Pharmacokinetics
Pyridazone dinitrile derivative
Trade name: Simdax. Orion Pharmaceuticals
Preparation
Yellow liquid in 100% ethanol and buffered with citrate to achieve pH of 3.0.
12.5mg in a 10ml vial
Stored in the fridge at 4-8 degrees celcius
Absorption
85% PO bioavailability but only ever given as IV formulation
Distribution
Vd 0.3l/kg 99% protein bound. pKa = 6.3 with poor water solubility
Metabolism
Hepatic with 95% to inactive metabolites and 5% to OR1896 (active metabolite with a long 80 hour half life)
Excretion
Renal
Dosing
0.025-0.2ug/kg/min for 24hrs (Usual dose = 0.1ug/kg/min for 24h)
- Dilute 12.5mg vial with 250ml 5% dextrose
- In the NEJM trial no loading dose was given whereas in other studies loading doses were advised but increased hypotension was observed.
- 0.2ug/kg/min was associated with significant hypotension in one study (septic patients) and a lower dose of 0.05-0.1ug/kg/min is probably more appropriate and what is used on Torrington CICU.
- Drug action lasts for 5 -10 days
Pharmacodynamics
"Calcium sensitizer binding to Troponin-C to increase inotropy without increasing intracellular calcium levels and without increasing myocardial oxygen demand.
Effects
Increased inotropy. Maintains Troponin C in the "open" state allowing activation by calcium at lower intracellular concentrations thereby increasing the sensitivity of the channel. This increased sensitivity is independent of calcium concentration meaning that ATP-ase pumps do not need to consume additional oxygen (Myocardial oxygen requirements stay the same)
Improved luisitropy. Levosimendan likely only binds to Troponin C when calcium concentrations are high i.e. during systole. In diastole where concentrations of calcium are low Troponin C can close in the normal manner resulting in improved luisitropy (relatively unique amongst inotropes which generally improve systolic calcium flux at the expense of impaired relaxation). This has been evidenced in a study demonstrating a reduction in isovolumetric relaxation time (IVRT - surrogate component of assessing diastolic function) following levosimendan administration.
Decrease in SVR and PVR. This is achieved via ATP-ase potassium channel activation. Resultant arterial, venous and pulmonary vasodilation occurs together with coronary vasodilatation.
Anti-inflammatory effects. A series of “special” effects on myocyte apoptosis and membrane stabilisation have been described at the experimental level. These are thought to be mediated via myocyte K+ATPase mitochondrial channels. Levosimendan may enhance the ability of cells to withstand ischaemia/refperfusion insults. The clinical relevance of this is uncertain.
Phosphodiasterase -3 inhibitor. This is only seen at high doses > 0.3umol/l (above the maximum recommended dose)
Maximal effect is achieved at 12-48hrs after dosing and so our center does not administer a loading dose (which frequently leads to hypotension necessitating a pause in the infusion). Avoiding a loading dose has the downside that onset is slower, often in the region of 2-5 hours. The long half-life of the active metabolise OR 1896 means that after one dose the actions persist for 5-7 days.
Adverse effects
- Vasodilatation can be a disadvantage if the shock state changes during the long 5-7 day working time of levosimendan or if the initial shock diagnosis was incorrect (e.g. low SVR and vasoplegic state following cardiac surgery)
- Headache and facial flushing resulting from aforementioned vasodilatation
- Arrhythmogenic with tachyarrhythmias predominating, likely dose-related as demonstrated in the REVIVE-II trial (see below)
Studies
Cardiogenic shock encompasses a heterogenous group of underlying pathologies. One cohort with potential to benefit from Levosimendan are patients post-cardiac surgery given the transient nature of the post-operative myocardial depression, the well-described catecholamine receptor down-regulation as well a high incidence of pre-operative beta-blocker therapy.
Post-operative ischaemia-reperfusion injury to the myocardium is universal and the theoretical cardioprotective benefits that Levosimendan may offer to mitochondrial potassium channels could be advantageous in this regard.
The pharmacological actions of levosimendan make it an attractive prospect with a “non-catecholamine” action to managing cardiogenic shock with early studies showing increased cardiac output and stroke volume. Levosimendan has also found a niche in those with end-stage heart failure as a bridge to transplant (See the LevoRep study below):
Overall the results of larger studies have been mixed with more recent RCT’s (three large and well designed ones all from 2017 especially) showing no mortality benefit. Dosing patients with reduced LVEF% prior to cardiac surgery has also not been proven to show benefit (although this is still considered possibly beneficial in those undergoing isolated CABG). Despite these problems Levosimendan remains a popular drug in cardiothoracic centres; improving cardiac output indices via an alternative mechanism to more “traditional” catecholamine-based inotrope regimens seems to retain it’s appeal.
Some of the results from recent trials are summarised below for illustrative purposes and an excellent and balanced “expert opinion” review article from France giving an overview of Levosimendan use can also be found here:
Study Name | Journal | Year | Trial Type | Size | Summary | Downsides | Link |
CHEETAH | NEJM | 2017 | Multi-center, randomised, double-blind placebo-controlled. | 248 Levosimendan 258 Placebo | Pre-op LVEF <25%, IABP or high-dose vasopressor support pre-surgery or post-CPB. Levosimendan dose given either post-CPB or in the first 24hrs post-op. Stopped due to futility. | Cardiac output data not recorded in all patients and possibly underpowered to detect a benefit in this very sick group | |
LEVO-CTS | NEJM | 2017 | Multi-center, randomised, placebo-controlled. | 428 Levosimendan 418 placebo | LVEF <35% undergoing CABG. Levosimendan infusion for 24hrs pre-surgery. No effect on 30d mortality, RRT, post-op MI or need for MCS. | Prophylactic use may be detrimental if vasoplegia predominates post-operatively. Likely underpowered (by authors admission in discussion) | |
LICORN | JAMA | 2017 | Randomised, double blind, placebo-controlled trial. | 335 patients; 167 placebo, 168 levo. Multiple centers in France | 24hr Levosimendan infusion started after anaesthetic induction with LVEF < 40%. 52% vs 61% outcomes in Levosimendan and placebo groups respectively (non-significant) | Use of composite end-point of need for inotrope infusion, MCS or RRT post-operatively. | |
Effect of levosimendan on clinical outcomes in adult patients undergoing cardiac surgery: a meta-analysis of randomised controlled trials | Interactive cardiothoracic and vascular surgery | 2018 | Meta-analysis | 3239 pooled patients | Overall mortality benefit for “perioperative” Levosimendan with absolute mortality risk reduced from 8.5% to 5.8%. Subanalysis of trials after 2015 failed to show the same benefit. | Extremely heterogenous meta-analysis and more recently included trials (after 2015) failed to show benefit. |
Effects compared to Dobutamine
A drug with similar pharmacodynamics to Levosimendan is Dobutamine with increased inotropy, tachycardia and decreased SVR all being seen.
The SURVIVE Trial published in JAMA (2007) directly compared the two drugs with over 600 patients in each arm of the study. Patients included had acute decompensated heart failure with LVEF% <30%
The results showed a non-significant trend towards decreased mortality with Levosimendan, albeit not in a post cardiac surgical patient population group. Subsequent commentary highlighted a potential concern that dobutamine had been administered to hypotensive patients in cardiogenic shock given the known dilatory effects of the drug.
One positive secondary outcome finding was serum BNP levels being significantly reduced by 43% in the Levosimendan group vs 11% in the Dobutamine group although the clinical relevance of this is likely to be minimal.
Effect | Levosimendan | Dobutamine |
Adrenergic receptor effect? | No | Yes |
Increased cardiac output | +++ | ++ |
Tachycardia | ++ | +++ |
PCWP | - - | - |
Attenuated with beta blockers? | No | Yes |
Reduction in BNP | - - - | - |
Cost | £894 | £11 |
Alternative uses:
Levosimendan has also be used in a small trial of patients who were difficult to wean from the ventilator. In a 2008 paper from Darwin, Australia 47 patients who were “ventilator dependent” at 10 days and who had failed one attempt at weaning or extubation were included for analysis.
12 patients identified from this group had an LVEF <40% were given a 24hr levosimendan infusion after which LVEF improved from 28% to 35% on average. 7 out of the 12 patients were then successfully weaned from the ventilator after 24hrs following the levosimendan dose.
https://pubmed.ncbi.nlm.nih.gov/18798715/#full-view-affiliation-1
Created 15/8/2023 - Dr Sean Edwards [sean.edwards1@nhs.net]