Pharmacotherapy of Heart Failure

1. Pharmacotherapy
of Heart Failure
Dr. Ashutosh Tiwari
PG Resident, IInd Year
Pharmacology Department
SAIMS Indore
14/02/2015

2. Contents
 Introduction
 Definition
 Epidemiology
 Signs and symptoms
 Pathophysiology
 Pharmacotherapy
 Classification of HF
 Management Guidelines for HF
 Recent advances
 Newer drug targets
 Conclusion

3. Introduction
 Considerable advances have been made in management
of heart failure over the past few decades.
 In outpatient-based clinical trials, mortality has more
than halved in people with established systolic chronic
heart failure; moreover, admissions have fallen and
patients’ quality of life has risen.
 Nevertheless, heart failure remains a major public-
health issue, with high prevalence and poor outcomes.
 Management of this condition includes appropriate non-
pharmacological strategies, use of drugs (particularly
those that inhibit key activated neurohormonal
systems), and implantation of devices in appropriate
patients.
 Surgery and transplantation are also options for selected
individuals with highly advanced disease.

4. Heart Failure
 The inability of the
heart to pump
sufficient blood to
meet the needs of
the tissues for
oxygen and nutrients

5. Symptoms

6. Definition
 HF is a complex clinical syndrome that
results from any structural or
functional impairment of ventricular
filling or ejection of blood.

7. Definition
I. Heart failure with reduced ejection fraction
(HFrEF)
– EF (%) ≤40
– Also referred to as systolic HF
– coronary artery disease (CAD) with antecedent
myocardial infarction (MI) is a major cause of
HFrEF

8. Definition
II. Heart failure with preserved ejection fraction
(HFpEF)
– EF (%) ≥50
– Also referred to as diastolic HF
– Hypertension, obesity, CAD, diabetes mellitus,
and hyperlipidemia are important cause of
HFpEF

9. Epidemiology
 The lifetime risk of developing HF is 20% for Americans
≥40 years of age.
 HF incidence: >650 000 new HF cases diagnosed
annually
 HF incidence increases with age, rising from
approximately 20 per 1000 individuals 65 to 69 years of
age to >80 per 1000 individuals among those ≥85 years
of age.
 Mortality rates for HF remain approximately 50% within
5 years of diagnosis
 The total cost of HF care in the United States exceeds
$30 billion annually, with over half of these costs spent
on hospitalizations.

10. Signs and symptoms
 Left-Sided Heart Failure:
– Results from LV dysfunction
– Blood backs up into Left atrium
– Pulmonary congestion and edema

12. Signs and symptoms
 Right-Sided Failure:
– Results from diseased right ventricle
– Blood backs up into right atrium and
venous circulation

14. Biomarkers in HF
 Natriuretic Peptides:
– BNP (B-type natriuretic peptide) or NT-proBNP
(N-terminal pro-B-type natriuretic peptide)
– generated by cardiomyocytes in response to
myocardial stretch
– useful to support clinical decision making
regarding the diagnosis of HF, especially in the
setting of clinical uncertainty
– useful for establishing prognosis or disease
severity in chronic HF

15. Pathophysiology of HF
 In order to maintain normal cardiac
output, several compensatory
mechanisms play a role:
– Compensatory enlargement in the form of
cardiac hypertrophy, cardiac dilatation, or
both.
– Tachycardia (i.e. increased heart rate) due to
activation of neurohumoral system e.g.
 release of norepinephrine and atrial natrouretic
peptide,
 activation of renin-angiotensin aldosterone
mechanism.

17. Pharmacotherapy of HF

18. Goals of Pharmacotherapy
 Relief of congestion/low cardiac
output symptoms & restoration
of cardiac performance:
o Inotropic drugs-digoxin,
dobutamine,amrinone/milrinone.
o Diuretics: furosemide, thiazides.
o Vasodilators: ACE inhibitors/AT1
antagonist, hydralazine, nitrate.
o Beta blockers:
metoprolol,bisprolol,carvedilol
 Arrest/reversal of disease
progression & prolongation of
survival
 ACE inhibitors/AT1 antagonist
(ARBs).
 Beta-blockers
 Aldosterone antagonist-
spironolactone

19. Survival
Morbidity
Exercise capacity
Quality of life
Neurohormonal changes
Progression of CHF
Symptoms
TREATMENT OBJECTIVES

20. Mechanism of action: Cardiac Glycosides
 Act by inhibiting Na+K+ATPase of cardiac cells
increased intracellular Na decreased extrusion of Ca by
Na+Ca2+exchanger  increased intracellular Ca 
increased contractility  increased CO  decreases
pulmonary congestion & systemic venous pressure & hence
compensatory sympathetic overactivity is withdrawn
 Decreases heart rate by direct & indirect actions  ↓
myocardial O2 demand

21. Mechanism of action: ACE Inhibitors
 inhibits generation of Angiotensin II,
– which is a potent vasoconstrictor,
– causes aldosterone secretion  Na &
water retention & causes cardiac
hypertrophy & remodeling (by collagen
deposition & fibrosis)
 Inhibits degradation of Bradykinin
(potent vasodilator, cough,
angioedema)

22. Mechanism of action:
Diuretics
 Heart failure  accumulation of fluid
in lungs & peripheral organs 
congestive symptoms
 Diuretics  promote Na & water
excretion  ↓ ECF vol  ↓ preload 
reduce symptoms

23. Mechanism of action:
Inotropes
 Dobutamine & Dopamine:
acts via β1 receptor  increase cardiac
contractility  increase CO
 Milrinone
 inhibit phosphodiesterase III  ↑ cAMP
in heart & blood vessels  ↑ myocardial
contractility & vasodilatation

24. HF: Classification
 ACCF/AHA (American College of
Cardiology Foundation/ American
Heart Association) stages of HF
 NYHA (New York Heart Association)
functional classification of HF
 ACCF/AHA stages of HF emphasize
the development and progression of
disease whereas NYHA classes focus
on exercise capacity and
symptomatic status of the disease

25. HF: Classification

26. Goals of HF management:
– Stage A: modifying risk factors
– Stage B: treating structural heart disease
– Stage C & D: reducing morbidity and
mortality

27. Stage A: Recommendations
 Class I
– Hypertension and lipid disorders
should be controlled to lower the
risk of HF.
– Other conditions that may lead to or
contribute to HF, such as obesity,
diabetes mellitus, tobacco use, and
known cardiotoxic agents, should be
controlled or avoided.

28. Stage A: Recommendations
 Diuretic-based antihypertensive therapy
has repeatedly been shown to prevent
HF in a wide range of patients;
 ACE inhibitors, ARBs, and beta blockers
are also effective.
 Data are less clear for calcium
antagonists and alpha blockers in
reducing the risk for incident HF.
 Treatment of hyperlipidemia with statins
reduces the likelihood of HF in at-risk
patients

29. Stage B: Recommendations
 ACE inhibitors and Beta blockers should be
used in all patients with a reduced EF to
prevent HF
 In patients with MI or history of MI and reduced EF,
ACE inhibitors or ARBs and beta blockers should be
used to prevent HF
 In patients with MI, statins should be used to
prevent HF
 Blood pressure should be controlled to prevent
symptomatic HF
 Nondihydropyridine calcium channel blockers
may be harmful in patients with low LVEF

30. Stage C HFrEF recomendations
 NYHA Class I: ACEI or ARB and Beta Blocker
 NYHA Class II,III,IV
– for volume overload: add Loop diuretics
– for persistently symptomatic: add
vasodilators (hydralazine and isosorbide
dinitrate)
– LVEF ≤35%, estimated creatinine >30
mL/min and K+ <5.0 mEq/dL: add
Aldosterone Antagonist
 Calcium channel blockers are not recommended
as routine treatment in HFrEF

31. Diuretics: recommendations
 Diuretics should be prescribed to all patients who
have evidence of or prior history of, fluid retention.
 Diuretics should generally be combined with an ACE
inhibitor, beta blocker, and aldosterone antagonist.
 Loop diuretics have emerged as the preferred
diuretic agents for use in most patients with HF.
 Thiazide diuretics may be considered in
hypertensive patients with HF and mild fluid
retention because they confer more persistent
antihypertensive effects.

32. Diuretics: recommendations
 Diuretics increase urinary sodium excretion and
decrease physical signs of fluid retention in
patients with HF
 Diuretics are the only drugs used for the
treatment of HF that can adequately control the
fluid retention of HF.
 The most commonly used loop diuretic for the
treatment of HF is furosemide, but some
patients respond more favorably to other
agents in this category (e.g., bumetanide,
torsemide) because of their increased oral
bioavailability

33. Diuretics: recommendations
 Patients may become unresponsive to high
doses of diuretic drugs if they consume large
amounts of dietary sodium or are taking agents
that can block the effects of diuretics (e.g.,
nonsteroidal anti-inflammatory drugs [NSAIDs],
or have a significant impairment of renal
function or perfusion
 Diuretic resistance can generally be overcome
by the intravenous administration of diuretics or
combination of different diuretic classes (e.g.,
metolazone with a loop diuretic)

34. Diuretics: recommendations
 Adverse effects:
– electrolyte and fluid depletion,
hypotension and azotemia
– depletion of potassium and magnesium,
which can predispose patients to serious
cardiac arrhythmias

35. ACE Inhibitors: recommendations
 ACE inhibitors are recommended in
patients with HFrEF and current or
prior symptoms, to reduce morbidity
and mortality
 The benefits of ACE inhibition were
seen in patients with mild, moderate,
or severe symptoms of HF and in
patients with or without CAD.

36. ACE Inhibitors: recommendations
 Contraindications
– H/O life-threatening adverse reactions (i.e.,
angioedema) during previous medication
exposure
– pregnancy
– systolic blood pressure <80 mm Hg
– markedly increased serum levels of
creatinine (>3 mg/dL)
– bilateral renal artery stenosis
– elevated levels of serum potassium (>5.0
mEq/L).

37. ARB: recommendations
 ARBs are recommended in patients with HFrEF with current or
prior symptoms who are ACE inhibitor intolerant (cough,
angioedema), to reduce morbidity and mortality
 ARBs were developed with the rationale that
– a) angiotensin II production continues in the presence of
ACE inhibition, driven through alternative enzyme
pathways and
– b) interference with the renin-angiotensin system without
inhibition of kininase would produce all of the benefits of
ACE inhibitors while minimizing the risk of adverse
reactions to them.
– However, it is now known that some of the benefits of
ACE inhibitors may be related to the accumulation of
kinins rather than to the suppression of angiotensin II
formation, whereas some of the adverse effects of ACE
inhibitors in HF are related to the suppression of
angiotensin II formation.

38. Beta Blockers: Recommendations
 Use of 1 of the 3 beta blockers proven to
reduce mortality (e.g., bisoprolol, carvedilol,
and sustained-release metoprolol succinate)
is recommended for all patients with current
or prior symptoms of HFrEF, to reduce
morbidity and mortality
 Like ACE inhibitors, beta blockers can
reduce the risk of death and the combined
risk of death or hospitalization

39. Beta Blockers: Recommendations
 Adverse effects:
– fluid retention and worsening HF; fatigue;
bradycardia or heart block; and hypotension.
– if the bradycardia is accompanied by
dizziness or lightheadedness or if second- or
third-degree heart block occurs, the dose of
the beta blocker should be decreased
– Abrupt withdrawal of treatment with a beta
blocker can lead to clinical deterioration and
should be avoided

40. Aldosterone receptor antagonists:
Recommendations
 Aldosterone receptor antagonists
(Spironolactone, Eplerenone) are recommended
in patients with NYHA class II–IV HF and who
have LVEF of 35% or less, to reduce morbidity
and mortality.
 Aldosterone receptor antagonists are
recommended to reduce morbidity and
mortality following an acute MI in patients who
have LVEF of 40% or less who develop
symptoms of HF or who have a history of
diabetes mellitus

41. Aldosterone receptor antagonists:
Recommendations
 To minimize the risk of life-
threatening hyperkalemia, patients
should have initial serum creatinine
<2.5 mg/dL and serum potassium
<5.0 mEq/L without a history of
severe hyperkalemia.

42. Hydralazine & Isosorbide dinitrate:
recommendations
 The combination of hydralazine and isosorbide
dinitrate is recommended to reduce morbidity
and mortality for patients with NYHA class III–
IV HFrEF who remain symptomatic despite
concomitant use of ACE inhibitors, beta
blockers, and aldosterone antagonists.
 Adverse effects include headache, dizziness,
and gastrointestinal complaints.

43. Digoxin: recommendaton
 Digoxin can be beneficial in patients with HFrEF, to
decrease hospitalizations for HF
 treatment with digoxin for 1 to 3 months can
improve symptoms, HRQOL (Health Related Quality
of Life), and exercise tolerance in patients with mild
to moderate HF
 treatment with digoxin for 2 to 5 years had no
effect on mortality but modestly reduced the
combined risk of death and hospitalization
 Digoxin can be used only in patients who remain
symptomatic despite therapy with the
neurohormonal antagonists or in patients with AF

44. Digoxin: recommendaton
 Adverse effects: cardiac arrhythmias (e.g.,
ectopic and re-entrant cardiac rhythms and
heart block), gastrointestinal symptoms (e.g.,
anorexia, nausea, and vomiiting), and
neurological complaints (e.g., visual
disturbances, disorientation, and confusion).
 Overt digoxin toxicity is commonly associated
with serum digoxin levels >2 ng/mL.
 However, toxicity may also occur with lower
digoxin levels, especially if hypokalemia,
hypomagnesemia, or hypothyroidism coexists

45. Stage D recommendations
 Intravenous inotropic support (Dopamine,
Dobutamine, Milrinone) to maintain systemic
perfusion and preserve end-organ performance.
 Chronic oral inotrope treatment increases
mortality, mostly related to arrhythmic events.
 Inotropes should be considered only in such
patients HF who are refractory to other
therapies, with systolic dysfunction,and who
have low cardiac index and evidence of
systemic hypoperfusion and/or congestion

46. Anticoagulation: Recommendations
 Patients with chronic HF with permanent/persistent/
paroxysmal AF and an additional risk factor for
cardioembolic stroke (history of hypertension,
diabetes mellitus, previous stroke or transient
ischemic attack, or ‡75 years of age) should receive
chronic anticoagulant therapy
 The selection of ananticoagulant agent
(warfarin,dabigatran, apixaban, or rivaroxaban)
should be individualized on the basis of risk factors,
cost, tolerability, patient preference, potential for
drug interactions, and other clinical characteristics.

47. Statins: recommendation
 Statins are not beneficial as adjunctive therapy when
prescribed solely for the diagnosis of HF in the absence
of other indications for their use
 Originally designed to lower cholesterol in patients with
cardiovascular disease, statins are increasingly
recognized for their favorable effects on inflammation,
oxidative stress, and vascular performance.
 However, 2 large RCTs have demonstrated that
rosuvastatin has neutral effects on long-term outcomes
in patients with chronic HFrEF
 At present, statin therapy should not be prescribed
primarily for the treatment of HF to improve clinical
outcomes.

48. Omega-3 Fatty Acids:
Recommendation
 Omega-3 polyunsaturated fatty acid (PUFA)
supplementation is reasonable to use as
adjunctive therapy in patients with NYHA class
II–IV symptoms and HFrEF or HFpEF, to reduce
mortality and cardiovascular hospitalizations
 Trials in primary and secondary prevention of
coronary heart disease showed that omega-3
PUFA supplementation results in a 10% to 20%
risk reduction in fatal and nonfatal
cardiovascular events.

49. Nutritional Supplements and
Hormonal Therapies
 Several nutritional supplements (e.g., coenzyme
Q10, carnitine, taurine, and antioxidants) and
hormonal therapies (e.g., growth hormone or
thyroid hormone) have been proposed for the
treatment of HF
 No clinical trials have demonstrated improved
survival rates with use of nutritional or hormonal
therapy, with the exception of omega-3 fatty acid
supplementation

50. Device Therapy for HF
 Implantable cardioverter-defibrillator
 Cardiac resynchronization therapy
 Mechanical Circulatory Support
 Cardiac Transplantation

51. Non-pharmacological Management
 Sodium Restriction to 2g/day
 Risk Factor Management
 Exercise
– Decreases mortality
– Decreases hospitalizations
 Multidisciplinary, Disease-Management Approach
– Aspirin, beta-blocker, Nitrates, ACE-I, Statin, Exercise,
Smoking Cessation, Dietary

52. Recent Advances in the
management of HF

54.  On August 30, 2014 at the European Society of Cardiology
congress and published simultaneously in the New England
Journal of Medicine, Novartis revealed that its investigational
heart failure medicine, LCZ696, was superior to ACE-inhibitor
enalapril on key endpoints in the largest heart failure study
ever done
 PARADIGM-HF is a randomized, double-blind, phase III study
evaluating the efficacy and safety profile of LCZ696 versus
enalapril (a widely studied ACE inhibitor) in 8,442 patients
with HF-REF.
 The trial was stopped early, according to prespecified
rules, because the boundary for an overwhelming
benefit with LCZ696 had been crossed.

55. LCZ696
 LCZ696, represents one of the most important
cardiology advances of the last decade
 It acts to enhance the protective neurohormonal
systems of the heart (NP system) while simultaneously
suppressing the harmful system (the RAAS)
 reduced the risk of death from cardiovascular causes by
20% (p=0.00004)
 reduced heart failure hospitalizations by 21%
(p=0.00004)
 reduced the risk of all-cause mortality by 16%
(p=0.0005)
 Overall there was a 20% risk reduction on the primary
endpoint, a composite measure of CV death or heart
failure hospitalization (p=0.0000002)

56. LCZ696
 LCZ696 is an ARNI (Angiotensin Receptor Neprilysin
Inhibitor)
 It harnesses the body's natural defences against heart
failure, simultaneously acting to enhance the levels of
natriuretic and other endogenous vasoactive peptides,
while also inhibiting the renin- angiotensin-aldosterone
system (RAAS).
 Neprilysin, a neutral endopeptidase, degrades several
endogenous vasoactive peptides, including natriuretic
peptides, bradykinin, and adrenomedullin.
 Inhibition of neprilysin increases the levels of these
substances, countering the neurohormonal
overactivation that contributes to vasoconstriction,
sodium retention, and mal- adaptive remodeling.

57. LCZ696
 Combined inhibition of the renin–angiotensin
system and neprilysin had effects that were
superior to those of either approach alone in
experimental studies
 but in clinical trials, the combined inhibition of ACE
and neprilysin was associated with serious
angioedema due to inhibition of enzymes
responsible for degradation of bradykinin.
 LCZ696, which consists of the neprilysin inhibitor
sacubitril (AHU377) and the ARB valsartan, was
designed to minimize the risk of serious
angioedema as it does not inhibit ACE.

58. New targets in clinical development for
acute heart failure

59. New targets in clinical development for
chronic heart failure

60. Activation of SERCA2a
 In patients with heart failure, there is decreased
calcium content in the sarcoplasmic reticulum,
which is partly due to the diminished sarcoplasmic
reticulum calcium adenosine triphosphatase isoform
2a (SERCA2a) pump activity.
 Istaroxime is a molecule that has the
unprecedented ability to increase the SERCA2a
pump activity and cause myocardial relaxation.
 It also causes inhibition of Na+/K+-ATPase

61. Cardiac myosin ATPase activation
 During myocardial contraction, the myosin head
works as an independent force generator if it is
bound tightly to actin.
 However, the majority of myosin heads are not
tightly bound to actin in the physiological state.
 This can be changed by omecamtiv mecarbil, which
increases the number of myosin heads that are in
force-generating configuration to get tightly bound
to actin that leads to enhanced cardiac contraction.

62. Relaxin
 Relaxin hormone, besides being produced by the
corpus luteum and placenta, is also produced by
the failing myocardium.
 It acts on a G-protein coupled receptor named
RXFP1 that is produced in the vasculature, heart
and the kidneys.
 As a result, cAMP & nitric oxide production is
increased
 Serelaxin (human recombinant relaxin) causes
greater vasodilation and improved vessel
compliance

63. Natriuretic peptides
 ANP is mainly produced in atrial myocytes. The
main stimulant for ANP release is atrial wall stretch
resulting from increased intravascular volume
 ANP has vasodilatory, natriuretic, diuretic, and
kaliuretic properties.
 Carperitide is a recombinant ANP for the treatment
of acute heart failure syndrome
 Urodilatin is a modified form of pro-ANP that is
synthesized and secreted from the distal convoluted
tubules in the kidney and regulates renal sodium
reabsorption and water homeostasis
 Ularitide is a synthetically derived form of urodilatin

64. Ryanodine receptor stabilizers
 The ryanodine receptors that are present in the
sarcoplasmic reticulum of the heart cause release of
calcium on activation.
 Under resting conditions, the ryanodine receptor
channel is maintained in a closed state by a protein
calstabin-2.
 JTV519 is a drug that can potentiate the binding of
calstabin to ryanodine, and thus help it to retain its
closed state
 S44121 is a ryanodine receptor stabilizer, studied in
patients with heart failure who are at increased risk
for ventricular arrhythmia.

65. Neuregulins
 The neuregulins are proteins that belong to the
epidermal growth factor family of ligands that bring
about their effects through ErbB tyrosine kinase
receptors.
 reduced ErbB signaling in the failing myocardium
increases its chance of cell death and rapid
worsening of heart failure
 Recombinant NRG-1β has been evaluated in several
animal models of cardiac failure and found to
improve the structural and functional indices for
ventricular remodeling
 recombinant neuregulin-1 improved the LVEF and
reduced the LV remodeling by decreasing EDV and
ESV

66. Sarcoplasmic reticulum calcium
ATPase 2A gene therapy
 The enzyme SERCA2a catalyzes the adenosine
triphosphate- dependent movement of calcium ions
into the sarcoplasmic reticulum from the cytosol
 Increase of calcium levels by augmenting SERCA2a
activity will improve cardiac function.
 Istaroxime causes overexpression of SERCA2a in
the cardiomyocytes of the failing heart in order to
improve the contraction velocity
 gene transfer using adenovirus as a vector for
delivery of SERCA2a complementary DNA is being
studied

67. NEED FOR NEWER
THERAPIES
 Available drugs treat only
symptomatically
 Even the available drugs do not
control symptoms effectively
 Associated side effects are more
 Needed life long treatment
 HF is associated with high morbidity
and mortality

68. Conclusion
 Despite advances in management of heart failure,
the condition remains a major public-health issue,
with high prevalence, poor clinical outcomes, and
large health-care costs.
 Risk factors are well known and, thus, preventive
strategies should have a positive effect on
disease burden.
 Emerging strategies for heart failure
management include individualisation of
treatment, novel approaches to diagnosis and
tracking of therapeutic response, pharmacological
agents aimed at new targets, and cell-based and
gene-based methods for cardiac regeneration.

69. Conclusion
 Agents directly acting on remodeling
process may even reverse current
pathological condition of heart failure.
 The newer therapeutics may be potential
candidates in future for heart as there is
increase in understanding of
pathophysiology of heart failure.