LONDON – Aldosterone blockade with oral spironolactone showed a disappointing lack of clinical benefit when initiated in the first hours after an acute MI without heart failure in the large, randomized ALBATROSS trial.
ALBATROSS did, however, flash a silver lining under one wing: A whopping 80% reduction in 6-month mortality in a prespecified subgroup analysis restricted to the 1,229 participants with ST-elevation MI, Dr. Gilles Montalescot reported at the annual congress of the European Society of Cardiology.
Bruce Jancin/Frontline Medical News
Dr. Gilles Montalescot
Although this finding is intriguing, hypothesis-generating, and definitely warrants a confirmatory study, he continued, mortality was nevertheless merely a secondary endpoint in ALBATROSS (Aldosterone Lethal Effects Blockade in Acute Myocardial Infarction Treated With or Without Reperfusion to Improve Outcome and Survival at Six Months Follow-up).
In contrast, the primary composite outcome was negative, so the takeaway message is clear: “The results of the ALBATROSS study do not warrant the extension of aldosterone blockade to MI patients without heart failure,” said Dr. Montalescot, professor of cardiology at the University of Paris.
ALBATROSS was a multicenter French trial that randomly assigned 1,603 acute MI patients to standard therapy alone or with added mineralocorticoid antagonist therapy started within the first 2 days of their coronary event. Often the aldosterone antagonist was begun in the ambulance en route to the hospital.
The primary endpoint was a composite of death, resuscitated cardiac arrest, ventricular fibrillation or tachycardia, heart failure, or an indication for an implantable cardioverter defibrillator. There were 194 such events, and they occurred at a similar rate in the patients who got 25 mg/day of spironolactone and those who did not.
The rationale for ALBATROSS was sound, according to the cardiologist. Aldosterone is a stress hormone released in acute MI. It has deleterious cardiac effects, including arrhythmias, heart failure, and a dose-dependent increase in mortality, so it makes good sense to block it as soon as possible in MI patients. In the EPHESUS trial, the aldosterone antagonist eplerenone, when started 3-14 days post MI in patients with early heart failure, significantly reduced mortality (N Engl J Med. 2003 Apr 3;348[14]:1309-2), with the bulk of the benefit occurring in patients in whom the drug was started 3-7 days post MI.
Last year, Dr. Montalescot and his coinvestigators published the REMINDER study, in which 1,012 ST-elevation MI (STEMI) patients without heart failure were randomized to eplerenone or placebo within the first 24 hours. The study showed a significant reduction in levels of brain natriuretic peptide or N-terminal pro-BNP in the eplerenone arm (Eur Heart J. 2014 Sep 7;35[34]:2295-302), but that’s not a clinical endpoint. ALBATROSS was the first study to look at the clinical impact of commencing mineralocorticoid antagonist therapy prior to day 3 post MI.
Discussant Dr. John McMurray, professor of cardiology at the University of Glasgow, said that ALBATROSS was simply underpowered and thus leaves unanswered the clinically important question of whether early initiation of aldosterone blockade post MI in patients without heart failure confers clinical benefit. The investigators projected a total of 269 events in the composite endpoint but got only 194 because the study participants were so well treated and contemporary medical and interventional therapies are quite effective.
He dismissed the sharp reduction seen in 6-month mortality with spironolactone in the STEMI patients as “just implausible – we don’t know of any treatments in medicine that reduce mortality by 80%.”
Noting that there were only 28 deaths in the study, Dr. McMurray asserted that “a subgroup analysis on such a small number of events is never going to give you a reliable result.” Moreover, he added, “subgroup analysis is even more treacherous when the overall trial is underpowered.”
Dr. Montalescot replied that, while he considers the signal of a mortality benefit for aldosterone blockade in STEMI patients worthy of pursuit in a large randomized trial, the prospects for mounting such a study are poor. The medications are now available as generics, so there is no commercial incentive. The French Ministry of Health, which funded ALBATROSS, isn’t prepared to back a follow-up study. The best hope is that eventually one of the pharmaceutical companies developing third-generation aldosterone antagonists, now in phase II studies, will become interested, he said.
Dr. Montalescot said that, while he receives research grants and consulting fees from numerous pharmaceutical companies, these commercial relationships aren’t relevant to the government-funded ALBATROSS trial.