Author + information
- Received October 20, 2015
- Revision received February 12, 2016
- Accepted February 15, 2016
- Published online April 26, 2016.
- Farzin Beygui, MD, PhDa,
- Guillaume Cayla, MD, PhDb,
- Vincent Roule, MDa,
- François Roubille, MD, PhDc,
- Nicolas Delarche, MDd,
- Johanne Silvain, MD, PhDe,
- Eric Van Belle, MD, PhDf,
- Loic Belle, MDg,
- Michel Galinier, MDh,
- Pascal Motreff, MD, PhDi,
- Luc Cornillet, MD, PhDb,
- Jean-Philippe Collet, MD, PhDe,
- Alain Furber, MD, PhDj,
- Patrick Goldstein, MDk,
- Patrick Ecollan, MDl,
- Damien Legallois, MDa,
- Alain Lebon, MDa,
- Hélène Rousseau, MScm,
- Jacques Machecourt, MDn,
- Faiez Zannad, MD, PhDo,
- Eric Vicaut, MD, PhDm,
- Gilles Montalescot, MD, PhDe,∗ (, )
- ALBATROSS Investigators
- 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 Hospitalier 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-Salpêtriėre, 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
- lACTION Study Group, SAMU, Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France
- mACTION Study Group, Unite de Recherche Clinique, Hôpital Lariboisière, Paris, France
- nService de Cardiologie, Centre Hospitalier Universitaire de Grenoble, Grenoble, France
- oINSERM, CIC 1433 et Pôle de Cardiologie, Centre Hospitalier Universitaire de Nancy, Nancy, France
- ↵∗Reprint requests and correspondence:
Dr. Gilles Montalescot, ACTION Study Group, Institut de Cardiologie, Pitié-Salpêtrière University Hospital, 47 Boulevard de l’Hôpital, 75013 Paris, France.
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 = 1,229), but not in non–ST-segment elevation MI (p for interaction = 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).
The mineralocorticoid receptor antagonists (MRA) spironolactone and eplerenone reduce mortality in the setting of heart failure (HF) with reduced ejection fraction (1,2). Eplerenone initiated 3 to 14 days after ST-segment elevation myocardial infarction (STEMI) or non–ST-segment elevation myocardial infarction (NSTEMI) complicated by left ventricular (LV) dysfunction and HF is also associated with a reduction of mortality (3). However, there is limited clinical evidence with MRAs in myocardial infarctions (MI) independent of HF. The REMINDER (Double-Blind, Randomized, Placebo-Controlled Trial Evaluating The Safety And Efficacy Of Early Treatment With Eplerenone In Patients With Acute Myocardial Infarction) trial (4) showed that eplerenone used within the first 24 h of STEMI was safe and effective on a composite outcome mainly driven by the biological outcome of a lower plasma level of B-type natriuretic peptide.
High aldosterone plasma levels early after STEMI or NSTEMI are associated with mortality, sudden cardiac death, and HF (5–8). Experimental studies have shown that early MRA administration after myocardial infarction (MI) could improve myocardial healing (9) as well as both electrical and structural remodeling (10). Small-sized studies have also reported benefits of MRA therapy initiated early after MI in the prevention of LV remodeling (11,12) and life-threatening arrhythmia (13,14).
Whether MRA use could improve clinical outcomes of acute MI independent of the type of MI, reperfusion strategy, or the presence of LV dysfunction or HF is unknown.
The objective of 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 was to investigate the clinical effects of a rapid and prolonged MRA regimen initiated early after the onset of any type of MI.
Study design and population
ALBATROSS is a multicenter, nationwide, randomized, open-labeled, blinded endpoint, clinical trial. The study was designed to assess the superiority of an MRA regimen initiated early after presentation for STEMI or high-risk NSTEMI plus standard therapy versus standard therapy alone (15). Patients were randomized as early as possible, including by pre-hospital medical teams (ambulance) when possible, to allow rapid administration of the treatment. The coordinating center was the ACTION (Allies in Cardiovascular Trials, Initiatives, and Organized Networks) Study Group at Pitié-Salpêtrière hospital. The study design and protocol have been published previously (16). The hypotheses used for the study’s sample size calculation are reported in the Online Appendix.
The study was undertaken according to the Declaration of Helsinki and approved by the French National Institutional Ethical Review Board. Written informed consent was obtained from all patients before randomization.
To be eligible, patients had to have an ischemic symptom within 72 h before randomization and at least 1 of the following indicators of MI: ST-segment elevation in at least 2 contiguous leads; new or undated left bundle branch block; Q waves in at least 2 contiguous leads (not known to be old); troponin levels ≥3 times the upper limit of normal; and Thrombolysis In Myocardial Infarction score ≥3 in the case of NSTEMI. Key exclusion criteria included known hyperkalemia, renal insufficiency, severe liver dysfunction, and cardiac arrest prior to randomization.
Eligible subjects were randomized in a 1:1 ratio to receive either the MRA regimen added to standard therapy or standard therapy alone. Randomization was conducted via a central interactive voice randomization system with stratification by center using random sequences of block sizes. All subjects were to be treated by the most adapted therapy based on international guidelines.
Patients assigned to the MRA regimen received a 200 mg intravenous (IV) bolus of potassium canrenoate as soon as possible. A first 25 mg oral dose of spironolactone was administered 12 to 24 h after the IV injection, after control of plasma concentrations of potassium and creatinine. The oral dose was not given if the first blood sample revealed a potassium level >5.5 mmol/l–1 or a creatinine level >220 μmol/l–1. Such patients were nevertheless kept in the intention-to-treat analysis.
Patients were followed for 6 months after randomization and visits after hospital discharge included measurements of LV ejection fraction. Spironolactone was suspended during follow-up if plasma potassium concentrations were >5.5 mmol/l–1 and/or plasma creatinine levels were >220 μmol/l–1 on any blood sample whether protocol-specified or not. The treatment was reintroduced after normalization of potassium and creatinine levels if the cause was considered reversible. The study treatment was permanently discontinued if hyperkalemia >5.5 mmol/l–1 recurred after reintroduction of spironolactone, if any plasma potassium level was >6 mmol/l–1, or in case of clinical intolerance.
The primary outcome was the composite of death, resuscitated cardiac arrest, significant ventricular arrhythmia, class IA indication (17) for implantable defibrillator, or new or worsening HF during 6-month follow-up.
Key secondary efficacy outcomes included each individual component of the primary outcome; the composite of death or resuscitated cardiac arrest; the composite of death or new or worsening HF; death of 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 monitored. All outcomes were adjudicated in a blinded manner by an independent adjudication committee.
We hypothesized that the 6-month rate of the primary endpoint would be 20% in the standard therapy alone arm. With a sample size of 793 per arm (for a total of approximately 1,600 subjects), a total event rate of 269 and an estimated constant hazard ratio (HR) of 0.71 associated with the MRA regimen, using a bilateral equality of survival log-rank test, the study would achieve an 80% power to detect a difference between a 0.853 proportion in 1 group and a 0.800 proportion in the other group at 6 months with a p value of 0.049.
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 withdrawal, 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-rank test. All patients were censored at the time of the last observation. A Cox survival model was used for the calculation of the HR presented with its 2-sided 95% confidence interval (CI) for the primary endpoint and for the analysis of all secondary outcomes at 6 months. Variables assessed at specific time points were analyzed using a logistic regression 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 compared between groups using chi-square or Fisher exact tests where appropriate. Consistency of the treatment effect was analyzed among 16 patient 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).
Between February 2010 and January 2014, a total of 1,622 patients consented and were randomly assigned to the MRA regimen plus standard therapy (n = 802) or standard therapy alone (n = 801) (Figure 1). The groups were well balanced with respect to baseline characteristics and treatment strategies (Table 1). The standard of care included an invasive strategy with coronary angiography performed in 1,582 (98.7%) and percutaneous coronary intervention in 1,447 (90.3%) of the patients. Three-quarters of the study population (n = 1,229) presented with ongoing STEMI, of whom 1,003 (81.6%) underwent primary percutaneous 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 the standard therapy alone group received an MRA (eplerenone in all) during follow-up based on physician decision.
After a median follow-up of 188 days (interquartile range: 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 therapy groups, respectively (HR: 0.97; 95% CI: 0.73 to 1.28). Death from any cause (Figure 3A), as well as all other components of the primary outcome (Table 2), did not differ between the 2 groups. All secondary outcomes occurred with comparable rates in the 2 groups (Table 2).
The results were consistent among all pre-specified subgroups with respect to the primary outcome (Figure 4). The primary outcome was numerically lower with MRA therapy in the STEMI group (p for interaction = 0.08). Considering mortality, a significant interaction (p = 0.01) was found between the treatment effect and type of MI (STEMI vs. NSTEMI) (Figure 5). Compared to standard therapy alone, MRA use reduced the odds of death (3 [0.5%] vs. 15 [2.4%]; HR: 0.20; 95% CI: 0.06 to 0.70; p = 0.0044) in the STEMI subgroup (n = 1,229), but not in the NSTEMI subgroup (Figure 3B). The rates of the components of the primary endpoint in STEMI and NSTEMI groups and the causes of death are reported in Table 3 and Online Table 1, respectively.
There was a trend (HR: 1.37; 95% CI: 0.97 to 1.95; p = 0.075) towards higher rates of protocol-defined acute renal failure associated with the MRA regimen. Hyperkalemia >5.5 mmol/l–1 occurred in 3% 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 = 0.5).
Despite a strong pre-clinical rationale and favorable clinical data from registries and small randomized studies, our randomized trial was unable to show a benefit of an MRA regimen administered early in patients presenting with acute MI, 92% of whom presented without HF (Central Illustration). Similarly, no significant difference was observed on rates of arrhythmia or HF over 6 months of follow-up. Intriguingly, there was a reduction of death in the group of patients with STEMI receiving the MRA regimen.
Experimental studies have shown that the early use of MRA therapy after MI reduces LV expansion and extensive fibrosis (9) by antagonizing activation of the mineralocorticoid receptor by aldosterone and cortisol (18). The clinical benefit reported previously with MRA use in HF was consistent across groups defined by the ischemic or nonischemic origin of HF (1,2) and associated with a reduction of mortality in post-MI patients (3). Thus, the addition of MRAs to beta-blockers and angiotensin-converting enzyme inhibitors has been highly recommended (19–21) in patients with HF and reduced LV function, irrespective of the etiology of HF.
In the EPHESUS (Eplerenone Post-Acute MI Heart Failure Efficacy and Survival Study) trial (3), eplerenone was initiated 3 to 14 days after the onset of MI complicated by HF and reduced LV function. The benefit observed was apparently driven by the 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 outcomes (5–7). The recent REMINDER study also reported encouraging results with eplerenone in low-risk STEMI patients, although the benefit was observed more on B-type natriuretic peptide levels than clinical outcomes (4).
The ALBATROSS study recruited a broad population of MI representing the general population hospitalized for this condition, rarely associated with concomitant HF or severe LV dysfunction. These patients 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 the STEMI cohort must be interpreted with great caution in the absence of stratification for this subgroup at the time of randomization. However, the previously mentioned pre-clinical and clinical data, as well as the strength of the association, support the plausibility of an MRA effect on mortality in the setting of STEMI, a more homogeneous patient population with more acute and severe myocardial ischemia than NSTEMI. Although STEMI and NSTEMI patient groups have similar long-term outcomes (15), their acute management is different with no need for either urgent reperfusion therapy or aggressive antithrombotic therapy in NSTEMI. Hence the early blunting of the previously reported early biological effects of MR activation after acute coronary artery occlusion (9,10,18), may lead to a favorable effect through the ‘un-triggering’ of neurohormonal activation and the subsequent post-MI fibrosis and remodeling, which are much more acute and enhanced processes in STEMI than NSTEMI.
The absence of effect on rates of ventricular arrhythmia in our study is not in contradiction with a possible MRA effect on mortality as in both the Randomized Aldosterone Evaluation Study (1) and EPHESUS (3) trials, where mortality was reduced in association with MRA therapy despite the absence of any effect on ventricular arrhythmia. Furthermore, ventricular arrhythmias were considered significant only 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 ventricular arrhythmia post-MI cannot be assessed by our study.
The ALBATROSS study also highlights the relative safety of the MRA regimen used. Although the rates of hyperkalemia were higher in the MRA group than in the control group, they remained lower than previously reported (3,4) and the rates of adverse events were equally distributed between the 2 study groups (data not shown).
Our study has limitations inherent to the sample size and to the open-label design. However, this study remains the largest experience in MI patients outside of the scope of HF and all the events were adjudicated blindly. The study suffered from a lack of power as the predicted event rate (269) was higher than the actual event rate (194). Despite nonrestrictive inclusion criteria, the study included predominantly STEMI patients at lower risk than expected with a possible selection bias. Our trial was not adequately powered to examine hard clinical outcomes. Although the study would have been adequately powered to demonstrate a mortality reduction in STEMI patients, randomization was not stratified on the type of ACS and our finding should be considered hypothesis generating at this point. Larger studies are needed to re-examine the effect of MRA therapy on such outcomes in STEMI patients. With respect to the multiple testing in the subgroup analyses, the risk of type I error may be important, both for the primary and the mortality endpoints, and the analysis should be considered as only exploratory. Finally, the present MRA regimen used potassium canrenoate and spironolactone, and our results may not be fully extrapolated to eplerenone.
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 patients without HF at this point.
COMPETENCY IN MEDICAL KNOWLEDGE: Administration of a mineralocorticoid receptor antagonist early after myocardial infarction did not reduce occurrence of the composite of death, ventricular arrhythmia, cardiac arrest, need for implantable defibrillator, 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.
For an expanded Methods section and a supplemental table, please see the online version of this article.
The trial was led by members of the nonprofit academic research organization ACTION, based at Pitié-Salpêtrière Hospital, Paris, 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.
- Abbreviations and Acronyms
- confidence interval
- heart failure
- hazard ratio
- myocardial infarction
- mineralocorticoid receptor antagonists
- non–ST-segment elevation myocardial infarction
- ST-segment elevation myocardial infarction
- Received October 20, 2015.
- Revision received February 12, 2016.
- Accepted February 15, 2016.
- American College of Cardiology Foundation
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