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5.3.1 Angiotensin-converting enzyme inhibitors ACE-Is were the first class of drugs shown to reduce mortality and morbidity in patients with HFrEF.110113 They have also been shown to improve symptoms.111 They are recommended in all patients unless contraindicated or not tolerated. They should be uptitrated to the maximum tolerated recommended doses. Practical guidance on how to use ACE-Is is given in Supplementary Table 2.

5.3.2 Beta-blockers Beta-blockers have been shown to reduce mortality and morbidity in patients with HFrEF, in addition to treatment with an ACE-I and diuretic.114120 They also improve symptoms.123 There is consensus that ACE-I and beta-blockers can be commenced together as soon as the diagnosis of symptomatic HFrEF is established. There is no evidence favouring the initiation of a beta-blocker before an ACE-I and vice versa.124 Beta-blockers should be initiated in clinically stable, euvolaemic, patients at a low dose and gradually uptitrated to the maximum tolerated dose. In patients admitted with AHF, betablockers should be cautiously initiated in hospital, once the patient is haemodynamically stabilized. An individual patient data (IPD) meta-analysis of all major betablocker trials in HFrEF has shown no benefit on hospital admissions and mortality in the subgroup of patients with HFrEF with AF.125 However, since this is a retrospective subgroup analysis, and because beta-blockers did not increase risk, the guideline committee decided not to make a separate recommendation according to heart rhythm. Practical guidance on how to use beta-blockers is given in Supplementary Table 3.

5.3.3 Mineralocorticoid receptor antagonists MRAs (spironolactone or eplerenone) are recommended, in addition to an ACE-I and a beta-blocker, in all patients with HFrEF to reduce mortality and the risk of HF hospitalization.121,122 They also improve symptoms.121 MRAs block receptors that bind aldosterone and, with different degrees of affinity, other steroid hormones (e.g. corticosteroid and androgen) receptors. Eplerenone is more specific for aldosterone blockade and, therefore, causes less gynaecomastia. Caution should be exercised when MRAs are used in patients with impaired renal function and in those with serum potassium concentrations >5.0 mmol/L. Practical guidance on how to use MRAs is given in Supplementary Table 4.

5.3.4 Angiotensin receptor-neprilysin inhibitor In the PARADIGM-HF trial, sacubitril/valsartan, an ARNI, was shown to be superior to enalapril in reducing hospitalizations for worsening HF, CV mortality, and all-cause mortality in patients with ambulatory HFrEF with LVEF <_40% (changed to <_35% during the study). Patients in the trial had elevated plasma NP concentrations, an eGFR >_30 mL/ min/1.73 m2 and were able to tolerate enalapril and then sacubitril/ valsartan during the run-in period.105 Additional benefits of sacubitril/ valsartan included an improvement in symptoms and QOL,105 a reduction in the incidence of diabetes requiring insulin treatment,126 and a reduction in the decline in eGFR,127 as well as a reduced rate of hyperkalaemia.128 Additionally, the use of sacubitril/valsartan may allow a reduction in loop diuretic requirement.129 Symptomatic hypotension was reported more commonly in patients treated with sacubitril/valsartan as compared to enalapril, but despite developing hypotension, these patients also gained clinical benefits from sacubitril/valsartan therapy.128,130

Table 8 Evidence-based doses of disease-modifying drugs in key randomized trials in patients with heart failure with reduced ejection fraction

Starting dose Target dose

ACE-I Captoprila 6.25 mg t.i.d. 50 mg t.i.d. Enalapril 2.5 mg b.i.d. 1020 mg b.i.d. Lisinoprilb 2.55 mg o.d. 2035 mg o.d. Ramipril 2.5 mg b.i.d. 5 mg b.i.d. Trandolaprila 0.5 mg o.d. 4 mg o.d. ARNI Sacubitril/valsartan 49/51 mg b.i.d.c 97/103 mg b.i.d. Beta-blockers Bisoprolol 1.25 mg o.d. 10 mg o.d. Carvedilol 3.125 mg b.i.d. 25 mg b.i.d.e Metoprolol succinate (CR/XL) 12.525 mg o.d. 200 mg o.d. Nebivolold 1.25 mg o.d. 10 mg o.d. MRA Eplerenone 25 mg o.d. 50 mg o.d. Spironolactone 25 mg o.d.f 50 mg o.d. SGLT2 inhibitor Dapagliflozin 10 mg o.d. 10 mg o.d. Empagliflozin 10 mg o.d. 10 mg o.d. Other agents Candesartan 4 mg o.d. 32 mg o.d. Losartan 50 mg o.d. 150 mg o.d. Valsartan 40 mg b.i.d. 160 mg b.i.d. Ivabradine 5 mg b.i.d. 7.5 mg b.i.d. Vericiguat 2.5 mg o.d. 10 mg o.d. Digoxin 62.5 mg o.d. 250 mg o.d. Hydralazine/ Isosorbide dinitrate 37.5 mg t.i.d./20 mg t.i.d. 75 mg t.i.d./40 mg t.i.d. ACE-I = angiotensin-converting enzyme inhibitor; ARNI = angiotensin receptorneprilysin inhibitor; b.i.d. = bis in die (twice daily); CR = controlled release; CV = cardiovascular; MRA = mineralocorticoid receptor antagonist; o.d. = omne in die (once daily); SGLT2 = sodium-glucose co-transporter 2; t.i.d. = ter in die (three times a day); XL = extended release. aIndicates an ACE-I where the dosing target is derived from post-myocardial infarction trials. bIndicates drugs where a higher dose has been shown to reduce morbidity/mortality compared with a lower dose of the same drug, but there is no substantive randomized, placebo-controlled trial and the optimum dose is uncertain. cSacubitril/valsartan may have an optional lower starting dose of 24/26 mg b.i.d. for those with a history of symptomatic hypotension. dIndicates a treatment not shown to reduce CV or all-cause mortality in patients with heart failure (or shown to be non-inferior to a treatment that does). eA maximum dose of 50 mg twice daily can be administered to patients weighing over 85 kg. fSpironolactone has an optional starting dose of 12.5 mg in patients where renal status or hyperkalaemia warrant caution. ESC 2021 Downloaded from academic.oup.com/eurheartj/article/42/36/3599/6358045 by guest on 07 October 2026