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May 3, 2022 Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 e932 CLINICAL STATEMENTS AND GUIDELINES are observed less often in patients who take eplerenone than in those who take spironolactone. Recommendation-Specific Supportive Text 1. Clinical trials taken on MRA together—RALES (Randomized Aldactone Evaluation Study)1 randomized highly symptomatic patients with LVEF ≤35%; EPHESUS (Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study)2 randomized patients post-MI with LVEF ≤40%; and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure)3 randomized patients with mild symptoms and LVEF ≤30%—suggest a benefit of MRA across the spectrum of HFrEF, inclusive of a wide range of etiologies and disease severities. Initiation in the ambulatory or hospital setting is appropriate.12 The starting dose of spironolactone and eplerenone is 25 mg orally daily, increased to 50 mg daily orally after a month; for eGFR 31 to 49 mL/min/1.73 m2, dosing should be reduced by half. Regular checks of serum potassium levels and renal function should be performed according to clinical status, approximately 1 week, then 4 weeks, then every 6 months after initiating or intensifying MRA, with more frequent testing for clinical instability. We elected to remove the 2013 recommendation “Aldosterone receptor antagonists are recommended to reduce morbidity and mortality following an acute MI in patients who have LVEF of 40% or less who develop symptoms of HF or who have a history of diabetes mellitus, unless contraindicated” because the new recommendation covers the spectrum of symptomatic patients with HF. 2. The economic value of MRA therapy was assessed by both RCTs (RALES5 and EPHESUS6,7) and a model-based analysis.4 The model-based analysis used generic MRA costs and found therapy was high value with a cost per QALY of under $1000.4 The earlier trial-based economic analyses of MRAs from RALES and EPHESUS also found MRA therapy was high value despite using previously higher MRA costs.5–7 3. Spironolactone and eplerenone are partially excreted through the kidneys, raising concerns about safety when eGFR is ≤30 mL/min/1.73 m2.10,11 Spironolactone and eplerenone decrease renal potassium excretion, raising the risk of hyperkalemia, particularly when MRA is initiated at serum potassium ≥5.0 mEq/L and continued ≥5.5 mEq/L. The incidence of clinically significant hyperkalemia events was <1% in EPHESUS and EMPHASIS-HF, without a significant difference between eplerenone and placebo.2,3 however, in the closely monitored setting of a RCT with enrollment of younger patients with fewer multiple chronic conditions than seen in the general HFrEF population, safety may be overstated. Observational data have raised concerns about less favorable outcomes of MRA use for HFrEF during usual care.8,9 Coadministration of MRA with ACEi or ARB mildly increases the risk of hyperkalemia. Hyperkalemia risk was lower with ARNi in patients with chronic HF in the PARADIGM-HF trial13 but not different in patients with HF who were decompensated in the PIONEER-HF trial14 when compared with ACEi. Diarrhea causing dehydration or loop diuretic therapy interruption, because of worsening renal function or hyperkalemia, should be a consideration for temporarily holding the MRA. The development of worsening renal function or hyperkalemia is often a reflection of acute clinical change or progressive disease, prompting careful evaluation of the entire medical regimen and other causes of hyperkalemia, in addition to holding the MRA. The efficacy of the use of potassium binders (eg, patiromer, sodium zirconium cyclosilicate) to improve outcomes by facilitating continuation of MRA is uncertain15,16 and is addressed in Section 7.3.6, “Other Drug Treatment.” 7.3.4 Sodium-Glucose Cotransporter 2 Inhibitors Recommendation for SGLT2i Referenced studies that support the recommendation are summarized in the Online Data Supplements. COR LOE Recommendation 1 A 1. In patients with symptomatic chronic HFrEF, SGLT2i are recommended to reduce hospitalization for HF and cardiovascular mortality, irrespective of the presence of type 2 diabetes.1,2 Value Statement: Intermediate Value (A) 2. In patients with symptomatic chronic HFrEF, SGLT2i therapy provides intermediate economic value.3,4 Synopsis Several RCTs in patients with type 2 diabetes and either established CVD or high risk for CVD have shown that SGLT2i prevent HF hospitalizations compared with placebo.5–7 The overall 31% reduction in HF hospitalizations was noted irrespective of the presence or absence of preexisting HF, although only 10% to 14% of participants had HF at baseline. The benefit appears independent of the glucose-lowering effects.8 Therefore, several trials were launched to examine the efficacy of SGLT2i on outcomes in patients with HF, irrespective of the presence of type 2 diabetes. The DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial and EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) showed the benefit of SGLT2i (dapagliflozin and empagliflozin, respectively) versus placebo on outcomes (median follow-up, 16–18 Downloaded from http://ahajournals.org by on October 7, 2026