Globally, approximately 26 million people suffer from heart failure, and an estimated 50% of those cases are heart failure with reduced ejection fraction (HFrEF).^1,2 HFrEF patients have seen improvement in the mortality rate, in light of the evolving pharmacological treatment options.³ The utilization of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have readily been employed.^1,3-5 Despite the advancements and the availability of a variety of treatments, the mortality rate of individuals with HFrEF remains high.^3,6 Therefore, it is necessary to ascertain optimal pharmacological therapy combinations supported by up-to-date global data, with the aim of further reducing HFrEF cases.² Recent findings by Tromp J and colleagues published in the Journal of the American College of Cardiology: Heart Failure estimated and compared which treatment options are the most advantageous for HFrEF.⁴

To compare various treatments, the investigators adopted a systematic literature search approach, using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controls trials published between 1987 and 2020.⁴ A primary outcome was centralized on all-cause mortality, while additional outcomes were cardiovascular (CV) death and hospitalizations for heart failure (HHF), CV death alone, and potential drug cessation.⁴ Investigators also used network meta-analysis models, adopting a frequentist statistical framework approach to compare different combinations of treatment on the background therapy within a trial.⁴ Secondary analyses estimated the potential of life years gained.⁴

Results from the systematic literature search of the 75 full-text papers, identified a total of 9,328 records.⁴ The studies included 95,444 patients and 199,978 participants in the follow-up years, among which, 17,685 all-cause death incidences were reported.⁴ The primary outcome results showed that the most effective combination in decreasing all-cause death compared with placebo was the use of angiotensin receptor-neprilysin inhibitor (ARNi), BB, MRA, and SGLT2i (HR=0.39; 95% CI: 0.31-0.49).⁴ Comparison of other combinations were as follows: ARNi, BB, MRA, and vericiguat (HR=0.41; 95% CI: 0.32-0.53), and ARNi, BB, and MRA (HR=0.44; 95% CI: 0.36-0.54).⁴

Results for secondary analyses showed that a total of 16 studies reported a composite outcome of CV death and HHF.⁴ The most effective combination of treatment in reducing the composite outcome was the use of ARNi, BB, MRA, and SGLT2i (HR=0.36; 95% CI: 0.29-0.46), followed by ARNI, BB, MRA, and vericiguat (HR=0.43; 95% CI: 0.34-0.05), and ARNi, BB, MRA, and omecamtiv-mecarbil (HR=0.44; 95% CI: 0.35-0.56).⁴

A total of 43 studies reported CV death alone.⁴ The most effective reduction in CV death alone was seen with the combination of ARNi, BB, MRA, and SGLT2i (HR= 0.33; 95% CI: 0.26-0.43) followed by ARNi, BB, MRA, and vericiguat (HR=0.35; 95% CI: 0.26-0.47) and ARNi, BB, MRA, and omecamtiv-mecarbil (HR=0.36; 95% CI: 0.27-0.46).⁴

Additionally, the investigators estimated the additional number of life-years gained for a 70-year-old patient was as much as 5 years in 2 independent heart failure populations.⁴ In the 58 studies, a total of 9,451 patients discontinued their drug treatment.⁴

In summary, the data supported the combination of ARNI, BB, MRA, and SGLT2i as the most beneficial pharmacotherapeutic course for the treatment of HFrEF.⁴ The improvement of life expectancy after drug treatment for HFrEF was significant.⁴ Thus, treating HFrEF patients with comprehensive pharmacological therapy is substantially advantageous.⁴