Levosimendan, a Promising Pharmacotherapy in Cardiogenic Shock: A Comprehensive Review

Authors, Journal, Affiliations, Type, DOI

• Hendri Susilo, Fan Maitri Aldian, Citrawati Dyah Kencono Wungu, Mochamad Yusuf Alsagaff, Henry Sutanto, Chaq El Chaq Zamzam Multazam
• European Cardiology Review, 2024
• Universitas Airlangga (Departments of Cardiology, Physiology, Internal Medicine), Surabaya, Indonesia; National Heart and Lung Institute, Imperial College London, UK
• Narrative comprehensive review
• DOI not provided in source

Overview

A CS-focused narrative review synthesising mechanistic, haemodynamic, and clinical trial evidence for levosimendan across the full spectrum of CS aetiologies — AMI-CS, post-cardiac surgery, PPCM, takotsubo, VA-ECMO weaning, septic shock, and hypothermia settings. Key additions beyond prior reviews include explicit characterisation of the mitochondrial KATP mPTP/cytochrome C cascade, the endothelial NO mechanism via p38 MAPK/ERK/Akt, PDE3 inhibition only at supratherapeutic doses, the complete LIDO 180-day mortality result (HR 0.57), enoximone head-to-head survival data (69% vs 37%), and practical SBP thresholds for monotherapy versus combination use. No systematic methods or GRADE applied; no COI statement visible.

Keywords

Cardiogenic shock, levosimendan, calcium sensitiser, KATP channel, inotrope, mechanical circulatory support, VA-ECMO, cardiogenic shock management

Key Takeaways

Cardiogenic Shock Definition and SCAI Classification

• CS = critical condition of insufficient organ perfusion due to primary cardiac dysfunction (AMI, HF exacerbation, myocarditis)
• SCAI A–E: At Risk (A) → Beginning (B, SBP <90 + tachycardia, no hypoperfusion) → Classic (C, hypotension + organ hypoperfusion) → Deteriorating (D, worsening despite initial resuscitation) → Extremis (E, refractory shock + MOF ± cardiac arrest)
• CS pathophysiology: decreased contractility → low CO → systemic hypoperfusion → SNS/RAAS activation → increased myocardial O₂ demand → worsening ischaemia → vicious cycle → lactic acidosis

Pharmacological Profile and Mechanisms of Action

Calcium Sensitisation (Primary Inotropic Mechanism)

• Binds cTnC at N-terminal domain in calcium-dependent manner; stabilises calcium-bound state → prolongs time calcium remains bound → enhances cross-bridge cycling
• Stronger contractions without additional calcium; does NOT increase intracellular calcium
• Does not impair diastolic relaxation: calcium decay occurs before peak contraction

Vascular KATP Channel Opening (Vasodilation)

• K⁺ efflux → membrane hyperpolarisation → prevents voltage-gated Ca²⁺ channel opening → smooth muscle relaxation → arterial and venous vasodilation
• Endothelial NO production via p38 MAPK/ERK/Akt pathways — secondary, complementary vasodilatory mechanism

Mitochondrial KATP Channel Opening (Cardioprotection)

• K⁺ influx into mitochondria → mitochondrial membrane potential preservation → ATP production maintained during reperfusion
• Prevents mitochondrial permeability transition pore (mPTP) opening → prevents calcium overload-triggered necrosis/apoptosis
• Mild ROS increase → enhances antioxidant defences
• Inhibits cytochrome C release from mitochondria → anti-apoptotic

PDE3 Inhibition

• Levosimendan is a highly selective PDE3 inhibitor in vitro
• Clinically significant only at supratherapeutic doses — primary mechanism in practice is calcium sensitisation, NOT PDE3 inhibition

Unique Profile: Zero Myocardial Oxygen Consumption Increase

• Table 2 comparison (levosimendan vs dobutamine, norepinephrine, epinephrine, dopamine, milrinone, vasopressin): levosimendan is the only agent with no myocardial oxygen consumption increase

Pharmacokinetics

• Linear kinetics within 0.05–0.2 µg/kg/min; therapeutic levels ~1h after infusion start; steady state ~5h
• OR-1896 t½ 70–80h in HF patients; max concentration ~2 days post 24h infusion; pharmacodynamic effect ≥1 week
• Distribution volume 0.2–0.3 L/kg; albumin binding 97–98%

Clinical Efficacy versus Other Inotropic Agents

vs Enoximone in Refractory CS/AMI

• Levosimendan vs enoximone: survival 69% vs 37% (p=0.023); higher cardiac index and lower cumulative catecholamine use at 72h

vs Dobutamine in AMI-CS

• Levosimendan: improved cardiac power output better than dobutamine within 24h post-PCI
• Long-term (180-day): no significant survival difference in that specific cohort (small sample, baseline CAD differences); broader LIDO data: HR 0.57 (95% CI 0.34–0.95; p=0.029) at 180 days
• Haemodynamic superiority: better CI, SVR, PCWP reduction

Safety vs Comparators

• Fewer tachyarrhythmias and ischaemia than catecholamine-based inotropes
• Less afterload increase than norepinephrine (vasodilatory)
• Better CI, SVI, NT-proBNP, and kidney function vs dobutamine in cardiac surgery

Clinical Usage in Specific Settings

AMI-CS

• Improves myocardial contractility and reduces preload/afterload without worsening ischaemia
• Cardioprotective effects (KATP, O₂-sparing) may mitigate infarct extension

VA-ECMO Weaning

• Multiple studies/meta-analyses: levosimendan → higher weaning success rate + reduced 28–30 day mortality (though longer ECMO duration in levosimendan group)
• One observational cohort (n=200): no significant difference in weaning failure rate — contradicts positive studies
• Temporary VAD adjuvant: levosimendan immediately post-VAD → improved MAP, reduced lactate, improved O₂/FiO₂, improved systolic function and PA pressure → higher weaning rate + lower 6-month mortality vs control
• No direct comparison with dobutamine for VA-ECMO weaning

PPCM

• Catecholamines (dobutamine) contraindicated due to teratogenicity
• Levosimendan: improves cardiac function, facilitates LV function recovery without teratogenic risk

Takotsubo Cardiomyopathy

• Dobutamine risks catecholamine surge/vasospasm and may induce TCM
• In one comparative study: LV systolic function recovery occurred only in the levosimendan group

Cardiac Surgery

• Peri-/preoperative levosimendan in LV dysfunction patients → reduced LCOS, reduced MCS need, decreased incidence of LCOS, reduced mortality vs placebo/dobutamine/milrinone
• Better CI, SVI, NT-proBNP, and kidney function vs dobutamine

Septic Shock

• Multiple meta-analyses suggest mortality reduction vs placebo/standard care
• Mechanism may include anti-inflammatory and organ-protective effects beyond cardiac

Safety and Adverse Effects

• Common: hypotension, headache (vasodilatory); nausea, dizziness, heart rate increase (mild and transient)
• Reduced mean haemoglobin vs dobutamine (mechanism unclear)
• Serious but rare: severe hypotension, cardiac arrhythmias including AF; more likely with concomitant vasodilators or negative chronotropes, or in severe AS
• VT controversy: REVIVE — higher VT vs placebo; SURVIVE — similar VT rates vs dobutamine → discordant signals
• Hypothermia safety: hiPSC-cardiomyocyte study at 26°C — milrinone and isoprenaline significantly increased action potential triangulation (arrhythmia risk); levosimendan did NOT increase triangulation and maintained contractile properties → potentially safer in hypothermic patients
• Ventricular arrhythmias less common than with β-adrenergic agonists

Application in Clinical Practice

• SBP threshold: levosimendan alone only when SBP >90 mmHg; below this → combine with vasopressors/inotropes
• Loading dose: 6–12 µg/kg over 10 min (omit in severe hypotension), then continuous infusion 0.1 µg/kg/min; can decrease to 0.05 µg/kg/min or increase to 0.2 µg/kg/min based on response
• Combination with dobutamine: complementary mechanisms (TnC sensitisation + intracellular Ca²⁺ augmentation); first combination study showed CI increase + PCWP decrease within 24h; longer follow-up showed prolonged survival vs dobutamine alone; n=89 RCT demonstrated superiority over dobutamine alone for preventing MACE

Future Perspectives

• Emerging evidence: RV failure, septic shock, advanced chronic HF, paediatric use
• Novel delivery systems: subcutaneous or oral formulations under investigation for outpatient chronic HF management

Limitations of the Document

• Narrative review without systematic search strategy, explicit inclusion/exclusion criteria, or GRADE evidence assessment
• No COI statement visible — potential bias cannot be excluded
• Some cited studies are small or preliminary; some conclusions (e.g., SURVIVE framed positively) are inconsistent with prevailing interpretation
• Primarily relies on secondary summaries of RCTs without detailed statistical appraisal
• Septic shock section relies on meta-analyses without large dedicated RCTs

Key Concepts Mentioned

• entities/Levosimendan — primary subject; comprehensive mechanistic and clinical update
• concepts/Vasoactive-Agents-in-CS — comparative framework; inotrope comparison table
• concepts/Cardiogenic-Shock — CS definition, pathophysiology, SCAI classification
• concepts/SCAI-Shock-Classification — A–E staging referenced throughout
• concepts/Right-Ventricular-Failure — RV haemodynamic effects and pre-LVAD context
• concepts/ECPELLA — VA-ECMO weaning evidence

Key Entities Mentioned

• REVIVE trial — showed higher VT incidence vs placebo
• SURVIVE trial — showed similar VT rates vs dobutamine; overall null on 180-day mortality
• LIDO trial — 180-day HR 0.57

Wiki Pages Updated

• wiki/entities/Levosimendan.md — major update: mechanisms, clinical trials, special populations, dosing, contradictions; source_count 2→3
• wiki/concepts/Vasoactive-Agents-in-CS.md — expanded levosimendan subsection; source_count updated
• wiki/sourceindex.md — new entry prepended
• wiki/wikiindex.md — Levosimendan entry updated