Effect of Levosimendan on the
Short-Term Clinical Course of
Patients With Acutely
Decompensated Heart Failure
Binu George , Heather Bury
Critical 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
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 !!