Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Primary options
captopril: 6.25 to 50 mg orally three times daily
OR
enalapril: 2.5 to 20 mg orally twice daily
OR
fosinopril: 5-40 mg orally once daily
OR
lisinopril: 2.5 to 40 mg orally once daily
OR
perindopril: 2-16 mg orally once daily
OR
quinapril: 5-20 mg orally twice daily
OR
ramipril: 1.25 to 10 mg orally once daily
OR
trandolapril: 1-4 mg orally once daily
OR
sacubitril/valsartan: treatment-naive patients: 24 mg (sacubitril)/26 mg (valsartan) orally twice daily initially, increase gradually according to response, maximum 97 mg (sacubitril)/103 mg (valsartan); treatment-experienced: 49 mg (sacubitril)/51 mg (valsartan) orally twice daily initially, increase gradually according to response, maximum 97 mg (sacubitril)/103 mg (valsartan)
MoreACE inhibitors have been shown to decrease the morbidity and mortality associated with heart failure, and should be given to all patients with left venticular dysfunction, both asymptomatic and symptomatic, unless there is a contraindication or prior intolerance to therapy.[2][7]
ACE inhibitors should be used with caution in patients in cardiogenic shock, with marginal renal output or hyperkalaemia.
If patients have an idiosyncratic reaction, with angio-oedema, ACE inhibitors should not be rechallenged.
However, in heart failure with reduced ejection fraction (New York Heart Association [NYHA] class II to IV and ejection fraction of 35% or less) a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin-II receptor antagonist, is superior to enalapril in reducing mortality and heart failure hospitalisation.[113] The drug combination has been approved in the US and in Europe for the treatment of heart failure. The American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines recommend that, in patients with chronic NYHA class II or III who tolerate an ACE inhibitor or angiotensin-II receptor antagonist, these drugs should be replaced by an angiotensin-II receptor antagonist plus neprilysin inhibitor to further reduce morbidity and mortality.[80] Concomitant administration of an angiotensin-II receptor antagonist plus neprilysin with an ACE inhibitor, or within 36 hours of the last dose of an ACE inhibitor, is not recommended.[80]
Treatment recommended for ALL patients in selected patient group
Dietary sodium intake is an easily modifiable factor that complements pharmacological therapy for heart failure. For stage A and B heart failure (stage A: at high risk for heart failure but without structural heart disease or symptoms of heart failure; stage B: structural heart disease but without signs or symptoms of heart failure), the recommendation is to limit sodium intake to 1.5 g/day. For stage C and D heart failure (stage C: structural heart disease with prior or current symptoms of heart failure; stage D: refractory heart failure requiring specialised interventions), the recommendation is to limit sodium intake to at least 3 g/day.[2]
Fluid restriction is mostly used as an in-hospital complementary measure in cases of acute exacerbations. In addition, fluid restriction may be warranted in cases of severe hyponatraemia. However, it would be of importance to advise the patient to keep a daily intake/output balance at home. Patients are advised to monitor their weight daily and to immediately contact their healthcare provider if a specified change in weight occurs.
Heart failure patients need continuous and close monitoring of their health. A variety of programmes have been shown to decrease morbidity and re-hospitalisation in this context, including home nursing, telephone advice/triage, telemedicine services, and specialised heart failure clinic-based care.[160]
[ 
]
Exercise training has also been shown to be beneficial.[100]
Treatment recommended for ALL patients in selected patient group
Primary options
carvedilol: 3.125 mg orally (immediate-release) twice daily initially, increase according to response, maximum 50 mg/day (body weight ≤85 kg) or 100 mg/day (body weight >85 kg)
Secondary options
metoprolol: 12.5 to 200 mg orally (extended-release) once daily
OR
bisoprolol: 1.25 mg orally once daily initially, increase according to response, maximum 10 mg/day
OR
nebivolol: 1.25 mg orally once daily initially, increase according to response, maximum 10 mg/day
All patients with chronic heart failure receive a beta-blocker once established on an ACE inhibitor, unless there is a contraindication based on bradycardia, reactive airway disease, and unstable or low-output heart failure.[2][7]
Carvedilol seems superior to metoprolol,[161] although there is no evidence of superiority to other beta-blockers. In the SENIORS study, nebivolol, a cardioselective beta-blocker with nitric oxide-mediated vasodilating properties, was found to be an effective and well-tolerated treatment for heart failure in patients aged 70 years or more.[162] Data suggest that initiation with moderate doses of nebivolol is not associated with the adverse haemodynamic effects usually observed with other beta-blockers in patients with heart failure; therefore, a long up-titration period may not be necessary with nebivolol.[163]
Beta-blockers have been shown to decrease the morbidity and mortality associated with heart failure.[2][7] They are initiated at low doses and titrated to target dosage.[2][101]
[ ]
One meta-analysis found that irrespective of pre-treatment heart rate, beta-blockers reduced mortality in patients with heart failure with reduced ejection fraction in sinus rhythm.[102]
Treatment recommended for SOME patients in selected patient group
Primary options
furosemide: 20-80 mg/dose orally initially, increase by 20-40 mg/dose increments every 6-8 hours according to response, maximum 600 mg/day
OR
bumetanide: 0.5 to 1 mg orally once or twice daily initially, increase according to response, maximum 10 mg/day
OR
torasemide: 5-20 mg orally once daily initially, increase according to response, maximum 40 mg/day
OR
chlorothiazide: 250-500 mg orally once or twice daily, maximum 1000 mg/day
OR
hydrochlorothiazide: 25 mg orally once or twice daily, increase according to response, maximum 200 mg/day
OR
indapamide: 2.5 to 5 mg orally once daily
OR
metolazone: 2.5 to 20 mg orally once daily
Secondary options
amiloride: 5-20 mg orally once daily
OR
triamterene: 50-100 mg orally twice daily initially, increase according to response, maximum 300 mg/day
Diuretics should be considered for patients who have evidence of, or a prior history of, fluid retention.[2] They should generally be combined with an ACE inhibitor and a beta-blocker. All patients with symptoms and signs of congestion should receive diuretics, irrespective of the left ventricular ejection fraction (LVEF).
Loop diuretics used for the treatment of heart failure and congestion include furosemide, bumetanide, and torasemide. The most commonly used agent appears to be furosemide, but some patients may respond more favourably to another loop diuretic. In resistant cases, loop diuretics should be combined with a thiazide diuretic (e.g., chlorothiazide, hydrochlorothiazide) or a thiazide-like diuretic (e.g., metolazone, indapamide). Careful monitoring of renal function and electrolytes is essential in these patients.
The minimum dose of diuretic should be used to relieve congestion, keep the patient asymptomatic, and maintain a dry weight. In patients with stable congestive heart failure, loop diuretics are the preferred agent. In patients with hypertension and only mild fluid retention, a thiazide diuretic may be considered.
Diuretics produce symptomatic benefits more rapidly than any other drug for heart failure. They can relieve pulmonary and peripheral oedema within hours or days. Few patients with heart failure and fluid retention can maintain sodium balance without the use of diuretic drugs.[164]
Diuretics alone are unable to maintain the clinical stability of patients with heart failure for long periods of time,[164] but the risk of clinical decompensation can be reduced when they are combined with an ACE inhibitor and a beta-blocker.[165] Diuretics should be used only in combination with an ACE inhibitor (or angiotensin-II receptor antagonist), a beta-blocker, and an aldosterone antagonist in patients with reduced LVEF.
In intermediate-term studies, diuretics have been shown to improve cardiac function, symptoms, and exercise tolerance in patients with heart failure.[164][166] There have been no long-term studies of diuretic therapy in heart failure, and thus their effects on morbidity and mortality are not known.
Amiloride and triamterene (potassium-sparing diuretics) should be used with caution with aldosterone antagonists, because of the increased risk of developing hyperkalaemia. Close monitoring of serum potassium levels is suggested in this situation.
Treatment recommended for SOME patients in selected patient group
Primary options
spironolactone: 25-100 mg orally once daily
OR
eplerenone: 25-50 mg orally once daily
Aldosterone antagonists, also known as mineralocorticoid receptor antagonists (e.g., spironolactone and eplerenone), decrease the morbidity and mortality associated with symptomatic chronic heart failure.
Aldosterone antagonists are recommended in patients with New York Heart Association class II to IV heart failure who have left ventricular ejection fraction (LVEF) of 35% or less, unless contraindicated.[2] They are also recommended to reduce mortality and morbidity following acute myocardial infarction in patients with LVEF of 40% or less who develop symptoms of heart failure or have a history of diabetes mellitus, unless contraindicated.
Aldosterone antagonists should be initiated after titration of standard medical therapy. Spironolactone and eplerenone can both cause hyperkalaemia, and precautions should be taken to minimise the risk.
These agents should be used with caution in patients with renal dysfunction and hyperkalaemia. They should not be initiated in patients with a serum creatinine above 221 micromols/L (>2.5 mg/dL) or a serum potassium above 5.0 millimols/L (>5.0 mEq/dL) and should be used with caution in patients with serum creatinine below 221 micromols/L (<2.5 mg/dL) plus a serum potassium above 5.0 millimols/L (>5.0 mEq/dL). Patients should discontinue potassium repletion.
Adherence to intensive monitoring of renal function and potassium levels has been shown to prevent hyperkalaemia, which is as likely to occur with eplerenone therapy as it is with spironolactone therapy.
Amiloride and triamterene (potassium-sparing diuretics) should be used with caution with aldosterone antagonists, because of the increased risk of developing hyperkalaemia. Close monitoring of serum potassium levels is suggested in this situation.
Treatment recommended for SOME patients in selected patient group
Primary options
isosorbide dinitrate: 20-40 mg orally (immediate-release) three times daily
and
hydralazine: 10-100 mg orally three times daily
OR
isosorbide dinitrate/hydralazine: 20 mg (isosorbide dinitrate)/37.5 mg (hydralazine) orally three times daily, maximum 40 mg (isosorbide dinitrate)/75 mg (hydralazine) three times daily
A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic heart failure with reduced ejection fraction (HFrEF) who cannot be given an ACE inhibitor or angiotensin-II receptor antagonist because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated.[2] The American College of Cardiology Foundation/American Heart Association guidelines recommend the combination of hydralazine and isosorbide dinitrate to "reduce morbidity and mortality in patients self-described as African Americans with NYHA class III to IV HFrEF receiving optimal therapy with ACE inhibitors and beta blockers, unless contraindicated".[2]
Nitrate therapy may decrease symptoms of dyspnoea at night and during exercise and may improve exercise tolerance in patients who have persistent limitations despite optimisation of other therapies.[167][168]
Development of nitrate tolerance seems to be minimised by prescription of a nitrate-free interval of at least 10 hours.[2] Carvedilol use has been shown to prevent nitrate tolerance in patients with CHF.[169][170]
Hydralazine may interfere with the biochemical and molecular mechanisms responsible for the development of nitrate tolerance.[171][172]
A combination pill containing 37.5 mg hydralazine and 20 mg isosorbide dinitrate is available, approved specifically for self-identified black patients with CHF.
Treatment recommended for SOME patients in selected patient group
Primary options
digoxin: 0.125 to 0.5 mg orally once daily
Digoxin can be beneficial in patients with reduced left ventricular ejection fraction (LVEF), especially those with atrial fibrillation.
When added to ACE inhibitors, beta-blockers, and diuretics, digoxin can reduce symptoms, prevent hospitalisation, control rhythm, and enhance exercise tolerance.
Digoxin reduces the composite end point of mortality or hospitalisations in ambulatory patients with chronic heart failure with New York Heart Association class III or IV symptoms, LVEF <25%, or cardiothoracic ratio of >55% and should be considered in these patients.[121]
Digoxin reduces the composite end point of mortality or hospitalisations, but does not reduce all-cause mortality.[121] Digoxin should be used cautiously with plasma level monitoring; one meta-analysis suggests that digoxin use in patients with heart failure is associated with a higher risk of all-cause mortality.[122]
Overt digitalis toxicity is commonly associated with serum digoxin levels >2.6 nanomols/L (2 nanograms/mL). However, toxicity may occur with lower levels, especially if hypokalaemia, hypomagnesaemia, or hypothyroidism co-exists.[173][174]
Low doses (0.125 mg/day or every other day) should be used initially if the patient is over 70 years old, has impaired renal function, or has a low lean body mass.[175]
Higher doses (e.g., 0.375 to 0.5 mg/day) are rarely used or needed.
There is no reason to use loading doses of digoxin to initiate therapy.
Treatment recommended for SOME patients in selected patient group
Primary options
ivabradine: 5 mg orally twice daily initially, may increase to 7.5 mg twice daily after 2 weeks if necessary; adjust dose according to heart rate
Ivabradine may be an option for patients with New York Heart Association class II, III, or IV heart failure who have a sinus rate >75 beats per minute and an ejection fraction <35%, and who remain symptomatic despite optimal therapy. It can also be used in patients who are unable to take beta-blockers.
Its use should be initiated by a specialist cardiologist and only after a stabilisation period of 4 weeks on optimised standard therapy.[126]
In a randomised, double-blind, placebo-controlled trial, addition of ivabradine to standard background therapy in patients with stable coronary artery disease without clinical heart failure (no evidence of left ventricular systolic dysfunction in the overall study population, mean ejection fraction was 56.4%) did not improve the outcome. In the subgroup analysis of this study, ivabradine was associated with an increase in the incidence of the primary end point (death from cardiovascular causes or non-fatal myocardial infarction) among patients who had angina of Canadian Cardiovascular Society class II or higher but not among patients without angina or those who had angina of class I. Ivabradine was associated with an increased incidence of bradycardia, QT prolongation, and atrial fibrillation.[124]
Treatment recommended for SOME patients in selected patient group
Primary options
tolvaptan: 15 mg orally once daily initially, increase gradually according to response, maximum 60 mg/day for up to 30 days
Considered for patients with symptomatic or severe hyponatraemia (<130 mmol/L) and persistent congestion despite standard therapy, to correct hyponatraemia and related symptoms.[2][127]
Primary options
carvedilol: 3.125 mg orally (immediate-release) twice daily initially, increase according to response, maximum 50 mg/day (body weight ≤85 kg) or 100 mg/day (body weight >85 kg)
-- AND --
candesartan: 4-32 mg orally once daily
or
losartan: 25-100 mg orally once daily
or
valsartan: 40-160 mg orally twice daily
Secondary options
metoprolol: 12.5 to 200 mg orally (extended-release) once daily
or
bisoprolol: 1.25 mg orally once daily initially, increase according to response, maximum 10 mg/day
or
nebivolol: 1.25 mg orally once daily initially, increase according to response, maximum 10 mg/day
-- AND --
candesartan: 4-32 mg orally once daily
or
losartan: 25-100 mg orally once daily
or
valsartan: 40-160 mg orally twice daily
All patients with chronic heart failure receive a beta-blocker, unless there is a contraindication based on bradycardia, reactive airway disease, and unstable or low-output heart failure.[2][7]
Carvedilol seems superior to metoprolol,[161] although there is no evidence of superiority to other beta-blockers. In the SENIORS study, nebivolol, a cardioselective beta-blocker with nitric oxide-mediated vasodilating properties, was found to be an effective and well-tolerated treatment for heart failure in patients aged 70 years or more.[162] Data suggest that initiation with moderate doses of nebivolol is not associated with the adverse haemodynamic effects usually observed with other beta-blockers in patients with heart failure; therefore, a long up-titration period may not be necessary with nebivolol.[163]
Angiotensin-II receptor antagonists should be added instead of ACE inhibitors in all patients who are intolerant of ACE inhibitors because of cough or angio-oedema.[2] Valsartan and candesartan have demonstrated benefit by reducing hospitalisations and mortality.[105]
Angiotensin-II receptor antagonists are as likely to produce hypotension, worsening renal function, and hyperkalaemia as ACE inhibitors. Although angio-oedema is much less frequent, there are cases of patients who developed angio-oedema to both ACE inhibitors and later to angiotensin-II receptor antagonists.
Treatment recommended for ALL patients in selected patient group
Dietary sodium intake is an easily modifiable factor that complements pharmacological therapy for heart failure. Thus the patient and family are advised to follow a daily dietary sodium intake between 2 and 3 g. Further restriction to 1 to 2 g/day may be necessary for patients with advanced symptoms refractory to therapy.
Fluid restriction is mostly used as an in-hospital complementary measure in cases of acute exacerbations. In addition, fluid restriction may be warranted in cases of severe hyponatraemia. However, it would be of importance to advise the patient to keep a daily intake/output balance at home. Patients are advised to monitor their weight daily and to immediately contact their healthcare provider if a specified change in weight occurs.
Heart failure patients need continuous and close monitoring of their health. A variety of programmes have been shown to decrease morbidity and re-hospitalisation in this context, including home nursing, telephone advice/triage, telemedicine services, and specialised heart failure-clinic-based care.
[ ]
Exercise training has also been shown to be beneficial.[100]
Treatment recommended for SOME patients in selected patient group
Primary options
furosemide: 20-80 mg/dose orally initially, increase by 20-40 mg/dose increments every 6-8 hours according to response, maximum 600 mg/day
OR
bumetanide: 0.5 to 1 mg orally once or twice daily initially, increase according to response, maximum 10 mg/day
OR
torasemide: 5-20 mg orally once daily initially, increase according to response, maximum 40 mg/day
OR
chlorothiazide: 250-500 mg orally once or twice daily, maximum 1000 mg/day
OR
hydrochlorothiazide: 25 mg orally once or twice daily, increase according to response, maximum 200 mg/day
OR
indapamide: 2.5 to 5 mg orally once daily
OR
metolazone: 2.5 to 20 mg orally once daily
Secondary options
amiloride: 5-20 mg orally once daily
OR
triamterene: 50-100 mg orally twice daily initially, increase according to response, maximum 300 mg/day
Diuretics should be considered for patients who have evidence of, or a prior history of, fluid retention.[2] They should generally be combined with an ACE inhibitor and a beta-blocker. All patients with symptoms and signs of congestion should receive diuretics, irrespective of the left ventricular ejection fraction (LVEF).
Loop diuretics used for the treatment of heart failure and congestion include furosemide, bumetanide, and torasemide. The most commonly used agent appears to be furosemide, but some patients may respond more favourably to other loop diuretics. In resistant cases, loop diuretics should be combined with a thiazide diuretic (e.g., chlorothiazide, hydrochlorothiazide) or a thiazide-like diuretic (e.g., metolazone, indapamide). Careful monitoring of renal function and electrolytes is essential in these patients.
The minimum dose of diuretic should be used to relieve congestion, keep the patient asymptomatic, and maintain a dry weight. In patients with stable congestive heart failure, loop diuretics are the preferred agent. In patients with hypertension and only mild fluid retention, a thiazide diuretic may be considered.
Diuretics produce symptomatic benefits more rapidly than any other drug for heart failure. They can relieve pulmonary and peripheral oedema within hours or days. Few patients with heart failure and fluid retention can maintain sodium balance without the use of diuretic drugs.[164]
Diuretics alone are unable to maintain the clinical stability of patients with heart failure for long periods of time,[164] but the risk of clinical decompensation can be reduced when they are combined with an ACE inhibitor and a beta-blocker.[165] Diuretics should be used only in combination with an ACE inhibitor (or an angiotensin-II receptor antagonist), a beta-blocker, and an aldosterone antagonist in patients with reduced LVEF.
In intermediate-term studies, diuretics have been shown to improve cardiac function, symptoms, and exercise tolerance in patients with heart failure.[164][166]
There have been no long-term studies of diuretic therapy in heart failure; therefore, their effects on morbidity and mortality are not known.
Amiloride and triamterene (potassium-sparing diuretics) should be used with caution with aldosterone antagonists, because of the increased risk of developing hyperkalaemia. Close monitoring of serum potassium levels is suggested in this situation.
Treatment recommended for SOME patients in selected patient group
Primary options
spironolactone: 25-100 mg orally once daily
OR
eplerenone: 25-50 mg orally once daily
Aldosterone antagonists, also known as mineralocorticoid receptor antagonists (e.g., spironolactone and eplerenone), decrease the morbidity and mortality associated with symptomatic chronic heart failure.
Aldosterone antagonists are recommended in patients with New York Heart Association class II to IV heart failure who have left ventricular ejection fraction (LVEF) of 35% or less, unless contraindicated.[2] They are also recommended to reduce mortality and morbidity following acute myocardial infarction in patients with LVEF of 40% or less who develop symptoms of heart failure or have a history of diabetes mellitus, unless contraindicated.[2]
Aldosterone antagonists should be initiated after titration of standard medical therapy. Spironolactone and eplerenone can both cause hyperkalaemia, and precautions should be taken to minimise the risk.
These agents should be used with caution in patients with renal dysfunction and hyperkalaemia. They should not be initiated in patients with a serum creatinine above 221 micromols/L (>2.5 mg/dL) or a serum potassium above 5.0 millimols/L (>5.0 mEq/dL) and should be used with caution in patients with serum creatinine below 221 micromols/L (<2.5 mg/dL) plus a serum potassium above 5.0 millimols/L (>5.0 mEq/dL). Patients should discontinue potassium repletion.
Adherence to intensive monitoring of renal function and potassium levels has been shown to prevent hyperkalaemia, which is as likely to occur with eplerenone therapy as it is with spironolactone therapy.
Amiloride and triamterene (potassium-sparing diuretics) should be used with caution with aldosterone antagonists, because of the increased risk of developing hyperkalaemia. Close monitoring of serum potassium levels is suggested in this situation.
Treatment recommended for SOME patients in selected patient group
Primary options
isosorbide dinitrate: 20-40 mg orally (immediate-release) three times daily
and
hydralazine: 10-100 mg orally three times daily
OR
isosorbide dinitrate/hydralazine: 20 mg (isosorbide dinitrate)/37.5 mg (hydralazine) orally three times daily, maximum 40 mg (isosorbide dinitrate)/75 mg (hydralazine) three times daily
The combined use of hydralazine and isosorbide dinitrate may be considered as a therapeutic option in patients who are intolerant of ACE inhibitors and angiotensin-II receptor antagonists.[176][177] A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic heart failure with reduced ejection fraction (HFrEF) who cannot be given an ACE inhibitor or angiotensin-II receptor antagonist because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated.[2] The American College of Cardiology Foundation/American Heart Association guidelines recommend the combination of hydralazine and isosorbide dinitrate to "reduce morbidity and mortality in patients self-described as African Americans with NYHA class III to IV HFrEF receiving optimal therapy with ACE inhibitors and beta blockers, unless contraindicated".[2]
Nitrate therapy may decrease symptoms of dyspnoea at night and during exercise and may improve exercise tolerance in patients who have persistent limitations despite optimisation of other therapies.[167][168]
Development of nitrate tolerance seems to be minimised by prescription of a nitrate-free interval of at least 10 hours.[2] Carvedilol use has been shown to prevent nitrate tolerance in patients with CHF.[169][170]
Hydralazine may interfere with the biochemical and molecular mechanisms responsible for the development of nitrate tolerance.[171][172]
A combination pill containing 37.5 mg hydralazine and 20 mg isosorbide dinitrate is available, approved specifically for self-identified black patients with CHF.
Treatment recommended for SOME patients in selected patient group
Primary options
digoxin: 0.125 to 0.5 mg orally once daily
Digoxin can be beneficial in patients with reduced left ventricular ejection fraction (LVEF), especially those with atrial fibrillation.
When added to ACE inhibitors, beta-blockers, and diuretics, digoxin can reduce symptoms, prevent hospitalisation, control rhythm, and enhance exercise tolerance.
Digoxin reduces the composite end point of mortality or hospitalisations in ambulatory patients with chronic heart failure with New York Heart Association class III or IV symptoms, LVEF <25%, or cardiothoracic ratio of >55% and should be considered in these patients.[121]
Digoxin reduces the composite end point of mortality or hospitalisations, but does not reduce all-cause mortality.[121] Digoxin should be used cautiously with plasma level monitoring. One meta-analysis suggests that digoxin use in patients with heart failure is associated with a higher risk of all-cause mortality.[122]
Overt digitalis toxicity is commonly associated with serum digoxin levels >2.6 nanomols/L (2 nanograms/mL). However, toxicity may occur with lower levels, especially if hypokalaemia, hypomagnesaemia, or hypothyroidism co-exists.[173][174]
Low doses (0.125 mg/day or every other day) should be used initially if the patient is over 70 years old, has impaired renal function, or has a low lean body mass.[175]
Higher doses (e.g., 0.375 to 0.5 mg/day) are rarely used or needed.
There is no reason to use loading doses of digoxin to initiate therapy.
Treatment recommended for SOME patients in selected patient group
Primary options
ivabradine: 5 mg orally twice daily initially, may increase to 7.5 mg twice daily after 2 weeks if necessary; adjust dose according to heart rate
Ivabradine may be an option for patients with New York Heart Association class II, III, or IV heart failure who have a sinus rate >75 beats per minute and an ejection fraction <35%, and who remain symptomatic despite optimal therapy. It can also be used in patients who are unable to take beta-blockers.
Its use should be initiated by a specialist cardiologist and only after a stabilisation period of 4 weeks on optimised standard therapy.[126]
In a randomised, double-blind, placebo-controlled trial, addition of ivabradine to standard background therapy in patients with stable coronary artery disease without clinical heart failure (no evidence of left ventricular systolic dysfunction in the overall study population, mean ejection fraction was 56.4%) did not improve the outcome. In the subgroup analysis of this study, ivabradine was associated with an increase in the incidence of the primary end point (death from cardiovascular causes or non-fatal myocardial infarction) among patients who had angina of Canadian Cardiovascular Society class II or higher but not among patients without angina or those who had angina of class I. Ivabradine was associated with an increased incidence of bradycardia, QT prolongation, and atrial fibrillation.[124]
Treatment recommended for SOME patients in selected patient group
Primary options
tolvaptan: 15 mg orally once daily initially, increase gradually according to response, maximum 60 mg/day for up to 30 days
Considered for patients with symptomatic or severe hyponatraemia (<130 mmol/L) and persistent congestion despite standard therapy, to correct hyponatraemia and related symptoms.[2][127]
Primary options
isosorbide dinitrate: 20-40 mg orally (immediate-release) three times daily
and
hydralazine: 10-100 mg orally three times daily
OR
isosorbide dinitrate/hydralazine: 20 mg (isosorbide dinitrate)/37.5 mg (hydralazine) orally three times daily, maximum 40 mg (isosorbide dinitrate)/75 mg (hydralazine) three times daily
The combined use of hydralazine and isosorbide dinitrate may be considered as a therapeutic option in patients who are intolerant of ACE inhibitors and angiotensin-II receptor antagonists.[176][177] A combination of hydralazine and isosorbide dinitrate can be useful to reduce morbidity or mortality in patients with current or prior symptomatic heart failure with reduced ejection fraction (HFrEF) who cannot be given an ACE inhibitor or angiotensin-II receptor antagonist because of drug intolerance, hypotension, or renal insufficiency, unless contraindicated.[2] The American College of Cardiology Foundation/American Heart Association guidelines recommend the combination of hydralazine and isosorbide dinitrate to "reduce morbidity and mortality in patients self-described as African Americans with NYHA class III to IV HFrEF receiving optimal therapy with ACE inhibitors and beta blockers, unless contraindicated".[2]
Nitrate therapy may decrease symptoms of dyspnoea at night and during exercise and may improve exercise tolerance in patients who have persistent limitations despite optimisation of other therapies.[167][168]
Development of nitrate tolerance seems to be minimised by prescription of a nitrate-free interval of at least 10 hours.[2] Carvedilol use has been shown to prevent nitrate tolerance in patients with CHF.[169][170]
Hydralazine may interfere with the biochemical and molecular mechanisms responsible for the development of nitrate tolerance.[171][172]
Treatment recommended for ALL patients in selected patient group
Primary options
carvedilol: 3.125 mg orally (immediate-release) twice daily initially, increase according to response, maximum 50 mg/day (body weight ≤85 kg) or 100 mg/day (body weight >85 kg)
Secondary options
metoprolol: 12.5 to 200 mg orally (extended-release) once daily
OR
bisoprolol: 1.25 mg orally once daily initially, increase according to response, maximum 10 mg/day
OR
nebivolol: 1.25 mg orally once daily initially, increase according to response, maximum 10 mg/day
All patients with chronic heart failure receive a beta-blocker, unless there is a contraindication based on bradycardia, reactive airway disease, and unstable or low-output heart failure.[2][7]
Carvedilol seems superior to metoprolol,[161] although there is no evidence of superiority to other beta-blockers. In the SENIORS study, nebivolol, a cardioselective beta-blocker with nitric oxide-mediated vasodilating properties, was found to be an effective and well-tolerated treatment for heart failure in patients aged 70 years or more.[162] Data suggest that initiation with moderate doses of nebivolol is not associated with the adverse haemodynamic effects usually observed with other beta-blockers in patients with heart failure; therefore, a long up-titration period may not be necessary with nebivolol.[163]
Treatment recommended for ALL patients in selected patient group
Dietary sodium intake is an easily modifiable factor that complements pharmacological therapy for heart failure. Thus the patient and family are advised to follow a daily dietary sodium intake between 2 and 3 g. Further restriction to 1 to 2 g/day may be necessary for patients with advanced symptoms refractory to therapy.
Fluid restriction is mostly used as an in-hospital complementary measure in cases of acute exacerbations. In addition, fluid restriction may be warranted in cases of severe hyponatraemia. However, it would be of importance to advise the patient to keep a daily intake/output balance at home. Patients are advised to monitor their weight daily and to immediately contact their healthcare provider if a specified change in weight occurs.
Heart failure patients need continuous and close monitoring of their health. A variety of programmes have been shown to decrease morbidity and re-hospitalisation in this context, including home nursing, telephone advice/triage, telemedicine services, and specialised heart failure-clinic-based care.
[ ]
Exercise training has also been shown to be beneficial.[100]
Treatment recommended for SOME patients in selected patient group
Primary options
furosemide: 20-80 mg/dose orally initially, increase by 20-40 mg/dose increments every 6-8 hours according to response, maximum 600 mg/day
OR
bumetanide: 0.5 to 1 mg orally once or twice daily initially, increase according to response, maximum 10 mg/day
OR
torasemide: 5-20 mg orally once daily initially, increase according to response, maximum 40 mg/day
OR
chlorothiazide: 250-500 mg orally once or twice daily, maximum 1000 mg/day
OR
hydrochlorothiazide: 25 mg orally once or twice daily, increase according to response, maximum 200 mg/day
OR
indapamide: 2.5 to 5 mg orally once daily
OR
metolazone: 2.5 to 20 mg orally once daily
Secondary options
amiloride: 5-20 mg orally once daily
OR
triamterene: 50-100 mg orally twice daily initially, increase according to response, maximum 300 mg/day
Diuretics should be considered for patients who have evidence of, or a prior history of, fluid retention.[2] They should generally be combined with an ACE inhibitor and a beta-blocker. All patients with symptoms and signs of congestion should receive diuretics, irrespective of the left ventricular ejection fraction (LVEF).
Loop diuretics used for the treatment of heart failure and congestion include furosemide, bumetanide, and torasemide. The most commonly used agent appears to be furosemide, but some patients may respond more favourably to other loop diuretics. In resistant cases, loop diuretics should be combined with a thiazide diuretic (e.g., chlorothiazide, hydrochlorothiazide) or a thiazide-like diuretic (e.g., metolazone, indapamide). Careful monitoring of renal function and electrolytes is essential in these patients.
The minimum dose of diuretic should be used to relieve congestion, keep the patient asymptomatic and maintain a dry weight. In patients with stable congestive heart failure, loop diuretics are the preferred agent. In patients with hypertension and only mild fluid retention, a thiazide diuretic may be considered.
Diuretics produce symptomatic benefits more rapidly than any other drug for heart failure. They can relieve pulmonary and peripheral oedema within hours or days. Few patients with heart failure and fluid retention can maintain sodium balance without the use of diuretic drugs.[164]
Diuretics alone are unable to maintain the clinical stability of patients with heart failure for long periods of time,[164] but the risk of clinical decompensation can be reduced when they are combined with an ACE inhibitor and a beta-blocker.[165] Diuretics should be used only in combination with an ACE inhibitor (or an angiotensin-II receptor antagonist), a beta-blocker, and an aldosterone antagonist in patients with reduced LVEF.
In intermediate-term studies, diuretics have been shown to improve cardiac function, symptoms, and exercise tolerance in patients with heart failure.[164][166]
There have been no long-term studies of diuretic therapy in heart failure; therefore, their effects on morbidity and mortality are not known.
Amiloride and triamterene (potassium-sparing diuretics) should be used with caution with aldosterone antagonists, because of the increased risk of developing hyperkalaemia. Close monitoring of serum potassium levels is suggested in this situation.
Treatment recommended for SOME patients in selected patient group
Primary options
spironolactone: 25-100 mg orally once daily
OR
eplerenone: 25-50 mg orally once daily
Aldosterone antagonists, also known as mineralocorticoid receptor antagonists (e.g., spironolactone and eplerenone), decrease the morbidity and mortality associated with symptomatic chronic heart failure.
Aldosterone antagonists are recommended in patients with New York Heart Association class II to IV heart failure who have left ventricular ejection fraction (LVEF) of 35% or less, unless contraindicated.[2] They are also recommended to reduce mortality and morbidity following acute myocardial infarction in patients with LVEF of 40% or less who develop symptoms of heart failure or have a history of diabetes mellitus, unless contraindicated.[2]
Aldosterone antagonists should be initiated after titration of standard medical therapy. Spironolactone and eplerenone can both cause hyperkalaemia, and precautions should be taken to minimise the risk.
These agents should be used with caution in patients with renal dysfunction and hyperkalaemia. They should not be initiated in patients with a serum creatinine above 221 micromols/L (>2.5 mg/dL) or a serum potassium above 5.0 millimols/L (>5.0 mEq/dL) and should be used with caution in patients with serum creatinine below 221 micromols/L (<2.5 mg/dL) plus a serum potassium above 5.0 millimols/L (>5.0 mEq/dL). Patients should discontinue potassium repletion.
Adherence to intensive monitoring of renal function and potassium levels has been shown to prevent hyperkalaemia, which is as likely to occur with eplerenone therapy as it is with spironolactone therapy.
Amiloride and triamterene (potassium-sparing diuretics) should be used with caution with aldosterone antagonists, because of the increased risk of developing hyperkalaemia. Close monitoring of serum potassium levels is suggested in this situation.
Treatment recommended for SOME patients in selected patient group
Primary options
digoxin: 0.125 to 0.5 mg orally once daily
Digoxin can be beneficial in patients with reduced left ventricular ejection fraction (LVEF), especially those with atrial fibrillation.
When added to ACE inhibitors, beta-blockers, and diuretics, digoxin can reduce symptoms, prevent hospitalisation, control rhythm, and enhance exercise tolerance.
Digoxin reduces the composite end point of mortality or hospitalisations in ambulatory patients with chronic heart failure with New York Heart Association class III or IV symptoms, LVEF <25%, or cardiothoracic ratio of >55% and should be considered in these patients.[121]
Digoxin reduces the composite end point of mortality or hospitalisations, but does not reduce all-cause mortality.[121] One meta-analysis suggests that digoxin use in patients with heart failure is associated with a higher risk of all-cause mortality.[122]
Overt digitalis toxicity is commonly associated with serum digoxin levels >2.6 nanomols/L (2 nanograms/mL). However, toxicity may occur with lower levels, especially if hypokalaemia, hypomagnesaemia, or hypothyroidism co-exists.[173][174]
Low doses (0.125 mg/day or every other day) should be used initially if the patient is over 70 years old, has impaired renal function, or has a low lean body mass.[175]
Higher doses (e.g., 0.375 to 0.5 mg/day) are rarely used or needed.
There is no reason to use loading doses of digoxin to initiate therapy.
Treatment recommended for SOME patients in selected patient group
Primary options
ivabradine: 5 mg orally twice daily initially, may increase to 7.5 mg twice daily after 2 weeks if necessary; adjust dose according to heart rate
Ivabradine may be an option for patients with New York Heart Association class II, III, or IV heart failure who have a sinus rate >75 beats per minute and an ejection fraction <35%, and who remain symptomatic despite optimal therapy. It can also be used in patients who are unable to take beta-blockers.
Its use should be initiated by a specialist cardiologist and only after a stabilisation period of 4 weeks on optimised standard therapy.[126]
In a randomised, double-blind, placebo-controlled trial, addition of ivabradine to standard background therapy in patients with stable coronary artery disease without clinical heart failure (no evidence of left ventricular systolic dysfunction in the overall study population, mean ejection fraction was 56.4%) did not improve the outcome. In the subgroup analysis of this study, ivabradine was associated with an increase in the incidence of the primary end point (death from cardiovascular causes or non-fatal myocardial infarction) among patients who had angina of Canadian Cardiovascular Society class II or higher but not among patients without angina or those who had angina of class I. Ivabradine was associated with an increased incidence of bradycardia, QT prolongation, and atrial fibrillation.[124]
Treatment recommended for SOME patients in selected patient group
Primary options
tolvaptan: 15 mg orally once daily initially, increase gradually according to response, maximum 60 mg/day for up to 30 days
Considered for patients with symptomatic or severe hyponatraemia (<130 mmol/L) and persistent congestion despite standard therapy, to correct hyponatraemia and related symptoms.[2][127]
LVEF <35%: no left bundle-branch block
An ICD is recommended in the following cases:[2]
1) For primary prevention of sudden cardiac death in selected patients with both non-ischaemic and ischaemic heart failure, at least 40 days post myocardial infarction, LVEF <35%, New York Heart Association (NYHA) class II or III symptoms on guideline-directed medical therapy, and expected to live for >1 year, or LVEF <30%, NHYA class I, on guideline-directed medical therapy, and expected to live for >1 year.
2) As secondary prevention to prolong survival in patients with current or prior symptoms of heart failure and reduced left ventricular ejection fraction (LVEF) who have a history of cardiac arrest, ventricular fibrillation, or haemodynamically destabilising ventricular tachycardia.
Patients with refractory end-stage disease who already carry an ICD may want to receive information about the option to inactivate defibrillation.
Mechanical circulatory support, which includes ventricular assist devices, helps to maintain sufficient end organ perfusion by unloading the heart and is considered in carefully selected patients who have end-stage heart failure, despite optimal medical and device therapy, and in whom definite management (e.g., cardiac transplantation) or cardiac recovery is anticipated.[1][2]
Currently in the US, the accepted indications for implantation of a durable left ventricular assist device (LVAD) are bridge to transplantation and destination therapy (permanent pump implantation in patients not eligible for cardiac transplantation).[158] In clinical practice, another indication for LVAD is to provide a bridge to decisions about future care.
The European Society of Cardiology has outlined the various indications for mechanical circulatory support:[1]
1) Bridge to decision/bridge to bridge: use of short-term support (e.g., extracorporeal life support [ECLS] or extracorporeal membrane oxygenation [ECMO] in patients with cardiogenic shock until haemodynamics and end-organ perfusion are stabilised, contraindications for long-term support are excluded, and therapeutic options including long-term VAD therapy or heart transplant can be evaluated.
2) Bridge to candidacy: use of support (usually LVAD) to make ineligible patient eligible for heart transplant.
3) Bridge to transplantation: use of LVAD or biventricular assist device to keep high-risk transplant candidate alive until donor organ becomes available.
4) Bridge to recovery: use of support (usually LVAD) to keep the patient alive until cardiac function recovers sufficiently to remove it.
5) Destination therapy: long-term use of LVAD as alternative to heart transplant.
Some of the absolute contraindications for providing durable mechanical support include irreversible hepatic, renal and neurological disease, medical non-adherence, and severe psychosocial limitations.[159]
Cardiac transplantation is an option for refractory end-stage disease. Before a patient is considered to have refractory end-stage disease, the accuracy of the diagnosis should be confirmed, any contributing conditions should be identified, and all conventional medical strategies should have been optimally employed.
LVEF <35%: left bundle-branch block
In patients with left ventricular (LV) systolic dysfunction and dyssynchronous ventricular activation, cardiac pacing provides simultaneous and coordinated electrical activation of both the left and right ventricle. This cardiac resynchronisation therapy (CRT) is provided either by a CRT-pacemaker (CRT-P) or by a combined CRT-implantable cardioverter-defibrillator (CRT-D).
The CRT-P prevents deterioration in LV function by correcting the LV dyssynchrony and the CRT-D prevents sudden cardiac death from ventricular arrhythmias.
As both CRT-P and CRT-D are indicated in patients with heart failure and low ejection fraction, there is considerable overlap in the indications for the use of these devices.
Long-term data from the REVERSE study suggest that improvements in left ventricular function and remodelling can be sustained for over 5 years.[155][156]
CRT decreases hospitalisation and, when combined with an ICD, significantly reduces mortality.[134][135][136][137][138][139]
In patients who have conduction delay and left ventricular dysfunction, biventricular pacemakers have been shown to improve exercise tolerance and quality of life while decreasing morbidity and mortality.[134][135][136][137][139][140][141][142]
CRT is indicated in patients with LVEF ≤35%, sinus rhythm, LBBB with QRS ≥150 ms, and NYHA class II, III or ambulatory NYHA IV on guideline-directed medical therapy.[2]
Recommendations for the use of CRT devices in heart failure are detailed in the 2013 American College of Cardiology/American Heart Association guidelines.[2]
Mechanical circulatory support, which includes ventricular assist devices, helps to maintain sufficient end organ perfusion by unloading the heart and is considered in carefully selected patients who have end-stage heart failure, despite optimal medical and device therapy, and in whom definite management (e.g., cardiac transplantation) or cardiac recovery is anticipated.[1][2]
Currently in the US, the accepted indications for implantation of a durable left ventricular assist device (LVAD) are bridge to transplantation and destination therapy (permanent pump implantation in patients not eligible for cardiac transplantation).[158] In clinical practice, another indication for LVAD is to provide a bridge to decisions about future care.
The European Society of Cardiology has outlined the various indications for mechanical circulatory support:[1]
1) Bridge to decision/bridge to bridge: use of short-term support (e.g., extracorporeal life support [ECLS] or extracorporeal membrane oxygenation [ECMO] in patients with cardiogenic shock until haemodynamics and end-organ perfusion are stabilised, contraindications for long-term support are excluded, and therapeutic options including long-term VAD therapy or heart transplant can be evaluated.
2) Bridge to candidacy: use of support (usually LVAD) to make ineligible patient eligible for heart transplant.
3) Bridge to transplantation: use of LVAD or biventricular assist device to keep high-risk transplant candidate alive until donor organ becomes available.
4) Bridge to recovery: use of support (usually LVAD) to keep the patient alive until cardiac function recovers sufficiently to remove it.
5) Destination therapy: long-term use of LVAD as alternative to heart transplant.
Some of the absolute contraindications for providing durable mechanical support include irreversible hepatic, renal and neurological disease, medical non-adherence, and severe psychosocial limitations.[159]
Cardiac transplantation is an option for refractory end-stage disease. Before a patient is considered to have refractory end-stage disease, the accuracy of the diagnosis should be confirmed, any contributing conditions should be identified, and all conventional medical strategies should have been optimally employed.
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