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Therapy of Heart Failure with Reduced Ejection Fraction: What's New in the 2021 Guidelines? The spectrum of treatment options for patients with heart failure with reduced ejection fraction (HFrEF) has substantially expanded over the last years. The 2021 guidelines of the European Society of Cardiology propose a new treatment algorithm for patients with HFrEF and define the role of the currently available drugs, interventions and devices in this context. The new standard is a basic therapy consisting of four drugs with different mechanisms of action for all patients with HFrEF: an angiotensin-converting enzyme inhibitor, a betablocker, a mineralocorticoid antagonist, and a sodium glucose co-transporter-2 inhibitor. Additional drugs and/or interventions/devices are indicated depending on the response to the four-drug basic therapy (which has to be up-titrated to the maximally tolerated doses) and the clinical phenotype. In the present article, we discuss the available drugs and devices, their role in the proposed HFrEF treatment algorithm and clinically relevant practical aspects.