EMPHASIS-HF

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Zannad F, et al. "Eplerenone in patients with systolic heart failure and mild symptoms". The New England Journal of Medicine. 2011. 364(1):11-21.
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Clinical Question

Among patients with HFrEF, does the addition of eplerenone to standard therapy improve survival?

Bottom Line

Eplerenone reduces the risk of death and hospitalization in patients with moderate systolic dysfunction and NYHA class II symptoms.

Major Points

The 1999 RALES trial revealed that the addition of spironolactone (a nonselective aldosterone antagonist) to usual medical care improved survival and reduced hospitalizations among individuals with moderate systolic dysfunction and NYHA class III-IV symptoms. The follow-up 2003 EPHESUS trial demonstrated similar results with eplerenone (a selective aldosterone antagonist) among patients with MI complicated by LV dysfunction. The role of aldosterone antagonism among patients with mild symptoms had not yet been studied in chronic HFrEF, however.

The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) randomized 2,737 patients with chronic HF with EF ≤35% and NYHA class II symptoms to either eplerenone or placebo, in addition to optimal medical therapy with ACE inhibitors, ARBs, and beta-blockers. Patients were similar to those enrolled in RALES; namely, patients were mostly male (78%), most had ischemic cardiomyopathy (70%), and had moderate-severe LV systolic dysfunction (mean LVEF 26%). At a mean follow-up of 1.8 years, eplerenone significantly reduced the rate of the composite primary outcome of CV death or HF hospitalization (18.3% vs. 25.9%; HR 0.63). The NNT to prevent one primary outcome at one year was 19, and the NNT to postpone one death per year was 51. As expected, eplerenone raised potassium levels; although it protected against hypokalemia, there were more episodes of hyperkalemia as well with eplerenone.

The striking benefit of eplerenone was somewhat unexpected.[1] RALES had demonstrated a significant benefit with spironolactone in patients with NYHA class III-IV symptoms, and in an era that predated the widespread use of beta-blockers. EMPHASIS-HF studied patients with NYHA class II symptoms, and most were receiving beta-blockers (85% vs. 10% in RALES). This suggests that aldosterone antagonism is beneficial to all patients with symptomatic heart failure with moderate-severe LV systolic dysfunction, and some have speculated that their benefits may extend to those with asymptomatic disease.[2]

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[3]

  • Aldosterone antagonists recommended if NYHA class II-IV, LVEF ≤35% unless contraindicated (class I, level A)
    • If NYHA class II, should have prior CV hospitalization or elevated BNP (or analogous test)
  • Aldosterone antagonists recommended after MI if LVEF ≤40% with HF symptoms or DM unless contraindicated (class I, level B)
  • Aldosterone antagonists harmful if creatinine >2.5 mg/dL in men or >2.0 mg/dL in women (GFR <30 mL/min/1.73 m2) or potassium ≥5.0 mEq/L (class III, level B)

Design

  • Randomized, double-blind, prospective, superiority, placebo-controlled trial
  • N=2,737
    • Eplerenone (n=1,364)
    • Placebo (n=1,373)
  • Timeline: 2006-2010 (stopped early after the second interim safety analysis)
  • Follow-up: 21 months
  • Sites: 278 centers in 29 countries
  • Analysis: Intention-to-treat

Population

Inclusion Criteria

  • Age ≥55 years
  • NYHA class II symptoms
  • EF ≤30% (or 30-35% with QRS duration >130ms)
  • Treatment with ACE inhibitor, ARB, or both, unless contraindicated
  • Treatment with beta-blocker unless contraindicated
  • Either:
    • CV hospitalization in prior 6 months or
    • BNP >250 pg/mL or pro-BNP >500 pg/mL (men) or >750 pg/mL (women)

Exclusion Criteria

  • NYHA class III-IV heart failure
  • Potassium >5.0 mmol/L
  • GFR <30 mL/min/1.73 m2
  • Need for a potassium-sparing duretic
  • Clinically significant, coexisting condition

Baseline Characteristics

Data is from the eplerenone group and does not differ from the placebo group except where otherwise specified.

  • Demographics: Age 68.7 years, female 22.7%, white race 82.9%, asian race 11.6%, black race 2.7%
  • Baseline health data: HR 72 BPM, BP 124/75 mmHg, LVEF 26.2%, QRS duration 121 msec, BMI 27.5 kg/m2
  • Heart failure etiology: Ischemic cardiomyopathy 69.7%, non-ischemic cardiomyopathy 30.1%
  • Time since HF diagnosis: 4.8 years
  • PMH: HTN 66.7%, angina pectoris 43.3%, MI 50.3%, A. fib or a. flutter 30.0%, LBBB 26.0%, DM 33.7% eplerenone vs. 29.1% placebo (P=0.01), stroke 10.0%
  • Previous hospitalization for heart failure: 52.3%
  • PSH: PCI 22.0%, ICD 13.0%, CRT 2.8% eplerenone vs. 1.6% (P=0.04), ICD with CRT 5.4%
  • Laboratory data: Hemoglobin 13.9 g/dL, creatinine 1.14 mg/dL, GFR 71.2 mL/min/1.73 m2 , potassium 4.3 mmol/L
  • Medications: Diuretic 84.3%, ACE-I 78.3%, ARB 19.1%, ACE-I, ARB, or both 94.0%, beta blocker 86.6%, digitalis 26.6%, antiarrhythmic 14.4%, antiplatelet or oral anticoagulant 88.3%, lipid-lowering agent 62.8%

Interventions

  • As tolerated by serum potassium, randomization to eplerenone starting at 25 mg PO qday, increased to 50 mg PO qday after 4 weeks
    • Alternative: if GFR was 30-49 mL/min/1.73 m2, starting dose was 25 mg QOD, increased to 25 PO qday after 4 weeks
  • Patient evaluated every 4 months with close monitoring of potassium levels

Outcomes

Comparisons are eplerenone vs. placebo.

Primary Outcome

CV death or HF hospitalization
18.3% vs. 25.9%, HR 0.63 (95% CI 0.54 to 0.74, P<0.001)

Secondary Outcomes

All-cause mortality or HF hospitalization
19.8% vs. 27.4%, HR 0.65 (95% CI 0.55 to 0.76, P<0.001)
All-cause mortality
12.5% vs. 15.5%, HR 0.76 (95% CI 0.62 to 0.93, P=0.008)
CV death
10.8% vs. 13.5%, HR 0.76 (95% CI 0.61 to 0.94, P=0.01)
Hospitalization
29.9% vs. 35.8%, HR 0.77 (95% CI 0.67 to 0.88, P<0.001)
HF hospitalization
12.0% vs. 18.4%, HR 0.58 (95% CI 0.47 to 0.70, P<0.001)
CV hospitalization
22.3% vs. 29.1%, HR 0.69 (95% CI 0.60 to 0.81, P<0.001)
Fatal or nonfatal MI
3.3% vs. 2.4%, HR 1.32 (95% CI 0.84 to 2.06, P=0.23)
All-cause mortality or hospitalization
33.9% vs. 41.4%, HR 0.75 (95% CI 0.66 to 0.85, P<0.001)
HF death or HF hospitalization
12.5% vs. 19.1%, HR 0.58 (95% CI 0.48 to 0.70, P<0.001)
Fatal or nonfatal stroke
1.5% vs. 1.9%, HR 0.79 (95% CI 0.44 to 1.41, P=0.42)
ICD placement
4.5% vs. 4.3%, HR 0.98 (95% CI 0.69 to 1.42, P=0.98)
CRT placement
2.4% vs. 3.0%, HR 0.77 (95% CI 0.49 to 1.22, P=0.27)
Hospitalization for worsening renal function
0.7% vs. 0.6%, HR 0.97 (95% CI 0.37 to 2.58, P=0.95)
Hospitalizaiton for hyperkalemia
0.3% vs. 0.2%, HR 1.15 (95% CI 0.25 to 5.31, P=0.85)
Sudden cardiac death (post hoc)
4.4% vs. 5.5%, HR 0.76 (95% CI 0.54 to 1.07, P=0.12)
Death from worsening heart failure (post hoc)
3.3% vs. 4.4%, HR 0.68 (95% CI 0.46 to 1.00, P=0.05)

Subgroup Analysis

Eplerenone outperformed placebo in all subgroup analyses except the following, in which there was no difference:

  • Beta blocker, ACE inhibitor, and ARB use at randomization visit
  • No beta blocker use at randomization visit
  • No ACE-I or ARB at randomization visit
  • QRS >130ms
  • LBBB

Adverse Events

Any adverse event
Any: 72.0% vs. 73.6% (P=0.37)
Leading to study withdrawal: 13.8% vs. 16.2% (P=0.09)
Hyperkalemia
Any: 8.0% vs. 3.7% (P<0.001)
Leading to study withdrawal: 1.1% vs. 0.9% (P=0.57)
Hypokalemia
Any: 1.2% vs. 2.2% (P=0.05)
Leading to study withdrawal: 0% vs. 0.2% (P=0.25)
Renal failure
Any: 2.8% vs. 3.0% (P=0.82)
Leading to study withdrawal: 0.3% vs. 0.4% (P=0.75)
Gynecomastia or other breast disorders
Any: 0.7% vs. 1.0% (P=0.54)
Leading to study withdrawal: 0.1% vs. 0.1% (P=1.00)
Discontinuation of intervention
16.3% vs. 16.8% (P not specified)
Time to discontinuation of intervention
533 vs. 494 days (P not specified)
Lost to follow-up
1.2% vs. 1.1% (P not specified)

Criticisms

  • Generalizability diminished because inclusion criteria require more than NYHA symptoms.
  • Use of ICDs was low in the study population.
  • Early discontinuation may have skewed the results.
  • Aldosterone antagonists lower BP, and, although these effects are marginal, they may account for some of the survival benefit.[2]

Funding

Supported by Pfizer, the makers of Inspra, the brand name of eplerenone. Authors with multiple disclosures.

Further Reading

  1. Armstrong PW. "Aldosterone Antagonists — Last Man Standing?" N Engl J Med. 2011; 364:79-8.
  2. 2.0 2.1 Various authors. "Correspondence: Eplerenone in Mild Heart Failure." N Engl J Med. 2011; 364:1370-1372.
  3. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.