ADVANCES IN MEDICAL

MANAGEMENT OF HEART FAILURE

Dr.N.PraveenFinal year PG

Introduction• Heart Failure (HF) is the epidemic of 21st century.• Historically, the only available medical treatment options for HF were

diuretics and digoxin.• Over the past four decades, neurohormonal blockers were found to be

effective in reducing the morbidity and mortality of patients with HF particularly HFrEF.

• With respect to ADHF, HFpEF – No drug has shown to be effective in reducing the long term clinical events substantially.

• Novel agents have the potential to enhance the armamentarium of HF therapuetics.

Mechanisms of

heart failure

William Withering

Types of Heart Failure

Chronic Heart Failure HFrEF (LVEF 40%) (Systolic HF) HFpEF(LVEF ≥ 50%) (Diastolic HF) HFpEF borderline (41 to 49) (treatment similar to HFpEF) HFpEF improved ( >40) ( Research needed)

Acute Decompensated Heart Failure Heart Failure term is preferred over congestive heart failure. Heart failure in not synonymous with either cardiomyopathy or LV

dysfunction. In most patients have systolic and diastolic dysfunction coexist

irrespective of LVEF.

Yancy et al;2013 ACCF/AHA HEART FAILURE GUIDELINES

Hydralazine and IsosorbideDinitrate

• Recommended for African Americans with HFrEF who remain symptomatic despite concomitant use of ACEI,BB,MRAs.

In non African Americans ?• Should not be used for Treatment of HFrEF – who have no prior use of

standard therapy,and should not be substitution for them.• 37.5mg of hydralazine hydrochloride and 20 mg of IDN tid.• Increased to two tablets tid.• 225 mg/120mg daily.• Increased adverse reactions.• RR reduction in mortality - 43% • NNT for achieving - 7.• RR reduction in HF hospitalizations – 33%

Class IA – symptomatic even on ACEI/ARBsClass IIA – intolerant to ACEI/ARBs

VHeFT II trial

Are there drugs beyond these ?

• Certainly Yes

Category Drug Name

Natriuretic Peptides Nesiritide

Ularitide

Cenderitide

Neprilysin Inhibitors Sacubitril

Recombinant Relaxin Serelaxin

Soluble Guanylate Cyclase Stimulators

Riociguat

Cinaciguat

Vericiguat

Direct Renin Inhibitors Aliskiren

Remikiren

Elikiren

Actin Myosin Stabilizer Omecamtiv Mecarbil

PDE3inhibitors Milirinone,Enoximone

Calcium Sensitizer Levosimendan

If Channel blocker Ivabradine

Metabolic modulator Trimetazidine

Inhibition of Na K ATPase Istaroxime

Neuregulin -1 Recombinant form

Glial Growth factor

Aquaretics

Tolvaptan

Ryanodine Receptor Stabilizers (RYCALS)

SERCA 2a activator

MMP inhibitors Batimastat

Ultrafiltration

Figure 2.Simplified schematic of the natriuretic peptide system (NPS). Atrial NP (ANP), B-type NP (BNP), and urodilatin (URO) stimulate cyclic GMP (cGMP) production by binding to the guanylyl cyclase (GC) receptor A, whereas CNP generates cGMP by binding to the GC-B receptor. cGMP modulates the activity of cGMP-dependent protein kinase G (PKG) to exert its pluripotent cardiac, vascular, and renal biological actions. cGMP also regulates phosphodiesterases (PDEs) and cation channels. The cGMP signal is terminated by a variety of PDEs that hydrolyze cGMP to GMP. The NPs are removed from the circulation and inactived by the clearance receptor (NPR-C) and also degraded by a variety of peptidases, including neprilysin (NEP) and dipeptidyl peptidase IV (DPPIV). In addition to the clearance capacity of NPR-C from the circulation, evidence has promoted the concept that the NPR-C mediates non–cGMP-regulated biological actions .

Nesiritide• Nesiritide, a recombinant B-type natriuretic peptide (BNP) with vasodilatory

properties, approved in 2001 for use in patients with AHF on the basis of studies showing a reduction in PCWP and improvement in dyspnea at 3 hours.

• VMAC – Nesiritide in Acute Heart Failure – FDA approval• However, subsequent pooled analyses of data from small, randomized trials

suggested that nesiritide, as compared with placebo, was associated with a rate of worsening renal function that was increased by a factor of 1.5 and a rate of early death that was increased by a factor of 1.8, although the confidence intervals associated with these estimates were wide.

• ASCEND HF - In summary, in this study, nesiritide neither increased nor decreased the rate of death and rehospitalization. The observed effect of nesiritide on dyspnea in this trial was small (and not significant) with the coadministration of other therapies that relieve congestion.

• Nesiritide was not associated with worsened renal function, but it was associated with an increase in the rate of hypotension

Dosage • Hypotension may persist longer because of longer effective half life than

nitroglycerin or nitroprusside.• Improve outcomes in the patients hospitalized with HF ?• Relief of dyspnea in the hospitalized patients with intact blood pressure.• Caution in patients with HFPEF – volume sensitive.• Class II b A • The recommended dose of NATRECOR® is an IV bolus of 2 mcg/kg

followed by a continuous infusion of 0.01 mcg/kg/min. The bolus dose may not be appropriate for those with low SBP.

• At doses higher than 0.01 mcg/kg/min (0.015 and 0.03 mcg/kg/min), there was an increased rate of elevated serum creatinine over baseline compared with standard therapies, although the rate of acute renal failure and need for dialysis was not increased.

• C/I in Cardiogenic Shock

Urodilatin

• Member of endogenous natriuretic peptides.• ANP, BNP, CNP, DNP, Urodilatin.• ANP, BNP, Urodilatin – act through NPR-A• NPR-A – activates guanylate cyclase – cyclic GMP - inhibition of

RAAS – vasodilation, anti fibrotic and antihypertrophic effects, and lusitropy.

Kidneys, heart, vascular smooth muscle cells.• Synthesised in distal tubule sec. to increased Na concentration• NPR C – Clearance receptor.• Main actions

– inhibition of resorption of sodium and water,– Increased diuresis and natriuresis– Preglomerular vasodilation,Post glomerular vasoconstriction– Maintenance of glomerular filtration.

URODILATIN

Cenderitide

Why it came into existence?• Recombinant human BNP has had disappointing results in the

treatment of ADHF.• Adverse effects might offset its potential benefits.

Sackner Bernstein et alKristeller et al

• Fusion of the human mature CNP with the C terminus of Dendroaspis natriuretic peptide – first isolated from the venom of green mamba – into designer natriuretic peptide –CENDERITIDE (also known as CD-NP)

Advantages• maximized therapeutic potential of natriuretic peptide activation

– CNP – high affinity for NPR-B– Dendroaspis – high affinity for NPR-A

• In HF, marked reductions in NPR-A activity and relatively unaltered NPR –B activity.

• Robust natriuretic peptide signalling in HF, possibly with less systemic vasodilation than seen with individual peptides.

• Antifibrotic effects in animal models.

Trial evidence

• Treatment with cenderitide has demonstrated improvements in hemodynamic parameters and preservation of renal function, compared with placebo.

Lee et al,2009.• BELIEVE III – Preservation of LV function in STEMI (Anterior

wall) – Nov 2013,presently recruiting – 60 pts with first STEMI (AW) 5ng kg/min vs 10 ng/kg/min vs palcebo (1:1:1)

DOSAGE

• IV infusion at 1.25, 2.5 and 3.75 ng/kg/min appeared to be well tolerated with a dose-dependent effect on blood pressure

• Dose escalation was limited by significant blood pressure reduction at 5 ng/kg/min

• Lower doses of Cenderitide appeared to preserve or enhance renal function compared to placebo, as evidenced by favorable trends in several biomarkers that correlated with kidney function

Istaroxime

• Inotropic agent• Inhibition of Na - K ATP ase• Increases Intracellular Na, inhibits extrusion of calcium ions• Improves the efficacy of the intracellular Ca on Sarcoplasmic

Reticulum• Inactivation of L type channels • Enhances Heart relaxation – Lusitropy• Increases SERCA2a activity upto 67%• Non arrhythmogenic • Effective for both Systolic and Diastolic heart failure

Trial EvidenceHORIZON AF trial

• 120 pts, 3:1 istaroxime vs placebo • 6 hr infusion IV• Baseline characteristics were similar among all groups,

mean age 55 +/- 11 years, 88% men, LVEF 27% +/- 7%,

SBP 116 +/- 13 mm Hg, PCWP 25 +/- 5 mm Hg.

• Istaroxime administration resulted in an increase in E' velocities, whereas there was a decrease in E' in the placebo group (P = .048 between groups).

• On pressure-volume analysis, istaroxime decreased end-diastolic elastance (P = .0001). • On multivariate analysis, increasing doses of istaroxime increased E' velocity (P

= .043) and E-wave deceleration time (P = 0.001), • and decreased E/E' ratio (P = 0.047), after controlling for age, sex, baseline ejection

fraction, change in PCWP, and change in SBP.

Ryanodine receptor stabilizer

• A critical component in regulating cardiac and skeletal muscle contractility is the release of Ca2+ via ryanodine receptor (RyR) Ca+ channels in the sarcoplasmic reticulum.

• In heart failure,the RyR is excessively phosphorylated or nitrosylated and depleted of the stabilizing protein CALSTABIN.

• Remodelling of the RyRCa channel complex – intracellular SR Ca2+ leak and impaired contractility.reduction in SRCa2+ content,with less Ca2+ available for release and consquently wekaer muscle contractions.

• Novels drugs RYCALS – Ryanodine Calcium Stabilizer .• BENZOTHIAZEPINE DERIVATIVES

• JTV 519 (non specific,acts on L type Ca2+ and Na + channels)• Structurally similar to Diltiazem.• S107(more specific)

SERCA2a activator• Decreased activity and expression of the cardiac sarcoplasmic reticulum

calcium ATPase (SERCA2a), a critical pump regulating calcium cycling in cardiomyocyte, are hallmarks of heart failure.

• Role for the small ubiquitin-like modifier type 1 (SUMO-1) as a regulator of SERCA2a have shown that gene transfer of SUMO-1 in rodents and large animal models of heart failure restores cardiac function.

• Small moecule, N106, which increases SUMOylation of SERCA2a. This compound directly activates the SUMO-activating enzyme, E1 ligase, and triggers intrinsic SUMOylation of SERCA2a.

• N106 treatment increases contractile properties of cultured rat cardiomyocytes and significantly improves ventricular function in mice with heart failure.

• This first-in-class small-molecule activator targeting SERCA2a SUMOylation may serve as a potential therapeutic strategy for treatment of heart failure.

N106 or vehicle solutions were continuously infused through the external jugular vein at a rate of 50 μl min−1 for 2 min in each dose.

Chanwon Kho et al,2015

Candoxatril• Neutral Endopeptidase inhibitor/Neprilysin inhibitor.• Asociated with a beneficial hemodynamic effect that is useful both in rest and

exercise. • In one study, 12 different patients of moderately severe heart failure. The drug

increased plasma ANP levels, suppressed aldosterone and decreased right atrial and pulmonary capillary wedge pressures. After treatment for 10 days, patients health had improved with an increase of basal ANP and a decrease of aldosterone, along with a reduced body weight that could be a reflection of chronic natriuretic, diuretic effects, or both. Effects lasted the same since day one..

• UK study - 110 patients, 56 vs 54 received the placebo. Over the time of the study, the patients who were taking candoxatril had an overall improvement in exercise time compared to the patients taking the placebo.

• The results of this study show the candoxatril offers a new, effective therapeutic in the treatment of people with mild heart failure.

• 10,50 and 200mg OD O’Connell et al, J Hypertens. 1992 Mar;10(3):271-7

Omapatrilat• A novel  antihypertensive agent  that inhibits both NEP and ACE .• NEP inhibition results in elevated natriuretic peptide levels,

promoting natriuresis, diuresis,vasodilation and reductions in preload and ventricular remodeling.

• This drug from Bristol -Meyers Squibb was not approved by the U.S. FDA due to angioedema safety concerns.

• Omapatrilat angioedema was attributed to its dual mechanism of action, inhibiting both ACE, and NEP, both of these enzymes are responsible for the metabolism of bradykinin which causes vasodilation, angioedema, and airway obstruction.

• 2.5,5,7.5,25,50,125,500mg dose

Rise and Fall of Omapatrilat – The Impress led to Overture and

unimpressed Octave

• IMPRESS HF – versus enalapril• OVERTURE• Increased incidence of angioedema – 0.5% of the patients in

IMPRESS HF trial, thought to be dose related and led to other trials – but angioedema was evident on the first day itself

• The patients at increased risk – black americans and smokers• The angioedema was 3.5 times more than that of enalapril.• Risk of worsening anigoedema requiring hospitalization was 9 times

more than enalapril. • OCTAVE trial• FDA denied approval based on 5:1 vote rate

Dual Action inhibitor LCZ696

• Most promising development is ARNi – PARADIGM shift in management of HF.

• LCZ 696 – contains a moiety each of valsartan (ARB) and of the neprilysin inhibitor prodrug SACUBITRIL.

• Sacubitril – hydrolysed(cleavage of ethyl ester) into the active neprilysin inhibitor LBQ657.

• 200mg bd vs 10mg bd enalapril

PARADIGM HF trial• Compared with enalapril• 8,436 pts with chronic stable HF,• LVEF <40%• Elevated BNP levels• Terminated prematurely, owing to overwhelming benefit with

LCZ696.• After a mean follow up of 27 months, a 20% risk reduction was

seen with LCZ696 relative to enalapril on the composite primary endpoint of CV mortality or hospitalization for HF.

• NTT to prevent one primary endpoint was 21.• Reduction of cardiac fibrosis and hypertrophy, reduction of

myocardial injury.

What about angioedema• Safer than omapatrilat• Nominal rate of angioedema was high with LCZ696 (19 vs 10 cases),

no increase was noted with serious angio edema requiring medical intervention.

• 20% of patients have been excluded before randomization because of adverse events.

• Neprilysin – amyloid degrading protein – increases brain amyloid levels with its inhibition.

• No such effect was noted in this trial.

ENTRESTO - reduced the risk of death from cardiovascular causes by 20%- reduced heart failure hospitalizations by 21%- reduced the risk of all-cause mortality by 16%Overall there was a 20% risk reduction on the primary endpoint, a composite measure of CV death or time to first heart failure hospitalization.

• $5460 /year• 100mg to 200mg bid.• Approved by US FDA on July 07th 2015.

PARAMOUNT trial• No effective therapy is available for HFPEF• 301 patients with HFPEF and NT pro BNP• 12 weeks • LCZ696 vs Valsartan• NT –proBNP – not a substrate for Neprilysin, so reduction of levels of

NT proBNP – reflects true reduction in cardiac filling pressures.• Reversed left atrial remodelling.• Renal function was better preserved.

• PARAGON HF – 4,300 pts with HFPEF• ONE DRUG IN FUTURE TO BE FOR RX OF HFPEF

(PARAGON – MODEL OF EXCELLENCE)

Celacade TM• Immunomodulation therapyACCLAIM trial• At the WCC, September 2006 the Advanced Chronic Heart

Failure Clinical Assessment of Immune Modulation Therapy (ACCLAIM) a phase III randomized, double-blind, placebo-controlled clinical trial involving some 2408 patients in 7 countries with LVEF of 30% or less, reported that patients with a previous cardiovascular event receiving celacade where 39% less likely to die or be hospitalized due to a heart attack or stroke and tended to have improved quality of life.

• Celacade is believed to inhibit inflammation, platelet aggregation and progression of arterial lesions by a mechanism independent of cholesterol lowering lowering. 

• Celcade 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. 

• The results of ACCLAIM support the  hypothesis  that immune dysfunction plays a role in the pathogenesis of  atherosclerosis and Immune Modulation therapy has a broad-spectrum positive effect on a number of immune mediators, including regulation and enhancement of  cytokines and the vascular dilator  nitric oxide. These molecules regulate inflammation and facilitate the healing process. 

• FDA has recommended that Vasogen conduct a further confirmatory study to support a pre-market approval filing. 

Batimastat

• MMP inhibitor• Could not be administered orally• Causes peritonitis

Soluble guanylate cyclase stimulation

• Reduced responsiveness to and decreased bioavailability of NO contributes to the progression of HF,CVD,Renal disease.

• Nitrates – inherent risk of low efficacy,off target effects and development of tolerance upon chronic exposure.

• Alternative approach is – increase SGC activation directly.• HF generally reduces the responsiveness of SGC to NO, mainly by

alteration of the redox state of sGC via oxidative stress.• Pulmonary hypertension has been investigated as the primary

indication for the use of these agents.

RIOCIGUAT• Major drawback – postural hypotension.• LEPHT -201 pts with pulHTN secondary to LV systolic

dysfunction.• No significant change in pulmonary pressures compared to placebo at

16 weeks.• Decrease in PVR and increased CI – 2mg tid.

CINACIGUAT

• ADHF, non controlled, proof of concept study.• Reduced cardiac afterload and filling pressures • Improvements in dyspnea.• Symptomatic hypotension was the most common adverse effect.• COMPOSE – low dose of (<200ug/h) in ADHF.• Terminated prematurely• Lack of effect on dyspnea and cardiac output• Increased hypotension.

Serelaxin• Recombinant form of the endogenous human peptide – relaxin -2.• Relaxins – Family of peptides – act through G protein coupled

receptors.• Role in maternal adaptations to pregnancy – rapid vasodilatory

responses.• Increase in relaxin levels – kidney, heart – increase in renal plasma

flow and Glomerular filtration – attenuation of vasoconstriction response to angiotensin II – increase in cardiac output and decrease in SVR.

• Vasodilation – mediated via activation of NO synthase, VEGF pathway, and the endothelin –B receptor.

Trial evidence

Pre RELAX AHF • 234 pts -48 hr IV infusion of placebo or one of four doses of

relaxin(10-250 ug/kg /day)RELAX AHF trial• 1161 pts• 30ug/kg/day for 48 hrs• Dyspnea relief was not significant• Similar response in both HFPEF and HFREF• Reduced CV mortality at 180 days• Reduced levels of BNP

For FDA approval

RELAX AHF 2 trial• 6800 pts with acute HF• Effects of 48 hrs infusion of serelaxin vs placebo• CV mortality at 180 days of follow up - 1 end pointRELAX AHF EU trial• 2,685 pts RELAX AHF ASIA trial • 1,520 pts

Direct Renin Inhibitors (DRI)• Activation of the RAAS – fundamental role in the pathogenesis and

progression of HF• Upstream of these established drugs targets (ACEI and ARBs),renin

itself contributes to adverse cardiac remodelling.• It can be independent of traditional RAAS signalling.by activation of

the prorenin receptor.• Loss of negative feedback inhibition of renin release, conventional

RAAS blocking agents – reflex increase in plasma renin activity, exaggeration of activity of renin and aldosterone.

• Aliskiren – most clinically advanced orally available DRI.

Direct Renin

Inhibitors

Trial evidenceALOFT trial – treatment of HF • 302 patients• NYHA II-IV, elevated BNP levels• Who had been treated with ACEI or ARBs• Placebo vs Aliskiren (150 mg) - daily for 3 months.• Significantly reduced BNP levels• Improved diastolic dysfunction• Reduced urinary aldosterone secretion.• Beneficial effects were seen irrespective of concomitant treatment

with mineralocorticoid receptor antagonists or ACEI.

ALTITUDE trial• 8562 pts• Type2diabetes mellitus CKD or CVD or both• Aliskiren vs placebo• Along with an ACEI/ARB• Stopped prematurely because of safety concerns and lack of effect of

treatment.• Did not improve the cardiorenal composite end point• Higher incidence of hyperkalemia and hypotension.• Very few had HF or LV dysfunction.

ATMOSPHERE trial

• To evaluate monotherapy with aliskiren (300mg /day) or enalapril (10mg bd) as well as their combination.

• 7,041 pts• LVEF<35%,elevated plasma BNP levels, and stable CHF with

NYHA II-IV.• Results to be released.

Remikiren• In 24 healthy volunteers, administration of single oral doses of remikiren 100,

600 or 1200mg rapidly and dose-dependently decreased PRA, angiotensin I and angiotensin II;

• Peak inhibition occurred within 15-30 min .• The acute haemodynamic effects of remikiren were very similar to those of

enalaprilat in 36 patients with NYHA class II or III congestive heart failure. After a 45 min IV infusion of remikiren 0.3 mg/kg then 0.1 mg/kg/h or enalaprilat 9 µg/kg then 1.5 µg/kg/h, resting BP rapidly decreased secondary to a decrease in SVR.

• These changes were significantly correlated with baseline PRA. • Pulmonary artery pressure, right atrial pressure and PCWP were also reduced

equally by both agents. • In addition, SVI was increased, and BP, pulmonary artery pressure, PCWP and

right atrial pressures were decreased during exercise (p < 0.05 vs baseline). Adding remikiren to enalaprilat and vice versa had no further effects on haemodynamic parameters 

Non steroidal MRAs

• Activation of aldosterone signalling via the mineralocorticoid receptor - a fundamental driver of deleterious cardiovascular remodelling in Hypertension and in HF as well as renal failure.

Mc Curley et al 2012• Efficacy of MRAs to reduce mortality and morbidity was demonstrated

in RALES trial – Class I recommendation.• Mineralocorticoid receptors – CVS, kidney, distal colon.• Lack of CV specificity of steroidal MRAs – potential for adverse effects –

gynaecomastia (spironolactone > eplerenone), hyperkalemia and worsening renal function.

• MRA s are underutilized - (1/5th of HF patients have renal failure). • But still survival benefit is more than the adverse effects as was evident in

EMPHASIS –HF trial.

Finerenone• BAY94-8862• First nonsteroidal MRA• Improved selectivity for Mineralocorticoid receptors• Distributes equally into renal and cardiac tissues.• Greater reduction of hypertrophy, plasma BNP levels, and the degree

of proteinuria than eplerenone.Kolkhof et al. EHJ,2013

• More potentiate in attenuating LV remodelling than eplerenone.

Trial evidence

• ARTS study : • Safety and tolerability of oral finerenone was tested in 65 patients

(Stable Chronic HFrEF).• Efficacy of finerenone was compared with palcebo and open label

spironolactone in 392 patients.• Doses at 5mg per day and 10 mg per day was as effective as 25mg/d

and 50 mg/d of spironolactone – in decreasing the NT-proBNP and albuminuria levels.

• Hyperkalemia and worsening renal failure was lower than with spironolactone.

• FINESSE HF study - 2015

ARTS HF trial

• Large randomized• Dose finding• Phase IIb study• Worsening HFrEF and Diabetes Chronic Renal Failure• 1,060pts• 2.5mg/d -20mg/d• Eplerenone at 25 mg/d and 50mg/d• Primary end point – change in levels of NT-proBNP at 90days• Secondary end points – biomarkers of collagen turnover,

inflammation, myocardial injury

Pitt et al ,Eur J Heart Fail 2015 Feb;17(2):224-32. doi: 10.1002/ejhf.218.

Ivabradine

Systolic Heart failure treatment withthe If inhibitor ivabradine Trial

Heart rate at baseline influences the effect of ivabradine on cardiovascular outcomes in chronic heart failure: analysis from the SHIFT study Effect of ivabradine on outcomes in patients with chronic heart failure and HR 75 bpm

www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22

In HF in sinus rhythm with HR ≥75 bpm heart rate reduction with

ivabradine improves outcomes, including all-cause death and

cardiovascular death reduces

Ivabradine-associated risk reductions are related to both HR

achieved and magnitude of HR reduction

Patients achieving <60 bpm or with >10 bpm reduction have the

best prognosis

Conclusions

www.shift-study.comBöhm M, Borer J, Ford I, et al. Clin Res Cardiol. 2013;102(1):11-22

Trimetazidine

Ultrafiltration

Inotropes• Classic inotropic agents – stimulate β adrenergic and α adrenergic

receptors – increase cardiac output – reducing systemic and pulmonary resistance.

• Dose dependent increases in Heart rate, arrhythmias, myocardial ischemia, apoptosis,and possibly excess mortality.

• Why ? – cAMP augmentation, supraphysiological increases in myocardial intracellular calcium transients.

Phosphodiesterase 3 inhibitors

• Milrinone and Enoximone• Largely neutral effects on end points including morbidity and

mortality.• Similar downstream signalling effects to adrenergic agonists –

elevation of cAMP.

Levosimendan

• Calcium sensitizing properties• Potasssium channel activator• Favourable effects on myocardial oxygen consumption

Omecamtiv mecarbil• LMW agent• CK 1827452• First direct activator of cardiac myosin • Binds to the catalytic domain of cardiac myosin ATPase – increases

the transition rate of myosin into the actin-bound,force generating state,resulting in prolongation of systolic ejection time rather than more powerful cardiac contraction.

• Does not lead to increase in calcium transients.

Trial evidence

• In FIM study , IV administration for 6 hrs in healthy men, induced dose dependent increase from baseline in systolic ejection time, together with clinically meaningful increases in LV fractional shortening, ejection fraction, and stroke volume, and no significant off target effects.

• 45 patients of HFrEF – placebo vs omecamtiv• Increased LV ejection time and stroke volume.• Reduced HR by aroung 30 bpm,without affecting the orthostatic

cardiovascular response.• ATOMIC –AHF - 613 pts ADHF – effect on dyspnea was similar to

placebo.• Highest dose – significant improvement in dyspnea.• COSMIC HF – 544 HFrEF – orally bd for 20 weeks.

Risk of myocardial ischemia

• No relevant myocardial ischaemia during treadmill exercise.• Elevated levels of troponin T and I• Duration of diastole decreased with increase in systole.

Omecamtiv mecarbil is a novel therapeutic agent with a unique mode of action

that could enter the clinical arena for the treatment of HF

Neuregulin -1• NEUREGULIN - Cardiac Growth factor, released by

endothelium,involved in regulation of CV development, growth, homeostasis and integrity.

• Expressed in the heart extensively and acts through ErbB receptors – Neuregulin-1.

• Disrupted ErbB2 or ErbB4 signalling – Dilated Cardiomyopathy.• Importance of Neuregulin-ErbB pathway for the growth and survival

of cardiac cells came from trials of Trastuzumab (A humanized antibody targeting the ErbB2 receptor ) in the treatment of breast cancer.

• Increased cancer survival, but a proportionate of patients developed cardiac dysfunction or new onset HF.

• Protective role against the cardiotoxicity of doxorubicin and other anticancer drugs.

• Therapeutic augmentation of ErbB – Neuregulin signalling is a potential treatment strategy for HF.

• Gao R et al – various doses of rhNRG-1 were tested against placebo in 44 patients with well treated,chronic,stable HF of NYHA class II or III (LVEF<40%) - 0.3 g/kg, 0.6g/kg, 1.2g/kg rhNRG-1 or palcebo – IV over 10 hrs for 10 consecutive days.

• Greater increases from baseline in LVEF,along with reduction in LV dimensions.

• Antiremodelling effects of NRG-1 in human HF.

Glial Growth Factor2(GGF2)

• NRG -1b isoform• Administration of GGF2 for 4 weeks – improved cardiac

function and indices of cardiac remodelling,compared to placebo.

• Galindo et al 2014.• Evaluation of safety, tolerability, pharmacokinetics and

immunogenicity of single intravenous administration of GGF2 has been completed- results unpublished.

AQUARETICS

• Loss of water without loss of electrolytes

Tolvaptan• Selective competitive vasopressin receptor2 antagonist used to treat

hyponatremia assosciated with CHF, cirrhosis and SIADH.

Trial evidence

• SALT-1 trial – 33% cases HF• SALT-2 trial – 29% cases HF• METEOR trial• EVEREST trial• ACTIV HF trial• TEMPO III trial

Newer Conventional Drugs

• AZILSARTAN – Diastolic Heart Failure

Conclusion

• Despite a number of encouraging advances,a tremendous unmet need exists in pharmacotherapy for HF – particularly ADHF,HFPEF.

• Development of effective new treatments calls for elucidation of important pathophysiological mechanisms and identification of putative drug targets (MMP,Soluble guanylate cyclase)

• The design of future clinical trials should increasingly take into consideration specific phenotypes of HF,characteristics of patients such as genetic and ethnic background,age,sex,neurohormonal status to decrease the neutral outcomes.

Initiative by AHA

THANK YOU