1. Drug Therapy of Heart Failure
Dr Ranjita Santra (Dhali)
Assistant Professor
Dept. of Clinical & Experimental Pharmacology
School of Tropical Medicine
Kolkata

2. Cardiac cycle
 The cardiac events that occur from the beginning of one heart beat to
the beginning of the next.
 Events : Electrical
Mechanical
 Electrical and mechanical events occur in a co-ordinated manner to
generate effective contractions
• Duration – 0.8 seconds ( systole – 0.27 seconds, diastole – 0.53
seconds when the HR = 75/minute)
William F. Ganong. The heart as a Pump. Review of Medical Physiology, Lange, 2010:
507-512

3. Cardiac Cycle

4. Atrial systole
• Prior to atrial systole, blood has
been flowing passively from the
atrium into the ventricle through the
open AV valve.
• During atrial systole the atrium
contracts and tops off the volume in
the ventricle with only a small
amount of blood. Atrial contraction
is complete before the ventricle
begins to contract.

5. …….. Atrial systole
JVP – ‘a’ wave
 ECG – P wave preceeds the atrial systole. PR segment – depolarization
proceeds to the AVN. The brief pause allows complete ventricular filling
 Heart sounds - S 4 – pathological. Vibration of the ventricular wall
during atrial contraction. Heard in ‘stiff’ ventricle like in hypertrophy and
in elderly. Also heard in massive pulmonary embolism, cor pulmonale,
TR

6. Isovolumetric contraction
• The atrioventricular (AV) valves close
at the beginning of this phase.
• Electrically, ventricular systole is
defined as the interval between the
QRS complex and the end of the T
wave (the Q-T interval).
• Mechanically, ventricular systole is
defined as the interval between the
closing of the AV valves and the
opening of the semilunar valves
(aortic and pulmonary valves).

7. ………… Isovolumetric contraction
 JVP – ‘c’ wave → due to the bulging of the Tricuspid valve into RA
secondary to increased pressure in the ventricle.
‘x’ descent
 ECG – Interval between QRS complex and T wave (QT interval)
 Heart Sounds – S1 : closure of the AV valves. Normally split as mitral
valve closure preceeds tricuspid valve closure.

8. Ejection
• When LV pres > 80 mm Hg
RV pres > 8 mm Hg,
The aortic and pulmonary valves open.
• Rapid Ejection – 70% emptying in first 1/3
• Slow Ejection – 30% in last 2/3
• The pressure in the ventricle keeps decreasing
until it becomes lower than that of the great
vessels

9. …………. ejection
 JVP – no waves
 ECG – T wave
 Heart sounds – none
 Aortic pressure - Rapid rise in the pressure = 120 mm Hg
Even at the end of systole pressure in the aorta
is maintained at 90 mm Hg because of the
elastic recoil

10. Isovoulumetric relaxation
• When ventricle pressure < arterial pressure→ backflow
of blood → forces semilunar valves to close.
• For 0.03-0.06 s, ventricle relaxes despite no change in
its volume
• Meanwhile, atria fill up and atrial pressure gradually
rises
• Pressures in ventricle keep falling till it is < atrial
pressure

11. …………… isovolumetric relaxation
 JVP – ‘v’ wave – due to venous return to the atria from SVC and IVC
 ECG- no deflections
 Heart sounds – S2 : closure of the semilunar valves. Normally split because
aortic valve closes slightly earlier than the pulmonary valve
 Aortic pressure curve – INCISURA - when the aortic valve closes. Caused by
a short period of backflow before the valve closes followed by sudden cessation
of the backflow when the valve closes.

12. Ventricular filling
• Begins with the opening of AV valves
• Rapid filling – first 1/3 of diastole
• Reduced filling (Diastasis) – middle 1/3 of
diastole
• Atrial contraction – last 1/3 of diastole
• As the atrial pressures fall, the AV valves close
and left ventricular volume is now maximum
→ EDV (120 ml in LV)

13. …………… ventricular filling
 JVP – ‘y’ descent
 ECG – no deflections
Heart sounds - S3 - Pathological in adults. Seen in dilated
congestive heart failure, MI, MR, severe hypertension. Normal in
children.

14. Various pressure values
CHAMBERS NORMAL RANGE (mm of Hg)
Right Atrium 2 – 6
Right Ventricle ( systolic)
(diastolic)
15 – 25
2 -8
Pulmonary Artery (systolic)
(diastolic)
15 – 25
8 - 15
Left Atrium 6 - 12
Left Ventricle (systolic)
(diastolic)
100 – 140
3 – 12

15. Heart Failure (HF): Definition
• Heart Failure (HF) is a complex clinical syndrome that results from any structural or
functional impairment of ventricular filling or ejection of blood
• Unlike western countries where heart failure is predominantly a disease of the elderly, in
India it affects younger age group
• Echocardiography is the primary imaging modality of choice, through recently cardiac
magnetic resonance imaging (MRI) has been found to play an increasing role
• The life time risk of developing heart failure is estimated at about 20 per cent both in men
and women.
Source: Yancy et al. 2013 ACCF/AHA Heart Failure Guidelines.Circulation; 2013:e245
ACCF indicates American College of Cardiology Foundation; AHA, American Heart
Association;

16. Definition of Heart Failure
Classification Ejection
Fraction
Description
I. Heart Failure with
Reduced Ejection Fraction
(HFrEF)
≤40% Also referred to as systolic HF. Randomized clinical trials have mainly
enrolled patients with HFrEF and it is only in these patients that
efficacious therapies have been demonstrated to date.
II. Heart Failure with
Preserved Ejection Fraction
(HFpEF)
≥50% Also referred to as diastolic HF. Several different criteria have been
used to further define HFpEF. The diagnosis of HFpEF is challenging
because it is largely one of excluding other potential noncardiac causes
of symptoms suggestive of HF. To date, efficacious therapies have not
been identified.
a. HFpEF, Borderline 41% to 49% These patients fall into a borderline or intermediate group. Their
characteristics, treatment patterns, and outcomes appear similar to
those of patient with HFpEF.
b. HFpEF, Improved >40% It has been recognized that a subset of patients with HFpEF previously
had HFrEF. These patients with improvement or recovery in EF may
be clinically distinct from those with persistently preserved or reduced
EF. Further research is needed to better characterize these patients.

17. New York Heart Association (NYHA)
Functional Classification
• Class I: No symptoms with ordinary activity
• Class II: Slight limitation of physical activity. Comfortable at rest,
but ordinary physical activity results in fatigue, palpitation,
dyspnoea, or angina
• Class III: Marked limitation of physical activity. Comfortable at
rest, but less than ordinary physical activity results in fatigue,
palpitation, dyspnoea, or anginal pain
• Class IV: Unable to carry out any physical activity without
discomfort. Symptoms of cardiac insufficiency may be present
even at rest

18. ACCF/AHA Stages of HF
• Stage A: At high risk for HF but without
structural heart disease or symptoms of HF
• Stage B: Structural heart disease but without
signs or symptoms of HF
• Stage C: Structural heart disease with prior or
current symptoms of HF
• Stage D: Refractory HF requiring specialized
interventions

19. Causes of HF
• Ischemic Heart Disease
• Hypertension
• Idiopathic Cardiomyopathy
• Infections (e.g., viral myocarditis, Chagas disease)
• Toxins (e.g., alcohol, cocaine, anabolic steroids, clozapine,
anticancer agents – anthracyclines , trastuzumab, 5-FU,
interferons)
• Valvular Disease
• Cardiac sarcoidosis, amyloidosis
• Iron overload (primary haemochromatosis, beta-
thalassemia major)
• Prolonged Arrhythmias

20. Left Ventricular Dysfunction: Systolic and Diastolic
 Symptoms
 Dyspnea on Exertion
 Paroxysmal Nocturnal
Dyspnea
 Tachycardia
 Cough
 Hemoptysis
 Physical Signs
 Basilar Rales
 Pulmonary Edema
 S3 Gallop
 Pleural Effusion
 Cheyne-Stokes
Respiration

21. Compensatory Mechanisms
• Frank-Starling Mechanism
• Neurohormonal Activation
• Ventricular Remodeling Phenomenon

22. • The Frank–Starling law of the heart (also known as Starling's law or
the Frank–Starling mechanism or Maestrini heart's law) states that
the stroke volume of the heart increases in response to an increase
in the volume of blood filling the heart (the end diastolic volume)
when all other factors remain constant.
Frank–Starling law

23. Ventricular dysfunction in heart failure
Systolic: Impaired contractility/ejection
Approximately two-thirds of heart failure patients have systolic
dysfunction (70%)
EF< 40%
Diastolic: Impaired filling/relaxation (30%)
EF> 40%
Ejection fraction (Ef) is the fraction of the end-diastolic volume that is ejected
with each beat; that is, it is stroke volume (SV) divided by end-diastolic volume
(EDV):Ef (%) = SV/EDV ×100
Where the stroke volume is given by: SV = EDV-ESV
Normal values: Ef (%) = 58% ( 55-70%)
EDV = 120ml(65–240ml), SV = 70ml (55–100 ml)

24. Left Ventricular Dysfunction
Volume
Overload
Pressure
Overload
Loss of
Myocardium
Impaired
Contractility
LV Dysfunction
EF < 40%
 Cardiac
Output
Hypoperfusion
 End Diastolic Volume
Pulmonary Congestion
End Systolic Volume

25. Neurohormonal Activation
o Sympathetic nervous system (SNS)
o Renin-angiotensin-aldosterone system (RAAS)
o Vasopressin (a.k.a. antidiuretic hormone, ADH)

26. Compensatory Mechanisms:
Renin-Angiotensin-Aldosterone (RAAS)
Angiotensinogen
Angiotensin I
Angiotensin II Aldosterone
Vasoconstriction
Oxidative Stress
Cell Growth
Proteinuria
LV remodeling
Angiotensin
Converting
Enzyme
Renin
Vascular remodeling

27.  CNS sympathetic outflow
 Cardiac sympathetic
activity
 Sympathetic
activity to kidneys
+ peripheral vasculature
1
receptors 2
receptors
1
receptors
1 1
Activation
of RAS
Myocardial toxicity
Increased arrhythmias
Vasoconstriction
Sodium retention
Disease progression

28. Other Neurohormones & Endothelium-derived
Vasoactive Substances
• Natriuretic Peptides
– Three known types:
• Atrial Natriuretic Peptide (ANP)
• Brain Natriuretic Peptide (hBNP)
• C-type Natriuretic Peptide (CNP)
• Endothelium-derived relaxing factors (EDRF) –
Vasodilators:
• Nitric Oxide (NO)
• Bradykinin
• Prostacyclin
• Endothelium-derived constricting factors
(EDCF) – Vasoconstrictors:
• Endothelin I

29. General Measures
Lifestyle Modifications:
Weight reduction
Discontinue smoking
Avoid alcohol and other
cardiotoxic substances
Exercise
Medical Considerations:
Treat HTN, hyperlipidemia,
diabetes, arrhythmias
Coronary revascularization
Anticoagulation
Immunization
Sodium restriction
Daily weights
Close outpatient monitoring

30. Right Ventricular Failure : Systolic and Diastolic
 Symptoms
 Abdominal Pain
 Anorexia
 Nausea
 Bloating
 Swelling
 Physical Signs
 Peripheral Edema
 Jugular Venous
Distention
 Abdominal-Jugular
Reflux
 Hepatomegaly

31. Determinants of Ventricular Function
Contractility
Stroke Volume
Preload Afterload
•Synergistic LV Contraction Heart rate
•Wall Integrity
•Valvular Competence
Cardiac
Output
Cardiac Output (CO) = Heart Rate (HR) x Stroke Volume (SV)

32. Stages, Phenotypes and Treatment of HF
STAGE A
At high risk for HF but
without structural heart
disease or symptoms of HF
STAGE B
Structural heart disease
but without signs or
symptoms of HF
THERAPY
Goals
· Control symptoms
· Improve HRQOL
· Prevent hospitalization
· Prevent mortality
Strategies
· Identification of comorbidities
Treatment
· Diuresis to relieve symptoms
of congestion
· Follow guideline driven
indications for comorbidities,
e.g., HTN, AF, CAD, DM
· Revascularization or valvular
surgery as appropriate
STAGE C
Structural heart disease
with prior or current
symptoms of HF
THERAPY
Goals
· Control symptoms
· Patient education
· Prevent hospitalization
· Prevent mortality
Drugs for routine use
· Diuretics for fluid retention
· ACEI or ARB
· Beta blockers
· Aldosterone antagonists
Drugs for use in selected patients
· Hydralazine/isosorbide dinitrate
· ACEI and ARB
· Digoxin
In selected patients
· CRT
· ICD
· Revascularization or valvular
surgery as appropriate
STAGE D
Refractory HF
THERAPY
Goals
· Prevent HF symptoms
· Prevent further cardiac
remodeling
Drugs
· ACEI or ARB as
appropriate
· Beta blockers as
appropriate
In selected patients
· ICD
· Revascularization or
valvular surgery as
appropriate
e.g., Patients with:
· Known structural heart disease and
· HF signs and symptoms
HFpEF HFrEF
THERAPY
Goals
· Heart healthy lifestyle
· Prevent vascular,
coronary disease
· Prevent LV structural
abnormalities
Drugs
· ACEI or ARB in
appropriate patients for
vascular disease or DM
· Statins as appropriate
THERAPY
Goals
· Control symptoms
· Improve HRQOL
· Reduce hospital
readmissions
· Establish patient’s end-
of-life goals
Options
· Advanced care
measures
· Heart transplant
· Chronic inotropes
· Temporary or permanent
MCS
· Experimental surgery or
drugs
· Palliative care and
hospice
· ICD deactivation
Refractory
symptoms of HF
at rest, despite
GDMT
At Risk for Heart Failure Heart Failure
e.g., Patients with:
· Marked HF symptoms at
rest
· Recurrent hospitalizations
despite GDMT
e.g., Patients with:
· Previous MI
· LV remodeling including
LVH and low EF
· Asymptomatic valvular
disease
e.g., Patients with:
· HTN
· Atherosclerotic disease
· DM
· Obesity
· Metabolic syndrome
or
Patients
· Using cardiotoxins
· With family history of
cardiomyopathy
Development of
symptoms of HF
Structural heart
disease

36. Classification of Recommendations and Levels of Evidence

37. Recommendations for Treatment of Stage B HF
Recommendations COR LOE
In patients with a history of MI and reduced EF, ACE inhibitors or
ARBs should be used to prevent HF
I A
In patients with MI and reduced EF, evidence-based beta blockers
should be used to prevent HF
I B
In patients with MI, statins should be used to prevent HF I A
Blood pressure should be controlled to prevent symptomatic HF I A
ACE inhibitors should be used in all patients with a reduced EF to
prevent HF
I A
Beta blockers should be used in all patients with a reduced EF to
prevent HF
I C
An ICD is reasonable in patients with asymptomatic ischemic
cardiomyopathy who are at least 40 d post-MI, have an LVEF ≤30%,
and on GDMT
IIa B
Nondihydropyridine calcium channel blockers may be harmful in
patients with low LVEF
III: Harm C

38. Pharmacological Therapy for Management
of Stage C HFrEF
Recommendations COR LOE
Diuretics
Diuretics are recommended in patients with HFrEF with fluid
retention
I C
ACE Inhibitors
ACE inhibitors are recommended for all patients with HFrEF
I A
ARBs
ARBs are recommended in patients with HFrEF who are ACE
inhibitor intolerant
I A
ARBs are reasonable as alternatives to ACE inhibitor as first
line therapy in HFrEF
IIa A
The addition of an ARB may be considered in persistently
symptomatic patients with HFrEF on GDMT
IIb A
Routine combined use of an ACE inhibitor, ARB, and
aldosterone antagonist is potentially harmful
III: Harm C

39. Pharmacological Therapy for Management
of Stage C HFrEF (cont.)
Recommendations COR LOE
Beta Blockers
Use of 1 of the 3 beta blockers proven to reduce mortality is
recommended for all stable patients
I A
Aldosterone Antagonists
Aldosterone receptor antagonists are recommended in
patients with NYHA class II-IV HF who have LVEF ≤35%
I A
Aldosterone receptor antagonists are recommended in
patients following an acute MI who have LVEF ≤40% with
symptoms of HF or DM
I B
Inappropriate use of aldosterone receptor antagonists may be
harmful
III:
Harm
B
Hydralazine and Isosorbide Dinitrate
The combination of hydralazine and isosorbide dinitrate is
recommended for African-Americans, with NYHA class III–
IV HFrEF on GDMT
I A
A combination of hydralazine and isosorbide dinitrate can be
useful in patients with HFrEF who cannot be given ACE
inhibitors or ARBs
IIa B

40. Pharmacologic Therapy for Management
of Stage C HFrEF (cont.)
Recommendations COR LOE
Digoxin
Digoxin can be beneficial in patients with HFrEF IIa B
Anticoagulation
Patients with chronic HF with permanent/persistent/paroxysmal AF and an
additional risk factor for cardioembolic stroke should receive chronic
anticoagulant therapy*
I A
The selection of an anticoagulant agent should be individualized I C
Chronic anticoagulation is reasonable for patients with chronic HF who have
permanent/persistent/paroxysmal AF but without an additional risk factor for
cardioembolic stroke*
IIa B
Anticoagulation is not recommended in patients with chronic HFrEF without
AF, prior thromboembolic event, or a cardioembolic source
III: No
Benefit
B
Statins
Statins are not beneficial as adjunctive therapy when prescribed solely for HF III: No
Benefit
A
Omega-3 Fatty Acids
Omega-3 PUFA supplementation is reasonable to use as adjunctive therapy in
HFrEF or HFpEF patients
IIa B

41. Treatment of HFpEF
Recommendations COR LOE
Systolic and diastolic blood pressure should be controlled
according to published clinical practice guidelines I B
Diuretics should be used for relief of symptoms due to
volume overload
I C
Coronary revascularization for patients with CAD in
whom angina or demonstrable myocardial ischemia is
present despite GDMT
IIa
C
Management of AF according to published clinical
practice guidelines for HFpEF to improve symptomatic
HF
IIa C
Use of beta-blocking agents, ACE inhibitors, and ARBs
for hypertension in HFpEF IIa C
ARBs might be considered to decrease hospitalizations in
HFpEF
IIb B
Nutritional supplementation is not recommended in
HFpEF
III: No
Benefit
C

42. Clinical Events and Findings Useful for
Identifying Patients With Advanced HF
Repeated (≥2) hospitalizations or ED visits for HF in the past year
Progressive deterioration in renal function (e.g., rise in BUN and creatinine)
Weight loss without other cause (e.g., cardiac cachexia)
Intolerance to ACE inhibitors due to hypotension and/or worsening renal function
Intolerance to beta blockers due to worsening HF or hypotension
Frequent systolic blood pressure <90 mm Hg
Persistent dyspnea with dressing or bathing requiring rest
Inability to walk 1 block on the level ground due to dyspnea or fatigue
Recent need to escalate diuretics to maintain volume status, often reaching daily
furosemide equivalent dose >160 mg/d and/or use of supplemental metolazone therapy
Progressive decline in serum sodium, usually to <133 mEq/L
Frequent ICD shocks

43. Pharmacologic Treatment for Stage C HFrEF
HFrEF Stage C
NYHA Class I – IV
Treatment:
For NYHA class II-IV patients.
Provided estimated creatinine
>30 mL/min and K+ <5.0 mEq/dL
For persistently symptomatic
African Americans,
NYHA class III-IV
Class I, LOE A
ACEI or ARB AND
Beta Blocker
Class I, LOE C
Loop Diuretics
Class I, LOE A
Hydral-Nitrates
Class I, LOE A
Aldosterone
Antagonist
AddAdd Add
For all volume overload,
NYHA class II-IV patients

44. Drugs Commonly Used for HFrEF
(Stage C HF)
Drug Initial Daily Dose(s) Maximum Doses(s)
Mean Doses Achieved in
Clinical Trials
ACE Inhibitors
Captopril 6.25 mg 3 times 50 mg 3 times 122.7 mg/d (421)
Enalapril 2.5 mg twice 10 to 20 mg twice 16.6 mg/d (412)
Fosinopril 5 to 10 mg once 40 mg once ---------
Lisinopril 2.5 to 5 mg once 20 to 40 mg once 32.5 to 35.0 mg/d (444)
Perindopril 2 mg once 8 to 16 mg once ---------
Quinapril 5 mg twice 20 mg twice ---------
Ramipril 1.25 to 2.5 mg once 10 mg once ---------
Trandolapril 1 mg once 4 mg once ---------
ARBs
Candesartan 4 to 8 mg once 32 mg once 24 mg/d (419)
Losartan 25 to 50 mg once 50 to 150 mg once 129 mg/d (420)
Valsartan 20 to 40 mg twice 160 mg twice 254 mg/d (109)
Aldosterone Antagonists
Spironolactone 12.5 to 25 mg once 25 mg once or twice 26 mg/d (424)
Eplerenone 25 mg once 50 mg once 42.6 mg/d (445)

45. Drugs Commonly Used for HFrEF
(Stage C HF) (cont.)
Drug Initial Daily Dose(s) Maximum Doses(s)
Mean Doses Achieved in
Clinical Trials
Beta Blockers
Bisoprolol 1.25 mg once 10 mg once 8.6 mg/d (118)
Carvedilol 3.125 mg twice 50 mg twice 37 mg/d (446)
Carvedilol CR 10 mg once 80 mg once ---------
Metoprolol succinate
extended release
(metoprolol CR/XL)
12.5 to 25 mg once 200 mg once 159 mg/d (447)
Hydralazine & Isosorbide Dinitrate
Fixed dose combination
(423)
37.5 mg hydralazine/
20 mg isosorbide
dinitrate 3 times daily
75 mg hydralazine/
40 mg isosorbide
dinitrate 3 times daily
~175 mg hydralazine/90 mg
isosorbide dinitrate daily
Hydralazine and
isosorbide dinitrate (448)
Hydralazine: 25 to 50
mg, 3 or 4 times daily
and isorsorbide
dinitrate:
20 to 30 mg
3 or 4 times daily
Hydralazine: 300 mg
daily in divided doses
and isosorbide dinitrate
120 mg daily in
divided doses
---------

46. Therapies in the Hospitalized HF Patient
Recommendation COR LOE
HF patients hospitalized with fluid overload should be treated with
intravenous diuretics
I B
HF patients receiving loop diuretic therapy, should receive an initial
parenteral dose greater than or equal to their chronic oral daily dose, then
should be serially adjusted
I B
HFrEF patients requiring HF hospitalization on GDMT should continue
GDMT unless hemodynamic instability or contraindications
I B
Initiation of beta-blocker therapy at a low dose is recommended after
optimization of volume status and discontinuation of intravenous agents
I B
Thrombosis/thromboembolism prophylaxis is recommended for patients
hospitalized with HF
I B
Serum electrolytes, urea nitrogen, and creatinine should be measured
during the titration of HF medications, including diuretics
I C

47. Therapies in the Hospitalized HF Patient (cont.)
Recommendation COR LOE
When diuresis is inadequate, it is reasonable to
a) Give higher doses of intravenous loop diuretics; or
b) add a second diuretic (e.g., thiazide)
IIa
B
B
Low-dose dopamine infusion may be considered with loop diuretics to
improve diuresis
IIb B
Ultrafiltration may be considered for patients with obvious volume
overload
IIb B
Ultrafiltration may be considered for patients with refractory congestion IIb C
Intravenous nitroglycerin, nitroprusside or nesiritide may be considered an
adjuvant to diuretic therapy for stable patients with HF
IIb B
In patients hospitalized with volume overload and severe hyponatremia,
vasopressin antagonists may be considered
IIb B

48. Hospital Discharge
Recommendation or Indication COR LOE
Performance improvement systems in the hospital and early postdischarge outpatient setting
to identify HF for GDMT
I B
Before hospital discharge, at the first postdischarge visit, and in subsequent follow-up visits,
the following should be addressed:
a) initiation of GDMT if not done or contraindicated;
b) causes of HF, barriers to care, and limitations in support;
c) assessment of volume status and blood pressure with adjustment of HF therapy;
d) optimization of chronic oral HF therapy;
e) renal function and electrolytes;
f) management of comorbid conditions;
g) HF education, self-care, emergency plans, and adherence; and
h) palliative or hospice care.
I B
Multidisciplinary HF disease-management programs for patients at high risk for hospital
readmission are recommended
I B
A follow-up visit within 7 to 14 days and/or a telephone follow-up within 3 days of hospital
discharge is reasonable
IIa B
Use of clinical risk-prediction tools and/or biomarkers to identify higher-risk patients is
reasonable
IIa B

49. Drug therapy
Digoxin
• Enhances inotropy of cardiac muscle
• Reduces activation of SNS and RAAS
• Recommended in symptomatic LV dysfunction with AF and in
symptomatic HF pts with standard therapy
• Controlled trials have shown long-term digoxin therapy:
 Reduces symptoms, increases exercise tolerance
 Improves hemodynamics, decreases risk of HF progression
 Reduces hospitalization rates for decompensated HF (DIG
trial)
 Does not improve survival, Mortality directly related to
serum digoxin level and more in women
 Increased Hospitalisation due to worsening heart failure on
withdrawal (RADIANCE,PROVED Study)

50. Diuretics
Used to relieve fluid retention
Improve exercise tolerance
Facilitate the use of other drugs (neurohormonal antagonists) indicated for
heart failure
Patients can be taught to adjust their diuretic dose based on changes in
body weight
Electrolyte depletion a frequent complication
Should never be used alone to treat heart failure
Diuretic resistance

51. ACE Inhibitors
• Blocks the conversion of angiotensin I to angiotensin II; prevents functional deterioration
• Recommended for all heart failure patients
• Relieves symptoms and improves functional status in HF patients ,only produce small benefits in
exercise capacity
• Reduces risk of death and decreases disease progression, stabilize LV remodeling
• Benefits may not be apparent for 1-2 months after initiation, dose titration upto highest
recommended range afforded maximun protection (GISSI-3,SOLVD trial)
• Abrupt withdrawal of ACEI should be avoided
• BP, renal function, potassium level should be evaluated within1-2wks of starting therapy and
regularly thereafter
• Efficacy in lowBP (<90mmHg),high creatinine(>2.5mg/ml)is not well established

52. Beta-Blockers
• Cardioprotective effects due to blockade of excessive SNS stimulation
• In the short-term, beta blocker decreases myocardial contractility; increase in EF after 1-3 months
of use
• Long-term, placebo-controlled trials have shown symptomatic improvement in patients treated
with certain beta-blockers–bisoprolol (CIBISI,II,III), sustained release metoprolol (MERIT-HF) and
carvedilol (COMET)
• When combined with conventional HF therapy, beta-blockers reduce the combined risk of
morbidity and mortality, or disease progression
• Current guidelines recommend starting with an ACE inhibitor followed by the subsequent addition
of a beta blocker
• Not a class effect , genetic polymorphism in Beta1 adrenergic receptor may influence( Bucindolol
significantly more effective in white>black-BEST trial).
• Can safely be started in hospitalised pts before discharge provided they are stable and not in IV HF
therapy.
• Should be started with low dose and uptitrated no sooner than 2 wks .
• Optimisation of diuretic dose is required

53. Aldosterone Antagonists
(Spironolactone,Eplerenone)
• Generally well-tolerated
• Shown to reduce heart failure-related morbidity and
mortality (RALES,EPHESUS trials)
• Generally reserved for patients with NYHA Class III-IV
HF (EF<35%) who are on standard therapy (diuretics,
betablockers, ACEI)
• Side effects include hyperkalemia and gynecomastia.
Potassium and creatinine levels should be closely
monitored (within 3 days and again at 1 wk)

54. Angiotensin Receptor Blockers (ARBs)
Block AT1 receptors, which bind circulating angiotensin II
Examples: valsartan, candesartan, losartan
Should not be considered equivalent or superior to ACE
inhibitors .Opinion varies in different trials (ELITE-II vs
VALIANT) but added benefit in combination with ACEI(CHARM
–Added trial)
In clinical practice, ARBs should be used to treat patients who
are ACE intolerant due to intractable cough or who develop
angioedema but not due to hyperkalemia or renal insufficiency
Triple combination of ARB, ACEI and Aldosterone antagonist is
not recommended because of hyperkalemia

55. IVABRADINE(Procoralan)
– Previously used as an antianginal drug
– It slows diastolic depolarisation in SA node (by reducing the ‘steepness’ of
the If current slope)
– It is recommended for slowing heart rate in moderate heart failure
– Evidence proved in SHIFT study (Systolic Heart failure treatment with If inhibitor
ivabradine Trial) (2006 -2010)
– Study population- stable symptomatic chronic heart failure (NYHA class II, III, or IV
in stable condition for > 4 weeks) with LVEF<35%, randomized to either ivabradine or
placebo treatment on the top of optimised cardiovascular therapy in accordance with
current guidelines.
– The primary endpoint was the composite of cardiovascular death or hospital
admission for worsening CHF.
– The starting dose of ivabradine was 5 mg (or matching placebo) twice daily in all
patients and dose adjusted on next visits according to resting heart rate, >60 bpm -
7.5 mg BD, <50 bpm or if patient is experiencing signs or symptoms of bradycardia -
2.5 mg BD, between 50 and 60 bpm -at 5 mg BD or matching placebo.

56. IVABRADINE-SHIFT study
(contd.)
• Ivabradine significantly reduced the risk of the primary composite endpoint of hospitalization for worsening heart
failure or cardiovascular death by 18% (P<0.0001) compared with placebo . These benefits were observed after 3
months of treatment.
• It also significantly reduced the risk of death from heart failure by 26% (P=0.014) and hospitalization for heart failure
by 26% (P<0.0001).
• The improvements were observed throughout all prespecified subgroups: female and male, with or without beta-
blockers at randomization, patients below and over 65 years of age, with heart failure of ischemic or non-ischemic
etiology, NYHA class II class III or IV, with or without diabetes, and with or without hypertension
• Elevated resting heart rate (HR) is a significant marker for mortality and morbidity in many cardiovascular diseases
including heart failure (HF). Moreover, despite background treatment with β-blockers more than half of patients with
heart failure and low ejection fraction have an elevated heart rate (≥70 bpm).
• Based on these findings the European Medicine Agency, granted a new indication for ivabradine in heart failure
patients in sinus rhythm with heart rate ≥75bpm in February 2012.
• In May 2012 the new ESC guidelines for the diagnosis and management of heart failure included ivabradine by name
in the main algorithm for the treatment of patients with chronic symptomatic systolic heart failure (NYHA functional
class II–IV) and a heart rate ≥70 bpm.

57. CXL-1427 is a novel, improved second-generation prodrug that
breaks down chemically to produce nitroxyl (HNO) and an inactive
byproduct following intravenous administration. In extensive pre-
clinical testing and in a Phase IIa human proof of concept study
with Cardioxyl’s first-generation prodrug, HNO was shown to
produce a unique and very attractive hemodynamic profile. The
novel combination of effects produced by Cardioxyl’s HNO
prodrugs distinguishes them from other therapies used in the
treatment of congestive heart failure and provides a strong
rationale for continuing the development of this important new
class of drugs.
Next-generation HNO prodrug targeting severe heart
failure was well tolerated and showed hemodynamic
activity in a Phase I clinical trial

58. About LCZ696 in heart failure
LCZ696, a twice a day medicine being investigated for heart failure, has a unique
mode of action which is thought to reduce the strain on the failing heart1. It acts to
enhance the protective neurohormonal systems of the heart (NP system) while
simultaneously suppressing the harmful system (the RAAS). Currently available
medicines for HFrEF primarily block the harmful effects and mortality remains very
high with up to 50% of patients dying within 5 years of a diagnosis of heart failure
The double-blind study is the largest ever of a heart failure treatment, and
involved 8,842 patients in 47 countries who were followed for 27 months. The
study targeted heart patients who had reduced ejection fraction, in which the
heart muscle does not contract effectively.
Results from the clinical trial showed the drug:
reduced the risk of death from cardiovascular causes by 20 percent
reduced heart failure hospitalizations by 21 percent
reduced the risk of all-cause mortality by 16 percent
Overall, the researchers also reported a 20 percent reduction in risk on the primary
endpoint, a composite measure of cardiovascular death or heart failure hospitalization.

59. Other DRUGS
• Nitroglycerine-relief by reducing the preload.
• Morphine (2-5 mg IV) can be repeated every 10-25
minutes until an effect is seen >> decreases anxiety and
increases venous capacitance >> lower of left atrial
pressure (i.e. decreasing pre-load) >> improve the
breathlessness.
• Dopamine, dobutamine, noradrenaline-improves cardiac
contraction in severe heart failure.
• Calcium Channel Blockers-Amlodipine-vasodilator
• Sodium nitroprusside- direct NO donor, rapid action
• Hydralazine-isosorbide-dinitrate-V-HeFT I trial)- mortality
in systolic dysfunction
• PDE III inhibitors- Milrinone, IV in acute decompensation

60. PHARMACOGENETICS
Tremendous heterogeneity in drug action among HF patients suggest underlying gene polymorphism
All guidelines recommend titration of drug dosage, shown to be beneficial in RCT
BUT-
It does not allow dose optimization in pts metabolise/distribute drugs differently
Clinical trials generally yeild binary results- beneficial/not beneficial
Careful analysis of gene polymorphisms may help clinicians to develop personalised therapeutic regimens in
HF pts
Important gene polymorphisms-
Pathway/Gene Polymorphism Functional Impact Impact on pharmacotherapy
RAS
ACE 287bp insertion(I) DD- ACE activity β blockers & ACEI - response DD
or Deletion(D) worse clinical no effect- II/ID
in intron 16 outcome
Β1-AR Arginin,Glycine switch Adenyl Cyclase activity ARG389- LVEF with β
at aa389 in response to agonist blocker & mortality
in ARG389 3× > Gly389 with bucindolol
Polygenic phenotype / SNP – Role of Human Genome Poject/HapMap

61. Metabolic MODULATION
FFA is the preferred fuel in normal heart but requires more oxygen than glycolysis to generate ATP, in failing
heart later is more efficient
Shifting energy utilisation from FFA to Glucose reverse abnormalities in cell & EF
Partial inhibitors of Fatty acid oxidation (pFox):
Carnitine palmitoyl transferaseI (CPT I) inhibitors-
Etomoxir- Not much effective
Oxfenicine- Toxicity ( hepatic, renal & cardiac mass)
Perhexiline- used as antianginal drug, peak oxygen uptake, LVEF & QOL,?hepatotoxicity
Adjunctive therapy in HF( Optimistic view)
3 keto acyl co-A thiolase inhibitor( 3 KAT inhibitor)
Trimetazidine- LVEF, LVESV, Remodeling, QOL, EC in both ischemic & nonischemic HF
Ranolazine-FDA approved for angina, No clinical studies in HF, Animal study- LVEF, SV,
Other approaches - glucose substrate or pyruvate oxidation
Till date insufficient studies, long duration well designed studies are required.

62. IMMUNOTHERAPY
Inflammation plays a role in the pathogenesis of HF
Methods-
• Transcription of inflammatory gene ( by intracellular cAMP)- vesnarinone, pentoxifylline,
milrinone, thalidomide and analogs.
• Translation of inflammatory mediators- Dexamethasone,Prednisone.p38 inhibitors
• TNF antagonists or anti TNF antidodies- Etanercept, Infliximab
• Broad-based immunomodulation- IVIG, Statins, Irradiated(oxydized) blood(Celacade therapy)
Clinical Trial Report- No favorable impact on mortality and morbidity in the following trials-
RENEWAL(Randomizes Etanercept Worldwide Evaluation) –Anti cytokine approach
ACCLAIM(Adavanced Chronic Heart Failure Clinical Assessment of Immuno Modulation Therapy)
with IM inj of autologus blood subjected to stress ex vivo using a proprietory device(Celacade)
Statins- Pleotropic effect –MOST PROMISING RESULT
• Retrospective analysis of RCT- incidence of HF, mortality in HF with CAD
• Also beneficial in dilated cardiomyopathy
• Conflicting result- UNIVERSE trial-Rosuvastatin - LDL, no effect in LV Dimension , LVEF

63. Conclusion
• HF is a syndrome with a high prevalence of comorbidities
and multiple chronic conditions
• Coexistence of additional diseases such as arthritis, renal
insufficiency, diabetes mellitus, or chronic lung disease with
the HF syndrome should logically require a modification of
treatment, outcome assessment, or follow-up care
• Finally, preventing the burden of this disease through more
successful risk modification, sophisticated screening,
perhaps using specific omics technologies (ie, systems
biology) or effective treatment interventions that reduce
the progression from stage A to stage B is an urgent need