No benefit of MRA in addition to standard therapy early after MI in patients without HFBeygui F et al., JACC Heart Failure 2016
Early Aldosterone Blockade in Acute Myocardial Infarction - The ALBATROSS Randomized Clinical Trial
Beygui F, Cayla G, Roule V, et al., on behalf of the ALBATROSS Investigators
JACC Heart Failure. VOL. 67, NO. 16, 2016 http://dx.doi.org/10.1016/j.jacc.2016.02.033
BackgroundMineralocorticoid receptor antagonists (MRA) spironolactone and eplerenone have been shown to reduce mortality in the setting of heart failure (HF) with reduced ejection fraction [1,2]. Initiating eplerenone 3 to 14 days after STEMI or NSTEMI, complicated by left ventricular (LV) dysfunction and HF was also associated with lower mortality . The clinical effect of MRAs in myocardial infarction (MI) without complicating HF is unclear.
High aldosterone plasma levels early after STEMI or NSTEMI have been associated with mortality, sudden cardiac death, and HF [4-7]. Experimental evidence suggests that early MRA administration after MI could improve myocardial healing  and remodelling . Small studies have also reported benefits of early MRA therapy for the prevention of LV remodelling [10,11] and life-threatening arrhythmia [12,13].
The open-label ALBATROSS (Aldosterone Lethal effects Blocked in Acute MI Treated with or without Reperfusion to improve Outcome and Survival at Six months follow-up) trial  aimed to investigate the clinical effects of a rapid and prolonged MRA regimen initiated within 72 hours after MI onset (any type). 1615 patients were randomised to MRA regimen in addition to standard therapy or to standard therapy alone (invasive strategy with coronary angiography in 1582 patients and percutaneous coronary intervention in 1447). 92% of patients presented without HF. Patients were followed up for 6 months after randomisation.
- After a median follow-up of 188 days (IQR: 179-210 days), the primary outcome of the composite of death, resuscitated cardiac arrest, significant ventricular arrhythmia, class IA indication for implantable defibrillator, or new or worsening HF was seen in 95 (11.8%) and 98 (12.2%) patients in the MRA and control group respectively (HR: 0.97, 95%CI: 0.73-1.28).
- No significant differences between treatment groups were seen for the components of the primary outcomes, or for secondary outcomes.
- A significant interaction (P=0.01) was seen between treatment effect and type of MI, with regard to mortality, such that in STEMI, MRA reduced the risk of death (0.5% vs. 2.4%, HR: 0.20, 95%CI: 0.06-0.70, P=0.0044) as compared with standard therapy alone, while it did not in NSTEMI patients (3.8% vs. 1.1%, HR: 3.47, 95%CI: 0.72-16.72).
- A trend was seen towards a higher rate of protocol-defined acute renal failure associated with the MRA regimen (HR: 1.37, 95%CI: 0.97-1.95, P=0.075).
- Hyperkalemia >5.5 mmol/l–1 occurred in 3% vs. 0.2% in the MRA vs. control groups, respectively (HR: 12.12, 95%CI: 2.87-51.29, P<0.0001).
ConclusionThis randomised trial failed to confirm previous observations that an MRA regimen administered early after acute MI could provide benefit. Interestingly, a reduction of death was seen in patients with STEMI who received the MRA regimen, as compared with standard therapy only.
It should be noted that the study was not adequately powered to examine hard clinical outcomes (actual event rate was lower than predicted event rate) and randomisation was not stratified on the type of ACS and the mortality reduction in STEMI patients should therefore be considered hypothesis-generating at this point.
Editorial comment “There are several reasons to believe MRA therapy might be beneficial in this setting, including the fact that aldosterone and cortisol levels are elevated early post-infarction, both aldosterone and cortisol can activate the mineralcorticoid receptor, and elevated levels of these neurohormones have been shown to predict cardiovascular (CV) outcomes in the post-MI setting. Additionally, MRAs can block the effects of both aldosterone and cortisol on the mineralcorticoid receptor, as well as reduce inflammatory cytokine activation, macrophage activation, myocardial fibrosis, vascular and ventricular remodeling, and reactive oxygen species; plus, these agents improve nitric oxide availability, reduce ventricular arrhythmias, and lower SCD risk.”
It is unclear why MRAs failed to show a benefit in the ALBATROSS trial, but it could be postulated that, despite the efforts of the investigators to select NSTEMI patients at increased CV risk, these patients had less neurohormonal activation than those with STEMI. NSTEMI patients may therefore have been less responsive to an MRA. This might explain the lack of effectiveness of MRA, especially in NSTEMI. It should, however, be noted that the study was underpowered to provide a definite answer.
Attention is currently also directed at cell-based and gene therapy to prevent ventricular remodelling, CV death and HFH in STEMI patients. Long-term safety and efficacy of these approaches remains to be determined, and costs are likely to high relative to MRA administration. Thus, the author still calls for “an adequately powered prospective randomised trial evaluating safety and efficacy of MRA administration early post-MI in patients without evidence of HF”. Their use in the current situation (without HF) is complicated by the need for serial monitoring of serum potassium and renal function and the risk of inducing hyperkalemia. The availability of new, apparently safe and well-tolerated potassium-lowering agents may in part alleviate the risk of serious hyperkalemia and allow the proposed prospective study to evaluate the role of MRAs in patients with acute STEMI, without HF.
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