EMPEROR-Reduced

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Packer M, et al. "Cardiovascular and renal outcomes with empagliflozin in heart failure". The New England Journal of Medicine. 2020. 383(15):1413-1424.
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Clinical Question

In patients with HFrEF (defined by a left ventricular ejection fraction of 40% or less), does empagliflozin reduce CV mortality and the progression of HF compared to placebo?

Bottom Line

In patients with HFrEF on guideline-directed medical therapy, irrespective of whether T2DM is present or not, the addition of empagliflozin reduces cardiovascular mortality and hospitalization for progression of HF.

Major Points

With the required inclusion of cardiovascular endpoints in trials of new pharmacotherapies for type 2 diabetes mellitus, two classes of agents, the sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the glucagon-like peptide 1 receptor agonists (GLP1-RAs), have unexpectedly been found to reduce major cardiovascular events, including death. The EMPA-REG OUTCOME trial demonstrated that in patients with type 2 diabetes mellitus and established atherosclerotic vascular disease, the SGLT2i empagliflozin reduced the composite outcomes of myocardial infarction, stroke, and cardiovascular death. Similarly, the CANVAS program demonstrated that in patients with type 2 diabetes mellitus and established or at high risk for atherosclerotic cardiovascular disease, reduced major cardiovascular events. Sub-group and post-hoc analyses of the EMPA-REG OUTCOME trial and the CANVAS program discovered reduction rates of hospitalization for heart failure. This latter finding spurred the investigation of the clinical benefits of SGLT2i in patients with HFrEF with or without T2DM. In 2019, the DAPA-HF trial demonstrated in patients with HFrEF (as defined with LVEF <40% and NYHA II-IV symptoms), the SGLT2i dapagliflozin reduced rates of worsening HF, CV death, and all-cause mortality, regardless of a co-morbid diagnosis of T2DM.

The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and Reduced Ejection Fraction (EMPEROR-Reduced) is the second large-scale true heart failure trial, after DAPA-HF, to investigate the effects of SLGTi on cardiovascular hard outcomes. Compared to DAPA-HF, the EMPEROR-Reduced trial enriched for patients with a greater severity of left ventricular systolic dysfunction. Like DAPA-HF, HFrEF patients with or without T2DM were enrolled.

Of note, the related EMPEROR-Preserved (2021) trial assessed SGLT2i use in HFpEF.

Guidelines

As of September 2020, no guidelines that reflect the results of this trial have been published.

Design

  • Multinational, multicenter, double-blind, parallel-group, randomized, controlled trial
  • N=3,730
    • Empagliflozin (n=1,863)
    • Placebo (n=1,867)
  • Setting: 520 centers in 20 countries
  • Enrollment: April 2017 through November 2019
  • Mean follow-up: 16 months
  • Analysis: Intention-to-treat
  • Primary outcome: composite outcome of death of cardiovascular causes or hospitalization for heart failure

Population

Inclusion Criteria

  • NYHA II-IV
  • Age > 18 yrs
  • Heart failure with reduced ejection fraction AND NT-proBNP > 600pg/mL (1200 in pt with AF)
  • If LVEF 31-40% + recent hospitalization for heart failure (in past 12 months) OR significantly elevated NT-proBNP (LVEF 31-35% > 1000, resp. 2000 in patient with AF, LVEF 36-40% > 2500, resp. 5000 in pt with AF)
  • Optimal medical treatment for heart failure (at discretion of screening clinician)

Exclusion Criteria

  • Myocardial infarction, coronary artery bypass graft surgery, or other major cardiovascular surgery, stroke or TIA in past 90 days
  • Heart transplant recipient, or listed for heart transplant
  • Acute decompensated HF
  • Systolic blood pressure >= 180 mmHg at Visit 2.
  • Symptomatic hypotension and/or a SBP < 100 mmHg
  • Indication of liver disease
  • Impaired renal function, defined as eGFR < 20 mL/min/1.73 m2 or requiring dialysis
  • History of ketoacidosis
  • Current use or prior use of a SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor
  • Women who are pregnant, nursing, or who plan to become pregnant while in the trial

Baseline Characteristics

  • Mean age: 67 years
  • 75% male
  • NYHA II 75%, NYHA III 24.5%, NYHA IV 0.5%
  • Mean LVEF 27%
  • Mean NT-proBNP 1900pg/mL
  • 50% pts diabetic

Interventions

  • Randomized to empagliflozin 10mg daily or placebo in addition to usual therapy for heart failure
  • Patients were evaluated every 2 to 3 months (vital signs, body weight, Hb A1c, NT-proBNP and renal function)
  • Reevaluation of renal functions 23 to 45 days after the discontinuation of the treatment

Outcomes

Comparisons are empagliflozin 10mg daily and placebo.

Primary Outcomes

Composite of carviovascular death and first hospitalization for decompensated heart failure
19.4% vs. 24.7% (HR 0.75; 95% CI 0.65-0.86; P<0.001)

Secondary Outcomes

Total number of hospitalizations for heart failure
388 vs. 553 (HR 0.70; 95% CI 1.58-0.85; P<0.001)
Decline in the eGFR
-0.55 ml/min/1.73m2/yr vs. -2,28 ml/min/1.73m2/yr (HR 1.73; 95% CI 1.10-2.37; P<0.001)

Subgroup Analysis

Composite of carviovascular death and first hospitalization for decompensated heart failure
in diabetics HR 0.72; 95% CI 0.60-0.87
in non diabetic HR 0.78; 95% CI 0.64-0.97

Adverse Events

Uncomplicated urinary tract infections
were more frequent in empagliflozin group.

Criticisms

Funding

Boehringer Ingelheim Eli Lilly

Further Reading