EMPEROR-Preserved proved to be a landmark trial in heart failure research. It demonstrated a clinically meaningful benefit of 21% reduction in the primary composite outcome as well as positive results in secondary outcomes with empagliflozin therapy for patients with heart failure with preserved ejection fraction (HFpEF).
The findings of the EMPEROR-Preserved (NCT03057951) trial were among those most eagerly awaited at this year´s ESC meeting1. The study aimed to assess empagliflozin as add-on to standard of care for HFpEF patients. It included 5,988 patients with HFpEF who had been hospitalised for HF within the last 12 months or were diagnosed with structural heart disease and ejection fraction over 40%. EMPEROR-Preserved was conducted as multinational trial at 622 different sites in 23 countries worldwide.
After randomisation, participants with NYHA class 2–4 and eGFR ≥20 mL/minute/1.73 m2 were treated with either 10 mg of empagliflozin daily or placebo and followed over a median time of 26 months. “The primary endpoint of the study was a composite of cardiovascular death and HF hospitalisation and the 2 key secondary endpoints are the first and recurrent adjudicated HF hospitalisation and the slope of change in the estimated GFR for these patients over time,” explained principle investigator Prof. Stefan Anker (Charité University Hospital, Germany).
The baseline characteristics included a mean age of about 72 years, 45% women, a mean eGFR of 60.6 mL/minute/1.73 m2, and 49% of diabetic patients. Prof. Anker pointed out that when it came to underlying medication, the study subjects were in many ways treated similarly to HF patients with reduced ejection fraction with ≥80% under inhibition of the renin-angiotensin-aldosterone system and more than 80% on β-blockers.
The results showed event rates of 415 (6.9/100 patient-years) in the empagliflozin and 511 (8.7/100 patient-years) in the placebo group. This led to a significant hazard ratio (HR) of 0.79 (95% CI 0.69–0.90; P=0.0003), which converts to a 21% reduction in the relative risk over time. Interestingly, this significant treatment difference was present from day 18 on. Evaluating the single components of the primary endpoint made clear that the effect was mainly driven by the reduction in first hospitalisation (HR 0.71; 95% CI 0.60–0.83) and not by a decrease in CV death (HR 0.91; 95% CI 0.76–1.09).
The analysis of 13 pre-specified subgroups like diabetes status, sex, ejection fraction corroborated the beneficial effect of the empagliflozin treatment. Also, the findings for the secondary endpoint of first and recurrent hospitalisation for HF demonstrated a clinically meaningful 27% amelioration (HR 0.73; 95% CI 0.61–0.88; P=0.0009). Furthermore, the decline of kidney function over time was significantly less under empagliflozin (P<0.0001), and, interestingly, in patients whose kidney function was re-evaluated 23–42 days post-withdrawal of the double-blind treatment, the eGFR was less reduced in the empagliflozin cohort. Empagliflozin also proved beneficial in terms of health-related quality of life and change in NYHA class. “EMPEROR-Preserved is the first trial to show unequivocal clinical benefits with a drug in patients with HFpEF,” Prof. Anker commented on the results.
1. Anker S. EMPEROR-Preserved: effect of empagliflozin on cardiovascular death and heart failure hospitalisations in patients with heart failure with a preserved ejection fraction, with and without diabetes. Hot Line Session, ESC Congress 2021, 27–30 August.