Levosimendan: New Drug Profile

Authors, Journal, Affiliations, Type, DOI

• David P. Figgitt, Peter S. Gillies, Karen L. Goa
• Drugs 2001; 61(5): 613–627
• Adis International Limited, Auckland, New Zealand
• New drug profile review
• DOI: https://doi.org/10.2165/00003495-200161050-00007

Overview

Levosimendan, a pyridazinone-dinitrile derivative, is a calcium sensitiser and first-in-class KATP channel activator approved in Sweden (2000) for acute decompensated heart failure. It enhances contractility without raising intracellular calcium or myocardial oxygen consumption by binding to cardiac troponin C in a calcium-dependent manner, and produces systemic, coronary, and pulmonary vasodilation via smooth-muscle KATP channel opening. Early trials (LIDO vs dobutamine, RUSSLAN post-AMI) showed favorable 30-day mortality and morbidity trends with a low arrhythmia risk compared to dobutamine and milrinone. This 2001 review provides the foundational pharmacological framework; subsequent RCTs (REVIVE-2, SURVIVE) produced more complex results not covered here.

Keywords

Calcium sensitiser, levosimendan, intravenous inotrope, decompensated congestive heart failure, troponin C, KATP channels, haemodynamics

Key Takeaways

Mechanism of Action

• Levosimendan is the active enantiomer of simendan; achieves enhanced contractility via calcium sensitisation — binds cardiac troponin C in a calcium-dependent manner, stabilising the calcium-induced conformational change of troponin C without increasing cAMP, intracellular calcium, or ATP consumption
• This mechanism distinguishes it from other calcium sensitisers (pimobendan, EMD 53998) which work via different pathways
• Calcium-dependent binding: high affinity during systole (high Ca²⁺) → low affinity during diastole (low Ca²⁺) — avoids slowing relaxation (a key theoretical concern for calcium sensitisers)
• Vasodilation attributed to opening of glibenclamide-sensitive ATP-sensitive K⁺ channels (KATP) in vascular smooth muscle → hyperpolarisation and myocyte relaxation; additional possible mechanism: blockade of endothelin-1 release

Haemodynamic Effects

• Dose-dependent increase in cardiac output / cardiac index, stroke volume; decrease in PCWP, SVR, and PVR in multiple controlled trials
• Increases LV myocardial blood flow (PET study: 0.76 → 1.02 ml/min/g) without increasing myocardial oxygen consumption
• RV efficiency increased by 24% (p<0.05 vs placebo)
• Dobutamine increased contractility at the expense of excess oxygen consumption; levosimendan and sodium nitroprusside both had neutral myocardial energetic effects
• Pulmonary effects: significantly decreases PVR (by 22–27% post-bypass) and PAP; PVR decrease superior to dobutamine at equivalent doses (NYHA III stable HF trial)
• Diastolic function: mild positive lusitropic effect at higher intracoronary doses; no clinically relevant impairment of diastolic function

Anti-Ischaemic and Antistunning Effects

• Reduced infarct size in animal models (isolated rabbit hearts, guinea-pig, dogs); effect attributed to KATP channel opening and oxygen-sparing from calcium sensitisation
• Improved contractility of stunned myocardium post-PTCA (hypokinetic segments −2.4 vs +0.8 for placebo, p=0.011) without increasing intracellular calcium
• No increase in troponin T or CK-MB observed during infusion in CHF patients — no myocardial damage signal

Arrhythmia Profile

• Levosimendan does NOT increase intracellular cAMP or calcium → theoretically non-arrhythmogenic
• Guinea-pig Langendorff model: 0% arrhythmia in levosimendan group vs 83% VT and 33% VF in dobutamine group (p<0.05)
• Ventricular fibrillation 0% with levosimendan vs 50% with milrinone in dog ischaemia model
• QTc not significantly prolonged (uncorrected QT actually shortened) in placebo-controlled trials
• Pooled ECG data from 386 patients: no increase in NSVT, no new SVT or VT (including torsades de pointes)
• Electrophysiology study (supratherapeutic concentration ~110 ng/mL): enhanced slow-tissue impulse formation and conduction; effects on ventricle not substantial → low likelihood of serious arrhythmias

Neurohumoral Effects

• No stimulation of sympathoadrenal system in healthy volunteers at rest (noradrenaline, adrenaline, ANP unchanged)
• Noradrenaline and adrenaline decreased 16% and 27% respectively in severe low-output HF patients during 24h infusion (similar effect seen with dobutamine)
• Significant reduction in endothelin-1 levels (11% at 6h, further 16% at 24h; p<0.001 vs placebo)

Pharmacokinetics

• Linear pharmacokinetics; rapid distribution (t½α ≈ 0.1–0.26h); t½β ≈ 1 hour; protein binding 97–98%
• Volume of distribution ≈ 20L; hepatically metabolised via glutathione conjugate intermediates (biologically inactive)
• Active metabolite OR-1896 formed via intestinal reduction (→OR-1855) then acetylation; similar pharmacological profile to parent drug; much longer half-life → may prolong haemodynamic effects after parent drug elimination
• Oral bioavailability ~85%; renal failure does not significantly alter clearance; mild/moderate hepatic impairment and children (congenital HD) do not significantly differ from healthy volunteers for parent drug kinetics
• Gender difference (women higher AUC) abolished when adjusted for bodyweight — no dose adjustment needed

Clinical Trials

LIDO trial (decompensated CHF, n=203):

• Levosimendan (24 µg/kg loading + 0.1–0.2 µg/kg/min for 24h) vs dobutamine (5–10 µg/kg/min)
• Primary endpoint (cardiac index ≥30% increase + PCWP ≥25% decrease): levosimendan 28% vs dobutamine 15% (p=0.022)
• 30-day worsening HF or death: 6.8% vs 17% (p=0.039)
• Serious adverse events: 6.8% vs 18.4% (p<0.05) favoring levosimendan

RUSSLAN trial (decompensated CHF post-AMI, n=504):

• 4 dose regimens of levosimendan vs placebo; 6-hour infusion
• Combined risk of worsening HF or death at 24h: dose-related decrease (4.0% vs 8.8% placebo, p=0.044)
• 14-day overall mortality: 11.4% vs 19.6% (p=0.029) favoring levosimendan

Stable HF (n=151, NYHA III):

• 5 dose regimens vs dobutamine vs placebo; 24h infusion
• ≥50% response rates at all levosimendan doses vs placebo (p≤0.038); cardiac output increased at all doses vs placebo

Post-cardiac surgery (CPB, n=18 and n=23):

• Both doses significantly increased cardiac output vs placebo; no increase in myocardial oxygen consumption or substrate utilisation; PVR decreased

Tolerability

• Well tolerated; most adverse events secondary to vasodilation (headache 8.7%, hypotension 6.5%, nausea 4%)
• Adverse events dose-related; fewer serious adverse events vs dobutamine (LIDO: 6.8% vs 18.4%)
• Higher doses (0.2–0.6 µg/kg/min): mild reductions in RBC/haematocrit/haemoglobin (~10–39%), small serum potassium decrease (~5%), modest blood glucose increase
• RUSSLAN: ischaemia/hypotension at highest recommended dose 13.4% vs 10.8% (NS overall); highest infusion rate (0.4 µg/kg/min) associated with 19% ischaemia/hypotension

Drug Interactions

• No significant interactions with: captopril, felodipine, β-blockers, digoxin, warfarin (modest warfarin t½β shortening — no clinical significance), isosorbide-5-mononitrate (only additive orthostatic tachycardia), carvedilol, alcohol (ethanol), itraconazole (CYP3A4 inhibitor — no pharmacokinetic effect)

Regulatory Status (as of 2001)

• First marketing approval: Sweden (2000) for acute decompensated HF
• Registration ongoing in other European, Latin American, Pacific, Asian, and African countries
• Late-phase clinical development in the USA at time of publication

Limitations of the Document

• 2001 review; predates definitive large RCTs (REVIVE-2, SURVIVE) that showed more complex mortality results
• LIDO and RUSSLAN published as abstracts only at time of writing — full manuscripts pending
• Small sample sizes in several haemodynamic substudy analyses
• Active metabolite OR-1896 pharmacokinetics incompletely characterised in special populations after single dosing
• Gender pharmacokinetic analysis limited (n=3 females)
• No head-to-head comparison with other vasodilators for pulmonary vasodilation in this review

Key Concepts Mentioned

• entities/Levosimendan — primary subject
• concepts/Vasoactive-Agents-in-CS — levosimendan as an inodilator
• concepts/Cardiogenic-Shock — context of decompensated HF

Key Entities Mentioned

• entities/Cardiac-Glycosides — digoxin: referenced for morbidity but not mortality benefit in sinus rhythm CHF

Wiki Pages Updated

• wiki/sources/levosimendan-drugs-2001.md — created (this file)
• wiki/entities/Levosimendan.md — created new concept page
• wiki/concepts/Vasoactive-Agents-in-CS.md — updated levosimendan mechanism section
• wiki/sourceindex.md — new entry added
• wiki/wikiindex.md — new levosimendan concept entry added