Initiating angiotensin II at lower vasopressor doses in vasodilatory shock: an exploratory post-hoc analysis of the ATHOS-3 clinical trial


Patrick M. Wieruszewski, Departments of Pharmacy and Anesthesiology, Mayo Clinic, Rochester, MN, USA.
Rinaldo Bellomo, Department of Critical Care, Melbourne Medical School, University of Melbourne, Parkville, Australia.
Laurence W. Busse, Department of Medicine, Emory University, Atlanta, GA, USA.
Kealy R. Ham, Department of Critical Care Medicine, Mayo Clinic Arizona, Phoenix, AZ, USA.
Alexander Zarbock, Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, University Münster, Munster, Germany.
Ashish K. Khanna, Department of Anesthesiology, Section on Critical Care Medicine, Wake Forest School of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.
Adam M. Deane, Department of Critical Care, Melbourne Medical School, University of Melbourne, Parkville, Australia.
Marlies Ostermann, Department of Critical Care, King's College London, Guy's and St Thomas' Hospital, Westminster Bridge Road, London, SE1 7EH, UK.
Richard G. Wunderink, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
David W. Boldt, Department of Anesthesiology and Critical Care Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Stew Kroll, La Jolla Pharmaceutical Company, Waltham, MA, USA.
Chuck R. Greenfeld, La Jolla Pharmaceutical Company, Waltham, MA, USA.
Tony Hodges, La Jolla Pharmaceutical Company, Waltham, MA, USA.
Jonathan H. Chow, Department of Anesthesiology and Critical Care Medicine, George Washington University School of Medicine and Health Sciences, 2700 M St. NW, 7Th Floor, Room 709, Washington, DC, 20037, USA. JChow@mfa.gwu.edu.

Document Type

Journal Article

Publication Date



Critical care (London, England)








Angiotensin; Catecholamine; Multimodal; Outcomes; Shock; Vasopressor


BACKGROUND: High dose vasopressors portend poor outcome in vasodilatory shock. We aimed to evaluate the impact of baseline vasopressor dose on outcomes in patients treated with angiotensin II (AT II). METHODS: Exploratory post-hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial data. The ATHOS-3 trial randomized 321 patients with vasodilatory shock, who remained hypotensive (mean arterial pressure of 55-70 mmHg) despite receiving standard of care vasopressor support at a norepinephrine-equivalent dose (NED) > 0.2 µg/kg/min, to receive AT II or placebo, both in addition to standard of care vasopressors. Patients were grouped into low (≤ 0.25 µg/kg/min; n = 104) or high (> 0.25 µg/kg/min; n = 217) NED at the time of study drug initiation. The primary outcome was the difference in 28-day survival between the AT II and placebo subgroups in those with a baseline NED ≤ 0.25 µg/kg/min at the time of study drug initiation. RESULTS: Of 321 patients, the median baseline NED in the low-NED subgroup was similar in the AT II (n = 56) and placebo (n = 48) groups (median of each arm 0.21 µg/kg/min, p = 0.45). In the high-NED subgroup, the median baseline NEDs were also similar (0.47 µg/kg/min AT II group, n = 107 vs. 0.45 µg/kg/min placebo group, n = 110, p = 0.75). After adjusting for severity of illness, those randomized to AT II in the low-NED subgroup were half as likely to die at 28-days compared to placebo (HR 0.509; 95% CI 0.274-0.945, p = 0.03). No differences in 28-day survival between AT II and placebo groups were found in the high-NED subgroup (HR 0.933; 95% CI 0.644-1.350, p = 0.71). Serious adverse events were less frequent in the low-NED AT II subgroup compared to the placebo low-NED subgroup, though differences were not statistically significant, and were comparable in the high-NED subgroups. CONCLUSIONS: This exploratory post-hoc analysis of phase 3 clinical trial data suggests a potential benefit of AT II introduction at lower doses of other vasopressor agents. These data may inform design of a prospective trial. TRIAL REGISTRATION: The ATHOS-3 trial was registered in the clinicaltrials.gov repository (no. NCT02338843). Registered 14 January 2015.


Anesthesiology and Critical Care Medicine