Individuals with heart failure with reduced ejection fraction (HFrEF) have an overall poor prognosis and high mortality. This study compares outcomes for existing and emerging pharmacological HFrEF therapies using data from recently published randomized controlled trials (RCTs). The Nested Knowledge AutoLit living review platform was used to identify and screen RCTs published between 2010 and 2021 that compared the use of pharmacological therapies for HFrEF against one another and against placebos. Risk of bias and levels of evidence for each study were scored using the Scottish Intercollegiate Guidelines Network (SIGN) criteria for RCTs. Primary outcomes included cardiovascular death, all-cause mortality, and event rates for first hospitalization. Secondary outcomes included the adverse events of hypotension, symptomatic hypotension, hypokalemia, hyperkalemia, and acute kidney injury. We included 12 relevant studies in our systematic review. Most of these trials compared angiotensin receptor-neprilysin inhibitors (ARNI) to angiotensin-converting enzyme inhibitors (ACEI) (5 trials) or sodium-glucose cotransporter 2 (SGLT2) inhibitors to placebo (2 trials). The results of our systematic review suggest the superiority of ARNI over ACEI, and the superiority of SGLT2 inhibitors over placebo. Our systematic review suggests that ARNI and SGLT2 inhibitors effectively reduce all-cause mortality and hospitalization for HFrEF. Several other therapies (e.g., soluble guanylate cyclase stimulators, HCN channel blockers, cardiac myosin activators, and selective aldosterone blockers) appear promising but need further investigation. Additional prospective studies are warranted to establish the therapeutic value of emerging drugs and to characterize the best therapies for HFrEF.