Use of levosimendan combined with Shenfu injection to treat acute heart failure patients with hypotension: a prospective randomized controlled single-blind study

Since 2000, levosimendan has been used to treat patients with acute decompensated heart failure (ADHF), because it produces safe hemodynamic stabilization [1]. Levosimendan promotes inotropy by sensitizing cardiac muscle troponin C (cTnC) to Ca²⁺ [2, 3]. In addition, it causes vasodilatation by activating ATP-dependent-K⁺ channels on smooth muscle. In a number of clinical trials, it was found that levosimendan elicited fewer adverse effects compared to other inotropic and vasoactive drugs; it is noteworthy that it still produced hypotension. One expert consensus report suggested the use of levosimendan in patients with pulmonary congestion. It is preferred to adrenoceptor agonists as first-line therapy for acute heart failure with acute coronary syndrome (ACS-AHF) patients on β-blocker medication, with unsatisfactory urine outputs after the administration of diuretics. It can be given as sole therapy or together with other inotropic or vasopressor drugs. However, patients should be closely monitored because of the risk of hypotension [4]. Lochner et al. [5] also reported that levosimendan combined with β-blockers or adrenergic inotropes did not inhibit the actions of levosimendan alone.

In patients with ADHF, levosimendan has been shown to significantly increase cardiac output (CO) and stroke and decrease pulmonary capillary wedge pressure (PCWP), mean blood, pulmonary artery and mean right atrial pressures, and total peripheral resistance [6]. For patients whose systolic blood pressure (SBP) is < 90 mmHg with hypoperfusion symptoms, it is necessary to raise CO, blood pressure and peripheral perfusion, to safeguard the functions of vital organs [7]. For acute heart failure (AHF) patients with low-output states, a drug that augments CO and increases the degree of vasodilatation would be expected to have better efficacy than one that augments CO alone.

Chemical analysis has shown that Shenfu injection mainly contains ginsenoside and higenamine [8, 9]. A Shenfu injection can increase arterial oxygen partial pressure and oxygen saturation [10, 11], increase hypoxia tolerance and anti-stress ability [12], reduce peripheral resistance and improve the microcirculation [13], increase myocardial contractility and cardiac output [14], dilate peripheral blood vessels [15], and improve the hypoxia-ischemic state of tissues and organs [16]. Ginsenosides can increase myocardial contractility, reduce small vascular resistance and increase cardiac, cerebral and renal perfusion [17]. Higenamine can not only improve myocardial contractility, but also dilate blood vessels and reduce cardiac load [18]. In the presence of ginsenosides, higenamine retains positive inotropic effects without positive frequency actions and thereby does not increase myocardial oxygen consumption [19]. In recent years, a number of clinical trials have shown that the Chinese patent medicine, Shenfu injection (SFI), greatly improved the symptoms of heart failure (HF) [7‐9]. The mechanisms involved in the actions of SFI include a significant reduction in taurine, glutathione and phospholipids concentrations. This was shown in an ischemic heart failure rat model, when the distribution of these molecules in the non-infarct zone was markedly altered [20]. In clinical trials, SFI not only improved CO but also the vasodilator dimension [14, 21].

Therefore, in the present study, we hypothesized that levosimendan combined with SFI would improve cardiac functions without producing hypotension and improve the symptoms of patients with both ADHF and hypotension.

The study involved a cohort of 101 patients suffering from ADHF from 2019.12 to 2021.6 They were diagnosed according to the 2018 Chinese guidelines [22] and randomly assigned into control (levosimendan + placebo) (n = 51) and study (levosimendan + SFI) (n = 50) groups. Inclusion criteria were based on the New York Heart Association grading guidelines [22] and were: patients had grade III or IV; an left ventricular ejection fraction (LVEF) ≤ 40%; and a brain natriuretic peptide (BNP) level > 400 pg/mL. Some patients were also diagnosed with low cardiac output syndrome (LCOS). All enrolled patients were not allergic to traditional Chinese herbal medicines.

The study followed the Declaration of Helsinki principles and was approved by the Institutional Review Board of Tongren Hospital affiliated to Shanghai Jiao Tong University School of Medicine. All enrolled patients provided informed consent. The registered trial number was ChiCTR2000039385.

The exclusion criteria for patients were: of childbearing potential; HF due to restrictive or hypertrophic cardiomyopathy or stenotic valvular disease that was uncorrected; had acute myocardial infarction 14 days prior to the study or had refractory angina; sustained ventricular arrhythmia; severe liver and/or kidney insufficiency; severe infection; malignant tumor; systemic immune disease; those who would not cooperate with treatment; withdrawal from the study; or death.

In the present study, we confirmed that levosimendan combined with SFI effectively increased blood pressure, which was reduced in patients with AHF due to insufficient peripheral blood volume. AHF refers to an attack or aggravation of the functions of the left heart, mainly due to reduced myocardial contractility, an increase in cardiac load, and pressure in the pulmonary circulation, and raised resistance of the peripheral circulation. Pulmonary congestion and edema, together with poor organ perfusion and cardiogenic shock are the most common clinical syndromes caused by pulmonary circulation congestion [23, 24]. Therefore, AHF has a relatively high in-hospital mortality rate of 3%, and 3- and 5-year mortality rates of 30% and 60%. The pathogenesis of AHF is complex, but most studies have demonstrated that it is related to hemodynamic disorders [25, 26].

The results of epidemiological investigation have shown that the incidence of AHF has been increasing in recent years in China, and has seriously affected people's physical and mental health and their quality of life [27]. Our results strongly suggest that the addition of an adjuvant significantly improved the hemodynamic indicators CO, CI, SVI and SVRI, which will naturally improve the survival rate and prognosis of patients.

Both levosimendan and SFI are relatively common drugs used to treat HF in China. Among them, levosimendan is a positive inotropic drug, which can bind with troponin C after drug action, increasing the sensitivity of contractile protein to Ca²⁺, thus improving myocardial contractility and reducing cardiac load. However, the effect of this drug alone is not ideal [28] for ADHF patients with hypotension. We also use SFI in clinical practice. Ginsenosides and aconitine alkaloids in SFI are the main active components [29]. Ginsenoside in red ginseng can reduce myocardial oxygen consumption and enhance myocardial contractility, while normethylidene alkaloid in aconitine alkaloids, has the effect of anti-myocardial ischemia and heart strengthening [30].

From ex vivo experiments in a septic shock rabbit model, we found that SFI could increase mean arterial pressure (MAP), decrease serum lipopolysaccharide (LPS), lactate dehydrogenase (LDH) and AST concentrations, and improve the tissue morphology of the heart, liver and kidney. In addition, SFI can re-increase the concentrations of ATP and taurine while reducing the concentration of AMP in cardiac muscle during septic shock [29].

Much research has been carried out on cardiac functions in patients with ADHF who have been treated with levosimendan or levosimendan combination drugs. Many studies have confirmed that levosimendan can significantly improve CO, reduce the BNP concentration and increase LVEF in patients with ADHF [31, 32]. In the present study, it was clear that similar effects of levosimendan combined with SFI and levosimendan therapies decreased the BNP concentration, although addition of SFI did not significantly improve the heart rate.

Levosimendan-nesiritide combination therapy produced the most pronounced improvements during the early stages of treatment, which gradually declined to the same levels produced by monotherapies at day 9 [33]. Therefore, for patients with ADHF, combination therapies achieved clinical efficacies faster than respective monotherapies, but improvements in the long term may well be similar.

Levosimendan and SFI have different mechanisms of action; levosimendan is a positive inotropic drug which does not raise the free intracellular Ca²⁺ concentration. In theory, a combination of these two drugs should produce synergistic effects greater than those produced by administration of only one of the drugs.

The results of this study should not be regarded as definitive regarding whether an SFI infusion affected BNP concentrations. Although BNP has a brief half-life, there was a delay of up to 48 h from cessation of drug administration to the determination of the BNP concentration. Due to the lack of measurements of proANP and aldosterone in laboratory tests, the BNP concentrations were only assessed 24 h after drug administration. In an ideal world, however, it would be desirable if all the concentrations (BNP, proBNP and aldosterone) were included. In addition, it is possible that a single-center study may introduce bias. Our study had a relatively small sample size, which would weaken the primary endpoint. Larger clinical trials are needed to confirm the improvement in hemodynamic parameters of SFI combined with levosimendan. Furthermore, SFI may not be available outside China, which leads to an issue of generalizability.

Intravenous infusion of levosimendan and SFI to acute decompensated heart failure patients with hypotension was a superior treatment compared to levosimendan monotherapy with regard to hemodynamic parameters.