CARDIAC INOTROPES

Speaker: Dr Sandeep Mohanan

OUTLINE• Introduction• Application & indications• Classification• Current cardiac inotropic drugs in use- Action- Pharmacology- Clinical application- Side effects- Evidence & guidelines

• Newer cardiac inotropes in the pipeline• General practice guidelines

CASE SCENARIO

• 56 year old gentleman, HTN ,DM-2, CAD, severe LV dysfunction• On proper evidence based CAD & HF medications + CRT-D• Presentation with progressive dyspnoea (NYHA IV), decreased urine output

and drowsiness• BP – 96/70 mmHg, JVP elevated, ascites, pedal edema• RFT- 106/2.1

Diagnosis: ADCHF with Type 1 cardiorenal syndrome, hemodynamically stable

Treatment: Diuresis, Vasodilators ….Should an inotrope be added?

Course : Worsening renal function and mentation....BP 102/72….

……..Should an inotrope be added? If yes which one?………..

INOTROPE

• Inotrope: A drug that alters the force or energy of myocardial contraction

• Greek origin : Ino = fibre, Tropic= relating to

• Positive inotropes: Increases myocardial contractility

- Cardiac contractile failure (HEART FAILURE) ( Cardiomyopathy, Acute myocardial infarction,

Myocarditis, Cardiogenic/septic chock)

• Inotropy --- No. of cross-bridges activated:

1) Amount of Ca available to bind Troponin C2) Ca affinity of Troponin C3) Alterations at level of cross-bridging:- promotion of cross-bridge state- cross-bridge force production- Duration of cross-bridged state

Clinical application of Inotropes• Cardiogenic shock : When SBP <90mmHg

• AHFS without shock with evidence of vital organ hypoperfusion

• Intermittent outpatient infusions

• Bridge until transplantation

• Destination therapy for end-of-life care

• Cardiopulmonary resuscitation

• CHF routine therapy

At what WHO stage to start?

At what NYHA class to start?

Acute Heart failure is a heterogenous syndrome

• Digoxin: CHF , AF

• I.V. Inotropes: Currently used in the clinical setting of SHOCK to preserve end-organ perfusion

• SHOCK: The state of inadequate perfusion where oxygen delivery fails to meet tissue oxygen demands.

• Hypotensive AHFS: ~5% all (In-hosp mortality >15%)(SBP is one of the most important prognosticator)

• In-hospital death increases by 21% for each 10mmHg decrease of SBP below 160mmHg (OPTIMIZE-HF registry)

SHOCK:

- Urine output < 0.5ml/kg/hr- Cold peripheries- Capillary filling time >2s- Confusion-SBP <80-90mmHg, MBP <30mmHg of baseline(<60-70mmHg)

- CI <1.8 l/min/m2 ; LVEDP >18mmHg

CLASSIFICATION OF INOTROPES• By mechanism of action:Class I : Increase intracellular cAMP (Beta adrenergic agonists,

PDE inhibitors)

Class II: Affect sarcolemmal ion pumps/channels (Digoxin)

Class III: Modulate intracellular Ca mechanism- 1) Release/Uptake of sarcoplasmic Ca 2) Increase sensitization of proteins to Ca

Class IV: Multiple mechanisms (Pimobendan, Vesnarinone)Arthur Feldmann. Classification of Positive Inotropic Agents. JACC Vol. 22, No . 4 ,October 1993 : 1 223-7

BETA ADRENERGIC AGONISTS

DOBUTAMINE

DOPAMINE

ISOPRENALINE

NORADRENALINE

Beta Adrenergic agonists-DOBUTAMINE

• Directly stimulate β receptors

• β1 >>>β2>>α1 (β1: β2 = 3:1)

• Developed by Eli Lilly company as a structural analogue of isoprenaline in 1975

• Potent inotrope , mild chronotropic and peripheral vascular effects

Tuttle RR, Mills J. Dobutamine: development of a new catecholamine to selectively increase cardiac contractility. Circ Res. 1975 Jan;36(1):185-96.

Dobutamine-Pharmacology

• Onset of action: 1-2 mins• Peak effect : ~ 10 mins• Half-life : 1-2mins• Metabolism : Methylation & conjugation --- Urine• 250mg/20 ml vials• 2-20micg/kg/min( max 40micg/kg/min1)

• Sodabicarb should not be given in the same i.v line (inctivation at alkaline pH)

Dobutamine- Clinical application• Mild vasodilation : <5micg/kg/min(At higher doses >15, peripheral effect becomes vasoconstriction)

• Used mainly for primary low COP states

• Better not used as single inotrope for cardiogenic shock

• Dose titration required due to variable sensitivity (especially elderly)

• ? Loss of efficacy in patients on chronic beta blocker therapy/acidosis/hypoxia

Inotrope and Vasopressors: review of physiology and clinical use. Circulation 2008;118.

Dobutamine –Side effects• Hypotension• Hypertension and Tachycardia – especially for those with

chronic beta blocker therapy • AF with increased ventricular rate• Ventricular arhhythmias (rare)• Worsening ischemia• Phlebitis (rarely)• Nausea, headache, chest discomfort, hypokalemia,

hypersensitivity (eosinophilic myocarditis)• No significant drug interactions

• Contraindicated in HCM

Dobutamine – Evidence base

• Experience from controlled trials do not extend beyond 48 hours

• Found superior to isoproterenol for increasing COP1

( A comparison of dopamine, dobutamine and isoproterenol in the treatment of shock. Intensive Care Med.1985;11(1):13-9)

• Found equivalent to Dopamine in increasing COP however at lower peak heart rates and LVEDP2

(Comparison of dobutamine and dopamine in treatment of severe heart failure. Br Heart J. 1977 May; 39(5): 536–539.)

• Dobutamine has no survival benefit and may even increase mortality in severe heart failure3

(Dobutamine for patients with severe heart failure: a systematic review and meta-analysis of randomised controlled trials. Intensive Care Med. 2012 Mar;38(3):359-67)

Dobutamine- Guidelines for HF

In the setting of hypotension (SBP<85-90mmHg) and/or hypoperfusion:

• ESC 2012 Class--- IIa, B

• ACC/AHA 2009 -- IIb, C

• HFSA 2010 ---- IIb, C

• Sympathomimetic & neurotransmitter

• Arvid Carlsson in 1957 (Sweden)(Nobel Prize in 2000)

• D > β1> α1>> β2

• Dose dependent receptor action

Beta Adrenergic agonists-DOPAMINE

Dopamine- Pharmacology

• Low dose (0.5-2µg/kg/min): (Vasodilation)D1 post-syn receptors -- Cor, ren, mes, cerebD2 presyn receptors – Renal tissue and vasculature

• Intermediate dose (2-10 µg/kg/min): (Inotropic)β 1 receptors of heart

• High dose (10-20 µg/kg/min) : (Vasoconstriction)α 1 receptors of vessels

• 200-400mg/5ml vial• Onset of action – 5 mins• T-half – 2 mins• Primarily renal excretion

Dopamine- Side effects• Hypotension at low doses• Hypertension and Tachycardia• Tachyarrythmias• Worsening ischemia

• Phlebitis , necrosis and gangrene (rarely) ( Phentolamine to be infiltrated when extravasation is noted)

• Nausea, vomiting, azotemia, headache, piloerection, dyspnoea, hypersensitivity• May worsen ventilatory requirements in hypoxic patients

• Drug interaction: - Halogenated anaesthetics – ventricular arrhythmias - Phenytoin – increased chance for bradycardia - MAO inhibitors and TCA s – potentiate dopamine effects

• Contraindicated in pheochromocytoma & tachyarhythmias

Dopamine- Evidence • PRIME-II study (Ibopamine) : Increased mortality in heart failure. (Hampton et al. Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure. (PRIME II). Lancet.

1997; 349: 971–977.)

• Enthusiasm of low dose Dopamine and renal vasodilation - (-Goldberg et al. Cardiovascular and renal actions of dopamine. Pharmacol Rev. 1972;183: 256–263.)

• Wide variations in dose-dependent renal effects, esp when associated with renal disease/septic shock, and no clinically relevant renal benefits.

(-Wee et al. Effect of intravenous infusion of low-dose dopamine on renal function in normal individuals and in patients with renal disease. Am J Nephrol. 1986, 6: 42–46.

- Girbes et al. Lack of specific renal haemodynamic effects of different doses of dopamine after infrarenal aortic surgery. Br J Anaesth. 1996; 77: 753–757.)

• However clinical benefit in improving renal function has been reported when used along with diuretics for congestive heart failure

(Varriale. Role of dopamine in congestive heart failure: a contemporary appraisal. Congest Heart Fail. 1999 May-Jun;5(3):120-124.)

- Elkayam et al. Renal Vasodilatory Action of Dopamine in Patients With Heart Failure. Circulation.2008; 117: 200-205 )

Dopamine – Guidelines for HF• In patients with shock, despite already

treatment with an inotrope

- ESC 2012 -- IIb, C

- ACC/AHA 2009 -- IIb, C

Beta adrenergics- ISOPROTERENOL

• Potent nonselective pure β agonist• Powerful chronotrope, inotrope and

peripheral vasodilator• Net neutral impact on COP.• Used clinically as a positive chronotrope

rather than as an inotrope.• Not used for cardiogenic (pump-failure) shock

management

NOREPINEPHRINE

• α1>>β1> β2• Powerful vasopressor, modest

inotropic effects

• Less chronotropic effect than Dob and Dop

Norepinephrine – Clinical applications

• In general, better studied and applied for septic shock than cardiogenic shock

• Cardiotoxic at high doses due to apoptosis in experimental models

( PKA mediated)

--Side effect profile similar to Dopamine

Dopamine vs Norepinephrine• Shock due to any cause – NE = Dop (Cochrane review , May 11 2011)

• Septic shock – NE > Dop- No significant mortality difference, Greater adverse effects due to Dopamine. (N Engl J Med. 2010 Mar 4;362(9):779-89)

- Mortality higher for dopamine ( 1) J Intensive Care Med. 2012 May-Jun;27(3):172-8 2) Crit Care Med 2012; 40:725–730)

• Cardiogenic shock – NE > Dop - Mortality as well as arrhythmias higher for Dopamine (N Engl J Med. 2010 Mar 4;362(9):779-89)

• AHA 2009/ESC 2012/HFSA 2010 guidelines do not comment on superiority/ priority of any single inotrope…. Dobutamine generally accepted as 1st inotrope of choice for heart failure.

• Additional support with ?Dop> NE inspite of contrary evidence....AHA guidelines.

PHOSPHODIESTERASE-3 INHIBITORS(Inodilators)

MILRINONE

AMRINONE

ENOXIMONE

VESNARINONE

PDIs - MILRINONE• Vasodilation (cAMP inhibits MLCK in

vessels) > positive inotropy• Inotropic, Chronotropic, Lusitropic

Systemic circulation effects: - Vasodilation - Increased organ perfusion - Decreased systemic vascular resistance - Decreased arterial pressureCardiopulmonary effects: - Increased contractility and heart rate - Increased stroke volume and ejection

fraction - Decreased ventricular preload - Decreased pulmonary capillary wedge

pressure

Milrinone - Pharmacology• Bolus: 50µg/kg bolus over 10 to 30 min (preferably avoided)

• Infusion: 0.375 to 0.75µg/kg/min (Dose adjustment required for GFR<30ml/min)

• Half life : 2.5 hours• Renal clearance – prolonged action if renal dysfunction

develops

Milrinone- Side effects• Ventricular arhythmias ~ 12% ( serious ~ 1.2%)• SVT ~3.8%• Hypotension, angina• Torsade de pointes – reports• Headaches ~ 2.9%• Hypokalemia, tremor, thrombocytopenia (rare ~ 0.4%)• Transaminitis, hypersensitivity

• No significant drug interactions• Should not be injected in same line as furosemide

Milrinone- Clinical application

• Acute heart failure

• Theoretical advantages compared to β agonists :- Chronotropic effect is less than β agonists- Less tachycardia for AF patients- Better efficacy for those on chronic BB therapy- Lusitropic and vasodilatory effects ( decrease afterload

and preload)

(However more expensive, hypotension and prolonged action with Milrinone)

Kaplan–Meier Analysis Showing Cumulative Rates of Survival in Patients with Class IV Heart Failure, According to Treatment Group.

Packer M et al. N Engl J Med 1991;325:1468-1475.

Milrinone- Evidence

Outcomes of a Prospective Trial of Intravenous Milrinone For Exacerbations of Congestive Heart Failure

OPTIME-CHF JAMA 2002Design Randomized, Control, Double Blinded

Milrinone 48-72 hours versus Placebo

Enrolled Broad Population with systolic dysfunction Without low output syndrome949 patients

Primary Endpoints Repeat hospitalization for cardiovascular causes within 60 days of discharge.

Outcomes No difference in primary end point between Milrinone and placebo.Higher instance of atrial arrhythmia and hypotension with Milrinone.Milrinone is associated a 30% increase in mortality

Conclusions Not indicated in routine use with standard medical therapy.

• Increases heart failure and SCD mortality when given for long term treatment iv/ oral for CHF

(Cochrane Database Syst Rev. 2013 Jan 31;(1):CD002230)

• It causes a higher post discharge 60-day mortality in CAD patients.(11.6% vs 7.5% ) (OPTIME CHF – JACC 2002)

Present guidelines for HF in acute setting:

• ESC 2012 --- IIb, C • ACC/AHA 2009 --- IIb, C• HFSA 2010 --- IIb, C

Milrinone- Evidence

CALCIUM SENSITIZERS- LEVOSIMENDAN

• Pyridazone-dinitrile derivative• Dual mechanism of action:1) Binds to Ca binding site of TnC in sarcomere2) KATP channel opener in smooth muscles

Levosimendan – Actions• Binds to Ca binding site (N-terminus) of TnC• Stabilizes the Ca-TnC complex and inhibits TnI --

prolongs actin-myosin cross bridge association rate• The binding affinity depends on the i.c Ca

concentration• Hence, inotropic action only during systole (On-off

action)

• PDI like action at higher concentrations1

1)Hasenfuss et al.Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium.Circulation1998;98:2141 – 2147.

Levosimendan - Pharmacology• Loading : 12-24µg/kg over 10 min• Infusion: 0.05-0.2µg/kg/min

• Can be given orally also (Bioavailability ~85%)

• T-half – 0.5-1.4 hours

• Hepatic + intestinal metabolism (no renal modification)

• Dose dependent action (linear pharmacokinetics)

• Active metabolite – OR-1896 (half life of 80 hours) – responsible for prolonged action upto several days after stopping infusion

Levosimendan – Side effects

• Hypotension (15- 50%)• Headache• Arrhythmias

• No significant drug interactions

Levosimendan – theoretical advantages over Dobutamine

• Vasodilatory action– decrease preload, after load and improves coronary blood flow.

• Does not increase intracellular Ca/ oxygen demand

• Does not impair diastolic relaxation (Positive lusitropy)

• Decreases LVEDP during coronary ischemia

• By action on mitochondrial KATP channels – decrease apoptosis– in vitro beneficial effects on remodelling.

• Beneficial in CAD, sepsis, paediatric sub groups

• Antioxidant and anti-inflammatory effects

• Beneficial renal and gastrointestinal effects

Levosimendan - Evidence• Credited with the largest available evidence among iv inotropes

(>3500 patients) • A 24 hour infusion increased COP ~40%, reduced PCWP ( -8.9mmHg) , 30% reduction in SVR & increased HR (~6bpm) (Kivikko M et al. Sustained hemodynamic effects of intravenous levosimendan. Circulation. 2003;107:81– 86)

• LIDO • RUSSLAN• CASINO • REVIVE I & II, • SURVIVE

LIDO (2002)-203 patients with low output failure-Levsoimendan vs Dobutamine for 24 hours-~32% relative mortality benefit at 120 days-Higher COP and lower PCWP

RUSSLAN(2002)- Post-infarction heart failure patients-Levosimendan vs placebo- Significant 14-day and 120day mortality benefit

CASINO-299 patients with NYHA IV ADCHF-Levosimendan vs Dobutamine vs placebo-Significant survival advantage at 6 months(15% vs 40% vs 25%)

• REVIVE -1 and REVIVE-2 (2005):- Severe ADHF (EF<35%)- Better study design than previous- Early improvement of symptoms over 5 days- No mortality benefit at 90 days, with higher incidence of

hypotension and arrhythmias.

• SURVIVE (2005):- Levosimendan vs Dobutamine for ADHF (EF<35%)- 1327 patients- Significant early symptomatic benefit and improvement in

hemodynamic parameters- No overall mortality benefit at 6 months- Significant 30 day mortality benefit for those with previous CHF (on

c/c BB therapy)

LEVOSIMENDAN - Evidence

• Significant mortality benefit for critically ill patients with heart failure and patients undergoing cardiac surgery

(Metanalysis from 11 controlled trials (2009) )

• Improves mortality after coronary revascularisation compared to standard therapy

(Critical Care 2011)

• Improves survival as well as hemodynamics compared to dobutamine

( metanalysis -- International Journal of Cardiology 2010)

Levosimendan cost analysis?

• Cost of Levosimendan (2.5mg/5ml) ~ 10 times cost of dobutamine

• However it is shown to be cost effective when compared to standard inotropic agents in acute severe low output heart failure considering re-hospitalisation rates.

(Fedele F et al. Cost-effectiveness of levosimendan in patients with acute heart failure. J Cardiovasc

Pharmacol.2011 Oct;58(4):363-6.)

Final word on Levosimendan?- guidelines

• Only intravenous positive inotrope that has had a mortality benefit consistently.

• Plenty of theoretical advantages over standard inotropes

• Uniform physiological benefits for coronary, renal and g.i systems

• Hypotension may be the main reason negating its efficacy

• ESC: Recommended as second line inotrope (IIa,B) for AHFS• Approved in Europe, Asia, South America & Australia

DIGOXIN

• A purified glycoside extracted from foxglove plant (Digitalis lanata)

• Discovered & described by William Withering in 1785

-English botanist, geologist, chemist & physician

• Initially a routine drug for ‘dropsy’ (edema)

• Oldest CVS drug that is still being used (>200years)

Digoxin - Action• Potent inhibitor of cellular Na-K ATP-ase -- blunts Ca extrusion• Positive inotropy ( LVEDP, LVEDV &LVESV )• Negative chronotropy and dromotropy ( vagal action)• Increased baroreceptor sensitization--withdrawal of

sympathetic stimulation-- vasodilation• Decreases neurohormonal activation• Induces diuresis

Digoxin- PharmacologyOral administration• T-half = 40 hours ( So steady state in around a week) ----- Digitalization• Bioavailability : 60-80%• Onset ~ 2hours ; Peak effect ~ 2-6 hours• Better taken in empty stomach• Intestinal absorption is inhibited by P-glycoprotein on

enterocytes (an efflux protein)• Large volume of distribution (500litres)• Crosses BBB and placenta• 25% bound to plasma proteins• Excretion – 70-80% unchanged by renal (1st order kinetics)

Oral digoxin administration- Narrow therapeutic levels (0.5-1.5ng/ml)- Body weight, age, renal function- For sick patients – loading dose(rapid digitalization)

Loading dose: ~20- 45 µg/kg (paed) / 10-15 µg/kg (adults)1/2 total dose initially--1/4 dose every 4-6 hours twice(Presently recommended only for AF rate control)

Maintenance dose: ~10µg/kg (paed) & ~5 µg/kg (adult)

(~ 1/4th of loading dose)

~ 0.125- 0.25mg for an adult male with HF and normal renal function

Digoxin – i.v

• Can cause systemic as well as coronary vasoconstriction (avoided by administration over 20-30mins)

• When carefully used is hemodynamically beneficial for AHFS.

• Effects see within an hour.• However not recommended by international

guidelines due to lack of evidence.

Digoxin- side effects• Dose dependent• ~ 5-20% ( 15-20% serious side effects)(~ 50% is cardiac toxicity)

• GI: nausea, vomiting, intestinal pain, hemorrhagic necrosis• CVS: Almost any arrythmias• CNS: blurring/yellow vision, delirium, headache, confusion,

depression, hallucination• Thromobocytopenia, gynaecomastia, skin reaction

Digoxin effect

• STD with inverted/biphasic T waves (‘Inverted tick-mark’)• QT shortening• Prominent U waves• PR prolongation• Peaking of T waves

Salvador- Dalis moustache sign

Digoxin – Drug interactions• No CYP related interaction• Substrate of P-glycoprotein (Pharmacokinetic interaction)

Significant increase in S.Digoxin concentrations (>50%)

Digoxin conc increased (<50%)

Amiodarone Atorvastatin

Dronedarone Carvedilol

Captopril Diltiazem

Clarithromycin Indomethazine

Gentamicin Nifedipine

Erythromycin Tolvaptan

Propafenone , Quinidine Trimethoprim

Ranolazine Telmisartan

Ritonavir Spironolactone

Tetracycline Quinine

Verapamil

Itraconazole

Pharmacodynamic interactions Mechanism

NSAIDS, ACE inhibitors Decreasing renal clearance

Diuretics Hypokalemia, hypomagnesemia

Dofetilide , Sotalol, Dronedarone Proarrhythmia– sudden death

Teriparatide Hypercalcemia—dig toxicity

Thyroxine (decrease S.digoxin) Increased clearance

Other Inotropic agents Tachyarrhythmias

BBs & CCBs Bradyarrhythmias

Digoxin toxicity• Hospitalisation for suspected toxicity in DIG ~ 2%• Dig-arrhythmia at 1.7ng/ml ~ 10% & at 2.5ng/ml ~ 50%

• Caution in elderly, females, CKD, drug interaction, cardiac amyloidosis, hypothyroidism, hypokalemia, hypoxia, severe acid-base imbalances

• Ideal SDC is 0.7-1.3ng/ml• SDC recommended for high risk patients ~ 14-21 days after initiation atleast

8hours after previous digoxin dose.

• GI symptoms, CNS symptoms, various arhhythmias, hyperkalemia should provoke suspicion.

• Stop digoxin, correction of precipitants, treatment of arhhythmias, Digibind Abs for lifethreatening arrhythmias and dialysis for hyperkalemia.

Digoxin- Evidence• Incidence of worsening of HF from 12 RCTs (including PROVED &

RADIANCE) was 24% for non-digitalis vs 5% for digitalis group when standard HF management was given.

Digitalis Investigation Group trial(NEJM 1997)

• Largest digoxin trial ~ 7800 patients• LVEF</= 45%, ischemic /nonischemic• Matched for ACEinhibitors and diuretics- No effect on overall mortality rates- Significantly reduced incidence of death/hospitalization caused by worsening

HF

- Women had higher mortality at 5 years(However no gender difference for SDC<1ng/ml)

• Ancillary trial with 988 patients with LVEF >45% --- Similar conclusions

• For LVEF<25%, CT ratio>55% or NYHA3/4 symptoms, total mortality benefit(RRR~ 39%) & re-hospitalization seen at 2 years

Evidence based beneficial effects of Digoxin in HF

• Stood the test of time (>220 years)• Orally once daily dosing• Easily tolerated and less frequency of serious S/E• Inexpensive• Reduces costs of HF treatment• Has multiple actions and hemodynamic benefits• Only inotrope showing long term mortality benefits

and fewer side effects in therapeutic range.

Rahimtoola. Digitalis Therapy for patients in HF. Circulation,2004.

Digoxin - Guidelines• Approved by FDA for HF in 1998• ACC/AHA : IIA recommendation for clinical HF with LV

dysfunction and II B for HFNEF • ESC 2012 : IIb B for HF, sinus rhythm & LVEF <45%

• Decreasing trend in digoxin prescription (80% to <30%):- Not promoted by pharmaceutical industry- Mostly ignored in national/international meetings- Fear of drug interaction & toxicity- ? Higher mortality in women

• No evidence hence not recommended for AHFS/ ACS

Summary of current inotropic interventions

Newer inotropic agents – Hope or Hype?

• Istaroxime

• Omecamtiv mecarbil

• SERCA gene (gene transfer) • Nitroxyl –HNO (nitroxyl donorCXL-1020 )• Ryanodine receptor stablilizer (S44121 )• Energetic modulation (Etomoxir, Pyruvate )

ISTAROXIME• Steroidal drug, non-glycoside• Luso-inotropic agent1) SERCA-2a stimulation (Lusitropism)2) Na-K ATPase inhibition (Inotropism)

• Improving the impaired Ca cycling of HF

- Reduced activity/expression of SERCA- Increased activity of NCX causing Ca

extrusion- Increased inhibitory function of

phospholamban on SERCA- Upregulation of RYR2 causing Ca leak

Istaroxime- Evidence

• Comparing istaroxime:- With digoxin: Greater inotropic effect, better safety margin, no

direct bradycardic effect- With dobutamine: Better cardiac work efficiency

• Physiological effects:- Increases SBP, does not affect DBP- Decreases PCWP- Improves CI, Decreases LVEDV and LVSV- Decreases HR- Shortens QT interval

Istaroxime- HORIZON-HF• Phase II dose-escalating RCT, 120 patients• Worsening HF, LV dysfunction, PCWP>20mmHg

• 0.5,1,1.5 µg/kg/min over 6 hours• 18-25 years, EF<35%, SBP 90-150

• Exclusion: AF, ACS, LBBB, ICD/CRT, iv inotropic usage, S. digoxin>0.5ng/ml, S.Cr>3mg/dl, altered LFT.

Series1

-4

-2

0

Series1

-0.8

-0.4

0

0.4

0.8

HORIZON-HF

• Significant changes in E’ velocity and PCWP.

• Nonsignificant increase in cardiac index

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.

(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

OMECANTIV MECARBIL

• Cardiac specific myosin activator

• Stimulate myosin-ATPase Accelerates the rate of actin-

dependent phosphate release from the actin-myosin crossbridge

Promotes transition to the force producing on-state of the cross bridge

More cross-bridges activated per unit time

Increased contractile force

Omecantiv - Evidence

• Phase II trials have shown an increase in LVEF, decreased LVEDP and HR

• (Phase II safety study evaluating the novel cardiac myosin activator,CK-1827452, in patients with ischemic cardiomyopathy and angina.J Card Fail 2009;15.

• The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet. 2011 Aug 20;378(9792):676-83. )

• Further large scale controlled trials necessary before definitive conclusions can be made

GENERAL PRACTICE PRINCIPLES – i.v Inotropes for ADCHF

• Unlike the effect of CRT on HF which also improves myocardial function…. Why no definite mortality benefit???

• Use of inotropes for heart failure increased all-cause mortality ( ESCAPE trial. Use and impact of inotropes and vasodilator therapy in hospitalized patients with severe heart failure. Am Heart J 2007;153:98 – 104)

--i.c. Ca overloading, neurohormonal activation, adverse myocardial energetics, apoptosis

Mortality data from the ADHERE registry

• Even short term use of positive inotropic agents for AHF compared to vasodilator therapy alone increased mortality ( ADHERE registry)

• Majority of ADHERE population had a ‘warm-wet’ profile.

• Calcium-sensitizers have been found life-saving in instances.• Even though long term mortality benefit is inconsistent, short term

symptomatic improvements are noted• Vasodilators are not tolerated by a significant fraction of acute HF• Inotropes for heart failure with obtundation, anuria, lactic acidosis• An important bridge before definitive therapy/recovery following

acute hemodynamic collapse

Guidelines on inotropes in HF:

-ACC & ESC do not recommend routine use of i.v inotropes for the treatment of Stage D HF (Class III)

-However they may be considered for symptom management as a palliative measure (Class IIb)

- Both ACC & ESC do recommend i.v inotropes in an appropriate clinical setting of hypotension (SBP<85mmhg) and hypoperfusion in Stage C HF (ACC Class 1C/ ESC IIa,C/ HFSA IIa,C)

- Dobutamine - ESC Class IIa, B / ACC IIb, C/ HFSA IIb, C- Levosimendan- ESC Class IIb, C (especially for patients on c/c BB therapy) - Milrinone - ESC IIb, C / ACC IIb, C/ HFSA IIb, C- Dopamine – ESC IIb, C / ACC IIb, C

Inotropes in cardiogenic shock• Goal of positive inotropes:

1) Increase in BP (COP) -- thus vital organ perfusion-- diuresis2) Decrease in LVEDP to unload the heart

• Usually Dopamine as 1st choice -- Increases BP without dangerous hypotension

• If hypotension is not immediately life-threatening– Dobutamine 1st choice

• 2nd choice – Vasopressor ( Noradrenaline/ Dopamine)• In ADCHF patients if COP persistently low, Milrinone may be added

to Dobutamine (bypasses β-downregulation)

• Vasodilators to be added once BP has been stabilized as hypotension does not imply low SVR

Inotropes in ACS with heart failure• Already excessive i.c Ca overloading and inotropes may further worsen

ischemia, cause arhhythmias and cell necrosis.• However, recovery of poor hemodynamic parameter may outweigh these

complications.

• ACC recommends Dobutamine as 1st line agent when SBP is between 70-100mmHg in the absence of shock.

• If shock is present ACC recommends Dopamine (??Norepinephrine)• Combination of Dobutamine +Dopamine at 7.5µg/kg/min had been

found better than individually uptitrating a single inotrope. (Circulation, 1983)

• If persistent <70mmHg Norepinephrine may be added (ACC STEMI guidelines, JACC 2004)

• For HF a/w RVMI, hypotension even after adequate hydration to an RAP~15mmHg---Dobutamine improves outcomes (AJC 1994)

Intravenous inotrope titration

- SBP--- invasive arterial BP monitoring- Urine output – Hourly monitoring- Ectopics/arrythmias – ECG monitoring- CVP/PAP monitoring – However ESCAPE trial did

not show much clinical benefit - Heart rate to be monitored

- Should be tapered at steps of 2micg/kg/min

Decision on inotropic therapy for AHFS

ACC/AHA Heart Failure guidelines

Conclusion• Inotropic therapy relieves symptoms but does not affect

prognosis, which is more dependent on LV structural improvement.

• Inotropes in general causes proarrythmia and maladaptation.• They should be used as short in duration & low in dose as

possible.• Moderate doses of inotrope combinations is recommended over

high doses of single inotrope.

• The ultimate aim of inotrope use should be to tide the ‘crisis’ until definite evidence based therapy is initiated, and hemodynamics & symptoms return to baseline.

THANK YOU

Sky is the limit………………..

Theoretically best inotropes to useSituation 1st agent 2nd agent

Severe persistent shock(any cause)

1)Noradrenaline (NA)2) Dopamine (Dop)

1) Dop2) NA3) Levosimendan(esp cardiogenic shock after PCI & cardiac surgery)4) Dob

Heart failure with borderline hypotension

1) Levosimendan (Lev)2) Dobutamine (Dob)

(If SBP>70)3) Dop4) Milrinone (Mil)

Lev> Dob> Mil > NA

>Dop

Heart failure with SBP >90mmHg

1) Lev2) Dob3) Dop

Dob> DopLev> DopLev>Dob

INOTROPES-QUIZ

• 1) Cohort of heart failure where i.v inotropes may be considered:

a) Cold & Dryb) Cold & Wetc) Warm & Dryd) Warm & Wete) All of the above

• 2) Which among the following parameters defines cardiogenic shock:

a) Urine output <1ml/kg/hrb) Mean BP < 30mmHg from baselinec) Capillary filling time <2sd) CI < 2l/min/msqe) LVEDP <18mmHg

• 3) Which of the following does not have an effect on intracellular cAMP levels:

a) Dobutamineb) Milrinonec) Levosimendand) Enoximonee) b, c & d are right

• 4) 1st line inotrope recommended by international guidelines in setting of AHFS

a) Dopamineb) Dobutaminec) Levosimendand) Milrinonee) Norepinephrine

• 5) When considering the result from recent studies which of the following may be the best 1st line inotrope for cardiogenic shock:

a) Dopamineb) Dobutaminec) Noradrenalined) Levosimendane) i.v digoxin

• 6) Theoretically and evidence-wise which of the following would be the best inotrope to use in ADCHF without presence of significant hypotension

a) Dopamineb) Dobutaminec) Milrinoned) Levosimendane) Digoxin

• 7) OPTIME-CHF study for Milrinone showeda) Improved early outcomes of Milrinone compared to

placebob) Milrinone was equivalent to Dobutamine in efficacyc) Milrinone had higher mortality compared to placebod) Milrinone was equivalent to placebo for heart failuree) Dobutamine had early mortality benefit compared

to Milrinone

• 8) Which of the following have luso-inotropic action:

a) Levosimendanb) Istaroximec) Milrinoned) a & be) a, b & c

• 9) Which of the following may not be due to digoxin effect:

a) ST depressionb) U wavesc) PR prolongationd) T wave inversione) QT shortening

• 10) Digoxin doses needs to be decreased when given along with:

a) Atorvastatinb) Ranolazinec) Telmisartand) Spironolactonee) Diltiazem

• 11) Optimal maintainence dose for digoxin is:a) 1 mic/kg/minb) 5 mic/kg/minc) 15mic/ kg/mind) 25 mic/kg/mine) Loading doses are routinely recommended

before maintainence doses.