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Secondary pharmacologic therapy of heart failure with reduced ejection fraction

Secondary pharmacologic therapy of heart failure with reduced ejection fraction
Type of therapy Drug Initial dose Target maximum dose Typical up titration interval*
Secondary agents:
Mineralocorticoid receptor antagonist Either of the following:
Spironolactone 12.5 to 25 mg dailyΔ 25 to 50 mg daily◊ Double the dose after 4 weeks§
Eplerenone 25 mg daily¥ 50 mg daily‡ Double the dose after 4 weeks§
Sodium-glucose cotransporter-2 inhibitor Either of the following:
Dapagliflozin 10 mg daily 10 mg daily Generally no uptitration is required
Empagliflozin 10 mg daily 10 mg daily Generally no uptitration is required
Soluble guanylate cyclase inhibitor Vericiguat 2.5 mg daily 10 mg daily Double the dose every 2 weeks
Selective sinus node inhibitor Ivabradine 2.5 to 5 mg twice daily† Titrate to heart rate of 50 to 60 bpm; maximum dose 7.5 mg twice daily Increase the dose at 2-week intervals**
Hydralazine plus nitrate Either fixed-dose combination or combined use of the two 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 mg isosorbide dinitrate 3 times daily and 25 mg hydralazine 3 times daily 40 mg isosorbide dinitrate 3 times daily and 75 mg hydralazine 3 times daily Increase the dose in 2 to 4 weeks
Cardiac glycoside Digoxin Typically 0.125 mg daily (ranges from 0.125 mg every other day to 0.25 mg per day)ΔΔ No target dose Generally no uptitration is required
The drug doses presented here are those suggested for patients who do not require dose adjustments due to factors such as comorbid illnesses, organ dysfunction, drug interactions, or other reasons. Consult a clinical drug reference, appropriate UpToDate topic reviews, and/or other resources to confirm there are no clinically significant drug interactions and to determine the appropriate dosing for a given patient.
HFrEF: heart failure with reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤40%); bpm: beats per minute.
* These are general suggestions for outpatient titration intervals. 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.
¶ The spironolactone doses in the table are for the tablet form. If spironolactone oral suspension is used, the initial dose is 10 to 20 mg once daily (consider a starting dose of 10 mg in patients at increased risk of hyperkalemia); target maximum dose is 37.5 mg once daily.
Δ If the eGFR is ≥50 mL/minute per 1.73 m2, the initial dose of spironolactone is 12.5 to 25 mg once daily. If the eGFR is 30 to 49 mL/minute per 1.73 m2, the initial dose of spironolactone is 12.5 mg once daily or every other day.
◊ If the eGFR is ≥50 mL/minute per 1.73 m2, the target dose of spironolactone is 25 to 50 mg once daily if serum potassium remains ≤5.0 meq/L. If the eGFR is 30 to 49 mL/minute per 1.73 m2, the target dose of spironolactone is 12.5 to 25 mg once daily if serum potassium remains ≤5.0 meq/L.
§ Drug titration requires periodic monitoring for drug interactions and adverse effects (eg, hyperkalemia). Electrolytes should be checked (eg, serum potassium, blood urea nitrogen, and serum creatinine) every 1 to 2 weeks after drug initiation or upward titration. Endocrine side effects of spironolactone include gynecomastia, breast pain, menstrual irregularities, impotence, and decreased libido; these side effects are much less common with eplerenone.
¥ If the eGFR is ≥50 mL/minute per 1.73 m2, the initial dose of eplerenone is 25 mg once daily. If the eGFR is 30 to 49 mL/minute per 1.73 m2, the initial dose of eplerenone is 25 mg every other day.
‡ If the eGFR is ≥50 mL/minute per 1.73 m2, the target dose of eplerenone is 50 mg once daily if serum potassium remains ≤5.0 meq/L. If the eGFR is 30 to 49 mL/minute per 1.73 m2, the target dose of eplerenone is 25 mg once daily if serum potassium remains ≤5.0 meq/L.
† The lower dose is used in patients with conduction defects or at risk for symptomatic bradycardia. Baseline assessment includes evaluation of heart rate on physical examination and 12-lead electrocardiogram. The patients should have no or minimal evidence of volume overload at the time of initiation of ivabradine.
** Monitoring includes follow-up of the patient's symptoms (including symptoms of bradycardia), heart rate, and blood pressure. The dose is adjusted every two weeks as tolerated to a maximum dose of 7.5 mg twice daily if the heart rate is >60 bpm. If the heart rate is 50 to 60 bpm, the dose is maintained. If the heart rate is <50 bpm or if the patient has symptoms or signs of bradycardia, the dose is decreased to 2.5 mg twice daily. The drug is discontinued if heart rate is <50 bpm or if the patient has symptoms or signs of bradycardia on 2.5 mg twice daily.
¶¶ Although direct evidence of efficacy is lacking, some clinicians prescribe isosorbide mononitrate (30 to 120 mg daily) in place of isosorbide dinitrate to improve compliance. The use of isosorbide mononitrate in this setting is not included in the 2017 American College of Cardiology/American Heart Association heart failure guideline update.
ΔΔ Digoxin dose is adjusted based upon the patient's renal function, ideal body weight, and the presence of concomitant medications that alter digoxin levels. A common strategy is to use standard initial dosing (particularly for individuals with ideal body weight, 61 to 80 kg) as follows: 0.125 mg per day for individuals with a creatinine clearance ≥30 mL/minute and 0.0625 per day (which can be given as 0.125 mg every other day) for individuals with a creatinine clearance <30 mL/minute. Refer to UpToDate content including a nomogram that may be helpful, particularly for patients with small or large body size or renal dysfunction.
Consensus is lacking on the role of routine monitoring of serum digoxin levels. Some experts do not routinely measure digoxin levels if low doses are used and there is no clinical evidence of toxicity. Alternatively, some experts routinely check a digoxin level after steady state is reached (which is 7 to 10 days for most patients and up to 3 weeks in patients with severe renal impairment). For patients with HFrEF, the target serum digoxin level for maximal efficacy and minimal risk of toxicity is between 0.5 and 0.8 ng/mL (0.64 to 1.0 nmol/L). The digoxin level should be monitored when there is worsening renal function.
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