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Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 May 3, 2022 e931 CLINICAL STATEMENTS AND GUIDELINES of bradykinin), and substance P.36,37 ACEi should not be administered to patients with any history of angioedema, but ARB do not interfere as directly with bradykinin metabolism and have been associated with low rates of angioedema.38,39 7.3.2 Beta Blockers Recommendation for Beta Blockers Referenced studies that support the recommendation are summarized in the Online Data Supplements. COR LOE Recommendation 1 A 1. In patients with HFrEF, with current or previous symptoms, use of 1 of the 3 beta blockers proven to reduce mortality (eg, bisoprolol, carvedilol, sustained-release metoprolol succinate) is recommended to reduce mortality and hospitalizations.1–3 Value Statement: High Value (A) 2. In patients with HFrEF, with current or previous symptoms, beta-blocker therapy provides high economic value.4–8 Synopsis Treatment with beta blockers reduces the risk of death and the combined risk of death or hospitalization in patients with HFrEF.1–3 In addition, this treatment can improve LVEF, lessen the symptoms of HF, and improve clinical status.1–3,9–11 Clinical trials have shown that beta blockers should be prescribed to all patients when HFrEF is diagnosed, including in-hospital, unless contraindicated or not tolerated.1–3,9–11 These benefits of beta blockers were observed in patients with or without CAD, and in patients with or without diabetes, older patients, as well as in women and across racial and ethnic groups but not in patients with AF.1–3,10–12 Even if symptoms do not improve, long-term treatment should be maintained to reduce the risk of major cardiovascular events. Beta blockers should be initiated at low doses, and every effort should be made to achieve the target doses of the beta blockers shown to be effective in major clinical trials, as tolerated1–3,9,10 (see Section 7.3.8, “GDMT Dosing, Sequencing and Uptitration”). Recommendation-Specific Supportive Text 1. Three beta blockers have been shown to be effective in reducing the risk of death in patients with HFrEF: bisoprolol, sustained-release metoprolol (succinate), and carvedilol.1–3 The favorable findings with these 3 agents, however, should not be considered a beta-blocker class effect in HFrEF. Other beta blockers are not included in this recommendation for use.13–15 Even when asymptomatic, or when symptoms are mild or improve with other therapies, beta-blocker therapy is important and should not be delayed until symptoms return or disease progression is documented.16 Data show that beta blockers can be safely initiated before hospital discharge, provided patients are clinically stabilized and do not require intravenous inotropic therapy for HF.17 If a contraindication or intolerance are noted, they should be documented, and the patient restarted on beta-blocker therapy in the future, so long as an absolute contraindication is not present. Even if symptoms or LVEF improve, long-term treatment with beta blockers and use of target doses should be maintained to reduce the risk of progression in LV dysfunction or major cardiovascular events.18,19 Abrupt withdrawal of betablocker therapy can lead to clinical deterioration and should be avoided unless indicated.18 2. Multiple analyses have shown the high value of beta-blocker therapy among HF patients. A modelbased analysis, using generic beta-blocker costs, found beta-blocker therapy was high value.4 These results were consistent with earlier model-based cost-effectiveness analyses5–7 and a trial-based economic analysis of the US Carvedilol Heart Failure (CHF) Trials Program.8 Each of these studies also found treatment with a beta blocker was high value despite using previously higher betablocker costs. 7.3.3 Mineralocorticoid Receptor Antagonists (MRAs) Recommendations for Mineralocorticoid Receptor Antagonists (MRAs) Referenced studies that support the recommendations are summarized in the Online Data Supplements. COR LOE Recommendations 1 A 1. In patients with HFrEF and NYHA class II to IV symptoms, an MRA (spironolactone or eplerenone) is recommended to reduce morbidity and mortality, if eGFR is >30 mL/min/1.73 m2 and serum potassium is <5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely monitored thereafter to minimize risk of hyperkalemia and renal insufficiency.1–3 Value Statement: High Value (A) 2. In patients with HFrEF and NYHA class II to IV symptoms, MRA therapy provides high economic value.4–7 3: Harm B-NR 3. In patients taking MRA whose serum potassium cannot be maintained at <5.5 mEq/L, MRA should be discontinued to avoid lifethreatening hyperkalemia.8,9 Synopsis MRA (also known as aldosterone antagonists or anti-mineralocorticoids) show consistent improvements in all-cause mortality, HF hospitalizations, and SCD across a wide range of patients with HFrEF.1–3 Patients at risk for renal dysfunction or hyperkalemia require close monitoring, and eGFR ≤30 mL/min/1.73 m2 or serum potassium ≥5.0 mEq/L are contraindications to MRA initiation.10,11 Because of the higher selectivity of eplerenone for the aldosterone receptor, adverse effects such as gynecomastia and vaginal bleeding Downloaded from http://ahajournals.org by on October 7, 2026