OBJECTIVES: Identify published RCTs assessing IVA and its impact on efficacy, safety, and patient reported outcomes (PROs) in patients with HF with reduced ejection fraction (HFrEF).

METHODS: Medical databases (MEDLINE®, Embase, Cochrane CENTRAL) and clinical trials registry were searched. Abstracts published before 2019 were excluded. No geographical scope or language restrictions were applied. Study selection was undertaken by two independent reviewers, discrepancies resolved by third reviewer; data extracted by one reviewer, another validated their accuracy.

RESULTS: Of 1911 records, and after exclusions, 24 trials (51 publications) focused on HFrEF. Sample size ranged from 21 to 6,505 patients. In the pooled analysis for SHIFT and BEAUTIFUL, 11,897 patients were studied. Duration of follow-up ranged from 7 days to 3 years. Treatment with IVA on top of background therapy (IVA+BT) significantly reduced major risks associated with HFrEF and demonstrated a significant trend on reducing composite outcomes including hospitalization and mortality outcomes (at 23 months; p<0.0001). Across all publications, IVA+BT was associated with a lower risk of all-cause death and CV death compared to placebo+BT. This difference was statistically significant only in Chinese patients (p=0.012). HF deaths decreased significantly with age increase (p=0.013 with significant changes for patients > 69 years), and all-cause death decreased significantly with HR increase (at 28 days; p<0.0001). Risk of total AEs was comparable between patients treated with IVA+BT and placebo. Encountered SAEs were overall lower in IVA group compared to placebo+BT in the SHIFT trial at 23 months (p=0.025). Statistically significant improvements in LVEF were reported in J-SHIFT at one year for IVA+BT vs placebo (p=0.0004). HR reduction with IVA was associated with improved QoL.

CONCLUSIONS: IVA was associated with reducing HR, risks of hospitalization and deaths, while improving clinical outcomes, LVEF level and QoL.