SEISMiC-C: Istaroxime Increases SBP and Improves Hemodynamics in Cardiogenic Shock

Istaroxime is associated with increased blood pressure and improved central hemodynamics in patients with Society for Cardiovascular Angiography and Interventions (SCAI) Class C cardiogenic shock while maintaining a favorable safety and tolerability profile, based on data from the SEISMiC-C trial.1

Presented at the Heart Failure Society of America Annual Scientific Meeting 2025 in Minneapolis, MN, by Jan Biegus, MD, PhD, associate professor at Wroclaw Medical University, the trial examined istaroxime, a novel first-in-class therapy dual-mechanism therapy for the improvement of both systolic and diastolic cardiac function. It increases myocardial contractility through inhibition of Na+/K+- ATPase, with a complimentary mechanism facilitating myocardial relaxation via activation of the SERCA2a calcium pump on the sarcoplasmic reticulum.2

The SEISMiC study enrolled patients who had been hospitalized for decompensated heart failure SCAI-C with persistent hypotension, measured as systolic blood pressure (SBP) 70-100 mmHg, clinically confirmed congestion, measured as NT-proBNP ≥1400 pg/mL, and LVEF ≤40%. Patients were then randomly assigned in a 1:1:1 ratio to receive a continuous, 60-hour infusion of either placebo or 1 of 2 istaroxime dosing regimens. These included (1) 1.0 µg/kg/min for 6 hours, 0.5 µg/kg/min for 42 hours, and 0.25 µg/kg/min for 12 hours, or (2) 0.5 µg/kg/min for 48 hours followed by placebo for 12 hours.1,3

A total of 20 patients were enrolled, with a mean age of 68.2 years (standard deviation [SD] 8.32 years). Of these, 11 were assigned to receive istaroxime, and 9 received placebo. Investigators recorded central hemodynamics, ECG Holter monitoring, cardiac ultrasound, and biomarkers at predefined time points during the trial. The primary endpoint was area under the curve for SBP during the first 6 hours.1

Compared to the SEISMiC-B trial, which included 30 patients and resulted in a gradual decrease in SBP after 4 hours from infusion, SEISMiC-C saw an overall increase in SBP, with least squares (LS) mean of 71.8 (11.31) among the istaroxime group compared to 78.4 (11.9) in SEISMiC-B. SEISMiC-C also saw an LS mean difference of 34.07 (95% CI, -1.5 to 69.7; P = .0594) versus 38.8 (95% CI, 1.3 to 76.2; P = .0429) in SEISMiC-B. Additionally, SEISMiC-C saw an overall decrease in estimated glomerular filtration rate (EGFR) and cardiac output from baseline.1

Regarding safety, 5 of 11 (45%) patients receiving istaroxime experienced worsening heart failure (HF), HF readmissions, or death, compared to 3 of 9 (33%) in the placebo group. Only 1 of 11 in the istaroxime group experienced all-cause mortality versus 2 in placebo, and 2 saw all-cause death or heart transplant in istaroxime versus 3 in placebo. This establishes a solidly tolerable safety profile.1

ECG Holter data indicated a mean post-treatment average heart rate of 82.7 (SD 12.45) BPM in the istaroxime group versus 92.2 (21.49) BPM in the placebo subgroup. Additionally, atrial fibrillation burden reached 20% (42.16%) in the istaroxime group versus 51.1% (50.1%) in placebo.1

“These findings suggest that while vericiguat may increase the risk of symptomatic hypotension modestly, it retains clinical benefit across a broad spectrum of patients with HFrEF, including those with lower SBP and more intensive background therapy,” Butler and colleagues wrote.3

References

1. Biegus J, Mebazaa A, Metra M, et al. Safety and Efficacy of Intravenous Administration of Istaroxime for 48 Hours in Patients with SCAI C Cardiogenic Shock due to Acute Heart Failure (SEISMiC-C trial). Presented at the Heart Failure Society of America Annual Scientific Meeting 2025. Minneapolis, MN. September 26-29, 2025.

2. Windtree Therapeutics. Windtree Therapeutics Provides Update on Istaroxime Clinical Development and Upcoming Clinical Trial Data. July 25, 2024. Accessed September 29, 2025. https://ir.windtreetx.com/news-releases/news-release-details/windtree-therapeutics-provides-update-istaroxime-clinical

3. Biegus J, Mebazaa A, Metra M, et al. Safety and efficacy of up to 60 h of iv istaroxime in pre-cardiogenic shock patients: Design of the SEISMiC trial. ESC Heart Fail. 2025;12(1):189-198. doi:10.1002/ehf2.15102