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and because of HF itself. Hyperkalaemia may increase the risk for arrhythmias and death.268 Hyperkalaemia, and the fear of inducing it, often results in under-utilization, dose reductions, or discontinuation of ACE-Is/ARNIs/ARBs and MRAs compromising their cardio-kidney benefit in HF. The gastrointestinal potassium binders patiromer and sodium zirconium cyclosilicate remove potassium by exchanging cations, leading to increased faecal excretion. Both agents have shown favourable results to treat and/or prevent hyperkalaemia in patients receiving ACE-Is/ARNIs/ ARBs and MRAs, therefore facilitating the continuation or uptitration of ACE-Is/ARNIs/ARBs and MRAs.269–272 Whether potassium binders improve clinical outcomes is still unclear. In the REALIZE-K trial, there was a signal towards more HF deterioration with sodium zirconium cyclosilicate as compared with placebo, although the trial was not powered to detect clinical outcomes.272 Potential adverse effects for the potassium binders include gastrointestinal symptoms (nausea, constipation, diarrhoea), hypomagnesaemia (for patiromer), and oedema (for sodium zirconium cyclosilicate). No specific recommendations for the use of potassium binders are included in the guideline at current time, due to insufficient evidence for clinical benefit.

6.1.4 Foundational medical therapy for heart failure

with reduced ejection fraction Modulation of the renin–angiotensin–aldosterone system, sympathetic nervous systems, and sodium–glucose co-transporter (SGLT2) inhibition has been shown to improve survival, reduce the risk of HFH, and reduce symptoms in patients with HFrEF. Treatment with optimal FMT, including ACE-Is/ARNIs/ARBs, beta-blockers, MRAs, and SGLT2-Is, is recommended as the foundation of treatment for all patients with HFrEF. There is no evidence favouring any particular sequencing during initiation and uptitration. Therefore, the consensus is that FMT can be commenced together with individual variations based on clinical assessment as soon as the diagnosis of HFrEF is established. Drugs should be uptitrated and continued at the doses used in the RCTs (or to the highest tolerated doses). Misinterpretation of changes in kidney function is a leading cause of insufficient dosing or inappropriate discontinuation of FMT and should be avoided (Section 6.1.6).273 Additional medical therapy may be used in selected patients with HFrEF (see Section 6.1.5). No large prospective RCT has been performed exclusively in patients with LVEF 41%–49%. Patients with LVEF 41%–49% appear to respond to FMT, similar to patients with LVEF <40%.36,38–41 Many patients with LVEF 41%–49% may already be on ACE-Is or ARBs and beta-blockers for other CV indications such as CAD, hypertension, or post-MI LV systolic dysfunction. Sodium–glucose co-transporter 2 inhibitors and MRAs are recommended for all ranges of LVEF, as covered in Section 6.1.2. The recommended doses of FMT and AMT are provided in Table 11. Practical guidance in the use and uptitration of FMT are provided in Supplementary material online, Tables S4–S9.

6.1.4.1 Angiotensin-converting enzyme inhibitors and

angiotensin receptor–neprilysin inhibitor Angiotensin-converting enzyme inhibitors were the first class of drugs shown to reduce mortality and morbidity and to improve symptoms in patients with HFrEF.137,138,274–277 They are recommended in all patients with HFrEF unless contraindicated or not tolerated and should be uptitrated to the highest recommended doses. If these doses are not tolerated, intermediate doses should be tried. In the higher end of LVEF, evidence is limited. The PEP-CHF trial (perindopril) was conducted in patients with an LVEF >40%, but it did not report outcomes according to LVEF.39 The PEACE trial reported a subgroup analysis showing a reduction in mortality with trandolapril in patients with LVEF from 40% to 50%.38

An ARNI is composed of an ARB and an inhibitor of neprilysin, an enzyme that degrades natriuretic peptides, bradykinin, adrenomedullin, and other vasoactive peptides. In the PARADIGM-HF trial, the ARNI, sacubitril–valsartan, was compared with enalapril in symptomatic patients with HFrEF who already tolerated an adequate dose of either an ACE-I or an ARB.278 ARNI significantly reduced the composite endpoint of CV death or HFH by 20% as compared with enalapril.278 Additional benefits included improvement in QoL, reduction in decline of eGFR, a reduction in loop diuretic dose, and lower risk of hyperkalaemia.279,280 If patients continue to have chronic symptomatic HFrEF and they tolerate an ACE-I or an ARB, it is recommended that they be switched to an ARNI to reduce morbidity and mortality. Pre- and post-discharge initiation of ARNIs in HFrEF patients have shown similar efficacy and safety, and larger NT-proBNP reductions compared with ACE-I treatment in ACE-I/ARB naïve patients.281–283 As such, the use of an ARNI may be efficacious as de novo treatment in patients with symptomatic chronic HFrEF to simplify management and maintain eGFR and QoL. Use of an ARNI is more frequently associated with symptomatic hypotension, and a washout period of at least 36 h after ACE-I therapy is required to minimize the risk of angio-oedema. Treatment with ACE-Is or ARNIs is indicated, but should be given with caution, to patients with low blood pressures (systolic blood pressure <100 mmHg), kidney insufficiency (eGFR <30 mL/min/ 1.73 m2), or elevated serum potassium (>5.2 mEq/L). Abrupt withdrawal of ACE-Is or ARNIs can lead to clinical deterioration and should be avoided, and in those patients for whom treatment with an ARNIs is not possible, continued use of an ACE-I remains strongly advised.

6.1.4.2 Angiotensin II type 1 receptor blockers

Angiotensin II receptor blockers are recommended for HFrEF patients who cannot tolerate ACE-Is or ARNIs due to side effects. Unlike ACE-Is, ARBs do not inhibit kininases and are associated with a much lower incidence of cough and angio-oedema. In the CHARM-Alternative study, candesartan reduced CV death and HFH in patients who were not receiving an ACE-I due to previous intolerance.284 In the HEAAL study, high-dose losartan reduced HFH compared with low-dose losartan in ACE-I intolerant patients.285 Valsartan, in addition to usual therapy, including ACE-Is, reduced HFH in the Val-HeFT trial.286 However, no ARB has reduced all-cause mortality in any trial, and combination with an ACE-I increases adverse effects. Also, in patients with higher LVEF, evidence is limited. The CHARM-Preserved trial did not show a reduction in its primary endpoint of CV death or HFH, but a retrospective analysis showed that candesartan reduced the number of patients hospitalized for HF among those with LVEF 40%–49%.40,41 Downloaded from academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehag100/8766302 by guest on 31 August 2026