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Early Aldosterone Blockade inAcute 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

Fro

Gr

tal

Stu

dio

Fra

Ho

d’AlAC

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Gr

Th

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.

m the aACTION Study Group, Service de Cardiologie, Centre Hospitalier Universitaire de Caen, Caen, France; bACTION Study

oup, Service de Cardiologie, Centre Hospitalier Universitaire de Nimes, Nîmes, France; cService de Cardiologie, Centre Hospi-

ier Universitaire de Montpellier, Montpellier, France; dService de Cardiologie, Centre Hospitalier de Pau, Pau, France; eACTION

dy Group, Institut de Cardiologie (AP-HP), Centre Hospitalier Universitaire Pitié-Salpêtri _ere, Paris, France; fService de Car-

logie, Centre Hospitalier Universitaire de Lille, Lille, France; gService de Cardiologie, Centre Hospitalier d’Annecy, Annecy,

nce; hService de Cardiologie, Centre Hospitalier Universitaire de Toulouse, Toulouse, France; iService de Cardiologie, Centre

spitalier Universitaire de Clermont Ferrand, Clermont Ferrand, France; jService de Cardiologie, Centre Hospitalier Universitaire

ngers, Angers, France; kService d’Accueil des Urgences et SAMU, Centre Hospitalier Universitaire de Lille, Lille, France;

TION Study Group, SAMU, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France; mACTION Study Group, Unite de

cherche Clinique, Hôpital Lariboisière, Paris, France; nService de Cardiologie, Centre Hospitalier Universitaire de Grenoble,

enoble, France; and oINSERM, CIC 1433 et Pôle de Cardiologie, Centre Hospitalier Universitaire de Nancy, Nancy, France.

e trial was led by members of the nonprofit academic research organization ACTION, based at Pitié-Salpêtrière Hospital, Paris,

ABBR EV I A T I ON S

AND ACRONYMS

CI = confidence interval

HF = heart failure

HR = hazard ratio

IV = intravenous

MI = myocardial infarction

MRA = mineralocorticoid

receptor antagonists

NSTEMI = non–ST-segment

elevation myocardial infarction

STEMI = ST-segment elevation

myocardial infarction

France (ww

funded by

Nutrition (

collection,

institution

and Therm

Dr. Cayla h

Pfizer, and

Institute of

Cardiologie

Algorythm,

Dr. Collet h

speakers fe

received co

from Eli Li

Bayer, Berl

Cardiologie

from Amge

Brigham W

Fondazione

and WebM

Manuscript

Beygui et al. J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6

Aldosterone Blockade in Myocardial Infarction A P R I L 2 6 , 2 0 1 6 : 1 9 1 7 – 2 7

1918

T he mineralocorticoid receptor an-tagonists (MRA) spironolactone andeplerenone reduce mortality in the

setting of heart failure (HF) with reducedejection fraction (1,2). Eplerenone initiated3 to 14 days after ST-segment elevationmyocardial infarction (STEMI) or non–ST-segment elevation myocardial infarction(NSTEMI) complicated by left ventricular(LV) dysfunction and HF is also associatedwith a reduction of mortality (3). However,there is limited clinical evidence withMRAs in myocardial infarctions (MI) inde-pendent of HF. The REMINDER (Double-

Blind, Randomized, Placebo-Controlled TrialEvaluating The Safety And Efficacy Of Early Treat-ment With Eplerenone In Patients With AcuteMyocardial Infarction) trial (4) showed that eplere-none used within the first 24 h of STEMI was safeand effective on a composite outcome mainly drivenby the biological outcome of a lower plasma level ofB-type natriuretic peptide.

SEE PAGE 1928

High aldosterone plasma levels early after STEMIor NSTEMI are associated with mortality, suddencardiac death, and HF (5–8). Experimental studieshave shown that early MRA administration aftermyocardial infarction (MI) could improve myocardialhealing (9) as well as both electrical and structuralremodeling (10). Small-sized studies have also re-ported benefits of MRA therapy initiated early after

w.action-coeur.org). The study was sponsored by the Assistance

public grants from the French Ministry of Health and the Fou

ICAN). The funding organizations had no involvement in the d

analysis of the results, or writing of the manuscript. Dr. Beygui

from AstraZeneca, Bayer, Eli Lilly, Fédération Française de Cardio

ofischer; and consulting or lecture fees from AstraZeneca, Bristo

as received lecture fees from AstraZeneca, Biotronik, Daiichi-Sank

Sanofi. Dr. Silvain has received research grants to the institution

Cardiometabolism (ICAN), INSERM, Fédération Française de Car

, and Sanofi; consulting fees from Actelion, AstraZeneca, Daiic

AstraZeneca, and Bristol-Myers Squibb; and travel fees from Astr

as received research grant support, consulting fees, and speaker

es and served on the Speakers Bureau for AstraZeneca, Boehring

nsulting fees from Pfizer, Novartis, BMS, Abbott Vascular, and S

lly. Dr. Montalescot has received research or educational grants

in Chimie AG, Boehringer Ingelheim, Bristol-Myers Squibb, Cellad

, Gilead, ICAN, Janssen, Medtronic, MSD, Pfizer, Sanofi, and The

n, AstraZeneca, Bayer, Berlin Chimie AG, Boehringer Ingelheim, B

omen’s Hospital, Cardiovascular Research Foundation, CME Re

Anna Maria Sechi per il Cuore, Lead-Up, Menarini, MSD, Pfizer,

D. All other authors have reported that they have no relationship

received October 20, 2015; revised manuscript received Februar

MI in the prevention of LV remodeling (11,12) and life-threatening arrhythmia (13,14).

Whether MRA use could improve clinical outcomesof acute MI independent of the type of MI, reperfu-sion strategy, or the presence of LV dysfunction or HFis unknown.

The objective of the ALBATROSS (AldosteroneLethal effects Blocked in Acute MI Treated with orwithout Reperfusion to improve Outcome and Sur-vival at Six months follow-up) trial was to investigatethe clinical effects of a rapid and prolonged MRAregimen initiated early after the onset of any typeof MI.

METHODS

STUDY DESIGN AND POPULATION. ALBATROSS is amulticenter, nationwide, randomized, open-labeled,blinded endpoint, clinical trial. The study wasdesigned to assess the superiority of an MRA regimeninitiated early after presentation for STEMI orhigh-risk NSTEMI plus standard therapy versusstandard therapy alone (15). Patients were random-ized as early as possible, including by pre-hospitalmedical teams (ambulance) when possible, to allowrapid administration of the treatment. The coordi-nating center was the ACTION (Allies in Cardiovas-cular Trials, Initiatives, and Organized Networks)Study Group at Pitié-Salpêtrière hospital. The studydesign and protocol have been published previously(16). The hypotheses used for the study’s sample sizecalculation are reported in the Online Appendix.

Publique-Hôpitaux de Paris (AP-HP) and exclusively

ndation of the Institute of Cardiometabolism And

esign or conduct of the study, site selection, data

has received research or educational grants to the

logie, Medtronic, Terumo, Biosensor, Pfizer, Sanofi,

l-Myers Squibb, Daiichi-Sankyo, Eli Lilly, and Pfizer.

yo, Bayer, BMS, Eli Lilly, Novartis, Medtronic, MSD,

from AstraZeneca, Brahms, Daiichi-Sankyo, Eli Lilly,

diologie, Fondation de France, Société Française de

hi-Sankyo, Eli Lilly, and Sanofi; lecture fees from

aZeneca, B. Braun, Bristol-Myers Squibb, and Pfizer.

s fees from AstraZeneca. Dr. Goldstein has received

er Ingelheim, BMS Pfizer, and Bayer. Dr. Vicaut has

orin; and his institution has received grant support

to the institution from ADIR, Amgen, AstraZeneca,

on, Daiichi-Sankyo, Eli Lilly, Fédération Française de

Medicines Company; and consulting or lecture fees

ristol-Myers Squibb, Beth Israel Deaconess Medical,

sources, Daiichi-Sankyo, Eli Lilly, Europa, Elsevier,

Sanofi, The Medicines Company, TIMI Study Group,

s relevant to the contents of this paper to disclose.

y 12, 2016, accepted February 15, 2016.

J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6 Beygui et al.A P R I L 2 6 , 2 0 1 6 : 1 9 1 7 – 2 7 Aldosterone Blockade in Myocardial Infarction

1919

The study was undertaken according to theDeclaration of Helsinki and approved by the FrenchNational Institutional Ethical Review Board. Writteninformed consent was obtained from all patientsbefore randomization.

To be eligible, patients had to have an ischemicsymptomwithin 72 h before randomization and at least1 of the following indicators of MI: ST-segment eleva-tion in at least 2 contiguous leads; new or undated leftbundle branch block; Q waves in at least 2 contiguousleads (not known to be old); troponin levels $3 timesthe upper limit of normal; and Thrombolysis InMyocardial Infarction score $3 in the case of NSTEMI.Key exclusion criteria included known hyperkalemia,renal insufficiency, severe liver dysfunction, and car-diac arrest prior to randomization.

Eligible subjects were randomized in a 1:1 ratio toreceive either the MRA regimen added to standardtherapy or standard therapy alone. Randomizationwas conducted via a central interactive voicerandomization system with stratification by centerusing random sequences of block sizes. All subjects

FIGURE 1 Patient Enrollment and Follow-Up Flow Chart

1622 Patients enrolle

1616 Patients randomiz

1615 patients were correctly ra

1603 included in the“intention-to-treat” anal

801 were analyzed in the “standardtreatment” arm

802

Patients were randomized to mineralocorticoid receptor antagonist (MR

were to be treated by the most adapted therapy basedon international guidelines.

Patients assigned to the MRA regimen received a200 mg intravenous (IV) bolus of potassium canre-noate as soon as possible. A first 25 mg oral dose ofspironolactone was administered 12 to 24 h after theIV injection, after control of plasma concentrations ofpotassium and creatinine. The oral dose was notgiven if the first blood sample revealed a potassiumlevel >5.5 mmol/l–1 or a creatinine level >220 mmol/l–1.Such patients were nevertheless kept in theintention-to-treat analysis.

Patients were followed for 6 months afterrandomization and visits after hospital dischargeincluded measurements of LV ejection fraction. Spi-ronolactone was suspended during follow-up ifplasma potassium concentrations were >5.5 mmol/l–1

and/or plasma creatinine levels were >220 mmol/l–1

on any blood sample whether protocol-specifiedor not. The treatment was reintroduced afternormalization of potassium and creatinine levels ifthe cause was considered reversible. The study

d

ed

1 Patient was randomized twice

ndomized

15 patients were excluded :- 12 patients withdrew or had invalid

consent

ysis

were analyzed in the “MRAregimen” arm

A) therapy or standard care.

TABLE 1 Patient Cha

Age, yrs

Female

Body mass index, kg/m

Risk factors and medic

Current smoking

Hypertension

Diabetes

Dyslipidemia

Prior MI

Prior heart failure

Prior CABG

Prior PCI

Prior stroke

Prior cancer

Presentation*

STEMI

NSTEMI

Killip class*

I

II

III

IV

>I

Creatinine clearance,

Potassium at admiss

Admission GRACE sc

In-hospital medication

Aspirin

P2Y12 antagonist

Beta-blocker

Statin

ACE inhibitor/ARB

Fibrinolysis†

Glycoprotein IIb/IIIa

Interventional or surgic

Coronary angiograph

PCI

Primary PCI†

CABG

Left ventricular ejectio

Values are median (interqinfarction and Killip class wMRA regimen (n ¼ 612) gr

ACE ¼ angiotensin-convgraft surgery; GRACE ¼ Galocorticoid receptor antagcoronary intervention; STE

Beygui et al. J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6

Aldosterone Blockade in Myocardial Infarction A P R I L 2 6 , 2 0 1 6 : 1 9 1 7 – 2 7

1920

treatment was permanently discontinued if hyper-kalemia >5.5 mmol/l–1 recurred after reintroductionof spironolactone, if any plasma potassium level was>6 mmol/l–1, or in case of clinical intolerance.

STUDY OUTCOMES. The primary outcome was thecomposite of death, resuscitated cardiac arrest, sig-nificant ventricular arrhythmia, class IA indication

racteristics and Management

Standard Treatment(n ¼ 801)

MRA Regimen(n ¼ 802)

58 (50.0–67.0) 58 (50.0–67.0)

143 (17.9) 129 (16.1)2 26.4 (24.0–29.7) 26.1 (23.8–28.9)

al history

414 (51.7) 377 (47.0)

352 (43.9) 335 (41.8)

126 (15.7) 128 (16.0)

368 (45.9) 375 (46.8)

73 (9.1) 65 (8.1)

5 (0.6) 9 (1.1)

11 (1.4) 13 (1.6)

86 (10.7) 74 (9.2)

18 (2.2) 24 (3.0)

41 (5.1) 32 (4.0)

617 (77.0) 612 (76.3)

183 (22.8) 186 (23.2)

732 (91.4) 750 (93.5)

52 (6.5) 39 (4.9)

6 (0.7) 9 (1.1)

7 (0.9) 3 (0.4)

65 (8.1) 51 (6.4)

ml/min–1* 101.35 (77.26–121.14) 95.96 (75.39–119.66)

ion, mmol/l–1 4.0 (3.7–4.3) 4.0 (3.7–4.3)

ore 132 � 31 133 � 29

796 (99.4) 797 (99.4)

796 (99.4) 797 (99.4)

744 (92.9) 750 (93.5)

779 (97.3) 769 (95.9)

718 (89.6) 702 (87.5)

72 (11.7) 64 (10.5)

inhibitor† 270 (43.8) 268 (43.8)

al procedures

y 792 (98.9) 793 (98.9)

727 (90.8) 720 (89.8)

501 (81.2) 502 (82.0)

23 (2.9) 26 (3.2)

n fraction, %* 50 (45–60) 50 (45–60)

uartile range), n (%), or mean � SD. *The information on the type of myocardialas missing in 5 patients. †In patients with STEMI in the standard therapy (n ¼ 617) andoups.

erting enzyme; ARB ¼ angiotensin receptor blocker; CABG ¼ coronary artery bypasslobal Registry of Acute Coronary Events; MI ¼ myocardial infarction; MRA ¼ miner-onist; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PCI ¼ percutaneousMI ¼ ST-segment elevation myocardial infarction.

(17) for implantable defibrillator, or new or worseningHF during 6-month follow-up.

Key secondary efficacy outcomes included eachindividual component of the primary outcome; thecomposite of death or resuscitated cardiac arrest; thecomposite of death or new or worsening HF; death ofcardiovascular origin; recurrent MI; and urgent orunplanned revascularization, all at 6 months.

Premature discontinuation of study treatment,acute renal failure, and hyperkalemia were closelymonitored. All outcomes were adjudicated in ablinded manner by an independent adjudicationcommittee.

STATISTICAL ANALYSIS. We hypothesized that the6-month rate of the primary endpoint would be 20%in the standard therapy alone arm. With a sample sizeof 793 per arm (for a total of approximately 1,600subjects), a total event rate of 269 and an estimatedconstant hazard ratio (HR) of 0.71 associated with theMRA regimen, using a bilateral equality of survivallog-rank test, the study would achieve an 80% powerto detect a difference between a 0.853 proportion in1 group and a 0.800 proportion in the other group at6 months with a p value of 0.049.

The main efficacy analysis was based on all eventsthat occurred in the intention-to-treat populationdefined as all randomized patients who signed aninformed consent form. In case of consent with-drawal, only data collected before withdrawal wereused.

The primary analysis based on all events corre-sponding to the primary outcome was carried outusing a Kaplan-Meier survival analysis with a log-rank test. All patients were censored at the time ofthe last observation. A Cox survival model was usedfor the calculation of the HR presented with its2-sided 95% confidence interval (CI) for the primaryendpoint and for the analysis of all secondary out-comes at 6 months. Variables assessed at specific timepoints were analyzed using a logistic regressionmodel with calculation of odds ratios and their2-sided 95% CI. Safety analyses were performed onthe per-protocol set. Rates of adverse events werecompared between groups using chi-square or Fisherexact tests where appropriate. Consistency of thetreatment effect was analyzed among 16 patientsubgroups. All tests had a 2-sided significance level of5% and were performed using SAS software, version9.3 (SAS Institute, Cary, North Carolina).

RESULTS

Between February 2010 and January 2014, a total of1,622 patients consented and were randomly assigned

FIGURE 2 Primary Outcome

1.0

0.8

0.6

0.4

0.2

0.00 50 100 150 200

Days Since Randomization

Prim

ary

End

Poin

t

0.20

0.15

0.10

0.05

0.000 50 100 150 200

Hazard ratio, 0.97 (95% CI 0.73-1.28)p = 0. 81

Standard Therapy

MRA regimen

N at risk

Standard Therapy

MRA Regimen801

802

687

705

669

683

645

660

273

183

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.

TABLE 2 Primary and Key Secondary Outcomes at 6-Month Follow-Up

StandardTherapy(n ¼ 801)

MRA Regimen(n ¼ 802) HR (95% CI) p Value

Primary composite outcome 98 (12.2) 95 (11.8) 0.97 (0.73–1.28) 0.81

Components of primary outcome

Death 17 (2.1) 11 (1.4) 0.65 (0.30–1.38) 0.26

Resuscitated cardiac arrest 3 (0.4) 2 (0.2) 0.66 (0.11–3.92) 0.64

Significant ventricular arrhythmia 48 (6) 45 (5.6) 0.94 (0.62–1.40) 0.75

Indication for implantable defibrillator 6 (0.7) 5 (0.6) 0.82 (0.25–2.67) 0.74

New or worsening HF 45 (5.6) 47 (5.9) 1.04 (0.69–1.57) 0.85

Death or resuscitated cardiac arrest 19 (2.4) 13 (1.6) 0.68 (0.34–1.38) 0.28

Death or new or worsening HF 53 (6.6) 54 (6.7) 1.02 (0.70–1.49) 0.93

Death of cardiovascular origin 14 (1.7) 9 (1.1) 0.64 (0.28–1.49) 0.30

Recurrent MI 8 (1) 5 (0.6) 0.62 (0.20–1.88) 0.39

Urgent or unplanned revascularization 17 (2.1) 19 (2.4) 1.10 (0.57–2.12) 0.77

Values are n (%).

CI ¼ confidence interval; HF ¼ heart failure; HR ¼ hazard ratio; other abbreviations as in Table 1.

J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6 Beygui et al.A P R I L 2 6 , 2 0 1 6 : 1 9 1 7 – 2 7 Aldosterone Blockade in Myocardial Infarction

1921

to the MRA regimen plus standard therapy (n ¼ 802)or standard therapy alone (n ¼ 801) (Figure 1). Thegroups were well balanced with respect to baselinecharacteristics and treatment strategies (Table 1). Thestandard of care included an invasive strategy withcoronary angiography performed in 1,582 (98.7%) andpercutaneous coronary intervention in 1,447 (90.3%)of the patients. Three-quarters of the study popula-tion (n ¼ 1,229) presented with ongoing STEMI, ofwhom 1,003 (81.6%) underwent primary percuta-neous coronary intervention whereas 136 (11.1%)received fibrinolysis. HF at presentation was presentin 116 (7.2%) patients. A total of 59 (3.7%) patients inthe standard therapy alone group received an MRA(eplerenone in all) during follow-up based on physi-cian decision.

After a median follow-up of 188 days (interquartilerange: 179 to 210 days), the primary outcome(Figure 2, Table 2) occurred in 95 (11.8%) and 98(12.2%) patients in the MRA and standard therapygroups, respectively (HR: 0.97; 95% CI: 0.73 to 1.28).Death from any cause (Figure 3A), as well as all othercomponents of the primary outcome (Table 2), didnot differ between the 2 groups. All secondary out-comes occurred with comparable rates in the 2 groups(Table 2).

The results were consistent among all pre-specifiedsubgroups with respect to the primary outcome(Figure 4). The primary outcome was numericallylower with MRA therapy in the STEMI group (p forinteraction ¼ 0.08). Considering mortality, a signifi-cant interaction (p ¼ 0.01) was found between thetreatment effect and type of MI (STEMI vs. NSTEMI)

FIGURE 3 Kaplan-Meier Estimates of Death

1.0

0.8

0.6

0.4

0.2

0.00 50 100 150 200

Days Since Randomization

Deat

h

0 50 100 150 200

0.05

0.04

0.03

0.02

0.01

0.00

1.0

0.8

0.6

0.4

0.2

0.00 50 100 150 200

Days Since Randomization

Deat

h

0 50 100 150 200

0.05

0.04

0.03

0.02

0.01

0.00

Standard Therapy

MRA regimen

Standard Therapy

MRA regimen

Hazard ratio, 0.65 (95% CI 0.30-1.38)p = 0. 26

Hazard ratio, 0.20 (95% CI 0.06-0.69)p = 0. 0044

N at risks

Standard Therapy

MRA Regimen801

802

760

776

746

763

719

741

311

211

N at risks

Standard Therapy

MRA Regimen617

612

587

595

579

587

556

571

236

162

A

B

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.

Beygui et al. J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6

Aldosterone Blockade in Myocardial Infarction A P R I L 2 6 , 2 0 1 6 : 1 9 1 7 – 2 7

1922

(Figure 5). Compared to standard therapy alone, MRAuse reduced the odds of death (3 [0.5%] vs. 15 [2.4%];HR: 0.20; 95% CI: 0.06 to 0.70; p ¼ 0.0044) in theSTEMI subgroup (n ¼ 1,229), but not in the NSTEMIsubgroup (Figure 3B). The rates of the components ofthe primary endpoint in STEMI and NSTEMI groups

and the causes of death are reported in Table 3 andOnline Table 1, respectively.

There was a trend (HR: 1.37; 95% CI: 0.97 to 1.95;p ¼ 0.075) towards higher rates of protocol-definedacute renal failure associated with the MRAregimen. Hyperkalemia >5.5 mmol/l–1 occurred in 3%

FIGURE 4 Subgroup Analyses: Primary Outcome

Subgroups Primary OutcomeHazard ratio

[95% confidence interval]p for

interaction

0.00 1.00 2.00 3.00 4.00 5.00Hazard Ratio

MRA better Standard therapy Better

All patientsAge >= 65Age < 65WomenMenSTEMINSTEMIPCINo PCIACE or ARB before randomizationNeither ACE nor ARB before randomizationACE or ARB after randomizationNeither ACE nor ARB after randomizationBB after randomizationNo BB after randomizationACE/ARB and BB after randomizationno ACE/ARB or no BB or neither after randomizationKillip Class >= 2Killip Class = 1Pulsed blood pressure < 45mm HgPulsed blood pressure >= 45mm HgLeft ventricular ejection fraction < 40%Left ventricular ejection fraction >= 40%Admission creatinine clearance > 60ml/minAdmission creatinine clearance <= 60ml/minAdmission plasma potassium level <4 mmol/lAdmission plasma potassium level >=4 mmol/lDiabetesNo DiabetesPre-hospital randomizationIn-hospital randomizationBMI <= 25BMI > 25

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 ]

0.97

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

Results were consistent across pre-specified subgroups. ACE ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; BB ¼ beta-

blocker; BMI ¼ body mass index; MRA ¼ mineralocorticoid receptor antagonist; NSTEMI ¼ non-ST-segment elevation myocardial infarction; PCI ¼percutaneous coronary intervention; STEMI ¼ ST-segment elevation myocardial infarction.

FIGURE 5 Subgroup Analyses: Mortality

0.00 1.00 2.00 3.00 4.00 5.00Hazard Ratio

MRA better Standard therapy Better

Subgroups DeathHazard ratio

[95% confidence interval]p for

interaction

All patientsAge >= 65Age < 65WomenMenSTEMINSTEMIPCINo PCIACE or ARB before randomizationNeither ACE nor ARB before randomizationACE or ARB after randomizationNeither ACE nor ARB after randomizationBB after randomizationNo BB after randomizationACE/ARB and BB after randomizationno ACE/ARB or no BB or neither after randomizationKillip Class >= 2Killip Class = 1Pulsed blood pressure < 45mm HgPulsed blood pressure >= 45mm HgLeft ventricular ejection fraction < 40%Left ventricular ejection fraction >= 40%Admission creatinine clearance > 60ml/minAdmission creatinine clearance <= 60ml/minAdmission plasma potassium level <4 mmol/lAdmission plasma potassium level >=4 mmol/lDiabetesNo DiabetesPre-hospital randomizationIn-hospital randomizationBMI <= 25BMI > 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 ]

0.57

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

The type of myocardial infarction in regard to ST-segment elevation significantly impacted mortality. Abbreviations as in Figure 4.

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TABLE 3 6-Month Outcomes: STEMI and NSTEMI Subgroups

STEMI NSTEMI

StandardTherapy(n ¼ 617)

MRARegimen(n ¼ 612)

StandardTherapy(n ¼ 183)

MRARegimen(n ¼ 186)

Primary composite outcome 89 (14.4) 77 (12.6) 9 (4.9) 17 (9.1)

Components of primary outcome

Death 15 (2.4) 3 (0.5) 2 (1.1) 7 (3.8)

Resuscitated cardiac arrest 3 (0.5) 1 (0.2) 0 (0) 1 (0.5)

Significant ventricular arrhythmia 46 (7.5) 42 (6.9) 2 (1.1) 3 (1.6)

Indication for implantable defibrillator 0 (0) 5 (0.8) 0 (0) 0 (0)

New or worsening HF 39 (6.3) 38 (6.2) 6 (3.3) 8 (4.3)

Values are n (%).

Abbreviations as in Tables 1 and 2.

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and 0.2% of patients in the MRA and standard therapyalone groups, respectively (HR: 12.12; 95% CI: 2.87 to51.29; p < 0.0001). The study medication waspermanently discontinued in 106 patients (13.2%).The 2 groups were balanced with respect to otheradverse events (data not shown) including endocrineand breast disorders which occurred in only 2 (0.25%)patients in the treatment group versus none in thestandard therapy arm (p ¼ 0.5).

DISCUSSION

Despite a strong pre-clinical rationale and favorableclinical data from registries and small randomizedstudies, our randomized trial was unable to show abenefit of an MRA regimen administered early in pa-tients presenting with acute MI, 92% of whom pre-sented without HF (Central Illustration). Similarly, nosignificant difference was observed on rates ofarrhythmia or HF over 6 months of follow-up.Intriguingly, there was a reduction of death in thegroup of patients with STEMI receiving the MRAregimen.

Experimental studies have shown that the earlyuse of MRA therapy after MI reduces LV expansionand extensive fibrosis (9) by antagonizing activationof the mineralocorticoid receptor by aldosterone andcortisol (18). The clinical benefit reported previouslywith MRA use in HF was consistent across groupsdefined by the ischemic or nonischemic origin of HF(1,2) and associated with a reduction of mortality inpost-MI patients (3). Thus, the addition of MRAs tobeta-blockers and angiotensin-converting enzymeinhibitors has been highly recommended (19–21) inpatients with HF and reduced LV function, irre-spective of the etiology of HF.

In the EPHESUS (Eplerenone Post-Acute MI HeartFailure Efficacy and Survival Study) trial (3),

eplerenone was initiated 3 to 14 days after the onsetof MI complicated by HF and reduced LV function.The benefit observed was apparently driven by thegroup of patients treated earlier (i.e., 3 to 7 days) (22).This finding is consistent with other studies reportinghigh aldosterone plasma levels early after MI (23,24)and the relationship of these levels with clinicaloutcomes (5–7). The recent REMINDER study alsoreported encouraging results with eplerenone in low-risk STEMI patients, although the benefit wasobserved more on B-type natriuretic peptide levelsthan clinical outcomes (4).

The ALBATROSS study recruited a broad popula-tion of MI representing the general population hos-pitalized for this condition, rarely associated withconcomitant HF or severe LV dysfunction. These pa-tients were enrolled early then received IV canre-noate for rapid mineralocorticoid receptor blockadeand they had good adherence to spironolactone over6 months. However, we were unable to show a benefitof early and sustained MRA therapy in this MI popu-lation, which cannot be compared to the much higherrisk EPHESUS trial population.

Although the STEMI population in our study wasat much higher risk than the REMINDER (4) popu-lation, our finding of a potential mortality benefit inthe STEMI cohort must be interpreted with greatcaution in the absence of stratification for this sub-group at the time of randomization. However, thepreviously mentioned pre-clinical and clinical data,as well as the strength of the association, supportthe plausibility of an MRA effect on mortality in thesetting of STEMI, a more homogeneous patientpopulation with more acute and severe myocardialischemia than NSTEMI. Although STEMI andNSTEMI patient groups have similar long-term out-comes (15), their acute management is different withno need for either urgent reperfusion therapy oraggressive antithrombotic therapy in NSTEMI. Hencethe early blunting of the previously reported earlybiological effects of MR activation after acute co-ronary artery occlusion (9,10,18), may lead toa favorable effect through the ‘un-triggering’ ofneurohormonal activation and the subsequent post-MI fibrosis and remodeling, which are muchmore acute and enhanced processes in STEMI thanNSTEMI.

The absence of effect on rates of ventriculararrhythmia in our study is not in contradiction with apossible MRA effect on mortality as in both the Ran-domized Aldosterone Evaluation Study (1) andEPHESUS (3) trials, where mortality was reduced inassociation with MRA therapy despite the absence ofany effect on ventricular arrhythmia. Furthermore,

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 reducedmortality 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.

J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6 Beygui et al.A P R I L 2 6 , 2 0 1 6 : 1 9 1 7 – 2 7 Aldosterone Blockade in Myocardial Infarction

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ventricular arrhythmias were considered significantonly if a therapy was required for their treatment (i.e.,electrical cardioversion or antiarrhythmic therapy).Hence, the effect of MRA use on global rates of ven-tricular arrhythmia post-MI cannot be assessed by ourstudy.

The ALBATROSS study also highlights the relativesafety of the MRA regimen used. Although the rates ofhyperkalemia were higher in the MRA group than inthe control group, they remained lower than previ-ously reported (3,4) and the rates of adverse events

were equally distributed between the 2 study groups(data not shown).STUDY LIMITATIONS. Our study has limitationsinherent to the sample size and to the open-labeldesign. However, this study remains the largestexperience in MI patients outside of the scope of HFand all the events were adjudicated blindly. Thestudy suffered from a lack of power as the predictedevent rate (269) was higher than the actual event rate(194). Despite nonrestrictive inclusion criteria, thestudy included predominantly STEMI patients at

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE:

Administration of a mineralocorticoid receptor antag-

onist early after myocardial infarction did not reduce

occurrence of the composite of death, ventricular

arrhythmia, cardiac arrest, need for implantable defi-

brillator, or new or worsening HF at 6 months, but

seemed to lower mortality among those presenting

with ST-segment elevation.

TRANSLATIONAL OUTLOOK: An adequately

powered trial is needed to specifically assess the

impact of early mineralocorticoid blockade in patients

presenting with STEMI.

Beygui et al. J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6

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lower risk than expected with a possible selection bias.Our trial was not adequately powered to examine hardclinical outcomes. Although the study would havebeen adequately powered to demonstrate a mortalityreduction in STEMI patients, randomization was notstratified on the type of ACS and our finding should beconsidered hypothesis generating at this point. Largerstudies are needed to re-examine the effect of MRAtherapy on such outcomes in STEMI patients. Withrespect to the multiple testing in the subgroup ana-lyses, the risk of type I error may be important, both forthe primary and the mortality endpoints, and theanalysis should be considered as only exploratory.Finally, the present MRA regimen used potassiumcanrenoate and spironolactone, and our results maynot be fully extrapolated to eplerenone.

CONCLUSIONS

The ALBATROSS trial failed to show a benefit of anMRA regimen initiated early post-MI when HF islargely not present. The results of the ALBATROSStrial do not warrant the extension of MRA use to MIpatients without HF at this point.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Gilles Montalescot, ACTION Study Group, Institut deCardiologie, Pitié-Salpêtrière University Hospital, 47Boulevard de l’Hôpital, 75013 Paris, France. E-mail:gilles.montalescot@aphp.fr.

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KEY WORDS left ventricular dysfunction,mineralocorticoid receptor antagonists,mortality

APPENDIX For an expanded Methods sectionand a supplemental table, please see the onlineversion of this article.