Inotropic therapy for heart failure

INOTROPIC THERAPY FOR HEART FAILURE

Dr RAGHU KISHORE GALLA



Stages, Phenotypes and Treatment of HF

STAGE AAt high risk for HF but

without structural heart

disease or symptoms of HF

STAGE BStructural 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 CStructural heart disease

with prior or current

symptoms of HF

THERAPYGoals· 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 DRefractory 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

THERAPYGoals· 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 HFStructural 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 totreat patients with heart failure since 1775 whenWithering introduced foxglove into practice



Positive Inotropic agents

• Inotropic drugs may be strictly defined as therapies thatenhance myocardial contractile performance independent ofchanges in heart rate and loading conditions.

• However, loading conditions and heart rate are highly variable inpatients with heart failure; they are subject to change, and maybe altered by some inotropic drugs.

• Many inotropic drugs increase heart rate, and some have director indirect vasodilator properties.

• Therefore, some of the improved systolic performance generatedby inotropic agents may also be due to changes in loadingconditions and heart rate inherent to many of these drugs.



• Today, positive inotropic drugs are typically used to stabilizepatients with acute decompensated heart failure in the intensivecare unit, as a bridge to heart replacement therapy, or a bridge-to-decision.

• Intravenous positive inotropic drugs are indicated when patientswith 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 seriousconcerns regarding increased morbidity and mortality.

• Problems include increased arrhythmia, induced myocardialischemia, and in some cases, hypotension .



• The largest database demonstrating increased mortality withinotropes is the ADHERE (Acute Decompensated Heart FailureNational Registry),where short-term inotropic therapy wasassociated with increased in-hospital mortality

• Despite clear evidence that inotropic therapy increasesmortality, there are clinical settings where inotropic supportwith dopamine, dobutamine, milrinone, or norepinephrine maybe life-saving measures.

• short-term use of intravenous positive inotropic drugs may havea clear therapeutic role in patients hospitalized with acutesystolic heart failure, where hypoperfusion of vital organs isobvious and the need for improved perfusion is immediate.

•



• Although temporary mechanical circulatory support devices(intra aortic balloon pumps, extracorporeal membraneoxygenation, impella etc.) are now available to augmentcardiac output and blood pressure, these short-term and lessdurable devices are reserved for special circumstances such asbridge-to-heart replacement therapy or bridge-to-decision.

• In some cases, such as in the setting of acute myocardialinfarction, short-term, less durable devices are also implantedfor temporary support while awaiting revascularization butstabilization therapy often begins with intravenous inotropicagents.



• Some patients require sustained inotropic support, as theycannot be weaned from drugs such as dobutamine or milrinonewithout experiencing hypoperfusion.

• Such patients are believed to be “inotrope-dependent” whenrepeated 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 onhemodynamic parameters alone but on clinical deterioration.



• Inotropic therapy is appropriate in hospitalized patients withevidence of end-organ hypoperfusion until resolution of theacute cause occurs and in situations requiring chronic criticalsupport until definitive therapy such as heart transplantation,mechanical circulatory support, or bridge-to-decision

• For those patients who are not candidates for advanced heartreplacement therapy, intravenous inotropes may also beconsidered as palliation at the end of life.

• In addition, new inotropic agents that use non catecholaminepathways are being developed, thereby adding positiveinotropy without necessarily increasing myocardial oxygenconsumption


Inotropic agents



DIGOXIN

• Digoxin is a cardiac glycoside with positive inotropiccharacteristics.

• There is still considerable debate regarding the role ofdigoxin for the treatment of patients with systolic heartfailure.

• It works by inhibiting the sodium-potassium adenosinetriphosphatase (ATPase) pump at the cellular level andprevents the transport of sodium from the intracellular to theextracellular space. This process in turn affects the activity ofthe sodium-calcium pump and raises the intracellular level ofcalcium by decreasing its efflux, which is responsible for theinotropic effect of the drug.



DIGOXIN

• Digoxin is one of the positive inotropic agents which improveshemodynamics at rest and during exercise and does not havea deteriorating effect on blood pressure or heart rate

• It tends not to increase myocardial oxygen demand and doesnot reduce coronary perfusion.

• It does not impair kidney function, and is available in bothintravenous and oral form.

• Digoxin plays a role in suppressing the neurohormonalactivation which is helpful in chronic systolic heart failurepatients and can be used as long term therapy for stable heartfailure.


DIGOXIN

• Digoxin was being extensively used for many years until in 1997the Digitalis Investigation Group (DIG) trial showed that digoxinhas no mortality benefit in this population, but helps reduce thefrequency of hospitalization with exacerbation of heart failuresymptoms .

• There are still controversies regarding the role of digoxin in thetreatment of HFrEF, as β blockers were not used in the DIG trial.

• Monitoring the serum concentration of digoxin in patients isimportant as a level of ≥1.2 ng/mL is associated with increasedmortality. Levels between 0.5 and 0.8 ng/mL are recommendedin these patients


DIGOXIN

DIGOXIN


DIGOXIN

• Post hoc subgroup analyses of the DIG trial showed thatwomen with HFrEF treated with digoxin had an increasedmortality.

• However, one of these studies showed that women with aleft ventricular ejection fraction (LVEF) less than 35%, and aserum digoxin concentration between 0.5 and 1.1 ng/mL, didnot have increased mortality and had reduced hospitalizationfor heart failure symptoms


DIGOXIN


DIGOXIN

• Atrial fibrillation is seen in 20-30% patients with chronic systolicheart failure due to chamber dilation and functional valvularregurgitation.

• Digoxin plays an important role in obtaining rate control in suchpatients, as non dihydropyridine calcium channel blockers, suchas diltiazem and verapamil, increase mortality in patients withHFrEF.

• Administration of digoxin has been shown to help in weaning offthe mechanical circulatory support and inotropic agents inpatients with left ventricular dysfunction.


DIGOXIN

• The Randomized Assessment of Digoxin on Inhibitors ofAngiotensin Converting Enzyme (RADIANCE) trial showed thatstable chronic heart failure patients with systolic dysfunctionhad worsening of symptoms when digoxin was withdrawn




DIGOXIN

Currently, the use of digoxin for treatment of HFrEF inpatients symptomatic despite optimal medical therapy has aclass Ila indication in the ACC/AHA 2013 HF guidelines], anda class IIb indication for treatment of HFrEF in patientssymptomatic despite optimal medical therapy in the ESCheart HF guidelines


DOPAMINE

• Dopamine, the immediate precursor to norepinephrine inthe catecholamine synthetic pathway, is an endogenousneurotransmitter with multiple clinically important effects .

• Use of exogenous dopamine was largely studied anddeveloped in the laboratories of Leon Goldberg at theUniversity of Chicago. It has been used intravenously to treatcardiogenic and septic shock since the 1970s.

• At low doses (<3 mg/kg/min), dopamine activatesdopaminergic (D1) receptors that sub serve vasodilatation invarious vascular beds, including the coronary and renalarteries.


DOPAMINE

• Despite the early observation demonstrating increased renalblood flow the benefits of “renal doses” of dopamine haveremained controversial.

• Estimated glomerular filtration rate does not improve withuse of low-dose dopamine infusions, and there is no apparentrenal protective effect

• A recent meta-analysis suggests that low-dose dopamine mayincrease urine output on the first day, associated with noeffect on creatinine clearance and a trend toward increasedadverse events


DOPAMINE

• The DAD-HF study (J Card Fail. 2010 Dec)of 60 patientshospitalized for AHF suggested that a combination of low-dosefurosemide and low-dose dopamine resulted in comparableurine output and dyspnea relief but improved renal functionprofile and potassium homeostasis compared with high-dosefurosemide.

• In contrast, the ROSE trial (JAMA. 2013 Dec) of 360 patientswith acute heart failure and renal dysfunction showed thatlow-dose dopamine did not enhance decongestion norimprove 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.


http://www.ncbi.nlm.nih.gov/pubmed/21111980

http://www.ncbi.nlm.nih.gov/pubmed/24247300

DOPAMINE


DOPAMINE

• Intermediate-dose dopamine (2 to 10 μg/kg/min) results inenhanced norepinephrine release, stimulating cardiacreceptors with an increase in inotropy and mild stimulation ofperipheral vasoconstricting receptors.

• Because the positive inotropic effect is largely dependent onmyocardial catecholamine stores, which often are depleted inpatients with advanced heart failure, dopamine is a poorinotrope in patients with severe systolic dysfunction.


DOPAMINE

• High-dose dopamine (10 to 20 μg/kg/min) causes peripheraland pulmonary artery vasoconstriction, mediated by directagonist effects on alpha1-adrenergic receptors.

• These doses carry a significant risk of precipitating limb andend-organ ischemia and should be used cautiously.


DOBUTAMINE

• Dobutamine was introduced in the late 1970s as a new,synthetic, intravenously administered catecholamine that hada direct agonist effect on β1- and β2- adrenergic receptorswith no vasoconstrictor properties and less tachycardia

• This drug was developed in the laboratories of Eli Lilly underthe direction of Dr. Ron Tuttle. Many of the early humanstudies were performed in the laboratories of Dr. Carl Leier atOhio State University.

• In principle, it was suggested that dobutamine might have anadvantage over dopamine, as it does not increase sympatheticnorepinephrine signaling or peripheral vasoconstriction.


DOBUTAMINE

• Dobutamine raises blood pressure solely by increasing cardiacoutput, whereas dopamine raises blood pressure via peripheralvasoconstriction .

• Both dobutamine and dopamine can reduce left ventricularend diastolic pressure (LVEDP), although dopamine has thepropensity to raise afterload when used in high doses andtheoretically could increase filling pressure.

• Dobutamine can reduce blood pressure in some patients dueto the peripheral vasodilatory properties, but the severity andimportance of this effect varies widely among patients.


DOBUTAMINE

• Dobutamine quickly became a popular drug to treat patientswith severe heart failure, as it clearly improves cardiac outputand lowers LVEDP with only a modest increase in heart rate .

• It exhibits a peripheral vasodilatory effect, most likely causedby β2-adrenergic stimulation in the peripheral vasculature incombination with reflex withdrawal of intensevasoconstriction.

• With time and experience, however, it became clear thatdobutamine infusions lasting longer than 72 h wereassociated with pharmacodynamic tolerance .


DOBUTAMINE

• Tachycardia, myocardial ischemia, and arrhythmia can occurduring dobutamine infusions, especially at doses of 15mg/kg/min or higher.

• Generally, these outcomes are rapidly reversible, as theplasma half-life is 2.37 min, indicating that > 98% of the drugis eliminated within 10 to 12 min after cessation of theinfusion.

• 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 significanthypotension and in the setting of significant renal dysfunction, inkeeping with the renal excretion of milrinone.

• Concomitant beta blocker therapy will result in competitiveantagonism of the effects of dobutamine, and higher doses ofdobutamine (10 to 20 μg/ kg/min) may be required to obtain thedesired 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 andclinical status reevaluated with each dose adjustment.


DOBUTAMINE

• Initial studies by Leier et al. indicated that dobutamineimproved regional blood flow to skeletal muscles and otherregional beds.

• Subsequent metabolic studies by Mancini et al. usingphosphorous-31 magnetic resonance spectroscopydemonstrated that even though dobutamine improves theoverall blood flow to the limb, it is unlikely to improveoxygen delivery to working skeletal muscle.


DOBUTAMINE

• During the early stages of dobutamine use, a potential durableclinical benefit of short-term infusion was observed

• Short-term infusion for 72 hrs selectively improves vascularendothelial function for 2 weeks.

• These observations led to the use of chronic home or outpatientinfusions of dobutamine.

• However, the tide turned when it became clear that infusion ofdobutamine for 7 to 52 days (median duration, 14 days) at anaverage dose of9 mg/kg/min was associated with a much higher6-month mortality compared with a vasodilator, epoprostenol.


DOBUTAMINE

• In the FIRST (Flolan International Randomized Survival Trial),dobutamine was associated with worse survival and poorerclinical outcomes and did not improve quality of life during orafter the infusions.

• Although the data were observational, subsequentexperience has verified that use of inotropic therapy for thetreatment of severe heart failure is associated with reducedsurvival.

• Long-term infusions are still used as a bridge to heartreplacement therapy and also in the palliative care setting



DOBUTAMINE

• Although the hemodynamic and other effects of dobutaminehave been studied, only one placebo-controlled, randomizedtrial has been conducted in patients with AHF.

• Although some methodologic concerns were raised, theCASINO (“CAlcium Sensitizer or Inotrope or NOne in lowoutput heart failure”) study demonstrate significantlyincreased mortality with dobutamine compared with placebo,consistent with the results of other studies of this class ofagents


CASINO (“CAlcium Sensitizer or Inotrope or NOne in low 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 failure


CASINO (“CAlcium Sensitizer or Inotrope or NOne in low output heart failure”) Study

Survival curves for the three treatment arms of the CASINO studybefore complete follow-up of patients



DOBUTAMINE

• Dobutamine is known to cause eosinophilic myocarditis andperipheral eosinophilia. This hypersensitivity reaction is notuncommon in patients awaiting heart transplant, while theyare on dobutamine.

• Higher doses of dobutamine is not preferred in patients withrecent myocardial ischemia, as it can increase myocardialoxygen demand and induce tachycardia.

• Dobutamine can also be pro-arrhythmic.


NOREPINEPHRINE

• Norepinephrine is an endogenous catecholamine normallysynthesized, stored, and released from sympathetic neurons.

• Norepinephrine has potent α- and β adrenergic receptoragonist properties including increased chronotropy,heightened inotropy, and increased peripheralvasoconstriction.

• Synthetically manufactured norepinephrine has beenavailable for decades for the treatment of severe septic andcardiogenic shock.


NOREPINEPHRINE

• Due to its β-agonist properties, Norepinephrine can lead totachycardia, which in turn can be harmful in patients with arecent myocardial infarction as it can increase myocardialoxygen demand.

• Similar to high-dose dopamine, it should be given through asecure intravenous cannula or, preferably, a central venouscatheter because of its potential to cause skin necrosis andsloughing 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 tothose of norepinephrine with similar attributes and adverseeffects.

• A comparator study published in 2010 indicated that a subsetof patients with cardiogenic shock derived more survivalbenefit from norepinephrine than from dopamine.

• However, it should be noted that the study included patientswith various types of shock, that the overall mortality rate wassimilar between dopamine and norepinephrine, and thatthere were more adverse effects with the use of dopaminethan with the use of norepinephrine.


NOREPINEHRINE

• Patients who present with cardiogenic shock are alsooccasionally in a vasodilated state causing hypotension.Norepinephrine should be used in such conditions.

• Patients who have a recent implantation of mechanicalcirculatory support for end-stage heart failure can alsobenefit from such a vasoactive agent when they have acomponent of vasodilatory shock post implant


EPINEPHRINE

• Epinephrine is a full beta receptor agonist and a potentinotropic agent with balanced vasodilator and vasoconstrictoreffects.

• The direct effect of epinephrine on increasing inotropyindependent of myocardial catecholamine stores makes it auseful agent in the treatment of transplant recipients withdenervated hearts


Phosphodiesterase Inhibitors (PDEIs)

• Cyclic AMP is a ubiquitous signaling molecule that increasesinotropy, chronotropy, and lusitropy in cardiomyocytes andcauses vasorelaxation in vascular smooth muscle

• Phosphodiesterase IIIa (PDE IIIa) is compartmentalized in thecardiac and vascular smooth muscle, where it terminates thesignaling activity of cAMP by degrading it to AMP.

• Many specific inhibitors of PDE IIIa, such as Milrinone andEnoximone, have been developed to provide organ specificimprovements in hemodynamics through increasingmyocardial and vascular smooth muscle cell cAMPconcentrations.



Phosphodiesterase Inhibitors

• Subcellular localization provides the possibility to stimulateinotropy without increasing heart rate with low doses of ahighly specific phosphodiesterase inhibitor (PDEI).

• The independence of the mechanism from adrenergicreceptors bypasses receptor downregulation, desensitization,and antagonism by beta blockers

• PDEIs cause significant peripheral and pulmonaryvasodilation, reducing afterload and preload, while increasinginotropy. These effects make them well suited for use inpatients with LV dysfunction and pulmonary hypertension orin transplant recipients.


MILRINONE

• Milrinone was introduced in the early 1990s for the treatmentof severe systolic heart failure.

• It is a bipyridine, noncatecholamine, positive inotropic agentthat can be given intravenously to patients with advancedsystolic heart failure to improve cardiac performance.

• It is both a positive inotropic agent and a peripheralvasodilator.

• Milrinone also has lusitropic properties which are manifestedby improvement in diastolic function

• It raises heart rate, but not to the same extent as dobutamine.


MILRINONE

• Milrinone reduces left ventricular filling pressure in chronicheart failure patients

• It may be the preferred inotropic drug for patients receiving β-adrenergic blocking drugs, as it does not use the β-adrenergicreceptor to drive cardiac contractility, unlike dobutamine anddopamine.

• Milrinone, through its enhancement of cAMP, may reducepulmonary artery pressure via a vasodilator mechanism and,therefore, may improve right heart failure due to pulmonaryhypertension


MILRINONE

• Milrinone can lead to hypotension, especially in patients withlow 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 orarrhythmia occurs, these adverse effects may persist forhours.

• A bolus infusion can sometimes cause hypotension and is notrecommended. An initial continuous infusion dose of 0.125mg/kg/min is generally reasonable.


MILRINONE

• The Acute Decompensated Heart Failure National Registry(ADHERE) registry also showed a significantly higher in-hospital mortality in patients admitted with acutedecompensated heart failure, when treated with Milrinoneor Dobutamine compared to intravenous Nitroglycerine orNesiritide.



MILRINONE

• In the Outcomes of Prospective Trial of Intravenous Milrinonefor Exacerbations of Chronic Heart Failure (OPTIME-CHF) triala total of 951 patients with a mean LVEF of 23% wererandomly assigned to either intravenous Milrinone or placeboadded to standard therapy for 48 h and followed for 60 days.

• Milrinone was associated with significant sustainedhypotension and atrial arrhythmias compared to placebo.

• No differences were seen in in-hospital mortality, 60-daymortality, or readmission.



OPTIME-CHF trial - MILRINONE


MILRINONE

• A post hoc analysis of patients randomized in the OPTIME-CHFstudy showed that intravenous Milrinone (0.5 μg/kg/minwithout a loading dose) was associated with higher mortalityand re-hospitalization rate in ischemic cardiomyopathypatients.

• A neutral beneficial effect was seen in patients with non-ischemic cardiomyopathy as the etiology for decompensatedheart 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 SurvivalEvaluation (PROMISE) trial, 1088 patients with severechronic heart failure and left ventricular dysfunction wererandomized to oral Milrinone or placebo to determine theeffect of Milrinone on the mortality of such patients whocontinue to be symptomatic on optimal medical therapy.


MILRINONE


MILRINONE

• All patients had symptoms of NYHA III or IV for at leastthree months. A six-month follow-up showed significantlyhigher mortality and more frequent hospitalizations in theMilrinone group.

• A meta-analysis of 21 randomized trials also showed thatphosphodiesterase inhibitors are associated withsignificantly higher mortality and cardiac arrhythmias whencompared to placebo




MILRINONE

• Can be used for long-term use as a bridge to heartreplacement therapy or as a form of palliative care whenother therapies are insufficient may be appropriate.

• Milrinone remains widely used to treat patients with acutedecompensated heart failure and should be consideredspecifically for patients who have preserved renal functionor pulmonary hypertension or patients who are receiving aβ-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 abolus dose of 0.25 to 0.75 μg/kg bolus over 10 to 20minutes, followed by an infusion of 1.25 μg/kg/min.

• It is extensively metabolized by the liver into renally clearedactive metabolites, so doses should be reduced in thesetting 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 exertits inotropic effect by increasing the sensitivity of cardiomyocyte to intracellular calcium.

• increases the sensitivity of cardiomyocyte to intracellularcalcium by binding to troponin C.

• Achieving an inotropic effect without increasing intracellularcalcium levels can prevent an increased risk of cardiacarrhythmia with this agent.


LEVOSIMENDAN

• Levosimendan also has vasodilatory properties by openingadenosine triphosphate (ATP)-sensitive potassium channels invascular smooth muscle, causing their relaxation.

• This mechanism reduces the preload and afterload which ishelpful in treating patients with acute decompensated heartfailure.

• It may also have some phosphodiesterase (PDE) inhibitoractivity.

• It is available in more than 40 countries but not in the UnitedStates


LEVOSIMENDAN

• In clinical trials, levosimendan has been shown to significantlyincrease cardiac output, reduce PCWP and afterload, anddecrease dyspnea.

• The potent vasodilating effects of levosimendan can causesignificant hypotension, which may be avoided by maintainingfilling pressures.

• Levosimendan has an active, acetylated metabolite with a half-life of over 80 hours, so that it can continue to exert itshemodynamic effects days after discontinuation of the infusion


LEVOSIMENDAN

• Levosimendan causes a rapid dose-dependent improvementin the deranged hemodynamic profile of patients with severeheart failure.

• Typically the dose is titrated upward over 4 h from 0.1mg/kg/min to 0.4 mg/kg/min and is maintained for severalhours.

• Metobolism in liver and excreted through kidneys. Should becareful in patients with liver and kidney disorders.


LEVOSIMENDAN

• Short-term use of levosimendan has been shown to causerapid dose-dependent improvement in hemodynamics andsymptoms in patients with decompensated heart failure.

• In the Levosimendan Infusion versus Dobutamine (LIDO)study, intravenous levosimendan was compared withdobutamine in severe low-output heart failure patients.

• A hemodynamic improvement (increase in cardiac outputand decrease in PCWP) was associated with a lower mortalityat one- and six-months with levosimendan compared todobutamine.


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 LIDOThe prospective benefit of levosimendan seen at 31 days was maintained up to 180 days


LEVOSIMENDAN

In the Randomized Study on Safety andEffectiveness of Levosimendan in Patients with LeftVentricular Failure after an Acute MyocardialInfarct (RUSSLAN) trial, levosimendan didn’t causehypotension or clinically significant ischemia, alsoreduced the risk of worsening heart failure anddeath.



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 IntravenousLevosimendan Efficacy (REVIVE-II) study showed that there isno difference in mortality at 90 days and levosimendan wasassociated with more adverse effects like hypotension andcardiac arrhythmias while providing improvement insymptoms in acutely decompensated heart failure patients



LEVOSIMENDAN

• In Survival of Patients with Acute Heart Failure in Need ofIntravenous Inotropic Support (SURVIVE) trial , levosimendanwas compared with dobutamine in 1,327 patients.

• An early reduction in mortality was not sustained through180 days, but levosimendan was associated with a higherincidence of atrial fibrillation and lower incidence ofworsening heart failure compared with dobutamine

• Levosimendan was associated with more peripheralvasodilation and hypotension than dobutamine.

• Few data are available regarding oral levosimendan, but atleast one study indicated improved quality of life scores withoral levosimendan.


• Survival curves for the three treatment arms of the CASINO study

• before complete follow-up of patients

Survival of Patients with Acute Heart Failurein Need of Intravenous Ionotropic Support (SURVIVE)trial

JAMA. 2007;297:1883-1891.INOTROPIC THERAPY FOR HEART FAILURE

PIMOBENDAN

• Pimobendan is an inotropic agent with phosphodiesterase-inhibiting and calcium-sensitizing effects.

• Acute intravenous administration of Pimobendan to patientswith heart failure with reduced ejection fraction (HFrEF)results in increases in stroke volume and cardiac index andreductions in left ventricular end-diastolic pressure, systemicvascular resistance, and mean arterial pressure withassociated small elevation in heart rate.


PIMOBENDAN

• In two randomized, placebo-controlled trials (PMRG andPICO) of patients with HFrEF, 12- to 24-week administration oforal Pimobendan resulted in improvements in exerciseduration, although in the larger study there was anonsignificant trend toward greater mortality (hazard ratio1.8, 95% CI 0.9 to 3.5).

• The long-term efficacy and safety of Pimobendan fortreatment 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 orIII HF and LVEF ≤45 % despite conventional therapy wererandomly assigned to 52 weeks of treatment with Pimobendanor placebo.

• The primary combined end point of sudden cardiac death,hospitalization for HF, or death from HF was less frequent in thePimobendan group (10.1 versus 15.3 percent) but this differencewas not statistically significant.

• The combined adverse cardiac event rate in the Pimobendangroup was significantly lower than in the placebo group (15.9versus 26.3 percent) but this end point included addition orincrease in doses of background medications and decrease inspecific activity scale


New and Emerging Positive Inotropic Agents

• The quest to develop more effective and safer positiveinotropic drugs has continued despite numerous setbacks anddisappointments.

• Some new agents do not target inotropy per se. Additionaltargets may include improved mitochondrial function throughmodulation of oxidative stress, iron handling, and biogenesis.

• Newer positive inotropic agents will also have greateradvantages if they can be given orally.


OMECAMTIV MECARBIL

• Formerly known as CK-1827452, Omecamtiv mecarbil wasdeveloped by Malik et al. at Cytokinetics, and it has emergedas an interesting new potential therapy for heart failure.

• Omecamtiv mecarbil is the first selective cardiac myosinactivator to be studied in humans

• These agents increase the transition rate from the weaklybound to the strongly bound state necessary for initiation of aforce-generating power stroke.


OMECAMTIV MECARBIL

• This increases the occupancy time of myosin on actin, leadingto increased numbers of myosin molecules bound to actin,which causes prolongation of the contractile force withoutincreasing left ventricular pressure development (dP/dt)

• Unlike current inotropes, they increase the systolic ejectiontime without altering the rate of LV pressure development,resulting in increased stroke volume and cardiac outputwithout increases in intracellular cAMP or calcium.


OMECAMTIV MECARBIL

• Omecamtiv mecarbil does not increase the heart’s demandfor energy, rather, it improves systolic performance byallowing the myocardium to make more efficient use ofenergy

• In both healthy volunteers and patients with chronic stableheart failure with reduced ejection fraction, administration ofOmecamtiv mecarbil produced dose-dependent increases insystolic ejection time, fractional shortening, stroke volume,and ejection fraction and was well tolerated over a broadrange of plasma concentrations.


OMECAMTIV MECARBIL


OMECAMTIV MECARBIL

• In the phase II dose ranging trial in 45 patients with stableheart failure, ATOMIC AHF (Acute Treatment with OmecamtivMecarbil to Increase Contractility–Acute Heart Failure;NCT01300013), drug appears to avoid the usual adverseeffects (e.g., tachycardia and arrhythmia) of traditionalinotropic agents.

• Early experience demonstrated an increase in LV ejectionfraction and stroke volume with decreased end-systolic andend-diastolic volumes.

• At high plasma concentrations, chest pain, tachycardia ,myocardial ischemia were noted.



ISTAROXIME

• Istaroxime, the prototype of a new class of drugs, exerts itsactions on the myocyte in two ways:

(1) through stimulation of the membrane bound Na+- K+ ATP ase)

(2) by enhancing the activity of the sarcoendoplasmicreticulum Ca2+-ATP ase type 2a (SERCA-2a).


ISTAROXIME

• These distinct mechanisms result in, increased cytosoliccalcium accumulation during systole, with positive inotropiceffects, and rapid sequestration of cytosolic calcium into thesarcoplasmic reticulum during diastole, leading to anenhanced lusitropic effect.

• In an ischemic chronic heart failure animal model, Istaroximeimproved both systolic and diastolic dysfunction without anincreased incidence of arrhythmias


ISTAROXIME

• The HORIZON-HF (Hemodynamic, Echocardiographic, andNeurohormonal Effects of Istaroxime, a Novel IntravenousInotropic and Lusitropic Agent: a Randomized ControlledTrial in Patients Hospitalized with Heart Failure) studyassessed the hemodynamic effects of Istaroxime in adouble- blind, placebo- controlled phase II trial in 120patients hospitalized with acute heart failure

• The primary end point, reduction in pulmonary capillarywedge pressure, was improved for all 3 doses compared toplacebo.


-4

-2

0

-0.8

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0

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HORIZON-HFF

• Change in E’ velocity: 0.5 cm/sec foristaroxime vs. -0.7 cm/sec for placebo (p =0.048)

• Change in pulmonary capillary wedgepressure: -3.7 mm Hg vs. -0.2 mm Hg (p =0.001), respectively

• Cardiac index: 0.12 L/min/m2 vs. 0.03L/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 improvinghemodynamics and diastolic function inpatients with acute decompensated HF.

Future studies are needed to address theimpact 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/s

ec

0.5

-0.7-3.7

-0.2

Change in E’ velocity

Change in pulmonary capillary wedge

pressure

mm

Hg

ISTAROXIME

• A particularly notable secondary end point was a dose-dependent reduction in heart rate, a distinguishing featurefrom traditional intravenous inotropes and there was anincrease in systolic blood pressure.

• The higher infusion dose increased cardiac index and reducedLV 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 urocortinfamily, a recently discovered group of peptide hormones ofthe corticotropin releasing factor (CRF) family.

• They bind with strong affinity to the corticotropin-releasinghormone receptor type 2 (CRH-R2),highly expressed in themyocardium and in the vascular endothelium.


• Urocortins exhibit potent inotropic and lusitropic effects onrat and sheep hearts and activate a group of myocyteprotective pathways collectively known as “reperfusion injurysalvage kinase” (RISK).

• Studies in patients with heart failure showed that briefintravenous infusions of stresscopin produced dose-relatedincreases 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 phasesof the cardiac cycle. Sarcoplasmic reticulum

• Ca2+-ATPase (SERCA2a) is an enzyme responsible for both myocardialrelaxation 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 incontractile dysfunction and arrhythmia.

• Experimental animal models of heart failure have demonstrated animprovement in contractility, cardiac metabolism, and survival whenSERCA2a expression is increased in cardiomyocytes leading torestoration of intracellular calcium cycling


GENE THERAPY FOR HEART FAILURE

• The first clinical trial of gene therapy for heart failure inthe United States was CUPID (Calcium Up-regulation by

Percutaneous administration of gene therapy In cardiacDisease)

• The trial was a multicenter open-label study designedto 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 anadequate safety profile in patients with advanced heart failure.

• In phase II of the CUPID study, 39 patients with advanced heartfailure (estimated 1-year mortality rate of 25%) were randomlyallocated to intracoronary AAV1-mediated SERCA2a gene deliveryor placebo

• Clinical efficacy was assessed using symptoms (NYHA class andMinnesota Living With Heart Failure Questionnaire),6-min walktest,VO2max,NT proBNP & LV function

• In addition to the clinical outcomes, time to death or heartreplacement therapy was assessed at 6 months



• The study was limited by a small sample size and requiredscreening 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 potentialtherapeutic target in patients with heart failure and providessupportive evidence for additional, larger randomized trials.

• Two clinical trials are currently targeting SERCA2a, one inpatients implanted with left ventricular assist devices andanother examining the effect on cardiac remodeling.


Inotropic Support – Guidelines ACC/AHA 2013

Until definitive therapy (e.g., coronaryrevascularization, MCS, heart transplantation) orresolution of the acute precipitating problem,patients with cardiogenic shock should receivetemporary intravenous inotropic support to maintainsystemic perfusion and preserve end-organperformance.

Continuous intravenous inotropic support isreasonable as “bridge therapy” in patients with stageD refractory to GDMT and device therapy who areeligible for and awaiting MCS or cardiactransplantation.

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Inotropic Support (cont.)

Short-term, continuous intravenous inotropicsupport may be reasonable in those hospitalizedpatients presenting with documented severe systolicdysfunction who present with low blood pressureand significantly depressed cardiac output tomaintain systemic perfusion and preserve end-organperformance.

Long-term, continuous intravenous inotropic supportmay be considered as palliative therapy for symptomcontrol in select patients with stage D despiteoptimal GDMT and device therapy who are noteligible for either MCS or cardiac transplantation.

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Inotropic Support (cont.)

Long-term use of either continuous or intermittent,intravenous parenteral positive inotropic agents, inthe absence of specific indications or for reasonsother than palliative care, is potentially harmful inthe patient with HF.

Use of parenteral inotropic agents in hospitalizedpatients without documented severe systolicdysfunction, low blood pressure, or impairedperfusion, and evidence of significantly depressedcardiac output, with or without congestion, ispotentially harmful.

I IIa IIb III

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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 beenassociated with no improvement or even increased overallmortality. This uncomfortable dilemma has led to expandeduse of heart replacement therapy.

• Development of novel inotropes has been hindered in recentdecades by the ambitious goal of achieving two seeminglyopposing effects with a single molecule.

• Clinicians want to use drugs that increase cardiac outputwithout increasing myocardial oxygen consumption.


Conclusions

• The second goal of newly developed inotropes is to maintainstable levels of, or even reduce, myocardial energyconsumption.

• The conserved energy may then be redirected for cellularrepair and promotion of mitochondrial health with reductionof oxidative stress.

• Effectively, this requires that the inotropic agent does notresult in increased chronotropy or calcium flux, as theseprocesses may be the primary cause of the increasedmortality associated with inotropic drugs.


Conclusions

• One would hope that the next generation of inotropic agentswill achieve enhanced myocardial performance withoutaltering the velocity of shortening or promoting excessivecalcium modulation at the level of the SR or the L-typecalcium channel

• Patients with end-stage heart failure are unstable bydefinition, thus presenting many additional challenges. Thesepatients are also highly complex medically, providing multipleopportunities for confounding influences.


Conclusions

• Large patient populations are usually necessary to testsurvival outcomes.

• Clinical trials in this group of patients are likely to continue tobe expensive, difficult, and uncertain with regard to properend points.

Nevertheless, the search for ideal inotropes should and will continue


THANK YOU


Health & Medicine

Inotropic therapy for heart failure