Prognostic impact of heart failure pharmacotherapies in acute heart failure: strong association in mildly reduced ejection fraction

This editorial refers to ‘Effect of heart failure pharmacotherapies in patients with heart failure with mildly reduced ejection fraction’, by T. Schupp et al., https://doi.org/10.1093/eurjpc/zwae121. Acute heart failure (AHF) constitutes a broad spectrum of disease states, with heterogeneous clinical presentations,1 various ejection fraction (EF) phenotypes,2 diverse non-cardiac comorbidity (NCC) burden,3 but commonly characterized by high rates of post-discharge mortality and readmissions.1–3 Guideline’s recommendation to initiate and up-titrate medical therapies before discharge is associated to significant decrease in mortality and remains the most successful evidence-based intervention.1,4 Heart failure therapies at discharge were associated with a consistent reduction in mortality in patients with recent AHF, regardless of left ventricular ejection fraction or the presence of comorbidities.5 Also, the favourable trends in AHF survival reported by the largest meta-regression analysis were directly associated with better neurohormonal inhibition over years.6 Heart failure patients should receive optimal medical treatment in order to prevent death when exposed to future AHF hospitalization. In clinical trials settings,4 rapid up-titration of GDMTs in the pre-discharge phase and early weeks after discharge has been associated to lower all-cause mortality and HF readmissions, and notably the benefit was independent of the EF7 and the number of individual NCCs8 reported in the trial. In the current study, Schupp et al.9 described a cohort of 2109 AHF patients with heart failure with mildly reduced ejection fraction (HFmrEF) who were discharged alive. The prognostic value of the treatment with beta-blockers (BB), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or receptor-neprilysin inhibitor (ACEi/ARB/ARNI), mineralocorticoid receptor antagonists (MRA), and sodium glucose transport protein 2 inhibitors (SGLT2i) was investigated for all-cause mortality and HF-related rehospitalization. In this study, treatment with BB, ACEi/ARB/ARNI, and SGLT2i, but not MRA, was independently associated with a lower risk of long-term all-cause mortality, even after multivariable adjustment and propensity score matching, specifically when applied in combination. In contrast, the risk of HF-related rehospitalization was not affected by HF-directed pharmacotherapies. Patients receiving ‘triple therapy’ (i.e. BB, ACEi/ARB/ARNI, and SGLT2i) had the lowest risk of all-cause mortality at 30 months compared to patients receiving 0 or 1 or 2 of these therapies (11.8% vs. 38.4% vs. 35.6% vs. 25.0%). However, the risk of HF-related rehospitalization was not affected by the number of HF pharmacotherapies. In patients with HFmrEF, the risk of all-cause mortality was higher in patients treated with lower doses of BB or ACEi/ARB/ARNI, but higher BB doses were not associated with improved outcomes in HFmrEF. The prescription rates of BB, ACEi/ARB/ARN, and SGLT2 inh have significantly increased during the study period, as well as the proportion of patients treated with a ‘HF triple therapy’ In the present study, proportion of patients with HFmrEF discharged with BB (77.5% vs. 77%), and ACEi/ARB/ARNI (75.0% vs. 79%), was similar to what reported in hospitalized AHF patients from ESC-HF-LT registry.2 The most important finding of this research investigating hospitalized patients with HFmrEF is the association between reduction in mortality and increased use of BB, ACEi/ARB/ARNI, and SGLT2i, but not to the use of MRAs. However, due to the study design, one important limitation of this study is that it didn’t capture new prescription, discontinuation, up- and down-titration of pharmacotherapies between discharge, and time to follow-up. The results are similar to other study, where HF therapies at discharge were associated with a consistent reduction in mortality in patients with recent AHF, regardless of LVEF or the presence of comorbidities.5 It cannot be excluded that neurohormonal antagonists offer mid- or long-term protection in the presence of cardiovascular comorbidities, such as hypertension and ischaemic heart disease, commonly associated with HFmrEF. In contrast, no associations were found between prescription rates of oral cardiovascular medications and long-term HF readmissions. Interesting, although ACEi/ARBs and SGLT2 inhibitors are beneficial in reducing the risk of HF hospitalization in patients at risk of HF,10 they do not have this effect in this cohort of AHF patients with HFmrEF. This may be due to the high burden of non-cardiovascular comorbidities in the present study. Although early HF readmissions after hospital discharge indicate incomplete in-hospital resolution of congestion, long-term readmissions are the result of the continuous deterioration of cardiac substrate and worsening of the associated non-cardiac comorbidities.3 It is also possible that some patients may discontinue HF medications and furthermore, HF medical therapies may destabilize some common comorbidities. Identification of the comorbidities that are predictors of the specific outcomes may provide opportunities to explore potential interactions between possible treatment effects and cause-specific risk in each category of EF.3 In addition to the initiation and up-titration of HF therapies, comprehensive management of comorbidities, as strategy to improve outcomes, received class I recommendation in patients with HFmrEF.1 A possible explanation for the lack of benefit of MRAs might be related to the more severe baseline characteristics in the present registry, and probably to the occurrence of severe hyperkalaemia in MRA-treated patients. A similar finding, with absence of benefit of MRAs on long-term mortality, was found in GREAT registry.5 Notably, a positive trend regarding prescription rates, as well as proportion of patients treated with a ‘HF triple therapy’, was reported during the study period. The results of present research reflect conceptual changes happened over time in AHF. Despite the absence of any new therapy, physicians have learned that treating beyond clinical congestion,11 with focus on pre-discharge initiation and up-titration of HF therapies, is associated to improving survival.1,4,6 Finally, the authors should be congratulated for performing a well-conducted study in AHF patients with HFmrEF aimed to evaluate prognostic impact of HF therapies and the temporal trends in mortality and readmissions in AHF. The results of current research may assist to update previous epidemiological knowledge and may be informative for future clinical trial design in these settings. None declared. The data underlying this article will be shared on reasonable request to the corresponding author.