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Effect of Levosimendan on theShort-Term Clinical Course of
Patients With Acutely Decompensated Heart Failure
Binu George , Heather BuryCritical care Journal Club
May 2014
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Background Over a million people hospitalised in the US for treatment of ADHF
Usually receive IV diuretics , peripheral vasdilators ,positive inotropes
Unclear how haemodynamics translate to clinical benefits
Average hospital stay 5 days
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Methods REVIVE 1 and 2 carried out in 103 centres in the US, Australia and Israel
between December 2001 and December 2004
All patients with ADHF who remained dyspneic inspite of treatmet with intravenous diuretics
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Study Plan Randomly assigned (double blind) to treatments with placebo or
levosimendan which was added to their existing treatment plan
Study endpoints- composite of clinically relevant measures
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Outcome measurement Primary end point in both trials -clinical course during first 5 days
characterized as improved , unchanged or worse.
Secondary endpoint- BNP at 24 hrs ,changes in global assessment at 6hrs ,changes in perception of dyspnoea at 6hrs ,numer of days alive (1-14 days after randomization),NHYA functional status at day 5,all cause mortality during first 90 days
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Worsening clinical status requiring rescue therapy in revive 1 and 2
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Results 12% of levosimendan group and 7% of placebo group discontinued before
24 hrs
Primary endpoints- patients improved on levosimendan compared to placebo
In both groups no differences in groupsin number of days alive over 14 days
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Results Levosimendan arm briefer hospital stays-46%vs37%
NYHA functional status was not significantly different between both groups
Safety- higher number of adverse effects with levosimendan
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discussion Robust study , demonstrates favourable effect on short term clinical course
of patients with ADHF
Likely reason for incresed mortality in levosimendan arm due to increased used of loading dose and approach which is no longer followed
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Levosimendan• Mode of Action– Calcium sensitisation– Increased cardiac contractility– K+ ATP channel opening
• Pharmacokinetics– Onset of action: 1 minute– Half life 1 hour– Excreted in faeces and urine– Prolonged haemodynamic effects
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Levosimendan effects…. Cardioprotective effect
Anti inflammatory effect
Neurohormonal effect
Improves coronary circulation
Antistunning effect
Haemodynamic effects
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LIDO Study Multicenter ,double blind,double dummy.randomized study
Designed to compare clinical and haematological effects of levosimendan vs Dobutamine in low output heart failure
203 patients- levosimendan improved haemodynamic performance and decreased mortality for upto 180 days
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RUSSLAN TRIAL Double blind placebo controlled
Evaluating different doses of levosimendan vs placebo in patients with heart failure secondary to MI
504 patients – higher dose , greater side effects
Overall mortality better than placebo group (at 14 days)
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CASINO TRIAL Randomised , double blinded, double dummy and parallel group study
299 patients NYHA 4 (LVEF less than 35%)
Stopped prematurely – significant survival benefit with levosimendan compared with dobutamine
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SURVIVE TRIAL• Randomized ,double blind, double dummy, prospective controlled study
• 1327 patients (LVEF-less than 35%)- not responding to IV diureticsand vasodilator therapy
• Primary endpoint- all cause mortality in 180 days – no statistical difference
• 25% lower mortality compared to dobutamine 6 hrs,24 hrs , 5,14,30 days
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Levosimendan Facts !!• Well tolerated
• Side effects – headache ,hypotension,dizzyness,nausea
• Can cause VT ,AF at higher doses
• Recommended dose 6-24 μg/kg/min administerted in 10-20 min and maintainance
dose- 0.05-0.2 μg/kg/min over 24 hrs
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Facts !! Not licensed for use in the UK and USA however still used
Not recommended for use in patients with Bp less than 90 systolic
Can be used in conjunction with betablockers, noradrenaline
Can also be used in septic shock (some proven benefit)
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Discussion New inodilator agent for therapy in end stage heart failure
Proven benefits compared to dobutamine
Further trials may help clarify its effects on mortality and use in clinical practice
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Any Questions ???
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Thank You !!