By
Mohamed Gamal Abdel-Aziz
Luxor, 16-1-2014
Background.
Why we need new inotropes?
Current new drugs.
Role
of
inotropes
in
the
guidelines.
5. Future directions.
6. Take home messages.
1.
2.
3.
4.
1
 Inotropic agents are drugs that improve
cardiac output and peripheral perfusion in
patients with systolic dysfunction and low
cardiac output. However, there is evidence
of increased mortality and adverse effects
associated with current inotropic agents.
 These adverse outcomes may be ascribed
to patient selection, increased myocardial
energy
expenditure
and
oxygen
consumption, or to specific mechanisms of
action.
Progress in Cardiovascular Diseases 54 (2011) 97–106
Inotropic mechanism
Drugs
Sodium-potassium-ATPase inhibition
Digoxin
Β-Adrenoceptor stimulation
Dobutamine, dopamine
Phosphodiesterase inhibition
Enoximone, milrinone
Calcium sensitization
Levosimendan
Sodium-potassium-ATPase inhibition
plus SERCA activation
Istaroxime
Acto-myosin cross-bridge activation
Omecamtiv mecarbil
SERCA activation
Gene transfer
SERCA activation plus vasodilation
Nitroxyl donor;
CXL-1020
Ryanodine receptor stabilization
Ryanodine receptor
stabilizer; S44121
Energetic modulation
Etomoxir, pyruvate
Hasenfuss G, Teerlink JR et al, Eur Heart J. 2011 Aug;32(15):1838-45.
2
 Digoxin has been used in patients with Chronic HF for
>200 yrs.
 It remains an important agent in the modern era.
 Its role in the treatment of acute HF is unclear.
In a study involving 60 patients with acute MI with
HF
IV Digoxin vs Dobutamine
 Digoxin
 No effect on LV filling pressure.
 Slight effect on cardiac index & stroke work index (in contrast
to marked favorable hemodynamic effects produced by IV
dobutamine).
Dobutamine: Post-hoc Analysis of the
FIRST Trial
 The results of several small clinical trials
demonstrated that dobutamine provides
symptomatic, hemodynamic and functional
improvement in patients with HF.
 However, some data from clinical studies
indicated that dobutamine may be associated
with increased mortality in patients with HF.
 Contraindicated in patients with:
 Idiopathic hypertrophic subaortic stenosis.
 Uncorrected hypovolemia.
 low cardiac output secondary to
uncorrected hypovolemia.
ACEIs=angiotensin-converting enzyme inhibitors; HF=heart failure; i.v.=intravenous
1. O’Connor et al. Am Heart J 1999;138:78–86.
3
FIRST trial: Dobutamine may be
detrimental to patients with advanced HF
Conclusions:
 Patients with advanced HF treated with
dobutamine may have a greater risk of
clinical events and mortality compared
with patients not receiving dobutamine.
 Dobutamine may be of limited benefit,
and may actually cause harm, to patients
with advanced HF.
HF=heart failure
O’Connor et al. Am Heart J 1999;138:78–86
4
 No randomized controlled trials studying
the effects of short-term, intermittent, or
long-term
continuous
infusion
of
dopamine.
 Major side effect of dopamine – tachycardia
(More pronounced with dopamine than
Dobutamine).
 A new or unexplained tachycardia or
arrhythmia in a patient receiving “lowdose” dopamine - suspect inappropriately
high dopamine infusion rate.
Levosimendan is a Calcium Sensitizer
N
 Levosimendan belongs to
a new class of drugs –
the calcium sensitizers.
C
Levosimendan
N
N
C
NH
HN
O
N
 Mechanism of action:
H3C
H
1. Calcium sensitization through binding to calciumsaturated cardiac troponin C, which increases cardiac
contractility without affecting relaxation.
2. Opening of KATP channels in vascular smooth muscle
cells, which results in vasodilation.
3. Opening of KATP channels in cardiomyocyte
mitochondria, which protects the heart against
ischemia-reperfusion injury.
KATP channels=adenosine triphosphate-sensitive potassium channels
Simdax® Product Monograph, Orion Pharma, 2012
5
Regimens of intravenous inotropes therapy:
 Short-term therapy:
•
•
Infused over several hours to a few days
in combination with diuretics.
Discontinued when patients are clinically
stable.
 Intermittent intravenous therapy:
•
4- to 6-hour pulse infusion for several
days per /wk or as a single 24- to 72-hour
infusion once weekly
 Continuous intravenous infusions.
Levosimendan versus Dobutamine:
LIDO trial.
CASINO trial.
SURVIVE–W trial.
6
Levosimendan Infusion versus
Dobutamine (LIDO) Study
 Enrolled 600 patients hospitalized with NYHA class IV HF.
 Randomized to Levosimendan, Dobutamine, or placebo 48
hrs after presentation.
 Primary end point of the study was mortality at one month,
6 months, or 1 yr.
Dobutamine was associated with lower 6-month survival compared with
Levosimendan or placebo in patients with decompensated low output HF
Heart Failure Update 2004 and Eur J Heart Fail.
7
Survival of Patients with Acute Heart Failure
in Need of Intravenous Ionotropic Support (SURVIVE) trial
JAMA. 2007;297:1883-1891.
Randomized Multicenter Evaluation of Intravenous
Levosimendan Efficacy Versus Placebo in the Short-Term
Treatment of Decompensated Heart Failure (REVIVE)
 Large-scale, placebo-controlled, double-blind study.
 in 600 patients hospitalized for AHFS with LVEF <0.35
& dyspnea at rest who required intravenous diuretics.
 Randomized to receive either Levosimendan or placebo
in addition to standard therapy.
REVIVE-1 data ( n=100) - Levosimendan treatment A/W
 Improvement in the composite end point at 24 hrs and 5
days.
 A significant reduction in BNP levels at 24 hours and 5
days.
 Shorter lengths of initial hospitalization.
8
Randomized Study on Safety and Effectiveness of
Levosimendan in Patients with Left Ventricular Failure
Due to an Acute Myocardial Infarction (RUSSLAN)
9
Altenberger J, Parissis JT. Et al, Eur J Heart Fail. 2010 Feb;12(2):186-92.
Levosimendan treatment did not significantly improve results in the six
minute walk test and the KCCQ score compared with placebo
Six min walk test
20% increase
p=0.69
KCCQ score
15% increase
p=0.56
p=0.71
35
25
33.3
31.7
28.1
28.1
8 weeks
24 weeks
20
15
10
% patients
% patients
30
5
0
Levosimendan
50
45
40
35
30
25
20
15
10
5
0
46.0
p=1.00
42.1
42.9 42.1
8 weeks
24 weeks
Placebo
KCCQ=Kansas city cardiomyopathy questionnaire
Altenberger J, Parissis JT. Et al, Eur J Heart Fail. 2010 Feb;12(2):186-92.
10
 Levo-Rep is the largest trial on repetitive,
ambulatory administration of inotropes in endstage heart failure.
 Levosimendan was not effective at improving the
primary endpoint compared with placebo (sixminute-walk-test ≥20%; KCCQ clinical summary
score ≥15%).
 Levosimendan did improve event-free survival by
50% compared with placebo.
 Levosimendan appears to be well-tolerated with a
good safety profile, even if administered on an
outpatient basis.
KCCQ=Kansas city cardiomyopathy questionnaire
Altenberger J, Parissis JT. Et al, Eur J Heart Fail. 2010 Feb;12(2):186-92.
 Objective: To test the hypothesis that levosimendan
is more effective than intra-aortic balloon pump
(IABP) support in cardiac surgical patients with low
left ventricular ejection fraction to decrease cardiac
troponin I levels (primary endpoint) and improve
hemodynamics.
 Conclusions: The infusion of levosimendan after
anesthesia induction in cardiac surgical patients
contributes to lower cardiac troponin I levels and
improved
hemodynamics
compared
with
a
preoperative IABP.
Journal of Cardiothoracic and Vascular Anesthesia, Vol 26, No 4 (August), 2012: pp 596-603
11
A subject of controversy.
Lack of prospective, placebo
controlled trials.
Lack of alternative therapies.
ESC HF Guidelines-2012
Recommendations for inotropes in AHF
12
Future inotropic compounds: the ryanodine receptor (RyR) stabilizers reduce sarcoplasmic
reticulum leak through the ryanodine receptor and reconstitute ryanodine receptor channel
function. Istaroxime inhibits sodium-potassium-ATPase and stimulates SERCA2a. Cardiac
myosin activators promote transition of cross-bridges from the weakly to the strongly bound
force-producing state. Energetic modulators improve myocardial energetics through switching
from fatty acid to glucose oxidation or by other mechanisms including means to increase the
cellular phosphorylation potential. Virus-mediated sarcoplasmic reticulum calcium pump gene
transfer (AV-SERCA) increases sarcoplasmic reticulum calcium uptake. Nitroxyl (HNO) may
increase sarcoplasmic reticulum calcium uptake by modification of sarcoplasmic reticulum
calcium pump and/or phospholamban (PL).
Hasenfuss G, Teerlink JR et al, Eur Heart J. 2011 Aug;32(15):1838-45.
 Positive inotropic + positive lusitropic properties.
 Inhibit sarcolemmal Na-K ATPase
→ cytosolic Ca accumulation → +ve inotropism
 Stimulate SR calcium ATPase.
→ rapid sequestration of cytosolic calcium into
the SR during diastole → Promotes myocardial
relaxation.
 Improves
myocardial
contractility,
hemodynamics, LVEF.
 Improves diastolic relaxation in the absence of
pro arrhythmic or ischemic effects.
Aditya S, Rattan A et al, J Pharmacol Pharmacother. 2012 Oct;3(4):353-5.
13
Trial design: Patients admitted with acute decompensated HF were
randomized to istaroxime, an inotropic and lusitropic agent (n = 89),
versus placebo (n = 31).
(p = 0.048)
(p = 0.001)

0
-0.2
cm/sec
mm Hg
0.5
Results

-2

-4
-0.7
Change in E’
velocity
Istaroxime
Change in E’ velocity: 0.5 cm/sec for
istaroxime vs. -0.7 cm/sec for placebo
(p = 0.048).
Change in pulmonary capillary wedge
pressure: -3.7 mm Hg vs. -0.2 mm Hg
(p = 0.001), respectively.
Cardiac index: 0.12 L/min/m2 vs. 0.03
L/min/m2 (p = 0.57), respectively.
Conclusions
-3.7

Change in
pulmonary capillary
wedge pressure
Placebo

Istaroxime may be beneficial in
improving
hemodynamics
and
diastolic function in patients with
acute decompensated HF.
Future studies are needed to address
the impact on clinical outcomes from
this agent.
Shah SJ, et al. Am Heart J. 2009 Jun;157(6):1035-41.
Omecamtiv is a cardiac muscle myosin
activator that increases cardiac output
 Omecamtiv can be administered
intravenously or orally.
 Omecamtiv is a small molecule
activator of cardiac myosin:
 Stimulates the activity of
cardiac muscle myosin without
increasing intracellular calcium
concentration.
o
o
CH3
N
N
o
N
H3C
F
NH
NH
Omecamtiv
 Lengthens

the systolic ejection time rather than
increasing the velocity of cardiac contraction.
The end result is increased cardiac muscle
contractility and improved cardiac output.
i.v.=intravenous
http://www.cytokinetics.com/; accessed June 2013
14
Omecamtiv is also currently being evaluated in
the ongoing COSMIC-HF Phase II clinical trial
 COSMIC-HF: Chronic Oral Study of Myosin activation to
Increase Contractility in Heart Failure.
 Multicentre, randomized, double-blind, placebo-controlled
Phase II trial to evaluate the efficacy and safety of an oral
modified release formulation of omecamtiv compared with
placebo in patients with HF and left ventricular systolic
dysfunction.
 The trial is ongoing and currently recruiting patients; the
estimated enrolment is 420 patients.
 The expected completion date is June 2015.
 Key inclusion criteria:
 history of chronic HF.
 treated with pharmacological therapy for ≥4 weeks.
 history of LVEF ≤40%.
 elevated NT-proBNP.
HF=heart failure; i.v.=intravenous; LVEF=left ventricular ejection fraction;
NT-proBNP=N-terminal pro-B-type natriuretic peptide
http://clinicaltrials.gov/ct2/show/NCT01786512?term=cosmic-hf&rank=1; accessed June 2013
Gene
therapy
approaches
to
increase
sarcoplasmic reticulum calcium pump activity —
stimulating the calcium pumps


A number of studies have been performed to evaluate the possibility of
SERCA gene transfer.
Up-regulating SERCA2a, the cardiac isoform of the sarco-endoplasmic
reticulum calciumATPase, in different animal models:
 improvement in systolic and diastolic function1,2 and may reduce
arrhythmias.3
 improves function and reduces the remodelling processes.4
The Calcium Up-regulation by Percutaneous Administration of Gene Therapy in
Cardiac Disease (CUPID) study, enrolled with a total of 39 patients with severe
heart failure randomized to adeno-associated virus-mediated transfer of
SERCA2a or placebo, has been recently presented.5
• As a phase II study, there was no single primary endpoint, but when a
broad range of efficacy and safety endpoints were evaluated, there were
very encouraging signals in improvement in symptoms and ventricular
remodelling.6
1.
2.
3.
4.
5.
6.
15
Sakata S. et al, Am J Physiol Heart Circ Physiol 2007;292:H2356–H2363.
Schmidt U. et al, Circulation 2000;101:790–796.
del Monte F. et al, Proc Natl Acad Sci USA 2004;101:5622–5627.
Beeri R. et al, Circ Heart Fail 2010;3:627–634.
Jaski BE. et al, J Card Fail 2009;15:171–181.
Stiles S. CUPID: first-in-human gene therapy for advanced heart failure promising in small study. http://www.theheart.org/article/1083549.do.
Nitroxyl—nitric oxide’s soon-to-be
famous sibling?
 Early in vitro experiments suggested positive
inotropic and lusitropic properties of HNO.
 Subsequent studies in healthy and heart failure dog
models with the HNO donor Angeli’s salt (Na2N2O3)
demonstrated significant improvements in loadindependent LV contractility, associated with
reductions in pre-load volume and diastolic
pressure.1,2
 Clinical studies are currently being conducted
(clinicaltrials.gov
NCT01092325,
clinicaltrials.gov
NCT01096043).
1. Paolocci N. et al, Proc Natl Acad Sci USA 2013;100:5537–5542.
2. Paolocci N. et al, USA 2011;98:10463–10468.
16
Ryanodine receptor stabilizers—
stopping the leak
 Several compounds that reduce calcium leak through the
RyR have been developed.
 JTV519, a 1,4-benzothiazepine, was one of the first
compounds that restored abnormal RyR function and
preserved contractile performance in heart failure models.1,2
 improved diastolic and systolic function in isolated
myocardium from failing human hearts.3
 inhibitor properties on L-type calcium channels,
potassium channels, and possibly other transporters.
Subsequently, molecules that may specifically act on
cardiac RyRs have been Cardiac inotropes developed,
including S44121.
 The study drug S44121 is currently being evaluated in a
phase II multicentre clinical study (ISRCTN Registration
number 14227980).
1. Yano M. et al, Circulation 2003;107:477–484.
2. Lehnart SE. et al, Cell 2005; 123:535–536.
3. Toischer K.et al, Basic Res Cardiol 2010;105:279–287.
 Pyruvate has numerous molecular
effects that may contribute to its
inotropic action.
 An increase in phosphorylation
potential.
 Reduction
of
inorganic
phosphate.
 Decrease in hydrogen ion
concentration.
 Modulation of the cytosolic
redox state.
 The most important mechanism for
its inotropic action may be an
increase in the phosphorylation
potential and an increase in free
energy of ATP hydrolysis.
Hasenfuss G, Teerlink JR et al, Eur Heart J. 2011 Aug;32(15):1838-45
17
Hasenfuss G et al. Circulation 2012;105:194-199
 Use of current intravenous inotropes has
a risk for:
• Hypotension.
• Atrial and ventricular arrhythmias.
• Increased post discharge mortality.
 Development of drugs that improve
contractility without producing calcium
overload represents an important but
unaccomplished
goal
in
the
management of patients with AHFS/LO.
 There is an unmet need for new agents
to safely improve cardiac performance
(contractility and/or active relaxation) in
this patient population.
18
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