Congestive heart failure chronic pharmacotherapy

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Congestive Heart Failure Microchapters
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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
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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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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Overview

There are several goals in the chronic management of systolic heart failure. The management of diastolic heart failure is discussed elsewhere. One goal of therapy is to improve the patient's symptoms, exercise tolerance and quality of life. Diuretics, along with regular assessment of the patient's weight, minimizes fluid accumulation and the accompanying symptoms of dyspnea and orthopnea. Another goal is to reduce hospitalization and mortality. To achieve the second goal, patients with chronic heart failure should be administered an ACE inhibitor (or ARB if they are ACE intolerant) and a beta blocker. If the patient remains symptomatic, additional therapy may include an aldosterone antagonist.

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 screening sleep apnea in patients with bradycardia or conduction disorder

(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

Other medications in HFrEF in patients with NYHA 2-4

Recommendations for heart failure with reduced ejection fraction and NYHA 2-4

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. who are unable to tolerate or have contraindications for a beta-blocker to reduce the risk of HF hospitalization and CV 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

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

Drugs recommended in all patients with heart failure with reduced ejection fraction (HFrEF)

Angiotensin-converting enzyme inhibitors

• ACE-Is are the first class of drugs that reduce mortality and morbidity in patients with HFrEF and improve symptoms.
• ACEI should be Uptitrated to the maximum tolerated recommended dose.

Beta-blockers

• Beta-blockers can reduce mortality and morbidity in patients with HFrEF, in addition to treatment with an ACE-I and diuretic and also improve symptoms.
• In symptomatic heart failure, ACE-I and beta-blockers can be used in combination.
• 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

• In all patients with HFrEF, MRAs (spironolactone or eplerenone) are recommended, in addition to an ACE-I and a beta-blocker, to reduce mortality and the risk of heart failure hospitalization.
• MRAs improve symptoms.
• MRAs block receptors that bind aldosterone and also other steroid hormones (corticosteroid and androgen) receptors.
• Eplerenone is more specific for aldosterone blockade and, therefore, causes less gynaecomastia.
• In patients with impaired renal function and in those with serum potassium concentrations >5.0 mmol/L, MRA should be used with causion.

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.

Sodium-glucose co-transporter 2 inhibitors

• 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

Beta blockers: Third Step in the Management of Heart Failure

Beta blockers reduce the heart rate which lowers the myocardial energy expenditure. They also prolong diastolic filling and lengthen the period of coronary perfusion. Beta blockers can also decrease the toxicity of catecholamines on the myocardium.

Once you have achieved a stable dose of a diuretic and an ACE inhibitor, then one of the three beta blockers that have been associated with improved survival (carvedilol, metoprolol succinate or bisoprolol) can be added and the dose titrated based upon the patient's tolerance. You should avoid beta-blockers with intrinsic sympathomimetic activity (pindolol or acebutolol). It should be noted that the 35% reduction in one year mortality observed in meta-analyses of beta-blockers in heart failure was when these drugs were added to ACE inhibitors. There are no direct comparisons of the various beta-blockers, but some data does suggest that carvedilol may improve LVEF more than the others, but it may not be as well tolerated due to its vasodilatory properties. If the patient has been over diuresed, they may not tolerate the addition of a beta blocker.

Relative contraindications to beta-blocker administration include the following:

• Asthma or bronchospasm
• Hypotension resulting in poor end organ perfusion or symptoms
• Bradycardia or heart block (first degree heart block with a PR interval > 0.24, second degree heart block, third degree heart block
• Peripheral arterial disease with limb ischemia at rest
• Moderate or greater peripheral edema
• Recent intravenous inotropic therapy

Given the potential for hemodynamic decompensation, the initiation of beta-blockers is best undertaken by an individual or center specializing in heart failure management. The patient should be aware of potential side effects, and should be aware that it may take one to three months for the beta-blockers to improve heart failure symptoms. Therapy is initiated with very low doses, and the dose of the beta-blocker should be doubled every two weeks until the target dose is achieved or symptoms prevent further dose escalation.

• Carvedilol: Initial dose 3.125 mg twice daily, target dose 25 to 50 mg twice daily
• Metoprolol succinate: Initial dose 12.5 mg daily, target dose 200 mg daily
• Bisoprolol: Initial dose 1.25 mg daily, target dose 5 to 10 mg daily

Weight gain or peripheral edema that is not responsive to diuresis may require a reduction in the dose of beta-blockers.

Aldosterone Antagonism: Fourth Step in the Management of Heart Failure

An aldosterone antagonist can be added to the regimen of 'select' patients. These selected patients include:

• Class III/IV heart failure and a LVEF <35%
• Class II heart failure and a left ventricular ejection fraction (LVEF) < 30%
• Post ST segment elevation MI and a LVEF < 40% who have either symptomatic heart failure or diabetes.
• The serum potassium must be under 5.0 meq/li and the glomerular filtration rate (GFR) should be > 30 cc per minute

A requirement for aldosterone antagonist is that the patient's renal function and potassium can be carefully monitored. Eplerenone has fewer endocrine side effects (1%) than spironolactone (10%), but is more costly. A reasonable strategy is to initiate therapy with spironolactone at a dose of 25 to 50 mg daily, and then switch to eplerenone at a dose of 25 to 50 mg daily if endocrine side effects develop.

Risk Factors for the Development of Hyperkalemia on an Aldosterone Antagonist

• Triple therapy with an ACE inhibitor and angiotensin II receptor blocker makes this combination a contraindication
• Higher doses of either an ACE inhibitor or an angiotensin receptor blocker (ARB)
• Hyperkalemia prior to initiation of spironolactone
• Comorbidities such as diabetes and chronic renal insufficiency
• Higher NYHA heart failure class
• Concomitant administration of beta blockers, nonsteroidal anti-inflammatory drugs (NSAIDs) or potassium supplements
• A daily dose of Spironolactone greater than 50 mg

The Combination of Hydralazine and a Nitrate: Fifth step in the Management of Heart Failure

The combination of hydralazine and a nitrate (particularly among black patients) can be added if the patient continues to have symptoms on a diuretic, ACE inhibitor (or ARB in the intolerant patient) and a beta blocker. The initial dose is isosorbide dinitrate 20 mg three times a day along with hydralazine 25 mg three times a day. The dose(s) can be increased every 2 to 4 weeks to a target dose of isosorbide dinitrate 40 mg three times a day and hydralazine 75 mg three times a day.

Digoxin: Sixth step in the Management of Heart Failure

Digitalis can strengthen the contractility of the heart and can also be useful to achieve rate control in patients with heart failure who also have atrial fibrillation. In the DIG trial, digoxin reduced the rate of re-hospitalization but did not improve mortality among all patients enrolled in the trial. However, in a retrospective analysis, mortality was reduced in male patients who had digoxin levels between 0.5 and 0.8 ng/mL and was increased in male patients with digoxin levels > 1.2 ng/ml. A similar trend was observed among women patients: there was a trend towards lower mortality at digoxin concentrations between 0.5 to 0.9 ng/ml, but significantly higher mortality at digoxin concentrations > 1.2 ng/ml.

Digoxin should not be used as primary therapy for congestive heart failure. The administration of digoxin is reasonable in patients with NYHA class II-IV heart failure symptoms who have an LVEF of < 40% despite treatment with diuretics, angiotensin-converting enzyme inhibitors, beta blockers, and an aldosterone antagonist. Small doses of 0.125 mg per day of digoxin are often effective in maintaining a serum digoxin level between 0.5 and 0.8 ng/ml.

Shown below is an image that summarizes the steps in the chronic management of patients with heart failure.

Management of chronic heart failure