This document provides information on the pharmacotherapy of heart failure. It begins with definitions of heart failure and its etiology. It then discusses the epidemiology, noting it is a prevalent disease that increases significantly with age. The pathophysiology section describes the compensatory mechanisms involved, including the Frank-Starling mechanism, renin-angiotensin-aldosterone system, sympathetic nervous system, and others. The document also covers classification systems, diagnosis, and treatment approaches for stages A through D of heart failure. It provides details on various drug classes used to treat heart failure, including ACE inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and diuretics.

1. Pharmacotherapy of Heart Failure
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2. Definition and etiology [1]
• Heart failure (HF) is inability of the heart to maintain an adequate cardiac
output to meet the metabolic demands of the body.
• HF is a progressive disease that can result from any structural or functional
changes of the heart,
 Leading to the impairment of ventricular filling or ejection of blood.
• The demonstration of an underlying cardiac dysfunction is essential for the
diagnosis of heart failure.
 This usually includes myocardial infarction, valve , pericardium, endocardium, heart
rhythm abnormalities or a combination of these alterations.
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3. Definition and etiology [2]
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4. Epidemiology [1]
• HF is an epidemic disease which affects about 1% to 2% of the adult population
worldwide.
 Affecting over 37 million individuals globally
 Increases significantly with advancing age to more than 10% in adults over 70
years of age
• It affects more than 6.5 million people in the United States and 920000 in UK
• It has a 50% mortality rate @ 5 years of diagnosis
• The lifetime risk of HF at 45 years of age is 30% for white men and 32% for white
women
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5. Epidemiology [2]
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6. Pathophysiology [1]
• The reduction in cardiac out put (CO), caused by loss of functional cardiac
myocytes through, results in haemodynamic changes, which activates a
succession of compensatory mechanisms in an attempt to maintain circulatory
integrity by preserving central arterial pressure and thereby vital organ
perfusion.
 Frank-Starling mechanism
• In a healthy heart, CO increases with increasing preload, due to a greater
stretch of myocardial fibers generating greater force of contraction.
 This is due to the unique length-tension relationship of cardiac muscle where increasing the length of the
sarcomere increases the number of possible actin–myosin interactions.
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7. Pathophysiology [2]
• However, the Frank-Starling mechanism is also central to the
pathophysiology of LVSD-HF,
As sustained increases in venous return, combined with myocardial
necrosis and scarring, cause pathological over-stretching of the
myocardium, disrupting the length-tension relationship , reducing
the number of potential actin-myosin interactions, and thus the
force of contraction.
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8. Pathophysiology [3]
 Renin–angiotensin–aldosterone system (RAAS)
• RAAS is another compensatory measure, which is activated through β1
and α1 receptors due to renal hypoperfusion and reduced sodium delivery
to macula densa of the distal tubule.
 This serves to maintain intravascular volume via vasoconstriction,
sodium retention and increased thirst.
• This is achieved by conversion of angiotensinogen to angiotensin I by renin
followed by conversion of angiotensin I to angiotensin II by angiotensin-
converting enzyme (ACE).
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9. Pathophysiology [4]
● Angiotensin II is a potent vasoconstrictor of systemic circulation and
mediates its effects in five ways by:
o Increasing sympathetic nervous system (SNS) activity
o Increasing Na+ and H2O absorption from the ascending loop of Henle
o Stimulating the release of aldosterone from the adrenal cortex
o Stimulating arteriolar vasoconstriction (systemic and renal)
o Stimulating the secretion of anti-diuretic hormone from the posterior
lobe of the pituitary gland
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10. Pathophysiology [5]
• The net effect is retention of salt and water.
This increases plasma volume and hence blood pressure, which, for
the short term, improves tissue perfusion.
However, this short-term gain comes at a long-term cost of an
increasing workload on an already failing myocardium.
 Both ACE inhibitors and ARBs work to reduce the afterload on the
heart by blocking this pathway, reducing total peripheral resistance and
so reducing myocardial work.
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11. Pathophysiology [6]
 Sympathetic nervous system
• The decrease in MAP is sensed by baroreceptors in the carotid sinuses and
aortic arch along with mechanoreceptors in the cardiopulmonary circulation
resulting in heightened sympathetic and diminished parasympathetic activity
with subsequent activation of neuro-hormones.
• The sympathetic nervous system (SNS) stimulation increases release of
catecholamines, which has direct effects on the cardiovascular system by
increasing HR ,contractility, as well as inducing peripheral vasoconstriction
which augment MAP.
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12. Pathophysiology [7]
• The SNS influences the myocardium through three adrenergic receptors
(β1, β2 and α1) and chronic stimulation by noradrenaline induces
myocyte growth and hypertrophy.
 Commonly used in HF, β-blockers work by blocking β receptors,
slowing the heart rate, lengthening the duration of diastole,
improving myocardial filling and reducing myocardial oxygen
demand.
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13. Pathophysiology [8]
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14. Pathophysiology [9]
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15. Pathophysiology [10]
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16. Pathophysiology [11]
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17. Classification [1]
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18. Classification [2]
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19. Classification [3]
• HF patients can be assigned a class based on NYHA classification
Class I: No physical limitation; ordinary physical activity does not
cause HF symptoms
Class II: No symptoms at rest, but ordinary physical activities cause
HF symptoms
Class III: No symptoms at rest, but less-than-ordinary physical
activities cause HF symptoms
 Class IV: Symptoms of HF at rest
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20. Classification [4]
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21. Diagnosis [1]
• No single test is available to confirm the diagnosis of HF.
• Heart failure is often initially suspected in a patient based on their
symptoms (slide 23).
• A complete history and physical examination targeted at identifying
cardiac or noncardiac disorders or behaviors that may cause or hasten
HF development or progression are essential in the initial evaluation of
a symptomatic patient.
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22. Diagnosis [2]
• A careful medication history should also be obtained
• Particular attention should be paid to cardiovascular risk factors and to other
disorders that can cause or exacerbate heart failure.
• Laboratory testing may assist in identification of disorders that cause or worsen heart
failure.
• Measurement of BNP may also assist in differentiating dyspnea caused by heart
failure from other causes.
• The echocardiogram is used to evaluate abnormalities in the pericardium, myocardium,
or heart valves and to quantify the LVEF to determine if systolic or diastolic
dysfunction is present.
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23. Diagnosis [3]
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24. Diagnosis [4]
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25. Diagnosis [5]
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26. Treatment [1]
 Desired outcomes
Improve the patient’s quality of life
Relieve or reduce symptoms
Prevent or minimize hospitalizations
Slow progression of the disease process
Prolong survival
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27. Treatment [2]
 Stage A HF
• Emphasis here is on identification and modification of risk factors to prevent
the development of structural heart disease and subsequent HF.
 Commonly encountered risk factors include hypertension, diabetes, obesity,
metabolic syndrome, smoking, and coronary artery disease.
• Effective control of blood pressure reduces the risk of developing HF by
approximately 40%
• In patients with type 2 diabetes and either established CVD or at high
cardiovascular risk, SGLT2i should be used to prevent hospitalizations for HF
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28. Treatment [3]
 Stage B HF
• These individuals are at risk for developing HF and treatment is
targeted at minimizing additional injury and preventing or slowing the
remodeling process.
• In addition to the treatment measures outlined in stage A, ACE
inhibitors and β-blockers are important components of therapy.
Patients with a previous MI or reduced LVEF should receive both
ACE inhibitors and β-blockers.
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29. Treatment [4]
• In patients with a recent or remote history of MI or ACS, statins
should be used to prevent symptomatic HF and adverse cardiovascular
events.
• In patients with LVEF <50%, thiazolidinediones should not be used
because they increase the risk of HF, including hospitalizations.
• In patients with LVEF <50%, nondihydropyridine calcium channel
blockers with negative inotropic effects may be harmful.
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30. Treatment [5]
 Stage C HF
o Non-pharmacologic
• For patients with stage C HF, avoiding excessive sodium intake is reasonable
to reduce congestive symptoms.
• For patients with HF, cardiac rehabilitation and regular physical activity are
recommended to improve functional status, exercise performance, and QOL.
• In patients with HF, vaccinating against respiratory illnesses is reasonable to
reduce mortality.
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31. Treatment [6]
o Pharmacologic
• In addition to treatments in stages A and B, most patients in stage C should be
routinely treated with three medications
 Diuretic, an ACE inhibitor, and a β-blocker
• Aldosterone receptor antagonists, ARBs, digoxin, and hydralazine-isosorbide dinitrate
are also useful in selected patients.
 Stage D HF
• These individuals have the most advanced form of heart failure and should be
considered for specialized therapies including
 Mechanical circulatory support, continuous intravenous positive inotropic therapy, cardiac
transplantation, or hospice care.
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32. Treatment [7]
 ARNi/ACEi /ARB
• In patients with HFrEF and NYHA class II to III symptoms, the use of ARNi is
recommended to reduce morbidity and mortality.
• In patients with previous or current symptoms of chronic HFrEF, the use of ACEi is
beneficial to reduce morbidity and mortality when the use of ARNi is not feasible.
• In patients with previous or current symptoms of chronic HFrEF who are intolerant
to ACE inhibitors because of cough or angioedema and when the use of angiotensin
receptor neripsyline inhibitor(ARNi) is not feasible, the use of ARB is recommended to
reduce morbidity and mortality.
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33. Treatment [8]
• ARNi should not be administered concomitantly with ACEi or within 36
hours of the last dose of an ACEi.
• ACEi or ARNi should not be administered to patients with any history of
angioedema.
• ACEi and ARB should be started at low doses and titrated upward to doses
shown to reduce the risk of cardiovascular events.
 The usual dosing strategy for ACE inhibitors is to initiate at a low dose and double
the dose every one to two weeks, if tolerated, up to the pre-specified target dose.
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34. Treatment [9]
• Abrupt withdrawal of ACE inhibition can lead to clinical deterioration and
should be avoided.
• Patients with pre-existing conditions that put them at a higher risk for side
effects
 Sodium levels less than 130 meq/L
 Creatinine clearance [CrCl] less than 30 ml/min
 An increase in diuretic dose in the past week
 Treatment with a potassium-sparing diuretic
May be
initiated at a
lower doses of
RAS inhibitors
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35. Treatment [10]
 β-Blockers
• In patients with HFrEF, with current or previous symptoms, use of 1 of the 3
beta blockers proven to reduce mortality (eg, bisoprolol, carvedilol, sustained-
release metoprolol succinate) is recommended to reduce mortality and
hospitalizations.
• Even if symptoms or LVEF improve, long-term treatment with beta blockers
and use of target doses should be maintained to reduce the risk of progression
in LV dysfunction or major cardiovascular events.
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36. Treatment [11]
• Beta blockers should be initiated at low doses and titrated slowly to target doses if
tolerable.
 Doses should be doubled no more often than every 2 weeks, as tolerated, until the
target or maximally tolerated dose is reached.
• Patients should be monitored closely for changes in vital signs and symptoms during
this titration period.
 If the target doses are not tolerated, the highest tolerated dose should be
continued.
• Abrupt withdrawal of beta-blocker therapy can lead to clinical deterioration and
should be avoided unless indicated.
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37. Treatment [12]
 Mineralocorticoid Receptor Antagonists (MRAs)
• In patients with HFrEF and NYHA class II to IV symptoms, an MRA
(spironolactone or eplerenone) is recommended to reduce morbidity and
mortality.
• These drugs are recommended for NYHA class II–IV HF patients with
 EF of 35% or less
 GFR of at least 30 mL/min/1.73 m2
 Potassium level of 5.0 mEq/dL or lower
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38. Treatment [13]
• Due to the risk of elevated potassium levels, potassium supplements should be
discontinued (or reduced) when initiating aldosterone antagonist therapy in a patient
already receiving an ACEi/ARBs.
• Careful monitoring of potassium levels and renal function should be performed at
initiation and closely checked within two to three days and again at seven days after
initiation.
 Patients should subsequently be monitored monthly for the first three months and
every three months thereafter.
o In patients taking MRA whose serum potassium cannot be maintained at <5.5
mEq/L, MRA should be discontinued to avoid life-threatening hyperkalemia
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39. Treatment [14]
 Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i)
• In patients with symptomatic chronic HFrEF, SGLT2i are recommended to
reduce hospitalization for HF and cardiovascular mortality, irrespective of the
presence of type 2 diabetes.
 Caution is warranted for euglycemic ketoacidosis, genital and soft tissue
infections, and adjustment of diuretics, if needed, to prevent volume
depletion.
• Both dapagliflozin and empagliflozin should be started and maintained at a dose of
10 mg once daily.
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40. Treatment [15]
 Diuretics
• Diuretics are the only agents that can adequately control the fluid retention
associated with HF.
 Unless contraindicated, diuretics are recommended in all HF patients
with fluid retention to improve symptoms.
• Loop diuretics, such as furosemide, are the preferred diuretic agents for most
HF patients.
 In comparison, thiazide diuretics are less potent and thus have a less
significant effect on fluid retention/edema.
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41. Treatment [16]
• Some HF patients may remain volume-overloaded despite the use of maximal
loop diuretic therapy.
 Such loop diuretic resistance may be overcome by intravenous
administration of loop diuretics or by the addition of a thiazide diuretic.
• Diuretic therapy is initiated at low doses and is titrated up as needed and as
tolerated.
 Adequate treatment is not determined by reaching a set target dose, but
rather by looking for an increase in urine output and a 0.5-kg to 1.0-kg
decrease in daily weight.
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42. Treatment [17]
 Vasodilators
• For patients self-identified as African American with NYHA class III-IV
HFrEF who are receiving optimal medical therapy, the combination of
hydralazine and isosorbide dinitrate is recommended to improve symptoms and
reduce morbidity and mortality.
• In patients with current or previous symptomatic HFrEF who cannot be
given first-line agents, such as ARNi, ACEi, or ARB, because of drug
intolerance or renal insufficiency, a combination of hydralazine and isosorbide
dinitrate might be considered to reduce morbidity and mortality.
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43. Treatment [18]
• A starting dose of hydralazine 37.5 mg/isosorbide dinitrate 20 mg (available
as a combination tablet) three times per day is recommended.
• When administering hydralazine and isosorbide dinitirate separately, the
recommendation is to start with hydralazine 25 mg to 50 mg three or four
times per day and isosorbide dinitirate 20 mg to 30 mg three or four times per
day.
• The maximum recommended dose is hydralazine 75 mg/isosorbide dinitrate 40
mg three times per day or hydralazine 300 mg daily in divided doses with
isosorbide dinitrate 120 mg daily in divided doses.
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44. Treatment [19]
 Digoxin
• In patients with symptomatic HFrEF despite GDMT (or who are
unable to tolerate GDMT), digoxin might be considered to decrease
hospitalizations for HF.
 How ever, digoxin did not demonstrate a mortality benefit in patients with HF.
• The initial dose of digoxin is typically 0.125 mg to 0.250 mg daily with
no need for a loading dose.
 Patients who are elderly, have poor renal function, or have low lean body mass
should start with 0.125 mg daily or every other day
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45. Treatment [20]
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46. Treatment [21]
• In patients with HFmrEF, SGLT2i can be beneficial in decreasing HF
hospitalizations and cardiovascular mortality.
• Among patients with current or previous symptomatic HFmrEF
(LVEF, 41%–49%), use of evidence-based beta blockers for HFrEF,
ARNi, ACEi, or ARB, and MRAs may be considered to reduce the risk
of HF hospitalization and cardiovascular mortality, particularly among
patients with LVEF on the lower end of this spectrum
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47. Treatment [22]
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48. Treatment [23]
• In patients with HFpEF, SGLT2i can be beneficial in decreasing HF
hospitalizations and cardiovascular mortality.
• In selected patients with HFpEF, the use of MRAs or ARBs or ARNi
may be considered to decrease hospitalizations, particularly among
patients with LVEF on the lower end of this spectrum.
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49. Treatment [24]
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50. Treatment [25]
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51. Treatment [26]
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52. Treatment [27]
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53. Treatment [28]
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