European Journal of Cardiovascular Medicine

Acute Decompensated Heart Failure (ADHF) represents a major global health burden, characterized by high rates of hospitalization, morbidity, and mortality [1]. A significant subset of these patients presents with a low-output syndrome, defined by severe systolic dysfunction and signs of peripheral hypoperfusion. In these critical scenarios, temporary inotropic support is often mandated to maintain cardiac output (CO) and preserve end-organ function while bridging the patient to diuresis or mechanical circulatory support [2].

For decades, Dobutamine, a synthetic catecholamine acting primarily on -adrenergic receptors, has been the mainstay of inotropic therapy. By increasing cyclic adenosine monophosphate (cAMP) levels, Dobutamine facilitates calcium influx into myocytes, thereby enhancing contractility [3]. However, this mechanism comes at a considerable physiological cost. The increase in cytosolic calcium concentration leads to elevated myocardial oxygen consumption () and creates an electrophysiological substrate prone to tachyarrhythmias. Several retrospective analyses and clinical trials have suggested that while Dobutamine improves hemodynamics, it may be associated with increased long-term mortality, earning it a reputation as a "double-edged sword" [4, 5].

Levosimendan represents a distinct class of inotropes known as calcium sensitizers. Its primary mechanism involves binding to cardiac troponin C in a calcium-dependent manner, which enhances the myofilament's sensitivity to calcium without increasing intracellular calcium concentrations [6]. Consequently, it improves contractility without a parallel increase in metabolic energy demand or impairment of diastolic relaxation (lusitropy). Furthermore, Levosimendan opens adenosine triphosphate (ATP)-dependent potassium channels in vascular smooth muscle, leading to peripheral and coronary vasodilation [7].

Despite the theoretical physiological superiority of Levosimendan, clinical trials comparing it to Dobutamine, such as the SURVIVE and LIDO trials, have yielded conflicting or heterogeneous results regarding mortality benefits [8, 9]. Moreover, the "reno-protective" effects of Levosimendan, attributed to its vasodilatory action on renal afferent arterioles, remain an area of intense research interest, particularly given the prevalence of cardiorenal syndrome in ADHF [10]. There is a continued need to evaluate these agents in real-world clinical settings, particularly focusing on safety endpoints like arrhythmias and renal preservation.

Therefore, this study aims to compare the clinical outcomes of Levosimendan versus Dobutamine in a cohort of patients with ADHF and reduced ejection fraction, specifically focusing on hemodynamic biomarkers, renal function trajectories, and short-term survival.

Study Design and Setting
This was a prospective, randomized, open-label, comparative study conducted at the Coronary Care Unit (CCU) of a tertiary care hospital.

Study Population
The study enrolled adult patients (aged  years) admitted with a primary diagnosis of ADHF.

• Inclusion Criteria: (1) Left Ventricular Ejection Fraction (LVEF)  confirmed by echocardiography within 24 hours of admission; (2) Systolic Blood Pressure (SBP)  mmHg but  mmHg; (3) Clinical signs of hypoperfusion (cold extremities, oliguria  mL/kg/h, or lactate  mmol/L); (4) Need for inotropic support as determined by the treating cardiologist.
• Exclusion Criteria: (1) Cardiogenic shock requiring immediate mechanical circulatory support (IABP/ECMO); (2) SBP  mmHg (severe hypotension); (3) Acute ST-elevation myocardial infarction requiring primary PCI; (4) Severe valvular stenosis; (5) Severe hepatic failure; (6) History of Torsades de Pointes.

Sample Size and Randomization
Based on previous studies estimating a 20% difference in adverse event rates, a sample size of 160 patients (80 per group) was calculated to achieve 80% power with an alpha error of 0.05. Patients were randomized 1:1 using a computer-generated sequence into two groups:

• Group L (Levosimendan): Patients received a continuous infusion of Levosimendan at a rate of 0.1 $\mu$g/kg/min for 24 hours. An initial loading dose was omitted to avoid hypotension.
• Group D (Dobutamine): Patients received a continuous infusion of Dobutamine starting at 5 $\mu$g/kg/min, titrated up to a maximum of 10 $\mu$g/kg/min to achieve hemodynamic targets, maintained for at least 24 hours or until clinical stabilization.

Procedures and Data Collection
Baseline demographics, comorbidities, and medication history were recorded. Clinical parameters (Heart Rate, BP, Urine Output) were monitored hourly.
Laboratory investigations, including serum creatinine, electrolytes, and B-type Natriuretic Peptide (BNP), were measured at admission (baseline), 48 hours, and at discharge. Transthoracic echocardiography was performed at baseline and day 5.
Renal function was assessed using the estimated Glomerular Filtration Rate (eGFR) calculated via the CKD-EPI equation.

Outcome Measures

• Primary Endpoint: Efficacy defined by the percentage reduction in BNP levels from baseline to 48 hours.
• Secondary Endpoints: (1) Change in eGFR at 48 hours; (2) Incidence of arrhythmias (Atrial Fibrillation, non-sustained or sustained VT) requiring intervention; (3) Length of CCU stay; (4) 30-day all-cause mortality.

Statistical Analysis
Data analysis was performed using SPSS software (Version 26.0). Continuous variables were presented as mean  standard deviation (SD) and compared using the independent Student’s t-test. Categorical variables were expressed as frequencies and percentages, compared using the Chi-square test or Fisher’s exact test. A -value of  was considered statistically significant

Baseline Characteristics
A total of 160 patients were randomized. The mean age of the cohort was  years, and  were male. The etiology of heart failure was predominantly ischemic (58%). Baseline clinical and biochemical characteristics, including LVEF and renal function, were well-matched between the Levosimendan (Group L) and Dobutamine (Group D) arms, with no statistically significant differences (Table 1).

Table 1: Baseline Demographic and Clinical Characteristics

Hemodynamic and Biochemical Response
At 48 hours post-initiation of therapy, both groups showed clinical improvement. However, the Levosimendan group demonstrated a superior reduction in neurohormonal stress. The mean reduction in BNP was significantly greater in Group L compared to Group D ().
Notably, renal function trajectories diverged significantly. While Group L patients experienced an improvement in eGFR, Group D patients showed a slight decline in renal function. The heart rate increased significantly more in the Dobutamine group compared to the Levosimendan group ( bpm vs.  bpm, ), indicating higher chronotropic stress with Dobutamine (Table 2).

Table 2: Changes in Clinical and Biochemical Parameters at 48 Hours

Clinical Outcomes and Safety
The safety analysis revealed a marked difference in arrhythmogenic events. Group D had a significantly higher incidence of arrhythmias requiring dose reduction or anti-arrhythmic therapy compared to Group L ( vs. , ).
Regarding length of stay (LOS), Group L patients were discharged from the CCU on average 1.5 days earlier than Group D patients ().
While in-hospital mortality rates were not statistically different, the 30-day follow-up revealed a survival benefit for the Levosimendan group, with a mortality rate of  compared to  in the Dobutamine group () (Table 3).

Table 3: Clinical Outcomes and Adverse Events

This randomized comparative study provides evidence supporting the superiority of Levosimendan over Dobutamine regarding safety profile, renal protection, and short-term survival in patients with HFrEF presenting with acute decompensation. While both agents successfully stabilized patients and reduced natriuretic peptide levels, the physiological "cost" of this stability differed significantly between the two groups.

Our finding that Levosimendan resulted in a greater reduction of BNP compared to Dobutamine aligns with the mechanism of action of calcium sensitizers. By improving cardiac contractility without increasing cytosolic calcium, Levosimendan avoids the diastolic dysfunction often exacerbated by catecholamines [11]. Dobutamine, while effective at increasing cardiac output, induces tachycardia (as seen in Table 2), which increases myocardial oxygen demand () and reduces the diastolic filling time, potentially blunting the net benefit on wall stress and BNP release [12].

A critical finding of our study is the divergent impact on renal function. Group L demonstrated a significant improvement in eGFR ( mL/min), whereas Group D showed a slight decline. This is consistent with the known vasodilatory properties of Levosimendan on the renal afferent arterioles via the opening of ATP-sensitive potassium channels () [13]. In contrast, Dobutamine, despite increasing global cardiac output, may not proportionally improve renal perfusion and can induce arrhythmias that compromise hemodynamic stability [14]. The "reno-protective" effect of Levosimendan is particularly vital in ADHF, as worsening renal function is a potent independent predictor of mortality [15].

The safety profile analysis strongly favored Levosimendan. We observed a significantly higher rate of complex arrhythmias (AF and VT) in the Dobutamine group ( vs ). Beta-adrenergic stimulation triggers calcium overload in the sarcoplasmic reticulum, promoting delayed after-depolarizations and triggered activity [16]. Levosimendan’s calcium-neutral inotropy avoids this pro-arrhythmic substrate. This finding corroborates the results of the LIDO study, which also reported fewer rhythm disturbances with Levosimendan [17].

Regarding mortality, our study showed a significant reduction in 30-day mortality in the Levosimendan group ( vs ). While the large-scale SURVIVE trial did not show a significant difference in long-term (180-day) mortality, several meta-analyses and subgroup analyses suggest a survival benefit in the short term and specifically among patients on chronic beta-blocker therapy [18, 19]. Since 75-77% of our cohort was on beta-blockers, Dobutamine’s efficacy might have been attenuated due to receptor competition, whereas Levosimendan acts downstream of the beta-receptor, maintaining its efficacy [20].

Limitations
Our study has limitations. First, the open-label design introduces potential bias in clinical management, although objective endpoints like BNP and creatinine mitigate this. Second, the sample size (), while sufficient for our power calculation, is small compared to multi-center international trials. Third, we did not assess cost-effectiveness; while Levosimendan is more expensive per vial, the reduced length of stay observed here may offset the acquisition cost [21-24].

In patients with acute decompensated heart failure and reduced ejection fraction, Levosimendan demonstrates distinct clinical advantages over Dobutamine. It provides effective decongestion and hemodynamic stabilization with a significantly lower risk of arrhythmogenic events. Furthermore, Levosimendan therapy is associated with improved renal function and superior 30-day survival.

These findings suggest that Levosimendan should be considered the inotrope of choice, particularly in patients with marginal renal function, those receiving chronic beta-blocker therapy, or those at high risk for arrhythmias. Dobutamine remains a viable alternative but requires vigilant monitoring for rhythm disturbances and renal deterioration.

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