EMPEROR PRESERVED sub-study shows no difference in outcomes when stratified by ejection fraction.

Key Points:

• In the original EMPEROR-PRESERVED study, patients with chronic heart failure with preserved ejection fraction (EF>40%) with or without diabetes were treated with empagliflozin and experienced significant reductions in combined CV death/HF hospitalizations, as well as first or recurrent HHF.
• In this sub-study, the outcomes above were compared between patients with “true” HFpEF (EF>50%) and patients with mid-range EF (HFmrEF, EF 41-49%).
• Patients with both true HFpEF and HFmrEF had a reduction in the primary endpoint (combined CV death and HF hospitalizations) as well as time to first HF hospitalizations at a median follow-up of 26 months; patients with HFmrEF additionally had a reduction in total HF hospitalizations. There were no differences in CV death alone or all-cause mortality.

While many medical therapies have been shown to reduce major adverse cardiovascular events in heart failure with reduced ejection fraction (HFrEF), there has been less success for patients with heart failure with preserved ejection fraction (HFpEF). Recently, several trials of SGLT-2 inhibitors have demonstrated improved cardiovascular outcomes in patients with HFrEF (EMPEROR-Reduced trial, DAPA-HF). Earlier this year, the EMPEROR-PRESERVED trial demonstrated an improvement in combined CV death/HF hospitalizations at two years in patients with HFpEF treated with empagliflozin (EF >40%); however, one important critique of this trial was the overly inclusive definition of HFpEF, as patients with EF 41-49% may not represent truly preserved EF. In a breaking presentation at the 2021 American Heart Association Scientific Sessions today, Dr. Stefan Anker (Charité University, Berlin) presented the results of their follow-up study of the EMPEROR-Preserved trial (NCT03057951), now examining the results stratified by ejection fraction (EF 41-49% vs ≥50%).

The aim of this follow-up study was to determine the efficacy and safety of 10mg daily empagliflozin versus placebo in patients with HFpEF, now stratified by “true” HFpEF (EF≥50%) vs HFmrEF (EF 41-49%). Patients were recruited from 622 sites in 23 countries. Adult patients an EF >40% and stage NHYA II-IV HF were included, with or without diabetes. Relevant exclusion criteria include eGFR<20. Patients were followed for a median of 26 months. 48% of patients with true HFpEF had diabetes, as did 52% of the HFmrEF group.

A total of 5,988 patients were randomized, of which 2,997 underwent empagliflozin treatment. 4,005 total had HFpEF, and 1,983 had HFmrEF.  The primary endpoint (time to adjudicated HHF or CV death) was significantly reduced in the empagliflozin group amongst true HFpEF patients (HR 0.83 (95% CI; 0.71-0.96), p=0.024). Additionally, patients with true HFpEF receiving empagliflozin had a reduction in time to first HF hospitalizations (HR 0.78 (95% CI; 0.64-0.95), p=0.013). There was no observed benefit in CV mortality alone, all-cause mortality, or total HF hospitalizations. There were similarly significant reductions observed in the HFmrEF group for the primary endpoint and time to first HHF, with an additional reduction in total heart failure hospitalizations (HR 0.57 (95% CI; 0.42-0.79), p<0.001). Both patients with HFpEF and HFmrEF experienced a significant reduction in the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 52 weeks, with no significant difference between the two groups (p-interaction 0.92). Patients with true HFpEF experienced a significantly reduced slope of decline of eGFR compared to placebo (1.24mL/min/1.73m2 per year, p<0.0001).

When discussing the implications of the study during his live presentation, Dr. Anker stated that “for the population of what is now classically accepted by guidelines [to be HFpEF] of ≥50% EF, there was a 17% significant benefit in the primary outcome…which also extends to quality of life, symptoms, and kidney function data. This is in summary, the first large-scale evidence of any drug improving the outcomes specifically for what we today consider HFpEF patients. ”