Levosimendan therapy in CHF in Clinical Hospital Mostar

Levosimendan therapy inCHF in Clinical Hospital MostarEmir Fazlibegović, ESC,FESCMustafa Hadžiomerović, ESC,FESCClinical Hospital Mostar, Bosnia and HercegovinaCardio Alex PanArab 2010Alexandria-Egypt, 11 Jun 2010

WHAT IS HEART FAILURE?• “HF is a complex clinical syndrome that can result from any structuralor functional cardiac disorder that impairs the ability of the ventricle tofill with or eject blood. The cardinal manifestations of HF are dyspneaand fatigue, which may limit exercise tolerance, and fluid retention,which may lead to pulmonary and peripheral edema.Both abnormalities can impair the functional capacity and quality of lifeof affected individuals, but they may not necessarily dominate theclinical picture at the same time.”Evaluation and Management of Chronic Heart Failure in the AdultA Report of the ACC/AHA Task Force on Practice GuidelinesFebruary 2002• Supply is less then demand• Failure of the heart as a pump

Systolic/Diastolic – does it matter?Systolic:• heart cannot contract normallyand cannot pump enough bloodinto the arteries (EF40%)

Left, right, or both?Right Heart Failure• Results in increased, systemic venouscongestion and peripheral edemaLeft Heart Failure• Results in pulmonary congestion

Different etiology – so what?• Many causes but clinical manifestationssimilar– Coronary artery disease is the underlying cause of HF inapproximately two thirds of patients with ischemic leftventricular systolic dysfunction.– The remainder have no ischemic causes, e.g. hypertension,valvular disease, myocardial toxins, or myocarditis– or may have no discernible cause (e.g., idiopathic dilatedcardiomyopathy).

Classification HFONSETETIOLOGYPATOPHYSIOLOGYLOCATION NYHA DIAGNOSISISCHEMICHEARTFAILUREACUTETOXICINFALMATORYSYSTOLICLEFTIIICardiacinsufficiencyCHRONICREUMATOIDDIASTOLICRIGHTIIICARDIOMIOPATHYIDIOPATICIVCardiacdysfunction

Congestive heart failure• The two primary goals of itsmanagement are preventing furtherdisease progression (mortality,hospitalizations and deterioration ofleft ventricular function) andalleviating patient suffering.

Treatment of Decompensated CHF67% 20% 8%5%DecompensatedHF PatientEdema (+)Warm ExtremitiesSBP > 90 mm HgHigh outputDecompensatedHF PatientEdema (+)Cold ExtremitiesSBP > 90 mm HgLow-output HFDecompensatedHF PatientEdema (-)Cold ExtremitiesSBP > 90 mm HgDecompensatedHF PatientEdema (+) or (-)Cold ExtremitiesSBP < 90 mm HgCardio shockOptimization of therapy:•Increase ACEI doses•IV diuretics•Other PO or IVvasodilators (nitroprusside)LevosimendanDobutamine/Dopamine/NorepinephrineInadequate response:• Increasing BUN• Persisting edema• Persisting dyspneaAdd Levo?

Contractile proteins in cardiomyocytesActinCa 2+TropomyosincTnCTnIMyosin head (S1 fragment)ATP pocketRLCTnTELC

Calcium-Induced ConformationalChanges in Troponin ComplexMyosin headTnIcTnCTnTCa 2+ Ca 2+ Ca 2+TnIActinTmTnTTmTnIActinTmMyosin headcTnCTmTnTTmActinMyosin headCa 2+Myosin headTnIcTnCTmTnTActinMyofilament lengthMyofilament length

Chemical DescriptionNLevosimendanNCCNHNNNHOH 3CHLipophilic pyridazinone-dinitrile derivative

Levosimendan• Calcium sensitisation through bindingto troponin C– increases cardiac contractility and efficiency• Opening of ATP-sensitive potassiumchannels in vascular smooth muscles– pulmonary, coronary, systemic vasodilation

Calcium Sensitization byLevosimendanNo increase in cAMPNo increase in i/c calcium•No increase in energy consumption•No arrhythmogenicity•No impairment in relaxation•Anti-stunning effect•No antagonism by -blockers

No Increase of EnergyConsumptionUkkonen et al. Abstract. Eur Heart J. 1998;(abstract suppl):547.

Myocardial Oxygen Consumption With PET(mean and SEM; N = 9)L/min0.08p=0.15300.070.060.050.04levosimendan (18 µg/kg+ 0.3 µg/kg/min for 5 h)placebo0.030.020.010Ukkonen et al, Clin Pharmacol Ther 2000

Oxygen consumption - factors• All preserved myocardial cells contract• For each myofilament contraction there isan ATP split:ATP= ADP – Pi• During the relaxation phase, there is lowCa ++ concentration in the myocite and highconcentration in the sarcoplasmic reticulum• Ca-ATPase transports Ca ++ against theosmolar grade[Note: Na + / Ca ++ exchange – no ATP is used, but rather theNa + transport (digitalis)]

Oxygen consumption - factors• Only about 25% of cross-bridges is used inthe healthy heart (~6-7 out of 30)• The rest is the „Myocardial Reserve‟• MR is significantly depressed in HF• ATP-ase is down regulated in HT, which letsCa ++ to stay in the cell longer (elderly)Levosimendan the # of crossbridgeswithout of i/c Ca ++

Calcium Sensitization by Levosimendancharacteristics• No excessive increase in oxygen consumption– does not “waste” energy for increased Ca 2+ cycling– does not change cross-bridge kineticsuneconomically– stabilizes myofilament proteins in the calciuminducedorientation required for contraction– increase the myocardial contractile force withoutimpairing relaxationJanssen et al.,EJ Pharm, 2002,404;191-199

Does not Increase Risk ofArrhythmiasChanges in ambulatory ECG compared with baselineSingh et al. Am J Cardiol. 1999;83:16(I)-20(I).

Timing of intracellular calcium transientrelative to contraction and relaxationIntracellular calcium transient and contraction–relaxation cycleLevosimendanForcedevelopmentRelaxationOther Ca 2+ sensitisers:stronger non-specificbinding of calciumto troponin-CTime

Coronary blood flowLilleberg et al. Eur Heart J. 1998;19:660-668.

Pharmacokinetics• Loading dose:– time to steady state -4 hours– peak effect - 0.2-0.5 hours• Maintenance infusion:– time to steady state -2 hours– peak effect - 4 hours– duration of effect - 2hours•Volume of distribution at steady state 0.19L/kg• Protein binding 98%• Half-life 1 hour

Levosimendan-Metabolites• Main metabolic route = conjugation withglutation.• After 24 h infusion about 5 % of the doseis metabolized to OR-1855 and OR-1896.• Levosimendan is reduced by intestinalbacteria to an amine metabolite (OR-1855)which is further acetylated (OR-1896)• Accumulation of OR-1896 occurs afterlonger infusions of levosimendan.• OR-1855 and OR-1896 in vivo are atequilibrium.

Active Metabolites ofLevosimendan• Correspond to 5% of total metabolism oflevosimendan• Elimination half-life about 80 h in patients• About 40% bound to plasma proteins• Haemodynamic profile similar to levosimendan• As potent a calcium sensitizer as levosimendan

Active Metabolite-PK parameters• OR-1896– half-life 80 hours– protein binding 61%– peak effect 48-72 hours afterlevosimendan infusion– duration of effect ~7 days (HR & BP)

Concentration (ng/ml)Pharmacokinetics of levosimendan in patientswith heart failure (Study 3001058, iv)807060Dose: 0.2 µg/kg/min for 24 hLevosimendanOR-189650403020t ½ (h)C max (ng/ml)T max (h)LevosimendanOR-189677 ± 91.3 ± 0.124 a 72 (48-120) b62.6 ± 8.4 5.5 ± 0.61024 h infusion00 1 2 3 4 5 6 7 8 9 10 11 12 13 Time (days)(mean ±SEM), n=12 a end of infusion, b median (range)(mean ±SEM), N=12 a end of infusion, b median (range)3001058, group 4

Mean plasma concentrations (ng/mL) of levosimendanduring and after one week continuous infusion (0.1 and0.05 µg/kg/min) (N = 12)Concentration (ng/mL)4440levosimendan 0.1 µg/kg/minlevosimendan 0.05 µg/kg/min36322824201612840Study 3001058Infusion time1 2 3 4 5 6 7 8Time (days)

Mean (±SEM) plasma concentrations of levosimendanand its metabolites during and after one week continuousinfusion (0.1 µg/kg/min) (N=12)Concentration (ng/mL)4540LevosimendanOR-1855OR-18963530252015105Infusion time01 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18Study 3001058Time (days)

Levosimendan in SpecialPopulations• Age- no differences• Sex- no difference when adjusted forweight• Liver dysfunction- reduced eliminationof metabolites• Renal dysfunction- decreased proteinbinding and slower elimination

Dose-escalation Study:Symptomatic Improvements at 6 HoursSlawsky et al. Circulation. 2000;102:2222-2227.Kivikko et all, Circulation, 2003

Dose-escalation Study:Haemodynamic Improvements at 6 HoursSlawsky et al. Circulation. 2000;102:2222-2227.Kivikko et all, Circulation, 2003

Dose-escalation StudyCombined Significant Haemodynamic Improvements at 6 HoursSlawsky et al. Circulation. 2000;102:2222-2227.Kivikko et all, Circulation, 2003

Dose-escalation Study:Change in Stroke Volume OverTimeSlawsky et al. Circulation. 2000;102:2222-2227.Kivikko et all, Circulation, 2003

Dose-escalation Study:Change in PCWP Over TimeSlawsky et al. Circulation. 2000;102:2222-2227.Kivikko et all, Circulation, 2003

IHD and Cardiac surgery• RUSSLAN study– 504 patients with recent MI, levo vs.placebo. Trend to lower mortality at 180days.• Small studies in cardiac surgery showlevosimendan increases cardiac outputand lowers SVR

Kaplan-Meier curve

Mostar study in 20 patientsNYHA III-IV• Aged 43-84, average 69• All patients treated with ACE inhibitors,diuretic, beta blockers, aldosteroneblockers, statins, and cardiotonics (digoxinchronically and dobutamin, dopamine in theshortly crisis period).• On follow-up 1-3 day after infusion and 3and 6 month, and 1-2-3 year after.

Dosing and Administration• Give a loading dose of 12-24 mcg/kg infused over 10 min• Follow with a maintenance infusion of 0.1 mcg/kg/minover 24h• Assess patient response after 30 to 60 min– If the response is deemed excessive, decreaseinfusion rate to 0.05 mcg/kg/min or discontinue– If the initial dose is tolerated and an increasedhemodynamic effect is required, increase infusion rateto 0.2 mcg/kg/min• Individualize dose and duration of treatmentaccording to the patient‟s clinical condition andresponse.

Levosimendan and NYHANYHA kl.4444 4 444444444 4 43,5333 3 3 3 3 3333 33 3333 3 32,522 222222221,510,501 2 3 4 1 2 3 1 2 3 1 2 1 2 1 2 1 2 3 1 2 1 2 1 2 1 2 1 2 1 2 1 1 1 2 1 2 1 2 1 2 1 2

Levosimendan and NYHAMean=-1.0000 Std Dev=0.6124 P< 0.0001

EFLV in patients withlevosimendanEF90%80%82%70%72%69%71%64%60%50%40%30%48%27%58%55%53%35%33%38%45%37%57%32%45%41%43%27%57%26%45%37%27%35%32%59%36%44%36%26%32%39%37%52%20%17%20%20%17%21%10%0%1 1 1 1 2 2 2 3 3 3 4 4 5 5 6 6 7 7 7 8 8 9 9 10 10 11 11 12 12 13 13 14 15 16 16 17 17 18 18 19 19 20 20

Levosimendan and EFLVMean=15.7059 Std Dev=14.3952 P= 0.0004

Levosimendan and ENDLVEndLV109876543217,3 7,7 6,15,66,8 6,9 6,95,95,4 5,655,69,27,95,5 5,25,9 5,7 5,8 5,99,89,27,976,67,36,6 6,4 6,3 6,55,7 5,9 5,96,15,44,88,7 8,8 9 8,7 8,88,101 1 1 1 2 2 2 3 3 3 4 4 5 5 6 6 7 7 7 8 8 9 9 10 10 11 11 12 12 13 13 14 15 16 16 17 17 18 18 19 19 20 20

Levosimendan and FSFS60%50%51%20%10%7%25%23%20%21%11%22%13%13%12%23%18%15%24%17%17%22%20%17% 18% 19%20%16%12%40%42%40%29% 31%17%28%18%16%13%39%41%30%30% 32% 35%31%32%0%01 1 1 1 2 2 2 3 3 3 4 4 5 5 6 6 7 7 7 8 8 9 9 10 10 11 11 12 12 13 13 14 15 16 16 17 17 18 18 19 19 20 20

Distrubtion of FS withlevosimendanMed=0.0818 SD=0.0915 P= 0.002

Conclusion 1• Experience from our practice showsthat single dose of Levosimendan inpatients with decompensatedadvanced heart failure producessignificant improvement, which reflectsin extension of life.

Conclusion 2• Use of Levosimendan seams to bebeneficial demonstrated by greatbenefit in the quality of life with bettersystolic function without anyarrythmogenic effect.

Conclusion 3• There are probably other benefitsmasked by uknown lusitropic andpleotropic influences of Levosimendanin the physiology and pathophysiologyof heart and others systems of body.

Conclusion 4• Almost all cases of death are results ofco-morbidity disease, and are notrelated to levosimendan effect• ICD device• Cardiac surgery• TransplantationIn the future