This document provides an overview of heart failure, including normal cardiac function, types of heart failure, pathophysiology, signs and symptoms, classification systems, pharmacological and non-pharmacological interventions. Key points include: there are two main types of heart failure - ischemic and non-ischemic; heart failure is further classified as preserved or reduced ejection fraction; pathophysiology involves neurohormonal activation of the sympathetic nervous system and renin-angiotensin-aldosterone system; signs and symptoms depend on whether the left or right side of the heart is predominantly affected; treatment focuses on ACE inhibitors, ARBs, beta-blockers, diuretics, and aldosterone antagonists according to clinical practice

1. Heart Failure
Daniel Brouwer
Kimberly Treier
PharmD candidates 2016
18 April 2016

2. Normal Cardiac Function
Preload = volume in ventricle immediately before
contraction (diastole)
Afterload = volume remaining in ventricle
immediately after contraction (systole)
CO = HR x stroke volume
MAP = CO x systemic vascular resistance

3. Normal Cardiac Function
Frank Starling mechanism:
 preload =  force of contraction
 myocardial sarcomere length =  cross bridges
between thick and thin myofilaments =  force of
contraction (i.e. CO)

4. Types of HF
• Two main characterizations
• Ischemic
• Decreased blood supply
• Non-ischemic
• Long-standing hypertension
• Two categories
• Preserved EF (HFpEF)
• EF ≥40%
• Reduced EF (HFrEF)
• EF <40%

5. Pathophysiology of HFrEF
Systolic dysfunction (decreased contractility)
•  muscle mass (e.g. MI)
• Dilated cardiomyopathies
• Ventricular hypertrophy
• Pressure overload (e.g. systemic or pulmonary
hypertension, aortic or pulmonic valve stenosis)
• Volume overload (e.g. valvular regurgitation, shunts,
high-output states)

6. Pathophysiology of HFpEF
Diastolic dysfunction (restricted ventricular filling)
•  ventricular stiffness
• Ventricular hypertrophy
• Infiltrative myocardial diseases (e.g. endomyocardial
fibrosis)
• Myocardial ischemia and infarction
• Mitral or tricuspid valve stenosis
• Pericardial diseases (e.g. pericarditis, pericardial
tamponade)

7. Drugs That Cause or Worsen
HF
• Chemotherapeutic drugs
• Anthracyclines (e.g.
doxorubicin)
• Tyrosine Kinase Inhibitors
(e.g. sunitinib)
• Sympathomimetics, illicit
drugs
• Amphetamines
• Cocaine
• Non-DHP CCBs
• Verapamil
• Diltiazem
• Antiarrhythmics
• ESPECIALLY Class I (e.g.
flecainide, propafenone)
• Strong immunosuppressants
• Interferons
• TNF inhibitors (e.g.
etanercept)
• Others
• Itraconazole
• NSAIDs
• Systemic steroids
• Triptans
• TZDs

8. Signs and Symptoms
• General
• Dyspnea/SOB
• Weakness/fatigue
• Exercise intolerance
• Left ventricular hypertrophy
•  BNP (>100 pg/mL)
•  N-terminal pro BNP (>300 pg/mL

9. Signs and Symptoms
• Left-sided
• Orthopnea
• Paroxysmal nocturnal
dyspnea or nocturnal
cough
• Bibasilar rales
• S3 gallop
• Right-sided
• Edema
• Ascites
• JVD
• Hepatojugular reflux
• Hepatomegaly

10. Pathophysiology of HF

11. Neurohormonal Activation
Beneficial in acute setting (severe hemorrhage, vomiting,
diarrhea, etc.)
• Decreased LV function  activation of SNS
•  inotropy and chronotropy
• Vasoconstriction
•  CO
• Decreased renal blood flow  RAAS stimulation (also directly by
SNS)
•  Blood volume and preload
• Vasoconstriction
• maintains  CO

12. Neurohormonal Activation
Detrimental in chronic setting (HF)
• Activation of SNS constricts arterioles
•  BP   afterload
•  cardiac workload   O2 demand
•  cardiac function over time
• Cardiac remodeling
• Activation of RAAS
•  blood volume and vasoconstriction
•  BP, edema,  cardiac workload   O2 demand
•  cardiac function over time
• Cardiac remodeling

13. RAAS

14. Pathophysiologic RAAS
Activation
• Activation in the absence of sodium and/or water
loss
• Potent activation overwhelms body’s natriuretic
peptide production
• In HF: α-adrenergic stimulation and elevated
angiotensin II
• Persistent aldosterone-mediated Na+ retention
• Lack of “mineralocorticoid escape”

15. Aldosterone
• Continued effects even with ACEi/ARB therapy
• “Aldosterone Escape”
• 3 predominant theories:
• Angiotensin II produced by non-ACE mediated pathways
• Angiotensin II production not completely inhibited by ACEi
therapy
• Angiotensin II-independent aldosterone production

16. Consequences of
Aldosterone in HF
• Hypervolemia
• Na+ and water retention
• HR changes
• Parasympathetic activation
• Intrinsic dysrhythmic properties
• Myocardial fibrosis
• Unknown mechanism
•  arterial compliance and impaired baroreceptor activity
• Impaired autonomic control
• Myocyte apoptosis
• In rats: aldosterone infusion  myocyte apoptosis  fibrotic
remodeling

17. • Remodeling
• Direct correlation of  aldosterone to  ventricular end
diastolic pressure and procollagen III N-terminal peptide
(PIIINP) – a marker of cardiac collagen turnover
• Necrosis
• In rats: angiotensin II infusion  necrosis of myocardium
and coronary vasculature
• Endothelial dysfunction
• Inhibition of nitric oxide
• Superoxide production in vasculature
Consequences of
Aldosterone in HF

18. Consequences of
Aldosterone in HF
• LV hypertrophy
• Augmented by myocardial aldosterone production
• Myocardial dysfunction
•  preload and afterload
•  compliance (fibrosis)
•  abnormal structure (remodeling)
•  functioning myocytes (necrosis)

19. Consequences of
Aldosterone in HF

20. Classification
New York Heart Association (NYHA)
Class Patient Symptoms
I No limitation on physical activity. Ordinary physical activity does not cause
undue fatigue, palpitation and dyspnea.
II Slight limitation of physical activity. Comfortable at rest. Ordinary physical
activity results in fatigue, palpitation and dyspnea.
III Marked limitation of physical activity. Comfortable at rest. Less than
ordinary activity causes fatigue, palpitation or dyspnea.
IV Unable to carry on any physical activity without discomfort.
Symptoms of heart failure at rest. If any physical activity is undertaken,
discomfort increases.

21. Classification
American College of Cardiology (ACC)/American Heart Association (AHA)
Class Patient Symptoms
A At risk for HF, but no objective evidence of cardiovascular disease. No
signs or symptoms.
B Objective evidence of minimal cardiovascular disease. No signs or
symptoms.
C Objective evidence of moderately severe cardiovascular disease. Prior or
current symptoms.
D Objective evidence of severe cardiovascular disease. Symptoms at rest
even with maximal medical treatment.

22. Non-Pharm Interventions
• Monitor and record daily body weight
• Restrict sodium to <1,500 mg/day
• Restrict fluid intake (1.5-2 L/day in stage D)
• Achieve and maintain appropriate weight
• Smoking cessation
• Limit alcohol consumption
• Exercise
• Vaccinations

23. Pharmacologic Interventions
• Cornerstones of therapy
• Loop diuretics
• Target fluid volume
• Symptomatic relief
• ACEi/ARBs
• Target RAAS
• Morbidity and mortality benefit
• Beta-blockers
• Target SNS
• Control HR and arrhythmias (if applicable)
• Morbidity and mortality benefit

24. ACCF/AHA 2013 Practice Guidelines
Management of Heart Failure
Quick Review of the Treatment Recommendations:
• Treatment modifying, evidence-based
recommendations
• ACE inhibitors
• ARBs
• Beta-Blockers
• (Loop) Diuretics
• Aldosterone Antagonists
• Hydralazine / Nitrates
• Digoxin

25. ACE Inhibitors
Class I Recommendation – Level of Evidence: A
• ACE inhibitors are recommended in patients with
HFrEF and current or prior symptoms, unless
contraindicated.
• Reduces morbidity, mortality and hospitalizations
• Based off the clinical study data from:
• Captopril (SOLVD)
• Enalapril (CONSENSUS)
• Lisinopril (ATLAS)
• Fosinopril (FEST)
• Ramapril (HOPE)
• Trandolapril (TRACE)

26. ARBs
Class I Recommendation – Level of Evidence: A
• ARBs are recommended in patients with HFrEF
and current or prior symptoms, who are ACE
inhibitor intolerant, unless contraindicated.
• Reduces morbidity, mortality and hospitalizations
• Based off the clinical study data from:
• Candesartan (CHARM)
• Losartan (ELITE, OPTIMAAL)
• Valsartan (Val-HeFT, VALIANT)

27. ACE inhibitors/ARBs
• MOA:
•  Angiotensin II production (ACEi)
•  Angiotensin II binding (ARB)
• Clinical uses:
•  RAAS activation
•  preload and afterload
•  cardiac remodeling
•  left ventricular function
•  morbidity and mortality
Recommend for HF
patients of all NYHA
classes

28. ACE inhibitors
Drug Starting Dose Target Dose
Captopril (Capoten) 6.25 mg TID 50 mg TID
Enalapril (Vasotec) 2.5 mg BID 10-20 mg BID
Fosinopril (Monopril) 5-10 mg daily 40 mg daily
Lisinopril (Prinvil, Zestril) 2.5-5 mg daily 20-40 mg daily
Perindopril (Aceon) 2 mg daily 8-16 mg daily
Quinapril (Accupril) 5 mg BID 20 mg BID
Ramipril (Altace) 1.25-2.5 mg daily 10 mg daily
Trandolapril (Mavik) 1 mg daily 4 mg daily

29. ARBs
Drug Starting Dose Target Dose
Candesartan (Atacand) 4-8 mg daily 32 mg daily
Losartan (Cozaar)* 25-50 mg daily 50-150 mg daily
Valsartan (Diovan) 20-40 mg BID 160 mg BID
*Benefit in clinical trials but no FDA indication for HF

30. Beta-Blockers
Class I Recommendation – Level of Evidence: A
• Use of 1 of the 3 beta-blockers proven to reduce
mortality is recommended for all patients with
current or prior symptoms of HFrEF, unless
contraindicated.
• Reduces morbidity, mortality and hospitalizations
• Based off the clinical study data from:
• Carvedilol (COPERNICUS, COMET)
• Metoprolol succinate (MERIT-HF, COMET)
• Bisoprolol (CIBIS-II)
• [Nebivolol (SENIORS): demonstrated a modest reduction in all cause
mortality or CV hospitilizations, but did not affect mortality alone in an
eldery poluation with HFpEF.]

31. Beta-Blockers
• MOA:
•  catecholamine binding at beta-1 and beta-2
receptors
• Clinical uses:
•  HR and  O2 demand
•  afterload
•  cardiac function
•  vasoconstriction
•  morbidity and mortality
Recommend for HF
patients of all NYHA
classes

32. Beta-Blockers
Drug Starting Dose Target Dose
Bisoprolol (Zebeta)* 1.25 mg daily 10 mg daily
Metoprolol succinate
extended release
(Toprol XL)
12.5-25 mg daily 200 mg daily
Carvedilol
(Coreg, Coreg CR)
IR: 3.125 mg BID
CR: 10 mg daily
IR: 25 mg BID (≤85 kg);
50 mg BID (>85 kg)
CR: 80 mg daily
Nebivolol (Bystolic) † 1.25 mg daily 10 mg daily
*Benefit in clinical trials but no FDA indication for HF
† Modest benefit in clinical trial. Occasionally used Off label, but not
recommended in the guidelines
Benefit is NOT a class effect – only these 3 agents are recommended

33. Diuretics
Class I Recommendation – Level of Evidence: C
• Diuretics are recommended in patients with
HFrEF who have evidence of fluid retention,
unless contraindicated. Loop diuretics are
preferred for most patients with HF.
• Improves patient symptoms
• Based off the clinical study data from:
• Furosemide (DOSE)
• Torsemide (DOSE, TORIC)
• Bumetanide (DOSE)

34. Loop Diuretics
• MOA:
•  Na+ and Cl- reabsorption in thick ascending loop
of Henle
•  Na+, Cl-, Mg+, Ca2+ and H2O excretion
• Clinical uses:
•  fluid volume
•  preload and afterload
•  O2 demand and  CO
•  symptoms (but no mortality benefit)

35. Loop Diuretics
Drug Dose
Furosemide (Lasix) 20-40 mg daily or BID (max 600 mg/day)
Bumetanide (Bumex) 0.5-1 mg daily or BID (max 10 mg/day)
Torsemide (Demadex) 10-20 mg daily (max 200 mg/day)
Ethacrynic Acid (Edecrin) 50-200 mg daily (max 400 mg/day)
Oral equivalence dosing:
furosemide 40 mg = bumetanide 1 mg = torsemide 20 mg = ethacrynic acid 50 mg

36. Aldosterone Antagonists
Class I Recommendation – Level of Evidence: A
• Aldosterone antagonists are recommended in
patients who have LVEF ≤ 35%, unless
contraindicated.
• Reduces morbidity, mortality and hospitalizations
• Based off the clinical study data from:
• Spironolactone (RALES)
• Eplerenone (EPHESUS, EMPHASIS-HF)

37. Aldosterone Receptor
Antagonists
• MOA:
•  aldosterone binding
• Clinical uses:
•  RAAS system
•  cardiac remodeling
•  risk of sudden cardiac death
•  morbidity and mortality

38. Aldosterone Receptor
Antagonists
Drug Indication Starting Dose Target Dose
Spironolactone
(Aldactone)
NYHA
Class II-IV
(LVEF ≤ 35%)
12.5-25 mg
daily
25 mg daily or
BID
Eplerenone
(Inspra)
25 mg daily 50 mg daily

39. Hydralazine / Nitrates
Class I Recommendation – Level of Evidence: A
• The combination of hydralazine and isosorbide
dinitrate is recommended for patients self-
described as African Americans with NYHA class
III-IV HFrEF and receiving optimal therapy with
ACE inhibitors and beta-blockers, unless
contraindicated.
• Reduces morbidity, mortality and hospitalizations
• Based off the clinical study data from:
• BiDil (A-HeFT)

40. Hydralazine/Nitrate
• MOA:
•  arterial vasodilation (direct action)
•  venous vasodilation ( nitric oxide)
• Clinical uses:
•  afterload and preload
•  survival (not as much as ACE inhibitors)
• Alternative therapy for ACE inhibitor
intolerant/contraindicated patients
• Self-identified black patients with NHYA Class III-IV
symptomatic despite optimal therapy (BiDil)

41. Hydralazine/Nitrate
Dose Starting Dose Target Dose
Hydralazine
(Apresoline)
25-50 mg TID-QID 300 mg daily, divided
Isosorbide dinitrate
(Isordil Titradose,
Dilatrate SR)
Isosorbide
mononitrate
(Monoket, Imdur)
20-30 mg TID-QID
Not listed in
guidelines
120 mg daily, divided
Not listed in
guidelines
Isosorbide dinitrate +
hydralazine (BiDil)
20/37.5 mg TID 40/75 mg TID

42. Cardiac Glycosides
Class IIa Recommendation – Level of Evidence: B
• Digoxin can be beneficial in patients with HFrEF,
unless contraindicated.
• Reduces hospitalizations for HF
• Based off the clinical study data from:
• Digoxin (DIG)

43. Digoxin
• MOA:
•  Na+/K+-ATPase
•  parasympathetic effects
• Clinical use:
•  CO
•  HR
•  symptoms
•  exercise tolerance, QOL (no mortality benefit)
Typical Dose Therapeutic Range Antidote
0.125-0.25 mg
daily
0.5-0.9 ng/mL (higher range for Afib) DigiFab

44. ARNIs
• MOA:
• ARB:  angiotensin II binding
• Neprilysin inhibitor:  vasodilatory peptide degradation
(BNP, adrenomedulin, substance P and bradykinin)
• Clinical uses:
•  RAAS activation
•  preload and afterload
•  cardiac remodeling
•  left ventricular function
•  HF hospitalizations and CV death

45. ARNIs
Drug Indication Starting dose Target dose
Sacubitril/V
alsartan
(Entresto)
NYHA Class II-IV 50-100 mg BID
Dose is the sum of
the two
components:
50 mg = 24/26 mg
100 mg = 49/51 mg
200 mg = 97/103
mg
200 mg BID

46. • MOA:
• Funny current (If) inhibitor
• Hyperpolarization-activated cyclic nucleotide-gated
channel blockers (HCN blockers)
• Clinical use:
•  HR
•  CO and  O2 demand
•  hospitalization (but not mortality)
Ivabradine (Corlanor)

47. Indications Starting Dose: Maintenance Dose:
Stable, symptomatic
chronic HF
LVEF ≤ 35%
Sinus rhythm, HR ≥
70 bpm
On maximally
tolerated beta-blocker
therapy (or
contraindicated)
5 mg twice daily 2.5-7.5 mg twice daily
Target resting HR 50-
60 bpm
Ivabridine (Corlanor)

48. References
• DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG,
Posey LM: Pharmacotherapy: A Pathophysiologic
Approach, Ninth Edition: www.accesspharmacy.com
• Odedra K, Ferro A. Neurohormones and Heart Failure:
The Importance of Aldosterone. International Journal of
Clinical Practice 2006;60(7):835-846. PMID: 16846401
• Yancy CW, Jessup M, Bozkurt B, 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. J Am Coll Cardiol. 2013 Oct
15;62(16):e147-239.

49. Thank you!
Questions?

50. The Body’s Defense
• B-type natriuretic peptide (BNP)
• Produced by ventricles in response to  pressure
and volume load
• Atrial natriuretic peptide (ANP)
• Produced by atria in response to atrial stretch
• Both reduce preload and afterload:
• Sequester plasma (short-term)
• Renal salt and water excretion
• Antagonize RAAS
• Antagonize hypertrophic effects of angiotensin II

51. Aldosterone
• Mineralocorticoid
• Stimulates Na+ reabsorption + K+ excretion by
epithelial cells in kidneys, intestine, sweat glands,
salivary glands
• De novo Na+ channel production in epithelial
membrane   intracellular Na+  Na+/K+-ATPase
activation  Na+ absorption + K+ secretion
• Independent role in HF progression

52. Pharmacologic Interventions
• Key points
• Hydralazine-isosorbide (BiDil)
• Morbidity and mortality benefit in black patients with
NYHA Class III-IV and in nonblack patients intolerant to
ACEi/ARB
• Aldosterone receptor antagonists
• Diuresis, improved EF, symptomatic relief
• Morbidity and mortality benefit in NYHA Class II-IV
• Digoxin
• Reduces HF-related hospitalizations
• Symptomatic relief

53. RALES Study
•  serum aldosterone =  mortality
• Double-blind, placebo-controlled
• 15 countries, 195 medical centers
• 1663 patients NYHA class IV HF + systolic
dysfunction (ejection fraction ≤ 35%) randomly
assigned to spironolactone or placebo
• Terminated due to obvious benefit
• Risk of death from progressive HF and sudden
cardiac death reduced ~30% in spironolactone
group

54. Potassium
• Clinical use:
• Replenish lost K+ (loop diuretics)
•  pro-arrhythmic risk with (digoxin)