Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial

• Type of Material: Article
• Authors: Kealy R. Ham, University of Minnesota; David W. Boldt, University of California Los Angeles; Michael T. McCurdy, University of Maryland; Laurence W. Busse, Emory University; Raphael Favory, Centre Hospitalier Universitaire de Lille; Michelle N. Gong, Albert Einstein College of Medicine; Ashish K. Khanna, Wake Forest School of Medicine; Stefan N. Chock, Sunrise Hospital; Feng Zeng, La Jolla Pharmaceutical Company; Lakhmir S. Chawla, La Jolla Pharmaceutical Company; George F. Tidmarsh, La Jolla Pharmaceutical Company; Marlies Ostermann, Kings College London
• Language: English
• Date: 2019-06-03
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © 2019, The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13613-019-0536-5
• Title of Journal or Parent Work: Annals of Intensive Care
• ISSN: 2110-5820
• Volume: 9
• Issue: 1
• Start Page: 63
• End Page: 63
• Grant/Funding Information: These analyses and the original study were funded by La Jolla Pharmaceutical Company.
• Keywords: Life Sciences & Biomedicine; Dose response; DOWN-REGULATION; Critical Care Medicine; Septic shock; Hypotension; NOREPINEPHRINE; Science & Technology; Shock; RECEPTORS; Angiotensin II; General & Internal Medicine
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Background: Early clinical data showed that some patients with vasodilatory shock are responsive to low doses of angiotensin II. The objective of this analysis was to compare clinical outcomes in patients requiring ≤ 5 ng kg−1 min−1 angiotensin II at 30 min (≤ 5 ng kg−1 min−1 subgroup) to maintain mean arterial pressure (MAP) ≥ 75 mmHg versus patients receiving > 5 ng kg−1 min−1 angiotensin II at 30 min (> 5 ng kg−1 min−1 subgroup). Data from angiotensin II-treated patients enrolled in the ATHOS-3 trial were used. Results: The subgroup of patients whose angiotensin II dose was down-titrated from 20 ng kg−1 min−1 at treatment initiation to ≤ 5 ng kg−1 min−1 at 30 min (79/163) had significantly lower endogenous serum angiotensin II levels and norepinephrine-equivalent doses and significantly higher MAP versus the > 5 ng kg−1 min−1 subgroup (84/163). Patients in the ≤ 5 ng kg−1 min−1 subgroup were more likely to have a MAP response at 3 h versus those in the > 5 ng kg−1 min−1 subgroup (90% vs. 51%, respectively; odds ratio, 8.46 [95% CI 3.63–19.7], P < 0.001). Day 28 survival was also higher in the ≤ 5 ng kg−1 min−1 subgroup versus the > 5 ng kg−1 min−1 subgroup (59% vs. 33%, respectively; hazard ratio, 0.48 [95% CI 0.28–0.72], P = 0.0007); multivariate analyses supported the survival benefit in patients with lower angiotensin II levels. The ≤ 5 ng kg−1 min−1 subgroup had a more favorable safety profile and lower treatment discontinuation rate than the > 5 ng kg−1 min−1 subgroup. Conclusions: This prespecified analysis showed that down-titration to ≤ 5 ng kg−1 min−1 angiotensin II at 30 min is an early predictor of favorable clinical outcomes which may be related to relative angiotensin II insufficiency.