• Patrick M Wieruszewski, Rinaldo Bellomo, Laurence W Busse, Kealy R Ham, Alexander Zarbock, Ashish K Khanna, Adam M Deane, Marlies Ostermann, Richard G Wunderink, David W Boldt, Stew Kroll, Chuck R Greenfeld, Tony Hodges, Jonathan H Chow, and Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) Investigators.
• Departments of Pharmacy and Anesthesiology, Mayo Clinic, Rochester, MN, USA.
• Crit Care. 2023 May 5; 27 (1): 175175.

BackgroundHigh 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).MethodsExploratory 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.ResultsOf 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.ConclusionsThis 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 RegistrationThe ATHOS-3 trial was registered in the clinicaltrials.gov repository (no. NCT02338843). Registered 14 January 2015.© 2023. The Author(s).

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