STEMI Survival Gains After Early Aldosterone Inhibition Seen in Trials

September 01, 2017

BARCELONA, SPAIN —Treatment with aldosterone antagonists started within 3 days of acute ST-segment elevation MI (STEMI) onset, along with standard therapy, appeared to lower the risk of death over the next 7 months by three-fourths in a pooled analysis of two randomized, controlled trials[1].

Benefits from the drugs, spironolactone and eplerenone, also called mineralocorticoid receptor antagonists (MRAs), came at the risk of mild hyperkalemia, one of their known side effects, but few other downsides.

The analysis took patient-level data from the STEMI population subset of the ALBATROSS trial, which tested early spironolactone 25 mg/day for acute MI of any stripe, in the absence of heart failure, and from the REMINDER trial looking at early eplerenone 25 to 50 mg/day in patients with STEMI but no HF or LV dysfunction. The current study was therefore able to "randomize" 1118 patients with STEMI to receive an MRA, either spironolactone or eplerenone, and 1123 to placebo, both on top of standard therapy.

Spironolactone had failed to show a clinical benefit in the mixed ALBATROSS population, whereas in REMINDER eplerenone did show such a benefit, but in a primary end point that included biomarkers along with clinical events. Neither trial was considered to have enough statistical power to render any firm conclusion about clinical outcomes.

Dr Farzin Beygui

In the pooled analysis, however, the patients who received an MRA showed 0.4% mortality over a median follow-up of 190 days, compared with 1.6% in the placebo group (P=0.006), reported Prof Farzin Beygui (Centre Hospitalier Universitaire de Caen, France) here at the European Society of Cardiology (ESC) 2017 Congress.

Based on earlier studies, it's thought that eplerenone is more specific for the mineralocorticoid receptor "and has, in other studies at least, fewer side effects," Beygui told | Medscape Cardiology. But that wasn't a finding of the analysis necessarily, he added. What the analysis does suggest is that the observed survival benefit STEMI is an MRA class effect.

Given that ALBATROSS and REMINDER were small studies, "it was correct to pool them," according to Prof Michael Böhm (University of the Saarland, Homburg/Saar, Germany), who wasn't involved in the analysis.

"And the data showed that, indeed, the trends that existed in the previous two underpowered studies have come into view," he said when interviewed.

But it would be wrong to conclude that the analysis means now MRAs should be started within 1 to 3 days of onset of any acute STEMI. "I doubt it generates evidence that can be transferred to guidelines, but it is a reassuring finding that aldosterone antagonists worked."

The EPHESUS trial, he noted, demonstrated that MRAs should be given to patients with left ventricular dysfunction after a recent acute MI. There may well be, in practice, some overlap between EPHESUS-like patients and those in the current analysis, many of whom likely had slight LV dysfunction. So for the STEMI patient with even mild LV dysfunction "and a little shortness of breath," Böhm said, "I would feel comfortable treating them with an MRA."

The patients pooled from ALBATROSS and REMINDER were similar with respect to STEMI interventions and other in-hospital management, including prevalence of PCI, CABG, fibrinolytic therapy, antiplatelets, ACE inhibitors or angiotensin-receptor blockers (ARBs), beta-blockers, and statins, and in LVEF and mean duration of follow-up.

Hazard Ratio (95% CI) for Outcomes in ALBATROSS-REMINDER Pooled Analysis

End points Adjusted HR (95% CI) P
Death* 0.24 (0.08–0.72) 0.01
Cardiovascular death 0.28 (0.09–0.88) 0.03
Potassium >5.5 mmol/L 1.89 (1.09–3.29)  0.03
*Pooled analysis primary end point

The MRAs probably confer their benefit in large part by attenuating myocardial fibrosis after infarction, lessening risk of adverse structural and electrical remodeling, Beygui said when interviewed. Studies in mice, certainly, show that the myocardial healing process accelerates when MRAs are on board, with less scarring.

That MRAs stem the damage caused by acute ischemic injury and subsequent myocardial necrosis might explain why spironolactone and eplerenone improve survival in STEMI but not NSTEMI or other forms of ACS, where necrosis is less of a factor, he said.

Beygui discloses receiving fees from AstraZeneca and Medtronic and receiving research contracts from those two companies and Biosensor and Boston Scientific unrelated to the current study. REMINDER was funded by Pfizer.

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