Levosimendan in Acute Decompensated Heart Failure

INTRODUCTION:

Heart failure (HF) is a clinical syndrome characterized by the reduced capacity of the left ventricle of the heart to pump or fill with blood, often leading to inadequate cardiac output and compensatory mechanisms such as neurohormonal activation and increased left ventricular filling pressures. Globally, HF affects an estimated 64.3 million people, marking it one of the major public health concern. Acute decompensated heart failure (ADHF), a clinical stage of HF, characterized by a rapid deterioration of symptoms and necessitates immediate medical attention. ADHF is particularly associated with high morbidity and mortality rates, significant healthcare utilization, and adverse long-term outcomes. ADHF contributes significantly to hospital admissions, especially among patients with heart failure with reduced ejection fraction (HFrEF). In high-income countries such as the United States and Europe, ADHF accounts for over one million hospitalizations annually. Alarmingly, approximately 24% of these patients are readmitted within 30 days, and 50% experience rehospitalization within six months. The recurrence of HF exacerbations often leads to a worsening prognosis, progressive multiorgan dysfunction, and increased mortality, with one in six patients succumbing within 30 days of hospitalization.

The burden of HF is even more in low- and middle-income countries (LMICs), including Bangladesh, though data is limited. In LMICs, delayed diagnosis, resource limitations, and late-stage presentation exacerbate the challenges of HF management. Bangladesh is experiencing a rising prevalence of cardiovascular diseases, with HF emerging as a leading cause of hospitalization and mortality along with increased life expectancy and aging of the population. Factors such as hypertension, diabetes, coronary artery disease, and rheumatic heart disease contribute significantly to the incidence of HF in the region. The healthcare infrastructure in Bangladesh is often ill-equipped to handle the complex needs of HF patients, with limited access to advanced diagnostic tools, medications, and specialized care. This leads to frequent hospitalizations and poor outcomes for patients with ADHF.

The management of ADHF involves a combination of pharmacological and non-pharmacological strategies aimed at stabilizing the patient, alleviating symptoms, and improving hemodynamic parameters. Diuretics, particularly loop diuretics, are the cornerstone of ADHF treatment, effectively reducing fluid overload. However, diuretics alone do not address the underlying pathophysiology of HF, leaving patients with severe symptoms inadequately managed. Inotropic agents such as dobutamine and dopamine are often employed to enhance cardiac output in more severe cases. Vasodilators like nitroglycerin and nitroprusside are additional options, particularly in patients with hypertension and pulmonary congestion.

Beside these pharmacotherapies, Levosimendan, a calcium-sensitizing inotropic agent, represents a significant advancement in the treatment of ADHF. Unlike traditional inotropes, Levosimendan enhances myocardial contractility without markedly increasing myocardial oxygen consumption, thereby reducing the risk of tachyarrhythmias and ischemic events. Its dual action as an inotrope and vasodilator allows it to improve both cardiac output and systemic vascular resistance, making it particularly effective in patients with severe low-output HF. Clinical evidence suggests that Levosimendan improves symptoms, reduces hospital length of stay, and, in some studies, decreases mortality. Additionally, it's unique mechanism of action and sustained hemodynamic effects-mediated through its active metabolite-offer an extended therapeutic window even after the cessation of infusion.

Despite the promising evidence supporting Levosimendan, its adoption as a standard treatment for ADHF remains limited in Bangladesh. In this context, understanding the efficacy and safety of levosimendan in improving clinical outcomes, reducing rehospitalizations, and mortality in ADHF is important in this country. Hence, the present study will aim to investigate the efficacy and safety of levosimendan in patients with ADHF in Bangladesh.

OBJECTIVES:

Primary objective:

• To investigate the efficacy and Safety of Levosimendan in patients with acutely decompensated heart failure (ADHF).

Secondary objectives:

* To investigate the short-term efficacy of Levosimendan in terms of clinical improvements in patients with ADHF * To investigate the long-term efficacy of Levosimendan in terms of mortality and hospital readmission in patients with ADHF * To investigate the adverse events of Levosimendan in patients with ADHF

RATIONALE:

Levosimendan has shown benefits in clinical trials by improving hemodynamics, reducing hospital stay, and enhancing survival in acute heart failure. However, its adoption in guidelines remains inconsistent, particularly in low- and middle-income countries like Bangladesh. Most evidence comes from Western populations, leaving gaps in contextual data for South Asia, where genetic and ethnic variations may affect drug response. Limited real-world evidence exists in Bangladesh, especially compared to other inotropes like dobutamine, and data on long-term outcomes such as mortality and re-hospitalization are scarce. This study aims to generate baseline evidence on the short- and long-term safety and efficacy of Levosimendan in Bangladeshi patients with acute decompensated heart failure.

Drug profile (Levosimendan) Levosimendan is a calcium-sensitizing inotropic agent with vasodilatory properties. Its primary mechanism of action is stabilizing the calcium-troponin C complex in cardiac myocytes, leading to increased myocardial contractility without raising intracellular calcium levels or myocardial oxygen consumption. Additionally, it activates ATP-sensitive potassium (K-ATP) channels in vascular smooth muscle and mitochondria, resulting in systemic and coronary vasodilation. These dual effects improve both myocardial and peripheral perfusion, addressing key hemodynamic abnormalities in ADHF.

The pharmacodynamic profile of levosimendan offers multiple hemodynamic benefits. By enhancing contractility and activating K-ATP channels, it effectively increases cardiac output, reduces pulmonary capillary wedge pressure (PCWP), and lowers systemic vascular resistance (SVR). These actions lead to improved peripheral organ perfusion and symptomatic relief for patients with ADHF. Unlike traditional inotropes such as dobutamine and dopamine, levosimendan does not rely on beta-adrenergic receptor activation or increase intracellular calcium, making it safer for patients with pre-existing arrhythmias or ischemic heart disease. Furthermore, its mitochondrial K-ATP channel activation may provide cytoprotective effects, reducing myocardial injury during ischemic episodes.

Administered intravenously with a typical regimen of a continuous infusion of 0.05-0.2 μg/kg/min for up to 24 hours, levosimendan is immediately bioavailable. It is highly protein-bound (\~97-98%), allowing efficient distribution to target tissues. It undergoes hepatic metabolism through conjugation, producing an active metabolite, OR-1896, which has a significantly prolonged half-life of 70-80 hours. This metabolite is primarily excreted via the kidneys and accounts for the drug's sustained hemodynamic effects, which can last for up to 7-9 days after the infusion.

Levosimendan has shown consistent efficacy across several clinical trials. RCTs, such as LIDO, REVIVE, and SURVIVE have highlighted its ability to improve hemodynamic parameters, alleviate symptoms, and reduce hospital length of stay. The drug's safety profile is also notable. Levosimendan is generally well-tolerated, with hypotension, headache, and hypokalemia being the most commonly reported adverse effects. Importantly, it is associated with a lower incidence of tachyarrhythmias compared to traditional inotropes, making it a safer option for patients with ADHF.

Study design The proposed study will be designed as a pragmatic, two-arm, open-labelled, randomized, controlled trial conducted in a real-world clinical setting.

METHODS:

Study setting

* The present study will be conducted in following institutions: * Chattogram Medical College Hospital, Chattogram, Bangladesh * National Institute of Cardiovascular Diseases, Dhaka, Bangladesh * Chattogram Maa-O-Shishu Hospital Medical College Hospital, Chattogram, Bangladesh * Dhaka Medical College Hospital, Dhaka, Bangladesh * United Hospital Limited, Dhaka, Bangladesh * Cox's Bazar Medical College * Apollo Imperial Hospital \& Max Hospital, Chattogram.

Study duration The duration of the present study will be 12 months, from July 2025 to June 2026.

Study population The study population will include adult patients aged over 18 years, who will present with acute decompensated heart failure (ADHF) with a history of left ventricular dysfunction as demonstrated by a left ventricular ejection fraction (LVEF) of less than 40% within the past 12 months (calculated by Simpson's method)

Sample size calculation Final sample is calculated as 166 patients in each arm, a total of 332 patients.

Sampling procedure A purposive sampling technique according to the inclusion and exclusion criteria will be used for recruitment of study participants.

Eligibility criteria Inclusion criteria

* Adult patients (age \>18 years) * Both male and female sex * Having left ventricular dysfunction, evidenced by a left ventricular ejection fraction \<40% within the prior 12 months * Hospitalized for the treatment of ADHF * Remained dyspneic at rest despite treatment with intravenous diuretics (NYHA class IV) * Patients might have received intravenous vasodilators and/or positive inotropic drugs (except amrinone and milrinone), but the infusion rates of these drugs must have remained constant for at least 2 h before entry into the study.

Exclusion criteria

* History of invasive cardiac procedure

* Cardiac surgery during lifetime within 3 months prior to screening * Cardiac revascularization within 3 months prior to screening * Left ventricular assist device (LVAD) implantation within 3 months prior to screening * A cardioversion within 4 h prior to screening, or * Cardiac re-synchronization procedure within 30 days prior to screening) * Rhythm disorders (e.g. earlier Torsades de Pointes, increased heart rate) * Severe ventricular outflow obstruction * Angina within 6 h prior to screening * Hypotension (a systolic blood pressure \<90 mmHg) \[Can be included after resuscitation, when SBP will be \>90 mmHg by noradrenaline infusion\] * Uncorrected hypokalemia * CNS disease (e.g. stroke, TIA) * Respiratory (e.g. COPD exacerbation requiring systematic steroids or intubation) * Renal insufficiency (e.g. increased serum creatinine clearance rate \<15 mL/min) * Hepatic impairment (e.g. significant increase in liver enzymes, \>5x the upper limit of normal) * Decompensation from active infection eg, sepsis * Acute bleeding * Patient required blood transfusion or Severe anemia (hemoglobin \<8 g/l) * Serum potassium concentration \<3.5 or \>5.4 mmol/l * Use of amrinone and milrinone prior to screening * A history of hypersensitivity to levosimendan or any of the excipients * Intubated or otherwise unable to communicate * Pregnancy * Post-partum cardiomyopathy * Previous participation in a clinical trial with any experimental treatment within the last 30 days

Study procedure

Following steps will be implemented for conducting the present study:

1. Recruitment and training of data collectors 2. Screening and enrollment of the participants 3. Treatment allocation, provision and administration of drugs and 4. Follow up of the participants

Recruitment and training of data collectors For data collection in the present study, one study physician/research assistant will be recruited for eac

• Safety Outcomes - Adverse Events and Serious Adverse Events [Срок оценки: From baseline to 90 days follow-up]
• Changes in Clinical and Functional Status [Срок оценки: From baseline to 90 days follow-up]
• Hospitalization and Mortality Outcomes [Срок оценки: During index hospitalization and up to 90 days post-treatment initiation]