Levosimendan

Definition

Levosimendan is a pyridazinone-dinitrile derivative inodilator (pro-drug) administered intravenously for acute decompensated and advanced heart failure, and increasingly studied in cardiogenic shock. It operates via a triple mechanism: calcium sensitisation of the myofilaments via troponin C binding, vasodilation via vascular KATP channel opening, and cardioprotective/organ-protective effects via mitochondrial KATP channel opening. Its active metabolite OR-1896 has an ~80h half-life, extending pharmacodynamic effects 10–14 days beyond the infusion.

Key Concepts

Mechanism of Action — Quadruple

1. Calcium sensitisation (inotropic): binds to cardiac troponin C (cTnC) at the N-terminal domain in a calcium-dependent manner (high affinity during systole, low during diastole); stabilises the calcium-induced conformational change → enhances actin-myosin cross-bridge formation without altering cycling rate, ATP consumption, or diastolic function; calcium decay occurs before peak contraction, so relaxation is not impaired sources/levosimendan-drugs-2001 (medium) sources/levosimendan-jcm-2022 (high) sources/levosimendan-ecr-2024 (medium)
2. Vascular KATP channel opening (vasodilation): opens glibenclamide-sensitive KATP channels in vascular smooth muscle → K⁺ efflux → membrane hyperpolarisation → prevents voltage-gated Ca²⁺ channel opening → smooth muscle relaxation → arterial and venous vasodilation + improved coronary O₂ delivery without increased demand; supplementary: endothelial NO production via p38 MAPK/ERK/Akt pathways (secondary mechanism) sources/levosimendan-drugs-2001 (medium) sources/levosimendan-jcm-2022 (high) sources/levosimendan-ecr-2024 (medium)
3. Mitochondrial KATP channel opening (cardioprotective): K⁺ influx → mitochondrial membrane potential preservation → ATP production maintained during reperfusion → prevents mPTP opening (prevents calcium overload-triggered necrosis/apoptosis) → mild ROS increase → antioxidant signalling → inhibits cytochrome C release → anti-apoptotic; organ-protective effects sources/levosimendan-jcm-2022 (high) sources/levosimendan-ecr-2024 (medium)
4. PDE3 inhibition: highly selective PDE3 inhibitor in vitro, but clinically significant only at supratherapeutic doses; primary mechanism in clinical practice is calcium sensitisation, NOT PDE3 inhibition sources/levosimendan-ecr-2024 (medium)

• Additional: anti-inflammatory and antiapoptotic systemic effects (clinical relevance uncertain) sources/levosimendan-jcm-2022 (high)
• Does NOT increase intracellular cAMP or calcium at therapeutic doses → avoids the arrhythmogenic and oxygen-wasting profile of conventional inotropes
• Unique: only inotrope with ZERO increase in myocardial oxygen consumption vs dobutamine, norepinephrine, epinephrine, dopamine, milrinone, vasopressin sources/levosimendan-ecr-2024 (medium)

Pharmacokinetics

• Pro-drug; linear pharmacokinetics within 0.05–0.2 µg/kg/min therapeutic range; Vd 0.2–0.3 L/kg; protein binding 97–98% (albumin)
• Parent drug t½β ≈ 1h; steady state ~5h; rapidly eliminated from circulation at end of infusion
• Minor metabolic pathway (~6%): intestinal reduction → OR-1855 → acetylation → OR-1896 (active metabolite) sources/levosimendan-jcm-2022 (high)
• OR-1896 half-life ≈ 70–80h in HF patients; peak plasma concentration 48–72h post-infusion; pharmacodynamic effects persist ≥1 week (typically 10–14 days) after a single infusion — explains pulsed dosing rationale sources/levosimendan-jcm-2022 (high) sources/levosimendan-ecr-2024 (medium)
• Mild-moderate renal and hepatic impairment: pharmacokinetics not significantly altered sources/levosimendan-drugs-2001 (medium)
• Severe renal dysfunction (CrCl <30 mL/min/1.73m²): OR-1855/OR-1896 half-life prolonged 1.5×; AUC 2-fold higher → dose must be reduced; avoid unless clear palliative benefit sources/levosimendan-jcm-2022 (high)

Haemodynamic Profile

• Dose-dependent increases in CO, CI, SV; decreases in PCWP, SVR, PVR — confirmed across healthy volunteers, stable CHF, decompensated CHF, and post-cardiac surgery sources/levosimendan-drugs-2001 (medium)
• Increases LV myocardial blood flow without increasing myocardial oxygen consumption (PET study); RV efficiency +24% (p<0.05) sources/levosimendan-drugs-2001 (medium)
• Neutral myocardial energetics — contrasts with all other inotropes, which all increase O₂ consumption sources/levosimendan-drugs-2001 (medium) sources/levosimendan-ecr-2024 (medium)
• Pulmonary effects: PVR reduced 22–27% post-CPB; PAP decreased at all infusion rates; greater PVR reduction than dobutamine; also reduces exercise PCWP in HFpEF sources/levosimendan-drugs-2001 (medium) sources/levosimendan-jcm-2022 (high)
• Pre-LVAD: CI +21% (p=0.014), pulmonary pressure −12% (p=0.003), PCWP −15% (p=0.028), CVP −15% (p=0.016) sources/levosimendan-jcm-2022 (high)
• Renal: vasodilatory effects improve renal perfusion and diuresis, relevant in CS-associated AKI sources/levosimendan-ecr-2024 (medium)

Anti-Ischaemic and Antistunning Effects

• Reduces infarct size in animal models: LV infarct 24% ± 2% → 11% ± 2% (dog model); 12% ± 13% vs 27% ± 15% control (pig model, p=0.03) sources/levosimendan-drugs-2001 (medium) sources/levosimendan-ecr-2024 (medium)
• Improves stunned myocardium post-PTCA: hypokinetic segments −2.4 vs +0.8 placebo (p=0.011) sources/levosimendan-drugs-2001 (medium)
• No troponin T or CK-MB increase during infusion sources/levosimendan-drugs-2001 (medium)

Arrhythmia Profile

• Ventricular arrhythmias: does NOT raise intracellular calcium or cAMP → ventricular arrhythmias unlikely; animal models confirm 0% VF vs 50% milrinone and 83% VT/33% VF dobutamine; pooled data (386 patients): no increase in NSVT, no torsades, QTc not prolonged sources/levosimendan-drugs-2001 (medium)
• VT signal discordance: REVIVE showed higher VT incidence vs placebo; SURVIVE showed similar rates vs dobutamine — overall VT risk appears lower than catecholamines but not definitively zero sources/levosimendan-ecr-2024 (medium)
• Real-world ICD/VT safety (LEVO-D, n=403): ICD therapy rate unchanged year before vs after levosimendan (16.2% vs 14.9%; P=0.39); VT/VF episodes unchanged (0.87 vs 0.91/year; P=0.94); only 3.7% of the whole cohort had levosimendan withdrawn due to adverse events — large real-world confirmation of ventricular safety in advanced HF sources/levosimendan-eschf-2023 (high)
• AF risk: levosimendan is associated with increased incidence of AF compared with both dobutamine and placebo — a clinically important signal sources/levosimendan-jcm-2022 (high)
• Hypothermia safety: hiPSC-cardiomyocyte study at 26°C — milrinone and isoprenaline significantly increased action potential triangulation (arrhythmia risk marker); levosimendan did NOT increase triangulation and maintained contractile properties → potentially safer inotrope in hypothermic patients sources/levosimendan-ecr-2024 (medium)

Side Effects and Contraindications

• Common: hypotension, headache, nausea (vasodilatory, dose-related); hypokalemia; reduced haemoglobin vs dobutamine
• Fewer serious adverse events than dobutamine (LIDO: 6.8% vs 18.4%, p<0.05) sources/levosimendan-drugs-2001 (medium)
• Contraindications: SBP <70 mmHg; severe symptomatic mechanical obstruction (severe MS or severe AS); severe renal impairment (CrCl <30 mL/min/1.73m²); severe hepatic impairment (MELD >30) sources/levosimendan-jcm-2022 (high)

Key Clinical Trials — Acute/Decompensated HF and CS

• LIDO (n=203 decompensated CHF vs dobutamine): haemodynamic endpoint 28% vs 15% (p=0.022); 30-day worsening HF or death 6.8% vs 17% (p=0.039); 180-day mortality HR 0.57 (95% CI 0.34–0.95; p=0.029) sources/levosimendan-drugs-2001 (medium) sources/levosimendan-ecr-2024 (medium)
• RUSSLAN (n=504 decompensated CHF post-AMI vs placebo): 14-day mortality 11.4% vs 19.6% (p=0.029) sources/levosimendan-drugs-2001 (medium)
• SURVIVE (n=1,327, 2007, vs dobutamine): no 180-day mortality benefit despite better short-term haemodynamics — pivotal null result
• Enoximone vs levosimendan (refractory CS/AMI): survival 69% vs 37% (p=0.023); levosimendan: higher CI and lower catecholamine use at 72h sources/levosimendan-ecr-2024 (medium)

Key Clinical Trials — Pulsed Infusion in Advanced HFrEF

• LevoRep (n=120; 6h every 2 weeks × 6 weeks): primary composite FAILED (19% vs 15%; p=0.810) sources/levosimendan-jcm-2022 (high)
• LION-HEART (n=69; 6h every 2 weeks × 12 weeks): HF hospitalisation HR 0.25 (95% CI 0.11–0.56; p=0.001); NT-proBNP (p<0.001); QoL (p=0.022) sources/levosimendan-jcm-2022 (high)
• LAICA (n=97; 24h every 4 weeks × 12 months): primary HF readmission MISSED (p=0.24); 12-month survival improved (log-rank p=0.044) sources/levosimendan-jcm-2022 (high)
• Meta-analysis (n=984): improved NYHA, LVEF, NT-proBNP; CV death lower (p=0.02) sources/levosimendan-jcm-2022 (high)
• LEVO-D registry (n=403; 23 Spanish hospitals; retrospective; destination therapy — not HT/LVAD candidates): HF hospitalisations 77.9% → 38.7% (P<0.0001); unplanned HF visits 43.7% → 22.7% (P<0.0001); combined event 81.4% → 56.3% (P<0.0001); 1-year mortality 26.8%; median survival 24.7 months; 43.7% responders; ICD/VT unchanged; side-effect withdrawal rate 3.7% sources/levosimendan-eschf-2023 (high)
• Ongoing: LEODOR, LEIA-HF

LEVO-D Score — Predicting Response to Pulsed Levosimendan

• 5-variable score derived from LEVO-D registry multivariate analysis; predicts 1-year "responder" status (alive + no HF event) sources/levosimendan-eschf-2023 (high)
• Scoring: TEER (+2), beta-blockers (+1.5), Hgb >12 g/dL (+1.5), amiodarone use (−1.5), unplanned HF visit in year before (−1.5), HR >70 bpm (−2); range −5 to +5
• Risk groups: Low probability (score ≤−1.5): 21.5% response; Intermediate (−1 to +1.5): 50.9%; High probability (≥2): 68.4%
• AUC 0.71 — outperforms MAGGIC score (AUC 0.60) in this population
• Clinical use: identifies patients likely to derive futile therapy — particularly score ≤−1.5 (21.5% response rate)
• Age NOT independently related to response — age alone should not preclude levosimendan trial

VA-ECMO Weaning

• Mixed evidence: multiple studies and meta-analyses found higher weaning success and reduced 28–30 day mortality in the levosimendan group (levosimendan patients had longer ECMO duration) sources/levosimendan-ecr-2024 (medium)
• Observational cohort (n=200): no significant difference in weaning failure rate — primary contradicting signal sources/levosimendan-ecr-2024 (medium)
• Dedicated weaning RCT: failed primary weaning endpoint — see concepts/Vasoactive-Agents-in-CS
• Temporary VAD adjuvant: immediate levosimendan post-VAD implantation → improved MAP, reduced lactate, improved O₂/FiO₂, improved systolic function and PA pressure → higher weaning rate + lower 6-month mortality vs control sources/levosimendan-ecr-2024 (medium)

Levosimendan Pre-LVAD Implantation

• RCT (n=84): pre-LVAD levosimendan vs placebo — RV failure rate NS (7.5% vs 13.6%; p=0.43); no mortality difference sources/levosimendan-jcm-2022 (high)
• Meta-analysis (n=106): haemodynamic improvement; no mortality reduction (low power) sources/levosimendan-jcm-2022 (high)
• Practical recommendation: 24h @ 0.2 µg/kg/min + vasopressor support if RV failure risk score >5.5 sources/levosimendan-jcm-2022 (high)

Special Populations

• PPCM: catecholamines (dobutamine) contraindicated due to teratogenicity; levosimendan improves LV function and haemodynamics without teratogenic risk sources/levosimendan-ecr-2024 (medium)
• 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 sources/levosimendan-ecr-2024 (medium)
• Cardiac surgery (perioperative): pre-/intraoperative levosimendan in patients with LV dysfunction → reduced LCOS, reduced MCS need, reduced mortality vs placebo/dobutamine/milrinone; better CI, SVI, NT-proBNP, and kidney function vs dobutamine sources/levosimendan-ecr-2024 (medium)
• Septic shock: multiple meta-analyses suggest mortality reduction vs standard care; anti-inflammatory/organ-protective mechanism sources/levosimendan-ecr-2024 (medium)

Bridge to Transplant

• Expert consensus supports use in non-LVAD candidates to maintain end-organ perfusion and avoid pulmonary pressure elevation that would exclude from transplant list; no RCT evidence sources/levosimendan-jcm-2022 (high)

Advanced HFpEF — HELP Trial

• n=37; exercise PCWP: −3.9 ± 2.0 mmHg (p=0.047); 6MWT: +29.3m vs placebo (p=0.033); preliminary/hypothesis-generating sources/levosimendan-jcm-2022 (high)
• Animal model (ZSF1 obese rat, HFpEF): chronic levosimendan improved LV relaxation, diastolic compliance, reduced hypertrophy and fibrosis sources/levosimendan-ecr-2024 (medium)

Practical Dosing Protocol

• Monotherapy threshold: use alone only when SBP >90 mmHg; below this, combine with vasopressors/inotropes sources/levosimendan-ecr-2024 (medium)
• Combination with dobutamine: complementary mechanisms (TnC sensitisation + intracellular Ca²⁺ augmentation); first combination study showed CI increase + PCWP decrease within 24h; prolonged survival vs dobutamine alone; n=89 RCT demonstrated superiority for preventing MACE vs dobutamine alone sources/levosimendan-ecr-2024 (medium)
• Acute CS dosing: loading dose 6–12 µg/kg over 10 min (omit in severe hypotension), then 0.1 µg/kg/min; adjust to 0.05 µg/kg/min if strong response or increase to 0.2 µg/kg/min if well tolerated sources/levosimendan-ecr-2024 (medium)
• Pulsed advanced HFrEF:
  • Standard (SBP >100 + eGFR >45 + no complex VA): 6.25 mg @ 0.2 µg/kg/min every 2 weeks
  • Reduced (SBP <100 or eGFR 30–45 or complex VA): 12.5 mg @ 0.1 µg/kg/min every 4 weeks
  • eGFR 15–30: palliative only sources/levosimendan-jcm-2022 (high)
• First infusion always inpatient, 24h; assess safety and efficacy before proceeding
• Strategy flexibility (LEVO-D real-world): bailout, fixed-number, and sine die strategies showed equivalent outcomes; no dosing strategy was superior; dose per administration (high vs low) NOT independently related to response rate or 1-year mortality — even low doses may reduce HF events sources/levosimendan-eschf-2023 (high)

Guideline Recommendation

• ESC 2021 HF Guidelines: periodic levosimendan infusion may be considered as palliative strategy or bridge to transplant/LVAD in advHFrEF with organ hypoperfusion sources/levosimendan-jcm-2022 (high)

Contradictions / Open Questions

• AF risk vs non-arrhythmogenic framing: 2001 drug profile reported no increase in AF; 2022 review explicitly documents increased AF incidence vs both dobutamine and placebo; ventricular arrhythmia risk remains low sources/levosimendan-drugs-2001 (medium) vs sources/levosimendan-jcm-2022 (high)
• VT signal discordance: REVIVE showed higher VT incidence vs placebo; SURVIVE showed similar rates vs dobutamine — VT risk uncertain, likely lower than catecholamines but not definitively zero sources/levosimendan-ecr-2024 (medium)
• Acute HF mortality: LIDO and RUSSLAN showed favorable early mortality trends; SURVIVE (n=1,327) showed no 180-day mortality benefit vs dobutamine — not fully resolved
• Pulsed infusion RCT inconsistency: LION-HEART positive; LevoRep and LAICA mixed/negative on primary endpoints — optimal protocol (dose, duration, interval) not established; LEODOR and LEIA-HF ongoing
• VA-ECMO weaning: multiple small positive studies vs one large negative cohort (n=200) and one failed dedicated RCT — current evidence does not support routine use for weaning
• Pre-LVAD preconditioning: haemodynamic benefit consistent; no mortality reduction in RCT or meta-analysis — patient-level outcomes unproven
• Septic shock: meta-analyses suggest benefit; no large dedicated RCT; mechanism in non-cardiac shock unclear
• OR-1896 long-duration effect: 10–14 day pharmacodynamic persistence raises questions about cumulative toxicity, retreatment intervals, and monitoring requirements
• Dosing strategy vs protocol-specified RCTs: LEVO-D shows no superiority of any strategy (bailout/fixed/sine die) or dose level — contradicts the implicit assumption that protocol-driven frequent dosing (e.g. LION-HEART 6 × 6h every 2 weeks) is necessary; a flexible bailout approach may suffice in real-world destination therapy sources/levosimendan-eschf-2023 (high)

Connections

• Related to concepts/Vasoactive-Agents-in-CS
• Related to concepts/Cardiogenic-Shock
• Related to concepts/Right-Ventricular-Failure
• Related to concepts/Invasive-Hemodynamic-Monitoring-CS
• Related to concepts/Right-Heart-Catheterization
• Related to concepts/ECPELLA

Sources

• sources/levosimendan-drugs-2001 (medium)
• sources/levosimendan-jcm-2022 (high)
• sources/levosimendan-ecr-2024 (medium)
• sources/levosimendan-eschf-2023 (high)