Levosimendan

Overview of Levosimendan

Levosimendan is a calcium sensitizer and an adenosine triphosphate-dependent potassium (KATP) channel opener that enhances myocardial contractility without significantly increasing intracellular calcium levels or oxygen demand.

Levosimendan increases the sensitivity of cardiac troponin C (cTnC) to calcium, which enhances heart contractility. Additionally, it acts as a vasodilator on both arterial and venous systems, reducing preload and afterload by lowering systemic vascular resistance (SVR). This combination allows for improved cardiac output while also decreasing myocardial oxygen demand.

Pharmacokinetic

Absorption: Administered intravenously.
Distribution: Volume of distribution (Vd) is 0.2 to 0.3 liters per kilogram, with 97% to 98% bound to albumin.
Metabolism: Metabolised in the liver and reduced by intestinal bacteria to OR-1855, which is acetylated to the active metabolte OR-1896. The metabolites are reponsible for its prolonged effects despite a short plasma half-life
Excretion: Excreted mainly through the gut and secondarily by the kidneys; OR-1896 has a long elimination half-life.

Following a 24-hour infusion of levosimendan, the pharmacodynamic effect persists for a minimum of 1 week.

Calcium and Troponin Complex

This image is a diagram illustrating the role of the troponin complex and calcium ions (Ca²⁺) in muscle contraction, specifically in cardiac muscle. It shows how calcium binding leads to the exposure of myosin-binding sites on actin filaments, enabling contraction.

The troponin complex includes:
- TnC (binds calcium),
- TnT (binds tropomyosin),
- TnI (inhibitory, blocks myosin binding).

Resting State – No Ca²⁺ Bound
- Tropomyosin (purple strand) covers the myosin-binding sites on actin, preventing myosin interaction.

Activated State – Ca²⁺ Bound
- Calcium ions (Ca²⁺) bind to Troponin C (TnC).
- Calcium-bound TnC causes a shift in tropomyosin, exposing the myosin-binding sites (yellow dots) on actin.
- This binding triggers a conformational change in the troponin complex.
- Myosin heads (blue structure) can now bind to these sites, initiating contraction.

Levosimendan enhances myocardial contractility by sensitizing cardiac troponin C (cTnC) to calcium without increasing intracellular calcium levels, avoiding excessive oxygen consumption. Unlike other inotropic agents that increase intracellular calcium levels, possibly leading to detrimental effects such as arrhythmias and increased oxygen demand.

It binds to cTnC in a calcium-dependent way, specifically at the N-terminal domain. This binding is crucial for the conformational changes that allow actin-myosin cross-bridge cycling and muscle contraction. The interaction between levosimendan and cTnC stabilizes the cTnC-calcium complex, extending the duration that calcium is bound to cTnC. Leading to an increase in contractility without the need for additional calcium. This results in an improved contractile function with less risk of calcium overload and subsequent cardiac dysfunction.

Levosimendan improves systolic function without negatively impacting diastolic relaxation. This is because the decay of the calcium transient occurs before the peak contraction and the onset of relaxation. As a result, while the heart's contractions become stronger, the relaxation phase of the cardiac cycle remains unaffected. This mechanism helps to maintain overall cardiac efficiency and function.

Effect on vascular smooth muscle cell

This effect occurs primarily through the opening of KATP channels in vascular smooth muscle cells. When these channels open, potassium ions exit the cells, causing hyperpolarization of the cell membrane. This hyperpolarization prevents the opening of voltage-dependent calcium channels, reducing intracellular calcium concentrations.

Levosimendan may enhance endothelial function by promoting the release of relaxing factors like nitric oxide (NO) through the p38 MAPK, ERK, and Akt pathways.

Clinical trials

Cardiogenic shock, acute decompensated heart failure

Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial: Patients were recruited for a multicenter, randomized, double-blind trial with continuous hemodynamic monitoring. An initial loading dose of levosimendan (24 μg/kg over 10 minutes) was followed by a continuous infusion of 0.1 μg/kg/min for 24 hours. Dobutamine was given at an initial rate of 5 μg/kg/min without a loading dose, with the option to double the rate if necessary.

The primary endpoint was the percentage of patients showing hemodynamic improvement, defined as a 30% or greater increase in cardiac output and a 25% or more decrease in pulmonary capillary wedge pressure at 24 hours.

In total, 103 patients received levosimendan, and 100 received dobutamine. Hemodynamic improvement was achieved in 29 patients (28%) in the levosimendan group and 15 patients (15%) in the dobutamine group (hazard ratio 1.9 [95% CI 1.1–3.3]; p = 0.022). At 180 days, 27 patients (26%) in the levosimendan group had died, compared to 38 patients (38%) in the dobutamine group (hazard ratio 0.57 [0.34–0.95]; p = 0.029).

Conclusion: Levosimendan improved hemodynamic performance more effectively than dobutamine and was associated with lower mortality over 180 days in patients with severe low-output heart failure.

Levosimendan vs Dobutamine for Patients With Acute Decompensated Heart Failure: The SURVIVE Randomized Trial:

A randomized, double-blind trial compared the efficacy and safety of intravenous levosimendan and dobutamine in 1,327 patients with acute decompensated heart failure requiring inotropic support. Conducted at 75 centers in 9 countries from March 2003 to December 2004, patients were randomized to receive either levosimendan (n = 664) or dobutamine (n = 663).

The primary outcome measure was all-cause mortality at 180 days. At this time, all-cause mortality was 26% in the levosimendan group and 28% in the dobutamine group (hazard ratio, 0.91; P = .40). While the levosimendan group showed significant decreases in B-type natriuretic peptide levels over the first 5 days (P < .001), no significant differences were found in other secondary endpoints, including all-cause mortality at 31 days and cardiovascular mortality. The dobutamine group had a higher incidence of cardiac failure, while the levosimendan group reported more cases of atrial fibrillation, hypokalemia, and headaches.

Conclusion: Despite reductions in B-type natriuretic peptide levels, levosimendan did not significantly lower all-cause mortality at 180 days or improve secondary clinical outcomes.

Acute myocardial infarction

Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction:

A clinical trial comparing levosimendan and enoximone for refractory cardiogenic shock was conducted with thirty-two patients experiencing shock for at least two hours. Participants were randomly assigned to receive either levosimendan or enoximone, in addition to standard treatments.

Levosimendan was given as a 12 micrograms/kg loading dose over 10 minutes, followed by 0.1 micrograms/kg/min for 50 minutes, and then 0.2 micrograms/kg/min for 23 hours. Enoximone was administered as a 0.5 mg/kg loading dose and a continuous infusion of 2 to 10 micrograms/kg/min.

Results showed a 30-day survival rate of 69% in the levosimendan group versus 37% in the enoximone group (p = 0.023). Both groups had similar hemodynamic parameters, but levosimendan indicated better cardiac performance and lower catecholamine usage. All cases of multiple organ failure occurred in the enoximone group.

In conclusion, Levosimendan may improve survival in severe, refractory cardiogenic shock due to acute myocardial infarction compared to enoximone.

Effects of levosimendan versus dobutamine on long-term survival of patients with cardiogenic shock after primary coronary angioplasty: In a study of twenty-two consecutive STEMI patients with cardiogenic shock after percutaneous coronary intervention (PCI), participants were randomly assigned to receive either levosimendan or dobutamine for 24 hours. All patients completed a twelve-month follow-up, with cardiac death as the primary endpoint. Baseline clinical and hemodynamic characteristics were similar between the two groups. Kaplan-Meier analysis showed no significant differences in survival rates (p=0.24).

In conclusion, levosimendan did not improve long-term survival compared to dobutamine in STEMI patients with cardiogenic shock following PCI.

Hemodynamic effects of commonly used inotropes and vasopressors

Agents	CI	SVR	PVR	PVR/SVR
Vasopressin
Dobutamine	↑↑	↓	↓	↑/↓
Milrinone	↑↑	↓↓	↓↓	↓
Levosimendan	↑↑	↓↓	↓↓	↑/↓
Vasopressors
Epinephrine	↑↑↑	↑↑	↑	↑/↓
Dopamine	↑	↑	↑	↑/↓
Norepinephrine	↑	↑↑	↑	↑/↓
Phenylephrine	↓	↑	↑↑	↑
Vasopressin	↑/↓	↑↑	↓	↓

Hemodynamic effects of commonly used inotropes and vasopressors

Agent

Dobutamine

Milrinone

Levosimendan

Epinephrine

Dopamine

Norepinephrine

Phenylephrine

Vasopressin

SVR

PVR

PVR/SVR

References

1) Hendri Susilo, Fan Maitri Aldian, Citrawati Dyah Kencono Wungu, Mochamad Yusuf Alsagaff, Henry Sutanto, Chaq El Chaq Zamzam Multazam, Levosimendan, a Promising Pharmacotherapy in Cardiogenic Shock: A Comprehensive Review, European Cardiology Review 2024;19:e21. https://doi.org/10.15420/ecr.2024.16

2) Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Follath, F et al. The Lancet, Volume 360, Issue 9328, 196 - 202.

3) Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs Dobutamine for Patients With Acute Decompensated Heart Failure: The SURVIVE Randomized Trial. JAMA. 2007;297(17):1883–1891. doi:10.1001/jama.297.17.1883.

4) García-González MJ, Domínguez-Rodríguez A, Ferrer-Hita JJ, Abreu-González P, Muñoz MB. Cardiogenic shock after primary percutaneous coronary intervention: Effects of levosimendan compared with dobutamine on haemodynamics. Eur J Heart Fail. 2006 Nov;8(7):723-8. doi: 10.1016/j.ejheart.2006.01.007. Epub 2006 Feb 21. PMID: 16492404.

5) Fuhrmann JT, Schmeisser A, Schulze MR, Wunderlich C, Schoen SP, Rauwolf T, Weinbrenner C, Strasser RH. Levosimendan is superior to enoximone in refractory cardiogenic shock complicating acute myocardial infarction. Crit Care Med. 2008 Aug;36(8):2257-66. doi: 10.1097/CCM.0b013e3181809846. Erratum in: Crit Care Med. 2008 Oct;36(10):2966. PMID: 18664782.

6) Samimi-Fard S, García-González MJ, Domínguez-Rodríguez A, Abreu-González P. Effects of levosimendan versus dobutamine on long-term survival of patients with cardiogenic shock after primary coronary angioplasty. Int J Cardiol. 2008 Jul 4;127(2):284-7. doi: 10.1016/j.ijcard.2007.04.143. Epub 2007 Jul 23. PMID: 17643519.