Transcript cardiac inotropes

CARDIAC INOTROPES
Speaker: Dr Sandeep Mohanan
OUTLINE
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Introduction
Application & indications
Classification
Current cardiac inotropic drugs in use
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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 C
2) Ca affinity of Troponin C
3) 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.
SHOCK:
- Urine output < 0.5ml/kg/hr
•- Cold
Hypotensive
AHFS: ~5% all (In-hosp mortality >15%)
peripheries
(SBP
is onefilling
of thetime
most>2s
important prognosticator)
- Capillary
- Confusion
<80-90mmHg,
MBP <30mmHg
(<60-70mmHg)
•-SBP
In-hospital
death increases
by 21%offorbaseline
each 10mmHg
- CI
<1.8 l/min/m
; LVEDP160mmHg
>18mmHg(OPTIMIZE-HF registry)
decrease
of SBP2 below
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 mechanism1) 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
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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
Beta Adrenergic agonists
-DOPAMINE
• Sympathomimetic & neurotransmitter
• Arvid Carlsson in 1957 (Sweden)
(Nobel Prize in 2000)
• D > β1> α1>> β2
• Dose dependent receptor action
Dopamine- Pharmacology
• Low dose (0.5-2µg/kg/min): (Vasodilation)
D1 post-syn receptors -- Cor, ren, mes, cereb
D2 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
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200-400mg/5ml vial
Onset of action – 5 mins
T-half – 2 mins
Primarily renal excretion
Dopamine- Side effects
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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
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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)
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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.
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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 pressure
Cardiopulmonary 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
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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
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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)
Milrinone- Evidence
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.
Outcomes of a Prospective Trial of Intravenous Milrinone For
Exacerbations of Congestive Heart Failure
OPTIME-CHF
JAMA 2002
Design
Randomized, Control, Double Blinded
Milrinone 48-72 hours versus Placebo
Enrolled
Broad Population with systolic dysfunction
Without low output syndrome
949 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.
Milrinone- Evidence
• 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
CALCIUM SENSITIZERSLEVOSIMENDAN
• Pyridazone-dinitrile derivative
• Dual mechanism of action:
1) Binds to Ca binding site of TnC in sarcomere
2) 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)
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LIDO
RUSSLAN
CASINO
REVIVE I & II,
SURVIVE
LIDO (2002)
-203 patients with low output failure
-Levsoimendan vs Dobutamine for 24 hours
RUSSLAN(2002)
-~32% relative mortality benefit at 120 days
CASINO
--Higher
Post-infarction
COP andheart
lowerfailure
PCWPpatients
-299
patients with
NYHA IV ADCHF
-Levosimendan
vs placebo
-Levosimendan
vs Dobutamine
placebobenefit
- Significant 14-day
and 120day vs
mortality
-Significant survival advantage at 6 months
(15% vs 40% vs 25%)
• REVIVE -1 and REVIVE-2 (2005):
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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
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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- Pharmacology
Oral 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
Salvador- Dalis moustache sign
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STD with inverted/biphasic T waves (‘Inverted tick-mark’)
QT shortening
Prominent U waves
PR prolongation
Peaking of T waves
Digoxin – Drug interactions
• No CYP related interaction
• Substrate of P-glycoprotein (Pharmacokinetic interaction)
Pharmacodynamic
Significant increase
interactions
in S.Digoxin
concentrations (>50%)
Digoxin
Mechanism
conc increased
(<50%)
Amiodarone
NSAIDS, ACE inhibitors
Dronedarone
Atorvastatin
Decreasing renal clearance
Carvedilol
Captopril
Diuretics
Clarithromycin
Dofetilide , Sotalol, Dronedarone
Gentamicin
Diltiazem
Hypokalemia, hypomagnesemia
Indomethazine
Proarrhythmia– sudden death
Nifedipine
Erythromycin
Tolvaptan
Propafenone , Quinidine
Teriparatide
Ranolazine
Thyroxine (decrease S.digoxin)
Ritonavir
Trimethoprim
Hypercalcemia—dig toxicity
Telmisartan
Increased clearance
Spironolactone
Tetracycline
Other
Inotropic agents
Quinine
Tachyarrhythmias
Verapamil
BBs & CCBs
Itraconazole
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 acidbase 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
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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
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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%):
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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
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SERCA gene (gene transfer)
Nitroxyl –HNO (nitroxyl donorCXL-1020 )
Ryanodine receptor stablilizer (S44121 )
Energetic modulation (Etomoxir, Pyruvate )
ISTAROXIME
• Steroidal drug, non-glycoside
• Luso-inotropic agent
1) 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.
HORIZON-HF
Trial design: Patients admitted with acute decompensated HF were randomized to istaroxime, an
inotropic and lusitropic agent (n = 89), versus placebo (n = 31).
(p = 0.048)
0.8
(p = 0.001)
-0.2
mm Hg
cm/sec
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Significant changes in E’ velocity
and PCWP.
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Nonsignificant increase in cardiac
index
0
0.5
0.4
-2
0
Conclusions
-0.4
-0.8
Results
-0.7
Change in E’
velocity
Istaroxime
-4
-3.7
Change in pulmonary
capillary wedge
pressure
•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.
Placebo
Shah SJ, et al. Am Heart J 2009;Apr24.
OMECANTIV
MECARBIL
• Cardiac specific myosin
activator
• Stimulate myosin-ATPase
Accelerates the rate of actindependent 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
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(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
Guidelines on inotropes in HF:
• Even short term use of positive inotropic agents for AHF compared
aloneroutine
increased
( ADHERE
-ACCto&vasodilator
ESC do nottherapy
recommend
usemortality
of i.v inotropes
forregistry)
the
• Majority
ADHERE
treatment
ofof
Stage
D HFpopulation
(Class III) had a ‘warm-wet’ profile.
-However
they may be have
considered
for symptom
management
• Calcium-sensitizers
been found
life-saving
in instances.as a
palliative
measure
(Class
• Even though
long
termIIb)
mortality benefit is inconsistent, short term
symptomatic improvements are noted
- Both ACC & ESC do recommend i.v inotropes in an appropriate
• Vasodilators
not tolerated
by a significant
fraction
of acute HF
clinical
setting ofare
hypotension
(SBP<85mmhg)
and
hypoperfusion
in
• Inotropes
forClass
heart1C/
failure
Stage
C HF (ACC
ESC with
IIa,C/obtundation,
HFSA IIa,C) anuria, lactic acidosis
• An important bridge before definitive therapy/recovery following
acute hemodynamic
- Dobutamine
- ESC Classcollapse
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)
2)
Increase in BP (COP) -- thus vital organ perfusion-- diuresis
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 70100mmHg 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 use
Situation
1st agent
2nd agent
Severe persistent shock
(any cause)
1)Noradrenaline (NA)
2) Dopamine (Dop)
1) Dop
2) NA
3) 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) Dop
4) Milrinone (Mil)
Lev> Dob> Mil >
NA
>Dop
Heart failure with SBP
>90mmHg
1) Lev
2) Dob
3) Dop
Dob> Dop
Lev> Dop
Lev>Dob
INOTROPES
-QUIZ
• 1) Cohort of heart failure where i.v inotropes
may be considered:
a) Cold & Dry
b) Cold & Wet
c) Warm & Dry
d) Warm & Wet
e) All of the above
• 2) Which among the following parameters
defines cardiogenic shock:
a) Urine output <1ml/kg/hr
b) Mean BP < 30mmHg from baseline
c) Capillary filling time <2s
d) CI < 2l/min/msq
e) LVEDP <18mmHg
• 3) Which of the following does not have an
effect on intracellular cAMP levels:
a) Dobutamine
b) Milrinone
c) Levosimendan
d) Enoximone
e) b, c & d are right
• 4) 1st line inotrope recommended by
international guidelines in setting of AHFS
a) Dopamine
b) Dobutamine
c) Levosimendan
d) Milrinone
e) Norepinephrine
• 5) When considering the result from recent
studies which of the following may be the best
1st line inotrope for cardiogenic shock:
a) Dopamine
b) Dobutamine
c) Noradrenaline
d) Levosimendan
e) 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) Dopamine
b) Dobutamine
c) Milrinone
d) Levosimendan
e) Digoxin
• 7) OPTIME-CHF study for Milrinone showed
a) Improved early outcomes of Milrinone compared
to placebo
b) Milrinone was equivalent to Dobutamine in efficacy
c) Milrinone had higher mortality compared to
placebo
d) Milrinone was equivalent to placebo for heart
failure
e) Dobutamine had early mortality benefit compared
to Milrinone
• 8) Which of the following have luso-inotropic
action:
a) Levosimendan
b) Istaroxime
c) Milrinone
d) a & b
e) a, b & c
• 9) Which of the following may not be due to
digoxin effect:
a) ST depression
b) U waves
c) PR prolongation
d) T wave inversion
e) QT shortening
• 10) Digoxin doses needs to be decreased
when given along with:
a) Atorvastatin
b) Ranolazine
c) Telmisartan
d) Spironolactone
e) Diltiazem
• 11) Optimal maintainence dose for digoxin is:
a) 1 mic/kg/min
b) 5 mic/kg/min
c) 15mic/ kg/min
d) 25 mic/kg/min
e) Loading doses are routinely recommended
before maintainence doses.