Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved

Literature - Anker SD, Butler J, Usman MS, et al. - Nat Med. 2022 Dec;28(12):2512-2520. doi: 10.1038/s41591-022-02041-5.

Introduction and methods

Background

Previously, the placebo-controlled EMPEROR-Preserved trial showed that the SGLT2 inhibitor empagliflozin reduces the risk of cardiovascular death or first hospitalization for HF in patients with HF and an LVEF >40% [3]. It is unclear whether the effect of empagliflozin differs between patients with HFmrEF and those with HFpEF.

Aim of the study

This predefined subgroup analysis of the EMPEROR-Preserved trial examined the effect of empagliflozin in patients with HFmrEF and those with HFpEF.

Methods

The EMPEROR-Preserved trial is an international, multicenter, double-blind phase 3 study in which 5988 adult patients with chronic HF and an LVEF >40% were randomized to empagliflozin 10 mg daily or placebo, in addition to usual therapy. Patients with NYHA class II-IV symptoms and a NT-proBNP level >300 pg/ml who had been hospitalized for HF in the past 12 months or in whom structural abnormalities were found on echocardiography were eligible for participation. Patients were divided into 2 groups based on their LVEF at baseline: (a) LVEF of 41-49% (HFmrEF); and (b) LVEF ≥50% (HFpEF).

Outcomes

The primary outcome was a composite of the time to cardiovascular death or first hospitalization for HF. Secondary outcomes were: (a) first hospitalization for HF; (b) cardiovascular mortality; (c) first and recurrent hospitalization for HF; and (d) the change in eGFR slope (in ml/min per 1.73 m2 per year). Also examined were the change in health-related quality of life (KCCQ-23) and NYHA class, measured at baseline and week 52.

Main results

• Patients with HFpEF, compared were patients with HFmrEF, were more likely to be older, be women, and have a higher BMI. They had a higher burden of hypertension, CKD, AF and valvular heart disease, but were less likely to have diabetes or a history of MI. Patients with HFpEF also had a lower mean KCCQ score.
• In patients with HFmrEF (7.2 vs. 10.0 per 100 patient-years; HR: 0.71; 95%CI: 0.57-0.88; P=0.002) and in patients with HFpEF (6.7 vs. 8.0 per 100 patient-years; HR: 0.83; 95%CI: 0.71-0.98; P=0.024), the primary composite outcome occurred less frequently in the empagliflozin group than in the placebo group.
• Compared with placebo, treatment with empagliflozin resulted in a 42% lower risk (3.8 vs. 6.5 per 100 patient-years; HR: 0.58; 95%CI: 0.44-0.77; P<0.001) in patients with HFmrEF and a 22% lower risk (4.5 vs. 5.7 per 100 patient-years; HR: 0.78; 95%CI: 0.64-0.95; P=0.013) of first hospitalization for HF in patients with HFpEF.
• Compared with placebo, treatment with empagliflozin did not lower cardiovascular mortality in patients with HFmrEF (4.4 vs. 4.7 per 100 patient-years; HR: 0.92; 95%CI: 0.69-1.22; P=0.54) and in patients with HFpEF (3.0 vs. 3.4 per 100 patient-years; HR: 0.89; 95%CI: 0.70-1.13; P=0.34).
• Compared with placebo, the effect of empagliflozin did not differ significantly between patients with HFmrEF and patients with HFpEF for the primary composite outcome (P-interaction=0.27), first hospitalization for HF (P-interaction=0.09) or cardiovascular mortality (P-interaction=0.88).
• Compared with placebo, treatment with empagliflozin resulted in a lower risk of first and recurrent hospitalization for HF in patients with HFmrEF (HR: 0.57; 95%CI: 0.42-0.79; P<0.001), but not in patients with HFpEF (HR: 0.83; 95%CI: 0.66-1.04; P=0.11); the difference in effect of empagliflozin between patients with HFmrEF and patients with HFpEF was not statistically significant (P-interaction=0.06).
• The number needed to treat to prevent a first hospitalization for HF with empagliflozin compared with placebo over 2.15 years of treatment was 20 (95%CI: 13-40) in the HFmrEF group and 44 (95%CI: 24-248) in the HFpEF group; for first and recurrent hospitalization for HF, these numbers were 9 (95%CI: 6-25) and 38 (95%CI: 15-69), respectively.
• Empagliflozin delayed the decrease in eGFR slope in patients with HFmrEF by 1.61 (95%CI: 1.09-2.13; P<0.001) and in patients with HFpEF by 1.24 (95%CI: 0.87-1.61; P<0.001) ml/min per 1.73 m2 per year; the difference in effect of empagliflozin between patients with HFmrEF and patients with HFpEF was not statistically significant (P-interaction=0.25).
• In the overall trial cohort, treatment with empagliflozin significantly improved health-related quality of life; this improvement applied to all KCCQ-23 scores and was similar between patients with HFmrEF and patients with HFpEF (P-interaction≥0.35).
• Patients treated with empagliflozin had higher odds of NYHA class improvement at week 52 than patients in the placebo group (odds ratio: 1.32; 95%CI: 1.10-1.56; P=0.0033).

Conclusion

References

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