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HR 0.85; 95% CI 0.69–1.05).304 Taken together, available evidence suggests that cardiac glycosides (digoxin or digitoxin), when added to FMT, can reduce the risk of HFH in patients with chronic symptomatic HFrEF. Both agents share a narrow therapeutic window and require careful monitoring but differ in their metabolic elimination: digoxin is primarily eliminated through the kidneys, whereas digitoxin undergoes hepatic elimination.

6.1.5.5 Cardiac myosin activator

Omecamtiv mecarbil, a cardiac myosin activator, reduced the risk of HF events modestly in the GALACTIC-HF trial, but without a significant mortality benefit. The drug is not currently approved for clinical use in HF.309

6.1.6 The importance of uptitrating foundational

medical therapy and maintaining adherence in heart failure with reduced ejection fraction Foundational medical therapy is essential in HFrEF and must be initiated and uptitrated to target (Table 11) or highest tolerated doses.306,307 A practical guidance for the use of medical therapies is available in Supplementary data online, Tables S4–S9. Randomized controlled trials of medical therapy in HF initiated therapy at low doses, with protocol-driven uptitration, irrespective of symptomatic improvement, unless limited by intolerance. The target doses used in these trials established the efficacy and safety of these therapies and therefore form the basis of guideline recommendations. When target doses are not achievable or tolerated, the maximal tolerated dose is recommended. Registry and real-life data have shown significant underimplementation of FMT in HFrEF, both with regard to number of drugs and doses used. Importantly, misinterpretation of changes in kidney function, leading to inappropriate discontinuation or down-regulation of doses of FMT, is a leading cause of insufficient FMT and should be avoided, both in decompensated and chronic HF.273,310 Many classes of FMT can safely be initiated in patients with lower eGFR (Supplementary data online, Tables S4–S9 and 2026 ESC Guidelines on cardiovascular disease and chronic kidney disease).122,259 No statistically significant interaction has been found between the presence of CKD and the treatment effect of the components of FMT on the primary endpoint of their respective trials.259 Therefore, in terms of relative risk reduction, these agents are equally effective in patients with CKD. Because patients with CKD are at the highest baseline risk for CV death or HFH, the absolute risk reduction effect is even more pronounced in patients with HF and CKD. Therefore, it is crucial that FMT is initiated, uptitrated, and maintained in patients with CKD.259 In trials that have evaluated dose responses for outcomes, composite event rates were lower with target doses compared with lower doses.274,311 Maintenance of FMT in patients with HFrEF is crucial for reducing the risk of HFH and improving survival and QoL. Even if symptoms and/or LVEF improve, it is recommended that optimal FMT is continued as lifelong treatment. Only in very selected cases of HFrEF with complete normalization of LV volumes and LVEF, including natriuretic peptides and in the context of a clear treatable reversible cause of HF, gradual discontinuation may be considered.

Non-adherence to FMT can be multifactorial. Patient-related factors such as side-effects, drug interactions, economic difficulties, psychosocial issues, or poor health literacy may be contributing factors. However, healthcare-related inappropriate discontinuation of FMT should not be neglected. In general, incurrent illness or infections without haemodynamic compromise should not lead to down-titration or discontinuation of FMT. Asymptomatic or tolerable hypotension should not lead to downtitration or discontinuation of FMT but may require re-evaluation of diuretic use. It is recommended that patients with HFrEF and CKD maintain FMT, as several trials have shown beneficial effects on kidney endpoints as well as CV endpoints.312 However, temporary discontinuation of MRAs/ARNIs/ACE-Is/ARBs and SGLT2-Is may be needed in cases with acute kidney injury and eGFR <15 mL/min/1.73 m2. Severe hyperkalaemia (potassium >5.5 or >6 mmol/L) should lead to temporary down-titration or discontinuation of MRAs and/or ARNIs/ACE-Is/ARBs (see Supplementary data online, Tables S4, S5 and S9). Temporary discontinuation of beta-blockers and ARNIs/ACE-Is/ARBs is advised in patients with severe haemodynamic instability. If FMT has been temporarily discontinued for less than 14 days, it should, in most cases, be safe to initiate FMT directly at the previously tolerated doses in stable patients. Euvolaemia is important prior to initiating beta-blockers.

6.1.7 Pharmacological therapy for heart failure with

preserved ejection fraction Foundational medical therapy for HFpEF includes SGLT2-Is and MRAs, as covered in Section 6.1.2. Heart failure with preserved ejection fraction differs from HFrEF as patients tend to be older, and more often female with a high burden of comorbidities including AF, CKD, obesity, diabetes, and non-CV comorbidities.313,314 There are numerous potential causes of HFpEF and, as the pathophysiology of various HFpEF syndromes differ, they also require distinct individualized therapies. Furthermore, it is important to exclude other conditions that might mimic the HFpEF syndrome (e.g. HCM, amyloidosis) or realize that certain diseases have similar symptoms but may coexist with HFpEF (pulmonary disease, anaemia, obesity, and deconditioning). There are Class I recommendations for SGLT2-Is and MRAs to be used in all symptomatic patients with HF, and diuretics to be used to treat signs and symptoms of congestion. Other pharmacological agents, such as ACE-Is, ARBs, and betablockers, may be used particularly for comorbidities, as there is uncertainty of the effect on morbidity and mortality. Recently, in RCTs, treatment with the GLP-1 RA semaglutide or the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA tirzepatide improved QoL in addition to weight reduction in patients with HFpEF and obesity, independently of diabetes status (see Section 10).315–317

6.1.7.1 Angiotensin receptor–neprilysin inhibitors

In the PARAGON-HF trial, sacubitril–valsartan compared with valsartan did not achieve a significant reduction in the primary composite endpoint of CV death or total HFH in patients with symptomatic HF and LVEF ≥45%.42 There was a reduction in Downloaded from academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehag100/8766302 by guest on 31 August 2026