Vascular Disease Burden, Outcomes and Benefits with Empagliflozin in Heart Failure: Insights From the EMPEROR-Reduced Trial

Muhammad Shahzeb Khan; Stefan D Anker; Gerasimos Filippatos; João Pedro Ferreira; Stuart J Pocock; James L Januzzi; Vijay K Chopra; Ileana L Piña; Michael Böhm; Piotr Ponikowski; Subodh Verma; Martina Brueckmann; Ola Vedin; Barbara Peil; Faiez Zannad; Milton Packer; Javed Butler

doi:10.1016/j.cardfail.2023.06.024

Vascular Disease Burden, Outcomes and Benefits with Empagliflozin in Heart Failure: Insights From the EMPEROR-Reduced Trial

J Card Fail. 2023 Oct;29(10):1345-1354. doi: 10.1016/j.cardfail.2023.06.024. Epub 2023 Aug 8.

Authors

Muhammad Shahzeb Khan¹, Stefan D Anker², Gerasimos Filippatos³, João Pedro Ferreira⁴, Stuart J Pocock⁵, James L Januzzi⁶, Vijay K Chopra⁷, Ileana L Piña⁸, Michael Böhm⁹, Piotr Ponikowski¹⁰, Subodh Verma¹¹, Martina Brueckmann¹², Ola Vedin¹³, Barbara Peil¹⁴, Faiez Zannad¹⁵, Milton Packer¹⁶, Javed Butler¹⁷

Affiliations

¹ Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
² Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies; German Centre for Cardiovascular Research Berlin, Germany; Charité Universitätsmedizin Berlin, Berlin, Germany; Institute of Heart Diseases, Wrocław Medical University, Wrocław, Poland.
³ National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece.
⁴ Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France; Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; Heart Failure Clinic, Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal.
⁵ Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK.
⁶ Harvard Medical School, Massachusetts General Hospital, Baim Institute for Clinical Research, Boston, MA, USA.
⁷ Department of Cardiology, Medanta, Gurgaon, Haryana, India.
⁸ Department of Medicine, Thomas Jefferson University, Philadelphia, PA.
⁹ Department of Internal Medicine III, University Hospital Saarland, Saarland University, Homburg, Saar, Germany.
¹⁰ Institute of Heart Diseases, Wrocław Medical University, Wrocław, Poland.
¹¹ Division of Cardiac Surgery, St Michael's Hospital, University of Toronto, Toronto, Canada.
¹² Boehringer Ingelheim International GmbH, Ingelheim, Germany; First Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
¹³ Boehringer Ingelheim AB, Stockholm, Sweden.
¹⁴ Boehringer Ingelheim Pharma, Ingelheim, Germany.
¹⁵ Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France.
¹⁶ Baylor University Medical Center, Dallas, TX, USA; Imperial College, London, UK.
¹⁷ Baylor Scott and White Research Institute, Dallas, TX, USA; Department of Medicine, University of Mississippi School of Medicine, Jackson, MS, USA. Electronic address: Javed.Butler@bswhealth.org.

PMID: 37558088
DOI: 10.1016/j.cardfail.2023.06.024

Abstract

Background: The presence of ischemic heart disease impacts prognosis in patients affected by heart failure and reduced ejection fraction (HFrEF). It is not well known how the extent of vascular disease impacts prognoses and responses to therapy in this setting.

Methods: In this post hoc analysis of the EMPEROR-Reduced trial, outcomes and the effects of empagliflozin, were assessed in study participants according to the extent (none vs mono¹ vs poly [≥ 2] vascular bed) of vascular disease. Vascular disease was defined as investigator-reported coronary artery disease (CAD), peripheral artery disease (PAD) and cerebrovascular disease at baseline. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Incidence rates are presented per 100 person-years (py) of follow-up.

Results: Of the 3730 study participants enrolled, 1324 (35.5%) had no vascular disease, 1879 (50.4%) had monovascular disease, and 527 (14.1%) had polyvascular disease. Participants with polyvascular disease tended to be older and male and to have had histories of hypertension, diabetes and smoking. In the placebo arm, a significantly higher risk for cardiovascular death existed in those with polyvascular disease (HR 1.57, 95% CI1.02, 2.44, compared to those with no vascular disease). In adjusted analysis, the benefit of empagliflozin in cardiovascular death or hospitalization due to HF, HF hospitalization, cardiovascular death, renal composite endpoint, estimated glomerular filtration slope changes, and health status scores were seen across the 3 groups (interaction P > 0.05 for all) but were attenuated in those with polyvascular disease. Adverse events were higher in those with polyvascular disease, but no major differences were noted between empagliflozin or placebo assignment in the 3 groups.

Conclusion: In patients with HFrEF, the extent of vascular disease is associated with the risk for adverse cardiovascular outcomes. Empagliflozin offers cardiovascular and renal benefits in HFrEF across the extent of vascular disease, but this benefit is attenuated in those with polyvascular disease.