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................................................................................................................................................................ Coronary angiography is recommended in patients with HF, who have angina pectoris or an ‘angina equivalent’ despite pharmacological therapy, in order to establish the diagnosis of CAD and its severity. Coronary angiography may also be considered in patients with HFrEF who have an intermediate to high pre-test probability of CAD and who are considered potentially suitable for coronary revascularization.5 5 Heart failure with reduced ejection fraction 5.1 The diagnosis of heart failure with reduced ejection fraction The diagnosis of HFrEF requires the presence of symptoms and/or signs of HF and a reduced ejection fraction (LVEF <_40%). This is most usually obtained by echocardiography. Details about the quality standards that should be adhered to when determining the presence of reduced LV systolic function by echocardiography can be found in the European Association of Cardiovascular Imaging (EACVI) position paper.99 If assessment of EF is not possible by echocardiography, then CMR or rarely, nuclear techniques can be employed. An algorithm for the diagnosis of HFrEF is depicted in Figure 1. For the investigation of the underlying aetiology, please refer to Table 5. 5.2 Pharmacological treatments for patients with heart failure with reduced ejection fraction 5.2.1 Goals of pharmacotherapy for patients with heart failure with reduced ejection fraction Pharmacotherapy is the cornerstone of treatment for HFrEF and should be implemented before considering device therapy, and alongside non-pharmacological interventions. There are three major goals of treatment for patients with HFrEF: (i) reduction in mortality, (ii) prevention of recurrent hospitalizations due to worsening HF, and (iii) improvement in clinical status, functional capacity, and QOL.100102 The key evidence supporting the recommendations in this section for patients with symptomatic HFrEF is given in Supplementary Table 1. Figure 2 depicts the algorithm for the treatment strategy, including drugs and devices in patients with HFrEF, for Class I indications for the reduction of mortality (either all-cause or CV). The recommendations for each treatment are summarized below. 5.2.2 General principles of pharmacotherapy for heart failure with reduced ejection fraction Modulation of the renin-angiotensin-aldosterone (RAAS) and sympathetic nervous systems with angiotensin-converting enzyme inhibitors (ACE-I) or an angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers, and mineralocorticoid receptor antagonists (MRA) has been shown to improve survival, reduce the risk of HF hospitalizations, and reduce symptoms in patients with HFrEF. These drugs serve as the foundations of pharmacotherapy for patients with HFrEF. The triad of an ACE-I/ARNI, a beta-blocker, and an MRA is recommended as cornerstone therapies for these patients, unless the drugs are contraindicated or not tolerated.103105 They should be uptitrated to the doses used in the clinical trials (or to maximally tolerated doses if that is not possible). This guideline still recommends the use of ARNI as a replacement for ACE-I in suitable patients who remain symptomatic on ACE-I, beta-blocker, and MRA therapies; however, an ARNI may be considered as a first-line therapy instead of an ACE-I.106,107 The recommended doses of these drugs are given in Table 8. Angiotensin-receptor blockers (ARBs) still have a role in those who are intolerant to ACE-I or ARNI. The sodium-glucose co-transporter 2 (SGLT2) inhibitors dapagliflozin and empagliflozin added to therapy with ACE-I/ARNI/betablocker/MRA reduced the risk of CV death and worsening HF in patients with HFrEF.108,109 Unless contraindicated or not tolerated, dapagliflozin or empagliflozin are recommended for all patients with HFrEF already treated with an ACE-I/ARNI, a beta-blocker, and an MRA, regardless of whether they have diabetes or not. Other drugs may be used for selected patients with HFrEF. These are discussed in section 5.4. Right heart catheterization should be considered in patients where HF is thought to be due to constrictive pericarditis, restrictive cardiomyopathy, congenital heart disease, and high output states. IIa C Right heart catheterization should be considered in patients with probable pulmonary hypertension, assessed by echo in order to confirm the diagnosis and assess its reversibility before the correction of valve/structural heart disease. IIb C Right heart catheterization may be considered in selected patients with HFpEF to confirm the diagnosis. IIb C EMB EMB should be considered in patients with rapidly progressive HF despite standard therapy when there is a probability of a specific diagnosis, which can be confirmed only in myocardial samples.97,98 IIa C CAD = coronary artery disease; CMR = cardiac magnetic resonance; CTCA = computed tomography coronary angiography; DCM = dilated cardiomyopathy; EMB = endomyocardial biopsy; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LGE = late gadolinium enhancement; LV = left ventricular; MCS = mechanical circulatory support; PET = positron emission tomography; SPECT = single-photon emission computed tomography. aClass of recommendation. bLevel of evidence. ESC 2021 Downloaded from academic.oup.com/eurheartj/article/42/36/3599/6358045 by guest on 07 October 2026