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Congestive Heart Failure Microchapters
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Pathophysiology Systolic Dysfunction Diastolic Dysfunction HFpEF HFrEF
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Medical Therapy:
Summary
Acute Pharmacotherapy
Chronic Pharmacotherapy in HFpEF
Chronic Pharmacotherapy in HFrEF Diuretics ACE Inhibitors Angiotensin receptor blockers Aldosterone Antagonists Beta Blockers Ca Channel Blockers Nitrates Hydralazine Positive Inotropics Anticoagulants Angiotensin Receptor-Neprilysin Inhibitor Antiarrhythmic Drugs Nutritional Supplements Hormonal Therapies Drugs to Avoid Drug Interactions Treatment of underlying causes Associated conditions
Exercise Training
Surgical Therapy: Biventricular Pacing or Cardiac Resynchronization Therapy (CRT) Implantation of Intracardiac Defibrillator Ultrafiltration Cardiac Surgery Left Ventricular Assist Devices (LVADs) Cardiac Transplantation
ACC/AHA Guideline Recommendations Initial and Serial Evaluation of the HF Patient Hospitalized Patient Patients With a Prior MI Sudden Cardiac Death Prevention Surgical/Percutaneous/Transcather Interventional Treatments of HF Patients at high risk for developing heart failure (Stage A) Patients with cardiac structural abnormalities or remodeling who have not developed heart failure symptoms (Stage B) Patients with current or prior symptoms of heart failure (Stage C) Patients with refractory end-stage heart failure (Stage D) Coordinating Care for Patients With Chronic HF Quality Metrics/Performance Measures
Implementation of Practice Guidelines
Congestive heart failure end-of-life considerations
Specific Groups: Special Populations Patients who have concomitant disorders Obstructive Sleep Apnea in the Patient with CHF NSTEMI with Heart Failure and Cardiogenic Shock
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Management of patients with heart failure with reduced ejection fraction (HFrEF)

ARNi: Angiotensin Receptor-Neprilysin inhibitor; ACEi: Angiotensin-Converting Enzyme inhibitor; ARB: Angiotensin II Receptor Blocker; MRA: Mineralocorticoid Receptor Antagonist; SGLT2i: Sodium Glucose Cotransporter 2 inhibitors; ICD: Implantable Cardioverter-Defibrillator; CRT-D: Cardiac Resynchronization Therapy with Defibrillator; CRT-P: Cardiac Resynchronization Therapy with Pacemaker; MCS: Mechanical Circulatory Support; LVAD: Left Ventricular Assist Device

2022 AHA/ACC/HFSA Guidelines for the Management of Heart Failure

Stage C HFrEF (LVEF ≤40%)

Initial Assessment • Assess congestion/hemodynamics • Fluid overloaded → Diuretics (Class I)

Initiate Foundational GDMT (Class I) • ARNi / ACEi / ARB • Beta-Blocker • MRA • SGLT2i

Titrate GDMT to Target/Max Tolerated Dose • Monitor labs & vitals • Reassess Symptoms & LVEF

LVEF >40% HFimpEF Continue GDMT

LVEF ≤40% Persistent HFrEF

Additional Therapies • African American + NYHA III-IV → Hydralazine-Nitrates • NYHA I-III + LVEF ≤35% + Survival >1 yr → ICD • NYHA II-III + LVEF ≤35% + NSR + LBBB + QRS ≥150 ms → CRT-D • Consider: Ivabradine, Vericiguat, IV Iron

Reassess Symptoms & Status

Symptoms Improved Continue GDMT

Refractory HF (Stage D)

Advanced HF Management • HF Specialty Referral • Durable MCS / LVAD • Cardiac Transplant • Palliative Care

Treatment Algorithm for Guideline-Directed Medical Therapy Including Novel Therapies

Heart failure reduced EF, stage C, treatment

ARNI, ACEI, ARB

For patients with eGFR≥ 30 mL/min/1.73m² or creatinine≤ 2.5 mg/dL in males or ≤2 mg/dL in females or K≤ 5 mEq/L, NYHA 2-4

For patients with eGFR criteria, NYHA 2-4

For patients with persistent volume overload, NYHA 2-4

For symptomatic black patients despite receiving ARNI, betablocker,aldosterone antagonist, SGLT2 inhibitor, NYHA 3-4

For patients with resting HR>70/min despite maximum tolerated betablocker dose, sinus rhythm, NYHA 2-3

Add

Add

Titrate

Add

Add

Aldosterone antagonist

SGLT2 inhibitor

Diuretic agents

Hydralazine + Isosorbide dinitrate

Ivabradine

The above algorithm adopted from 2021 AHA/ACC Guideline

Management of patients with heart failure with preserved ejection fraction (HFrEF)

Abbreviations: ARNi: Angiotensin Receptor-Neprilysin inhibitor; ACEi: Angiotensin-Converting Enzyme inhibitor; ARB: Angiotensin II Receptor Blocker; MRA: Mineralocorticoid Receptor Antagonist; SGLT2i: Sodium Glucose Cotransporter 2 inhibitors

2022 AHA/ACC/HFSA Guidelines for the Management of Heart Failure

Symptomatic HF LVEF ≥50%

Diuretics, as needed (Class I)

SGLT2i (Class IIa)

ARNi* (Class IIb)

MRA* (Class IIb)

ARB* (Class IIb)

*Greater benefit in patients with LVEF closer to 50%.

Congestive heart failure treatment summary based on 2021 AHA/ACC Guideline

Pathophysiology	Treatment
Renin-angiotensin-aldosterone system	ARNIs/ACEIs/ARBs, aldosterone antagonist
Sympathetic nervous system	Beta-blockers
Natriuretic and other vasodilator peptides	Neprilysin inhibitor (ARNI)
Sodium-glucose cotransporter-2	SGLT2 inhibitors
Balanced vasodilation and oxidative stress modulation	Hydralazine/Isosorbide dinitrate
Elevated heart rate	Betablocker, Ivabradine
Guanylyl cyclase	Soluble guanylyl cyclase stimulator
Relief of congestion	Diuretic
Ventricul;ar arrhythmia	Implantable cardioverter defibrilator
Ventricular dyssynchrony due to conduction abnormalities	Cardiac resynchronization therapy
Mitral regurgitation	Surgical or percutaneous Mitral repair
Reduced aerobic capacity	Aerobic exercise training

The above table adopted from 2021 AHA/ACC Guideline

Initiation, Titration, and Monitoring of Guideline-Directed Medical Therapy in HFrEF

ACEi / ARB

ACEI / ARB

Initiate if ARNI is not accessible

Initiate dose based on indication

Titrate every 2 weeks to target/max tolerated dose with monitoring of blood pressure, renal function, and potassium

ARNi

ARNI

Initiate ≥36 hours after discontinuing ACEI

Initiate dose based on indication

24/26 mg twice daily if taking enalapril ≤10 mg/day or valsartan ≤160 mg/day

49/51 mg twice daily if taking enalapril >10 mg/day or valsartan >160 mg/day

Reassess in 2 weeks for tolerance, blood pressure, electrolytes, and renal function then titrate to 97/103 mg twice daily

Beta-blocker

Beta blocker

Initiate dose based on indication

Titrate every 2 weeks to target/max tolerated dose with monitoring of heart rate and blood pressure

Mineralocorticoid Receptor Antagonist

MRA

Initiate dose based on indication

Titrate every 2 weeks to target/max tolerated dose with monitoring of electrolytes, renal function, and clinical status

SGLT2 Inhibitor

SGLT2 inhibitor

Initiate dose based on indication

Initiate dapagliflozin if eGFR ≥30 mL/min/1.73 m² or empagliflozin if eGFR ≥20 mL/min/1.73 m²

Diuretic

Diuretic

Initiate loop diuretic dose based on renal function and prior diuretic use

Titrate dose until recovery of congestion with monitoring of blood pressure, renal function, and electrolytes

If persistent congestion on high-dose loop diuretic, consider alternative loop diuretic or add thiazide diuretic

Hydralazine / Isosorbide Dinitrate

Hydralazine / isosorbide dinitrate

Titrate every 2 weeks to target/max tolerated dose with monitoring of blood pressure

Drug-Specific Considerations

Sacubitril/Valsartan	Ivabradine	SGLT2 Inhibitors
Indications HFrEF (EF ≤40%) NYHA class II–IV HF Use with background GDMT Used in place of an ACEI or ARB when feasible	Indications Heart failure with reduced EF (≤35%) On maximum tolerated dose of beta-blocker Sinus rhythm with resting heart rate ≥70 beats/min NYHA class II or III HF	Indications HFrEF (EF ≤40%) with or without diabetes NYHA class II–IV HF Combined with other treatment of heart failure
Contraindications Within 36 hours of ACEI use History of angioedema with or without an ACEI or ARB Pregnancy Lactation (no data) Severe hepatic impairment (Child-Pugh C) Concomitant aliskiren use in patients with diabetes Known hypersensitivity to either ARBs or ARNIs	Contraindications HFpEF Presence of angina with normal EF Hypersensitivity Severe hepatic impairment (Child-Pugh C) Acute decompensated HF Blood pressure <90/50 mm Hg Sick sinus syndrome without a pacemaker Sinoatrial node block 2nd or 3rd degree block without a pacemaker Resting heart rate <60 beats/min Persistent AF or atrial flutter Atrial pacemaker dependence	Contraindications Not approved for use in patients with type I diabetes due to increased risk of diabetic ketoacidosis Known hypersensitivity to drug Lactation (no data) On dialysis
Cautions Renal impairment: Mild-to-moderate (eGFR 30-59 mL/min/1.73 m2): no starting dose adjustment required Severe (eGFR <30 mL/min/1.73 m2): Reduce starting dose to 24/26 mg twice daily Double dose every 2–4 weeks to target maintenance dose of 97/103 mg twice daily as tolerated Hepatic impairment: Mild (Child-Pugh A): no starting dose adjustment required Moderate (Child-Pugh B): Reduce starting dose to 24/26 mg twice daily Double dose every 2–4 weeks to target maintenance dose of 97/103 mg twice daily as tolerated Renal artery stenosis Systolic blood pressure <100 mm Hg Volume depletion	Cautions Sinus node disease Cardiac conduction defects Prolonged QT interval	Cautions For HF care, dapagliflozin in eGFR <30 mL/min/1.73 m2 For HF care, empagliflozin in eGFR <20 mL/min/1.73 m2 Pregnancy Increased risk of mycotic genital infections May contribute to volume depletion, altering diuretic dose if applicable For prevention of ketoacidosis in patients with diabetes: Temporary discontinuation before scheduled surgery Assess patients presenting with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level For prevention of acute kidney injury and renal impairment: Temporarily discontinue in settings of reduced oral intake or fluid losses Urosepsis and pyelonephritis: Evaluate for signs and symptoms of urinary tract infections and treat appropriately Necrotizing fasciitis of the perineum (Fournier’s gangrene): Rare but life-threatening; assess for pain, erythema, swelling, fever, or malaise

The above table adopted from 2021 AHA/ACC Guideline

Ivabradine

Given Betablocker by maximum tolerable dose, sinus rhythm on ECG

Starting dose

Age ≥ 75 years, 2.5 mg twice daily with food

Age <75 years, 5 mg twice daily with food

Evaluation of heart rate in 2-4 weeks

Heart rate < 50 beats /min or symptoms of bradycardia

Heart rate 50-60 beats/ min

Heart rate>60 beats /min

Reduced dose 2.5 mg twice daily with food, or discontinued if already on 2.5 mg twice daily

Maintaing current dose with monitoring heart rate

Increased dose by 2.5 mg twice daily until maximum dose of 7.5 mg twice daily, monitoring heart rate

• Starting dose of Ivabradine

  If the patient taking maximum tolerated dose of betablocker but resting heart rate ≥ 70 beat/min , Ivabradine 5 mg twice a day with food is recommended.

  In the presence of conduction abnormality, age≥ 75 years, Ivabradine 2.5 mg twice a day with food is considered.

References

Congestive Heart Failure Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology Systolic Dysfunction Diastolic Dysfunction HFpEF HFrEF
Causes
Differentiating Congestive heart failure from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Clinical Assessment
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
Chest X Ray
Cardiac MRI
Echocardiography
Exercise Stress Test
Myocardial Viability Studies
Cardiac Catheterization
Other Imaging Studies
Other Diagnostic Studies
Treatment
Invasive Hemodynamic Monitoring
Medical Therapy:
Summary
Acute Pharmacotherapy
Chronic Pharmacotherapy in HFpEF
Chronic Pharmacotherapy in HFrEF Diuretics ACE Inhibitors Angiotensin receptor blockers Aldosterone Antagonists Beta Blockers Ca Channel Blockers Nitrates Hydralazine Positive Inotropics Anticoagulants Angiotensin Receptor-Neprilysin Inhibitor Antiarrhythmic Drugs Nutritional Supplements Hormonal Therapies Drugs to Avoid Drug Interactions Treatment of underlying causes Associated conditions
Exercise Training
Surgical Therapy: Biventricular Pacing or Cardiac Resynchronization Therapy (CRT) Implantation of Intracardiac Defibrillator Ultrafiltration Cardiac Surgery Left Ventricular Assist Devices (LVADs) Cardiac Transplantation
ACC/AHA Guideline Recommendations Initial and Serial Evaluation of the HF Patient Hospitalized Patient Patients With a Prior MI Sudden Cardiac Death Prevention Surgical/Percutaneous/Transcather Interventional Treatments of HF Patients at high risk for developing heart failure (Stage A) Patients with cardiac structural abnormalities or remodeling who have not developed heart failure symptoms (Stage B) Patients with current or prior symptoms of heart failure (Stage C) Patients with refractory end-stage heart failure (Stage D) Coordinating Care for Patients With Chronic HF Quality Metrics/Performance Measures
Implementation of Practice Guidelines
Congestive heart failure end-of-life considerations
Specific Groups: Special Populations Patients who have concomitant disorders Obstructive Sleep Apnea in the Patient with CHF NSTEMI with Heart Failure and Cardiogenic Shock
Sandbox On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Sandbox
CDC on Sandbox
Sandbox in the news
Blogs on Sandbox
Directions to Hospitals Treating Sandbox
Risk calculators and risk factors for Sandbox

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Zand, M.D.[2] Rim Halaby, M.D. [3]

Overview

Pharmacotherapy is the mainstay of therapy for heart failure with reduced ejection fraction (HFrEF) and should be initiated before considering device therapy.Three major goals of therapy for patients with HFrEF including reduction in mortality, prevention of hospitalization due to worsening HF, and improvement in clinical status. Suppression of renin-angiotensin-aldosterone (RAAS) and sympathetic nervous systems with angiotensin-converting enzyme inhibitors (ACE-I) or an angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers, and mineralocorticoid receptor antagonists (MRA) have been shown to improve survival, reducing the risk of HF hospitalizations, and reducing symptoms in patients with HFrEF. ACE-I/ARNI, a beta-blocker, and an MRA are recommended as cornerstone therapies for these patients, unless the drugs are not tolerated or contraindicated. 2021 ESC Guideline recommends the use of ARNI as a replacement for ACE-I in symptomatic patients with ACE-I, beta-blocker, and MRA therapies. ARNI may be considered as a first-line therapy instead of an ACE-I. Angiotensin-receptor blockers (ARBs) are recommended in patients intolerant to ACEI or ARNI. The sodium-glucose co-transporter 2 (SGLT2) inhibitors including dapagliflozin and empagliflozin added to therapy with ACE-I/ ARNI/ beta-blocker/ MRA to reduce the risk of cardiovascular death and worsening HF in patients with HFrEF.

Starting and target doses of medications and novel therapies for heart failure

Betablockers	Starting dose	Target dose
Bisoprolol	1.25 mg once daily	10 mg once daily
Carvedilol	3.125 mg twice daily	25 mg twice daily for weight <85 kg and 50 mg twice daily for weight≥ 85 kg
Metoprolol succinate	12.5–25 mg daily	200 mg daily
ARNIs
Sacubitril/valsartan	24/26 mg–49/51 mg twice daily	97/103 mg twice daily
ACEI
Captopril	6.25 mg 3× daily	50 mg 3× daily
Enalapril	2.5 mg twice daily	10–20 mg twice daily
Lisinopril	2.5–5 mg daily	20–40 mg daily
Ramipril	1.25 mg daily	10 mg daily
ARBs
Candesartan	4–8 mg daily	32 mg daily
Losartan	25–50 mg daily	150 mg daily
Valsartan	40 mg twice daily	160 mg twice daily
Aldosterone antagonists
Eplerenone	25 mg daily	50 mg daily
Spironolactone	12.5–25 mg daily	25–50 mg daily
SGL2 ihibitors
Dapagliflozin 10 mg daily	10 mg daily	10 mg daily
Empagliflozin	10 mg daily	10 mg daily
Vasodilators
Hydralazine	25 mg 3× daily	75 mg 3× daily
Isosorbide dinitrate	20 mg 3× daily	40 mg 3× daily
Fixed-dose combination isosorbide dinitrate/hydralazine	20 mg/37.5 mg (1 tab) 3× daily	2 tabs 3× daily
Ivabradine
Ivabradine	2.5–5 mg twice daily	Titrate to heart rate 50–60 beats/min, Maximum dose 7.5 mg twice daily

The above table adopted from 2021 AHA/ACC Guideline

Drugs recommended in all patients with heart failure with reduced ejection fraction

Medications indicated in patients with New York Heart Association (NYHA class II–IV) heart failure with reduced ejection fraction (LVEF ≤ 40%)

Recommendations for HFrEF (2022 AHA/ACC/HFSA Guidelines)

ARNi / ACEi / ARB (Class I; Level of Evidence A):

❑ In patients with HFrEF and NYHA class II to III symptoms, the use of ARNi is recommended to reduce morbidity and mortality. ❑ 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. ❑ 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.

ARNi replacement therapy (Class I; Level of Evidence B-R):

❑ 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.

Beta blockers (Class I; Level of Evidence A):

❑ In patients with HFrEF, with current or previous symptoms, use of 1 of the 3 beta blockers proven to reduce mortality (bisoprolol, carvedilol, or sustained-release metoprolol succinate) is recommended to reduce mortality and hospitalizations.

Mineralocorticoid Receptor Antagonists (Class I; Level of Evidence A):

❑ In patients with HFrEF and NYHA class II to IV symptoms, an MRA (spironolactone or eplerenone) is recommended to reduce morbidity and mortality, if eGFR is >30 mL/min/1.73 m² and serum potassium is <5.0 mEq/L. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely monitored thereafter to minimize risk of hyperkalemia and renal insufficiency.

SGLT2 Inhibitors (Class I; Level of Evidence A):

❑ 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.

The above table adopted from 2022 AHA/ACC/HFSA Guidelines

Recommendations for HFrEF (2021 ESC Guidelines)

(Class I, Level of Evidence A):

❑ ACE-I is recommended for patients with HFrEF to reduce the risk of HF hospitalization and death ❑ Beta-blocker is recommended for patients with stable HFrEF to reduce the risk of HF hospitalization and death ❑ MRA (Mineralocorticoid receptor antagonist) is recommended for patients with HFrEF to reduce the risk of HF hospitalization and death ❑ Dapagliflozin or empagliflozin are recommended for patients with HFrEF to reduce the risk of HF hospitalization and death

(Class I, Level of Evidence B):

❑ Sacubitril/valsartan is recommended as a replacement for an ACE-I in patients with HFrEF to reduce the risk of HF hospitalization and death

The above table adopted from 2021 ESC Guideline

Renin-Angiotensin System inhibition (ARNI / ACEi / ARB)

• Inhibition of the renin-angiotensin system is recommended to reduce morbidity and mortality for patients with HFrEF.
• ARNi, ACEi, or ARB are all recommended as first-line therapies, with ARNI preferred when feasible.
• If patients have chronic symptomatic HFrEF with NYHA class II or III symptoms and currently tolerate an ACEi or ARB, they should be switched to an ARNi to further improve morbidity and mortality.
• ARNi is recommended as a de novo treatment for hospitalized patients with acute HF prior to discharge.
• Benefits of ARNi over ACEi/ARB include improved health status, reduction in the prognostic biomarker NT-proBNP, and improvement in LV remodeling parameters.
• ARB is recommended when ACEi intolerant due to cough/angioedema and ARNI not feasible.
• When switching a patient from an ACEi to an ARNi, a strict washout period of at least 36 hours between doses is required.

Beta-blockers

• Treatment with beta-blockers reduces the risk of death and the combined risk of death or hospitalization in patients with HFrEF.
• Therapy should be initiated in all patients with HFrEF, including hospitalized patients once clinically stable, unless contraindicated or not tolerated.
• Initiation of a beta-blocker before an ACE-I and vice versa are not recommended.
• Beta-blockers should be initiated in clinically stable, euvolaemic, patients at a low dose and gradually titrated to the maximum tolerated dose.
• After stability of hemodynamic in patients admitted with acute heart failure, beta-blockers should be cautiously initiated in hospital
• Use of betablocker in patients with HFrEF with AF was not associated with reduction in mortality or hospital admission.

MRA or Mineralocorticoid receptor antagonists

• MRAs (spironolactone or eplerenone) show consistent improvements in all cause mortality, HF hospitalizations and sudden cardiac death across a wide range of patients with HFrEF.
• Patients at risk of renal dysfunction or hyperkalemia require close monitoring during therapy.
• An eGFR ≤ 30 mL/min/1.73 m2 or serum potassium ≥ 5.0 mEq/L are strict contraindications to initiating MRA therapy.
• Due to the higher selectivity of eplerenone for the aldosterone receptor, adverse effects such as gynecomastia are observed much less frequently compared to patients taking spironolactone.
• MRAs block receptors that bind aldosterone and also other steroid hormones (corticosteroid and androgen) receptors.

Sodium-glucose co-transporter 2 inhibitors

• In symptomatic chronic HFrEF, SGLT2 inhibitors are recommended to reduce HF hospitalization and cardiovascular mortality irrespective of diabetes status.
• The result of DAPA-HF trial showed the long-term effects of dapagliflozin (SGLT2 inhibitor) compared to placebo in addition to optimal medical therapy (OMT), on morbidity and mortality in patients with NYHA class II-IV, and had an LVEF≤ 40%.
• Elevated plasma NT-proBNP and an eGFR >_30 mL/min/1.73 m2 were needed to initiation of therapy.
• Benefits of dapagliflozin in heart failure including:

• Reduction in worsening HF (hospitalization)
• Reduction in cardiovascular death.
• Reduction in all-cause mortality
• Alleviated HF symptomS
• Improvement of physical function and quality of life in patients with symptomatic HFrEF

• Benefits were seen early after the initiation of dapagliflozin.
• Survival benefits were seen in patients with HFrEF with and without diabetes.
• EMPEROR-Reduced trial investigated that empagliflozin reduced the combined primary endpoint of CV death or HF hospitalization by 25% in patients with NYHA class II-IV symptoms, and an LVEF <_40% despiteOMT and eGFR >20 mL/min/1.73 m2.
• Reduction in the decline in eGFR and improvement in quality of life among patients receiving empagliflozin were also found.
• Dapagliflozin or empagliflozin are recommended, in addition to OMT with an ACE-I/ARNI, a beta-blocker and an MRA, for patients with HFrEF regardless of diabetes status.
• The need for diuretic may be reduced due to The diuretic/natriuretic properties of SGLT2 inhibitors and reducing congestion.
• The combined SGLT-1 and SGLT-2 inhibitors, sotagliflozin, has also been investigated in patients with diabetes who were hospitalized with HF.
• Side effects of SGLT2 inhibitors including:
• Increased risk of recurrent genital fungal infections
• A small reversible reduction in eGFR following initiation

Angiotensin receptor-neprilysin inhibitor

• In the PARADIGM-HF trial, sacubitril/valsartan, an ARNI, was superior to enalapril in reducing hospitalizations for worsening HF, cardiovascular mortality, and all-cause mortality in patients with ambulatory HFrEF with LVEF ≤ 40% (changed to <_35% during the study).
• Patients with elevated plasma NP concentrations, an eGFR≥ 30 mL/min/1.73 m2 and were able to tolerate enalapril and then sacubitril/valsartan.
• Use of sacubitril/valsartan was associated with improvement in symptoms and quality of life a reduction in the incidence of diabetes requiring insulin treatment,

and a reduction in the decline in eGFR as well as a reduced rate of hyperkalemia.

• In addition, the need for loop diuretic reduced while using of sacubitril/valsartan.
• Common side effect of sacubitril/valsartan is symptomatic hypotension as compared to enalapril, but despite developing hypotension, these patients also gained clinical benefits from sacubitril/valsartan therapy.
• The recommendation is that an ACE-I or ARB is replaced by sacubitril/valsartan in ambulatory patients with HFrEF, who remain symptomatic despite optimal treatment.
• Two studies have shown the use of ARNI in hospitalized patients with adequate blood pressure (BP), and an eGFR >_30 mL/min/1.73 m2, without previously treated with ACE-I, was associated with reduced subsequent cardiovascular death or HF hospitalizations.

Medications with reducing mortality in heart failure reduced EF

• ACE-I/ARNI, betablocker, mineralocorticoid receptos antagonist, SGLT2 inhibitor

Medications with reducing hospitalization in heart failure reduced EF

• Diuretic, digoxin, ivabradine, hydralazine, isosorbide dinitrate

Other medications in HFrEF in patients with NYHA 2-4

Recommendations for HFrEF (2022 AHA/ACC/HFSA Guidelines)

Diuretics (Class I; Level of Evidence B-NR):

❑ Diuretics are recommended to relieve congestion, improve symptoms, and prevent worsening HF. ❑ In patients with HF and persistent congestive symptoms, addition of a thiazide-type diuretic (e.g., metolazone) to loop diuretic therapy should be reserved for patients who do not respond to moderate- or high-dose loop diuretics to minimize electrolyte abnormalities.

Hydralazine and Isosorbide dinitrate (Class I; Level of Evidence A):

❑ In self-identified African American patients with NYHA class III-IV HFrEF receiving optimal medical therapy, the combination of hydralazine and isosorbide dinitrate is recommended to improve symptoms and reduce morbidity and mortality.

Hydralazine and Isosorbide dinitrate (Class IIb; Level of Evidence C-LD):

❑ In patients with current or previous symptomatic HFrEF who cannot be given first-line agents such as ARNi, ACEi, or ARB because of drug intolerance or renal insufficiency, the combination of hydralazine and isosorbide dinitrate might be considered to reduce morbidity and mortality.

Ivabradine (Class IIa; Level of Evidence B-R):

❑ In patients with symptomatic (NYHA class II-III) stable chronic HFrEF with LVEF ≤35% who are receiving guideline-directed medical therapy including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a resting heart rate ≥70 bpm, ivabradine can be beneficial to reduce HF hospitalizations and cardiovascular death.

Digoxin (Class IIb; Level of Evidence B-R):

❑ In patients with symptomatic HFrEF despite guideline-directed medical therapy (or who are unable to tolerate GDMT), digoxin might be considered to decrease hospitalizations for HF.

Vericiguat (Class IIb; Level of Evidence B-R):

❑ In selected high-risk patients with HFrEF and recent worsening of HF already on guideline-directed medical therapy, an oral soluble guanylate cyclase stimulator (vericiguat) may be considered to reduce HF hospitalization and cardiovascular death.

The above table adopted from 2022 AHA/ACC/HFSA Guidelines

Recommendations for HFrEF (2021 ESC Guidelines)

Loop diuretics (Class I, Level of Evidence C):

❑ Loop diuretics are recommended in patients with HFrEF with signs and/or symptoms of congestion to improve HF symptoms, exercise capacity, and reduce HF hospitalizations

ARB (Class I, Level of Evidence B):

❑ ARB is recommended in symptomatic patients to reduce the risk of HF hospitalization and cardiovascular death for whom unable to tolerate an ACE-I or ARNI (patients should also receive a beta-blocker and MRA)

If-channel inhibitor :(Class IIa, Level of Evidence B) :

❑Ivabradine should be considered in symptomatic patients with LVEF ≤35%, sinus rhythm on ECG and a resting heart rate≥ 70 b.p.m despite treatment with maximum tolerated beta-blocker, ACE-I/(or ARNI), and an MRA, to reduce the risk of HF hospitalization and cardiovascular death

If-channel inhibitor : (Class IIa, Level of Evidence C)

❑ Ivabradine should be considered in symptomatic patients with LVEF≤ 35%, in sinus rhythm and a resting heart rate≥ 70 b.p.m. when can not tolerate or have contraindications for a beta-blocker, for reduction the risk of HF hospitalization and cardiovascular death. Patients should also receive an ACE-I (or ARNI) and MRA

Soluble guanylate cyclase receptor stimulator: (Class IIb, Level of Evidence B)

❑ Vericiguat may be considered in patients in NYHA class II-IV with worsening HF despite therapy with an ACE-I (or ARNI), a beta-blocker and MRA to reduce the risk of cardiovascular death or HF hospitalization

Hydralazine, isosorbide dinitrate : (Class IIa, Level of Evidence B)

❑ Hydralazine and isosorbide dinitrate should be considered in black patients with LVEF ≤35% or with an LVEF<45% combined with a dilated left ventricle in NYHA class III-IV despite therapy with an ACE-I (or ARNI), a beta-blocker and an MRA to reduce the risk of HF hospitalization and death.1

Hydralazine, isosorbide dinitrate (Class IIb, Level of Evidence B):

❑ Hydralazine and isosorbide dinitrate may be considered in patients with symptomatic HFrEF who unable to tolerate any of an ACE-I, an ARB, or ARNI (or they are contraindicated) to reduce the risk of death

Digoxin: (ClassIIb, Level of Evidence B)

❑ Digoxin may be considered in patients with symptomatic HFrEF in sinus rhythm despite treating with an ACE-I (or ARNI), a beta- blocker and an MRA, to reduce the risk of hospitalization (both all-cause and HF hospitalizations)

The above table adopted from 2021 ESC Guideline

Diuretics

• Loop diuretics is recommended to reduce the signs and/or symptoms of congestion in patients with HFrEF.
• The effects of diuretics on morbidity and mortality have not been studied in RCTs.
• Loop diuretics and thiazide diuretics appear to reduce the risk of death and worsening HF compared with a placebo.
• Diuretics can improve exercise capacity.
• Loop diuretics and thiazides act synergistically and may be used to treat diuretic resistance.
• ARNI, MRAs, and SGLT2 inhibitors may also possess diuretic properties.
• Maintaining the euvolemia state is the aim of diuretic therapy with the lowest doses.
• Patients should be trained to self-adjust their diuretic dose based on monitoring of symptoms/signs of congestion and daily weight measurements.

Angiotensin II type I receptor blockers

• ARBs are recommended for patients who cannot tolerate ACE-I or ARNI because of serious side effects.
• CHARM-Alternative study showed candesartan reduced cardiovascular deaths and HF hospitalizations in patients who were not receiving an ACE-I due to previous intolerance.
• In the Val-HeFT trial, Valsartan, in addition to usual therapy, including ACE-I, reduced HF hospitalizations.
• ARBs have not reduced all-cause mortality in any trial.

If -channel inhibitor

• Ivabradine slows heart rate by inhibition of the If channel in the sinus node only in patients with sinus rhythm.
• Ivabradine reduced cardiovascular mortality and HF hospitalization in patients with symptomatic HFrEF with an LVEF <_35%, with HF hospitalization in recent 12 months, in sinus rhythm (SR) and with a heart rate≥70 b.p.m.
• Ivabradine has survival benefit.
• Before to considering ivabradine, uptitrate beta-blocker therapy to maximally tolerated doses is recommended.

Combination of hydralazine and isosorbide dinitrate

• In black patients with HFrEF and NYHA classes III-IV, combination of hydralazine and isosorbide dinitrate to conventional therapy (an ACE-I, a beta-blocker, and an MRA) reduced mortality and HF hospitalizations.
• In symptomatic patients with HFrEF who cannot tolerate any of an ACE-I, ARNI, or an ARB (or if they are contraindicated), combination of hydralazine and isosorbide dinitrate may be considered to reduce mortality.

Digoxin

• Digoxin may be considered in patients with HFrEF in sinus rhythm to reduce the risk of hospitalization.
• In the DIG trial, digoxin was not effective on mortality.
• The effects of digoxin in patients with HFrEF and AF have not been studied in RCTs. However, higher risk of events were observed in patients with AF receiving digoxin.
• Another meta-analysis concluded that digoxin has no deleterious effect on mortality in patients with AF and HFrEF.
• So, in patients with symptomatic HF and AF, digoxin may be useful for the treatment of patients with HFrEF and AF with rapid ventricular rate, when other therapeutic options are failed.
• Digoxin has a narrow therapeutic window and so levels should be checked for maintaing a serum digoxin concentration <1.2 ng/mL.
• Caution should also be exercised in patients as followes:

• Females
• The elderly
• Frail
• Hypokalaemia
• Malnourishment
• Reduced renal function

Soluble guanylate cyclase receptor stimulator

• The VICTORIA study investigated the efficacy and safety of the oral soluble guanylate cyclase receptor stimulator, vericiguat, in patients with HFrEF and recently decompensated CHF.
• Use of vericiguat was associated with reduced hospitalization. However, there were no reduction in all-cause or cardiovascular mortality.
• Vericiguat may be considered, in addition to standard therapy for HFrEF, to reduce the risk of cardiovascular mortality and hospitalizations for HF.

Cardiac myosin activator

• the efficacy and safety of the cardiac myosin activator, omecamtiv mecarbil, in HFrEF patients, was assessed by The GALACTIC-HF study.
• There was no significant reduction in cardiovascular mortality.
• Currently, there is no license for use of this drug.
• This drug may be considered in the future in addition to standard therapy for HFrEF to reduce the risk of cardiovascular mortality and hospitalization.

Management of chronic heart failure

Intensification 2-4 months, (1-4 weeks cycles)

• In the presence of volume overload, adjusting diuretic dose and reevaluation in 1-2 weeks
• In the setting of stable euvolumic status, medications initiation, increase, switch dose and follow-up in 1-2 weeks and checking basic metabolites panel, repeating cycles until no change in clinical status and reached appropriate titration

Assessment of response to medications and cardiac remodeling

• Repeating BNP, pro BNP and basic metabolic panel
• Pepeating ECG, Echocardiography
• Refferal eligible patients to electrophysiology specialist for CRT or ICD implantation

Lack of response, instability

• Referral to advanced heart failure specialist if there are:
• Use of IV inotropes
• NYHA 3B, 4, or persistently high level of natrioretic peptide
• End organ dysfunction
• LVEF ≤ 35%
• Defibrillator shocks
• Hospitalization > 1 day
• Edema despite increase dose of diuretics
• Low blood pressure, high heart rate
• Intolerance to medications

Assessment of response to medications

• Repeating laboratory tests such as NT pro BNP, BNP, electrolytes
• Repeating ECG
• Repeating echocardiography for evaluation of structure, function
• Referral to electrophysiologic for implantation of ICD, CRT in eligible patients