EMPEROR-Preserved: Empagliflozin in heart failure with preserved or mildly-reduced ejection fraction

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References:

Bottom Line: In patients with symptomatic heart failure with preserved (≥50%; HFpEF) or mildly-reduced (41-49%; HFmrEF) ejection fraction, empagliflozin reduced the risk of HF hospitalization vs placebo (-3.2%) and increased the probability of a clinically important improvement in quality of life (+3.8%), but did not reduce deaths or total hospitalizations at 2.2 years. Empagliflozin increased the risk of symptomatic hypotension (+1.4%), genital fungal infections (+1.5), and UTIs (+1.8%).

Patients (n=5988)

  • 11,583 screened -> 5988 randomized

    • Most common reasons for exclusion:

      • 78% NT-proBNP below inclusion criteria threshold

      • 5% LVEF <40%

      • 4% exclusion criteria based on safety

  • Enrolment 2017-April 2020

  • 23 countries

  • Included: Symptomatic chronic HFpEF or HFmrEF with elevated natriuretic peptide

    • Chronic HF (≥3 months)

    • NYHA 2-4

    • LVEF >40% without any prior LVEF ≤40%

    • NT-proBNP

      • >300 pg/mL if in sinus rhythm

      • >900 pg/mL if in atrial fibrillation

    • Either

      • Structural heart disease (LAE &/or LVH) documented on echo

      • HF hospitalization within past 12 months

  • Key exclusions:

    • SBP <100 mm Hg

    • eGFR <20

    • BMI ≥45

    • SGLT2i contraindication (history of ketoacidosis, allergy/hypersensitivity)

    • “Cardiovascular (CV) disease/treatment that increase the unpredictability of or change the patients’ clinical course independent of HF” (e.g. MI/stroke/TIA/CV surgery in past 90 days; infiltrative cardiomyopathy; heart transplant recipient/wait list; severe valvular disease)

    • “Untreated CV condition that might influence the course of HF/study drug tolerability” (e.g. AF with uncontrolled HR, SBP ≥180 mm Hg)

    • “Significant comorbidity that might influence clinical course” (e.g. pulmonary disease requiring O2, PO steroids or requiring hospitalization; acute/chronic liver disease)

  • Baseline characteristics:

    • Age 72, 45% female, 76% White/14% Asian

    • NYHA 2 (81%), 3 (18%)

    • Mean LVEF 54% (~1/3 each in categories 41-49%, 50-59%, ≥60%)

    • Median NT-proBNP ~950-1000 pg/mL

    • HF hospitalization in last 12 months ~23%

    • Comorbidities: HTN 90-91%, AF 51%, eGFR <60 50%, diabetes 49%

    • Meds: Beta-blocker 86%, ACEI/ARB 79%, ARNI ~2%, MRA 37-38%, digitalis 9-10%

    • SBP 132, HR 70

Intervention: Empagliflozin 10 mg qAM

Comparator: Matching placebo

Outcomes at median 26.2 months (2.2 years)

Efficacy outcomes

Effect on quality of life (using Kansas City Cardiomyopathy Questionnaire [KCCQ]; range 0 [worst] to 100 [best]):

  • More likely to have a clinically-important (≥5/100) improvement in quality of life with empagliflozin vs placebo

    • KCCQ-overall summary score at 1 year: Empagliflozin 49.6% vs placebo 45.8% (+3.8%)

    • Similar effect over time (e.g. difference +4.7% at 3 months vs 3.8% at 12 months)

    • Similar difference if considering clinically-important decline (-4.8% at 1 year) or different cutoffs for improvement (+2.3% for ≥10-point improvement & +3.6% for ≥15-point improvement)

    • Similar difference if considering KCCQ subscores (e.g. +4.6% for KCCQ-total symptoms score [HF symptom burden + frequency] at 1 year)

Cumulative incidence curve for the primary composite outcome showing immediate separation of empagliflozin and placebo curves (suggesting early benefit)

Cumulative incidence curve for the primary composite outcome showing immediate separation of empagliflozin and placebo curves (suggesting early benefit)

Safety outcomes

Effect on biometrics & biomarkers (difference vs placebo):

  • Body weight: -1.3 kg

  • SBP -1.2 mm Hg

  • A1c: -0.2%

  • NT-proBNP: -20 pg/mL

Internal validity: Low risk of bias

  • Computer-generated random sequence using permuted blocks

    • Stratified by geographic region, diabetes status, eGFR <60 or ≥60, & LVEF <50% or ≥50%

  • Allocation concealment by central randomization via interactive response technology

  • Blinding of participants and treating clinicians with matching placebo

  • Blinded outcome adjudication

  • Intention-to-treat analysis

  • 3% loss-to-follow-up for primary outcome, 0.6% for death

Other considerations

Are the results clinically important?

  • Maybe; this will very much depend on individual patient/clinician preferences

    • Overall, likely net clinical benefit based on composite of % who died or had a hospitalization due to any cause

      • HF hospitalizations only accounted for 18% of total hospitalization outcomes in this trial, and therefore the 3.2% absolute reduction in the risk of a first HF hospitalization is diluted in total hospitalizations

      • Neutral effect on all-cause death & inconclusive effect on CV deaths

        • CV death accounted for 55% of deaths (sudden death > HF > other), & non-CV deaths accounted for 45% (infection > malignancy > other)

    • QoL improvement with empagliflozin consistent with results of the PRESERVED-HF trial & effects of SGLT2i on QoL in HFrEF trials

      • Brief summary of PRESERVED-HF:

        • P: 324 patients with NYHA 2-4 HF & LVEF >=45% (mixed HFpEF/HFmrEF) + elevated NT-proBNP/BNP + receiving a diuretic + additional enrichment criteria + eGFR >=20 + SBP >=100

        • I: Dapagliflozin 10 mg daily

        • C: Placebo

        • O: KCCQ-23 @ 3 months

          • Mean +4.5/100 in overall-summary score with dapa

          • Clinically-important improvement: Dapa 45.4% vs placebo 34.9% (+10.5%) at 3 months

How do we apply these results to patient care (generalizability)?

  • Although the study defined “preserved” ejection fraction as >40%, the 2021 universal definition and classification of HF further sub-classify HF as HFmrEF if 41-49% (~1/3 of the study population) & HFpEF if ≥50%

    • Subgroup analysis of the primary outcome comparison based on baseline LVEF suggested attenuation of efficacy with increasing LVEF, with uncertain efficacy with LVEF ≥60%

      • Hazard ratio progressively attenuated from LVEF 41-49% (0.71, 95% CI 0.57-0.88), 50-59% (0.80, 95% CI 0.64-0.99), ≥60% (0.87, 0.69-1.10)

      • Risk of the primary outcome increased with lower LVEF, leading to a greater absolute risk reduction in those with lower baseline LVEF (even if we assume constant 21% relative risk reduction regardless of LVEF)

        • LVEF 41-49%: Risk in placebo group 19.5%, absolute risk reduction 4.1%

        • LVEF 50-59%: Risk in placebo group 16.8%, absolute risk reduction 3.5%

        • LVEF ≥60%: Risk in placebo group 14.9%, absolute risk reduction 3.1%

  • Efficacy on primary outcome (in terms of relative effect) similar in females/males, diabetes/no diabetes, AF/no AF, eGFR <60/≥60, & regardless of race/ethnicity

More to come…