Effect of Levosimendan on the Short-Term Clinical Course

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 l Over a million people hospitalised in the US for treatment of ADHF l Usually receive IV diuretics , peripheral vasdilators , positive inotropes l Unclear how haemodynamics translate to clinical benefits l Average hospital stay 5 days

Methods l REVIVE 1 and 2 carried out in 103 centres in the US, Australia and Israel between December 2001 and December 2004 l All patients with ADHF who remained dyspneic inspite of treatmet with intravenous diuretics

Study Plan l Randomly assigned (double blind) to treatments with placebo or levosimendan which was added to their existing treatment plan l Study endpoints- composite of clinically relevant measures

Outcome measurement l Primary end point in both trials -clinical course during first 5 days characterized as improved , unchanged or worse. l Secondary endpoint- BNP at 24 hrs , changes in global assessment at 6 hrs , changes in perception of dyspnoea at 6 hrs , 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 l 12% of levosimendan group and 7% of placebo group discontinued before 24 hrs l Primary endpoints- patients improved on levosimendan compared to placebo l In both groups no differences in groupsin number of days alive over 14 days

Results l Levosimendan arm briefer hospital stays-46%vs 37% l NYHA functional status was not significantly different between both groups l Safety- higher number of adverse effects with levosimendan

discussion l Robust study , demonstrates favourable effect on short term clinical course of patients with ADHF l 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 – – Increased cardiac contractility – • Calcium sensitisation K+ ATP channel opening Pharmacokinetics – Onset of action: 1 minute – Half life 1 hour – Excreted in faeces and urine – Prolonged haemodynamic effects

Levosimendan effects…. l Cardioprotective effect l Anti inflammatory effect l Neurohormonal effect l Improves coronary circulation l Antistunning effect l Haemodynamic effects

LIDO Study l Multicenter , double blind, double dummy. randomized study l Designed to compare clinical and haematological effects of levosimendan vs Dobutamine in low output heart failure l 203 patients- levosimendan improved haemodynamic performance and decreased mortality for upto 180 days

RUSSLAN TRIAL l Double blind placebo controlled l Evaluating different doses of levosimendan vs placebo in patients with heart failure secondary to MI l 504 patients – higher dose , greater side effects l Overall mortality better than placebo group (at 14 days)

CASINO TRIAL l Randomised , double blinded, double dummy and parallel group study l 299 patients NYHA 4 (LVEF less than 35%) l 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 !! l Not licensed for use in the UK and USA however still used l Not recommended for use in patients with Bp less than 90 systolic l Can be used in conjunction with betablockers, noradrenaline l Can also be used in septic shock (some proven benefit)

Discussion l New inodilator agent for therapy in end stage heart failure l Proven benefits compared to dobutamine l Further trials may help clarify its effects on mortality and use in clinical practice

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