Weekly Journal Scan: Estimated efficacy of a combined three-pillar drug treatment in the management of heart failure with mildly reduced or preserved ejection fraction

This comment refers to ‘Lifetime benefits of comprehensive medical therapy in heart failure with mildly reduced or preserved ejection fraction’ which was published in the Nature Medicine, https://doi.org/10.1038/s41591-025-04037-3. This cross-trial analysis1 of three randomized clinical trials, DELIVER (Dapagliflozin Evaluation to Improve the LIVEs of Patients with Preserved Ejection Fraction Heart Failure),2 FINEARTS-HF (FINerenone trial to investigate Efficacy and sAfety superioR to placebo in paTientS with Heart Failure),3 and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction),4 aimed to estimate the aggregate relative and absolute benefits of Type 2 sodium–glucose transporter inhibitors (SGLT2i) and non-steroidal mineralocorticoid receptor antagonists (nsMRA) in all enrolled patients with heart failure with mildly reduced and preserved ejection fraction (HFmrEF and HFpEF, respectively). Moreover, it analysed the effects of the combination of SGLT2i, nsMRA, and angiotensin receptor–neprilysin inhibitors (ARNI) in those with HFmrEF/HFpEF and a left ventricular ejection fraction (LVEF) of 5.5 mmol/L was more common with finerenone (vs placebo). Heart failure is a complex syndrome, characterized by different clinical presentations and heterogeneous phenotypes due to diverse pathophysiological mechanisms including cardiac structural abnormalities and remodelling, oxidative stress, fibrosis, mitochondrial dysfunction, and metabolic disorders.5 Different pharmacological strategies, consisting of angiotensin-converting enzyme inhibitors (ACEi) or ARNI, MRA, SGLT2i, and beta-blockers, have shown significant cardiovascular benefits in HF with reduced EF (HFrEF) and have been identified as the ‘four pillars’ of the therapeutic management of patients with LVEF < 40%.6,7 On the other hand, although an evident trend towards a reduction in hospitalization and mortality has been documented with neurohormonal inhibitors in HFmrEF and HFpEF,8,9 significant results across the entire spectrum of LVEF have been achieved only with SGLT2i.6,7 A pooled analysis of PARAGON-HF4 in chronic HFpEF and PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF)10 in the acute setting has demonstrated that ARNI significantly reduced the primary composite endpoint of worsening HF events (including first and recurrent HF hospitalizations) and cardiovascular death compared with valsartan, confirming previous observations of greater treatment benefits in subjects with LVEF < 60%.11 More recently, the FINEARTS-HF study has demonstrated that the nsMRA finerenone can improve cardiovascular outcomes in patients with HFmrEF and HFpEF on top of SGLT2i treatment.3 In spite of the evidence suggesting a benefit of each of these drug classes in HFmrEF and HFpEF, the potential advantage of a comprehensive therapy based on SGLT2i, nsMRA, and ARNI has not been investigated with the exception of limited real-world experience. Therefore, the present cross-trial analysis1 of DELIVER,2 FINEARTS-HF,3 and PARAGON-HF4 was designed to explore whether this combined strategy may improve outcomes. The results of this analysis confirmed both aggregate relative benefits and potential absolute long-term gains in event-free survival with comprehensive medical therapy across a wide age spectrum with a good safety profile also in a setting of elderly patients (mean age 72 years), with comorbidities such as obesity, atrial fibrillation (∽55%), and diabetes (∽40%). The main assumptions of the study were that (i) each individual therapy would provide additive benefits in patients with HFmrEF/HFpEF; (ii) the therapeutic effects observed during each trial would be sustained during lifetime use of therapies; and (iii) the long-term benefits projected in this cross-trial analysis would translate into clinically relevant benefits when implemented in ‘real-world’ settings. Among the explicit limitations of this approach, it should be underlined that event-free survival was estimated on the basis of the subgroup of 1754 participants with HFmrEF/HFpEF of the control arm of the DELIVER trial2 (main analysis) and in a subset of 1123 subjects with LVEF < 60% and not in the overall analysed population. The analysis projected long-term event-free survival gains with comprehensive medical therapy but did not consider additive effects on mortality outcomes since the individual trials did not demonstrate significant benefits on overall or cardiovascular mortality. Besides, the choice of selected trials may result somehow arbitrary especially in view of the exclusion of a landmark trial such as EMPEROR-Preserved.12 Overall, the data of this cross-trial analysis1 need to be taken with caution and should be interpreted as hypothesis generating, given the nature of the study and the multiple assumptions that were needed to estimate the aggregate effects of the combined therapy. Ad hoc prospective randomized trials will be needed to substantiate the current findings. In this regard, the ongoing EASi-HF Phase III trial (NCT06424288) is evaluating the efficacy and safety of the combination of vicadrostat, an aldosterone synthase inhibitor, and the SGLT2i empagliflozin in patients with symptomatic HF and an LVEF ≥ 40%. In conclusion, the present cross-trial analysis1 has explored a novel approach to the management of HFmrEF and HFpEF, and its results pave the way for further clinical studies specifically designed to investigate the potential benefits and safety of the combination of drug classes with recognized effects on the progression of HFmrEF and HFpEF and on the development of clinical outcomes. G.G. reports personal fees from AstraZeneca, Sandoz, and Sanofi Pasteur. M.V. reports personal fees for speaker bureau and/or consulting from AstraZeneca, Menarini Int, Novartis Pharma, Novo Nordisk, Sanofi Pasteur, and Servier. M.V. is supported by a research grant from the Italian Ministry of Health (‘Ricerca Corrente’). M.V. is supported by a research grant from the Italian Ministry of Health (‘Ricerca Corrente’).