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5.4.1 Diuretics Loop diuretics are recommended to reduce the signs and/or symptoms of congestion in patients with HFrEF. The quality of the evidence regarding diuretics is poor and their effects on morbidity and mortality have not been studied in RCTs. However, it should also be remembered that the major disease-modifying treatment trials for HFrEF were conducted with a high background use of loop diuretic therapy. One meta-analysis has shown that in patients with HFrEF, loop and thiazide diuretics appear to reduce the risk of death and worsening HF compared with a placebo, and compared with an active control, diuretics improve exercise capacity.137 Loop diuretics produce a more intense and shorter diuresis than thiazides, although they act synergistically (sequential nephron blockade) and the combination may be used to treat diuretic resistance. However, adverse effects are more likely, and these combinations should only be used with care. Of note, ARNI, MRAs, and SGLT2 inhibitors may also possess diuretic properties.129,145 The aim of diuretic therapy is to achieve and maintain euvolaemia with the lowest diuretic dose. In some euvolaemic/hypovolaemic patients, the use of a diuretic drug might be reduced or discontinued.146 Patients should be trained to self-adjust their diuretic dose based on monitoring of symptoms/signs of congestion and daily weight measurements. Practical guidance on how to use diuretics is given in Supplementary Table 7.

5.4.2 Angiotensin II type I receptor blockers The place of ARBs in the management of HFrEF has changed over the last few years. They are now recommended for patients who cannot tolerate ACE-I or ARNI because of serious side effects. Candesartan in the CHARM-Alternative study reduced CV deaths and HF hospitalizations in patients who were not receiving an ACE-I due to previous intolerance.138 Valsartan, in addition to usual therapy, including ACE-I, reduced HF hospitalizations in the Val-HeFT trial.147 However, no ARB has reduced all-cause mortality in any trial. 5.4.3 If -channel inhibitor Ivabradine slows heart rate by inhibition of the If channel in the sinus node and is therefore only effective in patients in SR. Ivabradine reduced the combined endpoint of CV mortality and HF hospitalization in patients with symptomatic HFrEF with an LVEF <_35%, with HF hospitalization in recent 12 months, in sinus rhythm (SR) and with a heart rate >_70 b.p.m. who were on evidence-based therapy including an ACE-I (or ARB), a beta-blocker, and an MRA.139,140 Our recommendation is based on the heart rate of >_70 b.p.m. used in the SHIFT trial. However, the European Medicines Agency (EMA) approved ivabradine for use in Europe in patients with HFrEF with LVEF <_35% and in SR with a resting heart rate >_75 b.p.m., because in this group ivabradine conferred a survival benefit148 based on a retrospective subgroup analysis. Every effort should be made to commence and uptitrate beta-blocker therapy to guideline recommended/maximally tolerated doses prior to considering ivabradine.

Practical guidance on how to use ivabradine is given in Supplementary Table 8.

5.4.4 Combination of hydralazine and isosorbide dinitrate There is no clear evidence to suggest the use of this fixed-dose combination therapy in all patients with HFrEF. A small RCT conducted in self-identified black patients showed that an addition of the combination of hydralazine and isosorbide dinitrate to conventional therapy (an ACE-I, a beta-blocker, and an MRA) reduced mortality and HF hospitalizations in patients with HFrEF and NYHA classes IIIIV.142 These results are difficult to translate to patients of other racial or ethnic origins. Additionally, a combination of hydralazine and isosorbide dinitrate may be considered in symptomatic patients with HFrEF who cannot tolerate any of an ACE-I, ARNI, or an ARB (or if they are contraindicated) to reduce mortality. However, this recommendation is based on the results of the relatively small Veterans Administration Cooperative Study, which included only male patients with symptomatic HFrEF who were treated with digoxin and diuretics.143

5.4.5 Digoxin Digoxin may be considered in patients with HFrEF in SR to reduce the risk of hospitalization,144 although its effect on those routinely treated with beta-blockers has not been tested. In the DIG trial, the overall effect on mortality with digoxin was neutral. The effects of digoxin in patients with HFrEF and AF have not been studied in RCTs. Some studies have suggested a potentially higher risk of events in patients with AF receiving digoxin,149,150 whereas another meta-analysis concluded, on the basis of non-RCTs, that digoxin has no deleterious effect on mortality in patients with AF and HF, most of whom had HFrEF.151 Therefore, in patients with symptomatic HF and AF, digoxin may be useful for the treatment of patients with HFrEF and AF with rapid ventricular rate, when other therapeutic options cannot be pursued.150,152155 Digoxin has a narrow therapeutic window and so levels should be checked aiming for a serum digoxin concentration <1.2 ng/mL.156,157 Caution should also be exercised when using it in females, the elderly, frail, hypokalaemic, and malnourished subjects. In patients with reduced renal function, digitoxin could be considered. Digitoxin use in HF and SR is currently being investigated.158

Hydralazine and isosorbide dinitrate may be considered in patients with symptomatic HFrEF who cannot tolerate any of an ACE-I, an ARB, or ARNI (or they are contraindicated) to reduce the risk of death.143 IIb B Digoxin Digoxin may be considered in patients with symptomatic HFrEF in sinus rhythm despite treatment with an ACE-I (or ARNI), a betablocker and an MRA, to reduce the risk of hospitalization (both all-cause and HF hospitalizations).144 IIb B

ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; b.p.m. = beats per minute; CV = cardiovascular; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NYHA = New York Heart Association; SR = sinus rhythm. aClass of recommendation. bLevel of evidence. cThe ARBs with evidence in HFrEF are candesartan, losartan, and valsartan. ESC 2021 Downloaded from academic.oup.com/eurheartj/article/42/36/3599/6358045 by guest on 07 October 2026