhythmias were considered significant
were equally distributed between the 2 study groups
only if a therapy was required for their treatment (i.e.,
(data not shown).
electrical cardioversion or antiarrhythmic therapy).
STUDY
Hence, the effect of MRA use on global rates of ven-
inherent to the sample size and to the open-label
tricular arrhythmia post-MI cannot be assessed by our
design. However, this study remains the largest
study.
experience in MI patients outside of the scope of HF
LIMITATIONS. Our
study has
limitations
The ALBATROSS study also highlights the relative
and all the events were adjudicated blindly. The
safety of the MRA regimen used. Although the rates of
study suffered from a lack of power as the predicted
hyperkalemia were higher in the MRA group than in
event rate (269) was higher than the actual event rate
the control group, they remained lower than previ-
(194). Despite nonrestrictive inclusion criteria, the
ously reported (3,4) and the rates of adverse events
study included predominantly STEMI patients at
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Beygui et al.
JACC VOL. 67, NO. 16, 2016 APRIL 26, 2016:1917–27
Aldosterone Blockade in Myocardial Infarction
lower risk than expected with a possible selection bias. Our trial was not adequately powered to examine hard
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
clinical outcomes. Although the study would have
Gilles Montalescot, ACTION Study Group, Institut de
been adequately powered to demonstrate a mortality
Cardiologie, Pitié-Salpêtrière University Hospital, 47
reduction in STEMI patients, randomization was not
Boulevard de l’Hôpital, 75013 Paris, France. E-mail:
stratified on the type of ACS and our finding should be
[email protected].
considered hypothesis generating at this point. Larger studies are needed to re-examine the effect of MRA
PERSPECTIVES
therapy on such outcomes in STEMI patients. With respect to the multiple testing in the subgroup ana-
COMPETENCY IN MEDICAL KNOWLEDGE:
lyses, the risk of type I error may be important, both for
Administration of a mineralocorticoid receptor antag-
the primary and the mortality endpoints, and the
onist early after myocardial infarction did not reduce
analysis should be considered as only exploratory.
occurrence of the composite of death, ventricular
Finally, the present MRA regimen used potassium
arrhythmia, cardiac arrest, need for implantable defi-
canrenoate and spironolactone, and our results may
brillator, or new or worsening HF at 6 months, but
not be fully extrapolated to eplerenone.
seemed to lower mortality among those presenting
CONCLUSIONS
with ST-segment elevation.
The ALBATROSS trial failed to show a benefit of an MRA regimen initiated early post-MI when HF is largely not present. The results of the ALBATROSS trial do not warrant the extension of MRA use to MI
TRANSLATIONAL OUTLOOK: An adequately powered trial is needed to specifically assess the impact of early mineralocorticoid blockade in patients presenting with STEMI.
patients without HF at this point.
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2. Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. 3. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–21. 4. Montalescot G, Pitt B, Lopez de Sa E, et al. Early eplerenone treatment in patients with acute STelevation myocardial infarction without heart failure: the Randomized Double-Blind Reminder Study. Eur Heart J 2014;35:2295–302. 5. Beygui F, Collet J-P, Benoliel J-J, et al. High plasma aldosterone levels on admission are associated with death in patients presenting with acute ST-elevation myocardial infarction. Circulation 2006;114:2604–10. 6. Palmer BR, Pilbrow AP, Frampton CM, et al. Plasma aldosterone levels during hospitalization are predictive of survival post-myocardial infarction. Eur Heart J 2008;29:2489–96. 7. Beygui F, Montalescot G, Vicaut E, et al. Aldosterone and long-term outcome after myocardial infarction: A substudy of the french nationwide Observatoire sur la Prise en charge hospitalière, l’Evolution à un an et les caRactéristiques de patients présentant un infArctus du myocarde avec
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11. Hayashi M, Tsutamoto T, Wada A, et al. Immediate administration of mineralocorticoid receptor antagonist spironolactone prevents post-
17. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/ AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the
infarct left ventricular remodeling associated with suppression of a marker of myocardial collagen synthesis in patients with first anterior acute myocardial infarction. Circulation 2003;107: 2559–65.
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12. Di Pasquale P, Cannizzaro S, Scalzo S, et al. Effects of canrenoate plus angiotensin-converting enzyme inhibitors versus angiotensin-converting
18. Mihailidou AS, Loan Le TY, Mardini M, Funder JW. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental
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Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012;33:1787–847. 20. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78–140.
Aldosterone Blockade in Myocardial Infarction
Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64: e139–228. 22. Adamopoulos C, Ahmed A, Fay R, et al. Timing of eplerenone initiation and outcomes in patients with heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction: insights from the EPHESUS trial. Eur J Heart Fail 2009;11:1099–105.
24. Foy SG, Crozier IG, Richards AM, et al. Neurohormonal changes after acute myocardial infarction. Relationships with haemodynamic indices and effects of ACE inhibition. Eur Heart J 1995;16:770–8.
KEY WORDS left ventricular dysfunction, mineralocorticoid receptor antagonists, mortality
21. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of
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A PP END IX For an expanded Methods section and a supplemental table, please see the online
Patients with Non-ST-Elevation Acute Coronary
1068–76.
version of this article.
1927
VOL. 67, NO. 16, 2016
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jacc.2016.02.033
Early Aldosterone Blockade in Acute Myocardial Infarction The ALBATROSS Randomized Clinical Trial Farzin Beygui, MD, PHD,a Guillaume Cayla, MD, PHD,b Vincent Roule, MD,a François Roubille, MD, PHD,c Nicolas Delarche, MD,d Johanne Silvain, MD, PHD,e Eric Van Belle, MD, PHD,f Loic Belle, MD,g Michel Galinier, MD,h Pascal Motreff, MD, PHD,i Luc Cornillet, MD, PHD,b Jean-Philippe Collet, MD, PHD,e Alain Furber, MD, PHD,j Patrick Goldstein, MD,k Patrick Ecollan, MD,l Damien Legallois, MD,a Alain Lebon, MD,a Hélène Rousseau, MSC,m Jacques Machecourt, MD,n Faiez Zannad, MD, PHD,o Eric Vicaut, MD, PHD,m Gilles Montalescot, MD, PHD,e on behalf of the ALBATROSS Investigators
ABSTRACT BACKGROUND Mineralocorticoid receptor antagonists (MRA) improve outcome in the setting of post–myocardial infarction (MI) heart failure (HF). OBJECTIVES The study sought to assess the benefit of an early MRA regimen in acute MI irrespective of the presence of HF or left ventricular (LV) dysfunction. METHODS We randomized 1,603 patients to receive an MRA regimen with a single intravenous bolus of potassium canrenoate (200 mg) followed by oral spironolactone (25 mg once daily) for 6 months in addition to standard therapy or standard therapy alone. The primary outcome of the study was the composite of death, resuscitated cardiac arrest, significant ventricular arrhythmia, indication for implantable defibrillator, or new or worsening HF at 6-month follow-up. Key secondary/safety outcomes included death and other individual components of the primary outcome and rates of hyperkalemia at 6 months. RESULTS The primary outcome occurred in 95 (11.8%) and 98 (12.2%) patients in the treatment and control groups, respectively (hazard ratio [HR]: 0.97; 95% confidence interval [CI]: 0.73 to 1.28). Death occurred in 11 (1.4%) and 17 (2.1%) patients in the treatment and control groups, respectively (HR: 0.65; 95% CI: 0.30 to 1.38). In a non–pre-specified exploratory analysis, the odds of death were reduced in the treatment group (3 [0.5%] vs. 15 [2.4%]; HR: 0.20; 95% CI: 0.06 to 0.70) in the subgroup of ST-segment elevation MI (n ¼ 1,229), but not in non–ST-segment elevation MI (p for interaction ¼ 0.01). Hyperkalemia >5.5 mmol/l–1 occurred in 3% and 0.2% of patients in the treatment and standard therapy groups, respectively (p < 0.0001). CONCLUSIONS The study failed to show the benefit of early MRA use in addition to standard therapy in patients admitted for MI. (Aldosterone Lethal effects Blockade in Acute myocardial infarction Treated with or without Reperfusion to improve Outcome and Survival at Six months follow-up; NCT01059136). (J Am Coll Cardiol 2016;67:1917–27) © 2016 by the American College of Cardiology Foundation.
From the aACTION Study Group, Service de Cardiologie, Centre Hospitalier Universitaire de Caen, Caen, France; bACTION Study Group, Service de Cardiologie, Centre Hospitalier Universitaire de Nimes, Nîmes, France; cService de Cardiologie, Centre HospiListen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
talier Universitaire de Montpellier, Montpellier, France; dService de Cardiologie, Centre Hospitalier de Pau, Pau, France; eACTION _ Study Group, Institut de Cardiologie (AP-HP), Centre Hospitalier Universitaire Pitié-Salpêtriere, Paris, France; fService de Cardiologie, Centre Hospitalier Universitaire de Lille, Lille, France; gService de Cardiologie, Centre Hospitalier d’Annecy, Annecy, France; hService de Cardiologie, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; iService de Cardiologie, Centre Hospitalier Universitaire de Clermont Ferrand, Clermont Ferrand, France; jService de Cardiologie, Centre Hospitalier Universitaire d’Angers, Angers, France; kService d’Accueil des Urgences et SAMU, Centre Hospitalier Universitaire de Lille, Lille, France; l
ACTION Study Group, SAMU, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France;
m
ACTION Study Group, Unite de
Recherche Clinique, Hôpital Lariboisière, Paris, France; nService de Cardiologie, Centre Hospitalier Universitaire de Grenoble, Grenoble, France; and oINSERM, CIC 1433 et Pôle de Cardiologie, Centre Hospitalier Universitaire de Nancy, Nancy, France. The trial was led by members of the nonprofit academic research organization ACTION, based at Pitié-Salpêtrière Hospital, Paris,
1918
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Aldosterone Blockade in Myocardial Infarction
T
ABBREVIATIONS AND ACRONYMS CI = confidence interval HF = heart failure HR = hazard ratio
he mineralocorticoid receptor an-
MI in the prevention of LV remodeling (11,12) and life-
tagonists (MRA) spironolactone and
threatening arrhythmia (13,14).
eplerenone reduce mortality in the
Whether MRA use could improve clinical outcomes
setting of heart failure (HF) with reduced
of acute MI independent of the type of MI, reperfu-
ejection fraction (1,2). Eplerenone initiated
sion strategy, or the presence of LV dysfunction or HF
3 to 14 days after ST-segment elevation
is unknown.
IV = intravenous
myocardial infarction (STEMI) or non–ST-
MI = myocardial infarction
segment
infarction
Lethal effects Blocked in Acute MI Treated with or
elevation
myocardial
The objective of the ALBATROSS (Aldosterone
MRA = mineralocorticoid
(NSTEMI) complicated by left ventricular
without Reperfusion to improve Outcome and Sur-
receptor antagonists
(LV) dysfunction and HF is also associated
vival at Six months follow-up) trial was to investigate
NSTEMI = non–ST-segment
with a reduction of mortality (3). However,
the clinical effects of a rapid and prolonged MRA
there
regimen initiated early after the onset of any type
elevation myocardial infarction
STEMI = ST-segment elevation
is
limited
clinical
evidence
with
MRAs in myocardial infarctions (MI) inde-
myocardial infarction
of MI.
pendent of HF. The REMINDER (DoubleBlind,
Randomized,
Placebo-Controlled
Trial
METHODS
Evaluating The Safety And Efficacy Of Early Treatment With Eplerenone In Patients With Acute
STUDY DESIGN AND POPULATION. ALBATROSS is a
Myocardial Infarction) trial (4) showed that eplere-
multicenter, nationwide, randomized, open-labeled,
none used within the first 24 h of STEMI was safe
blinded endpoint, clinical trial. The study was
and effective on a composite outcome mainly driven
designed to assess the superiority of an MRA regimen
by the biological outcome of a lower plasma level of
initiated early after presentation for STEMI or
B-type natriuretic peptide.
high-risk NSTEMI plus standard therapy versus
SEE PAGE 1928
standard therapy alone (15). Patients were randomized as early as possible, including by pre-hospital
High aldosterone plasma levels early after STEMI
medical teams (ambulance) when possible, to allow
or NSTEMI are associated with mortality, sudden
rapid administration of the treatment. The coordi-
cardiac death, and HF (5–8). Experimental studies
nating center was the ACTION (Allies in Cardiovas-
have shown that early MRA administration after
cular Trials, Initiatives, and Organized Networks)
myocardial infarction (MI) could improve myocardial
Study Group at Pitié-Salpêtrière hospital. The study
healing (9) as well as both electrical and structural
design and protocol have been published previously
remodeling (10). Small-sized studies have also re-
(16). The hypotheses used for the study’s sample size
ported benefits of MRA therapy initiated early after
calculation are reported in the Online Appendix.
France (www.action-coeur.org). The study was sponsored by the Assistance Publique-Hôpitaux de Paris (AP-HP) and exclusively funded by public grants from the French Ministry of Health and the Foundation of the Institute of Cardiometabolism And Nutrition (ICAN). The funding organizations had no involvement in the design or conduct of the study, site selection, data collection, analysis of the results, or writing of the manuscript. Dr. Beygui has received research or educational grants to the institution from AstraZeneca, Bayer, Eli Lilly, Fédération Française de Cardiologie, Medtronic, Terumo, Biosensor, Pfizer, Sanofi, and Thermofischer; and consulting or lecture fees from AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, and Pfizer. Dr. Cayla has received lecture fees from AstraZeneca, Biotronik, Daiichi-Sankyo, Bayer, BMS, Eli Lilly, Novartis, Medtronic, MSD, Pfizer, and Sanofi. Dr. Silvain has received research grants to the institution from AstraZeneca, Brahms, Daiichi-Sankyo, Eli Lilly, Institute of Cardiometabolism (ICAN), INSERM, Fédération Française de Cardiologie, Fondation de France, Société Française de Cardiologie, and Sanofi; consulting fees from Actelion, AstraZeneca, Daiichi-Sankyo, Eli Lilly, and Sanofi; lecture fees from Algorythm, AstraZeneca, and Bristol-Myers Squibb; and travel fees from AstraZeneca, B. Braun, Bristol-Myers Squibb, and Pfizer. Dr. Collet has received research grant support, consulting fees, and speakers fees from AstraZeneca. Dr. Goldstein has received speakers fees and served on the Speakers Bureau for AstraZeneca, Boehringer Ingelheim, BMS Pfizer, and Bayer. Dr. Vicaut has received consulting fees from Pfizer, Novartis, BMS, Abbott Vascular, and Sorin; and his institution has received grant support from Eli Lilly. Dr. Montalescot has received research or educational grants to the institution from ADIR, Amgen, AstraZeneca, Bayer, Berlin Chimie AG, Boehringer Ingelheim, Bristol-Myers Squibb, Celladon, Daiichi-Sankyo, Eli Lilly, Fédération Française de Cardiologie, Gilead, ICAN, Janssen, Medtronic, MSD, Pfizer, Sanofi, and The Medicines Company; and consulting or lecture fees from Amgen, AstraZeneca, Bayer, Berlin Chimie AG, Boehringer Ingelheim, Bristol-Myers Squibb, Beth Israel Deaconess Medical, Brigham Women’s Hospital, Cardiovascular Research Foundation, CME Resources, Daiichi-Sankyo, Eli Lilly, Europa, Elsevier, Fondazione Anna Maria Sechi per il Cuore, Lead-Up, Menarini, MSD, Pfizer, Sanofi, The Medicines Company, TIMI Study Group, and WebMD. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received October 20, 2015; revised manuscript received February 12, 2016, accepted February 15, 2016.
Beygui et al.
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Aldosterone Blockade in Myocardial Infarction
The study was undertaken according to the Declaration of Helsinki and approved by the French
were to be treated by the most adapted therapy based on international guidelines.
National Institutional Ethical Review Board. Written
Patients assigned to the MRA regimen received a
informed consent was obtained from all patients
200 mg intravenous (IV) bolus of potassium canre-
before randomization.
noate as soon as possible. A first 25 mg oral dose of
To be eligible, patients had to have an ischemic
spironolactone was administered 12 to 24 h after the
symptom within 72 h before randomization and at least
IV injection, after control of plasma concentrations of
1 of the following indicators of MI: ST-segment eleva-
potassium and creatinine. The oral dose was not
tion in at least 2 contiguous leads; new or undated left
given if the first blood sample revealed a potassium
bundle branch block; Q waves in at least 2 contiguous
level >5.5 mmol/l–1 or a creatinine level >220 mmol/l –1 .
leads (not known to be old); troponin levels $3 times
Such
the upper limit of normal; and Thrombolysis In
intention-to-treat analysis.
Myocardial Infarction score $3 in the case of NSTEMI.
patients
Patients
were
were
nevertheless
followed
for
6
kept
in
months
the after
Key exclusion criteria included known hyperkalemia,
randomization and visits after hospital discharge
renal insufficiency, severe liver dysfunction, and car-
included measurements of LV ejection fraction. Spi-
diac arrest prior to randomization.
ronolactone was suspended during follow-up if
Eligible subjects were randomized in a 1:1 ratio to
plasma potassium concentrations were >5.5 mmol/l–1
receive either the MRA regimen added to standard
and/or plasma creatinine levels were >220 m mol/l–1
therapy or standard therapy alone. Randomization
on any blood sample whether protocol-specified
was
or
conducted
via
a
central
interactive
voice
not.
The
treatment
was
reintroduced
after
randomization system with stratification by center
normalization of potassium and creatinine levels if
using random sequences of block sizes. All subjects
the cause was considered reversible. The study
F I G U R E 1 Patient Enrollment and Follow-Up Flow Chart
1622 Patients enrolled
1616 Patients randomized
1 Patient was randomized twice
1615 patients were correctly randomized
15 patients were excluded : - 12 patients withdrew or had invalid consent 1603 included in the “intention-to-treat” analysis
801 were analyzed in the “standard treatment” arm
802 were analyzed in the “MRA regimen” arm
Patients were randomized to mineralocorticoid receptor antagonist (MRA) therapy or standard care.
1919
Beygui et al.
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JACC VOL. 67, NO. 16, 2016 APRIL 26, 2016:1917–27
Aldosterone Blockade in Myocardial Infarction
treatment was permanently discontinued if hyper-
(17) for implantable defibrillator, or new or worsening
kalemia >5.5 mmol/l –1 recurred after reintroduction
HF during 6-month follow-up.
of spironolactone, if any plasma potassium level was
Key secondary efficacy outcomes included each
>6 mmol/l–1 , or in case of clinical intolerance.
individual component of the primary outcome; the
STUDY OUTCOMES. The primary outcome was the
composite of death or resuscitated cardiac arrest; the
composite of death, resuscitated cardiac arrest, sig-
composite of death or new or worsening HF; death of
nificant ventricular arrhythmia, class IA indication
cardiovascular origin; recurrent MI; and urgent or unplanned revascularization, all at 6 months. Premature discontinuation of study treatment, acute renal failure, and hyperkalemia were closely
T A B L E 1 Patient Characteristics and Management
monitored. All outcomes were adjudicated in a Standard Treatment (n ¼ 801)
Age, yrs
58 (50.0–67.0)
Female
143 (17.9)
Body mass index, kg/m2
26.4 (24.0–29.7)
MRA Regimen (n ¼ 802)
58 (50.0–67.0)
blinded manner by an independent adjudication committee.
129 (16.1)
STATISTICAL ANALYSIS. We hypothesized that the
26.1 (23.8–28.9)
6-month rate of the primary endpoint would be 20%
Risk factors and medical history
in the standard therapy alone arm. With a sample size
Current smoking
414 (51.7)
377 (47.0)
Hypertension
352 (43.9)
335 (41.8)
Diabetes
126 (15.7)
128 (16.0)
Dyslipidemia
368 (45.9)
375 (46.8)
constant hazard ratio (HR) of 0.71 associated with the
of 793 per arm (for a total of approximately 1,600 subjects), a total event rate of 269 and an estimated
73 (9.1)
65 (8.1)
MRA regimen, using a bilateral equality of survival
Prior heart failure
5 (0.6)
9 (1.1)
log-rank test, the study would achieve an 80% power
Prior CABG
11 (1.4)
13 (1.6)
to detect a difference between a 0.853 proportion in
Prior PCI
86 (10.7)
74 (9.2)
1 group and a 0.800 proportion in the other group at
Prior stroke
18 (2.2)
24 (3.0)
Prior cancer
41 (5.1)
32 (4.0)
6 months with a p value of 0.049.
Prior MI
Presentation* STEMI
617 (77.0)
612 (76.3)
NSTEMI
183 (22.8)
186 (23.2)
The main efficacy analysis was based on all events that occurred in the intention-to-treat population defined as all randomized patients who signed an informed consent form. In case of consent with-
Killip class* I
732 (91.4)
750 (93.5)
II
52 (6.5)
39 (4.9)
III
6 (0.7)
9 (1.1)
IV
7 (0.9)
3 (0.4)
>I
65 (8.1)
Creatinine clearance, ml/min–1*
101.35 (77.26–121.14) –1
Potassium at admission, mmol/l Admission GRACE score
4.0 (3.7–4.3) 132 31
51 (6.4) 95.96 (75.39–119.66)
drawal, only data collected before withdrawal were used. The primary analysis based on all events corresponding to the primary outcome was carried out using a Kaplan-Meier survival analysis with a log-
4.0 (3.7–4.3)
rank test. All patients were censored at the time of
133 29
the last observation. A Cox survival model was used for the calculation of the HR presented with its
In-hospital medication Aspirin
796 (99.4)
797 (99.4)
2-sided 95% confidence interval (CI) for the primary
P2Y12 antagonist
796 (99.4)
797 (99.4)
endpoint and for the analysis of all secondary out-
Beta-blocker
744 (92.9)
750 (93.5)
comes at 6 months. Variables assessed at specific time
Statin
779 (97.3)
769 (95.9)
ACE inhibitor/ARB
718 (89.6)
702 (87.5)
72 (11.7)
64 (10.5)
270 (43.8)
268 (43.8)
Coronary angiography
792 (98.9)
793 (98.9)
compared between groups using chi-square or Fisher
PCI
727 (90.8)
720 (89.8)
exact tests where appropriate. Consistency of the
Primary PCI†
501 (81.2)
502 (82.0)
treatment effect was analyzed among 16 patient
23 (2.9)
26 (3.2)
50 (45–60)
50 (45–60)
Fibrinolysis† Glycoprotein IIb/IIIa inhibitor†
Left ventricular ejection fraction, %*
model with calculation of odds ratios and their 2-sided 95% CI. Safety analyses were performed on the per-protocol set. Rates of adverse events were
Interventional or surgical procedures
CABG
points were analyzed using a logistic regression
Values are median (interquartile range), n (%), or mean SD. *The information on the type of myocardial infarction and Killip class was missing in 5 patients. †In patients with STEMI in the standard therapy (n ¼ 617) and MRA regimen (n ¼ 612) groups. ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker; CABG ¼ coronary artery bypass graft surgery; GRACE ¼ Global Registry of Acute Coronary Events; MI ¼ myocardial infarction; MRA ¼ mineralocorticoid receptor antagonist; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction.
subgroups. All tests had a 2-sided significance level of 5% and were performed using SAS software, version 9.3 (SAS Institute, Cary, North Carolina).
RESULTS Between February 2010 and January 2014, a total of 1,622 patients consented and were randomly assigned
Beygui et al.
JACC VOL. 67, NO. 16, 2016 APRIL 26, 2016:1917–27
1921
Aldosterone Blockade in Myocardial Infarction
F I G U R E 2 Primary Outcome
1.0 Hazard ratio, 0.97 (95% CI 0.73-1.28) p = 0. 81
Primary End Point
0.8
0.20
0.15
0.6 0.10
0.4 0.05
0.2
0.00 0
50
100
150
200
Standard Therapy MRA regimen
0.0 0
50
100
150
200
Days Since Randomization
N at risk Standard Therapy 801
687
669
645
273
MRA Regimen
705
683
660
183
802
Per the Kaplan-Meier estimate, there was no difference between the arms in terms of the primary outcome, which was a composite of death, resuscitated cardiac arrest, significant ventricular arrhythmia, indication for implantable defibrillator, or new or worsening heart failure. CI ¼ confidence interval; MRA ¼ mineralocorticoid receptor antagonist.
to the MRA regimen plus standard therapy (n ¼ 802)
The results were consistent among all pre-specified
or standard therapy alone (n ¼ 801) (Figure 1). The
subgroups with respect to the primary outcome
groups were well balanced with respect to baseline
(Figure 4). The primary outcome was numerically
characteristics and treatment strategies (Table 1). The
lower with MRA therapy in the STEMI group (p for
standard of care included an invasive strategy with
interaction ¼ 0.08). Considering mortality, a signifi-
coronary angiography performed in 1,582 (98.7%) and
cant interaction (p ¼ 0.01) was found between the
percutaneous coronary intervention in 1,447 (90.3%)
treatment effect and type of MI (STEMI vs. NSTEMI)
of the patients. Three-quarters of the study population (n ¼ 1,229) presented with ongoing STEMI, of whom 1,003 (81.6%) underwent primary percuta-
T A B L E 2 Primary and Key Secondary Outcomes at 6-Month Follow-Up
Standard Therapy MRA Regimen (n ¼ 801) (n ¼ 802)
neous coronary intervention whereas 136 (11.1%) received fibrinolysis. HF at presentation was present in 116 (7.2%) patients. A total of 59 (3.7%) patients in
Primary composite outcome
the standard therapy alone group received an MRA
Components of primary outcome
(eplerenone in all) during follow-up based on physi-
Death
cian decision.
Resuscitated cardiac arrest
After a median follow-up of 188 days (interquartile range: 179 to 210 days), the primary outcome
Significant ventricular arrhythmia Indication for implantable defibrillator
p Value
0.81
95 (11.8)
17 (2.1)
11 (1.4)
0.65 (0.30–1.38)
0.26
2 (0.2)
0.66 (0.11–3.92)
0.64
3 (0.4) 48 (6)
45 (5.6)
0.94 (0.62–1.40)
0.75
6 (0.7)
5 (0.6)
0.82 (0.25–2.67)
0.74 0.85
45 (5.6)
47 (5.9)
1.04 (0.69–1.57)
Death or resuscitated cardiac arrest
19 (2.4)
13 (1.6)
0.68 (0.34–1.38)
0.28
(12.2%) patients in the MRA and standard therapy
Death or new or worsening HF
53 (6.6)
54 (6.7)
1.02 (0.70–1.49)
0.93
groups, respectively (HR: 0.97; 95% CI: 0.73 to 1.28).
Death of cardiovascular origin
14 (1.7)
9 (1.1)
0.64 (0.28–1.49)
0.30
Death from any cause (Figure 3A), as well as all other
Recurrent MI
8 (1)
5 (0.6)
0.62 (0.20–1.88)
0.39
components of the primary outcome (Table 2), did
Urgent or unplanned revascularization
1.10 (0.57–2.12)
0.77
(Figure 2, Table 2) occurred in 95 (11.8%) and 98
not differ between the 2 groups. All secondary outcomes occurred with comparable rates in the 2 groups (Table 2).
New or worsening HF
HR (95% CI)
0.97 (0.73–1.28)
98 (12.2)
17 (2.1)
19 (2.4)
Values are n (%). CI ¼ confidence interval; HF ¼ heart failure; HR ¼ hazard ratio; other abbreviations as in Table 1.
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JACC VOL. 67, NO. 16, 2016 APRIL 26, 2016:1917–27
Aldosterone Blockade in Myocardial Infarction
F I G U R E 3 Kaplan-Meier Estimates of Death
A
1.0 Hazard ratio, 0.65 (95% CI 0.30-1.38) p = 0. 26 0.8
0.05
Death
0.04
0.6 0.03
Standard Therapy
0.4
0.02
0.01
MRA regimen
0.2
0.00
0
50
100
150
200
0.0 0
50
100
150
200
Days Since Randomization
N at risks Standard Therapy 801
760
746
719
311
MRA Regimen
776
763
741
211
B
802
1.0 Hazard ratio, 0.20 (95% CI 0.06-0.69) p = 0. 0044 0.8
0.05
0.04
Death
1922
0.6
0.03
Standard Therapy 0.02
0.4 0.01
0.2
MRA regimen
0.00
0
50
100
150
200
0.0 0
50
100
150
200
Days Since Randomization N at risks Standard Therapy 617
587
579
556
236
MRA Regimen
595
587
571
162
612
Overall, there was no difference in death from any cause among all patients (A), but the MRA regimen significantly reduced mortality odds in patients with ST-segment elevation myocardial infarction (B). Abbreviations as in Figure 2.
(Figure 5). Compared to standard therapy alone, MRA
and the causes of death are reported in Table 3 and
use reduced the odds of death (3 [0.5%] vs. 15 [2.4%];
Online Table 1, respectively.
HR: 0.20; 95% CI: 0.06 to 0.70; p ¼ 0.0044) in the
There was a trend (HR: 1.37; 95% CI: 0.97 to 1.95;
STEMI subgroup (n ¼ 1,229), but not in the NSTEMI
p ¼ 0.075) towards higher rates of protocol-defined
subgroup (Figure 3B). The rates of the components of
acute
the primary endpoint in STEMI and NSTEMI groups
regimen. Hyperkalemia >5.5 mmol/l–1 occurred in 3%
renal
failure
associated
with
the
MRA
Beygui et al.
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Aldosterone Blockade in Myocardial Infarction
F I G U R E 4 Subgroup Analyses: Primary Outcome
Subgroups
Hazard ratio [95% confidence interval]
Primary Outcome
All patients Age >= 65 Age < 65 Women Men STEMI NSTEMI PCI No PCI ACE or ARB before randomization Neither ACE nor ARB before randomization ACE or ARB after randomization Neither ACE nor ARB after randomization BB after randomization No BB after randomization ACE/ARB and BB after randomization no ACE/ARB or no BB or neither after randomization Killip Class >= 2 Killip Class = 1 Pulsed blood pressure < 45mm Hg Pulsed blood pressure >= 45mm Hg Left ventricular ejection fraction < 40% Left ventricular ejection fraction >= 40% Admission creatinine clearance > 60ml/min Admission creatinine clearance <= 60ml/min Admission plasma potassium level <4 mmol/l Admission plasma potassium level >=4 mmol/l Diabetes No Diabetes Pre-hospital randomization In-hospital randomization BMI <= 25 BMI > 25
p for interaction
0.97 [ 0.73 , 1.28 ] 0.95 [ 0.62 , 1.47 ] 0.96 [ 0.66 , 1.40 ] 1.53 [ 0.78 , 2.98 ] 0.88 [ 0.64 , 1.20 ] 0.87 [ 0.64 , 1.18 ] 1.88 [ 0.84 , 4.21 ] 0.93 [ 0.69 , 1.25 ] 1.32 [ 0.53 , 3.29 ] 1.48 [ 0.89 , 2.46 ] 0.80 [ 0.57 , 1.13 ] 0.98 [ 0.71 , 1.33 ] 0.94 [ 0.46 , 1.90 ] 0.92 [ 0.68, 1.25 ] 1.57 [ 0.72 , 3.43 ] 0.93 [ 0.67 , 1.29 ] 1.10 [ 0.61 , 1.97 ] 0.78 [ 0.41 , 1.49 ] 1.06 [ 0.77 , 1.45 ] 0.77 [ 0.48 , 1.23 ] 1.10 [ 0.76 , 1.57 ] 0.71 [ 0.36 , 1.38 ] 0.98 [ 0.71 , 1.34 ] 0.92 [ 0.67 , 1.27 ] 1.08 [ 0.59 , 2.00 ] 0.86 [ 0.58 , 1.27 ] 1.15 [ 0.76 , 1.74 ] 0.94 [ 0.49 , 1.78 ] 0.97 [ 0.71 , 1.33 ] 1.91 [ 0.85 , 4.28 ] 0.87 [ 0.64 , 1.18 ] 1.15 [ 0.73 , 1.81 ] 0.82 [ 0.57 , 1.19 ]
0.00
1.00
2.00 3.00 Hazard Ratio
MRA better
4.00
0.97 0.14 0.08 0.46 0.05 0.93 0.21 0.63 0.40 0.24 0.40 0.64 0.31 0.92 0.08 0.26
5.00
Standard therapy Better
Results were consistent across pre-specified subgroups. ACE ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; BB ¼ betablocker; BMI ¼ body mass index; MRA ¼ mineralocorticoid receptor antagonist; NSTEMI ¼ non-ST-segment elevation myocardial infarction; PCI ¼ percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction.
F I G U R E 5 Subgroup Analyses: Mortality
Subgroups
Hazard ratio [95% confidence interval]
Death
All patients Age >= 65 Age < 65 Women Men STEMI NSTEMI PCI No PCI ACE or ARB before randomization Neither ACE nor ARB before randomization ACE or ARB after randomization Neither ACE nor ARB after randomization BB after randomization No BB after randomization ACE/ARB and BB after randomization no ACE/ARB or no BB or neither after randomization Killip Class >= 2 Killip Class = 1 Pulsed blood pressure < 45mm Hg Pulsed blood pressure >= 45mm Hg Left ventricular ejection fraction < 40% Left ventricular ejection fraction >= 40% Admission creatinine clearance > 60ml/min Admission creatinine clearance <= 60ml/min Admission plasma potassium level <4 mmol/l Admission plasma potassium level >=4 mmol/l Diabetes No Diabetes Pre-hospital randomization In-hospital randomization BMI <= 25 BMI > 25
0.65 [ 0.30 , 1.38 ] 0.68 [ 0.30 , 1.54 ] 0.34 [ 0.04 , 3.26 ] 0.73 [ 0.12 , 4.37 ] 0.63 [ 0.27 , 1.46 ] 0.20 [ 0.06 , 0.70 ] 3.47 [ 0.72 , 16.72 ] 0.50 [ 0.20 , 1.25 ] 1.95 [ 0.19 , 4.70 ] 0.83 [ 0.25 , 2.71 ] 0.55 [ 0.20 , 1.48 ] 0.47 [ 0.14 , 1.51 ] 0.94 [ 0.30 , 2.96 ] 0.72 [ 0.23 , 2.27 ] 0.75 [ 0.25 , 2.23 ] 0.63 [ 0.15 , 2.64 ] 0.67 [ 0.26 , 1.74 ] 0.71 [ 0.24 , 2.11 ] 0.73 [ 0.25 , 2.11 ] 0.96 [ 0.28 , 3.33 ] 0.56 [ 0.21 , 1.52 ] 0.62 [ 0.20 , 1.94 ] 0.63 [ 0.21 , 1.92 ] 0.88 [ 0.32 , 2.43 ] 0.45 [ 0.14 , 1.49 ] 0.70 [ 0.20 , 2.49 ] 0.67 [ 0.26 , 1.77 ] 1.33 [ 0.30 , 5.00 ] 0.50 [ 0.20 , 1.24 ] 1.33 [ 0.41 , 33.18 ] 0.50 [ 0.18 , 1.07 ] 0.55 [ 0.20 , 1.51 ] 0.74 [ 0.23 , 2.32 ]
0.00
1.00
2.00
3.00
4.00
5.00
Hazard Ratio MRA better
Standard therapy Better
The type of myocardial infarction in regard to ST-segment elevation significantly impacted mortality. Abbreviations as in Figure 4.
p for interaction
0.57 0.88 0.01 0.50 0.60 0.40 0.96 0.95 0.97 0.51 0.98 0.40 0.96 0.27 0.08 0.70
1923
1924
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Aldosterone Blockade in Myocardial Infarction
eplerenone was initiated 3 to 14 days after the onset
T A B L E 3 6-Month Outcomes: STEMI and NSTEMI Subgroups
of MI complicated by HF and reduced LV function.
STEMI
Primary composite outcome
NSTEMI
The benefit observed was apparently driven by the
Standard Therapy (n ¼ 617)
MRA Regimen (n ¼ 612)
Standard Therapy (n ¼ 183)
MRA Regimen (n ¼ 186)
89 (14.4)
77 (12.6)
9 (4.9)
17 (9.1)
15 (2.4)
3 (0.5)
2 (1.1)
7 (3.8)
outcomes (5–7). The recent REMINDER study also
3 (0.5)
1 (0.2)
0 (0)
1 (0.5)
reported encouraging results with eplerenone in low-
46 (7.5)
42 (6.9)
risk STEMI patients, although the benefit was
group of patients treated earlier (i.e., 3 to 7 days) (22). This finding is consistent with other studies reporting high aldosterone plasma levels early after MI (23,24) and the relationship of these levels with clinical
Components of primary outcome Death Resuscitated cardiac arrest Significant ventricular arrhythmia Indication for implantable defibrillator New or worsening HF
0 (0) 39 (6.3)
5 (0.8) 38 (6.2)
2 (1.1)
3 (1.6)
0 (0)
0 (0)
6 (3.3)
8 (4.3)
observed more on B-type natriuretic peptide levels than clinical outcomes (4). The ALBATROSS study recruited a broad popula-
Values are n (%). Abbreviations as in Tables 1 and 2.
tion of MI representing the general population hospitalized for this condition, rarely associated with concomitant HF or severe LV dysfunction. These pa-
and 0.2% of patients in the MRA and standard therapy alone groups, respectively (HR: 12.12; 95% CI: 2.87 to 51.29; p < 0.0001). The study medication was permanently discontinued in 106 patients (13.2%). The 2 groups were balanced with respect to other adverse events (data not shown) including endocrine and breast disorders which occurred in only 2 (0.25%) patients in the treatment group versus none in the standard therapy arm (p ¼ 0.5).
tients were enrolled early then received IV canrenoate for rapid mineralocorticoid receptor blockade and they had good adherence to spironolactone over 6 months. However, we were unable to show a benefit of early and sustained MRA therapy in this MI population, which cannot be compared to the much higher risk EPHESUS trial population. Although the STEMI population in our study was at much higher risk than the REMINDER (4) population, our finding of a potential mortality benefit in
DISCUSSION
the STEMI cohort must be interpreted with great
Despite a strong pre-clinical rationale and favorable
group at the time of randomization. However, the
clinical data from registries and small randomized
previously mentioned pre-clinical and clinical data,
studies, our randomized trial was unable to show a
as well as the strength of the association, support
benefit of an MRA regimen administered early in pa-
the plausibility of an MRA effect on mortality in the
tients presenting with acute MI, 92% of whom pre-
setting of STEMI, a more homogeneous patient
sented without HF (Central Illustration). Similarly, no
population with more acute and severe myocardial
significant difference was observed on rates of
ischemia
arrhythmia or HF over 6 months of follow-up.
NSTEMI patient groups have similar long-term out-
Intriguingly, there was a reduction of death in the
comes (15), their acute management is different with
group of patients with STEMI receiving the MRA
no need for either urgent reperfusion therapy or
regimen.
aggressive antithrombotic therapy in NSTEMI. Hence
caution in the absence of stratification for this sub-
than
NSTEMI.
Although
STEMI
and
Experimental studies have shown that the early
the early blunting of the previously reported early
use of MRA therapy after MI reduces LV expansion
biological effects of MR activation after acute co-
and extensive fibrosis (9) by antagonizing activation
ronary
of the mineralocorticoid receptor by aldosterone and
a favorable effect through the ‘un-triggering’ of
cortisol (18). The clinical benefit reported previously
neurohormonal activation and the subsequent post-
with MRA use in HF was consistent across groups
MI
defined by the ischemic or nonischemic origin of HF
more acute and enhanced processes in STEMI than
(1,2) and associated with a reduction of mortality in
NSTEMI.
artery
fibrosis
occlusion
and
(9,10,18),
remodeling,
may
which
lead
are
to
much
post-MI patients (3). Thus, the addition of MRAs to
The absence of effect on rates of ventricular
beta-blockers and angiotensin-converting enzyme
arrhythmia in our study is not in contradiction with a
inhibitors has been highly recommended (19–21) in
possible MRA effect on mortality as in both the Ran-
patients with HF and reduced LV function, irre-
domized
spective of the etiology of HF.
EPHESUS (3) trials, where mortality was reduced in
In the EPHESUS (Eplerenone Post-Acute MI Heart Failure
Efficacy
and
Survival
Study)
trial
(3),
Aldosterone
Evaluation
Study
(1)
and
association with MRA therapy despite the absence of any effect on ventricular arrhythmia. Furthermore,
Beygui et al.
JACC VOL. 67, NO. 16, 2016 APRIL 26, 2016:1917–27
Aldosterone Blockade in Myocardial Infarction
CENTRAL ILLUSTRATION Aldosterone Blockade in MI: Mortality Outcomes
Beygui, F. et al. J Am Coll Cardiol. 2016;67(16):1917–27.
Although use of mineralocorticoid receptor antagonists (MRA) significantly reduced mortality in post–myocardial infarction (MI) patients with heart failure in the landmark randomized EPHESUS (Eplerenone Post-Acute MI Heart Failure Efficacy and Survival) study, mineralocorticoid receptor blockade did not decrease mortality compared to standard care in the ALBATROSS (Aldosterone Lethal effects Blocked in Acute MI Treated with or without Reperfusion to improve Outcome and Survival at Six months follow-up) trial in acute MI patients irrespective of the presence of heart failure (HF) or left ventricular dysfunction. CI ¼ confidence interval; HR ¼ hazard ratio; IV ¼ intravenous; Kþ ¼ potassium; NSTEMI ¼ non–ST-segment elevation myocardial infarction; RR ¼ relative risk; STEMI ¼ ST-segment elevation myocardial infarction.
ventricular arrhythmias were considered significant
were equally distributed between the 2 study groups
only if a therapy was required for their treatment (i.e.,
(data not shown).
electrical cardioversion or antiarrhythmic therapy).
STUDY
Hence, the effect of MRA use on global rates of ven-
inherent to the sample size and to the open-label
tricular arrhythmia post-MI cannot be assessed by our
design. However, this study remains the largest
study.
experience in MI patients outside of the scope of HF
LIMITATIONS. Our
study has
limitations
The ALBATROSS study also highlights the relative
and all the events were adjudicated blindly. The
safety of the MRA regimen used. Although the rates of
study suffered from a lack of power as the predicted
hyperkalemia were higher in the MRA group than in
event rate (269) was higher than the actual event rate
the control group, they remained lower than previ-
(194). Despite nonrestrictive inclusion criteria, the
ously reported (3,4) and the rates of adverse events
study included predominantly STEMI patients at
1925
1926
Beygui et al.
JACC VOL. 67, NO. 16, 2016 APRIL 26, 2016:1917–27
Aldosterone Blockade in Myocardial Infarction
lower risk than expected with a possible selection bias. Our trial was not adequately powered to examine hard
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
clinical outcomes. Although the study would have
Gilles Montalescot, ACTION Study Group, Institut de
been adequately powered to demonstrate a mortality
Cardiologie, Pitié-Salpêtrière University Hospital, 47
reduction in STEMI patients, randomization was not
Boulevard de l’Hôpital, 75013 Paris, France. E-mail:
stratified on the type of ACS and our finding should be
[email protected].
considered hypothesis generating at this point. Larger studies are needed to re-examine the effect of MRA
PERSPECTIVES
therapy on such outcomes in STEMI patients. With respect to the multiple testing in the subgroup ana-
COMPETENCY IN MEDICAL KNOWLEDGE:
lyses, the risk of type I error may be important, both for
Administration of a mineralocorticoid receptor antag-
the primary and the mortality endpoints, and the
onist early after myocardial infarction did not reduce
analysis should be considered as only exploratory.
occurrence of the composite of death, ventricular
Finally, the present MRA regimen used potassium
arrhythmia, cardiac arrest, need for implantable defi-
canrenoate and spironolactone, and our results may
brillator, or new or worsening HF at 6 months, but
not be fully extrapolated to eplerenone.
seemed to lower mortality among those presenting
CONCLUSIONS
with ST-segment elevation.
The ALBATROSS trial failed to show a benefit of an MRA regimen initiated early post-MI when HF is largely not present. The results of the ALBATROSS trial do not warrant the extension of MRA use to MI
TRANSLATIONAL OUTLOOK: An adequately powered trial is needed to specifically assess the impact of early mineralocorticoid blockade in patients presenting with STEMI.
patients without HF at this point.
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A PP END IX For an expanded Methods section and a supplemental table, please see the online
Patients with Non-ST-Elevation Acute Coronary
1068–76.
version of this article.
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