Optimized HF therapy in patients with very advanced cancer in palliative care: dosing strategies from the EMPATICC trial

Cardiac wasting occurs in patients with end-stage cancer, leading to the development of heart failure (HF)-like symptoms characterized by dyspnea, reduced physical function, and diminished quality of life. The EMPATICC (EMPower the heArt of patients with TermInal Cancer using Cardiac medicines) is a randomized controlled trial designed to evaluate the impact of optimized HF therapy in patients with very advanced cancer in palliative care. Given the susceptibility to adverse drug events in this vulnerable population, the trial employed a protocol-driven approach for the initiation and titration of each medication. EMPATICC is a multi-center, randomized, double-blind, controlled, proof-of-concept trial that enrolled 93 patients with stage IV solid tumors (per Union for International Cancer Control [UICC]), under palliative care, with clinical features indicating cardiovascular risk and functional limitation. Participants were randomized 1:1 to receive optimized HF therapy, including sacubitril/valsartan, empagliflozin, ivabradine, and ferric carboxymaltose (FCM), or 1-4 placebo therapies on top of usual care. All trial medications (or placebo) that were available in tablet form were provided in pre-packed containers to support blinding.  Blue placebo tablets were used for empagliflozin, white tablets for sacubitril/valsartan, and pink tablets for irbesartan. Blinded staff members did not have access to individual tablet packaging or knowledge of color allocations. Additionally, the meaning of the color-coded tablets was not disclosed to the blind staff members throughout the trial. Dosing protocols were guided by predefined criteria, including blood pressure, renal function, heart rate, hemoglobin, and body weight, and they were implemented by unblinded staff. Algorithms accounted for prior RAAS inhibitor exposure when initiating sacubitril/valsartan; ensured hemodynamic stability and sinus rhythm for ivabradine; assessed renal reserve when starting empagliflozin to support safe and effective titration; and accounted for body weight and hemoglobin levels when initiating FCM.  To ensure consistent implementation across five centers in Germany, visual flowcharts were designed. The EMPATICC trial provides a practical, protocol-driven approach for delivering HF therapy in the palliative oncology setting. Dosing algorithms outlined in this study could serve as a model for structured cardiovascular care in patients with advanced cancer.