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Slowing Progression of Cardiovascular Calcification with SNF472 in Patients on Hemodialysis: Results of a Randomized, Phase 2b Study. Circulation Raggi, P., Bellasi, A., Bushinsky, D., Bover, J., Rodriguez, M., Ketteler, M., Sinha, S., Salcedo, C., Gillotti, K., Padgett, C., Garg, R., Gold, A., Perello, J., Chertow, G. M. 2019

Abstract

Background: The high cardiovascular morbidity and mortality in patients with end-stage kidney disease (ESKD) could be partially due to extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits formation and growth of hydroxyapatite. Methods: This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium (CAC) volume score and other measurements of cardiovascular calcification by CT scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with ESKD receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log CAC volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least one dose of SNF472 or placebo and had an evaluable CT scan post-randomization. Results: The mean change in CAC volume score was 11% (95% CI, 7%-15%) for the combined SNF472 dose group and 20% (95% CI, 14%-26%) for placebo (P=0.016). SNF472 compared to placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5%-24%] vs 98% [95% CI, 77%-123%], P<0.001), but not in the thoracic aorta (23% [95% CI, 16%-30%] vs 28% [95% CI, 19%-38%], P=0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least one treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively. Conclusions: Compared with placebo, SNF472 significantly attenuated progression of CAC and aortic valve calcification in patients with ESKD receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique identifier: NCT02966028.

View details for DOI 10.1161/CIRCULATIONAHA.119.044195

View details for PubMedID 31707860