Empagliflozin: First drug with clear benefit in HFpEF patients

As the first positive study about a treatment drug in heart failure with preserved ejection fraction (HFpEF), EMPEROR-Preserved is considered a landmark trial. Besides a relevant 21% reduction in the primary composite outcome, key secondary endpoints results were also significant [1,2].

“We are about to have one of the most exciting clinical trials, I think, we’ve seen in a long time presented here in this Hotline-session at the ESC 2021–Digital experience and I have to say that I cannot think of any trial been more anticipated than the EMPEROR-Preserved trial,” Prof. John McMurray (University of Glasgow, Scotland) introduced the EMPEROR-Preserved (NCT03057951) [1]. The trial 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 (EF) over 40%. EMPEROR-Preserved was conducted as a multinational trial at 622 different sites in 23 countries worldwide.

After randomisation, participants with NYHA class II–IV 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 principal 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 patients had diabetes. 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 EF 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), with a 21% relative risk reduction overall. Interestingly, this significant treatment difference was present from day 18 on. Evaluating the single components of the primary endpoint showed that the benefit was mainly driven by the reduction in first hospitalisation (HR 0.71; 95% CI 0.60–0.83) and not by a decrease in cardiovascular death (HR 0.91; 95% CI 0.76–1.09).

The analysis of 13 pre-specified subgroups like diabetes status, sex, and EF corroborated the beneficial effect of the empagliflozin treatment. Also, the findings for the secondary endpoint of first and recurrent hospitalisation for HF demonstrated a 27% relative risk reduction (HR 0.73; 95% CI 0.61–0.88; P=0.0009). Furthermore, the decline of kidney function over time was significantly reduced with empagliflozin (P<0.0001), and in patients whose kidney function was re-evaluated 23–42 days after the double-blind treatment, the eGFR was less reduced in the empagliflozin cohort compared with the placebo group (see Figure). 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.

Figure: Results in terms of the slope of decline in eGFR over time [1]
* Analysed based on on-treatment data.

 

1. 
   
   1. Anker SD. 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.
   2. Anker SD, et al. N Engl J Med 2021; Aug 27. DOI:10.1056/NEJMoa2107038.

 

Read more on the EMPEROR-Preserved trial in a featured interview by Medicom with Prof. Stefan Anker.

 

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Posted on 26 October 20218 December 2021