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

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.