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Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3): protocol for a phase III, double-blind, randomised
Lakhmir S Chawla1, James A Russell2, Sean M Bagshaw3
1Department of Medicine, Veterans Affairs Medical Center, Washington, DC, USA. lchawla@ljpc.com.
Insights
This study evaluates adding angiotensin II (ANGII) to vasopressors for catecholamine-resistant hypotension (CRH). ANGII may improve blood pressure control and patient outcomes in critical shock.
Area of Science:
- Critical care medicine
- Cardiovascular pharmacology
- Shock management
Background:
- Catecholamine-resistant hypotension (CRH) presents a significant challenge in critical care, characterized by poor response to standard vasopressors and high mortality rates.
- Existing vasopressor therapies often prove insufficient in maintaining adequate mean arterial pressure (MAP) in severe shock states.
- Angiotensin II (ANGII) is being investigated as a potential adjunctive therapy to improve hemodynamic stability in patients with CRH.
Purpose of the Study:
- To compare the efficacy and safety of adding synthetic angiotensin II (ANGII) to standard-of-care (SOC) vasopressor therapy versus placebo in patients with CRH.
- To assess the ability of ANGII to increase MAP and improve hemodynamic parameters in critically ill patients.
- To evaluate the impact of ANGII on organ function and overall safety in the context of high-output shock.
Main Methods:
- A phase III, multicenter, randomized, placebo-controlled trial (ATHOS-3) involving up to 300 critically ill patients with CRH.
- Patients received standard-of-care vasopressor therapy with either continuous intravenous infusion of ANGII or placebo for 48 hours.
- The primary efficacy endpoint was achieving a MAP of ≥ 75 mmHg or an increase of ≥ 10 mmHg within 3 hours of treatment initiation.
Main Results:
- The study aimed to determine if ANGII supplementation effectively increases MAP in patients with CRH.
- Secondary outcomes included changes in Sequential Organ Failure Assessment (SOFA) scores, assessing impact on organ dysfunction.
- Safety data regarding the use of ANGII in this patient population was systematically collected and analyzed.
Conclusions:
- The ATHOS-3 trial investigates the potential of angiotensin II as a vital addition to current vasopressor strategies for managing CRH.
- Findings will elucidate the utility of ANGII in enhancing the efficacy and safety of treatment for high-output shock.
- This research contributes to optimizing therapeutic options for patients experiencing refractory hypotension in intensive care settings.
Objective:
Catecholamine-resistant hypotension (CRH) is characterised by inadequate response to standard doses of vasopressors, and increased mortality. Our Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) trial compares the efficacy and safety of angiotensin II (ANGII) versus placebo in CRH.
Design, Setting And Participants:
A phase III, multicentre, randomised, placebo-controlled trial of LJPC-501 (synthetic ANGII) for CRH in up to 120 intensive care units. We have set a target of 300 critically ill patients with CRH receiving standard-of-care (SOC) vasopressor therapy (ie, catecholamine dose > 0.2 µg/kg/min for 6-48 hours to maintain a mean arterial pressure [MAP] of 55-70 mmHg). Calculation of a norepinephrine-equivalent vasopressor dose is critical to determining patient eligibility, as ANGII will supplement ongoing vasopressor therapy.
Interventions:
Stable patients will be randomised 1:1 to SOC vasopressor plus continuous intravenous infusion of ANGII or placebo for 48 hours, with an aim of achieving MAP of 75 mmHg for the first 3 hours. ANGII (initiated at 20 ng/ kg/min) will be titrated according to pre-specified guidelines until 48 hours, with patients followed until Day 7. Frequent vital sign and haemodynamic monitoring will support ANGII titration, safety monitoring and efficacy assessments.
Main Outcome Measures:
The primary efficacy endpoint is MAP ≥ 75 mmHg or an increase of ≥ 10 mmHg at treatment Hour 3. Secondary endpoints include change in total and cardiovascular Sequential Organ Failure Assessment scores over 48 hours, and safety data.
Conclusion:
Our study will investigate the utility of adding ANGII to current SOC vasopressor options to increase the efficacy and safety of CRH therapy.
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