3. INTRODUCTION
• Chronic heart failure (HF) has 3 major subtypes defined by LVEF,
Heart failure with preserved ejection fraction (HFpEF) with LVEF
≥50%,
Heart failure with mid-range ejection fraction (HFmrEF) with LVEF
40-<50%, and
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.
• There is critical need to identify effective therapies in HFpEF
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4. • 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)
• 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).
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5. • 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.
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6. OBJECTIVE
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?
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7. STUDY DESIGN
• Multicenter, double-blind, randomized, controlled trial
• N=5988
Empagliflozin (n=2997)
Standard (n=2991)
• Setting: 622 centres 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
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8. POPULATION
INCLUSION CRITERIA:
• NYHA class II-IV with LVEF >40% while clinically stable (and no prior LVEF ≤40 while
clinically stable)
• NT-pro BNP >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 n engl j med 385;16 nejm.org October 14, 2021
9. 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
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10. • Atrial fibrillation or atrial flutter with resting HR >110 at screening
• SBP ≥180 or <100 mm Hg or symptomatic hypotension
• ICD in prior 3 months
• Prior receipt of cardiac resynchronization therapy
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11. 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% n engl j med 385;16 nejm.org October 14, 2021
12. • 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
• HF type: Ischemic 36%, non-ischemic 64%
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13. • CV history:
HF hospitalization in prior year 23%,
AF 52%,
diabetes 49%,
hypertension 91%
• eGFR: 61 mL/min/1.73 m2
• eGFR <60: 50%
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15. INTERVENTIONS
• Randomized to empagliflozin 10 mg daily or placebo
• Stratified by geographic region, diabetes status, eGFR of 50, and LVEF
50%
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16. OUTCOMES
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)
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17. PRIMARY OUTCOME, A COMPOSITE OF CARDIOVASCULAR DEATH
OR HOSPITALIZATION FOR HEART FAILURE.
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23. 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.
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24. CRITICISMS
• Boehringer Ingelheim designed the protocol and statistical analysis
plan as well as supervised the analysis of the data.
• Combined HFpEF and HFmreEF.
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25. CONCLUSION
• 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.
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26. • In patients with heart failure and a preserved ejection fraction,
SGLT2 inhibition with empagliflozin led to a 21% lower relative
risk in the composite of cardiovascular death or hospitalization
for heart failure, which was mainly related to a 29% lower risk of
hospitalization for heart failure with empagliflozin.
Editor's Notes
After a screening period of 4 to 28 days, eligible
patients were randomly assigned in a 1:1 ratio
