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SAN FRANCISCO – Early administration of the aldosterone blocker eplerenone improved cardiovascular outcomes in patients presenting with ST-elevation myocardial infarction without concomitant heart failure.
In the randomized, double-blind REMINDER trial, starting eplerenone within 24 hours after symptom onset without first checking serum potassium, as per the study protocol, proved reassuringly safe. There was no significant increase in hyperkalemia compared with placebo. Hypokalemia, defined as a serum potassium level less than 3.5 mEq/L, occurred in 1.4% of the eplerenone group and in 5.5% of controls (P = .0002). Rates of other adverse events were similar in the two study arms, Dr. Gilles Montalescot reported at the annual meeting of the American College of Cardiology.
REMINDER was an international clinical trial involving 1,012 patients presenting with acute STEMI with no history or current signs or symptoms of heart failure and with a left ventricular ejection fraction of at least 40%. A series of studies have shown that the more elevated the early aldosterone in acute STEMI, the worse the prognosis in terms of mortality, new or worsening heart failure, and ventricular fibrillation.
This was a low-risk STEMI population. Patients with renal failure were ineligible. Rates of guideline-recommended medications were strikingly high. Primary percutaneous coronary intervention was the means of myocardial reperfusion in 85% of participants.
The primary study endpoint during a mean 10.5 months of follow-up was a composite of cardiovascular death, hospitalization due to diagnosed heart failure, sustained ventricular tachycardia or fibrillation, an LVEF of 40% after more than 1 month, and an elevated level of brain natriuretic peptide (BNP) or N-terminal prohormone of BNP (NT-proBNP) occurring after 1 month of follow-up.
The rate of the primary endpoint was 18.4% in the eplerenone group, compared with 29.6% with placebo, for a significant 43% relative risk reduction, said Dr. Montalescot, chair of the REMINDER steering committee and professor of cardiology at Pitié-Salpêtrière Hospital, Paris.
The difference in the composite outcome was driven by a sharply lower incidence of elevated BNP/NT-proBNP in the eplerenone group: 16% as compared to 25.9% in controls. The other elements of the composite endpoint didn’t differ significantly between the two groups, although they tended to be lower in the eplerenone group.
Aldosterone has a multitude of cardiotoxic effects. It increases sodium retention, arrhythmogenic depletion of potassium and calcium, cardiac myocyte necrosis, myocardial remodeling, and endothelial dysfunction.
Earlier, in the landmark, randomized EPHESUS trial, investigators showed that prescribing eplerenone in patients with left ventricular systolic dysfunction and heart failure present 3-14 days after an acute MI resulted in a 17% reduction in cardiovascular mortality relative to placebo (N. Engl. J. Med. 2003;348:1309-21). Subsequently, in the EMPHASIS-HF trial eplerenone achieved a 24% reduction in cardiovascular mortality when prescribed for patients with left ventricular systolic dysfunction and mild, NYHA class II heart failure post-MI (N. Engl. J. Med. 2011;364:11-21). The goal in REMINDER was to preempt that systolic dysfunction from arising.
Dr. Montalescot noted that the ongoing 1,600-patient ALBATROSS (Aldosterone Blockade Early After Acute MI) trial, sponsored by the Public Assistance Hospital of Paris, is looking at the use of spironolactone in moderate-risk acute STEMI and has 6-month hard clinical endpoints.
The REMINDER trial was sponsored by Pfizer. Dr. Montalescot reported having no financial conflicts.
The long-term clinical relevance of an elevated BNP is questionable and constitutes "the fly in the ointment" in the REMINDER trial. The biomarker is not a rock-solid predictor of later major adverse clinical events.
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Eplerenone is already recommended in the European Society of Cardiology and American heart failure guidelines based upon firm evidence of clinical benefit. Yet this recommendation is the least followed, and hardly ever used in practice. In light of that situation, it’s unlikely that reliance on a biomarker endpoint will persuade many physicians to extend use of the aldosterone blocking agent to acute STEMI patients who don’t actually have heart failure.
Dr. Montalescot has said that to demonstrate a 20% reduction in the dual endpoint of mortality or onset of heart failure in low-risk STEMI patients would require 10,000 patients in each study arm, a preclusively costly endeavor.
The combined rate of the ‘hard’ clinical endpoints of cardiovascular mortality, heart failure, or severe ventricular arrhythmia in REMINDER was 3.2% in the control group and 1.8% with eplerenone therapy. Given eplerenone’s cost, prescribing it early on in all acute STEMI patients is unlikely when 97% of them do not appear to benefit.
Dr. E. Magnus Ohman is professor of medicine and director of the program for advanced coronary disease at Duke University, Durham, N.C. Dr. Ohman was the discussant of the study at ACC 13.
The long-term clinical relevance of an elevated BNP is questionable and constitutes "the fly in the ointment" in the REMINDER trial. The biomarker is not a rock-solid predictor of later major adverse clinical events.
|
|
Eplerenone is already recommended in the European Society of Cardiology and American heart failure guidelines based upon firm evidence of clinical benefit. Yet this recommendation is the least followed, and hardly ever used in practice. In light of that situation, it’s unlikely that reliance on a biomarker endpoint will persuade many physicians to extend use of the aldosterone blocking agent to acute STEMI patients who don’t actually have heart failure.
Dr. Montalescot has said that to demonstrate a 20% reduction in the dual endpoint of mortality or onset of heart failure in low-risk STEMI patients would require 10,000 patients in each study arm, a preclusively costly endeavor.
The combined rate of the ‘hard’ clinical endpoints of cardiovascular mortality, heart failure, or severe ventricular arrhythmia in REMINDER was 3.2% in the control group and 1.8% with eplerenone therapy. Given eplerenone’s cost, prescribing it early on in all acute STEMI patients is unlikely when 97% of them do not appear to benefit.
Dr. E. Magnus Ohman is professor of medicine and director of the program for advanced coronary disease at Duke University, Durham, N.C. Dr. Ohman was the discussant of the study at ACC 13.
The long-term clinical relevance of an elevated BNP is questionable and constitutes "the fly in the ointment" in the REMINDER trial. The biomarker is not a rock-solid predictor of later major adverse clinical events.
|
|
Eplerenone is already recommended in the European Society of Cardiology and American heart failure guidelines based upon firm evidence of clinical benefit. Yet this recommendation is the least followed, and hardly ever used in practice. In light of that situation, it’s unlikely that reliance on a biomarker endpoint will persuade many physicians to extend use of the aldosterone blocking agent to acute STEMI patients who don’t actually have heart failure.
Dr. Montalescot has said that to demonstrate a 20% reduction in the dual endpoint of mortality or onset of heart failure in low-risk STEMI patients would require 10,000 patients in each study arm, a preclusively costly endeavor.
The combined rate of the ‘hard’ clinical endpoints of cardiovascular mortality, heart failure, or severe ventricular arrhythmia in REMINDER was 3.2% in the control group and 1.8% with eplerenone therapy. Given eplerenone’s cost, prescribing it early on in all acute STEMI patients is unlikely when 97% of them do not appear to benefit.
Dr. E. Magnus Ohman is professor of medicine and director of the program for advanced coronary disease at Duke University, Durham, N.C. Dr. Ohman was the discussant of the study at ACC 13.
SAN FRANCISCO – Early administration of the aldosterone blocker eplerenone improved cardiovascular outcomes in patients presenting with ST-elevation myocardial infarction without concomitant heart failure.
In the randomized, double-blind REMINDER trial, starting eplerenone within 24 hours after symptom onset without first checking serum potassium, as per the study protocol, proved reassuringly safe. There was no significant increase in hyperkalemia compared with placebo. Hypokalemia, defined as a serum potassium level less than 3.5 mEq/L, occurred in 1.4% of the eplerenone group and in 5.5% of controls (P = .0002). Rates of other adverse events were similar in the two study arms, Dr. Gilles Montalescot reported at the annual meeting of the American College of Cardiology.
REMINDER was an international clinical trial involving 1,012 patients presenting with acute STEMI with no history or current signs or symptoms of heart failure and with a left ventricular ejection fraction of at least 40%. A series of studies have shown that the more elevated the early aldosterone in acute STEMI, the worse the prognosis in terms of mortality, new or worsening heart failure, and ventricular fibrillation.
This was a low-risk STEMI population. Patients with renal failure were ineligible. Rates of guideline-recommended medications were strikingly high. Primary percutaneous coronary intervention was the means of myocardial reperfusion in 85% of participants.
The primary study endpoint during a mean 10.5 months of follow-up was a composite of cardiovascular death, hospitalization due to diagnosed heart failure, sustained ventricular tachycardia or fibrillation, an LVEF of 40% after more than 1 month, and an elevated level of brain natriuretic peptide (BNP) or N-terminal prohormone of BNP (NT-proBNP) occurring after 1 month of follow-up.
The rate of the primary endpoint was 18.4% in the eplerenone group, compared with 29.6% with placebo, for a significant 43% relative risk reduction, said Dr. Montalescot, chair of the REMINDER steering committee and professor of cardiology at Pitié-Salpêtrière Hospital, Paris.
The difference in the composite outcome was driven by a sharply lower incidence of elevated BNP/NT-proBNP in the eplerenone group: 16% as compared to 25.9% in controls. The other elements of the composite endpoint didn’t differ significantly between the two groups, although they tended to be lower in the eplerenone group.
Aldosterone has a multitude of cardiotoxic effects. It increases sodium retention, arrhythmogenic depletion of potassium and calcium, cardiac myocyte necrosis, myocardial remodeling, and endothelial dysfunction.
Earlier, in the landmark, randomized EPHESUS trial, investigators showed that prescribing eplerenone in patients with left ventricular systolic dysfunction and heart failure present 3-14 days after an acute MI resulted in a 17% reduction in cardiovascular mortality relative to placebo (N. Engl. J. Med. 2003;348:1309-21). Subsequently, in the EMPHASIS-HF trial eplerenone achieved a 24% reduction in cardiovascular mortality when prescribed for patients with left ventricular systolic dysfunction and mild, NYHA class II heart failure post-MI (N. Engl. J. Med. 2011;364:11-21). The goal in REMINDER was to preempt that systolic dysfunction from arising.
Dr. Montalescot noted that the ongoing 1,600-patient ALBATROSS (Aldosterone Blockade Early After Acute MI) trial, sponsored by the Public Assistance Hospital of Paris, is looking at the use of spironolactone in moderate-risk acute STEMI and has 6-month hard clinical endpoints.
The REMINDER trial was sponsored by Pfizer. Dr. Montalescot reported having no financial conflicts.
SAN FRANCISCO – Early administration of the aldosterone blocker eplerenone improved cardiovascular outcomes in patients presenting with ST-elevation myocardial infarction without concomitant heart failure.
In the randomized, double-blind REMINDER trial, starting eplerenone within 24 hours after symptom onset without first checking serum potassium, as per the study protocol, proved reassuringly safe. There was no significant increase in hyperkalemia compared with placebo. Hypokalemia, defined as a serum potassium level less than 3.5 mEq/L, occurred in 1.4% of the eplerenone group and in 5.5% of controls (P = .0002). Rates of other adverse events were similar in the two study arms, Dr. Gilles Montalescot reported at the annual meeting of the American College of Cardiology.
REMINDER was an international clinical trial involving 1,012 patients presenting with acute STEMI with no history or current signs or symptoms of heart failure and with a left ventricular ejection fraction of at least 40%. A series of studies have shown that the more elevated the early aldosterone in acute STEMI, the worse the prognosis in terms of mortality, new or worsening heart failure, and ventricular fibrillation.
This was a low-risk STEMI population. Patients with renal failure were ineligible. Rates of guideline-recommended medications were strikingly high. Primary percutaneous coronary intervention was the means of myocardial reperfusion in 85% of participants.
The primary study endpoint during a mean 10.5 months of follow-up was a composite of cardiovascular death, hospitalization due to diagnosed heart failure, sustained ventricular tachycardia or fibrillation, an LVEF of 40% after more than 1 month, and an elevated level of brain natriuretic peptide (BNP) or N-terminal prohormone of BNP (NT-proBNP) occurring after 1 month of follow-up.
The rate of the primary endpoint was 18.4% in the eplerenone group, compared with 29.6% with placebo, for a significant 43% relative risk reduction, said Dr. Montalescot, chair of the REMINDER steering committee and professor of cardiology at Pitié-Salpêtrière Hospital, Paris.
The difference in the composite outcome was driven by a sharply lower incidence of elevated BNP/NT-proBNP in the eplerenone group: 16% as compared to 25.9% in controls. The other elements of the composite endpoint didn’t differ significantly between the two groups, although they tended to be lower in the eplerenone group.
Aldosterone has a multitude of cardiotoxic effects. It increases sodium retention, arrhythmogenic depletion of potassium and calcium, cardiac myocyte necrosis, myocardial remodeling, and endothelial dysfunction.
Earlier, in the landmark, randomized EPHESUS trial, investigators showed that prescribing eplerenone in patients with left ventricular systolic dysfunction and heart failure present 3-14 days after an acute MI resulted in a 17% reduction in cardiovascular mortality relative to placebo (N. Engl. J. Med. 2003;348:1309-21). Subsequently, in the EMPHASIS-HF trial eplerenone achieved a 24% reduction in cardiovascular mortality when prescribed for patients with left ventricular systolic dysfunction and mild, NYHA class II heart failure post-MI (N. Engl. J. Med. 2011;364:11-21). The goal in REMINDER was to preempt that systolic dysfunction from arising.
Dr. Montalescot noted that the ongoing 1,600-patient ALBATROSS (Aldosterone Blockade Early After Acute MI) trial, sponsored by the Public Assistance Hospital of Paris, is looking at the use of spironolactone in moderate-risk acute STEMI and has 6-month hard clinical endpoints.
The REMINDER trial was sponsored by Pfizer. Dr. Montalescot reported having no financial conflicts.
AT ACC 13
Major finding: The rate of the primary endpoint was 18.4% in the eplerenone group, compared with 29.6% with placebo, for a significant 43% relative risk reduction based on more than 10 months of follow-up.
Data source: REMINDER is an international, randomized, double-blind, placebo-controlled phase III trial involving 1,012 patients presenting with acute STEMI and no heart failure.
Disclosures: The REMINDER trial was funded by Pfizer. Dr. Montalescot reported having no financial conflicts.
