Drugs Used in Heart Failure Drugs without positive inotropic effects used in Heart Failure: Diuretics ACE/ARB & Related agents Vasodilators β-Adrenergic Blockers Others Drugs with positive inotropic effects used in Heart Failure: Digitalis Other positive inotropic drugs: Bipyridines Beta-Adrenergic agonists Investigational positive inotropic drugs: Istaroxime, Levosimanden, Omecamtiv mecarbil

1. Drugs Used in Heart
Failure
1
Presented by: Akash Agnihotri

2. Heart Failure - Introduction
• HF Most common cause-
• Coronary Artery Disease (CAD)
• CAD + Hypertension (important factor)
2

3. Risk factors for HF:
• Heart failure with reduced ejection
fraction (HFrEF)
• Heart failure with preserve ejection
fraction (HFpEF)
• COPD- Chronic Obstructive
Pulmonary Disease
• LVEF- Left Ventricular Ejection
Fraction

4. Introduction- Heart Failure (HF)
Heart Failure
• Heart can’t supply enough blood to meet the body’s demand
Heart Failure
Systolic HF Diastolic HF
• Ventricles can’t pump
blood hard enough
• Can't contract completely
• Ventricles not enough
filled with blood
HFrEF HFpEF

5. Heart Failure - Prevalence
• The overall prevalence of clinically identified heart failure is estimated
to be 3–20 cases/1000 population
• But rises to > 100 cases/1000 population in those aged ⩾65 years
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6. Initial Evaluation for Diagnosing Symptoms and
Signs in Heart Failure With Reduced Ejection
Fraction
Bendopnea:
Defined as shortness of breath when leaning forward
(such as when putting on shoes) is also suggestive of
heart failure. 6

7. Studies to Perform During the Initial Evaluation for Diagnosing
Heart Failure With Reduced Ejection Fraction
7

8. Definition of heart failure with reduced ejection
fraction, mildly reduced ejection fraction and
preserved ejection fraction
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9. Pathophysiology of heart failure
• Normal cardiac physiology
• Left ventricular dysfunction
• Right ventricular dysfunction
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10. Factors affecting CO
Stroke
Volume
Preload Afterload
Contractility
Cardiac Output
Heart Rate
Synergistic ventricular contraction
Ventricular wall integrity
Valvular competence
Amount of blood ejected by the
ventricle per heartbeat
Amount of myocardial fiber
stretch at the end of diastole
Resistance that must be overcome in
order for the ventricle to eject blood
Inotropic state of the heart
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11. Left ventricular dysfunction
• Left ventricular (LV) dysfunction can be divided into two categories:
• Systolic dysfunction (impaired ventricular contraction and ejection) and
diastolic dysfunction (impaired relaxation and ventricular filling)
• Depends on the ejection fraction (EF)
• Defined as the amount of blood pumped from the ventricle in one heartbeat
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12. Left ventricular dysfunction
12

13. Right ventricular dysfunction
• The most common cause of right ventricular (RV) failure is LV failure
• Increase in the amount of blood in the ventricle
• Elevated right atrial pressure
• Leads to increased pressure in the liver, the gastrointestinal tract, and
the lower extremities and to the clinical signs and symptoms of
abdominal pain, hepatomegaly, and peripheral edema
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14. Signs and symptoms of RV failure
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15. Neurohumoral effects
of heart failure:
15

16. Goals of pharmacologic intervention in HF
• Goals of treatment are to alleviate symptoms, slow disease progression,
and improve survival. Therapeutic agents act by:
• Increasing cardiac contractility
• Reducing preload
• Normalizing heart rate and rhythm
• Reduction in mortality
• Prevention of recurrent hospitalizations due to worsening HF
• Improvement in clinical status, and QOL
16

17. Pharmacologic
intervention in HF
β-Antagonists
ACE inhibitors
Spironolactone
Diuretics
Vasodilators
Vasodilators 17

18. Drugs Used in Heart Failure:
1. Drugs without positive inotropic effects used in Heart Failure:
I. Diuretics
II. ACE/ARB & Related agents
III. Vasodilators
IV. β-Adrenergic Blockers
V. Others
2. Drugs with positive inotropic effects used in Heart Failure:
I. Digitalis
3. Other positive inotropic drugs:
I. Bipyridines
II. Beta-Adrenergic agonists
III. Investigational positive inotropic drugs: Istaroxime, Levosimanden,
Omecamtiv mecarbil
18

19. I. Diuretics
• Fluid Retention/accumulation- Filling Pressure with fluid overload
• Increase Preload
• Most of HFrEF patients require diuretic to control fluid retention
Diuretics:
• Reduce sign & symptoms of volume overload
• Dyspnea on exertion, Orthopnea and peripheral edema
• Reduce venous pressure and ventricular preload
• There is no evidence of a mortality benefit from treatment with either
loop diuretics or thiazide diuretics
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20. I. Diuretics
• Loop diuretics- Furosemide, Bumetanide, Torsemide (Preferred)
• Furosemide- drug of choice in heart failure
• Thiazide-like agents- Most commonly metolazone or intravenous
chlorothiazide in hospitalized patients (Diuretic resistance)
• The aim of diuretic therapy is to achieve and maintain euvolaemia with
the lowest diuretic dose
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21. I. Diuretics- MOA
Diuretics
In the thick ascending limb of Henle
Inhibit Na+ -K+ -2Cl- co-transporter
Promote salt and water excretion
Circulating volume
Preload
• Improve cardiac function
• Decrease dyspnea and peripheral oedema
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22. I. Diuretics
• Spironolactone and eplerenone- Aldosterone (mineralocorticoid)
antagonist diuretics
• Additional benefit of decreasing morbidity and mortality in patients
with severe heart failure who are also receiving ACE inhibitors and other
standard therapy
• Finerenone is an investigational mineralocorticoid antagonist that may
be less likely to induce hyperkalemia
• Apararenone and esaxerenone are similar investigational nonsteroidal
mineralocorticoid antagon
22

23. II. ACEi/ARB & Related agents
Angiotensin-converting enzyme inhibitors:
• Standard therapy for all grade of CHF:
23
First class of drugs shown to reduce mortality and morbidity in patients with HFrEF

24. Angiotensin-converting enzyme inhibitors:
24
They should be uptitrated to the maximum tolerated recommended
doses
• As many as 20% of patients
treated with ACE inhibitors
develop a dry cough due to
pulmonary accumulation of
bradykinin
• which is not dose dependent
and is a class effect across
all ACE inhibitors

25. Angiotensin receptor blockers(ARBs):
• Highly selective, competitive receptor antagonists
• Act on AT1 receptor- which mediates the major effects of AngII
• Alternatives to ACEIs- 2nd choice in all stages of HF
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II. ACEi/ARB & Related agents

26. Angiotensin receptor blockers(ARBs):
• ARBs now - Recommended for patients who cannot tolerate ACE-I or
ARNI because of serious side effects
• CHARM-alternative study: Candesartan reduced CV deaths and HF
hospitalizations
• Val-HeFT trail: Valsartan + usual therapy (ACEI)- reduced HF
hospitalization
• However, no ARB has reduced all-cause mortality in any trial
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II. ACEi/ARB & Related agents

27. Angiotensin Receptor-Neprilysin Inhibitors (ARNI):
• Neprilysin:
• Enzyme responsible for breaking down vasoactive peptides
• Angiotensin I and II, bradykinin, and natriuretic peptides
• Inhibition of neprilysin augments the activity of the vasoactive peptides
• To maximize effect of natriuretic peptides, stimulation of the RAAS must
be offset without further increase in bradykinin
• ARB combined with neprilysin inhibitor- reduce angioedema
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II. ACEi/ARB & Related agents

28. Angiotensin Receptor-Neprilysin Inhibitors (ARNI):
• Sacubitril/valsartan:
• Feb,2015 -FDA approved for HF
• Oct,2019- FDA approved for Pediatric HF
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II. ACEi/ARB & Related agents

29. Angiotensin Receptor-Neprilysin Inhibitors (ARNI):
• PARADIGM-HF trial- Sacubitril/Valsartan, an ARNI,
• Shown to be superior to enalapril in reducing hospitalizations for worsening HF,
CV mortality, and all-cause mortality
• Orally active, Half-life- 10 hours
Therapeutic use:
• An ARNI should replace an ACE inhibitor or ARB in patients with HFrEF
who remain symptomatic on optimal doses of a β-blocker and an ACE
inhibitor or ARB
29
II. ACEi/ARB & Related agents

30. Aliskiren:
• A renin inhibitor approved for hypertension
• Found to have no definitive benefit in clinical trials for heart failure
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II. ACEi/ARB & Related agents

31. III. Vasodilators
• Effective in acute heart failure, causes:
• Reduction in preload (through venodilation)
• Reduction in afterload (through arteriolar dilation), or both
• Some evidence suggests- Long term Vasodilation by hydralazine and
isosorbide dinitrate can also reduce damaging remodeling of heart
Hydralazine and Isosorbide dinitrate:
• No clear evidence to suggest use of this fixed-dose combination therapy
in all patients with HFrEF
31

32. III. Vasodilators
• RCT on hydralazine and isosorbide dinitrate:
• Addition of this combination to conventional therapy (an ACE-I, a beta-blocker,
and an MRA) reduced mortality and HF hospitalization
• Neseritide:
• Synthetic form of the endogenous peptide brain natriuretic peptide (BNP)
• Approved for use in acute (not chronic) cardiac failure
• cGMP in smooth muscle cells, venous & arteriolar tone
• Also causes diuresis
• T1/2= 18 minutes (continuous infusion is needed)
• Most common Side effect: Excessive hypotension
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33. III. Vasodilators
Neseritide:
• ASCEND-HF trial:
• Concluded that, Nesiritide cannot be recommended for routine treatment of
acute heart failure
• Similar mixed results have been obtained with ularitide and serelaxin
• TRUE-AHF trial (2017) :
• Ularitide had no significant effect on either a short-term or long term
• RELAX-AHF-2 trial (2019):
• Serelaxin had no effect on worsening heart failure at 5 days or death due to
cardiovascular causes at 180 days
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34. IV. β-adrenergic blockers
• β‐blockers used to be contraindicated in patients with HF
• Evidence clearly demonstrates:
• Improved systolic function and reverse cardiac remodeling in patients receiving
β-blockers
• Theoretical justification of using β‐blockers in HF:
• Inhibition of the chronotropic and inotropic effects of the β1‐receptors
• Inhibition of renin release
• Prevention of myocardial ischemia
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35. IV. β-adrenergic blockers
• Bisoprolol, carvedilol, metoprolol, and nebivolol
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Properties and therapeutic doses of β blockers approved as therapy of HFrEF

36. 2. Drugs with positive inotropic effects
• Positive inotropic agents enhance cardiac contractility and, thus,
increase cardiac output
• Inotropic action is the result of an increased cytoplasmic calcium
concentration that enhances the contractility of cardiac muscle
• Associated with reduced survival
• For this reason- used for a short period (mainly inpatient setting)
36

37. 2. Drugs with positive inotropic effects
• Cardiac glycosides:
• Called digitalis glycosides
37
• Glycoside consist of an glycone (steroid nucleus
with an attached lactone ring) with one or more
sugar moieties attached to it
• They have a potent action on heart , hence are
referred to as cardiac glycoside
Source Glycosides
Digitalis purpurea (leaf) Digitoxin
Digitalis lanata ( leaf) Digoxin, Digitoxin
Strophanthus gratus (seed) Strophanthus-G (Ouabain)
Digitalis lanata (Foxglove)

38. 2. Drugs with positive inotropic effects
Digoxin:
• Digoxin, the only cardiac
glycoside used in the USA,
is 65–80% absorbed after
oral administration
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Increase Cardiac Contractility
Increase Cardiac Output
Symptomatic relief in HF patients

39. 2. Drugs with positive inotropic effects
• Digoxin:
• Digoxin therapy is indicated in patients with HFrEF who are
symptomatic on optimal HF pharmacotherapy
• Digoxin has therapeutic efficacy (including a small survival benefit) only
at serum concentrations between 0.5 and 0.8 ng/mL
• Concentrations greater than 1.2 ng/ mL - associated with increased
mortality
39

40. 3. Other positive inotropic drugs
I. Bipyridines:
• Milrinone
• Inhibits phosphodiesterase isozyme 3 (PDE-3)- cAMP- Ca+ - Cardiac contractility
• Active orally as well as parenterally but is available only in parenteral
form
• Elimination half-life of 3–6 hours,
• An older congener, inamrinone, is no longer available in the USA
• However, dobutamine and milrinone may also be considered for
intermediate-term treatment in the outpatient setting for palliative care
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41. 3. Other positive inotropic drugs
II. Beta adrenergic
agonists:
• Positive inotropic
effects and
vasodilation
• Improve cardiac
performance
41

42. 3. Other positive inotropic drugs
II. β-adrenergic agonists: Dobutamine and Dopamine
• Dobutamine
• Selective β1 agonist
• Most widely used in patients with acute decompensated heart failure
• Dopamine
• Used in acute heart failure
• May be particularly helpful if there is a need to raise blood pressure
• Both drugs must be given by intravenous infusion and are primarily
used in the short-term treatment of acute HF in the hospital setting
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43. Other- Ivabradine
• Ivabradine is a selective inhibitor of the sinoatrial pacemaker
modulating ‘’Funny current“ or “f-current" (If)
• Ivabradine slows the sinus rate by prolonging the slow depolarization
phase
• It is called "funny" because it has effects opposite to those of most
other heart currents. Funny currents have been associated with cyclic-
nucleotide-gated channels
• Because of the very selective role of the f-current in the heart, it is likely
that the mechanism of clinical benefit from ivabradine in patients with
HFrEF is related to heart rate reduction
• This concept is supported by the association between clinical benefit
and heart rate change
43

44. Other- Calcium channel blockers
• Non-dihydropyridine calcium channel blockers
eg, Diltiazem and Verapamil
• They have negative inotropic effects and reduce heart rate in patients
in sinus rhythm or atrial fibrillation but are not beneficial in patients
with HFrEF
• Since calcium channel blockers provide no direct clinical benefit in
patients with HFrEF, these agents are generally avoided in this clinical
setting
44

45. Investigational positive inotropic drugs
Istaroxime:
• Steroid derivative that increases contractility
• Inhibiting Na+/K+-ATPase (like cardiac glycosides) but in addition appears
to facilitate sequestration of Ca2+ by the sarcoplasmic reticulum (SR)
Levosimendan:
• Sensitizes the troponin system to calcium, also appears to inhibit
phosphodiesterase
• Cause some vasodilation & inotropic effects
• Clinical trials suggests: This drug may be useful in patients with HF
• Drug has been approved in some countries but not in the USA
45

46. Investigational positive inotropic drugs
Omecamtiv mecarbil:
• Parenteral agent that activates cardiac myosin and prolongs systole
without increasing oxygen consumption of the heart
• In animal models- shown to reduce signs of heart failure
• Drug is still under study.
46

47. Recent advances in HF drugs
• Cimaglermin: Neuregulin GGF2 protein
• In animal models- Shows benefit cardiac function
• Liraglutide: GLP-1 agonist used in diabetes
• Shown in some studies to non significantly reduce deaths from:
• Cardiovascular causes as well as the rates of myocardial infarction, nonfatal
stroke, and hospitalization for heart failure
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48. Recent advances in HF drugs
• SGLT2 Inhibitors:
• DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart
Failure) trial
• Evaluated the effect of dapagliflozin in patients with HFrEF with and without
type 2 diabetes
• Found that: Dapagliflozin reduced the primary end point of worsening heart
failure or cardiovascular death
• May,2020- FDA approved adults for HFrEF
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49. Recent advances in HF drugs
• Vericiguat:
• Oral soluble guanylate cyclase stimulator that increases activity of the
second messenger cyclic guanosine monophosphate (cGMP)
• Recent VICTORIA trial:
• Enrolled patients with higher-risk HFrEF
• Shows, small but significant benefit on death and hospitalization rates
• FDA Approved – Jan,2021
• To diminish the risk of cardiovascular death and heart-failure hospitalization
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50. Classification and treatment of chronic heart failure
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1American College of Cardiology/American Heart Association classification.
2New York Heart Association classification.
3Risk factors include hypertension, myocardial infarct, diabetes.
4For selected populations, eg, African Americans
ARNI, angiotensin receptor inhibitor plus neprilysin inhibitor, CRT, cardiac resynchronization therapy
LVAD, left ventricular assist device

51. Key changes in guidelines
To HFrEF treatment include:
• The SGLT2 inhibitors dapagliflozin and empagliflozin are now class I
recommend therapy
• The 4 key drug therapies ACE-I, betablockers, MRAs and ARNI should be
initiated as quickly and safely as possible
51

52. Key changes in guidelines
Key changes to diagnosis and treatment of HFmrEF and HFpEF include:
• Instead of heart failure with mid-range ejection fraction (HFmrEF) the
term has changed to heart failure with mildly reduced ejection
fraction (patients with HFmrEF may benefit from similar therapies to
those with HFrEF)
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53. Summary
53

54. Summary
54

55. Summary
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56. Summary
56

57. Clinical Trials of Medical Therapies for Heart Failure With
Reduced Ejection Fraction
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58. Clinical Trials of Medical Therapies for Heart Failure With
Reduced Ejection Fraction
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59. References
• McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and
treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726.
doi:10.1093/eurheartj/ehab368
• Murphy SP, Ibrahim NE, Januzzi JL Jr. Heart Failure With Reduced Ejection Fraction: A Review
[published correction appears in JAMA. 2020 Nov 24;324(20):2107]. JAMA.
2020;324(5):488-504. doi:10.1001/jama.2020.10262
• Curfman G. Vasodilator Therapy in Acute Heart Failure. JAMA. 2019;322(23):2288–2289.
doi:10.1001/jama.2019.20285
• Safi S, Korang SK, Nielsen EE, et al. Beta‐blockers for heart failure. Cochrane Database Syst
Rev. 2017;2017(12):CD012897. Published 2017 Dec 8. doi:10.1002/14651858.CD012897
• Havakuk O, Elkayam U. Angiotensin Receptor-Neprilysin Inhibition. J Cardiovasc Pharmacol
Ther. 2017;22(4):356-364. doi:10.1177/1074248416683049
• Kemp, C. D., & Conte, J. V. (2012). The pathophysiology of heart failure. Cardiovascular
Pathology, 21(5), 365-371.
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60. References
• Berliner D, Hänselmann A, Bauersachs J. The Treatment of Heart Failure with Reduced
Ejection Fraction. Dtsch Arztebl Int. 2020;117(21):376-386. doi:10.3238/arztebl.2020.0376
• Arrigo M, Jessup M, Mullens W, et al. Acute heart failure. Nat Rev Dis Primers. 2020;6(1):16.
Published 2020 Mar 5. doi:10.1038/s41572-020-0151-7
• Katzung, B. G. (2020). Basic and clinical pharmacology. Mc Graw Hill.
• Goodman LS. Goodman and Gilman's the pharmacological basis of therapeutics. New York:
McGraw-Hill; 2018.
• David E Golan’s “Principles of pharmacology” 4th edition. 2017.
• Harvey, R. A., Clark, M., Finkel, R., Rey, J., & Whalen, K. (2019). Lippincott’s illustrated
reviews: Pharmacology.
• https://www.uptodate.com/contents/pharmacologic-therapy-of-heart-failure-with-
reduced-ejection-fraction-mechanisms-of
action?search=heart%20failure&topicRef=3506&source=related_link
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61. Thank You
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