Inotropic therapy for heart failure

INOTROPIC THERAPY FOR HEART
FAILURE
Dr RAGHU KISHORE GALLA
INOTROPIC THERAPY FOR HEART FAILURE

Stages, Phenotypes and Treatment of HF
STAGE A
At high risk for HF but
without structural heart
disease or symptoms of HF
STAGE B
Structural heart disease
but without signs or
symptoms of HF
THERAPY
Goals
· Control symptoms
· Improve HRQOL
· Prevent hospitalization
· Prevent mortality
Strategies
· Identification of comorbidities
Treatment
· Diuresis to relieve symptoms
of congestion
· Follow guideline driven
indications for comorbidities,
e.g., HTN, AF, CAD, DM
· Revascularization or valvular
surgery as appropriate
STAGE C
Structural heart disease
with prior or current
symptoms of HF
THERAPY
Goals
· Control symptoms
· Patient education
· Prevent hospitalization
· Prevent mortality
Drugs for routine use
· Diuretics for fluid retention
· ACEI or ARB
· Beta blockers
· Aldosterone antagonists
Drugs for use in selected patients
· Hydralazine/isosorbide dinitrate
· ACEI and ARB
· Digoxin
In selected patients
· CRT
· ICD
· Revascularization or valvular
surgery as appropriate
STAGE D
Refractory HF
THERAPY
Goals
· Prevent HF symptoms
· Prevent further cardiac
remodeling
Drugs
· ACEI or ARB as
appropriate
· Beta blockers as
appropriate
In selected patients
· ICD
· Revascularization or
valvular surgery as
appropriate
e.g., Patients with:
· Known structural heart disease and
· HF signs and symptoms
HFpEF HFrEF
THERAPY
Goals
· Heart healthy lifestyle
· Prevent vascular,
coronary disease
· Prevent LV structural
abnormalities
Drugs
· ACEI or ARB in
appropriate patients for
vascular disease or DM
· Statins as appropriate
THERAPY
Goals
· Control symptoms
· Improve HRQOL
· Reduce hospital
readmissions
· Establish patient’s end-
of-life goals
Options
· Advanced care
measures
· Heart transplant
· Chronic inotropes
· Temporary or permanent
MCS
· Experimental surgery or
drugs
· Palliative care and
hospice
· ICD deactivation
Refractory
symptoms of HF
at rest, despite
GDMT
At Risk for Heart Failure Heart Failure
·Marked HF symptoms at
rest
·Recurrent hospitalizations
despite GDMT
· Previous MI
· LV remodeling including
LVH and low EF
· Asymptomatic valvular
disease
· HTN
· Atherosclerotic disease
· DM
· Obesity
· Metabolic syndrome
or
Patients
· Using cardiotoxins
· With family history of
cardiomyopathy
Development of
symptoms of HF
Structural heart
disease

Outline of treatment for heart failure
I. Initial and Serial Evaluation of the HF Patient (including HFpEF)
II. Treatment of Stage A thru D Heart Failure (including HFpEF)
III. The Hospitalized Patient
IV. Surgical/Percutaneous/ Transcatheter Interventional Treatment
V. Coordinating Care for Patients With Chronic HF
VI. Quality Metrics/Performance Measures

Positive inotropic agents
Positive inotropic agents have been used to
treat patients with heart failure since 1775 when
Withering introduced foxglove into practice

Positive Inotropic agents
• Inotropic drugs may be strictly defined as therapies that
enhance myocardial contractile performance independent of
changes in heart rate and loading conditions.
• However, loading conditions and heart rate are highly variable in
patients with heart failure; they are subject to change, and may
be altered by some inotropic drugs.
• Many inotropic drugs increase heart rate, and some have direct
or indirect vasodilator properties.
• Therefore, some of the improved systolic performance generated
by inotropic agents may also be due to changes in loading
conditions and heart rate inherent to many of these drugs.INOTROPIC THERAPY FOR HEART FAILURE

• Today, positive inotropic drugs are typically used to stabilize
patients with acute decompensated heart failure in the intensive
care unit, as a bridge to heart replacement therapy, or a bridge-
to-decision.
• Intravenous positive inotropic drugs are indicated when patients
with acute systolic heart failure exhibit signs or symptoms of end-
organ dysfunction due to hypoperfusion.
• The use of positive inotropic drugs has been plagued by serious
concerns regarding increased morbidity and mortality.
• Problems include increased arrhythmia, induced myocardial
ischemia, and in some cases, hypotension .INOTROPIC THERAPY FOR HEART FAILURE

• The largest database demonstrating increased mortality with
inotropes is the ADHERE (Acute Decompensated Heart Failure
National Registry),where short-term inotropic therapy was
associated with increased in-hospital mortality
• Despite clear evidence that inotropic therapy increases
mortality, there are clinical settings where inotropic support
with dopamine, dobutamine, milrinone, or norepinephrine may
be life-saving measures.
• short-term use of intravenous positive inotropic drugs may have
a clear therapeutic role in patients hospitalized with acute
systolic heart failure, where hypoperfusion of vital organs is
obvious and the need for improved perfusion is immediate.

• Although temporary mechanical circulatory support devices
(intra aortic balloon pumps, extracorporeal membrane
oxygenation, impella etc.) are now available to augment
cardiac output and blood pressure, these short-term and less
durable devices are reserved for special circumstances such as
bridge-to-heart replacement therapy or bridge-to-decision.
• In some cases, such as in the setting of acute myocardial
infarction, short-term, less durable devices are also implanted
for temporary support while awaiting revascularization but
stabilization therapy often begins with intravenous inotropic
agents.

• Some patients require sustained inotropic support, as they
cannot be weaned from drugs such as dobutamine or milrinone
without experiencing hypoperfusion.
• Such patients are believed to be “inotrope-dependent” when
repeated attempts to wean result in symptomatic hypotension,
worsening symptoms, and/or progressive organ dysfunction
(usually renal).
• Further use of inotropic agents should not be based on
hemodynamic parameters alone but on clinical deterioration.

• Inotropic therapy is appropriate in hospitalized patients with
evidence of end-organ hypoperfusion until resolution of the
acute cause occurs and in situations requiring chronic critical
support until definitive therapy such as heart transplantation,
mechanical circulatory support, or bridge-to-decision
• For those patients who are not candidates for advanced heart
replacement therapy, intravenous inotropes may also be
considered as palliation at the end of life.
• In addition, new inotropic agents that use non catecholamine
pathways are being developed, thereby adding positive
inotropy without necessarily increasing myocardial oxygen
consumption

Inotropic agents

DIGOXIN
• Digoxin is a cardiac glycoside with positive inotropic
characteristics.
• There is still considerable debate regarding the role of
digoxin for the treatment of patients with systolic heart
failure.
• It works by inhibiting the sodium-potassium adenosine
triphosphatase (ATPase) pump at the cellular level and
prevents the transport of sodium from the intracellular to the
extracellular space. This process in turn affects the activity of
the sodium-calcium pump and raises the intracellular level of
calcium by decreasing its efflux, which is responsible for the
inotropic effect of the drug.

DIGOXIN
• Digoxin is one of the positive inotropic agents which improves
hemodynamics at rest and during exercise and does not have
a deteriorating effect on blood pressure or heart rate
• It tends not to increase myocardial oxygen demand and does
not reduce coronary perfusion.
• It does not impair kidney function, and is available in both
intravenous and oral form.
• Digoxin plays a role in suppressing the neurohormonal
activation which is helpful in chronic systolic heart failure
patients and can be used as long term therapy for stable heart
failure.

DIGOXIN
• Digoxin was being extensively used for many years until in 1997
the Digitalis Investigation Group (DIG) trial showed that digoxin
has no mortality benefit in this population, but helps reduce the
frequency of hospitalization with exacerbation of heart failure
symptoms .
• There are still controversies regarding the role of digoxin in the
treatment of HFrEF, as β blockers were not used in the DIG trial.
• Monitoring the serum concentration of digoxin in patients is
important as a level of ≥1.2 ng/mL is associated with increased
mortality. Levels between 0.5 and 0.8 ng/mL are recommended
in these patients

DIGOXIN

DIGOXIN
• Post hoc subgroup analyses of the DIG trial showed that
women with HFrEF treated with digoxin had an increased
mortality.
• However, one of these studies showed that women with a
left ventricular ejection fraction (LVEF) less than 35%, and a
serum digoxin concentration between 0.5 and 1.1 ng/mL, did
not have increased mortality and had reduced hospitalization
for heart failure symptoms

DIGOXIN
• Atrial fibrillation is seen in 20-30% patients with chronic systolic
heart failure due to chamber dilation and functional valvular
regurgitation.
• Digoxin plays an important role in obtaining rate control in such
patients, as non dihydropyridine calcium channel blockers, such
as diltiazem and verapamil, increase mortality in patients with
HFrEF.
• Administration of digoxin has been shown to help in weaning off
the mechanical circulatory support and inotropic agents in
patients with left ventricular dysfunction.

DIGOXIN
• The Randomized Assessment of Digoxin on Inhibitors of
Angiotensin Converting Enzyme (RADIANCE) trial showed that
stable chronic heart failure patients with systolic dysfunction
had worsening of symptoms when digoxin was withdrawn

DIGOXIN
Currently, the use of digoxin for treatment of HFrEF in
patients symptomatic despite optimal medical therapy has a
class Ila indication in the ACC/AHA 2013 HF guidelines], and
a class IIb indication for treatment of HFrEF in patients
symptomatic despite optimal medical therapy in the ESC
heart HF guidelines

DOPAMINE
• Dopamine, the immediate precursor to norepinephrine in
the catecholamine synthetic pathway, is an endogenous
neurotransmitter with multiple clinically important effects .
• Use of exogenous dopamine was largely studied and
developed in the laboratories of Leon Goldberg at the
University of Chicago. It has been used intravenously to treat
cardiogenic and septic shock since the 1970s.
• At low doses (<3 mg/kg/min), dopamine activates
dopaminergic (D1) receptors that sub serve vasodilatation in
various vascular beds, including the coronary and renal
arteries.

DOPAMINE
• Despite the early observation demonstrating increased renal
blood flow the benefits of “renal doses” of dopamine have
remained controversial.
• Estimated glomerular filtration rate does not improve with
use of low-dose dopamine infusions, and there is no apparent
renal protective effect
• A recent meta-analysis suggests that low-dose dopamine may
increase urine output on the first day, associated with no
effect on creatinine clearance and a trend toward increased
adverse events

DOPAMINE
• The DAD-HF study (J Card Fail. 2010 Dec)of 60 patients
hospitalized for AHF suggested that a combination of low-dose
furosemide and low-dose dopamine resulted in comparable
urine output and dyspnea relief but improved renal function
profile and potassium homeostasis compared with high-dose
furosemide.
• In contrast, the ROSE trial (JAMA. 2013 Dec) of 360 patients
with acute heart failure and renal dysfunction showed that
low-dose dopamine did not enhance decongestion nor
improve renal function when added to diuretic therapy.
• If low-dose dopamine therapy is initiated, it should be discon-
tinued in the event of no response.INOTROPIC THERAPY FOR HEART FAILURE

DOPAMINE

DOPAMINE
• Intermediate-dose dopamine (2 to 10 μg/kg/min) results in
enhanced norepinephrine release, stimulating cardiac
receptors with an increase in inotropy and mild stimulation of
peripheral vasoconstricting receptors.
• Because the positive inotropic effect is largely dependent on
myocardial catecholamine stores, which often are depleted in
patients with advanced heart failure, dopamine is a poor
inotrope in patients with severe systolic dysfunction.

DOPAMINE
• High-dose dopamine (10 to 20 μg/kg/min) causes peripheral
and pulmonary artery vasoconstriction, mediated by direct
agonist effects on alpha1-adrenergic receptors.
• These doses carry a significant risk of precipitating limb and
end-organ ischemia and should be used cautiously.

DOBUTAMINE
• Dobutamine was introduced in the late 1970s as a new,
synthetic, intravenously administered catecholamine that had
a direct agonist effect on β1- and β2- adrenergic receptors
with no vasoconstrictor properties and less tachycardia
• This drug was developed in the laboratories of Eli Lilly under
the direction of Dr. Ron Tuttle. Many of the early human
studies were performed in the laboratories of Dr. Carl Leier at
Ohio State University.
• In principle, it was suggested that dobutamine might have an
advantage over dopamine, as it does not increase sympathetic
norepinephrine signaling or peripheral vasoconstriction.

DOBUTAMINE
• Dobutamine raises blood pressure solely by increasing cardiac
output, whereas dopamine raises blood pressure via peripheral
vasoconstriction .
• Both dobutamine and dopamine can reduce left ventricular
end diastolic pressure (LVEDP), although dopamine has the
propensity to raise afterload when used in high doses and
theoretically could increase filling pressure.
• Dobutamine can reduce blood pressure in some patients due
to the peripheral vasodilatory properties, but the severity and
importance of this effect varies widely among patients.

DOBUTAMINE
• Dobutamine quickly became a popular drug to treat patients
with severe heart failure, as it clearly improves cardiac output
and lowers LVEDP with only a modest increase in heart rate .
• It exhibits a peripheral vasodilatory effect, most likely caused
by β2-adrenergic stimulation in the peripheral vasculature in
combination with reflex withdrawal of intense
vasoconstriction.
• With time and experience, however, it became clear that
dobutamine infusions lasting longer than 72 h were
associated with pharmacodynamic tolerance .

DOBUTAMINE
• Tachycardia, myocardial ischemia, and arrhythmia can occur
during dobutamine infusions, especially at doses of 15
mg/kg/min or higher.
• Generally, these outcomes are rapidly reversible, as the
plasma half-life is 2.37 min, indicating that > 98% of the drug
is eliminated within 10 to 12 min after cessation of the
infusion.
• Tachyphylaxis may occur with infusions lasting longer than 24
to 48 hours, owing in part to receptor desensitization.

DOBUTAMINE
• dobutamine is the preferred inotrope in patients with significant
hypotension and in the setting of significant renal dysfunction, in
keeping with the renal excretion of milrinone.
• Concomitant beta blocker therapy will result in competitive
antagonism of the effects of dobutamine, and higher doses of
dobutamine (10 to 20 μg/ kg/min) may be required to obtain the
desired hemodynamic effects.
• The lowest effective dose of dobutamine should be used,
supported by continuous blood pressure and rhythm monitoring.
• The patient should be gradually weaned off dobutamine and
clinical status reevaluated with each dose adjustment.INOTROPIC THERAPY FOR HEART FAILURE

DOBUTAMINE
• Initial studies by Leier et al. indicated that dobutamine
improved regional blood flow to skeletal muscles and other
regional beds.
• Subsequent metabolic studies by Mancini et al. using
phosphorous-31 magnetic resonance spectroscopy
demonstrated that even though dobutamine improves the
overall blood flow to the limb, it is unlikely to improve
oxygen delivery to working skeletal muscle.

DOBUTAMINE
• During the early stages of dobutamine use, a potential durable
clinical benefit of short-term infusion was observed
• Short-term infusion for 72 hrs selectively improves vascular
endothelial function for 2 weeks.
• These observations led to the use of chronic home or outpatient
infusions of dobutamine.
• However, the tide turned when it became clear that infusion of
dobutamine for 7 to 52 days (median duration, 14 days) at an
average dose of9 mg/kg/min was associated with a much higher
6-month mortality compared with a vasodilator, epoprostenol.

DOBUTAMINE
• In the FIRST (Flolan International Randomized Survival Trial),
dobutamine was associated with worse survival and poorer
clinical outcomes and did not improve quality of life during or
after the infusions.
• Although the data were observational, subsequent
experience has verified that use of inotropic therapy for the
treatment of severe heart failure is associated with reduced
survival.
• Long-term infusions are still used as a bridge to heart
replacement therapy and also in the palliative care setting

DOBUTAMINE
• Although the hemodynamic and other effects of dobutamine
have been studied, only one placebo-controlled, randomized
trial has been conducted in patients with AHF.
• Although some methodologic concerns were raised, the
CASINO (“CAlcium Sensitizer or Inotrope or NOne in low
output heart failure”) study demonstrate significantly
increased mortality with dobutamine compared with placebo,
consistent with the results of other studies of this class of
agents

output heart failure”) Study
• Enrolled 600 patients hospitalized with NYHA class IV heart failure
• Randomized to Levosimendan, Dobutamine or Placebo after 48 hrs of presentation
• Primary end point was mortality at 1months, 6 months and 1 year
Dobutamine is associated with lower 6 months survival compared to
Levosimendan and placebo in decompensated low out put heart failureINOTROPIC THERAPY FOR HEART FAILURE

output heart failure”) Study
Survival curves for the three treatment arms of the CASINO study
before complete follow-up of patients

DOBUTAMINE
• Dobutamine is known to cause eosinophilic myocarditis and
peripheral eosinophilia. This hypersensitivity reaction is not
uncommon in patients awaiting heart transplant, while they
are on dobutamine.
• Higher doses of dobutamine is not preferred in patients with
recent myocardial ischemia, as it can increase myocardial
oxygen demand and induce tachycardia.
• Dobutamine can also be pro-arrhythmic.

NOREPINEPHRINE
• Norepinephrine is an endogenous catecholamine normally
synthesized, stored, and released from sympathetic neurons.
• Norepinephrine has potent α- and β adrenergic receptor
agonist properties including increased chronotropy,
heightened inotropy, and increased peripheral
vasoconstriction.
• Synthetically manufactured norepinephrine has been
available for decades for the treatment of severe septic and
cardiogenic shock.

NOREPINEPHRINE
• Due to its β-agonist properties, Norepinephrine can lead to
tachycardia, which in turn can be harmful in patients with a
recent myocardial infarction as it can increase myocardial
oxygen demand.
• Similar to high-dose dopamine, it should be given through a
secure intravenous cannula or, preferably, a central venous
catheter because of its potential to cause skin necrosis and
sloughing of tissue.
• Typically, Norepinephrine is infused at 0.2 to 1 mg/kg/min.

NOREPINEPHRINE
• High doses of dopamine (>3 mg/kg/ min) seem equivalent to
those of norepinephrine with similar attributes and adverse
effects.
• A comparator study published in 2010 indicated that a subset
of patients with cardiogenic shock derived more survival
benefit from norepinephrine than from dopamine.
• However, it should be noted that the study included patients
with various types of shock, that the overall mortality rate was
similar between dopamine and norepinephrine, and that
there were more adverse effects with the use of dopamine
than with the use of norepinephrine.

NOREPINEHRINE
• Patients who present with cardiogenic shock are also
occasionally in a vasodilated state causing hypotension.
Norepinephrine should be used in such conditions.
• Patients who have a recent implantation of mechanical
circulatory support for end-stage heart failure can also
benefit from such a vasoactive agent when they have a
component of vasodilatory shock post implant

EPINEPHRINE
• Epinephrine is a full beta receptor agonist and a potent
inotropic agent with balanced vasodilator and vasoconstrictor
effects.
• The direct effect of epinephrine on increasing inotropy
independent of myocardial catecholamine stores makes it a
useful agent in the treatment of transplant recipients with
denervated hearts

Phosphodiesterase Inhibitors (PDEIs)
• Cyclic AMP is a ubiquitous signaling molecule that increases
inotropy, chronotropy, and lusitropy in cardiomyocytes and
causes vasorelaxation in vascular smooth muscle
• Phosphodiesterase IIIa (PDE IIIa) is compartmentalized in the
cardiac and vascular smooth muscle, where it terminates the
signaling activity of cAMP by degrading it to AMP.
• Many specific inhibitors of PDE IIIa, such as Milrinone and
Enoximone, have been developed to provide organ specific
improvements in hemodynamics through increasing
myocardial and vascular smooth muscle cell cAMP
concentrations.

Phosphodiesterase Inhibitors
• Subcellular localization provides the possibility to stimulate
inotropy without increasing heart rate with low doses of a
highly specific phosphodiesterase inhibitor (PDEI).
• The independence of the mechanism from adrenergic
receptors bypasses receptor downregulation, desensitization,
and antagonism by beta blockers
• PDEIs cause significant peripheral and pulmonary
vasodilation, reducing afterload and preload, while increasing
inotropy. These effects make them well suited for use in
patients with LV dysfunction and pulmonary hypertension or
in transplant recipients.

MILRINONE
• Milrinone was introduced in the early 1990s for the treatment
of severe systolic heart failure.
• It is a bipyridine, noncatecholamine, positive inotropic agent
that can be given intravenously to patients with advanced
systolic heart failure to improve cardiac performance.
• It is both a positive inotropic agent and a peripheral
vasodilator.
• Milrinone also has lusitropic properties which are manifested
by improvement in diastolic function
• It raises heart rate, but not to the same extent as dobutamine.

MILRINONE
• Milrinone reduces left ventricular filling pressure in chronic
heart failure patients
• It may be the preferred inotropic drug for patients receiving β-
adrenergic blocking drugs, as it does not use the β-adrenergic
receptor to drive cardiac contractility, unlike dobutamine and
dopamine.
• Milrinone, through its enhancement of cAMP, may reduce
pulmonary artery pressure via a vasodilator mechanism and,
therefore, may improve right heart failure due to pulmonary
hypertension

MILRINONE
• Milrinone can lead to hypotension, especially in patients with
low filling pressure.
• Should be avoided in patients with impaired renal function,
as it is is renally cleared.
• It has a relatively long plasma elimination half-life (50 min,
may be longer in severe heart failure).If hypotension or
arrhythmia occurs, these adverse effects may persist for
hours.
• A bolus infusion can sometimes cause hypotension and is not
recommended. An initial continuous infusion dose of 0.125
mg/kg/min is generally reasonable.INOTROPIC THERAPY FOR HEART FAILURE

MILRINONE
• The Acute Decompensated Heart Failure National Registry
(ADHERE) registry also showed a significantly higher in-
hospital mortality in patients admitted with acute
decompensated heart failure, when treated with Milrinone
or Dobutamine compared to intravenous Nitroglycerine or
Nesiritide.

MILRINONE
• In the Outcomes of Prospective Trial of Intravenous Milrinone
for Exacerbations of Chronic Heart Failure (OPTIME-CHF) trial
a total of 951 patients with a mean LVEF of 23% were
randomly assigned to either intravenous Milrinone or placebo
added to standard therapy for 48 h and followed for 60 days.
• Milrinone was associated with significant sustained
hypotension and atrial arrhythmias compared to placebo.
• No differences were seen in in-hospital mortality, 60-day
mortality, or readmission.

OPTIME-CHF trial - MILRINONE

MILRINONE
• A post hoc analysis of patients randomized in the OPTIME-CHF
study showed that intravenous Milrinone (0.5 μg/kg/min
without a loading dose) was associated with higher mortality
and re-hospitalization rate in ischemic cardiomyopathy
patients.
• A neutral beneficial effect was seen in patients with non-
ischemic cardiomyopathy as the etiology for decompensated
heart failure

MILRINONE
Kaplan-Meier survival curves for in-hospital survival to 60 days by heart failure
etiology and treatment assignment in a post hoc analysis of the OPTIME-CHF trial.
(Adapted from J Am Coll Cardiol)INOTROPIC THERAPY FOR HEART FAILURE

MILRINONE
• In the Prospective Randomized Milrinone Survival
Evaluation (PROMISE) trial, 1088 patients with severe
chronic heart failure and left ventricular dysfunction were
randomized to oral Milrinone or placebo to determine the
effect of Milrinone on the mortality of such patients who
continue to be symptomatic on optimal medical therapy.

MILRINONE

MILRINONE
• All patients had symptoms of NYHA III or IV for at least
three months. A six-month follow-up showed significantly
higher mortality and more frequent hospitalizations in the
Milrinone group.
• A meta-analysis of 21 randomized trials also showed that
phosphodiesterase inhibitors are associated with
significantly higher mortality and cardiac arrhythmias when
compared to placebo

MILRINONE
• Can be used for long-term use as a bridge to heart
replacement therapy or as a form of palliative care when
other therapies are insufficient may be appropriate.
• Milrinone remains widely used to treat patients with acute
decompensated heart failure and should be considered
specifically for patients who have preserved renal function
or pulmonary hypertension or patients who are receiving a
β-adrenergic blocking agent.

ENOXAMINE
• Enoximone also is a type IIIa PDEI that is available in Europe.
• Dosing is essentially one-tenth that of milrinone, with a
bolus dose of 0.25 to 0.75 μg/kg bolus over 10 to 20
minutes, followed by an infusion of 1.25 μg/kg/min.
• It is extensively metabolized by the liver into renally cleared
active metabolites, so doses should be reduced in the
setting of either renal or hepatic insufficiency

LEVOSIMENDAN
3 mechanisms of action
1) Calcium sensitizing agent
2) Vasodilator by inhibiting KATP channels
3) PDE III inhibitor

LEVOSIMENDAN
• Levosimendan is a calcium sensitizing agent which can exert
its inotropic effect by increasing the sensitivity of cardio
myocyte to intracellular calcium.
• increases the sensitivity of cardiomyocyte to intracellular
calcium by binding to troponin C.
• Achieving an inotropic effect without increasing intracellular
calcium levels can prevent an increased risk of cardiac
arrhythmia with this agent.

LEVOSIMENDAN
• Levosimendan also has vasodilatory properties by opening
adenosine triphosphate (ATP)-sensitive potassium channels in
vascular smooth muscle, causing their relaxation.
• This mechanism reduces the preload and afterload which is
helpful in treating patients with acute decompensated heart
failure.
• It may also have some phosphodiesterase (PDE) inhibitor
activity.
• It is available in more than 40 countries but not in the United
States

LEVOSIMENDAN
• In clinical trials, levosimendan has been shown to significantly
increase cardiac output, reduce PCWP and afterload, and
decrease dyspnea.
• The potent vasodilating effects of levosimendan can cause
significant hypotension, which may be avoided by maintaining
filling pressures.
• Levosimendan has an active, acetylated metabolite with a half-
life of over 80 hours, so that it can continue to exert its
hemodynamic effects days after discontinuation of the infusion

LEVOSIMENDAN
• Levosimendan causes a rapid dose-dependent improvement
in the deranged hemodynamic profile of patients with severe
heart failure.
• Typically the dose is titrated upward over 4 h from 0.1
mg/kg/min to 0.4 mg/kg/min and is maintained for several
hours.
• Metobolism in liver and excreted through kidneys. Should be
careful in patients with liver and kidney disorders.

LEVOSIMENDAN
• Short-term use of levosimendan has been shown to cause
rapid dose-dependent improvement in hemodynamics and
symptoms in patients with decompensated heart failure.
• In the Levosimendan Infusion versus Dobutamine (LIDO)
study, intravenous levosimendan was compared with
dobutamine in severe low-output heart failure patients.
• A hemodynamic improvement (increase in cardiac output
and decrease in PCWP) was associated with a lower mortality
at one- and six-months with levosimendan compared to
dobutamine.

LEVOSIMENDAN
The prospective benefit observed at 31 days
for Levosimendan-treated patients was
maintained through the 180-day follow-up
period
Kaplan – Meiers analysis of the LIDO
The prospective benefit of levosimendan seen at 31 days was maintained up to 180 days

LEVOSIMENDAN
In the Randomized Study on Safety and
Effectiveness of Levosimendan in Patients with Left
Ventricular Failure after an Acute Myocardial
Infarct (RUSSLAN) trial, levosimendan didn’t cause
hypotension or clinically significant ischemia, also
reduced the risk of worsening heart failure and
death.

LEVOSIMENDAN
Kaplan–Meier survival analysis in the RUSSLAN trial
The prospective survival benefit of Levosimendan compared to placebo at 14 days
were maintained through 180 days of follow-up

LEVOSIMENDAN
The Randomized Multicenter Evaluation of Intravenous
Levosimendan Efficacy (REVIVE-II) study showed that there is
no difference in mortality at 90 days and levosimendan was
associated with more adverse effects like hypotension and
cardiac arrhythmias while providing improvement in
symptoms in acutely decompensated heart failure patients

LEVOSIMENDAN
• In Survival of Patients with Acute Heart Failure in Need of
Intravenous Inotropic Support (SURVIVE) trial , levosimendan
was compared with dobutamine in 1,327 patients.
• An early reduction in mortality was not sustained through
180 days, but levosimendan was associated with a higher
incidence of atrial fibrillation and lower incidence of
worsening heart failure compared with dobutamine
• Levosimendan was associated with more peripheral
vasodilation and hypotension than dobutamine.
• Few data are available regarding oral levosimendan, but at
least one study indicated improved quality of life scores with
oral levosimendan.

• Survival curves for the three treatment arms
of the CASINO study
• before complete follow-up of patients
Survival of Patients with Acute Heart Failure
in Need of Intravenous Ionotropic Support (SURVIVE)trial
JAMA. 2007;297:1883-1891.

PIMOBENDAN
• Pimobendan is an inotropic agent with phosphodiesterase-
inhibiting and calcium-sensitizing effects.
• Acute intravenous administration of Pimobendan to patients
with heart failure with reduced ejection fraction (HFrEF)
results in increases in stroke volume and cardiac index and
reductions in left ventricular end-diastolic pressure, systemic
vascular resistance, and mean arterial pressure with
associated small elevation in heart rate.

PIMOBENDAN
• In two randomized, placebo-controlled trials (PMRG and
PICO) of patients with HFrEF, 12- to 24-week administration of
oral Pimobendan resulted in improvements in exercise
duration, although in the larger study there was a
nonsignificant trend toward greater mortality (hazard ratio
1.8, 95% CI 0.9 to 3.5).
• The long-term efficacy and safety of Pimobendan for
treatment of HFrEF has not been established.
• Pimobendan is currently approved for use only in Japan

PIMOBENDAN
• In the EPOCH study, 306 patients with NYHA functional class II or
III HF and LVEF ≤45 % despite conventional therapy were
randomly assigned to 52 weeks of treatment with Pimobendan
or placebo.
• The primary combined end point of sudden cardiac death,
hospitalization for HF, or death from HF was less frequent in the
Pimobendan group (10.1 versus 15.3 percent) but this difference
was not statistically significant.
• The combined adverse cardiac event rate in the Pimobendan
group was significantly lower than in the placebo group (15.9
versus 26.3 percent) but this end point included addition or
increase in doses of background medications and decrease in
specific activity scale INOTROPIC THERAPY FOR HEART FAILURE

New and Emerging Positive Inotropic Agents
• The quest to develop more effective and safer positive
inotropic drugs has continued despite numerous setbacks and
disappointments.
• Some new agents do not target inotropy per se. Additional
targets may include improved mitochondrial function through
modulation of oxidative stress, iron handling, and biogenesis.
• Newer positive inotropic agents will also have greater
advantages if they can be given orally.

OMECAMTIV MECARBIL
• Formerly known as CK-1827452, Omecamtiv mecarbil was
developed by Malik et al. at Cytokinetics, and it has emerged
as an interesting new potential therapy for heart failure.
• Omecamtiv mecarbil is the first selective cardiac myosin
activator to be studied in humans
• These agents increase the transition rate from the weakly
bound to the strongly bound state necessary for initiation of a
force-generating power stroke.

OMECAMTIV MECARBIL
• This increases the occupancy time of myosin on actin, leading
to increased numbers of myosin molecules bound to actin,
which causes prolongation of the contractile force without
increasing left ventricular pressure development (dP/dt)
• Unlike current inotropes, they increase the systolic ejection
time without altering the rate of LV pressure development,
resulting in increased stroke volume and cardiac output
without increases in intracellular cAMP or calcium.

OMECAMTIV MECARBIL
• Omecamtiv mecarbil does not increase the heart’s demand
for energy, rather, it improves systolic performance by
allowing the myocardium to make more efficient use of
energy
• In both healthy volunteers and patients with chronic stable
heart failure with reduced ejection fraction, administration of
Omecamtiv mecarbil produced dose-dependent increases in
systolic ejection time, fractional shortening, stroke volume,
and ejection fraction and was well tolerated over a broad
range of plasma concentrations.

OMECAMTIV MECARBIL

OMECAMTIV MECARBIL
• In the phase II dose ranging trial in 45 patients with stable
heart failure, ATOMIC AHF (Acute Treatment with Omecamtiv
Mecarbil to Increase Contractility–Acute Heart Failure;
NCT01300013), drug appears to avoid the usual adverse
effects (e.g., tachycardia and arrhythmia) of traditional
inotropic agents.
• Early experience demonstrated an increase in LV ejection
fraction and stroke volume with decreased end-systolic and
end-diastolic volumes.
• At high plasma concentrations, chest pain, tachycardia ,
myocardial ischemia were noted.

ISTAROXIME
• Istaroxime, the prototype of a new class of drugs, exerts its
actions on the myocyte in two ways:
(1) through stimulation of the membrane bound Na+- K+
ATP ase)
(2) by enhancing the activity of the sarcoendoplasmic
reticulum Ca2+-ATP ase type 2a (SERCA-2a).

ISTAROXIME
• These distinct mechanisms result in, increased cytosolic
calcium accumulation during systole, with positive inotropic
effects, and rapid sequestration of cytosolic calcium into the
sarcoplasmic reticulum during diastole, leading to an
enhanced lusitropic effect.
• In an ischemic chronic heart failure animal model, Istaroxime
improved both systolic and diastolic dysfunction without an
increased incidence of arrhythmias

ISTAROXIME
• The HORIZON-HF (Hemodynamic, Echocardiographic, and
Neurohormonal Effects of Istaroxime, a Novel Intravenous
Inotropic and Lusitropic Agent: a Randomized Controlled
Trial in Patients Hospitalized with Heart Failure) study
assessed the hemodynamic effects of Istaroxime in a
double- blind, placebo- controlled phase II trial in 120
patients hospitalized with acute heart failure
• The primary end point, reduction in pulmonary capillary
wedge pressure, was improved for all 3 doses compared to
placebo.

-4
-2
0
-0.8
-0.4
0
0.4
0.8
HORIZON-HFF
• 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
Trial design: Patients admitted with acute decompensated HF were randomized to istaroxime,
an inotropic and lusitropic agent (n = 89), versus placebo (n = 31).
Results
Conclusions
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;Apr24:[Epub]
(p = 0.048) (p = 0.001)
Istaroxime Placebo
cm/sec
0.5
-0.7
-3.7
-0.2
Change in E’
velocity
Change in pulmonary
capillary wedge
pressure
mmHg

ISTAROXIME
• A particularly notable secondary end point was a dose-
dependent reduction in heart rate, a distinguishing feature
from traditional intravenous inotropes and there was an
increase in systolic blood pressure.
• The higher infusion dose increased cardiac index and reduced
LV end-diastolic volume.
• No changes were observed in neurohormones, renal function,
or troponin I levels during the short 6-hour infusion.

Other new inotropic agents
• Stresscopin, or urocortin 2, is a member of the urocortin
family, a recently discovered group of peptide hormones of
the corticotropin releasing factor (CRF) family.
• They bind with strong affinity to the corticotropin-releasing
hormone receptor type 2 (CRH-R2),highly expressed in the
myocardium and in the vascular endothelium.

• Urocortins exhibit potent inotropic and lusitropic effects on
rat and sheep hearts and activate a group of myocyte
protective pathways collectively known as “reperfusion injury
salvage kinase” (RISK).
• Studies in patients with heart failure showed that brief
intravenous infusions of stresscopin produced dose-related
increases in CO,HR , and LVEF while decreasing SVR.

INOTROPIC DRUGS-MECHANISMS-OUTCOMES

NOVEL THERAPEUTIC STRATEGIES
Sarcoplasmic Reticulum Ca2+-ATPase Modulation
• Calcium is critical in regulating the contraction and relaxation phases
of the cardiac cycle. Sarcoplasmic reticulum
• Ca2+-ATPase (SERCA2a) is an enzyme responsible for both myocardial
relaxation by reuptake of calcium into the sarcoplasmic reticulum
(SR) and contractility by controlling the amount of calcium in the SR.
• SERCA2a is downregulated in the failing human heart, resulting in
contractile dysfunction and arrhythmia.
• Experimental animal models of heart failure have demonstrated an
improvement in contractility, cardiac metabolism, and survival when
SERCA2a expression is increased in cardiomyocytes leading to
restoration of intracellular calcium cycling

GENE THERAPY FOR HEART FAILURE
• The first clinical trial of gene therapy for heart failure in
the United States was CUPID (Calcium Up-regulation by
Percutaneous administration of gene therapy In cardiac
Disease)
• The trial was a multicenter open-label study designed
to evaluate the safety profile and provide first in-
human data for the gene transfer of SERCA2a cDNA
(adeno-associated virus [AAV1]/SERCA2a).
• The cDNA was delivered by intracoronary infusion.

• The phase I dose escalation portion of the study demonstrated an
adequate safety profile in patients with advanced heart failure.
• In phase II of the CUPID study, 39 patients with advanced heart
failure (estimated 1-year mortality rate of 25%) were randomly
allocated to intracoronary AAV1-mediated SERCA2a gene delivery
or placebo
• Clinical efficacy was assessed using symptoms (NYHA class and
Minnesota Living With Heart Failure Questionnaire),6-min walk
test,VO2max,NT proBNP & LV function
• In addition to the clinical outcomes, time to death or heart
replacement therapy was assessed at 6 monthsINOTROPIC THERAPY FOR HEART FAILURE

• The study was limited by a small sample size and required
screening of over 500 patients due to the presence of cross-
reacting neutralizing antibodies to the viral vector capsid.
• The CUPID trial demonstrates that SERCA2a is a potential
therapeutic target in patients with heart failure and provides
supportive evidence for additional, larger randomized trials.
• Two clinical trials are currently targeting SERCA2a, one in
patients implanted with left ventricular assist devices and
another examining the effect on cardiac remodeling.

Inotropic Support – Guidelines ACC/AHA 2013
Until definitive therapy (e.g., coronary
revascularization, MCS, heart transplantation) or
resolution of the acute precipitating problem,
patients with cardiogenic shock should receive
temporary intravenous inotropic support to maintain
systemic perfusion and preserve end-organ
performance.
Continuous intravenous inotropic support is
reasonable as “bridge therapy” in patients with stage
D refractory to GDMT and device therapy who are
eligible for and awaiting MCS or cardiac
transplantation.
I IIa IIb III
I IIa IIb III

Inotropic Support (cont.)
Short-term, continuous intravenous inotropic
support may be reasonable in those hospitalized
patients presenting with documented severe systolic
dysfunction who present with low blood pressure
and significantly depressed cardiac output to
maintain systemic perfusion and preserve end-organ
performance.
Long-term, continuous intravenous inotropic support
may be considered as palliative therapy for symptom
control in select patients with stage D despite
optimal GDMT and device therapy who are not
eligible for either MCS or cardiac transplantation.
I IIa IIb III
I IIa IIb III

Inotropic Support (cont.)
Long-term use of either continuous or intermittent,
intravenous parenteral positive inotropic agents, in
the absence of specific indications or for reasons
other than palliative care, is potentially harmful in
the patient with HF.
Use of parenteral inotropic agents in hospitalized
patients without documented severe systolic
dysfunction, low blood pressure, or impaired
perfusion, and evidence of significantly depressed
cardiac output, with or without congestion, is
potentially harmful.
I IIa IIb III
I IIa IIb III
Harm
Harm

Conclusions
• End-stage heart failure is a progressive disease with high
mortality and limited medical therapeutic options.
• Longterm use of conventional inotropic agents has been
associated with no improvement or even increased overall
mortality. This uncomfortable dilemma has led to expanded
use of heart replacement therapy.
• Development of novel inotropes has been hindered in recent
decades by the ambitious goal of achieving two seemingly
opposing effects with a single molecule.
• Clinicians want to use drugs that increase cardiac output
without increasing myocardial oxygen consumption.INOTROPIC THERAPY FOR HEART FAILURE

Conclusions
• The second goal of newly developed inotropes is to maintain
stable levels of, or even reduce, myocardial energy
consumption.
• The conserved energy may then be redirected for cellular
repair and promotion of mitochondrial health with reduction
of oxidative stress.
• Effectively, this requires that the inotropic agent does not
result in increased chronotropy or calcium flux, as these
processes may be the primary cause of the increased
mortality associated with inotropic drugs.

Conclusions
• One would hope that the next generation of inotropic agents
will achieve enhanced myocardial performance without
altering the velocity of shortening or promoting excessive
calcium modulation at the level of the SR or the L-type
calcium channel
• Patients with end-stage heart failure are unstable by
definition, thus presenting many additional challenges. These
patients are also highly complex medically, providing multiple
opportunities for confounding influences.

Conclusions
• Large patient populations are usually necessary to test
survival outcomes.
• Clinical trials in this group of patients are likely to continue to
be expensive, difficult, and uncertain with regard to proper
end points.
Nevertheless, the search for ideal inotropes should
and will continue

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Inotropic therapy for heart failure

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