advances in pharmocotherapy of heart failure

1. Recent advances in management
of heart failure
Rahul arora
Junior resident 3

2. DEFINITION OF HF
Heart Failure is a pathophysiological state
in which the heart is unable to pump
blood at a rate to commensurate with
the requirements of the metabolizing
tissues (systolic failure) or can do so only
with elevated filling pressures (diastolic
failure ).
Eugene Braunwald

3. CLASSIFICATION OF HEART FAILURE
• DURATION:
• ACUTE
• CHRONIC
• PATHOPHYSIOLOGY:
• SYSTOLIC
• DIASTOLIC
•
•EJECTION FRACTION
•REDUCED
•NORMAL
WHY THIS IS IMPORTANT?

4. CurrentTreatment of Acute Heart
Failure
Diuretics
Reduce
fluid
volume
Vasodilators
Decrease
Preload
And
Afterload
ionotropes
Augment
Contract-
ility
Lasix
PDE 3 Inhibitors:
milrinone
Dobutamine,
norepinephrine,
levosimendan
Lasix
Ntg: sl, top, iv
MSO4
ACEi
BiPAP/CPAP

5. Norepinephrine
Endothelin
Aldosterone
RAAS
Vasopressin
Natreuretic peptide
Nitric oxide
Bradykinin

6. Soluble Guanylate Cyclase Activators
Cinaciguat : AHFS.
organic nitrates = Cinaciguat
DIRECTLY activates the soluble form of guanylate cyclase in
smooth muscle cells, thus leading to the synthesis of cGMP and
subsequent vasodilation
In AHFS - periods of increased oxidative stress, a significant
proportion of heme-bound iron may become oxidized,
potentially blunting the effects of nitric oxide donors.
cinaciguat is a heme-independent soluble guanylate cyclase
activator, with more predictable vasodilator response in
conditions of elevated oxidative stress.
cinaciguat improve hemodynamics in patients with AHFS. however,
at high doses, it has been associated with significant hypotension
but this was not associated with other major adverse events,
nor did it affect mortality at 30-days postdischarge.
The effects of cinaciguat are now being investigated in the
COMPOSE program that includes three phase II trials in
patients admitted with AHFS

7. Chimeric Natriuretic Peptides
 Nesiritide:
◦ natriuresis, vasorelaxation, inhibition of renin and aldosterone, inhibition
of fibrosis, and increased lusitropy.
◦ iv infusion of nesritide ; decrease in arterial and venous pressures,
increase in cardiac output, and suppression of neurohormonal
activation.
◦ FDA approved for use in ADHF (ASCEND HF Trial) with hypotension
being important side effect.
 Chimeric Natriuretic Peptide (CD-NP) combines the beneficial
aspects of C-type natriuretic peptide (CNP) with dendroaspis NP
(DNP) with absence of hypotension.
◦ CNP lacks the natriuretic effects of ANP or BNP but has the benefit of
less hypotension because it is a primary venodilator, as opposed to BNP,
which dilates both arteries and veins.
◦ DNP has significant natriuretic effects but also causes hypotension.
◦ CD-NP ideally combines the lack of unwanted arterial vasodilation of
CNP with the positive natriuretic effects of DNP.
◦ Preliminary studies in AHFS are ongoing (ClinicalTrials.gov Identifier
NCT00839007)

8. Ularitide
 a synthetic analogue of urodilatin, a natriuretic and diuretic
hormone of the family of A-type natriuretic peptides produced
by tubular renal cells.
 Besides the effects on sodium and water handling, ularitide
induces peripheral arterial vasodilation by activating the cGMP
pathway.
 The effects of a short-term infusion of ularitide in patients with
ADHF have been investigated in the SIRIUS (Safety and Efficacy
of an Intravenous Placebo-Controlled Randomized Infusion of
Ularitide in a Prospective Double-Blind Study in Patients with
Symptomatic Decompensated Chronic Heart Failure) trials I
and II.
 Compared with placebo, ularitide improved clinical status,
hemodynamics, and neurohormonal profile; however, it was
associated with significant hypotension.

9. Direct Renin Inhibitors: aliskerin
 inhibitor of the first enzymatic step in the RAAS
cascade, leading to a profound suppression of this
neurohormonal system.
 Aliskiren, the first oral direct renin inhibitor on
the market and currently approved for the
treatment of hypertension, is undergoing a phase
III trial (ASTRONAUT) to test whether the
addition of a direct renin inhibitor to standard
therapy delays time to events, including
cardiovascular death or HF rehospitalization
within 6 months in patients hospitalized for AHFS
and ejection fraction <40%.[127] (ClinicalTrials.gov
Identifier NCT00894387).

10. Adenosine Antagonists
 The glomerular filtration rate of the kidney is adapted to changes in the sodium
concentration in the early distal tubule through the mechanism termed tubuloglomerular
feedback.Tubuloglomerular feedback refers to a series of events whereby changes in the
Na+, Cl−, and K+ concentrations in the tubular fluid are sensed by the macula densa
through the Na+-K+-2Cl− cotransporter.An increase or decrease in Na+, Cl−, and K+
uptake elicits inverse changes in glomerular filtration rate by altering the vascular tone,
predominantly of the afferent arteriole. Studies indicate that adenosine (through activation
of the adenosine A1 receptor) and possibly ATP mediate this mechanism, which is
increased in HF. Given that adenosine levels are increased in HF patients and may
contribute to the progression of renal dysfunction, adenosine A1 receptor antagonists
have been developed to increase renal blood flow and to enhance diuresis without
activating the tubuloglomerular feedback. Rolofylline is a highly selective adenosine A1
receptor antagonist that has been studied in patients with HF. Despite the positive trends
seen in the PROTECT pilot study,[128] the phase III PROTECT II trial showed only a mild
benefit on symptoms, but no effects on renal protection and other prespecified outcomes,
and was associated with more central nervous system events compared with placebo
(ClinicalTrials.gov Identifier: NCT00354458).[129] Given these results, it is doubtful that
these agents will undergo further evaluation in AHFS

11. Endothelin Antagonists
 Endothelin 1
◦ most powerful endogenous vasoconstrictor
◦ produced by the vascular endothelial cells.
◦ exerts its effects by
 ETA
 ETB, located on the vascular smooth muscle cells, resulting in significant
systemic arterial vasoconstriction.
 Tezosentan, a nonselective ETA-B antagonist, has been shown
to improve hemodynamics in patients with AHFS.
 TheValue of Endothelin Receptor Inhibition with Tezosentan
in Acute Heart Failure Study (VERITAS) studied more than
1400 patients admitted with AHF in an international trial
The addition of intravenous tezosentan to standard therapy
did not improve symptoms or decrease mortality at 7 days
after randomization.[132]

12. Cardiac Myosin Activators
 Cardiac myosin activators (CMA) increase, specifically, cardiac myosin ATPase, enhancing the
release of inorganic phosphate, which strengthens binding between myosin and actin, the
fundamental power-stroke leading to shortening of the cardiac sarcomere.
 CMAs increase the efficiency with which ATP is utilized without increasing ATP consumption by
increasing the number and duration of actin-myosin crossbridges for each ATP molecule
consumed.This prolongs systole but not the rate at which force is developed.
 How it is different from other
 Unlike conventional inotropic agents that generally increase ATP consumption, increase the
velocity of contraction, and rate of force generation, but may shorten the duration of systole.
 Importantly, CMAs do not possess phosphodiesterase activity, do not increase diastolic calcium
concentrations and can increase cardiac performance in patients receiving beta-blockers.
 Preliminary data from studies of the CMA, omecamtiv mecarbil (CK-1827452), given
intravenously either to healthy volunteers or to patients with stable, mild-to-moderate HF show
marked dose-dependent increases in systolic ejection time, with a reflex decline in heart rate at
higher concentrations.
 Concentration-dependent increases were also observed in Doppler-derived stroke volume,
fractional shortening, and ejection fraction. OM was well tolerated with no serious adverse
events at intended doses in this group of HF patients.OM is well absorbed from the gut and an
oral formulation is being developed.

13. Ionotropes

14. Istaroxime
 has dual action on the myocyte:
◦ by inhibition of the membrane-bound Na+,K+-ATPase (similar to digoxin) and ;
◦ by enhancing the activity of the sarcoendoplasmic reticulum Ca2+-ATPase type 2a (SERCA-2a).
 These distinct mechanisms respectively result in positive inotropic effects, and enhanced
lusitropic effect.
 Experimentally, istaroxime appears to improve both systolic and diastolic function, to
reduce LV dimension in diastole, and to increase SBP. These beneficial effects were not
associated with an increase in myocardial oxygen consumption.
 The HORIZON-HF (A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in
Patients with Worsening HF and Reduced LV Systolic Function) studied 120 patients
admitted with AHF and decreased ejection fraction. The addition of istaroxime to
standard therapy lowered PCWP and heart rate and increased SBP. The higher infusion
dose (1.5 ?g/k/min) increased cardiac index and reduced LV end-diastolic volume. There
were no changes in neurohormones, renal function, or troponin I levels during the
short 6-hour infusion.
 This agent is being developed for patients presenting with AHFS and low cardiac output
because the majority of inotropes that are often required for these patients tend to
decrease blood pressure and have significant side effects.

15. Stresscopin
 member of the urocortin family,
 strong affinity to the corticotropin-releasing hormone receptor 2,
which is highly expressed in the myocardium and in the vascular
endothelium.
 Urocortins exhibit potent inotropic and lusitropic effects on rat and
sheep heart and activate a group of myocyte protective pathways
collectively known as reperfusion injury salvage kinase (RISK).
 Studies in healthy volunteers and HF patients showed that brief
intravenous infusions of urocortin 2 induced pronounced dose-related
increases in cardiac output, heart rate, and LV ejection fraction while
decreasing systemic vascular resistance. The hemodynamic effects of
stresscopin in patients admitted with AHFS is being studied now in a
Phase IIa trial.
 This molecule is presently being studied for its hemodynamic effects in
patients admitted with AHFS (ClihicalTrials.gov NCT01120210).

16. Relaxin
 major hormone of pregnancy
 powerful systemic and renal vascular effects.
 recent dose-finding phase IIb study Pre-RELAX-AHF
assessed the dose-response effects of 48-hour infusion
of relaxin versus placebo on symptom relief, other
clinical outcomes, and safety in patients with AHF and
normal to increased blood pressure.
 Relaxin therapy was associated with improvement in
dyspnea and other clinical outcomes, with an acceptable
safety profile.
 Relaxin is currently being evaluated in the RELAX-AHF
(Efficacy and Safety of Relaxin for the Treatment of
Acute Heart Failure) phase II/III clinical trial
(ClinicalTrials.gov Identifier: NCT00520806).