Clinical effects of istaroxime in acute heart failure and cardiogenic shock: A patient-level pooled analysis of four phase II randomized clinical trials

BACKGROUND: Istaroxime is an inotropic and lusitropic agent tested in acute heart failure (AHF) or AHF-related cardiogenic shock (AHF-CS). We aimed to assess its efficacy and concy in a pooled analysis of all randomized trials performed to date. METHODS: Patient-level data from four phase II randomized, double-blind, placebo-controlled trials were pooled. The effects of istaroxime 0.5-1.0 µg/kg/min for up to 48 hours vs. placebo on hemodynamics, cardiac function, and clinical outcomes were assessed. RESULTS: A total of 284 patients were included (n=200 AHF, n=84 AHF-CS). Compared with placebo, istaroxime increased systolic blood pressure through 6 hours (least square [LS] mean difference in the area under the change from baseline curve 28.9 mmHg*h, 95% CI 18.1 to 39.8 mmHg*h) and through 24 hours (LS mean difference 121.4 mmHg*h, 95% CI 63.9 to 179.0 mmHg*h). Reductions in heart rate, body weight, pulmonary capillary wedge pressure and echocardiographic E/e' ratio, and an increase in echocardiographic stroke work index and stroke volume were observed with istaroxime, with a numerically greater improvement in invasive cardiac output and creatinine. Numerically, dyspnea and quality of life were improved, and length of index hospitalization, worsening HF and death were lower with istaroxime. Serious adverse events were similar between the istaroxime and placebo arms. CONCLUSIONS: In this patient-level pooled analysis, istaroxime 0.5-1.0 µg/kg/min was associated with improvement in SBP and hemodynamic and echocardiographic measurements of cardiac performance, without tachycardia or serious safety concerns. These findings support a phase III program to investigate the impact of istaroxime administration on outcomes.