Heart Failure Pharmacotherapy

1. Lesson 5
Heart Failure
Tsegaye Melaku (BPharm, MSc)
[Assistant Professor of Clinical Pharmacy]
tsegayemlk@yahoo.com or tsegaye.melaku@ju.edu.et +251913765609January, 2020
Pharmacotherapy of Cardiovascular Disorders

2.  Session Hits
– Common underlying etiologies [ Ischemic, non-ischemic, idiopathic].
– Pathophysiology of HF [RAAS & SNS].
– Signs /symptoms , classify &staging
– Goals of therapy for a patient with acute or chronic HF.
– Non-pharmacologic treatment [patient education]
– Specific evidence-based pharmacologic treatment
– Monitor & Evaluate
2

3.  Essential functions of the heart
– To cover metabolic needs of body tissue (oxygen,
substrates) by adequate blood supply
– To receive all blood coming back from the tissue
 Essential conditions for fulfilling these functions
– Normal structure and functions of the heart
– Normal structure and function of tissue surrounding heart
– Adequate filling of the heart by blood

4.  HF : complex clinical syndrome that can result from any structural or
functional cardiac disorder that impairs the ability of the ventricle to
fill with or eject blood
– Caused by an abnormality in systolic function, diastolic
function, or both
– Making the distinction is important
4

5.  Can occur from any disorder damaging the pericardium, heart valves,
myocardium, or ventricle function
 Results from the heart‟s inability to pump sufficient blood to meet the
body‟s metabolic needs
– Progressive clinical syndrome
5

6.  HF is the final common pathway for numerous cardiac disorders including
those affecting the pericardium, heart, valves, and myocardium
 HF is a largely preventable disorder
– Management lifestyle risk factors
6
HF Vs CHF

7.  Any disorder which prevents:
– Contraction (Systolic Dysfunction) and/or
– Relaxation & filling (Diastolic Dysfunction)
 50% HF patients have preserved LVEF with presumed diastolic
dysfunction (HFpEF)
– Usually elderly, female, obese, HTN, atrial fibrillation, DM
 Systolic dysfunction is more prevalent????
 Systolic and diastolic dysfunction may coexist
7

8.  Reduction in muscle mass e.g. MI
– Degree of dysfunction is dependent on size of infarction
 Dilated cardiomyopathies (DCM)
– Leads to systolic contractile dysfunction
 Ventricular hypertrophy(HCM)
– Pressure overload : (e.g. systemic or pulmonary hypertension,
aortic or pulmonic valve stenosis)
– Volume overload: (e.g. valvular regurgitation, shunts, high
out-put states)
8

9.  Restricted ventricular filling, increased ventricular stiffness
– Ventricular hypertrophy, HCM
– Infiltrative myocardial diseases: amyloidosis, sarcoidosis,
Endomyocardial fibrosis
– Myocardial ischemia & infarction
 Mitral or tricuspid valve stenosis
 Pericardial disease
– Pericarditis, pericardial tamponade
9

10.  Generally :
– CAD & HTN: most common cause of HF ~70% of cases
10

11.  Essential functions of the heart are secured by integration of its
electrical and mechanical functions
Cardiac output (CO) = heart rate (HR) x stroke vol.(SV)
 Changes of SV
 Changes of HR
Control of HR:
 autonomic nervous system
 Hormonal (humoral) control
• Control of SV:
 Preload, contractility, afterload, number and size of myocytes, heart
architecture, synchronisation of function of the atrias and ventricles

12. ACC/AHA Guidelines 2013
– HF with reduced EF (HFrEF, EF ≤40%)
– HFpEF, improved (EF >40%)

13.  ~23 million people with HF worldwide
 ~46% increase in prevalence by 2030
 If >40 yrs: 1in 5 have a lifetime risk
 Lifetime risk > 20% for Americans >40 yo
 870,000 new cases diagnosed annually
 Prevalence in US: 5.7 million
– (1.5%–2% of population)

14. 14

15. ACC/AHA Guidelines 2013
Class I
Asymptomatic: No limitation of physical activity.
Ordinary activity does not cause sxs.
II Symptomatic with moderate exertion.
Ordinary physical activity causes SOB, fatigue
IV Symptomatic at rest. Unable to carry on any
activity without discomfort.
III Symptomatic with minimal exertion.
Less than usual activity causes sxs
NYHA Class
5-10%
5-10%
10-25%
25-60%
1-Yr Mortality

16. 16

17.  Related to compensatory Mechanisms
A. Sympathetic Nervous System (SNS) Activation
– Tachycardia and increased contractility
B. Increased preload by activating RAAS
– Na and water retention
C. Vasoconstriction
– Helps shunt blood away from non-essential organs
17

18. D. Ventricular Hypertrophy and Remodeling
– Key component of pathology progression
– Remodeling affects the heart at molecular & cellular levels
– Major focus for therapeutic interventions
– Therapies that reverse modeling, decrease mortality, slow
disease progression
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24.  Drive myocyte injury, oxidative stress, inflammation, and extracellular
matrix remodeling
 Angiotensin II
– Synthesis: ACE dependent/non–ACE-dependent pathways
– Stimulating ventricular hypertrophy, remodeling, myocyte
apoptosis, oxidative stress, inflammation, and alterations in
the myocardial extracellular matrix.
24

25.  Norepinephrine
– Role in the tachycardia, vasoconstriction, and increased
contractility and plasma renin activity in HF
– Increase the risk of arrhythmias and can cause myocardial cell
loss by stimulating both necrosis and apoptosis
– Contributes to ventricular hypertrophy and remodeling
25

26.  Aldosterone:
– Produce interstitial cardiac fibrosis through increased
collagen deposition in the extracellular matrix of the heart
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29. 29
HF may be classified based on
CO
Cardiac
Function
Side of
The Heart
Onset of
Symptom NYHA &
ACC/AHA
Low
output
HIGH
OUTPUT
Diastolic
HF
Systolic
HF
Lt. sided
HF
Rt. Sided
HF
Acute
HF
Chronic
HF

30.  According to Cardiac output :
High output HF:
 Uncommon type of HF
 The function of the heart may be supra-normal but inadequate owing to
excessive metabolic need for cardiac output.
– Causes : Severe anemia, Thyrotoxicosis.
30

31. Low output HF :
 The function of the heart is inadequate to meet tissues needs of blood.
 Caused by :
– Cause: Disorder that impair the pumping ability of the heart
such as : IHD , Cardiomyopathy.
31

32.  In terms of function :
Systolic dysfunction :
 There is impaired ejection of blood from the
heart during systole & cardiac contractility
32

33.  Ejection fraction : It's the % of the total amount of LV volume expelled
during systole, normal EF ≥ 40- 50 %
 EF misleading may occurred with mitral stenosis , aortic regurgitation.
 Causes :
– Conditions that impairs the contractile performance of the heart
ex. IHD, Cardiomyopathy.
– Increase pressure work on the heart [HTN , Valvular stenosis]
33

34. 34

35. Diastolic dysfunction :
 It account for 40%-50% of all cases of HF.
 There is impaired filling of the ventricles during
diastole,
 X-zed by decreased the ability to stretch during
filling,   Congestive symptoms are
predominate in diastolic dysfunction.
35

36.  Causes :
– Conditions that increase ventricular wall thickness ( ex.
Myocardial hypertrophy ), conditions that delay diastolic
relaxation ex. IHD , aging (ventricular stiffness )
36

37.  According to the side of the heart :
Right sided HF :
 Impairs the ability to move deoxygenated blood
from the systemic circulation into pulmonary
circulation    a dam back of blood
occurs, leading to its accumulation in the systemic
venous system.
37

38.  A major effect of Right sided HF is peripheral edema.
 Causes :
– Persistence left sided heart HF.
– Acute or chronic pulmonary diseases ex. pulmonary HTN.
– Conditions that weaken the heart muscle or restrict blood
flow into lung ex. tricuspid or pulmonary valve regurgitation.
38

39. Left sided HF :
 Impairs the pumping of blood from
pulmonary circulation into arterial side of
the systematic circulation,  
 There is a decrease in CO, Increase in LVEDP,
Congestion in the pulmonary circulation.
39

40.  Pulmonary edema symptoms often occur at night after the person has
been reclining
 Gravitational force has been removed from the circulatory system, the
edema fluid that had been sequestered in lower extremities is
redistributed into the pulmonary circulation.
40

41. Based on onset of symptoms :
 Acute HF : sudden onset of signs and symptoms of HF.
 Chronic HF : secondary to slow structural changes occurring in the
stressed myocardium.
 Acute decompensation: sudden exacerbation or worsening of
symptoms in chronic HF.
41

42.  New York Heart Association(NYHA)
– Class I: No limitation of physical activity
– Class II: Slight limitation of physical activity
– Class III: Marked limitation of physical activity
– Class IV: Unable to carry on any physical activity w/o
discomfort; symptomatic at rest
42

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44. 44
 Left-sided failure
– Blood not effectively pumped from the left ventricle to the
peripheral circulation
 Right-sided failure
– Blood not effectively pumped from the right ventricle into
the lungs
 General
– Patient presentation may range from asymptomatic to
cardiogenic shock

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51. 51
HF in infant

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Biventricular failure

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PULMONARY EDEMA Pericardial effusion

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60.  Goals of therapy
– To improve the patient’s quality of life
– Relieve or reduce symptoms
– Prevent or minimize hospitalizations for exacerbations of HF
– Slow progression of disease process, prolong survival
60

61.  Pharmacotherapy plays a key role in achieving these goals
 Identification of risk factors for HF development and recognition of its
progressive nature
– Have led to increased emphasis on preventing the
development of this disorder
61

62.  Determine etiology &/or precipitating factors
– Treat underlying disorders
– Identify, treat risk factors
– Eliminate/minimize precipitating factors
– Pharmacologic & non pharmacologic therapy
– Patient/family counseling
– Signs, symptoms
– Importance of appropriate medication use, compliance
– Close monitoring, follow up
62

63.  Exercise
– Improved exercise tolerance, functional capacity, may slow HF
progression.
– Restrict with acute congestive symptoms
 Dietary Na+ & fluid restriction
– Daily weight measurements to monitor volume retention
63

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 Poor at identifying or attributing risk
 Poor at communicating risk
 Poor at acting upon our risk assessment

66. 66

67. 67
“The relationship”
“People don't care how much you know until they know how much you care”
Theodore Roosevelt

68. 68
Andersonand Marrs. Adv Ther 2018

69. 69
Ventricular dysfunction limits a patients ability to perform the routine activities of
daily living…
The Donkey Analogy

70.  Standard drug therapies
– Diuretic if evidence of fluid retention
– ACE inhibitor or ARB
– β-blocker
 Select patients
– Digoxin
– Aldosterone antagonist
– Nitrates and/or hydralazine
70

71.  Stage A
– Patients do not have structural heart disease or symptoms
– High risk due to the presence of risk factors
– Emphasis: identify & modify of risk factors
– Prevent development of structural heart disease
71

72.  Stage A: Goals and Therapy
– Treat hypertension
– Encourage smoking cessation
– Treat lipid disorders
– Encourage regular exercise
– Discourage alcohol intake, illicit drug use
– Control metabolic syndrome
– Therapy:
– ACEI or ARB: for vascular disease or diabetes
72

73.  Stage B
– Structural heart disease present, but no symptoms
– At risk for development of HF
– Treatment is targeted at reducing further injury and preventing
(or slowing) remodeling
– Goals:
– All measures under Stage A
– Therapy:
– ACEI or ARB
– Beta-blockers
73

74.  Stage C
– Patients with structural disease and previous (or current) symptoms
– Goals
– All measures under Stage A and B
– Dietary sodium restriction
– Therapy
– Medications for routine use: ACEI, diuretics, beta blockers
– Medications in selected patients: aldosterone antagonists,
ARBs, digoxin, hydralazine/nitrates
74

75.  Stage D
– Patients who are symptomatic at rest despite maximal medical therapy
– Goals
– All measures under A, B and C (as appropriate)
– Therapeutic Options
– Treat acute HF decompensation
– Compassionate end of life care/hospice
– Extraordinary measures e.g. Heart transplant
– Specialized therapies
– Mechanical circulatory support , continuous IV positive inotrope
– Cardiac transplant
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78. Diuretics, ACEIs, ARBs
78
Reduce the number of sacks on the wagon

79.  Clinical benefits of ACE-I in HF:
– Symptoms improvement, improved exercise tolerance
– ↓ Frequency of acute CHF exacerbations
– Improvement of EF with long term use
 Decrease mortality & combined risk of death and hospitalizations
– Many trials have documented reductions in mortality of 25%
– SOLVD, V-HeFT, or CONSENSUS trials
79

80.  Benefits are observed in mild, moderate or severe HF
 All patients with LV dysfunction should receive an ACEI (unless intolerant)
– Symptomatic improvement may take several weeks
 Includes:
– Captopril, Enalapril, Lisinopril, Fosinopril
 Initiation of ACE I therapy
– Start with low dose & increase every 1-4 weeks.
– Target dose?
– Monitoring parameters: K, Scr, blood pressure
80

81. 81
 Dose consideration

82. 82
Limit donkey‟s speed, thus saving energy

83.  Best studied: carvedilol, metoprolol XL/CR and bisoprolol:
– CIBIS II –bisoprolol trial
– Study in 2600 pts with Class III HF
– MERIT HF trial –metoprolol XL trial
– Study in ~ 4000 patients with Class II or III HF
– COPERNICUS trial. Carvedilol Class IV HF
83

84.  Benefits of beta-blockers in HF:
– Prevent progression of disease
– Decrease mortality and combined risk of death or hospitalization
– Will increase EF with chronic therapy
– Reverse remodeling
 Symptomatic improvement may occur after several months.
84

85.  Initiation of beta-blocker therapy
– When HF symptoms are stable and patient is euvolemic
– Start low and go slow double dose every 2-4 weeks
– Initial doses
– Bisoprolol 1.25 mg qd,
– Carvedilol 3.125 bid,
– Metoprolol succinate CR/XL 12.5 mg qd
85

86.  Target doses
– Bisoprolol 10 mg qd,
– Carvedilol 25 mg bid,
– Metoprolol XL 200 mg qd
 Monitoring parameters: BP, HR, edema & fluid retention
86

87.  Reduce symptoms
 No effect on disease progression (never use as the only therapy)
 Adjust treatment to result in 1-2 pounds of weight loss per day
– (more aggressive inpatient)
 Na & fluid restriction is important.
 Monitor and replace K & Mg (goal: K≥4.0 mEq/L, Mg≥2.0 mEq/L)
 Loops : strong diuretics even with decreased renal function.
 Includes: furosemide , Bumetanide, Torsemide, Ethacrynic acid
87

88.  Initiation of diuretic therapy
– Initiate therapy with low doses of diuretic (i.e. Furosemide 20-40
mg/day) and
– Increase dose until patient maintains stable dry weight without
dyspnea
– Typical furosemide dose in HF 20-160 mg/day
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91. 91
Digitalis
Like the carrot placed in front of the donkey

92.  Positive inotropic effect.
 DIG trial: Conclusions:
– Mortality was the same in both groups
– Hospitalizations for worsening HF was reduced by 28% by
digoxin compared to placebo (p<0.001)
92

93.  Place in therapy:
– Early in therapy for patients with HF and atrial fibrillation to help
control ventricular response
– For HF patients in normal sinus rhythm, used with other standard HF
therapies (ACEI’s, beta-blockers, diuretics) in patients with
symptoms
93

94.  Initiation: 0.125 mg-0.25 mg qd
– Target serum concentration: 0.5 1.0 ng/mL
– Monitoring parameters: digoxin toxicity
– Read on digitalization
94

95.  Aldosterone: cause sodium and water retention and ventricular
remodeling (collagen deposition and cardiac fibrosis)
 ACEI or ARBS may not totally suppress aldosterone,
– Therefore, aldosterone antagonist needed
 Agents: spironolactone and eplerenone
95

96.  What is the evidence for using these agents?
– Randomized Aldactone Evaluation Study (RALES): NEJM 1999;341:709-17
– 1,663 patients with recent or current Class IV HF randomized to
spironolactone vs placebo
– Outcome: 30% reduction in total mortality and 35% reduction in
hospitalization (note: not evaluated in class I-III HF)
96

97. – Eplerenone Post MI HF Efficacy & Survival Study (EPHESUS): NEJM
2003;348:1309-21
– Evaluated effects of eplerenone in 6,642 patients s/p MI (NYHA Class
I) with LV dysfunction where patients were randomized to eplerenone
or placebo
– Outcome: 13% reduction in mortality and a 23% reduction in
hospitalization due to HF
97

98.  Place in therapy:
– Class III & IV HF
– Left ventricular dysfunction immediately after MI
 Initiation
– Spironolactone 25 mg qd, increased to 50 mg qd (same for
eplerenone)
– Monitoring parameters: Potassium within 1 week of treatment.
– Gynecomastia (Not with eplerenone)
98

99.  Chronic administration of ACEI may lead to “ACE Escape”
–   increased circulating concentrations of ANG II, NE &
aldosterone
 ARBs considered in patients intolerant to ACEIs
 Potential role of ARBs as adjunct therapy (controversial)
99

100.  Hypertension
– 2/3 HF patients have history of or current HTN
– 1st line: ACEIs, β-blockers, diuretics
– 2nd line: ARBs, aldosterone antagonists, isosorbide dinitrate/
hydralazine or 2nd generation CCBs (amlodipine, felodipine)
– Avoid CCBs with negative inotropic effects & direct acting
vasodilators that cause Na+ retention in patients with systolic
dysfunction
100

101.  Angina
– CAD: most common HF etiology
– 1st line: nitrates, β-blockers
– Must be fluid controlled for antianginal medications to be effective
101

102.  Atrial fibrillation
– 10 to 30% HF patients
– Increases risk of thromboembolism, decreases CO, leads to
hemodynamic compromise
– 1st line: ACEI , ARBs, β-blockers…early prevention
– Digoxin slows ventricular response but not HF progression
102

103. – β- blocker + digoxin better than either alone
– Avoid CCBs with negative inotropic function
– Amiodarone: preferred antiarrhytmic, dofetilide also safe &
effective; avoid class I antiarrhythmic agents
103

104.  Antithrombotic therapy for atrial fibrillation
– high risk patients: paroxysmal, persistent, or permanent AF (target
INR: 2 to 3) at high risk for stroke
– Warfarin
– Intermediate risk patients (age 65 to 75, no stroke risk factors)
– Warfarin or ASA
– Low risk patients (age < 65 years, no stroke risk factors)
– ASA
104

105.  DM
– ~1/3 of HF patients;
– Concerns of adverse effects with TZDs, metformin
– TZDs: contraindicated in class III & IV HF patients
– Metformin labeling: CI in HF
– Retrospective analysis > 3000 HF patients shows
metformin safe „‟decreases mortality & hospitalizations‟‟
– No prospective data
– Monitor volume & renal status
105

106.  Refractory HF/patients with persistent symptoms
– Stage D ACC/AHA
– NYHA class III or IV HF
 Decompensated HF/HF exacerbation: patients with new or worsening
signs & symptoms
 Clinical syndrome: systemic volume overload, low output, acute
pulmonary edema
 Periods of relative stability with increased frequency in episodes of
decompensation as HF progresses
106

107.  Bedside Assessment: Tissue perfusion and volume in patients
with acute heart failure

108.  Unlike chronic heart failure therapies, whose primary role is to improve
survival, treatment goals for ADHF are directed toward:
– Relief of congestive symptoms
– Restoration of systemic oxygen transport & tissue perfusion through
improved myocardial contractility
– Minimization of further cardiac damage & other adverse effects
108

109.  Maximizing oral chronic heart failure therapy may assist with
optimizing cardiac output and relieving congestion
109

110.  Mild insult (e.g. dietary indiscretion, medication)
 Medical non-compliance
 Concurrent non-cardiac illness (e.g. infection)
 New cardiac event
– MI
– AF
– Myocarditis
– Acute valvular insufficiency
110

111.  Diagnosis primarily based on signs, symptoms
– Orthopnea , jugular venous pressure , heart sounds, murmurs
– Lower extremity edema , pulmonary rales, crackles
– Plasma BNP
 Goals
– Relieve congestive symptoms
– Optimize volume status
– Treat symptoms of low CO
– Discharge patients on PO drug therapy
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112.  Rx
 Diuretics, vasodilators, positive inotropic therapy effective
– Must balance against potential toxicities
 Evaluate potential etiologies, precipitating factors
112

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115. 1. The nurse is caring for a hospitalized client with heart failure who is
receiving captopril (Capoten) and spironolactone (aldactone). Which lab
value will be most important to monitor?
A. Sodium
B. Blood urea nitrogen (BUN)
C. Potassium
D. Alkaline phosphatase (ALP)
115
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117.  Efficacy & safety
– Clinical signs and symptoms
– Laboratory tests and investigations
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