Dose and schedule of primary pharmacologic therapies for heart failure with reduced ejection fraction in adults

Type of therapy	Role in therapy	Drug	Typical initial dose (oral)	Target dose	Minimum dose titration interval
Renin-angiotensin system inhibitors/neprilysin inhibitors	Preferred	Sacubitril-valsartan (ARNI)	24/26 to 49/51 mg twice daily*	97/103 mg twice daily	Double dose after 1 to 2 weeks or as tolerated^¶
	Alternatives	Lisinopril	2.5 to 5 mg once daily	20 to 40 mg once daily
		Ramipril	1.25 to 2.5 mg once daily	10 mg once daily
		Enalapril	2.5 mg twice daily	10 to 20 mg twice daily
		Captopril	6.25 mg three times daily	50 mg three times daily
		Trandolapril	1 mg once daily	4 mg once daily
		Losartan	25 to 50 mg once daily	150 mg once daily
		Candesartan	4 to 8 mg once daily	32 mg once daily
		Valsartan	20 to 40 mg twice daily	160 mg twice daily
Beta blockers	Preferred	Carvedilol	3.125 mg twice daily	≤85 kg: 25 mg twice daily	Double every 2 weeks^¶
		Carvedilol	3.125 mg twice daily	>85 kg: 50 mg twice daily
		Carvedilol CR	10 mg once daily	80 mg once daily
		Metoprolol succinate CR	12.5 to 25 mg once daily	200 mg once daily
		Bisoprolol	1.25 mg once daily^Δ	10 mg once daily
Mineralocorticoid receptor antagonists	Preferred	Spironolactone	12.5 to 25 mg once daily	25 to 50 mg once daily or in two divided doses	Double every 4 weeks^¶
Mineralocorticoid receptor antagonists	Preferred	Eplerenone	25 mg once daily	50 mg once daily	Double every 4 weeks^¶
SGLT2 inhibitors	Preferred	Dapagliflozin	10 mg once daily		Fixed dose
	Preferred	Empagliflozin	10 mg once daily
	Alternative	Canagliflozin	100 mg once daily

Only 1 drug from each type of therapy should be used. The drug doses and intervals for dose changes are for patients who do not require dose adjustments due to factors such as comorbid illnesses, kidney or hepatic dysfunction, drug interactions, or other reasons. Consult appropriate UpToDate content, Lexicomp drug monographs, or other resources to determine the appropriate dosing for a given patient. The drug interactions program included within UpToDate may be used to confirm there are no clinically significant drug interactions. Monitoring of therapy is discussed in UpToDate content on treatment of heart failure with reduced ejection fraction.

CR: controlled release; SGLT2: sodium-glucose co-transporter 2; ARNI: angiotensin receptor-neprilysin inhibitor; ACE: angiotensin converting enzyme; ARB: angiotensin II receptor blocker; HFrEF: heart failure with reduced ejection fraction.

* Selection of initial dose of ARNI is dependent upon whether patient has been treated previously with a moderate to high dose of an ACE inhibitor or ARB; to reduce risk of toxicity, a 36-hour washout period is required if switching from ACE inhibitor to ARNI. Refer to Lexicomp monograph.

¶ Dose increases may be performed more rapidly in a management program or with other forms of monitoring for complications. The requirements for monitoring are described in UpToDate content on pharmacologic therapy for HFrEF.

Δ In the United States, the lowest available bisoprolol tablet strength is 5 mg. A 1.25 mg dose requires splitting a round tablet into quarters, which may be difficult and inaccurate.

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Dose and schedule of primary pharmacologic therapies for heart failure with reduced ejection fraction in adults