Significant improvement in BP from istaroxime, a novel non-adrenergic agent

In a pilot study, istaroxime significantly increased the systolic blood pressure (SBP) of patients with pre-cardiogenic shock. The agent was well tolerated at a low dose and was not associated with worsening arrhythmias or renal function. These results encourage further investigation of this non-adrenergic agent.

“Istaroxime was designed to improve both systolic contraction and diastolic relaxation.” clarified Prof. Marco Metra (University of Brescia, Italy) [1]. Istaroxime is a positive inotropic agent that elevates intracellular sodium levels by inhibiting sacrolemma sodium/potassium adeonosine triphosphatase and enhances the heart’s relaxation phase by activating Sarco/endoplasmic Reticulum Calcium ATPase, isotype 2a (SERCA2a). The current, randomised, double-blind, placebo-controlled, phase 2 SEISMiC study (NCT04325035) assessed the efficacy and safety of 24-hour infusion of istaroxime in 60 participants with Society for Cardiovascular Angiography and Interventions (SCAI) stage B cardiogenic shock (SBP <90 mmHg, or MAP <60 mmHg, or >30 mm drop from baseline). Focussing on the systolic contraction effect of istaroxime, the primary endpoint was the change in the Area Under Curve (AUC) for SBP over 6 hours.

Participants on istaroxime (n=30) had a significantly larger increase in SBP AUC over 6 hours compared with placebo (44.6 vs 28.1 mmHg/hr; P=0.017). After withdrawal from istaroxime, the SBP of patients who had received this agent returned to the level of placebo-receivers. The investigators did not observe differences in heart rate alterations between participants in the experimental arm and those in the placebo arm nor was there any evidence of an adverse effect of istaroxime on renal function. Furthermore, echocardiographic parameters displayed a benefit of istaroxime over placebo: the cardiac index change from baseline was 0.16 versus -0.057 (P=0.016); left ventricular end-diastolic volume was -6.51 mL versus 5.64 mL (P=0.034); and left atrium area was -1.82 cm² versus 0.04 cm² (P=0.008), respectively.

In each study group, 6 serious adverse events were reported. Adverse drug reactions occurred in 52% of the participants, mostly being gastrointestinal complaints (31%) or infusion site pain (14%). Notably, serious adverse events occurred only in participants receiving 1.5 μg/kg/min but not in participants receiving 1.0 μg/kg/min, while the haemodynamic effects of istaroxime were similar.

“This study supports the continuance of the development of istaroxime as a potential treatment for both acute heart failure and cardiogenic shock,” concluded Prof. Metra.

1. Metra M, et al. The safety and efficacy of istaroxime for PreCardiogenic Shock. LBT Pharmacological treatment II, Heart Failure 2022, 21–24 May, Madrid, Spain.

 

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Posted on 28 July, 2022