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. 2022 Oct;24(10):1883-1891.
doi: 10.1002/ejhf.2677. Epub 2022 Oct 4.

Heart failure outcomes according to heart rate and effects of empagliflozin in patients of the EMPEROR-Preserved trial

Michael Böhm  1   2 , Javed Butler  3   4 , Felix Mahfoud  1 , Gerasimos Filippatos  5 , João Pedro Ferreira  6   7 , Stuart J Pocock  8 , Jonathan Slawik  1 , Martina Brueckmann  9   10 , Bruno Linetzky  11 , Elke Schüler  12 , Christoph Wanner  13 , Faiez Zannad  6   7 , Milton Packer  14   15 , Stefan D Anker  16 ; EMPEROR-Preserved Trial Committees and Investigators
Affiliations

Heart failure outcomes according to heart rate and effects of empagliflozin in patients of the EMPEROR-Preserved trial

Michael Böhm et al. Eur J Heart Fail. 2022 Oct.

Abstract

Aims: Empagliflozin reduces cardiovascular death (CVD) or heart failure hospitalization (HHF) in patients with heart failure and preserved ejection fraction (HFpEF). Treatment effects and safety in relation to resting heart rate (RHR) have not been studied.

Methods and results: The interplay of RHR and empagliflozin effects in EMPEROR-Preserved was evaluated. We grouped patients (n = 5988) according to their baseline RHR (<70 bpm [n = 2650], 70-75 bpm [n = 967], >75 bpm [n = 1736]) and explored the influence of RHR on CVD or HHF (primary outcome) and its components in sinus rhythm or atrial fibrillation/flutter (AF) and adverse events. We studied the efficacy of empagliflozin across the RHR spectrum. Compared to placebo, empagliflozin did not change heart rate over time. The primary outcome (p for trend = 0.0004) and its components CVD (p trend = 0.0002), first HHF (p for trend = 0.0099) and all-cause death (p < 0.0001) increased with RHR only in sinus rhythm but not AF. The risk increase with RHR was similar in patients with heart failure and mildly reduced ejection fraction (left ventricular ejection fraction [LVEF] 40-49%) and HFpEF (LVEF ≥50%). Baseline RHR had no influence on the effect of empagliflozin on the primary outcomes (p for trend = 0.20), first HHF (p for trend = 0.49). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the RHR groups.

Conclusion: Resting heart rate associates with outcomes only in sinus rhythm but not in AF. Empagliflozin reduced outcomes over the entire RHR spectrum without increase of adverse events.

Keywords: Atrial fibrillation; Cardiovascular outcomes; Empagliflozin; Heart failure; Resting heart rate.

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Figures

Figure 1
Figure 1
Incidence of heart failure outcomes by resting heart rate. Cumulative incidence function of the primary outcome (composite of first heart failure hospitalization or cardiovascular death) (A), first hospitalization for heart failure (B), cardiovascular death (C) and all‐cause death (D) according to resting heart rate. Data were adjusted for competing risk by death types, which were not part of the endpoint under investigation (e.g. all‐cause death for heart failure hospitalization).
Figure 2
Figure 2
Outcomes according to resting heart rate. Hazard ratio for the primary endpoint (A), first hospitalization for heart failure (B), first and recurrent hospitalization for heart failure (C), cardiovascular death (D) and all‐cause death (E) according to resting heart rate. <70 bpm is given as a reference. CI, confidence interval.
Figure 3
Figure 3
Outcomes according to ejection fraction, rhythm and heart rate. Hazard ratio and incidence per 100 patient‐years for the primary endpoint (A), first hospitalization for heart failure (B), cardiovascular death (C) and all‐cause death (D) in patients with atrial fibrillation/flutter (AF), sinus rhythm, left ventricular ejection fraction (LVEF) 40–49% and LVEF ≥50%. <70 bpm is given as reference. CI, confidence interval.
Figure 4
Figure 4
Outcomes according to resting heart rate as a continuous variable. Hazard ratio for the primary endpoint (A), first hospitalization for heart failure (B) in all patients and the primary endpoint (C) and first hospitalization for heart failure (D), by presence of sinus rhythm or atrial fibrillation/flutter according to resting heart rate as a continuous variable. CI, confidence interval.
Figure 5
Figure 5
Empagliflozin effects across resting heart rate. Hazard ratio (left) and incidence rate per 100 patient‐years (right) for empagliflozin compared to placebo according to resting heart rate for the primary endpoint (A), first hospitalization for heart failure (B), cardiovascular death (C) and all‐cause death (D). CI, confidence interval.
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