Use of Levosimendan in Patients with Advanced Heart Failure: An Update

Authors, Journal, Affiliations, Type, DOI

• Daniele Masarone, Michelle M. Kittleson, Piero Pollesello, Marco Marini, Massimo Iacoviello, Fabrizio Oliva, Angelo Caiazzo, Andrea Petraio, Giuseppe Pacileo
• Journal of Clinical Medicine 2022; 11(21): 6408
• Heart Failure Unit, AORN dei Colli-Monaldi Hospital Naples; Cedars-Sinai (Kittleson); Orion Pharma (Pollesello — COI)
• Narrative review
• DOI: https://doi.org/10.3390/jcm11216408

Overview

This 2022 narrative review synthesises the pharmacology and clinical evidence for levosimendan in advanced HFrEF (advHFrEF), covering its triple mechanism of action, updated pharmacokinetics (active metabolite OR-1896 with 80h half-life and 10–14 day pharmacodynamic effect), and three randomised controlled trials of pulsed outpatient infusion (LevoRep, LION-HEART, LAICA). Evidence for pre-LVAD preconditioning, bridge-to-transplant, and preliminary data in advanced HFpEF (HELP trial) are also reviewed. Practical dosing guidance is provided with dose adjustment recommendations for renal impairment and haemodynamic instability. A conflict of interest exists: co-author Piero Pollesello is a full-time employee of Orion Pharma, the developer of levosimendan.

Keywords

Advanced heart failure, inodilators, levosimendan, pharmacologic therapy

Key Takeaways

Pharmacokinetics — Updated

• Levosimendan is a pro-drug with linear kinetics; oral bioavailability 85%, Vd 0.2 L/kg, protein binding 97–98%; extensively metabolised via glutathione conjugation (inactive metabolites)
• Minor metabolic pathway (~6% of dose): intestinal reduction to OR-1855 → acetylation to active metabolite OR-1896
• Parent drug t½ ≈ 1h; rapidly eliminated at end of infusion
• OR-1896 half-life ≈ 80h; peak concentration at 48–72h post-infusion → pharmacodynamic effects persist 10–14 days after a single infusion
• Mild-moderate renal and hepatic impairment: pharmacokinetics not significantly altered
• Severe renal dysfunction: OR-1855 and OR-1896 half-life prolonged 1.5×; AUC and peak concentrations 2-fold higher → dose and infusion rate should be reduced; levosimendan use generally avoided if CrCl <30 mL/min/1.73m²

Pharmacodynamics — Triple Mechanism

1. Calcium sensitisation: selective binding to calcium-bound form of cardiac troponin C → increased contractility without altering cardiomyocyte electrophysiology or myocardial relaxation
2. Vascular KATP channel opening: improved O₂ delivery to myocardium without increased demand; arterial and venous vasodilation
3. Mitochondrial KATP channel opening: cardioprotective and organ-protective effect

• Additional effects: anti-inflammatory and antiapoptotic (clinical relevance uncertain)

Side Effects and Contraindications

• Common: hypotension, headache, nausea (all vasodilation-mediated)
• Increased AF incidence vs dobutamine and placebo (in contrast to low ventricular arrhythmia risk)
• Ventricular arrhythmias unlikely (does not increase intracellular calcium)
• Hypokalemia: a typical side effect; mechanism unknown
• Contraindications: SBP <70 mmHg; significant mechanical obstruction (severe MS or severe AS); CrCl <30 mL/min/1.73m²; severe hepatic impairment (MELD >30)

Pulsed Levosimendan Infusion in advHFrEF — Non-Randomised Evidence

Multiple small non-randomised registries and observational studies showed improvements in LVEF, cardiac index, PASP, E/e' ratio, NT-proBNP, and reduction in HF hospitalisations with repeated levosimendan infusions at intervals ranging from 2 weeks to 4 weeks over 6–12 months (see Table 1 in source for full details).

Pulsed Levosimendan — Randomised Clinical Trials

LevoRep (n=120; advHFrEF outpatients):

• Levosimendan 0.2 µg/kg/min for 6h every 2 weeks × 6 weeks vs placebo
• Primary composite (≥20% improvement in 6MWT + ≥15-point KCCQ improvement): FAILED (19% vs 15%; OR 1.25; 95% CI 0.44–3.59; p=0.810)

LION-HEART (n=69; advHFrEF):

• Levosimendan 0.2 µg/kg/min for 6h every 2 weeks × 12 weeks vs placebo
• NT-proBNP: mean change −1446 vs −1320 pg/mL (p<0.001)
• HF-related hospitalisation: HR 0.25 (95% CI 0.11–0.56; p=0.001)
• Lowest probability of clinically significant QoL decline (p=0.022)

LAICA (n=97; advHFrEF):

• Levosimendan 0.1 µg/kg/min for 24h every 4 weeks × 12 months vs placebo
• Primary (HF readmissions): MISSED (HR 0.66; 95% CI 0.32–1.32; p=0.24)
• Cumulative incidence of decompensation+death at 1 month: 5.7% vs 25.9% (p=0.004)
• Cumulative incidence of decompensation+death at 3 months: 17.1% vs 48.1% (p=0.001)
• Survival at 12 months: improved (log-rank p=0.044)

Meta-analysis of pulsed levosimendan (n=984; 727 levosimendan, 257 control):

• Improved NYHA class (p<0.001), LVEF (p<0.001), NT-proBNP (p<0.001)
• All-cause mortality: NS
• Cardiovascular death: lower with levosimendan (p=0.02)

Ongoing trials (as of 2022):

• LEODOR (NCT03437226): intermittent levosimendan in post-discharge vulnerable phase
• LEIA-HF (NCT04705337): 24h infusions every 4 weeks × 48 weeks; outpatient advHFrEF

Levosimendan Pre-LVAD Implantation

• Up to 25% of LVAD patients develop post-implant RV failure with high morbidity/mortality
• Levosimendan pretreatment: CI +21% (p=0.014), pulmonary pressure −12% (p=0.003), PCWP −15% (p=0.028), CVP −15% (p=0.016); improvements persisted 24h post-infusion in survivors but not in those who died of RV failure
• Haemodynamic response to levosimendan may predict mortality and post-LVAD RV dysfunction
• RCT (n=84): levosimendan vs placebo pre-LVAD — RV failure rate NOT reduced (7.5% vs 13.6%; p=0.43); no difference in in-hospital or long-term mortality
• Meta-analysis (n=106): hemodynamic improvement and better organ perfusion; no mortality reduction (insufficient statistical power)
• Conclusion: hemodynamic benefit plausible; mortality benefit unproven; multicenter RCT needed

Bridge to Transplant

• Single-center study (n=11): scheduled levosimendan infusions (6h every 2 months; 0.1–0.2 mg/kg/min) for patients on transplant waiting list
• Reduced rehospitalisation and urgent transplantation (22% vs 44% Spanish registries)
• Expert consensus: levosimendan viable as bridge to transplant in non-LVAD candidates — maintains end-organ perfusion and avoids pulmonary pressure elevation that would exclude from transplant list or require heart-lung transplant
• Preliminary and inconclusive — awaiting RCT data

Levosimendan in Advanced HFpEF — HELP Trial

• 37 patients with advHFpEF randomised to levosimendan vs placebo
• Exercise PCWP: −3.9 ± 2.0 mmHg (p=0.047); trend toward increased exercise CI (2.5 → 3.2 L/min/m² at 25W)
• 6MWT: +29.3m vs placebo (95% CI 2.5–56.1; p=0.033)
• Preliminary — further studies needed to confirm role in advHFpEF

Practical Dosing Protocol (Authors' Recommendation)

• First infusion: inpatient, 24h, 0.2 µg/kg/min — assess safety (hypotension, VA) and efficacy (symptoms/NT-proBNP or echo/RHC for bridge strategy)
• Standard protocol (SBP >100 mmHg + eGFR >45 mL/min/1.73m² + no complex VA history): 6.25 mg @ 0.2 µg/kg/min every 2 weeks
• Reduced protocol (SBP <100 or eGFR 30–45 or complex VA history): 12.5 mg @ 0.1 µg/kg/min every 4 weeks
• Carefully selected patients with eGFR 15–30 may receive the reduced protocol for palliative purposes if marked symptomatic improvement documented
• Pre-LVAD: 24h infusion @ 0.2 µg/kg/min + noradrenaline/adrenaline 0.1–0.2 µg/kg/min if high RV failure risk (e.g., RV failure risk score >5.5), given the day before implantation

ESC 2021 Guideline Recommendation

• Periodic levosimendan infusion may be considered as palliative strategy or bridge to transplant/LVAD in patients with advHFrEF with evidence of organ hypoperfusion (ESC 2021 HF Guidelines)

Limitations of the Document

• Narrative (not systematic) review
• One key co-author (Pollesello) is a full-time Orion Pharma employee — potential framing bias
• Three pulsed-infusion RCTs small (n=69–120), inconsistent protocols, mixed results
• No head-to-head comparison of 6h vs 24h pulsed infusion protocols in RCTs
• Pre-LVAD evidence mainly observational/underpowered; only one small RCT
• HELP trial (HFpEF) only n=37 — hypothesis-generating
• Ongoing trials (LEODOR, LEIA-HF) not yet reported

Key Concepts Mentioned

• entities/Levosimendan — primary subject; substantially updated by this source
• concepts/Vasoactive-Agents-in-CS — context for levosimendan as inodilator
• concepts/Right-Ventricular-Failure — post-LVAD RV failure and levosimendan preconditioning

Key Entities Mentioned

• HeartMate 3 LVAD — referenced as new-generation device with survival comparable to transplant

Wiki Pages Updated

• wiki/sources/levosimendan-jcm-2022.md — created (this file)
• wiki/entities/Levosimendan.md — substantially updated: triple mechanism, OR-1896 kinetics, renal dosing, AF risk, contraindications, pulsed infusion RCTs, LVAD preconditioning, bridge-to-transplant, HELP trial, ESC guideline, practical dosing
• wiki/sourceindex.md — new entry added
• wiki/wikiindex.md — levosimendan entry updated