Therapeutics of Heart Failure

Noon Conference
February 20th, 2018
Ashley Bailey, Pharm.D.
 Outline
• Definition
• Incidence
• Chronic Heart Failure
– RAAS inhibition
• ACE Inhibitors
• ARBs
• ARNIs
• Aldosterone Antagonists
– ß-Blockers
– Ivabradine
– Digoxin
– Hydralazine/Isosorbide
– Diuretics

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 Definition
• What is Heart Failure (HF)?
– Difficulty in filling and/or ejecting blood from heart to body
• Measured by ejection fraction (EF)
– Diastolic Heart Failure
• Preserved EF (HFpEF)
• EF >50%
• “Filling Problem”
– Systolic Heart Failure***
• Reduced EF (HFrEF)
• EF <40%
• Pumping/ejecting problem
• No longer recommend using term "Congestive” HF

Yancy CW, et al. Circulation 2016; 134

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 Further Defining Heart Failure
New York Heart Association American Heart Association
(NYHA) (AHA)
• Classes I – IV • Stages A-D
• I – Asymptomatic • A – At risk of HF w/o
• II – Symptomatic with structural disease
moderate exertion • B – Structural disease w/o
• III – Symptomatic with symptoms
minimal exertion • C – Structural disease with
• IV – Symptomatic at rest current or prior symptoms
• D – Refractory heart
disease requiring
specialized intervention
Yancy CW, et al. Circulation 2016; 134
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 Incidence
• ~5.7 million adults in US living with HF
• 5 year mortality as high as 50%
– 1 in 9 deaths in 2009 listed HF as contributory
cause
• HF costs the in US >$30billion each year
– Health care services, medications, missed work

Heidenreich PAD, et al. Circulation. 2011;123.

Mozzafarian D, et al. Circulation. 2016;133.
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 Cardiac Output (CO)
• CO = Heart Rate (HR) X Stroke Volume (SV)
– HR - # contractions of the ventricle each minute
– SV – The amount of blood ejected from each
ventricle with each contraction
•Contractility + Preload – Afterload (vascular
resistance)
– CO – the amount of blood pumped by each
ventricle in 1 min

Yancy CW, et al. Circulation 2016; 134.

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Renin-Angiotensin-Aldosterone System
• Angiotensin-converting enzyme (ACE) inhibitors
– Captopril, enalapril, fosinopril, lisinopril, perindopril,
quinapril, ramipril, trandolapril
• Angiotensin receptor blockers (ARB)
– Candesartan, losartan, valsartan
• Angiotensin receptor blocker + neprilysin inhibitor (ARNI)
– Entresto (sacubitril/valsartan)
• Aldosterone Antagonists
– Spironolactone, eplerenone

Yancy CW, et al. Circulation 2016; 134.

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 Angiotensin-converting enzyme
(ACE) inhibitors
Captopril, enalapril, fosinopril, lisinopril, perindopril,
quinapril, ramipril, trandolapril
• MOA: Inhibit production of angiotentsion II
• HF Benefit?
– Decrease morbidity and mortality
• ATLAS
• Contraindications
– Angioedema, pregnancy
• Caution
– Low SBP, renal insufficiency, elevated K
• Side Effects
– Postural hypotension, angioedema, cough
• Monitoring
Packer M, et al. Circulation. 1999
– SCr, K Yancy CW, et al. Circulation 2016
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 Angiotensin receptor blockers
(ARB)
Candesartan, Losartan, and Valsartan
• MOA: block binding of angiotension II
• HF Benefit?
– Improve acute symptoms, reduce mortality and hospitalizations
– ELITE I and ELITE II
• ARBs secondary to ACE
– ARB trial after ACE inhibitor failure
• Angioedema or Cough
• Caution
– Low SBP, renal insufficiency, elevated K
• Monitoring
– Same as ACEI
• Any preferred? Massie BM, et al. N. Engl. J Med. 2008
Pitt B,, et al. Lancet. 1997
Yancy CW, et al. Circulation 2016
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 Renin-Angiotensin-Aldosterone
System (RAAS)

ACE Inhibitors

https://upload.wikimedia.org/wikipedia/commons/a/a2/Renin-angiotensin-aldosterone_system.png

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 Angiotensin receptor blocker +
neprilysin inhibitor (ARNI)
Entresto (sacubitril/valsartan)
• MOA: ARB + inhibits breakdowns of natriuretic peptides
• HF Benefit?
– Decreased mortality and hospitalization
• PARADIGM-HF and PIONEER (in progress)

• Dosing
– New Start vs Previous ACE/ARB
– 36 hour wash out period
• Caution
– Hypotension, renal insufficiency
• Contraindicated
– Hx angioedema
• OVERTURE and OCTAVE

• Monitoring
Kostis JB, et al..Am J Hypertens. 2004
– SCr McMurray J, et al. N ENG J MED 2014
Packer M, et al. Circulation. 2002
– BNP vs pro-BNP Yancy CW, et al. Circulation 2016
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 RAAS and NP Systems

https://www.researchgate.net/profile/Massimo_Volpe/publication/264982341/
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 Aldosterone Antagonists
Eplerenone and Spironolactone
• MOA: Block aldosterone effects in heart, vasculature and kidneys
• Patient selection
– NYHA class II-IV patients, LVEF <35%, GFR>30 mL/min, and K+ <5
• HF Benefit?
– ↓ Mortality, morbidity, hospitalizations
• RALES
• Monitoring
– K, sCr
• Increased risk of hyperkalemia
– ACE/ARB
– Renal dysfxn
» EMPHASIS
• Adverse Effects
– Gynecomastia
• Spironolactone ~10%
Eschalier R, et al. J Am Coll Cardiol. 2013
Pitt B, et al. N. Engl. J. Med. 1999
Yancy CW, et al. Circulation 2016
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 Aldosterone Effects

http://circres.ahajournals.org/content/circresaha/116/1/206/F1.large.jpg

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 ß-Blockers
Bisoprolol, carvedilol, metoprolol succinate
• MOA:
– ↓sympathetic nervous activity and vagal withdrawal
• HF Benefit?
– ↓morbidity and mortality
• CIBIS-II, COPERNICUS
MERIT-HF, COMET
• Caution
– Reactive airway disease and bradycardia
• Adverse Effects https://www.medscape.com/viewarticle/463477_1

– Fatigue, bradycardia/heart block, hypotension, CIBIS-II investigators. Lancet. 1999.

MERIT-HF Study Group. Lancet. 1999.
worsening of HF sxs. Packer M, et al. Circulation. 2002.
Poole‐Wilson PA, et al. Lancet. 2003.
Yancy CW, et al. Circulation 2016.
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 If Channel Inhibitor
Corlanor
(ivabradine)
• MOA: ↓ HR

• HF Benefit?
• ↓ Hospitalizations
• SHIFT
• Patient selection
• EF <35%, HR >70,
NSR, recent HF
admission, and
maximum tolerated BB
• Side Effects
• Bradycardia, HTN, new http://heart.bmj.com/content/99/2/72

afib, phosphene
Swedberg K, et al. Lancet 2010; 376.
Yancy CW, et al. Circulation 2016.
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 Vasodilators
BiDil (Isosorbide dinitrate/hydralazine)
• MOA: Veno/vasodilator
• HF Benefit?
– ↓ morbidity and mortality
•Combination but not individually
– A-HEFT, V-HeFT II, NEAT-HF

• Adherence barriers
– TID dosing
– SE: HA, dizziness, GI distress, drug-induced lupus
(hydralazine)
Cohn JN, et al. N Engl J Med 1986.
Cohn JN, et al. N Engl J Med 1991.
Redfield MM, et al. N Engl J Med. 2015.
Yancy CW, et al. Circulation 2013.
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 Digoxin
• MOA: Inhibit Na/K ATPase -> increase intracellular Ca
• HF Benefit?
– ↓ Hospitalizations
• DIG Study

• Caution
– Use with amiodarone and beta-blocker (bradycardia)
– Renal dysfxn
• Monitoring
– Tx range – 0.5-0.9ng/ml
• Toxicity
– GI, visual disturbances, cardiac arrhythmia
– Reversal with Digibind
The Digitalis Investigation Group. N Engl J Med. 1997
Yancy CW, et al. Circulation 2013.
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 Diuretics
• Loop
– Furosemide
– Torsemide
– Bumetanide
• Thiazide
– Metolazone
– Hydrocholorthiazide
– Chlorthiazide
– Chlorthalidone
– Indapamide
• Potassium sparing
http://www.doctorshangout.com/profiles/blogs/diuretics-sites-of-action – Spironolactone*
– Eplerenone*
Yancy CW, et al. Circulation. 2016; 134
– Triamterene Yancy CW, et al. Circulation. 2013;128
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 Review
• Maximize agents with most heart failure
benefit.
– BB*, ACEI/ARB/ARNI, Aldosterone antagonist
• Add additional agents if above not tolerated
and/or other indications.
– Digoxin, Isosorbide/hydralazine, Ivabradine
• Medications only beneficial in HFrEF not pEF

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 References
1. CIBIS II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;
353: 9146, 9–13.
2. Cohn JN, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure results of a Veterans Administration
cooperative study. N Engl J Med 1986; 314: 1547-52.
3. Cohn JN, et al. A comparision of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart
failure. N Engl J Med 1991;325:3-3-10.
4. Eschalier R, McMurray JJV, Swedberg K, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or
worsening renal function: analyses of the EMPHASIS‐HF study subgroups (Eplerenone in Mild Patients Hospitalization And
SurvIval Study in Heart Failure). J Am Coll Cardiol. 2013; 62:1585‐93.
5. Ferraria CM, et al. Role of Mineralocorticoid Receptor Antagonists in Cardiovascular Disease. Circ Res. 2015;116:206-213.
6. Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, et al. Forecasting the future of cardiovascular
disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123(8):933–44.
7. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N.
Engl. J Med. 2008; 359:2456‐67.
8. McMurray J, et al. Angiotnesin-Neprilysin Inhibition versus Enalapril in Heart Failure. N ENG J MED 2014; 371:993-1004.
9. Mozzafarian D, Benjamin EJ, Go AS, et al. on behalf of the American Heart Association Statistics Committee and Stroke Statistics
Subcommittee. Heart disease and stroke statistics—2016 update: a report from the American Heart Association. Circulation.
2016;133:e38-e360.
10. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Study Group. Effect of metoprolol CR/XL
in chronic heart failure. Lancet. 1999;353:2001–2007.
11. Nohria, A, et al. Medical Management of Advanced Heart Failure. JAMA. 2002; 287:628-640.
12. Packer M, Poole‐Wilson PA, Armstrong PW, et al. Comparative effects of low and high doses of the angiotensin‐converting
enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999;
100:2312‐8.
13. Packer M, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure. Results of the carvedilol
prospective randomized cumulative survival (COPERNICUS) Study. Circulation. 2002;106:2194-2199.

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 14. Pitt B, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone
Evaluation Study Investigators. N Engl J Med. 1999;341:709-17.idelines. Circulation. 2013;128:e240–327.
15. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure
(Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997; 349:747-52.
16. Poole‐Wilson PA, Swedberg K, Cleland JG, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients
with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet.
2003; 362:7‐13.
17. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N.
Engl. J Med. 2015; 373:2314‐24.
18. Swedberg K, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study. Lancet
2010; 376: 875-85.
19. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med.
1997;336:525–33
20. Yancy CW, et al. Heart Failure Focused Updated on Pharmacological Therapy. Circulation 2016; 134.
21. Yancy CW, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128:e240–327.
22. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the
Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002; 106:920‐6.
23. Kostis JB, Packer M, Black HR, et al. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat
Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004; 17:103‐11.

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 QUESTIONS???

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