Four aces of heart failure therapy: systematic review of established and emerging therapies for heart failure with reduced ejection fraction

Heart failure with reduced ejection fraction (HFrEF) is a common disease requiring multi-drug therapy. Moreover, it is associated with a poor prognosis, with increasing prevalence in the community. In the last decade, two major drug classes were introduced to the heart failure (HF) specialist's arsenal: angiotensin receptor neprilysin inhibitors (ARNIs) and sodium-glucose-cotransporter 2 inhibitors (SGLT2is). The current paradigm of sequential drug therapy is changing, favoring a multi-drug combination therapy upfront, including four “pillar” classes: beta-blockers, mineralcorticoid receptor antagonists (MRAs), ARNIs, and SGLT-2is. Recent putative placebo analyses of large-scale randomized clinical trials compared a combination of all four drug classes with a standard of care and was in favor of the multi-drug combination revealing a hazard ratio for cardiovascular (CV) death and HF hospitalization of 0.5 and 0.32, respectively. We reviewed the approval landmark trials for the four drug classes and have subincluded a short comment about the implications and impact of each study in clinical practice. Moreover, we present more detailed trials concerning the use of these drugs in different settings (eg, acute phase, in-hospital, and outpatient) and more data about the clinical, biochemical, functional, and echographic remodeling effects of the molecules. The results of the meta-analyses and putative placebo analyses in the literature we reviewed suggest the benefit of offering all the best therapy available upfront. This approach ensures maximal life expectancy gain, especially in younger patients, and cuts the costs of rehospitalizations. Thus, this review underlines the importance of the four-drug approach to HFrEF therapy, as recently stated in the ESC guidelines.