Congestive heart failure chronic pharmacotherapy

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Systolic Dysfunction
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HFpEF
HFrEF

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Treatment

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Medical Therapy:

Summary
Acute Pharmacotherapy
Chronic Pharmacotherapy in HFpEF
Chronic Pharmacotherapy in HFrEF
Diuretics
ACE Inhibitors
Angiotensin receptor blockers
Aldosterone Antagonists
Beta Blockers
Ca Channel Blockers
Nitrates
Hydralazine
Positive Inotropics
Anticoagulants
Angiotensin Receptor-Neprilysin Inhibitor
Antiarrhythmic Drugs
Nutritional Supplements
Hormonal Therapies
Drugs to Avoid
Drug Interactions
Treatment of underlying causes
Associated conditions

Exercise Training

Surgical Therapy:

Biventricular Pacing or Cardiac Resynchronization Therapy (CRT)
Implantation of Intracardiac Defibrillator
Ultrafiltration
Cardiac Surgery
Left Ventricular Assist Devices (LVADs)
Cardiac Transplantation

ACC/AHA Guideline Recommendations

Initial and Serial Evaluation of the HF Patient
Hospitalized Patient
Patients With a Prior MI
Sudden Cardiac Death Prevention
Surgical/Percutaneous/Transcather Interventional Treatments of HF
Patients at high risk for developing heart failure (Stage A)
Patients with cardiac structural abnormalities or remodeling who have not developed heart failure symptoms (Stage B)
Patients with current or prior symptoms of heart failure (Stage C)
Patients with refractory end-stage heart failure (Stage D)
Coordinating Care for Patients With Chronic HF
Quality Metrics/Performance Measures

Implementation of Practice Guidelines

Congestive heart failure end-of-life considerations

Specific Groups:

Special Populations
Patients who have concomitant disorders
Obstructive Sleep Apnea in the Patient with CHF
NSTEMI with Heart Failure and Cardiogenic Shock

Congestive heart failure chronic pharmacotherapy On the Web

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Ongoing Trials at Clinical Trials.gov

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FDA on Congestive heart failure chronic pharmacotherapy

CDC on Congestive heart failure chronic pharmacotherapy

Congestive heart failure chronic pharmacotherapy in the news

Blogs on Congestive heart failure chronic pharmacotherapy

Directions to Hospitals Treating Congestive heart failure chronic pharmacotherapy

Risk calculators and risk factors for Congestive heart failure chronic pharmacotherapy

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

Beta-blockers

MRA or Mineralocorticoid receptor antagonists

Angiotensin receptor-neprilysin inhibitor

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

Sodium-glucose co-transporter 2 inhibitors

  • A small reversible reduction in eGFR following initiation

Medications with reducing mortality in heart failure reduced EF

Medications with reducing hospitalization in heart failure reduced EF

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

Angiotensin II type I receptor blockers

If -channel inhibitor

Combination of hydralazine and isosorbide dinitrate

Digoxin

Soluble guanylate cyclase receptor stimulator

Cardiac myosin activator

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

Lack of response, instability

Assessment of response to medications

References

  1. 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 (February 2021). "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". J Am Coll Cardiol. 77 (6): 772–810. doi:10.1016/j.jacc.2020.11.022. PMID 33446410 Check |pmid= value (help).
  2. 2.0 2.1 McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, Burri H, Butler J, Čelutkienė J, Chioncel O, Cleland J, Coats A, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam C, Lyon AR, McMurray J, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano G, Ruschitzka F, Kathrine Skibelund A (September 2021). "2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure". Eur Heart J. 42 (36): 3599–3726. doi:10.1093/eurheartj/ehab368. PMID 34447992 Check |pmid= value (help). Vancouver style error: initials (help)
  3. 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 (October 2005). "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". Circulation. 112 (16): 2426–35. doi:10.1161/CIRCULATIONAHA.105.582320. PMID 16143696.
  4. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J (September 1999). "The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators". N Engl J Med. 341 (10): 709–17. doi:10.1056/NEJM199909023411001. PMID 10471456.
  5. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR (September 2014). "Angiotensin-neprilysin inhibition versus enalapril in heart failure". N Engl J Med. 371 (11): 993–1004. doi:10.1056/NEJMoa1409077. PMID 25176015.
  6. Seferovic JP, Claggett B, Seidelmann SB, Seely EW, Packer M, Zile MR, Rouleau JL, Swedberg K, Lefkowitz M, Shi VC, Desai AS, McMurray J, Solomon SD (May 2017). "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". Lancet Diabetes Endocrinol. 5 (5): 333–340. doi:10.1016/S2213-8587(17)30087-6. PMC 5534167. PMID 28330649. Vancouver style error: initials (help)
  7. 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 J (June 2018). "Renal Effects and Associated Outcomes During Angiotensin-Neprilysin Inhibition in Heart Failure". JACC Heart Fail. 6 (6): 489–498. doi:10.1016/j.jchf.2018.02.004. PMID 29655829. Vancouver style error: initials (help)
  8. Desai AS, Vardeny O, Claggett B, McMurray JJ, Packer M, Swedberg K, Rouleau JL, Zile MR, Lefkowitz M, Shi V, Solomon SD (January 2017). "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". JAMA Cardiol. 2 (1): 79–85. doi:10.1001/jamacardio.2016.4733. PMID 27842179.
  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)
  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.
  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)
  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)
  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).
  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)
  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).
  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)
  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.
  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)
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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)
  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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