Pharmacotherapy for HFrEF: A comprehensive network meta-analysis

25 Feb 2022

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

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