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............................. Therefore, it is recommended that an ACE-I or ARB is replaced by sacubitril/valsartan in ambulatory patients with HFrEF, who remain symptomatic despite optimal treatment outlined above. Two studies have examined the use of ARNI in hospitalized patients, some of whom had not been previously treated with ACE-I. Initiation in this setting appears safe and reduces subsequent CV death or HF hospitalizations by 42% compared to enalapril.106,107,131 As such, initiation of sacubitril/valsartan in ACE-I naive (i.e. de novo) patients with HFrEF may be considered (class of recommendation IIb, level of evidence B). Patients being commenced on sacubitril/valsartan should have an adequate blood pressure (BP), and an eGFR >_30 mL/min/1.73 m2. A washout period of at least 36 h after ACE-I therapy is required in order to minimize the risk of angioedema. Practical guidance on how to use ARNI is given in Supplementary Table 5.

5.3.5 Sodium-glucose co-transporter 2 inhibitors The DAPA-HF trial investigated the long-term effects of dapagliflozin (SGLT2 inhibitor) compared to placebo in addition to optimal medical therapy (OMT), on morbidity and mortality in patients with ambulatory HFrEF.108 Patients participated in the trial if they were in NYHA class IIIV, and had an LVEF <_40% despite OMT. Patients were also required to have an elevated plasma NT-proBNP and an eGFR >_30 mL/min/1.73 m2.108 Therapy with dapagliflozin resulted in a 26% reduction in the primary endpoint: a composite of worsening HF (hospitalization or an urgent visit resulting in i.v. therapy for HF) or CV death. Both of these components were significantly reduced. Moreover, dapagliflozin reduced all-cause mortality,108 alleviated HF symptoms, improved physical function and QOL in patients with symptomatic HFrEF.132 Benefits were seen early after the initiation of dapagliflozin, and the absolute risk reduction was large. Survival benefits were seen to the same extent in patients with HFrEF with and without diabetes, and across the whole spectrum of HbA1c values.108 Subsequently, the EMPEROR-Reduced trial found that empagliflozin reduced the combined primary endpoint of CV death or HF hospitalization by 25% in patients with NYHA class IIIV symptoms, and an LVEF <_40% despite OMT.109 This trial included patients with an eGFR >20 mL/min/1.73 m2 and there was also a reduction in the decline in eGFR in individuals receiving empagliflozin. It was also associated with an improvement in QOL.133 Although there was not a significant reduction in CV mortality in the EMPEROR-Reduced trial, a recent meta-analysis of the DAPA-HF and EMPEROR-Reduced trials found no heterogeneity in CV mortality.134 Therefore, dapagliflozin or empagliflozin are recommended, in addition to OMT with an ACE-I/ARNI, a beta-blocker and an MRA, for patients with HFrEF regardless of diabetes status. The diuretic/ natriuretic properties of SGLT2 inhibitors may offer additional benefits in reducing congestion and may allow a reduction in loop diuretic requirement.135 The combined SGLT-1 and 2 inhibitor, sotagliflozin, has also been studied in patients with diabetes who were hospitalized with HF. The drug reduced CV death and hospitalization for HF.136 It is discussed further in the AHF and comorbidity sections. Therapy with SGLT2 inhibitors may increase the risk of recurrent genital fungal infections. A small reduction in eGFR following initiation is expected and is reversible and should not lead to premature discontinuation of the drug.

Practical guidance on how to use the SGLT2 inhibitors dapagliflozin and empagliflozin are given in Supplementary Table 6.

5.4 Other drugs recommended or to be

considered in selected patients with heart failure with reduced ejection fraction

Other pharmacological treatments indicated in selected patients with NYHA class II–IV heart failure with reduced ejection fraction (LVEF 40%)

Recommendations Classa Levelb

Loop diuretics Diuretics are recommended in patients with HFrEF with signs and/or symptoms of congestion to alleviate HF symptoms, improve exercise capacity, and reduce HF hospitalizations.137 I C ARB An ARBc is recommended to reduce the risk of HF hospitalization and CV death in symptomatic patients unable to tolerate an ACE-I or ARNI (patients should also receive a beta-blocker and an MRA).138 I B If-channel inhibitor Ivabradine should be considered in symptomatic patients with LVEF <_35%, in SR and a resting heart rate >_70 b.p.m. despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose below that), ACE-I/(or ARNI), and an MRA, to reduce the risk of HF hospitalization and CV death.139 IIa B Ivabradine should be considered in symptomatic patients with LVEF <_35%, in SR and a resting heart rate >_70 b.p.m. who are unable to tolerate or have contraindications for a beta-blocker to reduce the risk of HF hospitalization and CV death. Patients should also receive an ACE-I (or ARNI) and an MRA.140 IIa C Soluble guanylate cyclase stimulator Vericiguat may be considered in patients in NYHA class IIIV who have had worsening HF despite treatment with an ACE-I (or ARNI), a beta-blocker and an MRA to reduce the risk of CV mortality or HF hospitalization.141 IIb B Hydralazine and isosorbide dinitrate Hydralazine and isosorbide dinitrate should be considered in self-identified black patients with LVEF <_35% or with an LVEF <45% combined with a dilated left ventricle in NYHA class IIIIV despite treatment with an ACE-I (or ARNI), a beta-blocker and an MRA to reduce the risk of HF hospitalization and death.142 IIa B

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