CHF latest guidelines. Recent advances in drug treatment of CHF included. Recent FDA approved drugs for treatment of CHF also included.

1. Recent guidelines for the
treatment of CHF
By-Dr. Rahul Kumar Bhati
PG Pharmacology

2. Contents
• Introduction
• Definition
• Epidemiology
• Signs and symptoms
• Pathophysiology
• Pharmacotherapy
• Classification of HF
• Treatment 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.

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 contd...
• 1. Heart failure with reduced ejection fraction
(HFrEF)
— EF (%)<or=40
— Also referred to as systolic HF
— coronary artery disease (CAD) with
antecedent myocardial infarction (MI) is a
major cause of HFrEF

8. Definition contd...
• 2. Heart failure with preserved ejection
fraction (HFpEF)
— EF(%) >or=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
>or=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 >or=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 Heart 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
natriuretic peptide,
• activation of renin-angiotensin aldosterone
mechanism.

17. Pharmacotherapy of HF

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

20. 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

22. 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
• Goals of HF management:
— Stage A: modifying risk factors
— Stage B: treating structural heart disease
— Stage C & D: reducing morbidity and
mortality

23. Stage A: Recommendations
• 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.

24. • Diuretic-based antihypertensive therapy has
repeatedly been shown to prevent HF in a
wide range of patients;
• ACE inhibitors, ARBs, 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

25. 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(in patients intolerant to ACEI)
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

26. Stage C HFrEF recomendations
• NYHA Class 1: ACEI or ARB and Beta Blocker
• NYHA Class 2,3,4
— for volume overload: add Loop diuretics
— for persistently symptomatic: add vasodilators
(hydralazine and isosorbide dinitrate)
— LVEF <or=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

27. 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.

28. Diuretics: recommendations contd...
• 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

29. Diuretics: recommendations contd...
• 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)

30. 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.

31. 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 are reasonable to reduce morbidity and
mortality as alternatives to ACE inhibitors as
first line therapy for patients with HFrEF,
especially for patients already taking ARBs for
other indications.

32. ARB: recommendations contd...
• Addition of an ARB may be considered in
persistently symptomatic patients with HFrEF
who are already being treated with an ACE
inhibitor and a beta blocker in whom an
aldosterone antagonist is not indicated or
tolerated.
• Routine combined use of an ACE inhibitor,
ARB, and aldosterone antagonist is potentially
harmful for patients with HFrEF.

33. 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

34. Aldosterone receptor antagonists:
Recommendations
• Aldosterone receptor antagonists
(Spironolactone, Eplerenone) are recommended
in patients with NYHA class 2—4 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

35. Aldosterone receptor antagonists:
Recommendations contd...
• To minimize the risk of life-threatening
hyperkalemia, patients should have initial
serum creatinine <2.5 mg/dL(<2.0 mg/dL for
women) and serum potassium <5.0 mEq/L
without a history of severe hyperkalemia.

36. Hydralazine & Isosorbide dinitrate:
recommendations
• The combination of hydralazine and isosorbide
dinitrate is recommended to reduce morbidity and
mortality for patients with NYHA class Ill— IV HFrEF
who remain symptomatic despite concomitant use of
ACE inhibitors, beta blockers, and aldosterone
antagonists.
• A combination of hydralazine and isosorbide dinitrate
can be useful to reduce morbidity or mortality in
patients with current or prior symptomatic HFrEF who
cannot be given an ACE inhibitor or ARB because of
drug intolerance, hypotension, or renal insufficiency.

37. Digoxin: recommendation
• 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

38. 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 >or= 75 years of age) should receive chronic
anticoagulant therapy.
• The selection of anticoagulant 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.
• Chronic anticoagulation is reasonable for patients with chronic HF
who have permanent/persistent/paroxysmal AF but are without an
additional risk factor for cardioembolic stroke.
• Anticoagulation is not recommended in patients with chronic HFrEF
without AF, a prior thromboembolic event, or a cardioembolic
source.

39. 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.

40. Omega-3 Fatty Acids:
Recommendation
• Omega-3 polyunsaturated fatty acid (PUFA)
supplementation is reasonable to use as
adjunctive therapy in patients with NYHA class
2—4 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.

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

43. Stage C HFpEF recommendations
• Systolic and diastolic blood pressure should be controlled
according to published clinical practice guidelines
• Diuretics should be used for relief of symptoms due to
volume overload
• Management of AF according to published clinical practice
guidelines for HFpEF to improve symptomatic HF
• Use of beta-blocking agents, ACE inhibitors, and ARBs for
hypertension in HFpEF
• ARBs might be considered to decrease hospitalizations in
HFpEF
• Nutritional supplementation is not recommended in HFpEF

44. Stage D recommendations
 Water Restriction:
• Fluid restriction (1.5 to 2 L/d) is reasonable in stage D, especially in
patients with hyponatremia, to reduce congestive symptoms.
 Inotropic Support:
• Until definitive therapy (e.g., coronary revascularization, MCS, heart
transplantation) or resolution of the acute precipitating problem,
patients with cardiogenic shock should receive temporary
intravenous inotropic support to maintain systemic perfusion and
preserve end-organ performance.
• Continuous intravenous inotropic support is reasonable as "bridge
therapy" in patients with stage D HF refractory to GDMT and device
therapy who are eligible for and awaiting MCS or cardiac
transplantation.

45. • Short-term, continuous intravenous inotropic support may be
reasonable in those hospitalized patients presenting with
documented severe systolic dysfunction who present with low
blood pressure and significantly depressed cardiac output to
maintain systemic perfusion and preserve end-organ performance.
• Long-term, continuous intravenous inotropic support may be
considered as palliative therapy for symptom control in select
patients with stage D HF despite optimal GDMT and device therapy
who are not eligible for either MCS or cardiac transplantation.
• Long-term use of either continuous or intermittent, intravenous
parenteral positive inotropic agents, in the absence of specific
indication or for reasons other than palliative care, is potentially
harmful in the patient with HF.
• Use of parenteral inotropic agents in hospitalized patients without
documented severe systolic dysfunction, low blood pressure, or
impaired perfusion and evidence of significantly depressed cardiac
output, with or without congestion, is potentially harmful.

46.  Mechanical Circulatory Support:
• MCS is beneficial in carefully selected patients with stage D HFrEF in
whom definitive management (e.g., cardiac transplantation) or
cardiac recovery is anticipated or planned.
• Nondurable MCS, including the use of percutaneous and
extracorporeal ventricular assist devices, is reasonable as a "bridge
to recovery" or a "bridge to decision" for carefully selected patients
with HFrEF with acute, profound hemodynamic compromise.
• Durable MCS is reasonable to prolong survival for carefully selected
patients with stage D HFrEF.
 Cardiac Transplantation:
• Evaluation for cardiac transplantation is indicated for carefully
selected patients with stage D HF despite GDMT , device, and
surgical managernent.

48. Recommendations for Therapies in the
Hospitalized HF Patient

49. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological
Therapy for Heart Failure: An Update of the 2013 ACCF/AHA
Guideline for the Management of Heart Failure
• The ACC, the AHA, and the Heart Failure Society of America
(HFSA) recognize that the introduction of effective new
therapies that potentially affect a large number of patients
presents both opportunities and challenges.
• The introduction of an angiotensin receptor–neprilysin
inhibitor (ARNI) (valsartan/sacubitril) and a sinoatrial node
modulator (ivabradine), when applied judiciously,
complements established pharmacological and device-
based therapies and represents a milestone in the
evolution of care for patients with heart failure (HF).
• Accordingly, the writing committees of the “2016
ACC/AHA/HFSA Focused Update on New Pharmacological
Therapy for Heart Failure” developed recommendations for
the incorporation of these therapies into clinical practice.

50. Pharmacological Treatment for Stage C HF With
Reduced Ejection Fraction: Recommendations
 Renin-Angiotensin System Inhibition With Angiotensin-
Converting Enzyme Inhibitor or Angiotensin Receptor
Blocker or ARNI: Recommendations
• The clinical strategy of inhibition of the renin-angiotensin system
with ACE inhibitors, OR ARBs, OR ARNI in conjunction with
evidence-based beta blockers, and aldosterone antagonists in
selected patients, is recommended for patients with chronic HFrEF
to reduce morbidity and mortality.
• The use of ACE inhibitors is beneficial for patients with prior or
current symptoms of chronic HFrEF to reduce morbidity and
mortality

51. • The use of ARBs to reduce morbidity and mortality is
recommended in patients with prior or current symptoms
of chronic HFrEF who are intolerant to ACE inhibitors
because of cough or angioedema.
• In patients with chronic symptomatic HFrEF NYHA class II or
III who tolerate an ACE inhibitor or ARB, replacement by an
ARNI is recommended to further reduce morbidity and
mortality.
• ARNI should not be administered concomitantly with ACE
inhibitors or within 36 hours of the last dose of an ACE
inhibitor.
• ARNI should not be administered to patients with a history
of angioedema.

52. Ivabradine: Recommendation
• Ivabradine can be beneficial to reduce HF
hospitalization for patients with symptomatic
(NYHA class II-III) stable chronic HFrEF (LVEF
≤35%) who are receiving GDEM, including a
beta blocker at maximum tolerated dose, and
who are in sinus rhythm with a heart rate of
70 bpm or greater at rest.

53. Recent Advances in the
management of HF

54. ARNI(valsartan/sacubitril)

60. Ivabradine

69. 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

70. 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.

71. 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 RXFPI 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
• In the end the trial(RELAX-AHF-2) was not strong enough to
gain approval for serelaxin from the FDA or in Europe.

72. 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 that is currently
approved in JAPAN 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

73. 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.
• In HF the ryanodine receptor channel tends to remain
inappropriately in the open state during diastole, resulting in
calcium leakage from the sarcoplasmic reticulum. The depletion of
calcium from the SR leads to weak muscle contractions in heart
failure. This phenomenon is termed as diastolic sarcoplasmic
reticulum calcium leak.
• 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.

74. 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-l improved the LVEF and reduced
the LV remodeling by decreasing EDV and ESV

75. 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.
• This has led to the concept of 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.
• But the HF Gene-Therapy Trial CUPID-2 failed to meet the primary
end point, a composite of of HF hospitalization or ambulatory
treatment for worsening heart failure at 12 months.

76. 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

77. 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.

78. 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.