Acute Decompensated Heart Failure

1. Prof. U. C. SAMAL
MD, FICC, FACC, FIACM, FIAE, FISE, FISC, FAPVS
Ex- Prof. Cardiology & Ex-HOD Medicine
Patna Medical College, Patna, Bihar
Past President, Indian College of Cardiology
Permanent & Chief Trustee, ICC-Heart Failure Foundation
National Executive Member, Cardiological Society of India
President, CSI Bihar
Acute Decompensated Heart Failure :
What Is New ?
1

2. AHFS : NOT VERIFIED
Similarities and differences between acute MI & AHFS in
hospitalization in the US
Incidence 1 million per year 1 million per year
Mortality
Pre hospitalization
In hospital
After discharge [ 60-90 d]
High
3-4%
2%
?
3-4%
10%
Myocardial injury Yes Likely
Pathophysiological target Clearly defined
[coronary thrombosis]
Uncertain
Clinical benefits of
interventions in published
clinical trial
Beneficial Minimal / no benefit or
deleterious compared with
placebo
ACC / AHA recommendation LEVEL A NONE
2

3. Acute Heart Failure Syndrome(s)
• Acute heart failure (AHF) is defined as a rapid
onset or change in the signs and symptoms of
HF, resulting in the need for urgent therapy.
• Symptoms are primarily the result of severe
pulmonarycongestion due to elevated left
ventricular (LV) filling pressures(with or without
low cardiac output).
• AHFS can occur in patientswith preserved or
reduced ejection fraction (EF).
• Concurrentcardiovascular conditions such as
coronary heart disease (CHD),hypertension,
valvular heart disease, atrial arrhythmias, and/or
noncardiac conditions (including renal
dysfunction, diabetes,anemia) are often present
and may precipitate or contributeto the
pathophysiology of this syndrome 3
ESC Guidelines

4. Mortality %
Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793
4
Mortality in AHFS

5. Proposed classification for patients who present with acute
heart failure syndromes
ACCF/AHA
stage
Explanation of stage
Worsening
chronic HF
(75%)
Stage C C: structural heart disease with
prior or current symptoms of
HF
Advanced HF
(5%)
Stage D D: refractory HF requiring
specialized interventions
De novo HF
(20%)
Stage B most
common, but
also Stage A
Also neither A
nor B
B: structural heart disease but
without signs or symptoms of
HF
A: at high risk for HF but
without structural heart disease
or symptoms of HF
5
Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793

6. • diuretics
• ultrafiltration
Vasodilators
• nitroglycerin
• nesiritide
• nitroprusside
INOTROPES
• dobutamine
• dopamine
• levosimendan
• nitroprusside
Fluid retention or redistribution ?
“dry out” “warm up & “dry out”
Assessment of hemodynamic profile : therapeutic
implications
Adapted from Stevenson L W, Eur Heart j
6

7. HF Management:
Principal changes from the 2008 guidelines
o An expansion of the indication for mineralocorticoid
receptor antagonists (MRAs)
o A new indication for the sinus node inhibitor
Ivabradine
o An expanded indication for cardiac resynchronisation
therapy (CRT)
o New information on the role of coronary
revascularisation in HF (PCI / CABG)
o Recognition of the growing use of ventricular assist
devices (LVAD)
o The emergence of transcatheter valve interventions
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure
7

8. Linking Short- term intervention with long-term benefit:
What is needed?
Better understanding of Acute Heart Failure pathophysiology
MORTALITY
• Myocardial injury [Tn
release]
• Renal dysfunction [CRS]
• Liver dysfunction
PREVENTION OF END-
ORGAN DAMAGE
Congestion
Viable but
dysfunctional
myocardium
Neurohormonal
& inflammatory
activation
Mechanisms which
can be targeted
Metabolic
factors
Hemodynamic
deterioration
[↑LVFP,↓ CO, ↓ PERFUSION]
Vascular resistance
/stiffness ↑
ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 Reviewed by Ponikowski

9. Neurohormones
Norepinephrine
Renin
Angiotensin II
Copeptin
Endothelin
Vascular system
Homocysteine
Adhesion molecules
(ICAM, P-selectin)
Endothelin
Adiponectin
C-type natriuretic
peptide
Inflammation
C-reactive protein
sST2
Tumor necrosis
factor
FAS (APO-1)
GDF-15
Pentraxin 3
Adipokines
Cytokines
Procalcitonin
Osteoprotegerin
Myocardial stress
Natriuretic
peptides
Mid-regional
pro-adrenomedullin
Neuregulin
sST2
Myocardial injury
Cardiac troponins
High sensitivity cardiac troponins
Myosin light-chain kinase 1
Heart-type fatty acid binding
protein
Pentraxin 3
Matrix and cellular
remodeling
Galectin-3
sST2
GDF-15
MMPs
TIMPs
Collagen
propeptides
Osteopontin
Cardio-renal syndrome
Creatinine
Cystatin C
NGAL
ß-Trace protein
Oxidative stress
Oxidized LDL
Myeloperoxidase
Urinary biopyrrins
Urinary and plasma
isoprostanes
Plasma malondialdehyde
HF as a systemic illness & organ cross-talk
9
Nature Review Cardiology
Vol.9 June 12 pg 349
And organ
cross talk

10. Using Biomarkers across the ARC of Heart Failure Hospitalisation
Therapy
decisions
Measure delta
change
Look for
decline
Obtain
baseline
Monitor
therapy
Present to
ED
Decisions
on triage
Determine
prognosis
In-hospital
treatment
Discharge
Outpatient
follow-up
Therapy
decisions
Nov 1, 2013 - Dr Yancy interviews Drs Pang and Januzzi on the use of biomarkers ... Cardiac
Intensive Care Unit, Massachusetts General Hospital, Boston,

11. BNP Status
This pilot study demonstrates that home BNP testing is feasible and that trials using
home monitoring for guiding therapy are justifiable in high-risk patients. Daily weight
monitoring is complementary to BNP, but BNP changes correspond to larger changes
in risk, both upward and downward. (Heart Failure [HF] Assessment with B-type
Natriuretic Peptide [BNP] In the Home [HABIT]; NCT00946231)

12. Clinical RELEVANCE of promising novel biomarkers(AHFS)
Biomarker Diagnosis Prognosis Therapy guidance Cardiac
Production
NT-proBNP and
BNP
++++ ++++ ++ Solely
Serum Sodium + +++ ++ No
Serum Creatinine - +++ ++ No
MR-proANP +++ ++++ Likely similar to NT-
ProBNP/BNP
Solely
sST2 + ++++ ? Not Exclusively
Hs troponin-I
[EFFECT]
+ ++++ ? Solely
MR-proADM - ++++ ? No
Cystatin C - ++++ ? No
NGAL - ++++ ? No
GDF-15 - +++ ? Not Exclusively
β- Trace protein - +++ ? No
Gal-3 - +++ ? Not exclusively
CRP - ++ ? No
TNF-α - ++ ? No
IL-6 - ++ ? No
PTX3 - ++ ? Unknown
MPO - ++ ? Not exclusively
ET-1 - ++ ? Not exclusively
Copeptin - ++ ? No
PCT ++ ++ ++ No
12
Clinical Chemistry 58:1 127–138 (2012)

13. Pulmonary congestion evaluated by lung ultrasound
predicts admission in pts with HF
•97 HF outpts followed up during a
period of 106 ± 12 days
•21 hospitalizations for acute
pulmonary edema
•Multivariate analysis showed that
pulmonary congestion assessed by
lung ultrasound is strongest
predictor of hospital admission
Conclusion – in a HF outpt setting, B-lines assessment by lung
ultrasound may help to identify pts who are most likely to decompensate

14. The four chest areas per side considered for complete eight
zone lung ultrasound examination. These areas are used to
evaluate for the presence of interstitial syndrome. Areas 1 and
2 denote the upper anterior and lower anterior chest areas,
respectively. Areas 3 and 4 denote the upper lateral and basal
lateral chest areas respectively. 14
Echo windows

15. Multiple reflections
of ultrasound beams
ultrasound
beams
ultrasound
beams
Comet-tails
echographic
image
Normal
echographic
image horizontal
lines
Regular
intervalReverberations
Transducer Transducer
Edematous
Interlobular Septa
Normal Interlobular
Septa
Ultrasound Comet-Tail Images: A Marker Of Pulmonary Edema
A: Typical comet-tail artifacts: hyperechogenic, coherent
vertical bundles with narrow basis spreading from the
transducer to the further border of the screen. This
artifact is composed of multiple microreflections of the
ultrasound beam.
A B
B: Normal subject, with regular, parallel,
roughly horizontal hyperechogenic lines due to
the lung-wall interface.
Chest. 2005;127(5):1690-1695.
doi:10.1378/chest.127.5.1690
15

16. HF: Monitoring to predict/ prevent ADHF
admissions
• Devices: Externally applied Impedance Cardiography
(PREDICT study 211 pts)
• Internally placed devices measuring intra thoracic
impedance(PARTNER 2HF: CRT device with Impedance
monitoring): predicted subsequent admission for ADHF
• PA / LA/ LVEDP monitoring devices
Usefulness uncertain for mortality benefit
16

17. Heart Failure Risk Scores
Circ HF 2013
End point: Death/ transplant/ Assist device
• Heart Failure Survival Score(200pts):
– IHD, QRS>120ms, LVEF, Resting HR, mean BP, O2
consumption, ser Na
• Seattle Heart Failure model: (1100pts)
– Age, LVEF, NYHA class, SBP, Diuretic dose, Na+, uric
acid, ser. Chol., lymph. count
- Sex, IHD, QRS >120ms, ICD, CRT, betablockers, ACEI,
Statins, Allopurinol,
• SHOCKED predictor: (900pts):
Age>75, NYHA>II, AF, COPD, CKD, LVEF<20%, DM
• PACE: (900 pts) PVD, Age >70, Creatinine >2, EF < 20%,
• ADHERE registry( for acute mortality): SBP, Ser creatinine
and BUN
• Frankenstein: BNP , 6′WT

18. … We found that in a large, diverse contemporary HF
population, risk assessment was strikingly similar across all
LVEF categories. These data suggest that, although many HF
therapies are uniquely applied to patients with reduced
LVEF, individual prognostic factor performance does not seem
to be significantly related to level of left ventricular systolic
function.
(Circ Heart Fail. 2013;6:635-646.)

19. AHF Treatment Goals
Immediate [ED/ICU/CCU]
•Treat symptoms and restore oxygenation
•Improve hemodynamic and organ
perfusion
•Limit cardiac and renal damage
•Prevent thromboembolism
•Minimize length of ICU stay
Intermediate [in –hospital]
• stabilise pt and optimize treatment
strategy
•Initiate and up-titrate disease modifying
pharmacologic therapy
•Consider device therapy in appropriate
pts
• identify etiology and relevant
comorbidities
Pre-discharge and long term management
•Plan follow up stratergy
•Enroll in ds management programme,
educate and initiate life style adjustments
•Plan to up-titrate / optimise disease
modifying pharmacologic therapy
•Ensure assessed for appropriate device
therapy
•Prevent early readmission
•Improve symptoms
Http://www.Peerviewpress.Com/01/r286

20. 20
While pharmaceutical innovation has been highly successful in reducing mortality in chronic heart
failure, this has not been matched by similar success in decompensated heart failure syndromes.
Despite outstanding issues over definitions and end points, we argue in this paper that an
unprecedented wealth of pharmacologic innovation may soon transform the management of these
challenging patients. Agents that target contractility, such as cardiac myosin activators and novel
adenosine triphosphate-dependent transmembrane sodium-potassium pump inhibitors, provide
inotropic support without arrhythmogenic increases in cytosolic calcium or side effects of more
traditional agents. Adenosine receptor blockade may improve glomerular filtration and diuresis by
exerting a direct beneficial effect on glomerular blood flow while vasopressin antagonists promote
free water excretion without compromising renal function and may simultaneously inhibit myocardial
remodeling. Urodilatin, the renally synthesized isoform of atrial natriuretic peptide, may improve
pulmonary congestion via vasodilation and enhanced diuresis. Finally, metabolic modulators such as
perhexiline may optimize myocardial energy utilization by shifting adenosine triphosphate production
from free fatty acids to glucose, a unique and conceptually appealing approach to the management of
heart failure. These advances allow optimism not only for the advancement of our understanding and
management of decompensated heart failure syndromes but for the translational research effort in
heart failure biology in general.

21. 21
The main stay of AHF Therapy

22. Some new therapeutic agents for acute heart
failure and their potential targets
Agent For patients with these
clinical features
Diuretics, vasopressin
antagonists,
adenosine antagonists
Patients with signs of fluid
overload, high BNP
Vasodilators Normal to high SBP, high BNP
Inotropes Low SBP, signs of
Hypoperfusion
Renal preservation agents Renal dysfunction
Myocardial protection agents CAD, or ongoing ischaemia
22

23. Short- and long-term novel therapies for AHF syndromes
Short term Long term Both
Levosimendan [LIDO, CASINO, SURVIVE] ? ?
Nesiritide[ ASCEND-HF, ROSE-AHF]
Relaxin [RELAX-AHF]
Myosin Activators Omecamtiv Mecarbil
[ATOMIC-AHF]
RyR2 stabilizers/ rycals
Cinaciguat (UIT)
Adenosine regulating agents
Stresscopin
Istaroxime [HORIZON-HF]
Ularitide [TRUE-AHF, SIRIUS II, URGENT]
Urocrotins [UNICORN]
Hypertonic Saline
Ultrafiltration [RAPID-CHF, UNLOAD]
IABP
EECP [PEECH]
CAFA
IMT
Direct renin
Inhibitors (DRI)
[ASTRONAUT]
Macronutrients
Micronutrients
CRT/AICD
Adenosine Antagonists
[PROTECT, REACH UP rolofylline]
Vasopressin Antagonists
[EVEREST, TACTICS-HF]
Digoxin [DIG]
CD-NP
Frontiers in Cardiovascular Medicine EHJ 2010:31;784-793 modified 2013
23

24. Newer Drugs/Devices and
targeted Therapy
Group A
• Managing fluids
• Preserving renal function
Group B
• Contractility
• Diastole/ Vascular Resistance
Group C
• Vasomotion
24

25. Group A
Managing fluids
Preserving renal function
25

26. • Loop diuretics are an essential component of therapy for patients with acute decompensated
heart failure, but there are few prospective data to guide their use.
• In a prospective, double-blind, randomized trial, we assigned 308 patients with ADHF to
receive furosemide administered intravenously by means of either a bolus every 12 hours or
continuous infusion and at either a low dose (equivalent to the patient’s previous oral dose) or
a high dose (2.5 times the previous oral dose).
• DOSE Trial: Among patients with ADHF, there were no significant differences in patients’
global assessment of symptoms or in the change in renal function when diuretic therapy was
administered by bolus as compared with continuous infusion or at a high dose as compared
with a low dose.
• Low dose dopamine increases GFR and RBF. DAD-HF investigated 60 pts randomized to low
dose furosemide (continuous infusion 05 mg/hr) and 5 µg/kg/min per eight hours was found
effective in terms of dyspnoea relief with improved renal function. High dose combination
though was equally effective caused WRF . 20 mg/hr F + 5µg/kg/min Dopamine.
Furosemide
26

27. • The study tests the hypothesis that in patients admitted with acutely decompensated heart failure
(ADHF), achievement of adequate body hydration status with intensive medical therapy, modulated by
combined bioelectrical vectorial impedance analysis (BIVA) and B-type natriuretic peptide (BNP)
measurement, may contribute to optimize the timing of patient’s discharge and to improve clinical
outcomes.
• 300 ADHF pts underwent serial BIVA and BNP measurement. Therapy was titrated to reach a BNP
value of 250 pg/ml, whenever possible.
• Our study confirms the hypothesis that combined BNP/BIVA sequential measurements help to achieve
adequate fluid balance status in patients with ADHF and can be used to drive a ‘‘tailored therapy,’’
allowing clinicians to identify high-risk patients and possibly to reduce the incidence of complications
secondary to fluid management strategies.
27

28. Ultrafiltration
28
• UNLOAD(200pts):
• superior to diuretics as it reduces volume at a rate
more than 500 ml/hr which is Isotonic ultrafiltrate
(both salt and water)
• UF leads to a lower plasma renin, norepinephine
and aldosterone levels as compared to diuretics.
• CARESS study: High risk ADHF pts.: Similar outcome
for weight reduction, but higher rise in ser creatinine,
need for dialysis, and other adverse events…. UF a
new therapy as primary beyond diuresis resistance in
ADHF??
• AVOID HF: Ongoing trial (to be completed in 2016)
J Am Coll Cardiol 2012:59:2145-53

29. Investigational drugs in ADHF
Adenosine A1 receptor antagonist:
Rolofylline
• A1 receptor blockade results in afferent arteriolar
vasodilation which leads to improved GFR and enhanced
diuresis and natriuresis without activation of
tubuloglomerular feedback.
• Preserve GFR, improve diuresis, increase sodium
excretion by kidney.
• Phase 2 trial: better relief of dyspnoea and lesser renal
dysfunction.
• Phase 3 trial: PROTECT:2033 pts.: negative trial with
none of the primary end points significant and safety was
questioned due to neurological side effects: seizure and
stroke.
29

30. • Small studies have indicated that adenosine A1
receptor antagonists enhance diuresis and may
improve renal function in patients with chronic heart
failure or AHF.
• 2,033 AHF pts, volume overload, eCrCl 20 - 80
ml/min, and elevated BNP randomized (2:1) within 24
h of hospital presentation to rolofylline 30 mg/day or
intravenous placebo for up to 3 days.
• In this large, phase III clinical trial, the adenosine A1
receptor antagonist rolofylline did not prevent
persistent worsening renal function in AHF patients
with volume overload and renal dysfunction.
Rolofylline
30
SCr↑
BUN↑

31. •Effects of rolofylline on endpoints in relation to baseline renal function.
•The secondary morbidity/mortality endpoint, the risk of death or cardiovascular or renal
rehospitalization through day 60, was lower in the rolofylline group compared with the
placebo group only in patients with a baseline eCrCl 30 ml/min (hazard ratio: 0.64; 95% CI:
0.43 to 0.95), but not in the other subgroups
Rolofylline
31

32. Group B
Contractility
Diastole/ Vascular Resistance
32

33. Levosimendan enhances contractility by increasing responsiveness of myofilaments to calcium. The
cardiac myosin activator Omecamtiv mecarbil stimulates myosin adenosine triphosphatase
(ATPase), thereby increasing force generation. Istaroxime inhibits activity of plasma membrane
sodium-potassium ATPase and increases the activity of sarcoplasmic/endoplasmic reticulum
calcium ATPase (SERCA).
Mechanism of action of novel contractility-enhancing
medications.
Omecamtiv mecarbil
(Modified from Tavares M, Rezlan E, Vostroknoutova I, et al. New pharmacologic therapies for acute heart failure. Crit Care Med
2008; 36[Suppl]:S112-S120.)
33
Istaroxime
Levosimendan

34. Omecamtiv Mecarbil (OM) is a Novel Selective
Cardiac Myosin Activator
Malik Fl, et al. Science 2011; 331:1439-43
Teerlink JR, et al. Lancet 2011; 378:667-75; Cleland JGF, et al. Lancet 2011; 378:676-83
Mechanochemical Cycle of Myosin
•
• Increases duration of systole
• Increases stroke volume
• No Increase in myocyte calcium
• No change in dp/dtmax
• No increase in MVO2
ATOMIC-AHF Phase 2; 613 pts .X 48 hrs
random IV dose 115; 230; 310 ng/ml.
ATOMIC-AHF Phase 2; 613 pts .X 48 hrs
random IV dose 115; 230; 310 ng/ml.
COSMIC-HF chronic oral therapy;
oral alone or IV to oral transition.
COSMIC-HF chronic oral therapy;
oral alone or IV to oral transition.
Omecamtiv mecarbil increases the
entry rate of myosin into the tightly-
bound, force-producing state with
actin
“More hands pulling on the rope”
34

35. Study Design: Sequential Dosing Cohort
Cohort 1 Cohort 2 Cohort 3
Omecamtiv
Placebo
1:1 Randomization (n≈200)
Omecamtiv
Placebo
1:1 randomization (n≈200)
Placebo
Omecamtiv
1:1 randomization (n≈200)
DMC DMC
Cohort 1 Cohort 2 Cohort 3
15 mg/hr @ 0-4 hr
3 mg/hr @ 4-48 hr
Target: 230 ng/mL
Cmax: 75-500
ng/mL
SET: ~8-55 msec
20 mg/hr @ 0-4 hr
4 mg/hr @ 4-48 hr
Target: 310 ng/mL
Cmax: 125-700
ng/mL
SET: ~14-78 msec
7.5 mg/hr @ 0-4 hr
1.5 mg/hr @ 4-48 hr
Target: 115 ng/mL
Cmax: 30-250 ng/mL
SET: ~3-28 msec
Pharmacokinetic simulations
Teerlink JR, et al. Lancet 2011; 378: 667–75; Cleland JGF, et al. Lancet 2011; 378: 676–83.

36. ATOMIC –AHF Omecamtiv Mecarbil Dyspnea Response
Teerlink J R ESC 2013, Symposium 4503
Response rate
ratio
1.02 1.02 1.41
95% CI [0.74 -1.42] [0.76 – 1.37] [1.02 -1.93]
Response rate ratio : ratio of response rate to placebo with each cohort

37. Omecamtiv Mecarbil : time dependent changes in
echocardiogram measures
Http://www.Peerviewpress.Com/01/r286

38. • Efficacy
– OM did not meet the 1° endpoint of dyspnoea relief
– Appeared to improve dyspnoea in Cohort 3
– Trends towards reduction of worsening HF
• Safety
– Overall SAE profile and tolerability similar to placebo
– Increase in troponin; no clear relationship to OM concentration
– Numerical imbalance in MIs in Cohort 3
– No evidence of pro-arrhythmia
• Pharmacology
– PK similar to healthy volunteers and stable HF patients
– Systolic ejection time significantly increased consistent with MOA
– Small fall in heart rate & rise in systolic BP at higher doses
ATOMIC- AHF Summary
Though at present investigational the drug of the future in AHF
Janccin B: New Heart failure inotrope could be ‘Holy Grail’. IMNG Medical Media September 5, 2013
John J. V. McMurray et al, on behalf of the ATOMIC-AHF Investigators and Patients

39. • Istaroxime is a novel intravenous agent with inotropic and lusitropic properties
related to inhibition of Na/K adenosine triphosphatase (ATPase) and stimulation
of sarcoplasmic reticulum calcium ATPase.
• 120 AHF pts and reduced systolic function. Three sequential cohorts of 40
patients each were randomized 3:1 istaroxime:placebo to a continuous 6-h
infusion. The first cohort received 0.5 g/kg/min, the second 1.0 g/kg/min, and the
third 1.5 g/kg/min istaroxime or placebo.
• In patients hospitalized with HF, istaroxime improved PCWP and possibly
diastolic function. In contrast to available inotropes, istaroxime increased SBP
and decreased HR.
Istaroxime
Mihai Gheorghiade et al JACC 2008:03;015
39
[HORIZON-HF Trial]

40. •Urocortins are a recently discovered group of peptide hormones of the corticotropin
releasing factor family. They bind with a strong affinity to the CRH-R2 receptor, which
is highly expressed in the myocardium and in the vascular endothelium.
•Urocortins exhibit potent inotropic and lusitropic effects on rat and sheep hearts and
activates a group of myocyte protective pathways collectively known as ‘reperfusion
injury salvage kinase’.
•In healthy humans show that brief intravenous infusions of urocortin 2 in healthy
humans induce pronounced dose-related increases in cardiac output, heart rate, and
left ventricular ejection fraction while decreasing systemic vascular resistance;
similar effects were seen in HF patients.
Urocortins
40

41. Stresscopin
Human stresscopin is a corticotropin-releasing factor type 2 receptor
selective agonist and a member of the CRF peptide family. Stimulation of
CRFR2 improves cardiac output and LVEF.
62 pts with HF and LVEF ≤ 35% were instrumented with a pulmonary
artery catheter and randomly assigned (ratio 3:1) to receive an
intravenous infusion of stresscopin or placebo. The main study was an
ascending dose study of three doses (5, 15, and 30 ng/kg/min) of study
drug or placebo administered in sequential 1 h intervals (3 h total).
Statistically significant increases in CI and reduction in SVR were
observed with both the 15 ng/kg/min (2 h time point) and 30 ng/kg/min (3
h time point) doses of stresscopin without significant changes in HR or
SBP. No statistically significant reductions in PCWP were seen with any
dose tested in the primary analysis, although a trend towards reduction
was seen.
In HF patients with reduced LVEF and CI, ascending doses of stresscopin
were associated with progressive increases in CI and reductions in SVR
without significant effects on PCWP, HR, or SBP.
41

42. Group C
Vasomotion
42

43. Vaso active drugs in ADHF
Relaxin: Serelaxin
• A recombinant human relaxin -2- a naturally occurring peptide that
regulates maternal adaptations
• RELAX AHF:1160 pt. of ADHF with preserved SBP >115 mmHg.
• Serelaxin 30 ug/kg/day x48 hrs or Placebo
• Significant improvement in dyspnoea scale
• No impact on short term mortality/ HF readmission at 60 days,
though 180 day mortality was significantly lower.
• Hypotensive episodes higher but renal dysfunction less than
placebo group
• No limitation: dobutamine milrinone (increase intercellular calcium
in myocytes leading to tachycardia and arrhythmias, levosimendon
calcium sensitiser causes atrial and ventricular arrhythmias, and
like milrinone may be limited by hypotension.
• FDA grants Breakthrough Therapy designation to Novartis'
serelaxin (RLX030) for acute heart failure.
43

44. Biology of Relaxin and Potential Beneficial Effects in HF
Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M - Curr Heart Fail Rep (2010)
Endogenous peptide
associated with
pregnancy, and acts
through relaxin receptor:
reduce inflammation,
decrease fibrosis,
attenuate ventricular
remodeling, increase
vasodilation, promote
renal blood flow,
increase vascular
endothelial growth
factor, and angiogenesis.
↓Inflammation↓Inflammation ↓Fibrosis↓Fibrosis ↑Vasodilation↑Vasodilation Renal effectsRenal effects AngiogenesisAngiogenesis
Relaxin ReceptorRelaxin Receptor
RelaxinRelaxin
Pregnancy associated endogenous peptide
Relaxin ReceptorRelaxin
44

45. Pre-RELAX-AHF : Rapid dyspnea improvement through
24 hours [Likert Scale]
Teerlink J R Lancet 2009,373:1429-1439

46. RELAX-AHF : Cardiovascular and All Cause Mortality
Teerlink J R Lancet 2013, 381:29-39

47. RELAX-AHF : Biomarker Changes
Metra M Et Al J Am Coll Cardiol 2013, 61: 196 -206

48. RELAX-AHF
• 1161 pts with AHF
• 19% improvement in dyspnea
• Decreases in worsening HF
• Improvement of in-hospital signs and symptoms of HF
• Decreased length of hospital stay
• No significant difference in second primary efficacy endpoint of the
proportion of pts with dyspnea relief
• No significant effect on secondary endpoints of cardiovascular death
or hospital readmission for HF or renal failure [RELAX –AF was not
powered as a mortality trial]
Teerlink J R Lancet 2013, 381:29-39

49. Seralaxin
• Increased renal function
• Improved vascular compliance
• Improved cardiac output
Beneficial effects on dyspnea and post-discharge clinical outcomes

50. • Cinaciguat (BAY 58-2667) is a soluble guanylate cyclase (sGC, second messenger that internalizes the
message carried by intercellular messengers such as peptide hormones and NO) activator that is
being developed as a first-in-class treatment for acute decompensated heart failure (ADHF). It acts
independently of the sGC ligand nitric oxide.
• Cardioprotective effects in animal models, and pilot clinical studies found that it was well tolerated,
unloaded the heart and increased cardiac output.
• This placebo-controlled, randomized, double-blind, multicenter, international phase IIb study
investigated the safety and efficacy of intravenous cinaciguat (per-protocol) as add-on to standard
therapy in 139 patients with ADHF (NYHA functional class III and IV; pulmonary capillary wedge
pressure [PCWP] ≥ 18 mmHg).
• Cinaciguat rapidly and significantly reduced PCWP and PVR and increased cardiac output in patients
with ADHF, without impairing cardiac or renal function. Hypotension occurred in some patients;
further dose titration studies are therefore required to establish the optimal dosing strategy for this
promising new therapy.
Cinaciguat
JACC Mar 9,2010 Vol:55 issue 10A
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51. These molecules have been engineered to combine the beneficial aspects of different
natriuretic peptides into a single molecule while minimizing potentially negative
actions.
CD-NP is a combination of C-type natriuretic peptide (CNP) and Dendroapsis NP
(DNP).
Although lacking natriuretic effects, CNP is a more selective venodilator than BNP,
thus reducing the risk of significant hypotension. On the other side, DNP possesses
significant natriuretic activity, at the expense of possible hypotensive effects.
The chimeric peptide CD-NP combines the favourable natriuretic effects of DNP with
the venodilatory profile of CNP, reducing the risk for harmful side effects.
Preliminary studies in AHFS patients are ongoing.
Chimeric natriuretic peptides
51

52. Adenosine regulating agents
•This new class of drugs, whose prototype is represented by acadesine, has been
developed to mimic the protective effects of adenosine during ischaemia.
•Acadesine exerts its pharmacological actions by increasing adenosine bioavailability
and by activating 50adenosine monophosphate (AMP) signalling cascade via its
metabolite 5-aminoimidazole-4-carboxamide riboside (ZMP).
•The first mechanism leads to multiple anti-ischaemic effects (maintenance of
endothelial function and vasodilation, inhibition of platelet aggregation and neutrophil
activation), whereas the latter ameliorates glucose uptake and free fatty acid
oxidation thus increasing ATP synthesis. Importantly, acadesine exerts its actions
only in areas undergoing net ATP catabolism (such as ischaemic tissues) thereby
avoiding potentially harmful peripheral vasodilator effects.
Acadesine
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53. • Nesiritide is approved in the United States for early relief of dyspnea in patients with acute
heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the
mortality associated with this agent.
• We randomly assigned 7141 patients [ASCEND-HF trial]
• Co-primary end points were the change in dyspnea at 6 and 24 hours, and the composite end
point of rehospitalization for heart failure or death within 30 days.
• Nesiritide was not associated with an increase or a decrease in the rate of death and
rehospitalization and had a small, nonsignificant effect on dyspnea when used in
combination with other therapies.
• It was not associated with a worsening of renal function, but it was associated with an
increase in rates of hypotension. On the basis of these results, nesiritide cannot be
recommended for routine use in the broad population of patients with acute heart failure.
Nesiritide
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54. Ularitide
• Synthetic form of Urodilantin: human natriuretic
peptide produced in kidney: induces natriuresis
and diuresis. Also potent vasodilator( increases
intracellular cyclic GMP) and increased renal
blood flow) : Two double blind studies have
shown favorable outcome in ADHF by symptom
improvement and hemodynamics.
• Phase 3 trial(TRUE-AHF >2110 pts) - ongoing
study.
54

55. Summary• AHFS is a complex condition with heterogenous pathophysiology
and varied etiology with unpredictable and often stormy course.
• Present management rests on therapeutic optimisation of
congestion, perfusion & protection against kidney injury & finally
myocardial preservation and enhancement. Needless to point out,
too much reliance on inotropics and pressor amines could be
ominous.
• Simplistic biometrics like HR, B.P. and eGFR are inexpensive and
dependable. Measures of clinical assesment while BNP and other
monitoring devices may be superior but often unaffordable and
expensive and make HF management imposible.
• The safe path on part of ED Physician is to follow updated guideline
pathways till future breakthrough and safe newer drugs are
available.
• All stabilised discharged pts must have GDMT/ Devices/
revascularisation as could be indicated. Multi disciplinary care
approach is inevitable at all stage.
• Serelaxin, Omecamtiv Mecarbil , Istaroxime & Ularitide appear to be
new drugs of the near future.
• … Future trials conducted in aHFs must abandon the ‘one-sizefits-
all’ approach in favor of an approach that takes into account the
varied and distinct pathophysiologies of aHFs.
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56. 56

59. (1) Symptom relief.
(2) Measures of congestion relief (i.e. improvement in
clinical signs).
(3) Index hospitalization data (e.g. length of stay).
(4) Prevention of end-organ damage (heart and
kidney).
(5) Post-discharge: death and rehospitalization data.
Federal Drug Administration (FDA) Study Group as a general
guide for choosing the components of the endpoints to be
included when testing different types of drugs in different patient
subgroups, although not all of them would be necessary in a
single trial
Position Statement European Journal of Heart Failure (2011)
59