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hospitalizations due to worsening HF (WHF); and (iii) improvements in clinical status, functional capacity and QoL. The recommendations for each treatment depending on LVEF are summarized below. Overall, there are no sex differences in recommendations for HF pharmacotherapy. In this section, we address the management of predominantly left-sided HF. Management of right-sided HF is covered comprehensively in a recent HFA consensus paper.48

6.1.2 Foundational medical therapy in all patients with

heart failure, independent of left ventricular ejection fraction Mineralocorticoid receptor antagonists and SGLT2-Is are recommended for all symptomatic patients with HF, regardless of LVEF, as these drugs reduce mortality and the risk of HFH. The recommended doses of these drugs are given in Table 11. Other agents can be used in selected patients.

6.1.2.1 Sodium–glucose co-transporter 2 inhibitors

The SGLT2-Is dapagliflozin and empagliflozin have been shown to reduce the composite endpoint of HFH or CV mortality in symptomatic ambulatory patients with HF.241–245 Although there were consistent reductions in the primary endpoint across the LVEF ranges studied, the individual endpoint of CV mortality was only reduced in HFrEF.44,241,246 Thus, it is recognized that in HFpEF the reduction in the primary endpoint is driven by a reduction in HFH. The guideline Task Force has decided to base recommendations on the primary endpoints. SGLT2-Is also improve QoL.247,248 Common side effects include genital and urinary infections. A mild initial decline in eGFR is expected, but long-term kidney function is improved.249–253 Practical guidance in the use and initiation of SGLT2-Is are provided in Supplementary material online, Table S9.

The use of SGLT2-Is in DHF is discussed in Section 7.

6.1.2.2 Mineralocorticoid receptor antagonists

Mineralocorticoid receptor antagonists have been shown to reduce the composite endpoint of HFH or death in patients with HF.43,254–257 The guideline Task Force decided to base recommendations on the primary endpoints. Although there were consistent reductions in the primary endpoint across the LVEF ranges studied, the individual endpoint of mortality was only reduced in HFrEF.43,254,256 There were differences in the mortality endpoints used in HFrEF and HFpEF trials, with all-cause mortality used in HFrEF trials and CV mortality used in HFpEF trials. Furthermore, different RCTs have included patients with different LVEF ranges not entirely consistent with the distinction between HFrEF and HFpEF. Whereas spironolactone was studied across LVEF ranges, eplerenone was only studied in HFrEF (LVEF up to 35%) and finerenone in patients with LVEF >40%. Although finerenone reduced the composite endpoint of HFH and CV mortality in the FINEARTS-HF trial, spironolactone did not in the overall results of the TOPCAT trial.255,257 However, a meta-analysis demonstrated a significant effect of the MRAs used in FINEARTS-HF and TOPCAT on the primary endpoint of HFH and CV mortality in patients with LVEF >40%.43 Mineralocorticoid receptor antagonists are chemically and structurally different; they block the receptors that bind aldosterone with different affinity and distribution in the heart and kidneys and also block other steroid hormones with different degrees of affinity (e.g. corticosterone blockade) (see Supplementary data online, Table S3).258 Eplerenone and the non-steroidal MRA finerenone are more mineralocorticoid receptor-specific and therefore induce less gynaecomastia. Caution should be exercised when MRAs are started in patients with impaired kidney function (MRAs have not been tested in patients with eGFR <25 mL/min/1.73 m2) and in those with potassium levels ≥5.0 mmol/L.259 In patients taking MRAs whose serum potassium is >5.5 mEq/L, there might be an indication for dose reduction of the MRA or temporary discontinuation of the MRA to avoid life-threatening hyperkalaemia. The first step would be to recheck potassium levels. If the MRA dose is reduced or temporarily discontinued, the drug should be restarted if hyperkalaemia resolves. Practical guidance in the use and uptitration of MRAs are provided in Supplementary material online, Table S8.

6.1.3 Additional medical therapy in all patients with

heart failure, independent of left ventricular ejection fraction 6.1.3.1. Loop diuretics Loop diuretics are recommended to reduce signs and/or symptoms of congestion in patients with HF and volume overload. Their effects on morbidity and mortality have not been studied in adequately powered RCTs. However, the major diseasemodifying treatment trials for HF were always conducted with a high background use of loop diuretic therapy. One meta-analysis has shown that in patients with HF, diuretics appear to reduce the risk of death and WHF compared with a placebo, and compared with an active control, diuretics improved exercise capacity.260 Several observational studies have linked loop diuretic use to higher mortality, even after adjustment or propensity matching.261 However, several biases remain as sicker patients are generally prescribed higher doses of loop diuretics. Clearly, patients benefit from maintenance therapy with a loop diuretic to prevent or control congestion. However, the use of loop diuretics may result in electrolyte disturbances, further neurohormonal activation, accelerated kidney function decline, and symptomatic hypotension. The latter may be especially relevant as it could result in treatment with lower doses of FMT. It is generally advised to use the lowest possible dose of diuretics to maintain euvolaemia. Importantly, the individual diuretic dose may change significantly over time.262 Therefore, dynamic and individualized dosing of loop diuretic is recommended.263,264 The use of a multiparameterbased evaluation to assess congestion, using clinical assessment at rest and during dynamic manoeuvres, as well as biomarkers (eGFR, electrolytes, natriuretic peptides), supplemented with imaging assessment according to local expertise, is probably the best contemporary strategy to optimize diuretic dosing.265 Optimal FMT and GDIT often results in less need for diuretic treatment.266,267 The chronic use of thiazide diuretics in stable patients should be avoided, as this often induces severe electrolyte disturbances that could go undetected in the ambulatory setting. Treatment of DHF and approach to diuretic treatment in this setting is covered in Section 7.

6.1.3.2 Potassium binders

Hyperkalaemia is common in HF, often as a result of comorbidities (e.g., diabetes, CKD), concomitant use of renin–angiotensin– aldosterone system inhibitors (ACE-Is/ARNIs/ARBs and MRAs), Downloaded from academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehag100/8766302 by guest on 31 August 2026