EMPHASIS-HF Trial - Aldosterone antagonists for NYHA class II heart failure

EMPHASIS HF

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Name: EMPHASIS-HF

Specialty: cardiology, CHF 

Problem: CCF (NYHA II & EF < 35%*)

Population: 2737 patients

Inclusion criteria:
Age > 55 years
NYHA functional class II symptoms
Ejection fraction of no more than 30% (or, if >30 to 35%, a QRS duration of >130 msec)
Treatment with an angiotensin-converting–enzyme (ACE) inhibitor, an angiotensin-receptor blocker (ARB), or both and a beta-blocker (unless contraindicated) at the recommended dose or maximal tolerated dose.
Exclusion criteria:
Acute myocardial infarction
NYHA class III or IV heart failure
Serum potassium > 5.0 mmol per liter
eGFR < 30 ml per minute per 1.73 m2
Need for a potassium-sparing diuretic
Any other clinically significant, coexisting condition.
Intervention: Eplerenone

Control: Placebo

Follow-up: Median 21 months

Primary endpoint:
Composite of death from cardiovascular causes or a first hospitalization for heart failure
Secondary endpoint(s):
Hospitalization for heart failure or death from any cause
Death from any cause
Death from cardiovascular causes
Hospitalization for any reason
Hospitalization for heart failure (among others)
Details:
* = Ejection fraction of no more than 30% (or, if >30 to 35%, a QRS duration of >130 msec)
Patients were randomized to two placebo or eplerenone 25 mg once daily. This dosage increased to 50 mg once daily after 4 weeks or 25 mg on alternate days increased to 25 mg daily. Serum potassium levels were used to guide dose increases and decreases.

Results:
 Eplerenone vs. placebo
-37% reduction in death from CV causes or hospitalisation for HF
--Benefits across all prespecified subgroups -Significant reduction in death from any cause
-Trend towards fewer adverse events in eplerenone group
--Significantly increased risk of hyperkalaemia

How the article changed CHF guidelines: Read below.

In early 2012 HFSA issued new guidelines recommending use of aldosterone antagonists in NYHA class II HF. 

But study was conducted using Pfizer's brand-child drug - Eplerenone.

CAVEATS:

Composite primary outcome – confusing to apply clinically

Pharma funded (Pfizer, maker of eplerenone)

–Eplerenone: $113/month

–Spironolactone: $14/month

NNH for hyperkalemia lower than NNT for reducing death.

However no deaths from hyperkalemia, no difference in hyperK hospitalization rates

Papers

Eplerenone in patients with systolic heart failure and mild symptoms.

 PUBMED LINK TO THE ARTICLE.

NEJM LINK TO THE ARTICLE

EPHESUS Trial - LV dysfunction post MI

Name: EPHESUS (Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study)

Why is this trial a landmark trial:  Just like the RALES trial showed effectiveness of aldosterone receptor blockade in both ischemic and non-ischemic heart failure. EPHESUS trial showed efficacy of Eplerenone (selective cousin of spironolactone) in post-MI HF.

What was not good about this trial: I think investigators limited themselves to post-MI heart failure, if they had included non-ischemic patients as well then they would have had much larger market for Eplerenone. (now Eplerenone use is pretty much limited to post-MI HF and CHF with intolerant SE's to Spironolactone).

The fact that Eplerenone showed only 15% RRR in all cause mortality (half of spironolactone) also made clinicians a bit jittery in using Eplerenone as first choice instead of Spironolactone.

They also had tough time proving efficacy of Eplerenone because of more than 75% participants were on beta blockers which may have knocked down the true efficacy of the Eplerenone when compared to Spironolactone in RALES trial. (remember in RALES trial only 10% participants were on beta-blockers, and also RALES recruits had average EF of 25% where as in EPHESUS average EF was much higher - so it may be easier to prove improvement of EF from 25% to 45% THAN to prove improvement from 40% to 45%).

Specialty: cardiology,CHF

Problem: LV dysfunction post-MI (ischemic HF or ischemic cardiomyopathy with EF  < 40%)

Population: 6452 patients

Inclusion criteria:
Patients in whom the following criteria were met were eligible for randomization 3 to 14 days after acute myocardial infarction:
Acute myocardial infarction as documented according to standard criteria
Left ventricular dysfunction as documented by a left ventricular ejection fraction of 40 percent or lower on echocardiography, radionuclide angiography, or angiography of the left ventricle after the index acute myocardial infarction and before randomization
Heart failure as documented by the presence of pulmonary rales, chest radiography showing pulmonary venous congestion, or the presence of a third heart sound.
In patients with diabetes who met the criteria for left ventricular dysfunction after acute myocardial infarction, symptoms of heart failure did not have to be demonstrated, since such patients have an increased risk of cardiovascular events similar to that of nondiabetic patients with symptoms of heart failure.
Exclusion criteria:
Use of potassium-sparing diuretics
Serum creatinine concentration of more than 2.5 mg per deciliter (220 μmol per liter)
Serum potassium concentration of more than 5.0 mmol per liter before randomization
Intervention: Eplerenone
Control: Placebo

Follow-up: Mean 16 months

Primary endpoint:
Time to death from any cause
Time to death from cardiovascular causes or first hospitalization for a cardiovascular event, including heart failure, recurrent acute myocardial infarction, stroke, or ventricular arrhythmia
Secondary endpoint(s):
Death from cardiovascular causes and death from any cause or any hospitalization
Details:
Patients received optimal medical therapy, which could include ACE inhibitors, angiotensin-receptor blockers, diuretics, and beta-blockers, as well as coronary reperfusion therapy.

Results:

 -15% RRR in deaths (versus 30% RRR in RALES with Spironolactone)

-16% RRR in CV death or hospitalization for CV events
-8% RRR in death from any cause or any hospitalization
-21% RRR in sudden death from cardiac causes
-Increased risk of serious hyperkalaemia

Original Paper - Link

Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction

3 Apr 2003 N Engl J Med. 2003 Apr 3;348(14):1309-21.: CLICK HERE FOR NEJM LINK

PUBMED LINK CLICK HERE

Eplerenone vs. placebo

SUMMARY TRIAL:

RALES Trial (NYHA II and IV Paients')

Name: RALES (Randomized Aldactone Evaluation Study)

Specialty: cardiology,CHF

Problem: CCF (NYHA III & IV)

Participants: 1663

Inclusion criteria:
Must have all of:
New York Heart Association (NYHA) class IV heart failure within the six months before enrolment
In NYHA class III or IV at the time of enrolment
Diagnosis of heart failure at least six weeks before enrolment
Being treated with an ACE inhibitor (if tolerated) and a loop diuretic
Had a left ventricular ejection fraction of no more than 35 percent within the six months before enrollment (with no clinically significant intercurrent event)
Treatment with digitalis and vasodilators was allowed, but potassium-sparing diuretics were not permitted.
Exclusion criteria:
Primary operable valvular heart disease (other than mitral or tricuspid regurgitation with clinical symptoms due to left ventricular systolic heart failure)
Congenital heart disease
Unstable angina
Primary hepatic failure
Active cancer
Any life-threatening disease (other than heart failure)
Those undergone or awaiting heart transplant
Serum creatinine concentration of more than 2.5 mg per deciliter (221 μmol per liter)
Serum potassium concentration of more than 5.0 mmol per liter
Intervention: Spironolactone
Control: Placebo

Follow-up: Mean 24 months

Primary endpoint:
Death from any cause
Secondary endpoint(s):
Death from cardiac causes
Hospitalization for cardiac causes
Combined incidence of death from cardiac causes or hospitalization for cardiac causes
Change in NYHA class
The effect of spironolactone was also assessed with the use of six prerandomization variables: left ventricular ejection fraction, the cause of heart failure, the serum creatinine concentration, age, the use of ACE inhibitors, and the use of digitalis.
Details:

Patients started on 25mg, could be uptitrated to 50mg @ 8 weeks if progression of disease without hyperkalaemia
If patients developed hypokalaemia, dose reduced to 25mg alternating days - however, advice was to adjust other medications first

Results:

- Early termination of the trial due to significant (30%) reduction in the mortality in the
   Spironolactone ara. (p<0.001)
- Significant reduction in sudden death and all cause mortality
- Improvement in the NYHA class  inependent of age, etiology of HF and other therapy.

Original Paper:

The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators

2 Sep 1999 N Engl J Med. 1999 Sep 2;341(10):709-17.:Trial stopped early due to 30% relative risk reduction (p<0.001)
In patients with severe HF and LVEF < 35%, spironolactone vs. placebo:
-Significant reduction in all cause mortality
--Significant reduction in sudden death and progression of CCF
--Similar across all subgroups
-NYHA improved significantly more and worsened in significantly fewer
Benefits independent of age, EF, aetiology of HF and other therapy.

Deaths Per all causes:



Kaplan Meier Survival Curve - Spironolactone versus Placebo+standard therapy.




Special Points:

Participants with serum creatinine > 2.5 mg/dl were excluded.

Hyperkalemia was defined as potassium > 6.0

Hypokalemia as K+ < 3.0

Initial starting dose of spironolactone was 25 mg daily and topped at 50 mg daily.

Investigators waited till creatinine to hit 4 md/dl before they stopped spironolactone. (provided starting creatinine was less than 2.5).

Majority of participants (>85%) were caucasians and majority males (>70%).

Average EF 25%.

Almost equal number of ischemic and non-ischemic participants.

Almost > 90% were on ACEI.

Only 10% were on beta blockers.

41% percent participants had improvement in their NYHA class of HF.

Gynecomastia occured in 10% of patients.

SUMMARY SLIDE: