This document discusses recent advances in the medical management of heart failure. It begins by describing the types of heart failure and the historically available treatment options of diuretics and digoxin. It then discusses neurohormonal blockers that have been effective in reducing morbidity and mortality for HFrEF. The document reviews evidence for drugs like hydralazine/isosorbide and goes on to describe several novel drug categories and agents that may further improve heart failure treatment, such as neprilysin inhibitors, soluble guanylate cyclase stimulators, calcium sensitizers, and metabolic modulators.

1. ADVANCES IN
MEDICAL MANAGEMENT OF
HEART FAILURE
Dr.N.Praveen
Final year PG

3. 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.

4. Mechanisms
of
heart failure

5. William Withering

10. 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

12. 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/ARBs
Class IIA – intolerant to ACEI/ARBs

14. VHeFT II trial

18. Are there drugs beyond these ?
• Certainly Yes

20. 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
Aquaretics
Tolvaptan
Ryanodine Receptor Stabilizers (RYCALS)
SERCA 2a activator
MMP inhibitors Batimastat
Ultrafiltration

21. 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.

22. 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

23. 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

24. 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.

26. URODILATIN

30. 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 al
Kristeller 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)

31. 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.

33. 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)

34. 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

35. 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

37. Trial Evidence
HORIZON 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.

41. 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)

42. 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

46. 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

47. 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

48. 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

51. 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

54. 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.

57. 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.

61. 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.

62. • $5460 /year
• 100mg to 200mg bid.
• Approved by US FDA on July 07th 2015.

63. 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)

64. Celacade TM
• Immunomodulation therapy
ACCLAIM 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.

65. • 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.

67. Batimastat
• MMP inhibitor
• Could not be administered orally
• Causes peritonitis

68. 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.

69. 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.

70. 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.

72. 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.

73. 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

74. 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 point
RELAX AHF EU trial
• 2,685 pts
RELAX AHF ASIA trial
• 1,520 pts

75. 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.

76. Direct
Renin
Inhibitors

78. Trial evidence
ALOFT 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.

79. 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.

82. 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.

83. 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

84. 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.

90. 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.

92. 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

93. 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.

95. Ivabradine

96. Systolic Heart failure treatment with
the 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

99.  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

100. Trimetazidine

102. Ultrafiltration

104. 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.

105. 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.

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

110. 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.

112. 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.

114. 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

115. 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.

117. • 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, 0.6g/kg, 1.2g/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.

118. 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.

119. AQUARETICS
• Loss of water without loss of electrolytes

120. Tolvaptan
• Selective competitive vasopressin receptor2 antagonist used to treat
hyponatremia assosciated with CHF, cirrhosis and SIADH.

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

125. Newer Conventional Drugs
• AZILSARTAN – Diastolic Heart Failure

126. 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.

127. Initiative by AHA

128. THANK YOU