Lead Investigator: Joao Pedro Ferreira, Porto University
Title of Proposal Research: Effect of Empagliflozin on Blood Pressure in Acute Heart Failure
Vivli Data Request: 10293
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Heart failure (HF) is a condition where the heart struggles to pump blood adequately to the body’s organs. This condition typically occurs due to harm to the heart such as ischemic (reduced blood flow to tissues), hypertensive (high blood pressure) or inflammatory conditions. It affects over 55 million people worldwide, particularly individuals aged 65 and older. Heart failure often worsens over time, leading to symptoms like breathlessness, swollen ankles, and extreme fatigue, which often require hospitalization.
Patients who are hospitalized for new onset or the worsening of chronic heart failure (acute heart failure (AHF)), often require intravenous treatment which is medication administered directly in the veins with diuretics and vasodilators. Diuretics are medicines which increase urinary output and vasodilators are medicines dilate the vessels.
These treatments may lead to a decrease in the blood pressure (BP) of AHF patients. (both systolic and diastolic BP i.e., blood pressure during heart’s contraction and relaxation, respectively). The decrease in BP may be associated with poor organ perfusion, a decrease in the quantity of blood arriving to the organs, and an unfavorable prognosis.
Blood pressure influences treatment decisions and is strongly associated with outcomes in AHF. In chronic heart failure both low and high BP are associated with a worse prognosis. However, acute heart failure patients admitted with high BP usually have a better prognosis compared to those admitted with low BP. Additionally, low BP may hinder the adjustment of diuretic therapy (medications that increase urine output) and the initiation of guideline-directed medical therapies (GDMT), treatments recommended based on established medical guidelines for managing a particular condition.
Empagliflozin is a medication that is used to treat type 2 diabetes and has been researched for the outcomes and reduced hospitalizations in patients with heart failure, as well. It increases the urinary excretion of glucose and sodium, thus it is a drug able to reduce fluid retention, which is an effect of interest in AHF, a condition with frequent fluid retention. However, by eliminating glucose and sodium in the urine, empagliflozin may also lower BP; therefore, assessing the efficacy and safety of empagliflozin across the spectrum of BP, including among patients with a low BP at hospital entry is clinically relevant because, to date, we do not know if empagliflozin should be prescribed to patients admitted for AHF with a low BP.
In this study we aim to explore the relationship between BP, outcomes and the effect of empagliflozin (versus placebo, a pill without any active medication) in the EMPULSE trial, which compared empagliflozin to placebo inpatients with AHF across a wide spectrum of BP values.
Statistical Analysis Plan:
Blood pressure (BP), both systolic (SBP) and diastolic (DBP) blood pressure at randomization will be divided in tertiles (with a similar number of patients across tertiles). Patient characteristics will be compared across tertiles of SBP and DBP.
The association between randomization SBP and DBP (both as tertiles and continuous “spline” transformed variables) and outcomes will be tested, both in unadjusted and adjusted models, in the placebo and empagliflozin groups, separately. The studied outcomes will include: 1) primary outcome: hierarchical composite endpoint of time to all-cause death, number of Heart Failure (HF) events, time to first HF event, and a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire – Total Symptom Score (KCCQ-TSS) change from baseline to day 90; 2) (KCCQ-TSS) change from baseline to day 90; 3) first HF event or cardiovascular of death; 4) total HF events; 5) >40% eGFR decline from baseline or end-stage renal disease; 6) all-cause mortality. Additionally, (N-terminal pro-B-type natriuretic peptide (NT-pro) BNP (B-type natriuretic peptide) changes from baseline to day 90 and weight changes during hospitalization will be explored.
Landmark analyses exploring the association between changes in BP from baseline to day 15 will be performed.
The effect of empagliflozin on the above referenced outcomes will be explored across BP tertiles and also BP as a continuous variable, with a treatment-by-BP interaction term in the model.
Missing values will be excluded from the analysis.
Requested Studies:
A Multicentre, Randomised, Double-blind, 90-day Superiority Trial to Evaluate the Effect on Clinical Benefit, Safety and Tolerability of Once Daily Oral EMPagliflozin 10 mg Compared to Placebo, Initiated in Patients Hospitalised for acUte Heart faiLure (de Novo or Decompensated Chronic HF) Who Have Been StabilisEd (EMPULSE)
Data Contributor: Boehringer Ingelheim
Study ID: NCT04157751
Sponsor ID: 1245-0204
Public Disclosure:
Ferreira, J.P., Vasques-Nóvoa, F., Angermann, C.E., Biegus, J., Collins, S.P., Kosiborod, M., Nassif, M.E., Psotka, M.A., Tromp, J., Mentz, R.J. and Ponikowski, P., Low blood pressure and the effect of empagliflozin in acute heart failure: An EMPULSE analysis. European journal of heart failure. Doi: 10.1002/ejhf.3626