Congestive heart failure chronic pharmacotherapy: Difference between revisions

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Latest revision as of 11:38, 19 August 2022

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

^[1]

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 and NYHA class II–IV

(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

^[2]

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.^[3]
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.^[4]
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).^[5]
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,^[6]

and a reduction in the decline in eGFR ^[7]as well as a reduced rate of hyperkalemia^[8].

In addition, the need for loop diuretic reduced while using of sacubitril/valsartan.^[9]
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.^[10]^[11]

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%.^[12]
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.^[13]
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.^[14]
The combined SGLT-1 and SGLT-2 inhibitors, sotagliflozin, has also been investigated in patients with diabetes who were hospitalized with HF.^[15]
Side effects of SGLT2 inhibitors including:

Increased risk of recurrent genital fungal infections

A small reversible reduction in eGFR following initiation

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 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. 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

^[2]

Diuretics

Loop diuretics is recommended to reduce the signs and/or symptoms of congestion in patients with HFrEF.^[16]
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.^[17]
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.^[18]
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.^[19]
In the Val-HeFT trial, Valsartan, in addition to usual therapy, including ACE-I, reduced HF hospitalizations.^[20]
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.^[21]
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.^[22]
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.^[23]

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.^[24]^[25]
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.^[26]
Caution should also be exercised in patients as followes:

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.^[27]
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.^[28]
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

Serial clinical evaluation , titration of Medications

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

References

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↑ Mullens W, Damman K, Harjola VP, Mebazaa A, Brunner-La Rocca HP, Martens P, Testani JM, Tang W, Orso F, Rossignol P, Metra M, Filippatos G, Seferovic PM, Ruschitzka F, Coats AJ (February 2019). "The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology". Eur J Heart Fail. 21 (2): 137–155. doi:10.1002/ejhf.1369. PMID 30600580. Vancouver style error: initials (help)
↑ Faris R, Flather M, Purcell H, Henein M, Poole-Wilson P, Coats A (February 2002). "Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials". Int J Cardiol. 82 (2): 149–58. doi:10.1016/s0167-5273(01)00600-3. PMID 11853901.
↑ Rohde LE, Rover MM, Figueiredo Neto JA, Danzmann LC, Bertoldi EG, Simões MV, Silvestre OM, Ribeiro A, Moura LZ, Beck-da-Silva L, Prado D, Sant'Anna RT, Bridi LH, Zimerman A, Raupp da Rosa P, Biolo A (November 2019). "Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial". Eur Heart J. 40 (44): 3605–3612. doi:10.1093/eurheartj/ehz554. PMID 31424503. Vancouver style error: initials (help)
↑ Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K (September 2003). "Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial". Lancet. 362 (9386): 772–6. doi:10.1016/S0140-6736(03)14284-5. PMID 13678870.
↑ Cohn JN, Tognoni G (December 2001). "A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure". N Engl J Med. 345 (23): 1667–75. doi:10.1056/NEJMoa010713. PMID 11759645.
↑ Böhm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, Reil JC, Swedberg K, Tavazzi L (January 2013). "Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study". Clin Res Cardiol. 102 (1): 11–22. doi:10.1007/s00392-012-0467-8. PMID 22575988.
↑ Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L (September 2010). "Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study". Lancet. 376 (9744): 875–85. doi:10.1016/S0140-6736(10)61198-1. PMID 20801500.
↑ Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN (November 2004). "Combination of isosorbide dinitrate and hydralazine in blacks with heart failure". N Engl J Med. 351 (20): 2049–57. doi:10.1056/NEJMoa042934. PMID 15533851.
↑ Vamos M, Erath JW, Hohnloser SH (July 2015). "Digoxin-associated mortality: a systematic review and meta-analysis of the literature". Eur Heart J. 36 (28): 1831–8. doi:10.1093/eurheartj/ehv143. PMID 25939649.
↑ Washam JB, Stevens SR, Lokhnygina Y, Halperin JL, Breithardt G, Singer DE, Mahaffey KW, Hankey GJ, Berkowitz SD, Nessel CC, Fox KA, Califf RM, Piccini JP, Patel MR (June 2015). "Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF)". Lancet. 385 (9985): 2363–70. doi:10.1016/S0140-6736(14)61836-5. PMID 25749644.
↑ Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM (February 2003). "Association of serum digoxin concentration and outcomes in patients with heart failure". JAMA. 289 (7): 871–8. doi:10.1001/jama.289.7.871. PMID 12588271.
↑ Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, Lam C, Ponikowski P, Voors AA, Jia G, McNulty SE, Patel MJ, Roessig L, Koglin J, O'Connor CM (May 2020). "Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction". N Engl J Med. 382 (20): 1883–1893. doi:10.1056/NEJMoa1915928. PMID 32222134 Check |pmid= value (help). Vancouver style error: initials (help)
↑ Teerlink JR, Diaz R, Felker GM, McMurray J, Metra M, Solomon SD, Legg JC, Büchele G, Varin C, Kurtz CE, Malik FI, Honarpour N (April 2020). "Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF". JACC Heart Fail. 8 (4): 329–340. doi:10.1016/j.jchf.2019.12.001. PMID 32035892 Check |pmid= value (help). Vancouver style error: initials (help)

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[pmid30741494-9] Vardeny O, Claggett B, Kachadourian J, Desai AS, Packer M, Rouleau J, Zile MR, Swedberg K, Lefkowitz M, Shi V, McMurray J, Solomon SD (March 2019). "Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial". Eur J Heart Fail. 21 (3): 337–341. doi:10.1002/ejhf.1402. PMC 6607492 Check |pmc= value (help). PMID 30741494. Vancouver style error: initials (help)

[pmid31825471-10] DeVore AD, Braunwald E, Morrow DA, Duffy CI, Ambrosy AP, Chakraborty H, McCague K, Rocha R, Velazquez EJ (February 2020). "Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure: Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial". JAMA Cardiol. 5 (2): 202–207. doi:10.1001/jamacardio.2019.4665. PMC 6990764 Check |pmc= value (help). PMID 31825471.

[pmid31134724-11] Wachter R, Senni M, Belohlavek J, Straburzynska-Migaj E, Witte KK, Kobalava Z, Fonseca C, Goncalvesova E, Cavusoglu Y, Fernandez A, Chaaban S, Bøhmer E, Pouleur AC, Mueller C, Tribouilloy C, Lonn E, A L Buraiki J, Gniot J, Mozheiko M, Lelonek M, Noè A, Schwende H, Bao W, Butylin D, Pascual-Figal D (August 2019). "Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study". Eur J Heart Fail. 21 (8): 998–1007. doi:10.1002/ejhf.1498. PMID 31134724. Vancouver style error: missing comma (help)

[pmid31535829-12] McMurray J, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman C, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM (November 2019). "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction". N Engl J Med. 381 (21): 1995–2008. doi:10.1056/NEJMoa1911303. PMID 31535829. Vancouver style error: initials (help)

[pmid32865377-13] Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F (October 2020). "Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure". N Engl J Med. 383 (15): 1413–1424. doi:10.1056/NEJMoa2022190. PMID 32865377 Check |pmid= value (help).

[pmid32673497-14] Jackson AM, Dewan P, Anand IS, Bělohlávek J, Bengtsson O, de Boer RA, Böhm M, Boulton DW, Chopra VK, DeMets DL, Docherty KF, Dukát A, Greasley PJ, Howlett JG, Inzucchi SE, Katova T, Køber L, Kosiborod MN, Langkilde AM, Lindholm D, Ljungman C, Martinez FA, O'Meara E, Sabatine MS, Sjöstrand M, Solomon SD, Tereshchenko S, Verma S, Jhund PS, McMurray J (September 2020). "Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF". Circulation. 142 (11): 1040–1054. doi:10.1161/CIRCULATIONAHA.120.047077. PMC 7664959 Check |pmc= value (help). PMID 32673497 Check |pmid= value (help). Vancouver style error: initials (help)

[pmid33200892-15] Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, Lund LH, Komajda M, Testani JM, Wilcox CS, Ponikowski P, Lopes RD, Verma S, Lapuerta P, Pitt B (January 2021). "Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure". N Engl J Med. 384 (2): 117–128. doi:10.1056/NEJMoa2030183. PMID 33200892 Check |pmid= value (help).

[pmid30600580-16] Mullens W, Damman K, Harjola VP, Mebazaa A, Brunner-La Rocca HP, Martens P, Testani JM, Tang W, Orso F, Rossignol P, Metra M, Filippatos G, Seferovic PM, Ruschitzka F, Coats AJ (February 2019). "The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology". Eur J Heart Fail. 21 (2): 137–155. doi:10.1002/ejhf.1369. PMID 30600580. Vancouver style error: initials (help)

[pmid11853901-17] Faris R, Flather M, Purcell H, Henein M, Poole-Wilson P, Coats A (February 2002). "Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials". Int J Cardiol. 82 (2): 149–58. doi:10.1016/s0167-5273(01)00600-3. PMID 11853901.

[pmid31424503-18] Rohde LE, Rover MM, Figueiredo Neto JA, Danzmann LC, Bertoldi EG, Simões MV, Silvestre OM, Ribeiro A, Moura LZ, Beck-da-Silva L, Prado D, Sant'Anna RT, Bridi LH, Zimerman A, Raupp da Rosa P, Biolo A (November 2019). "Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial". Eur Heart J. 40 (44): 3605–3612. doi:10.1093/eurheartj/ehz554. PMID 31424503. Vancouver style error: initials (help)

[pmid13678870-19] Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K (September 2003). "Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial". Lancet. 362 (9386): 772–6. doi:10.1016/S0140-6736(03)14284-5. PMID 13678870.

[pmid11759645-20] Cohn JN, Tognoni G (December 2001). "A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure". N Engl J Med. 345 (23): 1667–75. doi:10.1056/NEJMoa010713. PMID 11759645.

[pmid22575988-21] Böhm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, Reil JC, Swedberg K, Tavazzi L (January 2013). "Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study". Clin Res Cardiol. 102 (1): 11–22. doi:10.1007/s00392-012-0467-8. PMID 22575988.

[pmid20801500-22] Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L (September 2010). "Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study". Lancet. 376 (9744): 875–85. doi:10.1016/S0140-6736(10)61198-1. PMID 20801500.

[pmid15533851-23] Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN (November 2004). "Combination of isosorbide dinitrate and hydralazine in blacks with heart failure". N Engl J Med. 351 (20): 2049–57. doi:10.1056/NEJMoa042934. PMID 15533851.

[pmid25939649-24] Vamos M, Erath JW, Hohnloser SH (July 2015). "Digoxin-associated mortality: a systematic review and meta-analysis of the literature". Eur Heart J. 36 (28): 1831–8. doi:10.1093/eurheartj/ehv143. PMID 25939649.

[pmid25749644-25] Washam JB, Stevens SR, Lokhnygina Y, Halperin JL, Breithardt G, Singer DE, Mahaffey KW, Hankey GJ, Berkowitz SD, Nessel CC, Fox KA, Califf RM, Piccini JP, Patel MR (June 2015). "Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF)". Lancet. 385 (9985): 2363–70. doi:10.1016/S0140-6736(14)61836-5. PMID 25749644.

[pmid12588271-26] Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM (February 2003). "Association of serum digoxin concentration and outcomes in patients with heart failure". JAMA. 289 (7): 871–8. doi:10.1001/jama.289.7.871. PMID 12588271.

[pmid32222134-27] Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, Lam C, Ponikowski P, Voors AA, Jia G, McNulty SE, Patel MJ, Roessig L, Koglin J, O'Connor CM (May 2020). "Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction". N Engl J Med. 382 (20): 1883–1893. doi:10.1056/NEJMoa1915928. PMID 32222134 Check |pmid= value (help). Vancouver style error: initials (help)

[pmid32035892-28] Teerlink JR, Diaz R, Felker GM, McMurray J, Metra M, Solomon SD, Legg JC, Büchele G, Varin C, Kurtz CE, Malik FI, Honarpour N (April 2020). "Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF". JACC Heart Fail. 8 (4): 329–340. doi:10.1016/j.jchf.2019.12.001. PMID 32035892 Check |pmid= value (help). Vancouver style error: initials (help)

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@@ Line 2: / Line 2: @@
 {| class="infobox" style="float:right;"
 |-
-| [[File:Siren.gif|30px|link= Congestive heart failure resident survival guide]]|| <br> || <br>
+| [[File:Siren.gif|30px|link= Chronic heart failure resident survival guide]]|| <br> || <br>
-| [[Acute decompensated  heart failure resident survival guide|'''Resident'''<br>'''Survival'''<br>'''Guide''']]
+| [[Chronic heart failure resident survival guide|'''Resident'''<br>'''Survival'''<br>'''Guide''']]
 |}
-{| class="infobox" style="float:right;"
+{{Congestive heart failure}}
+{{CMG}}; {{AE}} {{Sara.Zand}} {{Rim}}
+==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]]==
+{| style="border: 2px solid #4479BA; align="left"
+! style="width: 200px; background: #4479BA;" | {{fontcolor|#FFF| Betablockers}}
+! style="width: 300px; background: #4479BA;" | {{fontcolor|#FFF|Starting dose}}
+! style="width: 400px; background: #4479BA;" | {{fontcolor|#FFF|Target dose}}
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Bisoprolol]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 1.25 mg once daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 10 mg once daily
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Carvedilol]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 3.125 mg twice daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 25 mg twice daily for weight <85 kg and 50 mg
+twice daily for weight≥ 85 kg
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Metoprolol succinate]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 12.5–25 mg daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 200 mg daily
+|-
+! style="width: 200px; background: #4479BA;" | {{fontcolor|#FFF| ARNIs}}
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Sacubitril/valsartan]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 24/26 mg–49/51 mg twice daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 97/103 mg twice daily
+|-
+! style="width: 200px; background: #4479BA;" | {{fontcolor|#FFF| ACEI}}
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Captopril]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 6.25 mg 3× daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 50 mg 3× daily
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Enalapril]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 2.5 mg twice daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" |  10–20 mg twice daily
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Lisinopril]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 2.5–5 mg daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 20–40 mg daily
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Ramipril]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 1.25 mg daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 10 mg daily
+|-
+! style="width: 200px; background: #4479BA;" | {{fontcolor|#FFF| ARBs}}
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Candesartan]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 4–8 mg daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 32  mg  daily
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Losartan]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 25–50 mg daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 150 mg daily
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Valsartan]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 40 mg twice daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 160 mg twice daily
+|-
+! style="width: 200px; background: #4479BA;" | {{fontcolor|#FFF|Aldosterone antagonists }}
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Eplerenone]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 25 mg daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 50 mg daily
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Spironolactone]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 12.5–25 mg daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" |  25–50 mg daily
+|-
+! style="width: 200px; background: #4479BA;" | {{fontcolor|#FFF| SGL2 ihibitors}}
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Dapagliflozin ]] 10 mg daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 10 mg daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 10 mg daily
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Empagliflozin]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 10 mg daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 10 mg daily
+|-
+! style="width: 200px; background: #4479BA;" | {{fontcolor|#FFF| Vasodilators}}
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Hydralazine]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 25 mg 3× daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 75 mg 3× daily
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Isosorbide dinitrate]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 20 mg 3× daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 40 mg 3× daily
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Fixed-dose combination [[isosorbide dinitrate]]/[[hydralazine]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 20 mg/37.5 mg (1 tab) 3× daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 2 tabs 3× daily
+|-
+|-
+! style="width: 200px; background: #4479BA;" | {{fontcolor|#FFF| Ivabradine}}
+|-
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | [[Ivabradine]]
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | 2.5–5 mg twice daily
+| style="padding: 0 5px; background: #F5F5F5; text-align: left;" | Titrate to [[heart rate]] 50–60 beats/min, Maximum dose 7.5 mg twice daily
 |-
-| [[File:Critical_Pathways.gif|88px|link= Congestive heart failure critical pathways]]|| <br> || <br>
 |}
-{{Congestive heart failure}}
+{|
-{{CMG}}; {{AE}} {{Rim}}
+! colspan="2" style="background: PapayaWhip;" align="center" + |The above table adopted from 2021 AHA/ACC Guideline
+|-
+|}<ref name="pmid33446410">{{cite journal |vauthors=Maddox TM, Januzzi JL, Allen LA, Breathett K, Butler J, Davis LL, Fonarow GC, Ibrahim NE, Lindenfeld J, Masoudi FA, Motiwala SR, Oliveros E, Patterson JH, Walsh MN, Wasserman A, Yancy CW, Youmans QR |title=2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee |journal=J Am Coll Cardiol |volume=77 |issue=6 |pages=772–810 |date=February 2021 |pmid=33446410 |doi=10.1016/j.jacc.2020.11.022 |url=}}</ref>
+== 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%)===
+{| style="cellpadding=0; cellspacing= 0; width: 600px;"
+|-
+| style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF;" align=center |'''Recommendations for HFrEF and NYHA class II–IV
+|-
+|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |'''  ([[ESC guidelines classification scheme|Class I, Level of Evidence A]]):'''
+|-
+|style="padding: 0 5px; font-size: 100%; background: #F5F5F5; width: 70%" align=left|
+❑  [[ACE-I]] is recommended for [[patients]] with [[HFrEF]] to reduce the risk of [[HF]] [[hospitalization]] and [[death]]<br>
+❑ [[Beta-blocker]] is recommended for [[patients]] with stable [[HFrEF]] to reduce the risk of [[HF]] [[hospitalization]] and [[death]]<br>
+❑ [[MRA]] ([[ Mineralocorticoid receptor antagonist]]) is recommended for [[patients]] with [[HFrEF]] to reduce the risk of [[HF]] hospitalization and [[death]]<br>
+❑ [[Dapagliflozin]] or [[empagliflozin]] are recommended for [[patients]] with [[HFrEF]] to reduce the risk of [[HF]] hospitalization and [[death]]<br>
+|-
+|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |'''  ([[ESC guidelines classification scheme|Class I, Level of Evidence B]]):'''
+|-
+|style="padding: 0 5px; font-size: 100%; background: #F5F5F5; width: 70%" align=left|
+❑ [[Sacubitril/valsartan]] is recommended as a replacement for an [[ACE-I]] in [[patients]] with [[HFrEF]] to reduce the risk of [[HF]] hospitalization and [[death]]<br>
+|}
+{|
+! colspan="2" style="background: PapayaWhip;" align="center" + |The above table adopted from 2021 ESC Guideline
+|-
+|}<ref name="pmid34447992">{{cite journal |vauthors=McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A |title=2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure |journal=Eur Heart J |volume=42 |issue=36 |pages=3599–3726 |date=September 2021 |pmid=34447992 |doi=10.1093/eurheartj/ehab368 |url=}}</ref>
+===[[Angiotensin-converting enzyme inhibitors]]===
+*[[ACE-I]]s 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.<ref name="pmid16143696">{{cite journal |vauthors=Willenheimer R, van Veldhuisen DJ, Silke B, Erdmann E, Follath F, Krum H, Ponikowski P, Skene A, van de Ven L, Verkenne P, Lechat P |title=Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III |journal=Circulation |volume=112 |issue=16 |pages=2426–35 |date=October 2005 |pmid=16143696 |doi=10.1161/CIRCULATIONAHA.105.582320 |url=}}</ref>
+* [[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]].
-==Overview==
+=== [[MRA]] or [[Mineralocorticoid receptor antagonists]]===
-There are several goals in the chronic management of systolic [[heart failure]].  The management of [[diastolic heart failure]] is discussed elsewhere.  The first goal is to treat the patient's symptoms of heart failure and to improve the patient's exercise tolerance and quality of life.  The use of [[diuretics]] and regular assessment of the patient's weight helps in avoiding excess body fluids that are associated with [[dyspnea]] and [[orthopnea]].  Another goal of the chronic treatment of [[heart failure]] is to decrease the rate of 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]].
+*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.<ref name="pmid10471456">{{cite journal |vauthors=Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J |title=The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators |journal=N Engl J Med |volume=341 |issue=10 |pages=709–17 |date=September 1999 |pmid=10471456 |doi=10.1056/NEJM199909023411001 |url=}}</ref>
+*[[MRA]]s  improve [[symptoms]].
+* [[MRA]]s 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.
-==Diuresis: First Step in the Management of Heart Failure==
+===[[Angiotensin receptor-neprilysin inhibitor]]===
-The treatment of chronic [[heart failure]] often begins with the administration of [[diuretics]], particularly if the patient has signs or symptoms of volume overload.  While increased left ventricular volume increases contractility to a point, if the heart is filled beyond that point, its contractility diminishes (the patient "falls of the [[Staring curve]]").  Diuretics can reduce volume overload and reduce [[shortness of breath]] and [[edema]].  There are three kinds of diuretics, [[loop diuretics]], [[thiazides]] and [[potassium-sparing diuretics]].  [[Diuretics]] rapidly improve the symptoms of [[heart failure]] (within hours to days).  [[Diuretics]] reduce excess volume that accumulates with [[heart failure]] and decrease [[pulmonary edema]] that causes symptoms of [[dyspnea]] and [[orthopnea]]<ref name="pmid20653715">{{cite journal| author=Michael Felker G| title=Diuretic management in heart failure. | journal=Congest Heart Fail | year= 2010 | volume= 16 Suppl 1 | issue=  | pages= S68-72 | pmid=20653715 | doi=10.1111/j.1751-7133.2010.00172.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20653715  }} </ref>.  [[Lasix]] 20 to 40 mg PO daily is a conventional starting dose, but in some patients, [[torsemide]] may be a better choice due to its more predictable absorption.  Once a day dosing of a given [[diuretic]] is preferred to twice a day dosing at a lower dose.  A rise in [[BUN]] and [[Cr]] may reflect a reduction in renal perfusion, and further [[diuresis]] should only be undertaken with careful monitoring of renal function.  The patient should weigh themselves each morning at the same time on the same scale, and the [[diuretic]] dosing should be adjusted to maintain a constant weight.  Given the risk of [[hypokalemia]] or [[hyperkalemia]], the blood level of electrolyes should be checked regularly.
+* 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).<ref name="pmid25176015">{{cite journal |vauthors=McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR |title=Angiotensin-neprilysin inhibition versus enalapril in heart failure |journal=N Engl J Med |volume=371 |issue=11 |pages=993–1004 |date=September 2014 |pmid=25176015 |doi=10.1056/NEJMoa1409077 |url=}}</ref>
-:*'''Simultaneous With Initiating Diuresis'''
+* [[Patients]] with elevated plasma [[NP]] concentrations, an [[eGFR]]≥ 30 mL/min/1.73 m2 and were able to tolerate [[enalapril]] and then [[sacubitril/valsartan]].
-::*[[Congestive heart failure treatment of underlying causes|Treat the underlying cause of heart failure]] such as [[ischemic heart disease]], [[hypertension]], and [[valvular heart disease]].
+*  Use of [[sacubitril/valsartan]] was associated with  improvement in [[symptoms]] and [[quality of life]] a reduction in the incidence of [[diabetes]] requiring [[insulin]] treatment,<ref name="pmid28330649">{{cite journal |vauthors=Seferovic JP, Claggett B, Seidelmann SB, Seely EW, Packer M, Zile MR, Rouleau JL, Swedberg K, Lefkowitz M, Shi VC, Desai AS, McMurray JJV, Solomon SD |title=Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial |journal=Lancet Diabetes Endocrinol |volume=5 |issue=5 |pages=333–340 |date=May 2017 |pmid=28330649 |pmc=5534167 |doi=10.1016/S2213-8587(17)30087-6 |url=}}</ref>
-::*[[Congestive heart failure treatment of associated conditions|Treat other non cardiac diseases that might contribute to the symptoms of heart failure]] such as [[diabetes]] and [[hyperthyroidism]]<ref name="pmid4903771">{{cite journal| author=DeGroot WJ, Leonard JJ| title=Hyperthyroidism as a high cardiac output state. | journal=Am Heart J | year= 1970 | volume= 79 | issue= 2 | pages= 265-75 | pmid=4903771 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4903771  }} </ref>.
+and a reduction in the decline in [[eGFR]] <ref name="pmid29655829">{{cite journal |vauthors=Damman K, Gori M, Claggett B, Jhund PS, Senni M, Lefkowitz MP, Prescott MF, Shi VC, Rouleau JL, Swedberg K, Zile MR, Packer M, Desai AS, Solomon SD, McMurray JJV |title=Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure |journal=JACC Heart Fail |volume=6 |issue=6 |pages=489–498 |date=June 2018 |pmid=29655829 |doi=10.1016/j.jchf.2018.02.004 |url=}}</ref>as well as a reduced rate of [[hyperkalemia]]<ref name="pmid27842179">{{cite journal |vauthors=Desai AS, Vardeny O, Claggett B, McMurray JJ, Packer M, Swedberg K, Rouleau JL, Zile MR, Lefkowitz M, Shi V, Solomon SD |title=Reduced Risk of Hyperkalemia During Treatment of Heart Failure With Mineralocorticoid Receptor Antagonists by Use of Sacubitril/Valsartan Compared With Enalapril: A Secondary Analysis of the PARADIGM-HF Trial |journal=JAMA Cardiol |volume=2 |issue=1 |pages=79–85 |date=January 2017 |pmid=27842179 |doi=10.1001/jamacardio.2016.4733 |url=}}</ref>.
-::*Treat with a low salt diet<ref name="pmid18437067">{{cite journal| author=Evangelista LS, Shinnick MA| title=What do we know about adherence and self-care? | journal=J Cardiovasc Nurs | year= 2008 | volume= 23 | issue= 3 | pages= 250-7 | pmid=18437067 | doi=10.1097/01.JCN.0000317428.98844.4d | pmc=PMC2880251 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18437067  }} </ref>
+* In addition, the need for [[loop diuretic]] reduced while using of  [[sacubitril/valsartan]].<ref name="pmid30741494">{{cite journal |vauthors=Vardeny O, Claggett B, Kachadourian J, Desai AS, Packer M, Rouleau J, Zile MR, Swedberg K, Lefkowitz M, Shi V, McMurray JJV, Solomon SD |title=Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial |journal=Eur J Heart Fail |volume=21 |issue=3 |pages=337–341 |date=March 2019 |pmid=30741494 |pmc=6607492 |doi=10.1002/ejhf.1402 |url=}}</ref>
-::*Follow the patient's weight to check for [[fluid overload]]
+* 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.
-::*Treat with vaccines for [[influenza]] and [[pneumococcus]] <ref name="pmid21271169">{{cite journal| author=Martins Wde A, Ribeiro MD, Oliveira LB, Barros Lda S, Jorge AC, Santos CM et al.| title=Influenza and pneumococcal vaccination in heart failure: a little applied recommendation. | journal=Arq Bras Cardiol | year= 2011 | volume= 96 | issue= 3 | pages= 240-5 | pmid=21271169 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21271169}} </ref><ref name="pmid14610160">{{cite journal |author=Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Køber L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM |title=Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both |journal=[[The New England Journal of Medicine]] |volume=349 |issue=20 |pages=1893–906 |year=2003 |month=November |pmid=14610160 |doi=10.1056/NEJMoa032292 |url=http://www.nejm.org/doi/abs/10.1056/NEJMoa032292?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov |accessdate=2013-04-29}}</ref>
+* 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.<ref name="pmid31825471">{{cite journal |vauthors=DeVore AD, Braunwald E, Morrow DA, Duffy CI, Ambrosy AP, Chakraborty H, McCague K, Rocha R, Velazquez EJ |title=Initiation of Angiotensin-Neprilysin Inhibition After Acute Decompensated Heart Failure: Secondary Analysis of the Open-label Extension of the PIONEER-HF Trial |journal=JAMA Cardiol |volume=5 |issue=2 |pages=202–207 |date=February 2020 |pmid=31825471 |pmc=6990764 |doi=10.1001/jamacardio.2019.4665 |url=}}</ref><ref name="pmid31134724">{{cite journal |vauthors=Wachter R, Senni M, Belohlavek J, Straburzynska-Migaj E, Witte KK, Kobalava Z, Fonseca C, Goncalvesova E, Cavusoglu Y, Fernandez A, Chaaban S, Bøhmer E, Pouleur AC, Mueller C, Tribouilloy C, Lonn E, A L Buraiki J, Gniot J, Mozheiko M, Lelonek M, Noè A, Schwende H, Bao W, Butylin D, Pascual-Figal D |title=Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study |journal=Eur J Heart Fail |volume=21 |issue=8 |pages=998–1007 |date=August 2019 |pmid=31134724 |doi=10.1002/ejhf.1498 |url=}}</ref>
-==ACE Inhibition and Angiotensin Receptor Blockade: Second Step in the Management of Heart Failure==
+===[[Sodium-glucose co-transporter 2 inhibitors]]===
-After diuretics are started or at the same time they are started, an [[ACE inhibitor]] can be initiated <ref name="pmid1117548">{{cite journal| author=Shiokawa Y| title=Proceedings: Streptococcus surveys in Ryukyu Islands, Japan. | journal=Jpn Circ J | year= 1975 | volume= 39 | issue= 2 | pages= 168-71 | pmid=1117548 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1117548  }} </ref>. This includes a large group of drugs, such as [[Enalapril]] (Vasotec/Renitec), [[Ramipril]] (Altace/Tritace/Ramace/Ramiwin), [[Quinapril]] (Accupril), [[Perindopril]] (Coversyl/Aceon), [[Lisinopril]] (Lisodur/Lopril/Novatec/Prinivil/Zestril) and [[Benazepril]] (Lotensin). They can improve symptoms and prognosis of heart failure in several ways including [[afterload]] reduction and favorable ventricular remodeling. Usual side effects include [[dry cough]] and [[angioedema]].  Patients with bilateral [[renal artery stenosis]] or severe [[renal impairment]] are not appropriate for [[angiotensin converting enzyme inhibitor]] (ACEI).
+*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%.<ref name="pmid31535829">{{cite journal |vauthors=McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM |title=Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction |journal=N Engl J Med |volume=381 |issue=21 |pages=1995–2008 |date=November 2019 |pmid=31535829 |doi=10.1056/NEJMoa1911303 |url=}}</ref>
+* 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% despite[[ OMT]] 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.<ref name="pmid32865377">{{cite journal |vauthors=Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F |title=Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure |journal=N Engl J Med |volume=383 |issue=15 |pages=1413–1424 |date=October 2020 |pmid=32865377 |doi=10.1056/NEJMoa2022190 |url=}}</ref>
+* [[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]].<ref name="pmid32673497">{{cite journal |vauthors=Jackson AM, Dewan P, Anand IS, Bělohlávek J, Bengtsson O, de Boer RA, Böhm M, Boulton DW, Chopra VK, DeMets DL, Docherty KF, Dukát A, Greasley PJ, Howlett JG, Inzucchi SE, Katova T, Køber L, Kosiborod MN, Langkilde AM, Lindholm D, Ljungman CEA, Martinez FA, O'Meara E, Sabatine MS, Sjöstrand M, Solomon SD, Tereshchenko S, Verma S, Jhund PS, McMurray JJV |title=Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF |journal=Circulation |volume=142 |issue=11 |pages=1040–1054 |date=September 2020 |pmid=32673497 |pmc=7664959 |doi=10.1161/CIRCULATIONAHA.120.047077 |url=}}</ref>
+*The combined [[SGLT-1]] and [[SGLT-2]] inhibitors, [[sotagliflozin]], has also been investigated in [[patients]] with [[diabetes]] who were hospitalized with [[HF]].<ref name="pmid33200892">{{cite journal |vauthors=Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, Lund LH, Komajda M, Testani JM, Wilcox CS, Ponikowski P, Lopes RD, Verma S, Lapuerta P, Pitt B |title=Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure |journal=N Engl J Med |volume=384 |issue=2 |pages=117–128 |date=January 2021 |pmid=33200892 |doi=10.1056/NEJMoa2030183 |url=}}</ref>
+*Side effects of  [[SGLT2 inhibitors]] including:
+:* Increased risk of recurrent [[genital]] [[fungal]] infections
+* A small reversible reduction in [[eGFR]] following initiation
-During or after the initiation of diuresis, one could start, for example, [[lisinopril]] 5 mg Q day.  Every 1 - 2 weeks, the dose would be escalated to achieve a target dose of 15 to 20 mg Q day.  An [[ACE inhibitor]] is initiated before a [[beta blocker]] because an [[ACE inhibitor]] achieves its hemodynamic effect more rapidly, and is less likely to cause a decline in hemodynamics.  Although there is some data to suggest that [[aspirin]] blunts the hemodynamic effect of [[ACE inhibitors]], there is no data to suggest that [[aspirin]] reduces the clinical efficacy of [[ACE inhibitors]] in [[heart failure]] patients.  [[Aspirin]] should be administered to patients with [[ischemic heart disease]], but not to patients without it.
+=== Medications with reducing [[mortality]] in [[heart failure reduced EF]]===
+*[[ACE-I]]/[[ARNI]], [[betablocker]], [[mineralocorticoid receptos antagonist]],  [[SGLT2]] inhibitor
-If a patient cannot tolerate a an [[ACE inhibitor]] (develops a cough), then an [[Angiotensin II receptor blocker]] can be administered in its place.  [[Angiotensin II receptor antagonists]] block the activation of angiotensin II AT1 receptors. Blockade of AT1 receptors directly causes [[vasodilation]], reduces secretion of [[vasopressin]], reduces production and secretion of [[aldosterone]]. Because angiotensin II receptor antagonists do not inhibit the breakdown of [[bradykinin]] or other [[kinin]]s, and are thus only rarely associated with the persistent [[dry cough]] and/or [[angioedema]] that limit ACE inhibitor therapy. Commonly administered agents in the management of heart failure include [[Candesartan]], [[Valsartan]], [[Telmisartan]], [[Losartan]], [[Irbesartan]], and [[Olmesartan]].  The effectiveness of switching to an [[ARB]] from and [[ACE inhibitor]] was demonstrated for [[candesartan]] in the CHARM Alternative trial <ref name="pmid13678870">{{cite journal |author=Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K |title=Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial |journal=[[Lancet]] |volume=362 |issue=9386 |pages=772–6 |year=2003 |month=September |pmid=13678870 |doi=10.1016/S0140-6736(03)14284-5 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(03)14284-5 |accessdate=2013-04-29}}</ref>.
+=== Medications with reducing [[hospitalization]] in [[heart failure reduced EF]]===
+*[[Diuretic]], [[digoxin]], [[ivabradine]], [[hydralazine]], [[isosorbide dinitrate]]
-In general, [[ARBs]] are as effective or slightly less effective than [[ACE inhibitors]] in the treatment of [[congestive heart failure]].<ref name="pmid11823085">{{cite journal |author=Jong P, Demers C, McKelvie RS, Liu PP |title=Angiotensin receptor blockers in heart failure: meta-analysis of randomized controlled trials |journal=[[Journal of the American College of Cardiology]] |volume=39 |issue=3 |pages=463–70 |year=2002 |month=February |pmid=11823085 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0735109701017752 |accessdate=2013-04-29}}</ref><ref name="pmid10821361">{{cite journal |author=Pitt B, Poole-Wilson PA, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam MA, Riegger G, Klinger GH, Neaton J, Sharma D, Thiyagarajan B |title=Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial--the Losartan Heart Failure Survival Study ELITE II |journal=[[Lancet]] |volume=355 |issue=9215 |pages=1582–7 |year=2000 |month=May |pmid=10821361 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S0140673600022133 |accessdate=2013-04-29}}</ref>  It is a class 2a recommendation to substitute an [[ARB]] as an alternative to ACE inhibitors if the patient is already taking an [[ARB]] for another indication.<ref name="pmid19324966">{{cite journal |author=Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW |title=2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation |journal=[[Circulation]] |volume=119 |issue=14 |pages=e391–479 |year=2009 |month=April |pmid=19324966 |doi=10.1161/CIRCULATIONAHA.109.192065 |url=http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=19324966 |accessdate=2013-04-29}}</ref>
+==Other medications in [[HFrEF]] in [[patients]] with [[NYHA]] 2-4==
+{| style="cellpadding=0; cellspacing= 0; width: 600px;"
+|-
+| style="padding: 0 5px; font-size: 100%; background: #4682B4; color: #FFFFFF;" align=center |'''Recommendations for heart failure with reduced ejection fraction  and NYHA 2-4'''
+|-
+|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left | '''[[Loop diuretics]]  ([[ 2021 ESC guidelines classification scheme|Class I, Level of Evidence C]]):'''
+|-
+|style="padding: 0 5px; font-size: 100%; background: #F5F5F5; width: 70%" align=left|
+❑ [[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<br>
+|-
+|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left | '''[[ARB]]  ([[ 2021 ESC guidelines classification scheme|Class I, Level of Evidence B]]):'''
+|-
+|style="padding: 0 5px; font-size: 100%; background: #F5F5F5; width: 70%" align=left|
+❑ [[ 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]])<br>
+|-
+|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |'''[[If-channel inhibitor]] :([[ESC guidelines classification scheme|Class IIa, Level of Evidence B]]) :'''
+|-
+|style="padding: 0 5px; font-size: 100%; background: #F5F5F5; width: 70%" align=left|
+❑[[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 <br>
+|-
+|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |'''[[If-channel inhibitor]] : ([[ESC guidelines classification scheme|Class IIa, Level of Evidence C]])'''
+|-
+|style="padding: 0 5px; font-size: 100%; background: #F5F5F5; width: 70%" align=left|
+❑ [[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]] <br>
+|-
+|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |'''[[Soluble guanylate cyclase receptor stimulator]]: ([[ESC guidelines classification scheme|Class IIb, Level of Evidence B]])'''
+|-
+|style="padding: 0 5px; font-size: 100%; background: #F5F5F5; width: 70%" align=left|
+❑ [[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<br>
+|-
+|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |'''[[Hydralazine]], [[isosorbide dinitrate]] : ([[ESC guidelines classification scheme|Class IIa, Level of Evidence B]])'''
+|-
+|style="padding: 0 5px; font-size: 100%; background: #F5F5F5; width: 70%" align=left|
+❑ [[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<br>
+|-
+|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left | '''[[Hydralazine]], [[isosorbide dinitrate]] ([[ESC guidelines classification scheme|Class IIb, Level of Evidence B]]):'''
+|-
+|style="padding: 0 5px; font-size: 100%; background: #F5F5F5; width: 70%" align=left|
+❑ [[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<br>
+|-
+|style="font-size: 100; padding: 0 5px; background: #B8B8B8" align=left |'''[[Digoxin]]: ([[ESC guidelines classification scheme|ClassIIb, Level of Evidence B]])'''
+|-
+|style="padding: 0 5px; font-size: 100%; background: #F5F5F5; width: 70%" align=left|
+❑ [[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)<br>
-The efficacy of adding an [[ARB]] to an [[ACE inhibitor]] was assessed in the CHARM Added trial<ref name="pmid13678869">{{cite journal |author=McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, Olofsson B, Yusuf S, Pfeffer MA |title=Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial |journal=[[Lancet]] |volume=362 |issue=9386 |pages=767–71 |year=2003 |month=September |pmid=13678869 |doi=10.1016/S0140-6736(03)14283-3 |url=http://linkinghub.elsevier.com/retrieve/pii/S0140-6736(03)14283-3 |accessdate=2013-04-29}}</ref>. While there was a reduction in the composite primary endpoint in the study, there was no reduction in mortality.  Furthermore, the VALIANT trial demonstrated that an [[ARB]] should not be added to an [[ACE inhibitor]] in the post [[MI]] setting.   These results for [[ARBs]] are in contrast to the results of the EMPHASIS HF trial showed that the addition of [[eplerenone]] (an [[aldosterone antagonist]]) to [[ACE inhibition]] improved clinical outcomes including mortality among patients with class II or III [[heart failure]] with a reduced [[LVEF]].<ref name="pmid21073363">{{cite journal |author=Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B |title=Eplerenone in patients with systolic heart failure and mild symptoms |journal=[[The New England Journal of Medicine]] |volume=364 |issue=1 |pages=11–21 |year=2011 |month=January |pmid=21073363 |doi=10.1056/NEJMoa1009492 |url=http://www.nejm.org/doi/abs/10.1056/NEJMoa1009492?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov |accessdate=2013-04-29}}</ref>  Thus, based upon the mortality benefit observed in the EMPHASIS HF trial, an [[aldosterone antagonist]] rather than and [[ARB]] should be added to an [[ACE inhibitor]] in patients with NYHA class II [[heart failure]] and an [[LVEF]] < 30%, in the post-[[MI]] patient who has an [[LVEF]] <u><</u> 40% who has [[heart failure]] symptoms or [[diabetes]], and the patient with class III or IV [[heart failure]] who has an [[LVEF]] < 35%.
+|-
+|}
+{|
+! colspan="2" style="background: PapayaWhip;" align="center" + |The above table adopted from 2021 ESC Guideline
+|-
+|}<ref name="pmid34447992">{{cite journal |vauthors=McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A |title=2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure |journal=Eur Heart J |volume=42 |issue=36 |pages=3599–3726 |date=September 2021 |pmid=34447992 |doi=10.1093/eurheartj/ehab368 |url=}}</ref>
-"Triple therapy", the combined use of an [[ACE inhibitor]], an [[ARB]] and an [[aldosterone antagonist]] is a relative contraindication.
+===[[Diuretics]]===
+*[[Loop diuretics]] is recommended to reduce the signs and/or symptoms of [[congestion]] in [[patients]] with [[ HFrEF]].<ref name="pmid30600580">{{cite journal |vauthors=Mullens W, Damman K, Harjola VP, Mebazaa A, Brunner-La Rocca HP, Martens P, Testani JM, Tang WHW, Orso F, Rossignol P, Metra M, Filippatos G, Seferovic PM, Ruschitzka F, Coats AJ |title=The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology |journal=Eur J Heart Fail |volume=21 |issue=2 |pages=137–155 |date=February 2019 |pmid=30600580 |doi=10.1002/ejhf.1369 |url=}}</ref>
+* 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]].<ref name="pmid11853901">{{cite journal |vauthors=Faris R, Flather M, Purcell H, Henein M, Poole-Wilson P, Coats A |title=Current evidence supporting the role of diuretics in heart failure: a meta analysis of randomised controlled trials |journal=Int J Cardiol |volume=82 |issue=2 |pages=149–58 |date=February 2002 |pmid=11853901 |doi=10.1016/s0167-5273(01)00600-3 |url=}}</ref>
+* [[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.<ref name="pmid31424503">{{cite journal |vauthors=Rohde LE, Rover MM, Figueiredo Neto JA, Danzmann LC, Bertoldi EG, Simões MV, Silvestre OM, Ribeiro ALP, Moura LZ, Beck-da-Silva L, Prado D, Sant'Anna RT, Bridi LH, Zimerman A, Raupp da Rosa P, Biolo A |title=Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial |journal=Eur Heart J |volume=40 |issue=44 |pages=3605–3612 |date=November 2019 |pmid=31424503 |doi=10.1093/eurheartj/ehz554 |url=}}</ref>
+* [[Patients]] should be trained to self-adjust their [[diuretic]] dose based on monitoring of symptoms/signs of [[congestion]] and daily [[weight]] measurements.
-==Beta blockers: Third Step in the Management of Heart Failure==
+===[[Angiotensin II type I receptor blockers]]===
-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]].
+* [[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.<ref name="pmid13678870">{{cite journal |vauthors=Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, Ostergren J, Pfeffer MA, Swedberg K |title=Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial |journal=Lancet |volume=362 |issue=9386 |pages=772–6 |date=September 2003 |pmid=13678870 |doi=10.1016/S0140-6736(03)14284-5 |url=}}</ref>
+*In the [[Val-HeFT]] trial,  [[Valsartan]], in addition to usual therapy, including [[ACE-I]], reduced [[HF]] hospitalizations.<ref name="pmid11759645">{{cite journal |vauthors=Cohn JN, Tognoni G |title=A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure |journal=N Engl J Med |volume=345 |issue=23 |pages=1667–75 |date=December 2001 |pmid=11759645 |doi=10.1056/NEJMoa010713 |url=}}</ref>
+* [[ARB]]s have not reduced [[all-cause mortality]] in any trial.
-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]]<ref name="pmid11281737">{{cite journal |author=Brophy JM, Joseph L, Rouleau JL |title=Beta-blockers in congestive heart failure. A Bayesian meta-analysis |journal=[[Annals of Internal Medicine]] |volume=134 |issue=7 |pages=550–60 |year=2001 |month=April |pmid=11281737 |doi= |url=http://www.annals.org/article.aspx?volume=134&page=550 |accessdate=2013-04-28}}</ref>.  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]].
+===[[If -channel inhibitor]]===
-:Relative contraindications to beta-blocker administration include the following:
+*[[Ivabradine]] slows [[heart rate]] by inhibition of the If channel in the [[sinus node]] only in [[patients]] with [[sinus rhythm]].<ref name="pmid22575988">{{cite journal |vauthors=Böhm M, Borer J, Ford I, Gonzalez-Juanatey JR, Komajda M, Lopez-Sendon J, Reil JC, Swedberg K, Tavazzi L |title=Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study |journal=Clin Res Cardiol |volume=102 |issue=1 |pages=11–22 |date=January 2013 |pmid=22575988 |doi=10.1007/s00392-012-0467-8 |url=}}</ref>
-:*[[Asthma]] or [[bronchospasm]]
+* 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.<ref name="pmid20801500">{{cite journal |vauthors=Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L |title=Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study |journal=Lancet |volume=376 |issue=9744 |pages=875–85 |date=September 2010 |pmid=20801500 |doi=10.1016/S0140-6736(10)61198-1 |url=}}</ref>
-:*[[Hypotension]] resulting in poor end organ perfusion or symptoms
+* [[Ivabradine]] has survival benefit.
-:*[[Bradycardia]] or [[heart block]] ([[first degree heart block]] with a [[PR interval]] > 0.24, [[second degree heart block]], [[third degree heart block]]
+* Before to considering [[ivabradine]], uptitrate [[beta-blocker]] therapy to maximally tolerated doses is recommended.
-:*[[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.
+=== Combination of [[hydralazine]] and [[isosorbide dinitrate]]===
-:*[[Carvedilol]]: Initial dose 3.125 mg twice daily, target dose 25 to 50 mg twice daily
+* 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.
-:*[[Metoprolol succinate]]: Initial dose 12.5 mg daily, target dose 200 mg daily
+*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.<ref name="pmid15533851">{{cite journal |vauthors=Taylor AL, Ziesche S, Yancy C, Carson P, D'Agostino R, Ferdinand K, Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN |title=Combination of isosorbide dinitrate and hydralazine in blacks with heart failure |journal=N Engl J Med |volume=351 |issue=20 |pages=2049–57 |date=November 2004 |pmid=15533851 |doi=10.1056/NEJMoa042934 |url=}}</ref>
-:*[[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==
+===[[ Digoxin]]===
-An [[aldosterone antagonist]] can be added to the regimen of 'select' patients.  These selected patients include:
+*[[Digoxin]] may be considered in [[patients]] with [[HFrEF]] in [[sinus rhythm]] to reduce the risk of hospitalization.
-:*Class II [[heart failure]] and a [[left ventricular ejection fraction]] ([[LVEF]]) < 30%
+* In the [[DIG trial]], [[digoxin]] was not effective on [[mortality]].
-:*Class III/IV [[heart failure]] and a [[LVEF]] <35%
+*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]].<ref name="pmid25939649">{{cite journal |vauthors=Vamos M, Erath JW, Hohnloser SH |title=Digoxin-associated mortality: a systematic review and meta-analysis of the literature |journal=Eur Heart J |volume=36 |issue=28 |pages=1831–8 |date=July 2015 |pmid=25939649 |doi=10.1093/eurheartj/ehv143 |url=}}</ref><ref name="pmid25749644">{{cite journal |vauthors=Washam JB, Stevens SR, Lokhnygina Y, Halperin JL, Breithardt G, Singer DE, Mahaffey KW, Hankey GJ, Berkowitz SD, Nessel CC, Fox KA, Califf RM, Piccini JP, Patel MR |title=Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) |journal=Lancet |volume=385 |issue=9985 |pages=2363–70 |date=June 2015 |pmid=25749644 |doi=10.1016/S0140-6736(14)61836-5 |url=}}</ref>
-:*Post [[ST segment elevation MI]] and a [[LVEF]] < 40% who have either symptomatic [[heart failure]] or diabetes.
+* Another meta-analysis concluded that [[digoxin]] has no deleterious effect on [[mortality]] in [[patients]] with [[AF]] and [[HFrEF]].
-:*The [[serum potassium]] must be under 5.0 meq/li and the [[glomerular filtration rate]] ([[GFR]]) should be > 30 cc per minute
+* 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.
-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.
+*[[Digoxin]] has a narrow therapeutic window and so levels should be checked  for maintaing a serum [[digoxin]] concentration <1.2 ng/mL.<ref name="pmid12588271">{{cite journal |vauthors=Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM |title=Association of serum digoxin concentration and outcomes in patients with heart failure |journal=JAMA |volume=289 |issue=7 |pages=871–8 |date=February 2003 |pmid=12588271 |doi=10.1001/jama.289.7.871 |url=}}</ref>
+*Caution should also be exercised in [[patients]] as followes:
+:*[[Females]]
+:* The [[elderly]]
+:*[[Frail]]
+:* [[Hypokalaemia]]
+:* [[Malnourishment ]]
+:*Reduced [[renal]] function
-'''Risk Factors for the Development of Hyperkalemia on an Aldosterone Antagonist'''
+===Soluble [[guanylate cyclase receptor stimulator]]===
-:*Triple therapy with an [[ACE inhibitor]] and [[angiotensin II receptor blocker]] makes this combination a contraindication
+*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]].<ref name="pmid32222134">{{cite journal |vauthors=Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, Lam CSP, Ponikowski P, Voors AA, Jia G, McNulty SE, Patel MJ, Roessig L, Koglin J, O'Connor CM |title=Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction |journal=N Engl J Med |volume=382 |issue=20 |pages=1883–1893 |date=May 2020 |pmid=32222134 |doi=10.1056/NEJMoa1915928 |url=}}</ref>
-:*Higher doses of either an [[ACE inhibitor]] or an [[angiotensin receptor blocker]] ([[ARB]])
+* Use of [[ vericiguat]] was associated with reduced hospitalization. However, there were no reduction in [[all-cause]] or [[cardiovascular]] [[mortality]].
-:*[[Hyperkalemia]] prior to initiation of [[spironolactone]]
+* [[Vericiguat]] may be considered, in addition to standard therapy for [[HFrEF]], to reduce the risk of [[cardiovascular]] [[mortality]] and hospitalizations for [[HF]].
-:*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==
+===[[Cardiac myosin activator]]===
-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.
+* the efficacy and safety of the [[cardiac myosin]] activator, [[omecamtiv mecarbil]], in [[HFrEF]] [[patients]], was assessed by The [[GALACTIC-HF]] study.<ref name="pmid32035892">{{cite journal |vauthors=Teerlink JR, Diaz R, Felker GM, McMurray JJV, Metra M, Solomon SD, Legg JC, Büchele G, Varin C, Kurtz CE, Malik FI, Honarpour N |title=Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF |journal=JACC Heart Fail |volume=8 |issue=4 |pages=329–340 |date=April 2020 |pmid=32035892 |doi=10.1016/j.jchf.2019.12.001 |url=}}</ref>
+* 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.
-==Digoxin: Sixth step in the Management of Heart Failure==
+== Management of [[chronic 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.<ref name="pmid9036306">{{cite journal |author= |title=The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group |journal=[[The New England Journal of Medicine]] |volume=336 |issue=8 |pages=525–33 |year=1997 |month=February |pmid=9036306 |doi=10.1056/NEJM199702203360801 |url=http://www.nejm.org/doi/abs/10.1056/NEJM199702203360801?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov |accessdate=2013-04-29}}</ref> 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.<ref name="pmid12588271">{{cite journal |author=Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM |title=Association of serum digoxin concentration and outcomes in patients with heart failure |journal=[[JAMA : the Journal of the American Medical Association]] |volume=289 |issue=7 |pages=871–8 |year=2003 |month=February |pmid=12588271 |doi= |url=http://jama.jamanetwork.com/article.aspx?volume=289&page=871 |accessdate=2013-04-29}}</ref>  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.<ref name="pmid16053964">{{cite journal |author=Adams KF, Patterson JH, Gattis WA, O'Connor CM, Lee CR, Schwartz TA, Gheorghiade M |title=Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis |journal=[[Journal of the American College of Cardiology]] |volume=46 |issue=3 |pages=497–504 |year=2005 |month=August |pmid=16053964 |doi=10.1016/j.jacc.2005.02.091 |url=http://linkinghub.elsevier.com/retrieve/pii/S0735-1097(05)01049-1 |accessdate=2013-04-29}}</ref>
+===Serial clinical evaluation , titration of [[Medications]]===
+===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
-[[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.
+===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
-==Cardiac Resynchronization Therapy==
+===Lack of response, instability===
-[[Cardiac Resynchronization Therapy]] ([[CRT]]) is recommended in [[congestive heart failure]] patients with:
+* Referral to advanced [[heart failure]] specialist if there are:
-:*Symptoms: NYHA Class II-IV
+* Use of IV  [[inotropes]]
-:*QRS: A prolonged [[QRS interval]] <u>></u> 0.12
+* [[NYHA]] 3B, 4, or persistently high level of [[natrioretic peptide]]
-:*LVEF: A [[LVEF]] < 30% to 35%
+* [[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]]
-;Shown below is an image that summarizes the steps in the chronic management of patients with heart failure.
+===Assessment of response to [[medications]]===
-[[Image:Management_of_heart_failure.png‎|center|600px|Management of chronic heart failure]]
+* 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]]
 ==References==
 {{Reflist|2}}
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