Intermittent levosimendan infusion in ambulatory patients with end-stage heart failure: a systematic review and meta-analysis of 984 patients

Abstract

We sought to synthesize the available evidence regarding safety and efficacy of intermittent levosimendan (LEVO) infusions in ambulatory patients with end-stage heart failure (HF). Safety and efficacy of ambulatory intermittent LEVO infusion in patients with end-stage HF are yet not established. We systematically searched MEDLINE, EMBASE, SCOPUS, Web of Science, and Cochrane databases, from inception to January 30, 2021 for studies reporting outcome of adult ambulatory patients with end-stage HF treated with intermittent LEVO infusion. Fifteen studies (8 randomized and 7 observational) comprised 984 patients (LEVO [N = 727] and controls [N = 257]) met the inclusion criteria. LEVO was associated with improved New York Heart Association (NYHA) functional class (weighted mean difference [WMD] −1.04, 95%CI: −1.70 to −0.38, p < 0.001, 5 studies, I2 = 93%), improved left ventricular (LV) ejection fraction (WMD 4.0%, 95%CI: 2.8% to 5.3%, p < 0.001, 6 studies, I2 = 9%), and reduced BNP levels (WMD −549 pg/mL, 95%CI −866 to −233, p < 0001, 3 studies, I2 = 66%). All-cause death was not different (RR 0.65, 95%CI: 0.38 to 1.093, p = 0.10, 6 studies, I2 = 0), but cardiovascular death was lower on LEVO (RR 0.34, 95%CI: 0.13 to 0.87, p = 0.02, 3 studies, I2 = 0) compared to controls. Furthermore, health-related quality of life (HRQoL) was improved alongside with reduced LV size following LEVO infusions. Major adverse events were not different between LEVO and placebo. In conclusion, intermittent LEVO infusions in ambulatory patients with end-stage HF is associated with less frequent cardiovascular death alongside with improved NYHA class, quality of life, BNP levels, and LV function. However, the current evidence is limited by heterogeneous and relatively small studies.

Levosimendan and Continuous Outpatient Support With Inotropes in Patients With Advanced Heart Failure: A Single-Centre Descriptive Study

“…Historically, ventricular arrhythmia had been a concern with levosimendan use; however, we did not observe any hemodynamically significant arrhythmias requiring defibrillation, and only one that required antitachycardia pacing. This finding is consistent with previous studies that examined single- and intermittent-dose levosimendan infusions, 6,12–14 with 1 recent systematic review and meta-analysis finding that major adverse event rates were no higher among who received intermittently dosed levosimendan compared with placebo. 6 As such, we suggest that safety profile should not be a prohibitive factor in the use of levosimendan.…”

“…5 Large-scale, randomized, controlled data are difficult to obtain given the targeted population in which levosimendan may play a role. 6,7 Importantly, no study to date has explored a single-dose regimen of levosimendan as an alternative to intermittent dosing for bridge to decision (BTD) and bridge to transplant (BTT). At present, bridge therapy most commonly consists of continuous outpatient support with inotropes (COSI), usually dobutamine or milrinone, [8][9][10] and/or mechanical circulatory support devices.…”

Perioperative Levosimendan Infusion in Patients With End-Stage Heart Failure Undergoing Left Ventricular Assist Device Implantation

“…In early studies, LEVO has been shown to decrease mortality ( 5 ), improve hemodynamics and reduce symptoms. In two recent systemic reviews, our group clearly showed the incremental value of LEVO infusions in the setting of end-stage HF ( 6 ), and cardiogenic shock patients needing VA-ECMO support ( 7 ).…”

“…In a recently published meta-analysis by our group, LEVO use in patients undergoing ECMO was associated with significant VA-ECMO weaning success and lower risk of mortality ( 7 ). In addition, another meta-analysis by our group demonstrated that LEVO use in ambulatory patients with refractory HF has been associated with wide range of improved hemodynamics, echocardiographic parameters, reverse LV remodeling, lower filling pressures, and lower biomarkers of LV failure ( 6 ). On the other hand, long-term treatment with conventional intravenous inotropes increases mortality ( 6 ).…”

“…In addition, another meta-analysis by our group demonstrated that LEVO use in ambulatory patients with refractory HF has been associated with wide range of improved hemodynamics, echocardiographic parameters, reverse LV remodeling, lower filling pressures, and lower biomarkers of LV failure ( 6 ). On the other hand, long-term treatment with conventional intravenous inotropes increases mortality ( 6 ). More recently, Yalcin et al ( 10 ) reported a successful use of intermittent LEVO infusion for treatment of a late RHF patient post LVAD.…”