| Type of therapy | Drug | Initial dose | Target maximum dose | Typical up titration interval* |
| Initial agents: | ||||
| ACE inhibitor, ARNI, or ARB¶ | ||||
| ACE inhibitor | Any oral ACE inhibitor including the following: | |||
| Captopril | 6.25 mg 3 times daily | 50 mg 3 times daily | Increase dose (eg, double) at 1- to 2-week intervalsΔ | |
| Enalapril | 2.5 mg twice daily | 10 to 20 mg twice daily | Increase dose (eg, double) at 1- to 2-week intervalsΔ | |
| Lisinopril | 2.5 mg to 5 mg once daily | 20 to 40 mg once daily | Increase dose (eg, double dose up to 10 mg increment as per FDA approved labeling) at 1- to 2-week intervalsΔ | |
| Ramipril | 1.25 mg once daily | 10 mg once daily | Increase dose (eg, double) at 1- to 2-week intervalsΔ◊ | |
| ARNI | Sacubitril-valsartan | 24/26 mg twice daily if 1) patient not recently taking an ACE inhibitor or ARB, or 2) patient has been taking a low dose of ACE inhibitor (≤10/day of enalapril or equivalent) or ARB (≤160 mg/day of valsartan or equivalent)§ | 97/103 mg twice daily | Double the dose at 2- to 4-week intervalsΔ |
| 49/51 mg twice daily if patient has been taking a moderate to high dose ACE inhibitor (ie, >10 mg/day of enalapril or equivalent) or ARB (ie, >160 mg/day of valsartan or equivalent) | ||||
| ARB | Prefer 1 of the ARBs in the key RCTs: | |||
| Candesartan | 4 to 8 mg once daily | 32 mg once daily | Double the dose at 1- to 2-week intervalsΔ | |
| Valsartan | 20 to 40 mg twice daily | 160 mg twice daily | Double the dose at 1- to 2-week intervalsΔ | |
| Some experts use the following ARB: | ||||
| Losartan | 25 to 50 mg once daily | 150 mg once daily | Double the dose at 1- to 2-week intervalsΔ | |
| Beta blocker | Limited to 1 of the beta blockers in the key RCTs: | |||
| Carvedilol | 3.125 mg twice daily | For weight <85 kg: 25 mg twice daily For weight >85 kg: 50 mg twice daily | Double the dose at 2-week or greater intervals | |
| Carvedilol CR | 10 mg once daily | 80 mg once daily | Double the dose at 2-week or greater intervals | |
| Metoprolol succinate extended release (metoprolol CR/XL) | 12.5 to 25 mg once daily | 200 mg once daily | Double the dose at 2-week or greater intervals | |
| Bisoprolol | 1.25 mg once daily | 10 mg once daily | Double the dose at 2-week or greater intervals | |
| Alternative agent (used in patients with intolerance of ACE inhibitor, ARNI, and ARB)¥ | ||||
| Hydralazine plus nitrate | Either fixed-dose combination or combined use of the 2 separate drugs | |||
| Fixed-dose combination | 20 mg isosorbide dinitrate/37.5 mg hydralazine 3 times daily | 40 mg isosorbide dinitrate/75 mg hydralazine 3 times daily | Double the dose in 2 to 4 weeks | |
| Combined use of isosorbide dinitrate and hydralazine | 20 to 30 mg isosorbide dinitrate 3 or 4 times daily and 25 to 50 mg hydralazine 3 or 4 times daily | 40 mg isosorbide dinitrate 3 times daily and 100 mg hydralazine 3 times daily | Increase the dose in 2 to 4 weeks | |
ACE: angiotensin converting enzyme; ARNI: angiotensin receptor-neprilysin inhibitor; ARB: angiotensin II receptor blocker; FDA: US Food and Drug Administration; RCTs: randomized controlled trials; CR: controlled release; CR/XL: controlled release/extended release; HF: heart failure; HFrEF: heart failure with reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤40%).
* These are general suggestions for time intervals and doses for outpatient titration. Titration should be continued only as tolerated. Slower titration may be appropriate for individual patients. Down titration should be performed whenever indicated to manage patient intolerance (eg, hypotension). Refer to UpToDate content on management of intolerances.
¶ Each patient should receive only 1 angiotensin system blocker (an ARNI, ACE inhibitor, or ARB). When switching from an ACE inhibitor to an ARNI, a 36-hour washout period should be strictly observed given the risk of angioedema with combined used of these agents.
Δ Monitoring during drug titration includes periodic clinical evaluation, including screening for contraindications and adverse effects (eg, hypotension), and checking blood tests (electrolytes, particularly serum potassium; blood urea nitrogen; and serum creatinine) obtained 1 to 2 weeks following drug initiation or upward titration. Titration should be continued only as tolerated and generally requires a systolic blood pressure ≥100 mmHg and no symptomatic hypotension.
◊ FDA-approved labeling specifies 3-week intervals for HF post-myocardial infarction.
§ The lower starting dose (24/26 mg) is generally recommended in patients taking sacubitril-valsartan as a component of initial therapy for HFrEF. However, some clinicians will use a higher starting dose (49 mg/51 mg orally twice daily) in hypertensive patients, provided hepatic function is normal or only mildly impaired (Child-Pugh class A cirrhosis).
¥ This table describes use of hydralazine plus nitrate in patients who are unable to take an ACE inhibitor, ARNI, and ARB. Use of hydralazine plus nitrate in addition to therapy with an ACE inhibitor, ARNI, or ARB is discussed in UpToDate content on secondary pharmacologic therapy of HFrEF.