Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction - EMPEROR-Preserved

Contribution To Literature:

The EMPEROR-Preserved trial showed that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFpEF (EF >40%) on excellent baseline GDMT, irrespective of diabetes status.

Description:

The goal of the trial was to assess the safety and efficacy of empagliflozin in patients with symptomatic heart failure with preserved ejection fraction (HFpEF), irrespective of diabetes status.

Study Design

Patients were randomized in a 1:1 fashion to either empagliflozin 10 mg (n = 2,997) or matching placebo (n = 2,991). The trial was stratified by geographic region, diabetes status, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF; <50%/≥50%). All the patients were receiving appropriate treatments for HF.

  • Total screened: 11,583
  • Total number of enrollees: 5,988
  • Duration of follow-up: 26.2 months (median)
  • Mean patient age: 72 years
  • Percentage female: 45%

Inclusion criteria:

  • Age ≥18 years
  • Chronic HF, New York Heart Association (NYHA) functional class II/III/IV
  • Preserved LVEF (EF >40%)
  • HF hospitalization within 12 months
  • N-terminal pro–B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml without atrial fibrillation (AF), >900 pg/ml with AF
  • Structural heart disease within 6 months or documented HF hospitalization within 12 months
  • Stable dose of oral diuretics, if prescribed

Exclusion criteria:

  • Acute coronary syndrome, stroke, or transient ischemic attack within 90 days
  • Listed for orthotopic heart transplantation (OHT) or OHT recipient
  • Acute decompensated HF
  • Systolic blood pressure BP ≥180 mm Hg
  • Symptomatic hypotension or SBP ≤100 mm Hg
  • Liver or kidney disease (eGFR <20 ml/min/1.73 m2)
  • Current use or prior use of a sodium-glucose co-transporter (SGLT)-2 inhibitor or combined SGLT-1 and -2 inhibitor

Other salient features/characteristics:

  • White 76%, Asian 14%
  • North America: 12%, Europe: 45%, Asia: 11%, Latin America: 25%
  • NYHA class II: 82%
  • Mean LVEF: 54.3%
  • Type 2 diabetes mellitus: 49%
  • eGFR <60 ml/min/1.73 m2: 50%
  • AF: 51%

Principal Findings:

The primary outcome, cardiovascular (CV) death or HF hospitalization, for empagliflozin vs. placebo, was 13.8% vs. 17.1% (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.69-0.90, p < 0.001).

  • CV death: 7.3% vs. 8.2% (HR 0.91, 95% CI 0.76-1.09)
  • HF hospitalization: 8.6% vs. 11.8% (HR 0.71, 95% CI 0.60-0.83)
  • For the primary outcome, the benefit was similar among patients with or without type 2 diabetes. The benefit appeared somewhat attenuated among patients with EF ≥60%.

Secondary outcomes for empagliflozin vs. placebo:

  • Total hospitalizations: 407 vs. 541 (p < 0.001)
  • Change in mean eGFR slope/year: -1.25 vs. -2.62 (p < 0.001)
  • Composite renal outcome 3.6% vs. 3.7% (p > 0.05)
  • All-cause mortality: 13.4% vs. 14.2% (HR 0.92, 95% CI 0.77-1.10, p > 0.05)
  • New-onset type 2 diabetes among patients with prediabetes: 12.0% vs. 14.0% (p > 0.05)

Pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved on renal outcomes (profound and sustained decreases in eGFR or renal replacement therapy), total n = 9,718: 2.8% vs. 3.5% for empagliflozin vs. placebo, with significant heterogeneity between both trials (p = 0.016 for interaction).

Interpretation:

The results of this trial indicate that empagliflozin is superior to placebo in improving HF outcomes among patients with symptomatic stable HFpEF (EF >40%), irrespective of diabetes status. The benefit is primarily driven by a reduction in HF hospitalizations, not mortality. There was also a benefit in eGFR, but not in renal outcomes per se. The benefit appeared somewhat attenuated among patients with EF ≥60%.

Even though the SGLT-2 inhibitors were introduced as type 2 diabetes management drugs, the results of EMPA-REG OUTCOME, EMPEROR-Reduced, and others indicated a clear benefit in HF management. This trial enrolled a dedicated HFpEF population, and shows a benefit in this patient population, irrespective of diabetes status. Most routinely used drugs for HFrEF have not shown to be effective among patients with HFpEF, and some drugs such as candesartan, spironolactone, and sacubitril/valsartan appear to mostly have a benefit among patients with EF between 40-49% rather than true HFpEF. The exact mechanism of benefit is unclear. The pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved suggests that the renal benefit is primarily among patients with HFrEF, and eGFR slope analysis may not be predictive of renal outcomes among patients with HF.

References:

Anker SD, Filippatos BG, Ferreira JP, et al., on behalf of the EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure With a Preserved Ejection Fraction. N Engl J Med 2021;385:1451-61.

Letter to the Editor: Packer M, Butler J, Zannad F, et al. Empagliflozin and Major Renal Outcomes in Heart Failure. N Engl J Med 2021;385:1531-3.

Editorial: Drazner MH. SGLT2 Inhibition in Heart Failure With a Preserved Ejection Fraction — A Win Against a Formidable Foe. N Engl J Med 2021;385:1522-4.

Presented by Dr. Stefan Anker at the European Society of Cardiology Virtual Congress, August 27, 2021.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: ESC21, ESC Congress, Atrial Fibrillation, Diabetes Mellitus, Type 2, Diuretics, Geriatrics, Glomerular Filtration Rate, Heart Failure, Metabolic Syndrome, Natriuretic Peptide, Brain, Prediabetic State, Renal Insufficiency, Secondary Prevention, Stroke Volume, Ventricular Function, Left


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