Effect of Levosimendan on theShort-Term Clinical Course of

Patients With Acutely Decompensated Heart Failure

Binu George , Heather BuryCritical care Journal Club

May 2014

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

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

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

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

Worsening clinical status requiring rescue therapy in revive 1 and 2

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

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

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

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

Levosimendan effects…. Cardioprotective effect

Anti inflammatory effect

Neurohormonal effect

Improves coronary circulation

Antistunning effect

Haemodynamic effects

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

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)

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

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

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

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)

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

Any Questions ???

Thank You !!