Binu George , Heather Bury Critical care Journal Club May 2014 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 This study evaluated the efficacy and safety of levosimendan , a positive inotropic drug with vasodilator effects, given intravenously to patients with acute decompensated heart failure This apparent dissociation between haemodynamic and symptomatic effects of IV drugs reflect difficulties in designing , performing and analysing clinical trials in these acutely ill patients

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 Under direct supervision of an independent steering committee, an independent data monitoring panel (4 cardiologists and one statistician ) periodically reviewed (in an unblinded manner) the interim results and were enpowered to recommend eary termination of the programme if a safety concern emerged during the studies Inclusion criteria- all patients admitted to hospital with LV failure who were no better inspite of IV diuretics but they could have also received IV vasodialtors or positive inotropic drugs (except amrinone , milrinone) evidenced by left ventricular ejection fraction of less than 35 % within 12 months of study Exclusion criteria – intubated patients , systolic Bp of less than 90 or hr above 120 beats per min, had significant untreated valvular obstruction, undergone cardiac resynchronisation procedure within 30 days , recent tia or stroke, severe liver impairment severe renal impairment , copd , acute bleeding or anaemia ,abnormal K levels , and patients with history of torsade de pointes

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 IV 12 μg/kg over 10 min (6μg/kg if receiving vasodilator or positive inotrope) followed by continuous infusion of 0.1μg/kg/min If tolerated the infusion was increased after 50 min to 0.2 μg/kg/min over 23 hrs (if not tolerated the 0.05- 0.1μg/kg/min over 23 hrs \) At randomisation physicians could use any clinical intervention including initiation of new treatment of adjustment of concomitant medication but these changes were recorded as 1 continuation of existing stratergy (maintainence therapy or intensification of treatment in patient who was deteriorating clinically or failing to improve by 24 hrs(rescue therapy ) Phosphodiesterase inhibitors were not allowed within the first 24 hrs of randomization At 6 hrs , 24 hrs and after 2.3 and 5 days , patients were asked to evaluate changes in overall clinical status and in dyspnoea charecterised by mild , morderate or markedly improved or worsened (self directed mark on case report form and physicians independantly rated the changes in overall clincal status of patients In addition circulating BNP was measured at randomisation , 24 hour, 5 days , 31 days NYHA functional status assessed at 5.14.31.60 and 90 days Unlike other studies which focused on a single measure at a single point in time the composite approach uses combination of measures to charecterize clinical course over several days

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 In the definative trial (revive 2) patients were classified as imorved only if they considered themselves moderately or markedly improved at all prespecified points(6hrs, 24hrs ,and 5 days ) Patients classified as worse (during the 5 days ) if they died ,experienced persisitanty or unresponsive symptoms of heart failure 5 days corresponds with average stay in hospital with ADHF Secomndary

Participant flow through revive clinical trials

Baseline charecteristics in revive 1 and 2 trials

Worsening clinical status requiring rescue therapy in revive 1 and 2

Changes in plasma B type Natriuteric peptide during and after levosimendan in REVIVE 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 Revive 1 100 patients (49 to placebo and 51 to levosimendan) Revive 2 600 patients (301 to placebo and 299 to levosimendan) In both trials more than 90% of patients tolerated 0.2μg/kg/min at 2hrs and 85% at 24 hrs Primary endpoints- In revive 1 24 patients (L ) improved compared to 15 (p) at 24 hrs and at 5 days whereas 10 patients (l) got worse compared to 13 in placebo group Revive 2 – 58 patients (l ) against 44 patients in placebogroup improved at 6, 24 hrs and 5 days Secondary end points Plasma BNP – low in levosimendan group at 24 hrs and 5 days compared to placebo however this effect was not seen at 31 days follow up In revive 2 global assessmet at 6 hrs , greted proportion of patients reported moderate or marked improvement in the levosimendan arm compared to placebo (p=0.081) And this shift persisted after 24 hrs(p=0.027), 48 hrs (p=0.053), 3 days p=0.013 and 5 days (p=0.002)

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 Analysis over entire 5 days indicated a significant difference in favour of levosimendan( p less tha 0.002), greater intensification of treatment on placebo group A similar pattern seen with respect to patient dyspnoea assessment at 6h (p=0.078) 24 hrs p-0.018, 48 hrs p=0.035 and 5 days p=0.035 Safety- hypotension – 50% vs 36% VT 25% vs 17% Headache 30% vs 15% AF 9% vs 2 %

Hazard ratio for all cause mortality (levosimendan/placebo ) at 14 days as function of systolic blood pressure at randomisation

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 Improvement in symptoms, less likely to need any futher intervention, benefits aparent even after 5 days of treatment even though treatment stopped after 24 hs Safe use with betablockers Benefits of levosimendan are consistant with known pharmocological properties Positive inotropic effects, lowered BP – sideeffects , hypotension and headache, risk of arrythmias Revive 2 risk of death numerically high in levosimendan treated patients , it is possible this represents play of chance 23 trials including revieve 1 and 2 demonstrate significant risk in all cause mortality in levosimendan treated patients

Levosimendan Mode of Action Pharmacokinetics 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 has three key mechanisms of action: calcium sensitisation and opening of adenosine triphosphate dependent-potassium (KATP) channels both on the sarcolemma of the smooth muscle cells in the vasculature and in the mitochondria of cardiomyocytes. Calcium sensitisation by selective binding to calcium-saturated cardiac troponin C increases the contractile force of the cardiac myocytes without affecting relaxation. 2. Opening of KATP channels in vascular smooth muscle cells elicits both arterial90 and venous vasodilation as well as improvement in coronary artery circulation. 3. Opening of KATP channels in the mitochondria of cardiomyocytes causes a cardioprotective effect in situations when the heart is subjected to ischemic events. Through calcium sensitisation, levosimendan improves cardiac contractility in the failing heart without affecting muscle electrophysiology. Through the opening of KATP channels in vascular smooth muscle cells, levosimendan improves oxygen supply to the myocardium. Because levosimendan increases myofibril contractions by increasing calcium sensitivity rather than by increasing intracellular calcium it is not associated with greater myocardial oxygen demand. Levosimendan has a peak on set of 1 minute and a half life of an hour meaning when the infusion is discontinued the desired effect is rapidly discontinued also. However, the are prolonged haemodynamic effects seen for 7-9 after discontinuation due to the metabolites OR-1855 and OR-1896. These effects are mainly a reduction in BP. Excretion is via the urine 55% and kidneys 45%.

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 European study , muticentre double blinded , double dummy randomized study designed to compare clinical and heamatological effects of levosimendan vs dobutamine in low output heart failure In patients with severe, low output heart failure , levosimendan improved haemodynamic peformance more effectively than dobutamine and this benefit was accompanied by lower mortality in the levosimendan group than dobutamine group for upto 18- 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) The randomized study on safety and effectiveness of levosimendan in patients with left ventricular failure due to acute myocardial infarction (RUSSLAN) First large study , 504 patients 4 different levosimendan dose groups and placebo group No significant side effects at low dose however greater incidence of arterial hypotension and ischaemia in patients who received highest dose of levosimendan Worsening heart failure at 6 hrs and 24 hrs were significantly less in levosimendan arm compared to placebo

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 Calcium sensitizer or inotrope or none in low output heart failure study (CASINO) Initially designed for recruiting 600 patients but was stopped prematurely at 299 as there was a clear benefit with use of levosimendan compared to dobutamine which increased mortality at one months and 6 months

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 Decreased mortality at 180 days compared to dobutamine Decreased BNP compared to dobutamine at 24 hrs and persisted till 5 days Higher incidence of cardiac failure in the dobutamine arm Higher incidence of AF , hypokalemia and headache in levosimendan group Despite initial reduction in plasma BNP in patients on levosimendan compared to dobtamine group it did not significantly reduce all cause mortality at 180 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) Cardiology recommend use in patients with symptomatic ,low output heart failure secondary to systolic dysfunction which is not accompanied by severe hypotension

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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