Angiotensin II in Catecholamine-Refractory Shock: A Systematic Review and Exploratory Analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) Trial

Abstract

Vasodilatory shock that does not respond to high-dose catecholamine vasopressors remains a life-threatening condition and is characterized by severe hypotension and high mortality. Angiotensin II, a non-catecholamine vasopressor that activates angiotensin type 1 receptors, has emerged as a potential therapeutic agent for restoring vascular tone in this setting. This systematic review aimed to evaluate the efficacy, safety, and hemodynamic effects of intravenous angiotensin II in adult patients with vasodilatory shock unresponsive to catecholamines, with a focus on data from the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) randomized trial and related studies. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, a systematic search was performed to identify randomized controlled trials and protocol-based investigations involving angiotensin II administration in adult patients with catecholamine-refractory vasodilatory shock. Eligible studies included the ATHOS-3 randomized trial, a renal-focused post hoc analysis, and the DARK-Sepsis protocol. Extracted outcomes included the proportion of patients achieving target mean arterial pressure, changes in catecholamine dose requirements, incidence of renal replacement therapy, and adverse event profiles. Risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. Three studies involving a total of 321 patients were included. In the ATHOS-3 trial, angiotensin II significantly increased mean arterial pressure within 30 minutes. The proportion of patients achieving the target pressure threshold was 69.9% in the angiotensin II group versus 23.4% in the placebo group (P < 0.001). Angiotensin II administration was associated with a reduction in concurrent catecholamine use and a lower rate of renal replacement therapy initiation (19.0% versus 32.4%; P = 0.015). The overall incidence of adverse events, including thromboembolic and ischemic complications, did not differ significantly between groups. Exploratory findings indicated a greater therapeutic response in patients with elevated baseline plasma renin levels. All studies included were rated as low risk of bias. Angiotensin II appears to be a safe and effective adjunct to conventional vasopressor therapy in catecholamine-refractory vasodilatory shock, offering rapid hemodynamic improvement and potential organ protection. The observed reduction in renal replacement therapy initiation and the enhanced response in renin-elevated subgroups warrant further investigation in biomarker-guided clinical trials.

Keywords: angiotensin ii; athos-3; catecholamine-refractory shock; renal replacement therapy; renin-angiotensin system; vasodilatory shock; vasopressor therapy.

Figure 1. Illustration of the intracellular signaling pathways activated by angiotensin II, binding to the angiotensin type 1 (AT₁) receptor.

Figure created by the authors AT₁ receptor, angiotensin type 1 receptor; G protein, guanine nucleotide-binding protein; PLC, phospholipase C

Figure 2. Modulation of the renin-angiotensin-aldosterone system (RAAS) response across different age groups.

Figure created by the authors ACE, angiotensin-converting enzyme

Figure 3. Conceptual framework of the ATHOS-3 trial design, renin sub-study, and primary/secondary endpoints related to angiotensin II therapy in vasodilatory shock.

RAAS, renin-angiotensin-aldosterone system

Figure 4. Flowchart showing eligibility requirements for patient inclusion in the ATHOS-3 trial.

Figure 5. Flowchart showing key conditions excluding patients from the ATHOS-3 trial.

Figure 6. PRISMA 2020 flow diagram showing the study selection process for the systematic review on angiotensin II in catecholamine-refractory vasodilatory shock.

Figure 7. Proportion of patients achieving the primary MAP endpoint at 3 hours in the Ang II versus placebo group.

Ang II, angiotensin II; MAP, mean arterial pressure

Figure 8. Angiotensin II significantly improved MAP over 48 hours compared to placebo, with a rapid and sustained hemodynamic response.

MAP, mean arterial pressure

Figure 9. Comparison of absolute event counts for key secondary outcomes (norepinephrine reduction, RRT initiation, 28-day mortality, and adverse events) between angiotensin II and placebo groups in patients with catecholamine-refractory vasodilatory shock.

RRT, renal replacement therapy