recent advance in pharmacotherapy of heart failure

RECENT ADVANCES IN MANAGEMENT OF HEART FAILURE

DR. PRIYANKA KUMAWATPharmacology deptt.PGIMS, Rohtak

Heart failure

• A pathophysiologic state in which an abnormality of cardiac function is responsible for failure of the heart to pump blood at a rate commensurate with metabolic requirements of the tissues -E Braunwald

• Heart failure (HF) is a clinical syndrome that occurs, because of an inherited or acquired abnormality of • Cardiac structure • Cardiac function

develop a constellation of • Clinical symptoms - dyspnea and fatigue • Signs- edema and rales

that lead to frequent hospitalizations, a poor quality of life, and a shortened life expectancy- Harrison’s princilple of internal medicine 18th ed.

Epidemiology

• More than 20 million people affected worldwide

• Affects 10% of people over 65 year

• It is the most common condition for which patients 65 + require admission to hospital

• ”our country is set to be the heart disease capital of the world in a few years”

• Prevalance in india- 1.87 %

Prevalance- 2% in developed countries

Affects over 50% of people with 85+ years

Approx 10% of patients with HF die each yr.

Why HF is increasing ?

• Almost any disease of heart can cause it

• More of HT, DM, Obesity – CVD

• CAD - which is its commonest cause

• Better tools for diagnosis and availability

• Better detection and treatment of causes

• Better Rx. of RF, CAD, MI - PTCA, CABG

• Increasing longevity of the population

Classification • BY EJECTION FRACTION

• Reduced ejection fraction(<40-50%)- systolic heart failure• Preserved ejection fraction(>40-50%)- diastolic heart failure

• BY TIME COURSE• Chronic heart failure(CHF)• Acute heart failure (Cardiogenic Shock)

• ANATOMICALLY • Left sided- LHF• Right sided- RHF(CHF)

• BY OUTPUT• High output failure-Thyrotoxicosis, Paget's dis, Anemia, Pregnancy,

A-V fistula• Low output failure – 95% of HF is this

McMurray J. N Engl J Med 2010;362:228-238

Clinical Classifications of Heart Failure Severity

Etiology • Reduced ejection fraction(< 50%)

• Condition that leads to an alteration in LV structure or function can predispose a patient to developing HF.• Coronary artery dis- MI, Angina (60- 70 %)• Chronic pressure overload dis- Hypertension( 75%), valvular dis• Chronic volume overload- intracardiac and extracardiac shunting

• Non ischaemic cardiomyopathy• Drug induced damage- metabolic disorder• Disorders of rate and rhythm

• Preserved ejection fraction(> 50%)• Pathologic hypertrophy• Restrictive cardiomyopathy• Fibrosis• Aging

• Pulmonary heart dis- Cor pulmonale, pulmonary vascular dis

• High output states- metabolic disorders, anemia, systemic AV shunting

Risk factors

PATHOPHYSIOLOGY OF HF

Consequences of Neurohormonal Activation in HF

SIGN AND SYMPTOMS

MANAGEMENT OF HF

Non Pharmacological

• Activity- • Routine modest exercise for class I-III• For euvolemic patients- regular isotonic exercise such as walking

or riding a stationary-bicycle ergometer

• Diet-• Restriction of sodium (2-3 g daily) is recommended in all patients,

Extra < 2g reduction in moderate to severe cases.• Fluid restriction (<2 L/day) if hyponatremia (<130 meq/L)• Caloric supplementation- with advanced HF and unintentional

weight loss or muscle wasting (cardiac cachexia)

Three things for preventing heart diseases are – Eat less fried food, less butter and ghee. Second, exercise daily for around 45 minutes.

And third, reduce stress in life

Pharmacological measures DRUGS FOR

ACUTE DECOMPENSATED HF

• DIURETICS- Furosemide /hydrochlorthiazide

• VASODILATORS- Nitroprusside, Nitroglycerin, Nesiritide

• INOTROPIC AGENTS- dobutamine, dopamine, milrinone, levosimendan

Drug Therapy for Chronic HF Due to Systolic Dysfunction

DIURETICS-furosemide /

hydrochlorthiazide

ACE-INHIBITORS*-captopril

• ARBs*- losartan

• HYDRALAZINE + ISOSORBIDE*-

when ACE-I or ARB

contraindicated or not fully

effective

• BETA BLOCKERS*

• SPIRONOLACTONE*

• DIGOXIN

* = SURVIVAL BENEFIT

Surgical measures

• Cardiac Resynchronization

• Implantable Cardiac Defibrillators

• Intraaortic balloon counter pulsation

• Percutaneous and surgically implanted LV assist devices

• Cardiac transplantation

Medicines used in the first line management of heart failure

DRUG CLASS DOSE REGIME SIDE EFFECTS

ACEIsRamiprilPerindoprilLisinoprilEnalaprilCaptopril

1.25 – 10mg daily (2 divided doses)2.5 – 5mg daily2.5 – 35mg daily2.5mg daily – 10-20mg twice daily6.25 – 50mg three times daily

Postural hypotension; dry cough; ↑ plasma K+;caution with renal dysfunction. Rarely angio-oedema.Not to be used during pregnancy

β-blockersBisoprolol§Nebivolol§Carvedilol§§

1.25 – 10mg daily1.25 – 10mg daily3.125 – 25mg twice daily

Bradycardia; worsening of heart failure; hypotension;fatigue; GI disturbances; cold extremities

Diuretics:FurosemideBumetanideBendroflumethiazide

20 – 40mg once or twice daily0.5 - 2mg daily 2.5mg daily – 10mg daily

Loop diuretics: ↓ K+ and ↓ Na+ ; hypovolaemia;hypotension; ↑ creatinine; ↑ risk of goutThiazides: ↓ K+ ; ↑ risk of gout; ↑ riskof diabetes mellitus. Rarely ↓ Na+

Medicines used in the second-line management of heart failure

DRUG CLASS DOSE REGIME CLASS SIDE EFFECTS

ARBsValsartanLosartanCandesartan

40-160mg twice daily12.5 – 150mg daily4 – 32mg daily

Postural hypotension; ↑ plasma K+; caution with renal dysfunction.Not to be used during pregnancy

Aldosterone(mineralocorticoidreceptor) AntagonistsSpironolactoneEplerenone 12.5 – 50mg+ daily

25 – 50mg daily

↑ plasma K+ - discontinue if K+ levels > 5mmol/L; caution with↓ renal function.Gynaecomastia (with spironolactone).Do not use eplerenone with strong inhibitors of CYP 3A4

Other drugs which can be used in HF-INOTROPIC AGENTS- Cardiac Glycosides, Phosphodiesterase inhibitors, dopamine receptor agonists IvabradinAnticoagulantsAntiarrhythmic agents

PHARMACOTHERAPY OF HEART FAILURE

Diagnosis

• Detailed history, clinical examination, ECHO and/or serum natriuretic peptide levels

• Confirm heart failure and Assess the severity of symptoms

Treatment• Education on lifestyle management and

exercise training

Step- 1

• ACE inhibitor (or ARB if ACEI not tolerated) +/- β-blocker**

• Concomitant therapy with β-blocker + ACEI (or ARB if ACEI not tolerated)

• If still symptomatic with optimised triple therapy (ACEI, β-blocker, diuretic)

Step- 2

• ADD mineralocorticoid receptor antagonist (MRA) (ARB may be considered if

• MRA not suitable)§• hydralazine + isosorbide may be useful in black

populations / patients not• responding or intolerant of step 2 combinations

Step- 3• Consider adding in digoxin / ivabradine /

use of non-surgical interventional• therapies (ICD, CRT)

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

Novel agents in HF• Newer Inotropes-

• Cardiac myosin activators- Omecamtive mecarbil

• Na/K-ATPase inhibitors- Istaroxime

• Ryanodine receptor stabilizers- JTV-519(K 201),S107,S44121

• SERCA2a activators- MYDICAR

• Vasodilators- Relaxin

• Neuregulins-• recombinant human NRG-1β2

• Novel RAAS blockers- • Direct renin inhibitors- Oral Aliskiren,IV Remikiren, IV Enalkiren

• Angiotensin receptor & neprilysin inhibitors- LCZ696, AHU377 ,Candoxatril,

Ecadotril

• Aldosterone blockers-

• Non steroidal minrelocorticoid receptor antagonist-PF3882845,BR-4628

• Aldosterone synthase inhibitors- FAD286, LCI699

• Dual ACE/NEP Inhibition – Vasopeptidase Inhibitors• Omapatrilat, sampatrilat, fasidotrilat, MDL 100240, Z13752A, BMS 189921

and mixanpril• Dual NEP & ECE(endothelin converting enz.) inhibitors

• GGS34043, GGS34226, GGS26303, SLV306• Triple enzyme inhibitors of ECE/NEP/ACE

• GGS26670 • Dual dopamine D2-α2 agonist

• Nolomirol • Dopamine β-Hydroxylase inhibitor

• Nepicastat• Adenosine A1 receptor antagonists

• BG9719,BG9928• Carnitine palmitoyl transferase-1(CPT-1) inhibitors

• Etoxomir, Oxenicine• Matrix Metalloproteinase (MMP) Inhibitors

• Batimastat, ilomastat, marimastat and prinomastat• Immune modulator

• CelacadeTM

Cardiac Myosin Activators- Omecamtive Mecarbil

• MOA:

accelerate transition of actin-myosin complex from a weakly bound to strongly bound configuration

↓

↑ myosin head interaction with actin

↓ nonproductive ATP hydrolysis

↓

↑duration of systole↑stroke vol -improvement in myocardial systolic function in absence of arrythmogenesis & ↑ O2 consumption

OMECAMTIVE MECARBIL

• ↑stoke vol & CO

• ↓HR & ↓LV end diastolic pressure.

• No effect on BP

• Do not ↑rate of rise of LV pressure but ↑LV ejection time & do not

change myocardial O2 consumption

• No untoward effect on exercise tolerance

• Disadvantage :As it prolongs systole, shorten diastole-

inadequate coronary flow & ventricular filling so lowers threshold

for myocardial ischemia in patients with CAD

• Currently under phase 2b trial.

Istaroxime • MOA-

• Inhibition of sodium/potassium adenosine triphosphatase (Na+/K+ ATPase).

• Stimulation of the sarcoplasmic reticulum calcium ATPase(SERCA) isoform 2 (SERCA2) – Lucitropic action(rapid sequestration of cytosolic calcium into the sarcoplasmic reticulum during diastole) Enhances the heart’s relaxation phase, protects from arrhythmogenesis caused by calcium overload

• Significantly reducing PCWP.• Improves ejection fraction, stroke volume and systolic

blood pressure, while also enhancing ventricular filling.• Reduces heart rate and ventricular diastolic stiffness• Wider margin of safety• Drug is under phase 2 trial.

Vasodilators - Serelaxin• Recombinant human relaxin- 2• Relaxin- circulating peptide found in pregnant women • Regulates systemic vasodilation • The rapid vasodilatory responses of relaxin are mediated

by activation of endothelial NOS. Reduces pulmonary capillary wedge pressure and systemic vascular resistance

• Improves dyspnea significantly• Reduces hospital stay with HF• Dose 30 μg/kg/day infusion• Currently under phase 3 trial.

SERCA 2a activators• SERCA2a mediates the reuptake of Ca2+ back into the SR

during the early diastolic phase .• Adeno-associated virus 1 (AAV1) is used for delivery of

SERCA2a complementary DNA by intracoronary infusion in trials.

• Improved systolic and diastolic functions, improved ventricular metabolic reserve, and reducing the likelihood of ventricular arrhythmias during ischemia-induced Ca2+ overload

• Drawbacks- inhomogeneous SERCA2 overexpression may be pro-arrhythmic , implantation of a cardioverter defibrillator was an inclusion criterion for the trial.

• Currently under phase 3 trial.

Ryanodine receptor stabilizers (JTV519 )

• Ca+2 entry in SR triggers further its release via activating the ryanodine receptor 2 (RyR2)

• Diastolic Ca2+ leak through dysfunctional RyR2, leak may lead to a reduction in SR Ca2+ content, with less Ca2+ available for release and consequently weaker muscle contractions.

• Calstabin proteins increase the probability of the channel to be in its closed state, RyR channel stabilizers.

• MOA- JTV519 (originally called K201), S107, S44121 enhances RyR-calstabin binding and stabilizes the closed state of the RyR thus preventing SR Ca2+ leak

• preserve left ventricular systolic and diastolic function • prevents left ventricular remodeling

Neuregulins• Growth-promoting proteins of the epidermal growth factor family .• Neuregulin-1 (NRG-1) plays a key role in cardiac chamber differentiation and

trabeculation in the developing embryo and in cardiac function.

• Act through the ErbB family of tyrosine kinase receptors.• In the later stages of HF, both NRG-1 expression and NRG-1/ErbB signaling

are inhibited, enhanced susceptibility of cardiomyocytes to cell death and progression of HF.

• Recombinant human NRG-1β2 infusion improve cardiac structure and function by 90 days

• Increase in cardiac output as well as vasodilator effect

• Drawbacks- potential for acceleration of tumor growth , administered intravenously over many hours on a daily basis, thus limiting its utility in chronic HF , Nausea

• Currently under phase 3 trial.

Novel blockers of the renin–angiotensin aldosterone system

Direct renin inhibitors• Oral Aliskiren,IV Remikiren, IV Enalkiren• Reduce increased plasma renin activity directly

independent of plasma levels of BNP, background effect of beta blockers & ACEI.

• MOA- inhibit conversion of Angiotensinogen to angiotensin-I

• Reduces systemic vascular resistance & PCWP• Ventricular remodeling significantly attenuated• Delays cardiovascular death and hospitalization• Drawback- hyperkalemia, hypotension

Angiotensin receptor and neprilysin inhibitors

• Atrial natriuretic peptide, B, C and exogenous D-type, possess differing degrees of hemodynamic, neurohormonal, renal and cardiac effects

• Candoxatril, Ecadotril• LCZ696 (Angiotensin receptor blocker)• AHU377 moiety (neprilysin inhibitor)

• Preservation of systemic blood pressures while causing significant reductions in central pressures

• Increases in urine sodium excretion and increased urinary volume while preserving glomerular filtration

• Currently under phase 2 trial

Novel approaches to aldosterone blockade

Non-steroidal mineralocorticoid receptor antagonists• PF3882845 -greater blood pressure reduction and renal

protection • BR-4628 -dihydropyridine (DHP) structure • specific MR antagonist without pronounced L-type calcium

channel activity .

Aldosterone synthase inhibitors• There is induction of aldosterone synthase (CYP11β2) or

angiotensin II in the failing ventricle• FAD286 - improved cardiac hemodynamic parameters,

preventing progressive LV remodeling • LCI699 - reduction in blood pressure

Dual ACE/NEP Inhibition – Vasopeptidase Inhibitors

• Omapatrilat, sampatrilat, fasidotrilat, MDL 100240, Z13752A, BMS 189921 and mixanpril

• Superior to ACE inhibitors in increasing glomerular filtration rate and sodium excretion and decreasing PCWP

• Improvement in ventricular function in NYHA class II to IV heart failure.

• Drawback- Severe angioedema than ACEI

Dual Neutral Endopeptidase (NEP) and Endothelin

Converting Enzyme (ECE) Inhibitors

• Endothelin converting enzyme helps in production of ET-1- a potent vasoconstrictor

• NEP degrades BNP and ANP- helps in natriuresis

• GGS 34226 and GGS 26303 are dual inhibitors of above enzymes

• Decreased preload, afterload and LV hypertrophy and increased cardiac output.

• Reducing right and left cardiac filling pressures

Triple Enzyme Inhibitors of ECE/NEP/ACE

• GGS 26670• Improved LV function and reduced LV collagen accumulation

better than either ACE alone or ECE-NEP inhibition

Dual Dopamine D2- 2 Adrenoceptor agonist• Nolomirole• Inhibits catecholamine release from sympathetic

nerve endings and also inhibits the release of TNF- from cardiac tissue

• Significantly reduces hypertrophy and attenuates signs and symptoms

Dopamine -Hydroxylase Inhibitor• DBH catalyses the conversion of dopamine (DA) to

norepinephrine (NE) in sympathetic nerves• Nepicastat- reduce norepinephrine synthesis.• Attenuates ventricular remodeling and prevents systolic

dysfunction• Augments level of DA leading to renal vasodilation.• Phase 2

Adenosine A1 receptor antagonists• BG 9928, BG 9719• Protects renal function and exerts additive natriuretic effects

without excessive potassium loss

Carnitine Palmitoyl Transferase-1 (CPT-1) Inhibitors

• CPT-1 enz helps in metabolism of fatty acid which is a source of energy production in heart

• Etoxomir, Oxfenicine• Convert energy production of heart from fatty acids to glucose• Preserves cardiac function and prevents ventricular dilation,

reduced PCWP. prevents ventricular remodeling.

Matrix Metalloproteinase (MMP) Inhibitors• Enhanced expression of MMP triggers signaling cascade of

cardiac remodeling• Batimastat, ilomastat, marimastat and prinomastat, PG-53072• Prevent ventricular dysfunction and delay heart failure

progression

Immune modulator• CelacadeTM• Prevents chronic inflammation and apoptotic cell death by activating

physiological immune system’s IL -10 mediated anti-inflammatory process

• Celacade is a device-based outpatient procedure involving ex vivo exposure of 10ml autologous blood to heat, ultraviolet irradiation, controlled oxidative ozone therapy and subsequent intramuscular administration at monthly intervals.

• Improve quality of life in patients of NYHA class III or IV heart failure.• Reduce the risk of death and hospitalization due to chronic heart

failure

Conclusion • The newer therapeutics may be potential candidates in

future for heart as increasing in understanding of pathophysiology of heart failure.

• Agents directly acting on remodeling process may even reverse current pathological condition of heart failure.

• Newer agents are seems to be beneficial over the older one in efficacy and safety wise eg: newer inotropes, RAAS antagonists…

• Gene therapy is also emerging as newer technique for HF seems to be promising in near future.

References • Harrison’s principles of internal medicine 18th ed.• Pharmacology & Therapeutics Volume 135, Issue 1, July

2012, Pages 1–17• Novel Strategies for the Treatment of Heart Failure.

RMMJ|www.rmmj.org.il.1 April 2012.Volume 3(2).0011 • Emerging Drug Therapies for Heart Failure.Ijpt. July 2006

| vol. 5 | no. 2 | 87-94• Wikipedia

THANK YOU

HF FORMS• Systolic ventricle unable to contract normally LVEF is <50% Sx due to inadequate out- put

• Diastolic ventricle unable to relax and fill normally LVEF is preserved >50% Sx related to increased fill- ing pressures Estimated at 20-50% of HF More in elderly women

ACUTE HEART FAILURE PRECIPITATING CAUSES

Arrhyhthmias ThyrotoxicosisPregnancy MyocarditisMyocardial infarction PEInfective endocarditis InfectionHTN AnemiaPhysical,dietary,fluid,environmental or emotional excesses

PATHOGENESIS of HEART FAILURE

ACUTE Acute stress for a chronically burdened heartCHRONIC Adaptive changes evolve over time Patient adjusts and tolerates Acute decompensation occurs with precipitating causes

SIGN AND SYMPTOMS

DRUGS for CHF THERAPYDiuretic-furosemide / hydrochlorthiazideInotrope-digoxinACE-I-captoprilARB-losartanIsosorbide- hydralazine when ACE-I or ARB contraindicated or not fully effective

Aldosterone receptor blocker-spironolactoneBeta-blocker-metoprololSodium nitroprusside

Epidemiology of Heart FailureClinical criteria – Prevalence 1-2 %

Males > Females; in 65+ Prevalence 7%

50% of LVSD is asymptomatic

NEF HF varies from 15 to 50%

Incidence 0.2 to 0.3 %; with age

Metabolic Modulators

• MOA: Shift in energy utilisation from FFA glucose• FFA require larger O2 for oxidation ,myocardial efficiency is

low• FFA derivative may inhibit PDH & glucose oxidation↑

conversion of pyruvate to lactatelactic acidosisimpaired myocyte contractility

PERHEXILINE:• Inhibitor of carnitine palmitoyl transferase-1shift of

myocardial substrate to carbohydrate• Disadv: narrow TI,hepatotoxicity,peripheral neuropathy• Clinical trial: improvement in peak O2 uptake,quality

oflife,LVEF

• RANOLAZINE: • Acts through inhibition of late sod channel current prevent

intracellular Ca++ overload during myocardial ischemia• Also inhibits FFA oxidation• Beneficial effects on LV diastolic function,LV remodelling &

myocardial fibrosis.

• TRIMETAZIDINE:• Improvement in NYHA functional class• ↓ LV end diastolic vol & ↑LVEF• Improved exercise tolerance• ↓FFA oxidation & unchanged myocardial oxidative rate↑ glucose

utilisation

TREATMENT ALGORYTHM

Signs and symptomsAcute heart failure

• Fluid overload-• Weight gain• Dyspnea on exertion• Paroxysmal nocturnal• dyspnea (PND)• Orthopnea• Rales• Peripheral edema• Jugular venous• distension• Ascites• Hepato-/splenomegaly

• Low Cardiac Output• Fatigue• Nausea and vomiting• Early satiety• Weight loss• Increased serum• creatinine

Chronic heart failure

• breathing difficulties during the night or when lying down

• coughing and wheezing• fatigue and weakness• shortness of breath• swollen ankles.• abdominal pain, bloating, or loss of

appetite• accumulation of fluid in the abdomen• bluish skin around the mouth• constipation• pale skin and cold hands or feet• urination at night

Systolic Heart Failure

• LVSD – Left Ventricular Systolic Dysfunction

• Most common type of Heart Failure; 60-70%

• LV is usually dilated & enlarged.

• Fails to contract normally due to WMA, Ischemia

• Cannot pump sufficient blood to meet needs

• In LVSD heart failure the EF is <40 -45%

• This carries a 10% mortality per annum

Diastolic Heart Failure

• Accounts for 20-40% of patients

• Ventricles are normal-sized with normal emptying

• But there is an impairment in the ability of the ventricles to fill with blood during diastole.

• Because of stiff myocardium due to hypertrophy

• The heart fails to relax normally (relaxation poor)

• Generally older women

• Hypertension is the commonest cause

• This carries a 5-8% mortality per annum

Important Points

• Chronic Heart Failure (CHF) can be caused by any type of cardiac dysfunction

• Most commonly attributable to LV Dysfunction

• Rarely HF is due to isolated RV dysfunction

• Most common and best studied cause of CHF is LV Systolic Dysfunction (LVSD)

• Normal Ejection Fraction Heart Failure (NEFHF) is due to LV Diastolic Dysfunction – (HFPSF)

• It is difficult to diagnose and quantify.

• 30- 40% of patients die within 1 year of diagnosis and 60-70%

die within 5 years, mainly from worsening HF or as a sudden

event (probably because of a ventricular arrhythmia)

NYHA classification

I. No visible sign and symptom

II. Sign and symptom on high level of exercise

III. Sign and symptom on low level of exercise

IV. No physical exercise possible, bed rest necessary

Novel agents with inotropic effects

• Cardiac myosin activators- Omecamtive mecarbil

• Agents acting on SERCA2a- MYDICAR

• Na/K-ATPase inhibitors- Istaroxime

• Ryanodine receptor stabilizers- JTV-519(K

201),S107,S44121

• Metabolic modulators-Perhexiline,

Trimetazidine, Ranolazine