Drug Therapy of Heart Failure

Dr Ranjita Santra (Dhali)Assistant Professor

Dept. of Clinical & Experimental PharmacologySchool of Tropical Medicine

Kolkata

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

Cardiac Cycle

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.

…….. 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

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).

………… 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.

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

…………. 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

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

…………… 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.

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)

…………… 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.

Various pressure values

CHAMBERS NORMAL RANGE (mm of Hg)

Right Atrium 2 – 6

Right Ventricle ( systolic) (diastolic)

15 – 25

2 -8Pulmonary Artery (systolic)

(diastolic)

15 – 25

8 - 15

Left Atrium 6 - 12

Left Ventricle (systolic)

(diastolic)

100 – 140

3 – 12

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;

Definition of Heart FailureClassification Ejection

FractionDescription

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.

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

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

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

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

Compensatory Mechanisms

• Frank-Starling Mechanism• Neurohormonal Activation• Ventricular Remodeling Phenomenon

• 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

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 ×100Where the stroke volume is given by: SV = EDV-ESV

Normal values: Ef (%) = 58% ( 55-70%)EDV = 120ml(65–240ml), SV = 70ml (55–100 ml)

Left Ventricular DysfunctionVolume Overload

Pressure Overload

Loss of Myocardium

Impaired Contractility

LV Dysfunction

EF < 40% Cardiac

Output

Hypoperfusion

End Diastolic Volume

Pulmonary Congestion

End Systolic Volume

Neurohormonal Activation

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

Compensatory Mechanisms: Renin-Angiotensin-Aldosterone (RAAS)

Angiotensinogen

Angiotensin I

Angiotensin II Aldosterone

Vasoconstriction

Oxidative Stress

Cell Growth Proteinuria

LV remodeling

AngiotensinConverting

Enzyme

Renin

Vascular remodeling

Sympathetic activation in heart failure

CNS sympathetic outflow

Cardiac sympatheticactivity

Sympatheticactivity to kidneys

+ peripheral vasculature1

receptors 2

receptors

1 receptors

1 1

Activation of RAS

Myocardial toxicityIncreased arrhythmias

Vasoconstriction Sodium retention

Disease progression

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

General MeasuresLifestyle

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

Right Ventricular Failure : Systolic and Diastolic

Symptoms Abdominal Pain Anorexia Nausea

Bloating Swelling

Physical Signs Peripheral Edema Jugular Venous

Distention Abdominal-Jugular

Reflux Hepatomegaly

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)

Stages, Phenotypes and Treatment of HF

STAGE AAt high risk for HF but without structural heart

disease or symptoms of HF

STAGE BStructural heart disease

but without signs or symptoms of HF

THERAPYGoals 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 CStructural heart disease

with prior or current symptoms of HF

THERAPYGoals 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 DRefractory HF

THERAPYGoals 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

THERAPYGoals 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

THERAPYGoals 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 orPatients Using cardiotoxins With family history of

cardiomyopathy

Development of symptoms of HF

Structural heart disease

Classification of Recommendations and Levels of Evidence

Recommendations for Treatment of Stage B HF

Recommendations COR LOEIn 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 ABlood 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

Pharmacological Therapy for Management of Stage C HFrEF

Recommendations COR LOEDiureticsDiuretics are recommended in patients with HFrEF with fluid retention I C

ACE InhibitorsACE inhibitors are recommended for all patients with HFrEF

I A

ARBsARBs 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

Pharmacological Therapy for Management of Stage C HFrEF (cont.)

Recommendations COR LOEBeta BlockersUse of 1 of the 3 beta blockers proven to reduce mortality is recommended for all stable patients I A

Aldosterone AntagonistsAldosterone 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 DinitrateThe 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

Pharmacologic Therapy for Management of Stage C HFrEF (cont.)

Recommendations COR LOEDigoxinDigoxin can be beneficial in patients with HFrEF IIa BAnticoagulation 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 CChronic 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

StatinsStatins are not beneficial as adjunctive therapy when prescribed solely for HF III: No

Benefit A

Omega-3 Fatty AcidsOmega-3 PUFA supplementation is reasonable to use as adjunctive therapy in HFrEF or HFpEF patients IIa B

Treatment of HFpEFRecommendations 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

Clinical Events and Findings Useful for Identifying Patients With Advanced HFRepeated (≥2) hospitalizations or ED visits for HF in the past yearProgressive 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 functionIntolerance to beta blockers due to worsening HF or hypotensionFrequent systolic blood pressure <90 mm HgPersistent dyspnea with dressing or bathing requiring restInability to walk 1 block on the level ground due to dyspnea or fatigueRecent need to escalate diuretics to maintain volume status, often reaching daily furosemide equivalent dose >160 mg/d and/or use of supplemental metolazone therapyProgressive decline in serum sodium, usually to <133 mEq/LFrequent ICD shocks

Pharmacologic Treatment for Stage C HFrEF

HFrEF Stage CNYHA 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 AACEI or ARB AND

Beta Blocker

Class I, LOE CLoop Diuretics

Class I, LOE AHydral-Nitrates

Class I, LOE AAldosterone Antagonist

AddAdd Add

For all volume overload, NYHA class II-IV patients

Drugs Commonly Used for HFrEF (Stage C HF)

Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials

ACE InhibitorsCaptopril 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 ---------ARBsCandesartan 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 AntagonistsSpironolactone 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)

Drugs Commonly Used for HFrEF (Stage C HF) (cont.)

Drug Initial Daily Dose(s) Maximum Doses(s) Mean Doses Achieved in Clinical Trials

Beta BlockersBisoprolol 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

---------

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

Therapies in the Hospitalized HF Patient (cont.)

Recommendation COR LOE

When diuresis is inadequate, it is reasonable toa) 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

Hospital DischargeRecommendation 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; andh) 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

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)

Diuretics

Used to relieve fluid retentionImprove exercise toleranceFacilitate 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 weightElectrolyte depletion a frequent complicationShould never be used alone to treat heart failureDiuretic resistance

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

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

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)

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

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.

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.

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

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 percentreduced heart failure hospitalizations by 21 percentreduced the risk of all-cause mortality by 16 percentOverall, the researchers also reported a 20 percent reduction in risk on the primary endpoint, a composite measure of cardiovascular death or heart failure hospitalization.

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

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 RCTBUT-It does not allow dose optimization in pts metabolise/distribute drugs differentlyClinical 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 pharmacotherapyRASACE 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

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 & EFPartial inhibitors of Fatty acid oxidation (pFox):

Carnitine palmitoyl transferaseI (CPT I) inhibitors- Etomoxir- Not much effectiveOxfenicine- Toxicity ( hepatic, renal & cardiac mass)Perhexiline- used as antianginal drug, peak oxygen uptake, LVEF & QOL,?hepatotoxicityAdjunctive 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 HFRanolazine-FDA approved for angina, No clinical studies in HF, Animal study- LVEF, SV, Other approaches - glucose substrate or pyruvate oxidationTill date insufficient studies, long duration well designed studies are required.

IMMUNOTHERAPYInflammation plays a role in the pathogenesis of HFMethods-• 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

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