Similar effect of SGLT2 inhibitor in HFmrEF and HFpEF
The EMPEROR-Preserved trial showed that empagliflozin reduced the risk of CV death or HF hospitalization in patients with HF and LVEF >40%. However, it is unknown whether the effect of empagliflozin differs between patients with HFmrEF and those with HFpEF. This subgroup analysis of the EMPEROR-Preserved trial offers more clarity.
Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-PreservedLiterature - 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
This subgroup analysis of the placebo-controlled EMPEROR-Preserved trial shows that empagliflozin significantly improves the time to cardiovascular death or first hospitalization for HF in both patients with HFmrEF and patients with HFpEF. This beneficial effect was largely driven by a reduction in hospitalizations for HF. Empagliflozin also improved health-related quality of life and NYHA class.
References
1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891-975.
2. Bozkurt, B. et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. J Card Fail. 2021;27:387-413.
3. Anker SD, Butler J, Filippatos G, et al; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385:1451-1461.