Non cardiovascular hospitalizations in heart failure and preserved ejection fraction (HFpEF) and the effect of empagliflozin

Lead Investigator: João Pedro Ferreira, University of Porto
Title of Proposal Research: Non cardiovascular hospitalizations in heart failure and preserved ejection fraction (HFpEF) and the effect of empagliflozin
Vivli Data Request: 8933
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Heart failure is a condition in which the heart muscle is unable to pump enough blood to meet the body’s nutrition and oxygen needs. Patients with heart failure and a preserved ejection fraction (HFpEF) (ejection fraction is measured as a percentage of the total amount of blood in your heart that is pumped out with each heartbeat; PRESERVED ejection factor is when the heart “pumps” the blood effectively to the body but has problems “filling” the blood back [to the lower left chamber /ventricle] from another part of the heart [upper left chamber/atrium]) usually have multiple cardiovascular and non-cardiovascular comorbid conditions (i.e., other medical conditions that commonly occur concomitantly with HFpEF) which increase the risk of hospitalizations both from cardiovascular and non-cardiovascular reasons. Additionally, non-cardiovascular hospitalizations often aggravate heart failure and pose additional challenges in the diagnosis and treatment of heart failure.

Non-cardiovascular hospitalizations (e.g., respiratory infections, urinary tract infections, skin infection, cancer, renal failure) are the cause of around half of the hospitalizations in patients with HFpEF; therefore, non-cardiovascular hospitalizations are at least as important as cardiovascular hospitalizations in terms of health and resource use impact. Still, little is known about the causes and associated prognosis of non-cardiovascular hospitalizations in HFpEF.

Thus, I aim to study the reasons leading to hospitalization in HFpEF using the EMPEROR-Preserved dataset and assess the impact of empagliflozin (a sodium glucose co-transporter 2 inhibitor [SGLT2i]) on non-cardiovascular hospitalizations. Empagliflozin reduced heart failure hospitalizations and cardiovascular mortality compared to placebo in patients with HFpEF in the the EMPEROR-Preserved trial. The mechanisms by which SGLT2i benefit heart failure patients are not fully explained and is not clear if SGLT2i can also reduce hospitalizations for causes other than heart failure.

This proposal aims to describe the non cardiovascular reasons leading to hospitalization (i.e., specific causes and their incidence), their association with subsequent mortality, and the effect of empagliflozin (vs. placebo) on non cardiovascular hospitalizations.
This proposal is relevant because little is known about the reasons leading to hospitalizations from non-cardiovascular causes among patients with HFpEF and by improving the knowledge about these non-cardiovascular causes may help improving prevention strategies (e.g., vaccination for pneumonia).

I will retrospectively analyze the EMPEROR-Preserved dataset, retrieving the reasons leading to hospitalization as written in the Case Report Forms. Then I will describe the reasons leading to hospitalization by groups of most common conditions and I will study the prognostic impact of such conditions.

Statistical Analysis Plan:

Hospitalization reasons will be retrieved from “free text” in the dataset e.g., pneumonia, respiratory infection, pyelonephritis, urinary tract infection etc
The association between hospitalization reason and subsequent mortality will be assessed using time-updated Cox models.
For time-to-first-event analyses, differences between the placebo and empagliflozin groups will be assessed using a Cox proportional hazards model, with prespecified covariates of age, gender, geographical region, diabetes status at baseline, left ventricular ejection fraction, and estimated glomerular filtration rate at baseline.
All variables will be used as “complete cases” and no data imputation will be performed.

The requested study was selected because it comprises a large sample (almost 6000 patients) of HFpEF patients treated with either empagliflizin or placebo, allowing to study the reasons leading to hospitalization as well as the potential impact of treatment on hospitalizations.

Requested Studies:

A Phase III Randomised, Double-blind Trial to Evaluate Efficacy and Safety of Once Daily Empagliflozin 10 mg Compared to Placebo, in Patients With Chronic Heart Failure With Preserved Ejection Fraction (HFpEF)
Data Contributor: Boehringer Ingelheim
Study ID: NCT03057951
Sponsor ID: 1245.110

Public Disclosures:

Ferreira, J.P., Zannad, F., Packer, M., Filippatos, G., Pocock, S.J., Vasques‐Nóvoa, F., Böhm, M., Butler, J. and Anker, S., 2024. Empagliflozin and risk of lower respiratory tract infection in heart failure with mildly reduced and preserved ejection fraction: An EMPEROR‐Preserved analysis. European Journal of Heart Failure. Doi: 10.1002/ejhf.3180