Comparative efficacy of novel drugs as an addition to guideline-directed medical therapy for heart failure with reduced ejection fraction: a network meta-analysis of randomised controlled trials

Abstract

Background: Heart failure with reduced ejection fraction (HFrEF) is the global public health burden with a prevalence of 1% of adults. The current guidelines suggest the use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), angiotensin receptor-neprilysin inhibitors (ARNIs), and sodium-glucose cotransporter-2 inhibitors (SGLT2i) to reduce mortality. Soluble guanylyl cyclase (sGC) and omecamtiv mecarbil (OMM) have also been studied in HFrEF. However, there has been no head-to-head comparison of the efficacy and cumulative incidence interpretation of the outcome of the novel drugs. Purpose: To compare all drugs and possible combinations of guidelinedirected medical therapy (GDMT) including ACEI, ARB, BB, and MRA, and novel drugs including ivabradine (IVA), ARNI, SGLT2i, sGC and OMM to find the best additional novel drug to the GDMT. Methods: This network meta-analysis (MA) is part of the study registered on PROSPERO (CRD42021262029). A systematic search of MAs and randomised controlled trials (RCT) was performed on biomedical databases from inception to June 2021. All MAs and RCTs were selected against eligibility criteria. A primary composite outcome or a composite of cardiovascular death or heart failure hospitalisation was the outcome of focus. In addition, secondary outcomes, i.e., cardiovascular death and heart failure hospitalisation were analysed. Individual patient data was constructed from Kaplan-Meier-extracted data; then data from all studies were combined. A mixed-effect parametric survival model with accelerated failure time was used, considering individual study as random effects and treatments as a fixed-effect. Median failure time for each regimen and hazard ratios (HR) comparing between regimens with 95% confidence intervals (CI) were then estimated from KM data. Results: Cumulative incidence of the primary outcome from each regimen is displayed in Figure 1. Compared to the GDMT or ACEI+BB+MRA, BB+MRA+ARNI (HR 0.80, 95% CI 0.74-0.88), ACEI+BB+MRA+IVA (HR 0.82, 95% CI 0.75-0.90), ACEI+BB+MRA+SGLT2i (HR 0.75, 95% CI 0.68-0.82), ACEI+BB+MRA+sGC (HR 0.91, 95% CI 0.83-0.99), and ACEI+BB+MRA+OMM (HR 0.92, 95% CI 0.86-0.99) showed superior benefits. However, ACEI+BB (HR 0.68, 95% CI 0.59-0.79) and ACEI+BB+ARB (HR 0.81, 95% CI 0.67-0.98) were both statistically significantly inferior to the GDMT. The treatment combination of ACEI+BB+MRA+SGLT2i showed the highest risk reduction of 25%. More details are provided in Figure 2. The analysis of secondary outcomes showed a corresponding trend with ACEI+BB+MRA+SGLT2i combination reducing the risk of cardiovascular death by 25% (HR 0.75, 95% CI 0.68-0.82) and heart failure hospitalisation by 25% (HR 0.75, 95% CI 0.68-0.82) versus the GDMT. Conclusion: The network MA showed that the SGT2i is currently the best additional drug to the GDMT in the treatment of HFrEF.