EMPEROR-Preserved

Published

Anker S, et al. "Empagliflozin in Heart Failure with a Preserved Ejection Fraction". New England Journal of Medicine. 2021. epub 2021-08-27:1-11.
PubMed • Full text • ClinicalTrials.gov

Clinical Question

In adults with heart failure with mid-range or preserved ejection fraction, does empagliflozin reduce the risk of the composite of cardiovascular death or hospitalization for heart failure?

Bottom Line

Among adults with heart failure with mid-range or preserved ejection fraction (LVEF >40%), empagliflozin decreased the risk of the cardiovascular death or heart failure hospitalization. This benefit was mainly driven by fewer heart failure hospitalizations.

Major Points

Chronic heart failure (HF) has 3 major subtypes defined by LVEF, 1. Heart failure with preserved ejection fraction (HFpEF) with LVEF ≥50%, 2. Heart failure with mid-range ejection fraction (HFmrEF) with LVEF 40-<50%, and 3. Heart failure with reduced ejection fraction (HFrEF) with LVEF <40%. HFpEF accounts for about 50% of chronic HF. Unlike HFrEF, there are few therapies that improve HFpEF endpoints. (Of note, emerging evidence that HFmrEF may respond to HFrEF interventions, including ARBs, beta-blockers, and angiotensin receptor blockade.) There is critical need to identify effective therapies in HFpEF. The CHARM-Preserved trial compared candesartan to placebo in patients with HFpEF, but was not found to decrease the risk of the composite outcome of cardiovascular death or HF admission in a statistically significant manner (HR 0.86; 95% CI 0.74-1.00). TOPCAT compared spironolactone to placebo and did not find a difference in the composite of cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization (HR 0.89; 95% CI 0.77-1.04). Subgroup analysis comparing Eastern European participants vs.other participants did find a significant reduction in the primary endpoint for those outside Eastern Europe. Spironolactone were undetectable in a much larger proportion of Eastern European participants, which was thought to mean they may have not been receiving the study medication. PARAGON-HF compared sacubitril-valsartan to valsartan and also did not find a statistically significant difference in the composite of cardiovascular mortality and HF hospitalizations (RR 0.87; 95% CI 0.75-1.01).

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) inhibit renal glucose reabsorption and were brought to market as oral diabetes medications. They were shown to lower CKD risk and CVD events among adults with diabetes in EMPA-REG OUTCOME (2015) and CANVAS (2017). More recently, they were found to have benefit in reducing HF events among patients with HFrEF in EMPEROR-Reduced (2020), regardless of diagnosis of diabetes. The role of this class among adults with HFpEF is unclear.

Published in 2021, EMPEROR-Preserved trial randomized about 6,000 patients with NYHA class II-IV symptoms, LVEF >40% (i.e., HFmrEF and HFpEF), and NT-proBNP >300 pg/mL (no AF) or >900 pg/mL (AF) regardless of diabetes history to the SGLT2i empagliflozin or placebo. With 26.2 months of follow-up, empagliflozin was associated with a lower risk of HF hospitalization or CVD mortality (13.8% vs.17.1%; HR 0.79; 95% CI 0.69-0.90), which was primarily driven by fewer HF hospitalization events. About 1/3rd of the participants had HFmrEF, which appeared to have the greatest benefit in the subgroup analysis. There also appeared to be a benefit among those with traditionally-considered HFpEF. Ultimately, EMPEROR-Preserved provides initial clinical evidence for the use of SGLT2i therapy in HFmrEF and HFpEF. These were later confirmed in DELIVER (2022).

Guidelines

ACC/AHA/HFSA heart failure (2022, adapted)

• If symptomatic chronic HFrEF, SGLT2i recommended to reduce HF hospitalizations and CVD mortality, regardless of diabetes status (COR 1, LOE A)
• If HFpEF or HFmrEF, SGLT2i can be useful for lowering HF mortality and HF hospitalizations (COR 2a, LOE B-R)

Design

• Multicenter, double-blind, parallel-group, randomized, controlled trial
• N=5988
  • Empagliflozin (n=2997)
  • Standard (n=2991)
• Setting: 622 centers in 23 countries
• Enrollment: 2017-2020
• Median follow-up: 26.2 months
• Analysis: Intention-to-treat
• Primary outcome: Death from cardiovascular causes or hospitalization for heart failure

Population

Inclusion Criteria

• NYHA class II-IV with LVEF >40% while clinically stable (and no prior LVEF ≤40 while clinically stable)
• NT-proBNP >300 pg/mL if no AF or >900 pg/mL if AF
• Aged ≥18 years
• Evidence of hypertensive heart failure or structural heart disease characterized by LAE or LVH
• Stable diuretic use
• BMI <45 kg/m²

Exclusion Criteria

• MI, CABG or other major CV surgery, or stroke/TIA in prior 90 days
• Cardiomyopathy based on infiltrative diseases, muscular dystrophies, hypertrophic obstructive cardiomyopathy, or pericardial constriction
• Severe valvular heart disease
• Acute decompensated heart failure requiring intravenous diuretics, vasodilators, inotropic agents, or mechanical support within 1 week of screening
• Atrial fibrillation or atrial flutter with resting HR >110 at screening
• SBP ≥180 or <100 mm Hg or symptomatic hypotension
• ICD in prior 3 mo
• Prior receipt of cardiac resynchronization therapy
• Significant comorbidities listed on page 17 of the supplemental appendix

Baseline Characteristics

From the empagliflozin group.

• Demographics: Age 72 years, 45% female sex, 76% white race, 4% Black race, 14% Asian
  • Geographical region: N America 12%, Latin America 25%, Europe 45%, Asia 11%, other 6%
• NYHA class: I <1%, II 81%, III 18%, IV <1%
• Measurements: BMI 30 kg/m², HR 70 BPM, SBP 132 mm Hg
• Echo details: LVEF 54%
  • HFmrEF (LVEF 41 to <50%): 33%
  • HFpEF, LVEF ≥50 to <60%: 34%
  • HFpEF, LVEF ≥60%: 32%
• Median NT-proBNP: 994 (IQR 501-1740)
• HF type: Ischemic 36%, nonischemic 64%
• CV history: HF hospitalization in prior year 23%, AF 52%, diabetes 49%, hypertension 91%
• eGFR: 61 mL/min/1.73 m²
  • eGFR <60: 50%

Interventions

• Randomized to empagliflozin 10 mg daily or placebo
• Stratified by geographic region, diabetes status, eGFR of 50, and LVEF 50%

Outcomes

Comparisons are empagliflozin vs. placebo.

Primary Outcomes

Death from cardiovascular causes or hospitalization for heart failure

13.8% vs.17.1% (HR 0.79; 95% CI 0.69-0.90; P<0.001; NNT=30)

Secondary Outcomes

Hospitalization for heart failure

8.6% vs.11.8% (HR 0.71; 95% CI 0.60-0.83; NNT=31)

Death from cardiovascular causes

7.3% vs.8.2% (HR 0.91; 95% CI 0.76-1.09)

Subgroup Analysis

The authors reported that there was no heterogeneity across subgroups, but do not provide statistical comparisons to support this claim. Visual inspection of Figure 2 reveals a stepwise difference in effect across LVEF groups (LVEF 40 to <50% or HF with midrange EF aka HFmrEF, 50 to <60%, and ≥60%). The largest benefit was among participants with HFmrEF.

Adverse Events

Patients with any serious adverse event

47.9% vs.51.6%

Genital infections

2.2 vs.0.7%

Hypotension

10.4 vs.8.6%

Symptomatic Hypotension

6.6% vs.5.2%

No significant difference in rates of urinary tract infections, hypoglycemic events, ketoacidosis, acute renal failure, or lower limb amputation between trial arms.

Criticisms

• Boehringer Ingelheim designed the protocol and statistical analysis plan as well as supervised the analysis of the data.
• Combined HFpEF and HFmreEF.

Funding

Eli Lilly; Boehringer Ingelheim