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May 3, 2022 Circulation. 2022;145:e895–e1032. DOI: 10.1161/CIR.0000000000001063 e928 CLINICAL STATEMENTS AND GUIDELINES volume overload to decrease congestion while maintaining serum sodium. Recommendation-Specific Supportive Text 1. Controlled trials with diuretics showed their effects to increase urinary sodium excretion, decrease physical signs of fluid retention, and improve symptoms, QOL, and exercise tolerance.1–5 Recent data from the nonrandomized OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry revealed reduced 30-day all-cause mortality and hospitalization for HF with diuretic use compared with no diuretic use after hospital discharge for HF.9 The most commonly used loop diuretic for the treatment of HF is furosemide, but some patients respond more favorably to other agents in this category (eg, bumetanide, torsemide), potentially because of their increased oral bioavailability.10–12 In outpatients with HF, diuretic therapy is commonly initiated with low doses, and the dose is increased until urine output increases and weight decreases, generally by 0.5 to 1.0 kg daily. Patients may become unresponsive to high doses of diuretic drugs if they consume large amounts of dietary sodium, are taking agents that can block the effects of diuretics (eg, NSAIDs), or have significant impairment of renal function or perfusion. 2. Diuretic resistance can be overcome in several ways, including escalation of loop diuretic dose, intravenous administration of diuretics (bolus or continuous infusion),6 or combination of different diuretic classes.13–16 The use of a thiazide or thiazide-like diuretic (eg, metolazone) in combination with a loop diuretic inhibits compensatory distal tubular sodium reabsorption, leading to enhanced natriuresis. However, in a propensity-score matched analysis in patients with hospitalized HF, the addition of metolazone to loop diuretics was found to increase the risk for hypokalemia, hyponatremia, worsening renal function, and mortality, whereas use of higher doses of loop diuretics was not found to adversely affect survival.17 Although randomized data comparing the 2 diuretic strategies are limited, the DOSE (Diuretic Optimization Strategies Evaluation) trial lends support for the use of high-dose intravenous loop diuretics.18 7.3 Pharmacological Treatment* for HFrEF 7.3.1 Renin-Angiotensin System Inhibition With ACEi or ARB or ARNi Recommendations for Renin-Angiotensin System Inhibition With ACEi or ARB or ARNi 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 III symptoms, the use of ARNi is recommended to reduce morbidity and mortality.1–5 1 A 2. In patients with previous or current symptoms of chronic HFrEF, the use of ACEi is beneficial to reduce morbidity and mortality when the use of ARNi is not feasible.6–13 1 A 3. In patients with previous or current symptoms of chronic HFrEF who are intolerant to ACEi because of cough or angioedema and when the use of ARNi is not feasible, the use of ARB is recommended to reduce morbidity and mortality.14–18 Value Statement: High Value (A) 4. In patients with previous or current symptoms of chronic HFrEF, in whom ARNi is not feasible, treatment with an ACEi or ARB provides high economic value.19–25 1 B-R 5. In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACEi or ARB, replacement by an ARNi is recommended to further reduce morbidity and mortality.1–5 Value Statement: High Value (A) 6. In patients with chronic symptomatic HFrEF, treatment with an ARNi instead of an ACEi provides high economic value.26–29 3: Harm B-R 7. ARNi should not be administered concomitantly with ACEi or within 36 hours of the last dose of an ACEi.30,31 3: Harm C-LD 8. ARNi should not be administered to patients with any history of angioedema.32–35 3: Harm C-LD 9. ACEi should not be administered to patients with any history of angioedema.36–39 *See Section 7.2, “Diuretics and Decongestion Strategies in Patients with HF,” for diuretic recommendations. Synopsis Inhibition of the renin-angiotensin system is recommended to reduce morbidity and mortality for patients with HFrEF, and ARNi, ACEi, or ARB are recommended as first-line therapy.1–18 If patients have chronic symptomatic Table 12. Commonly Used Oral Diuretics in Treatment of Congestion for Chronic HF Drug Initial Daily Dose Maximum Total Daily Dose Duration of Action Loop diuretics Bumetanide 0.5–1.0 mg once or twice 10 mg 4–6 h Furosemide 20–40 mg once or twice 600 mg 6–8 h Torsemide 10–20 mg once 200 mg 12–16 h Thiazide diuretics Chlorthiazide 250–500 mg once or twice 1000 mg 6–12 h Chlorthalidone 12.5–25 mg once 100 mg 24–72 h Hydrochlorothiazide 25 mg once or twice 200 mg 6–12 h Indapamide 2.5 mg once 5 mg 36 h Metolazone 2.5 mg once 20 mg 12–24 h HF indicates heart failure. Downloaded from http://ahajournals.org by on October 7, 2026