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SCOMPENSO CARDIACO AVANZATO La terapia con Amine e Levosimendan

Alessandra ChinagliaASL Città di Torino

NO CONFLITTI DI INTERESSE CON LE AZIENDE INTERESSATE

European Journal of Heart Failure (2018) 20, 1505–1535

SUPPORTO EMODINAMICO AL CIRCOLO

PREVENZIONE DELLA RIACUTIZZAZIONE

Insufficienza cardiaca avanzata riacutizzata Quando usare :

• Amine ?

• Dopamina a bassa dose ?

• Levosimendan ?

Amine

↑ contrattilità↑ flusso periferico↑ Pressione arteriosa↑ Flusso agli organi vitali

↑ consumo miocardico di O2Effetto proaritmicoEffetto miocardiotossicoAssociazione con ↑ mortalità

Mebazaa, Intensive Care Med (2011) 37:290–301

4953 patients from nine countries

International Journal of Cardiology 2019

Cotter, JACC, 2004; 44: 340–8

Overgaard, Circulation. 2008;118:1047-1056

Overgaard, Circulation. 2008;118:1047-1056

European Journal of Heart Failure (2018) 20, 1505–1535

Morici, Am Heart J. 2018 Oct;204:196-201

Insufficienza cardiaca avanzataQuando usare :

• Amine ?

• Dopamina a bassa dose ?

• Levosimendan ?

360 patients

International Journal of Cardiology 172 (2014) 115–121

161 ADHF patients

Insufficienza cardiaca avanzataQuando usare :

• Amine ?

• Dopamina a bassa dose ?

• Levosimendan ?

Farmakis, International Journal of Cardiology 222 (2016) 303–312

J Cardiovasc Pharmacol 2018;71:129–136

levosimendan incrementa la gittata cardiaca senza aumentare il consumo di ossigeno

1155 patients, 14 randomized controlled trials of perioperative levosimendan

Journal of Cardiothoracic and Vascular Anesthesia, 2013: 1224–1232

MORTALITA’

FIBRILLAZIONE ATRIALE

DIALISI

5480 patients in 45 randomized clinical trials

Crit Care Med 2012 Vol. 40, No. 2

23 in decompensated heart failure4 intermittent 24-hr infusions17 in cardiac surgery 2 in septic patients 2 in interventional cardiology setting 1 in vascular surgery

MORTALITA’

Durata ospedalizzazione

NNT 17

LIDO Trial(Levosimendan vs dobutamine in 203 pts)

1.00

0.90

0.80

0.70

0.60

Days

0.50Pro

po

rtio

n o

f p

ati

en

ts a

live

levosimendan

dobutamine

120 15090300 60 180

Follath et al. Lancet 2002

All-cause mortality26% vs 38%, p 0.029

• 1327 patients

• acute decompensated heart failure

Mebazaa, JAMA. 2005;293:1900-1905

J Am Coll Cardiol HF 2013;1:103–11

600 patients

Change in Plasma B-Type Natriuretic

Peptide

No bolo !!!

SUPPORTO EMODINAMICO AL CIRCOLO

PREVENZIONE DELLA RIACUTIZZAZIONERIDURRE I SINTOMI

MIGLIORARE LA QUALITA’ DI VITA

Intensive Care Med (2012) 38:359–367

Mortality in patients with severe heart failure

International Journal of Cardiology 174 (2014) 360–367

Cardiovascular Drugs and Therapy (2018) 32:617–624

Fruhwald, EXPERT REVIEW OF CARDIOVASCULAR THERAPY, 2016

Oliva, European Heart Journal Supplements (2018) 20 (Supplement I), I11–I20

7 randomized trial, 438 patients

Silvetti, International Journal of Cardiology 202 (2016) 138–143

MORTALITA’

Silvetti, ESC Heart Failure 2017; 4: 595–604

319 patients from six trials

RIOSPEDALIZZAZIONI

69 patientsevery 2weeks6-hour intravenous infusion (0.2 𝜇g/kg/min, without bolus) for 12weeks (6 cycles) in an ambulatory administration setting

Comin-Colet, European Journal of Heart Failure (2018) 20, 1128–1136

69 patientsevery 2weeks by a 6-hour intravenous infusion(0.2 𝜇g/kg/min, without bolus) for 12weeks (6 cycles) in an ambulatory administration setting

All-cause death or heart failure hospitalisation

Comin-Colet, European Journal of Heart Failure (2018) 20, 1128–1136

European Journal of Heart Failure (2014) 16, 898–906

120 outpatients with advanced heart failure (EF ≤35%, NYHA class III or IV11 centres in Austria, Greece, and Germanyor placebo was6 h at 2-week intervals over 6 weeks

primary endpoint (concomitant improvement in 6 min walktest of ≥20% and Kansas City Cardiomyopathy Questionnaireclinical summary score of ≥15%)

European Journal of Heart Failure (2014) 16, 898–906

120 outpatients with advanced heart failure (EF ≤35%,. NYHA class III or IVLevosimendan (0.2 μg/kg/min) or placebo wasadministered for 6 h at 2-week intervals over 6 weeks

185 AAHF NYHA class III–IV patients, ≥ 2 HF ospitalizations/emergency visits in the previous 6 months systolic dysfunction

treated with LEVO at tailored doses without prior bolus every 3–4 week

Oliva, International Journal of Cardiology 272 (2018) 255–259

One-year survival was 86% overall and 78% free from death/LVAD/urgent transplant.

32 patients with heart failure and renal impairment

levosimendan (0.1 lg/kg per minute) dobutamine (7.5 lg/kg per minute)

J Am Heart Assoc. 2018;7: e008455

Cardiacindex

GFRFlusso renale

Cardiovascular Drugs and Therapy (2018) 32:617–624

• Caution in patients with low blood pressure• Avoid hypovolemia • Avoid hypokalemia

Conclusioni:nei pazienti con insufficienza cardiaca avanzata

• Il trattamento con amine è consigliato solo in caso di ipotensione e evidenza di ipoperfusione (shock cardiogeno) alla minima dose necessaria, e solo se l’ipotensione è considerata una condizione reversibile o è prevista una terapiadefinitiva

• Necessario scegliere il farmaco in base al contesto clinico (Noradrenalina e Dobutamina nello shock / adrenalina /Levosimendan)

• La dopamina a basse dosi non ha dimostrato un’efficacia sulla diuresi.

• Nella scelta degli inotropi il Levosimendan risulta sicuro ed ha permesso di otteneremiglioramento dell’outcome in diversi setting clinici

• Trattamenti intermittenti e ripetuti con levosimendan sono utilizzabili con sicurezzain pazienti avanzati con ripetute ospedalizzazioni, con probabile beneficio in termini di riospedalizzazioni e sintomi.

Cardiovascular Drugs and Therapy (2018) 32:617–624

J Am Coll Cardiol HF 2013;1:103–11)

Farmakis, International Journal of Cardiology 222 (2016) 303–312

32 pazientiShock da 2 oreDopo rivascolarizzazione, IABP, inotropi

Fuhrmann JT. Crit Care Med 2008; 36:2257-66

Husebye, European Journal of Heart Failure (2013) 15, 565–572

61 patients clinical signs of HF within 48 h after a primary PCI-treated STEMI Primary endpoint: change in wall motion score index (WMSI) from baseline to day 5

P 0.031

219 pazienti Shock cardiogeno

CardShock study

Tarvasmäki et al. Critical Care (2016) 20:208

Pirracchio, PLoS One. 2013;8, e71659.

3 observational cohorts1,272 patients

• J Cardiothorac Vasc Anesth. 2015 Dec;29(6):1415-25. doi: 10.1053/j.jvca.2015.03.023. Epub 2015 Mar 26.

• Levosimendan Treatment for Heart Failure: A Systematic Review and Meta-Analysis.

• Gong B1, Li Z2, Yat Wong PC2.

• MEASUREMENTS AND MAIN RESULTS:

• The authors performed a meta-analysis of trials comparing levosimendan therapy with dobutamine or placebo in patients with decompensated heart failure. Twenty-five trials, involving 5,349 patients, were included. Two reviewers performed independent article review and study quality assessment. Data on overall mortality, early-term mortality, midterm mortality, long-term mortality, efficacy outcomes, and adverse events were collected. Mortality outcomes were according to follow-up duration: early term (≤30-day), midterm (30-day to≤6-month), and long term (>6-month). Levosimendan was compared with dobutamine or placebo, calculating pooled relatives risk (RRs) and associated 95% confidence intervals (CIs). A random-effects model was selected for meta-analysis if there was significant heterogeneity. Levosimendan significantly reduced total mortality (17.1% versus 20.8%; RR, 0.84; 95% CI, 0.75-0.94). Compared with dobutamine, levosimendan was associated with significant reduction in mortality at final follow-up (RR, 0.86; 95% CI, 0.76-0.97; I(2) = 7%; p = 0.02).Compared with placebo, levosimendan was associated with a nonsignificant trend in favor of placebo in mortality at final follow-up (11.6% versus 16.2%, RR, 0.75; 95% CI, 0.56-1.01; p = 0.06), but it was associated with a significant reduction in long-term mortality (RR, 0.34; 95%CI, 0.15-0.76; p = 0.009). Compared with dobutamine or placebo, levosimendan therapy was associated with improvements in hemodynamically- and echocardiographically-derived cardiac parameters. Levosimendan therapy increased the risks of extrasystoles (RR, 1.88; 95% CI, 1.26-2.81), hypotension (RR, 1.33; 95% CI, 1.15-1.53), and headache or migraine (RR, 1.94; 95% CI, 1.54-2.43) when compared with control therapy.

• CONCLUSIONS:

• As compared to placebo or dobutamine, levosimendan in patients with heart failure seemed to have hemodynamic and cardiac benefits. It reduced total mortality and was associated with an increased risk of cardiovascular adverse events.

Thongprayoon et al. BMC Pharmacology and Toxicology (2016) 17:19

NA

NA

DA

DA

Beta 1 -Adrenergic receptor stimulation results in enhanced myocardial contractility through Ca-mediated facilitation of the actin-myosin complex binding with troponin C and enhanced chronicity through Ca2 channel activation.Beta 2-Adrenergic receptor stimulation on vascular smooth muscle cells results in increased Ca2 uptake by the sarcoplasmic reticulum and vasodilation. Alfa 1-adrenergic receptors on arterial vascular smooth muscle cells results in smooth muscle contraction and an increase in systemic vascular resistance D1 and D2 dopaminergic receptors in the kidney and splanchnic vasculature results in renal and mesenteric vasodilation

Overgaard, Circulation. 2008;118:1047-1056

quiz• L’utilizzo dei farmaci vasopressori è indicato:

– nei pazienti con ipotensione e segni di ipoperfusione

– Nei pazienti con severa riduzione della funzione ventricolare

– Nei pazienti con congestione polmonare

– Nei pazienti con pressione sistolica<110

• Nel trattamento dell’insufficienza cardiaca avanzata la dobutamina ha dimostrato.

– Una riduzione della mortalità rispetto al placebo

– Un miglioramento del filtrato glomerulare rispetto al levosimendan

– Una riduzione della mortalità rispetto ai vasodilatatori

– Nessuna delle precedenti

Il levosimendan:

- Ha un effetto vasodilatatore

- Ha un effetto inotropo positivo

- Ha un effetto cardioprotettivo

- Tutte le precedenti

Mebazaa, Intensive Care Med (2011) 37:290–301

4953 patients from nine countries

MANTENERE LA PERFUSIONEInotropi

• Vasopressors are given to raise blood pressure and to redistribute blood volume to the vital organs.

• The lowest possible doses of inotropic and pressor agents should be used to adequately support vital tissue perfusion while limiting adverse consequences, some of which may not be immediately apparent.

• Moderate doses of combinations of medications may potentially be more effective than maximal doses of any individual agent.

• The choice of the catecholamine is mainly based on individual experience, institutional policy, and pathophysiological considerations.

AdrenalinaEpinephrine is an endogenous catecholamine with high affinityfor 1-, 2-, and 1-receptors present in cardiac andvascular smooth muscle (Figure 3A; Table). -Adrenergiceffects are more pronounced at low doses and 1-adrenergiceffects at higher doses. Coronary blood flow is enhancedthrough an increased relative duration of diastole at higherheart rates and through stimulation of myocytes to releaselocal vasodilators, which largely counterbalance direct 1-mediated coronary vasoconstriction.14 Arterial and venouspulmonary pressures are increased through direct pulmonaryvasoconstriction and increased pulmonary blood flow. Highand prolonged doses can cause direct cardiac toxicity throughdamage to arterial walls, which causes focal regions ofmyocardial contraction band necrosis, and through directstimulation of myocyte apoptosis.15

DopaminaAt low doses (0.5to 3 g kg1 min1), stimulation of dopaminergic D1postsynaptic receptors concentrated in the coronary, renal,mesenteric, and cerebral beds and D2 presynaptic receptorspresent in the vasculature and renal tissues promotes vasodilationand increased blood flow to these tissues. Dopaminealso has direct natriuretic effects through its action on renaltubules.7 The clinical significance of “renal-dose” dopamineis somewhat controversial, however, because it does notincrease glomerular filtration rate, and a renal protectiveeffect has not been demonstrated.8 At intermediate doses (3 to10 g kg1 min1), dopamine weakly binds to 1-adrenergic receptors, promoting norepinephrine release andinhibiting reuptake in presynaptic sympathetic nerve terminals,which results in increased cardiac contractility andchronotropy, with a mild increase in SVR. At higher infusionrates (10 to 20 g kg1 min1), 1-adrenergic receptor–mediated vasoconstriction dominates.

Thackray, Eur J Heart Failure 4 (2002) 515–529

Calcium-Sensitizing Agents• calcium sensitization of contractile proteins and the opening of ATP-dependent potassium (K)

channels.• Calcium-dependent binding to troponin C enhances ventricular contractility without increasing

intracellular Ca2 concentration or compromising diastolic relaxation, which may favorably impact myocardial energetics relative to traditional inotropic therapies.

• The opening of K channels on vascular smooth muscle leads to arteriolar and venous vasodilation and may confer a degree of myocardial protection during ischemia.

• Il Levosimendan è un sensibilizzatore al calcio che esercita la sua azione inotropo positiva (incremento della contrattilità cardiaca) aumentando la sensibilità al calcio dei miociti senza un aumento del calcio intracellulare, legandosi alla troponina C cardiaca in misura calcio-dipendente.

• Il farmaco ha anche un effetto vasodilatatore, aprendo i canali del potassio sensibili all'ATP della muscolatura liscia dei vasi per provocarne il rilassamento.

De Backer, NEJM 2010;362:779-89.

219 pazienti Shock cardiogeno

CardShock study

Tarvasmäki et al. Critical Care (2016) 20:208

Overgaard, Circulation. 2008;118:1047-1056

Overgaard, Circulation. 2008;118:1047-1056

0

219 pazienti Shock cardiogeno

CardShock study

Tarvasmäki et al. Critical Care (2016) 20:208

• these agents should• be reserved for patients with low systolic blood pressure

and• evidence of organ hypoperfusion (cardiogenic shock) at the• lowest dose that obtains the desired clinical goals, and only

if• the low blood pressure is considered a reversible condition• or definitive therapy (long-term MCS or transplantation) is• planned.

JAMA. 2013;310(23):2533-2543

• Vasopressors (dopamine, norepinephrine, epinephrine) are broadly associated with worse outcomes in observational studies,

• low-dose dopamine does not improve congestion or cardiovascular outcomes compared to placebo in acute decompensated heart failure.

• these agents should be reserved for patients with low systolic blood pressure and evidence of organ hypoperfusion (cardiogenic shock) at the lowest dose that obtains the desired clinical goals, and only if the low blood pressure is considered a reversible condition or definitive therapy (long-term MCS or transplantation) is planned.

Delaney, International Journal of Cardiology 138 (2010) 281–289

The effect of levosimendan compared to dobutamine on mortality.

Delaney, International Journal of Cardiology 138 (2010) 281–289

The effect of levosimendan compared to placebo on mortality.

• random allocation to treatment, at least one group receiving an inotropic or vasopressor drug compared with at least one group receiving a non-inotropic/vasopressor treatment,

• 28280 patients from 177 trials

Belletti, British Journal of Anaesthesia, 115 (5): 656–75 (2015)

47 pt, scompenso acuto

• Sensibilizza la troponina C nei confronti del calcio aumentando gli effetti del calcio stesso sulle fibre contrattili cardiache nel corso della sistole e migliorando la contrazione cardiaca1,2; la sensibilizzazione si riduce o si annulla al ridursi dei livelli di ioni calcio durante la fase diastolica, consentendo un normale rilasciamento fisiologico. La sua attività di blocco sulla fosfodiesterasi III e di apertura dei canali del potassio ATP-dipendenti a livello della muscolatura liscia vascolare si traduce in una vasodilatazione sia coronarica che sistemica2,3. Abbinando l'effetto inotropo e vasodilatatorio, il levosimendan incrementa la gittata cardiaca senza aumentare il consumo di ossigeno

• e haemodynamic effect may last for >7

• days after a 12–24 h infusion because of the pharmacologically

• active metabolite with a long half-life.155

• While meta-analyses of several heterogeneous small trials of a repeated infusion strategy

• have suggested a positive effect on survival156 and a reduction

• in hospitalizations,157 such a survival effect has not been

• demonstrated in a single, adequately sized, prospective study. The

• LION-HEART pilot study randomized 69 patients with advanced

• heart failure to placebo or levosimendan 0.2 μg/kg/min over 6 h

• every 2 weeks for 12 weeks.158 NT-proBNP over time, the

• primary endpoint, was significantly lower in the levosimendan

Inotropes may also be used as short-term therapyin patients with low cardiac output and evidence of end-organdysfunction, for instance during decongestion.

Insufficienza cardiaca acuta: evidenze ?

SHOCK

SCA STEMI SCOMPENSO ACUTO

69 patientsevery 2weeks by a 6-hour intravenous infusion(0.2 𝜇g/kg/min, without bolus) for 12weeks (6 cycles) in an ambulatory administration setting

All-cause death or heart failure hospitalisation

Comin-Colet, European Journal of Heart Failure (2018) 20, 1128–1136

69 patientsevery 2weeks by a 6-hour intravenous infusion(0.2 𝜇g/kg/min, without bolus) for 12weeks (6 cycles) in an ambulatory administration setting

European Journal of Heart Failure (2018) 20, 1128–1136

CardShock study

Tarvasmäki et al. Critical Care (2016) 20:208

• 219 patients

• 81 % ACS

• 90-day mortality: 41 %

• <24 h: 96%

94%

6%

INOTROPI

NO INOTROPI

International Journal of Cardiology xxx (xxxx) xxx

Delaney, International Journal of Cardiology 138 (2010) 281–289

The effect of dobutamine compared to placebo on mortality

30 patients cardiac index <2.2 MAP<60 mm Hg resistant to dopamine-dobutamine treatment

Levy, Crit Care Med 2011; 39:450–455

EpinephrineNorepinephrine - dobutamine

SENSIBILIZZAZIONE AL CALCIO