In a comprehensive 2025 review article, angiotensin II was evaluated for efficacy, safety, and hemodynamic effects in adult patients with catecholamine-refractory vasodilatory shock. The review included three studies involving a total of 321 patients, including the ATHOS-3 randomized trial, a renal-focused post hoc analysis, and the DARK-Sepsis protocol. Angiotensin II significantly increased mean arterial pressure (MAP) compared with placebo, with 69.9% of patients achieving the target MAP threshold compared with 23.4% receiving placebo (p<0.001). Angiotensin II was also associated with reduced concurrent catecholamine requirements and a lower rate of renal replacement therapy initiation. Exploratory analyses suggested that patients with elevated baseline plasma renin levels may have a greater response to angiotensin II, supporting further investigation of biomarker-guided patient selection. However, the review did not evaluate whether prior exposure to angiotensin-converting enzyme inhibitors (ACE inhibitors) or angiotensin receptor blockers (ARBs) influenced response to angiotensin II. [1]
A separate post hoc subgroup analysis of the ATHOS-3 trial specifically evaluated the impact of prior ACE inhibitor or ARB exposure on angiotensin II responsiveness (see Table 1). Among 321 patients, 29 had prior ACE inhibitor exposure, 22 had prior ARB exposure, and 270 had no prior ACE inhibitor or ARB exposure. Patients with prior ACE inhibitor exposure demonstrated a greater hemodynamic response to angiotensin II compared with patients without prior ACE inhibitor/ARB exposure. This finding may be explained by ACE inhibitor-mediated inhibition of angiotensin II formation, resulting in relative angiotensin II deficiency that may be more responsive to exogenous angiotensin II administration. Conversely, patients with prior ARB exposure demonstrated reduced responsiveness compared with patients without prior ACE inhibitor/ARB exposure, potentially due to continued angiotensin II type 1 receptor blockade, which may limit the vasoconstrictive effects of administered angiotensin II. Overall, available evidence suggests that prior ACE inhibitor exposure may identify patients who are more likely to respond to angiotensin II, whereas prior ARB exposure may attenuate response. However, evidence remains limited to a single small post hoc analysis, and prospective studies are needed to determine whether baseline ACE inhibitor or ARB exposure can reliably guide angiotensin II selection in clinical practice. [1]
A 2023 systematic review evaluated four studies, including one randomized controlled trial (RCT), to assess the clinical outcomes of angiotensin II (ATII) in treating vasodilatory shock. When examining its effect on mean arterial pressure (MAP), ATII significantly increases MAP in responders at 3 hours post-administration (p<0.001). However, mortality outcomes varied. One multicenter, retrospective study reported a higher mortality rate when AT II was used as a third-line agent compared to the standard of care vasopressors (91.1% vs 78%; p= 0.04). In contrast, ATII therapy in patients with elevated renin showed a reduced risk of death (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.39 to 0.98). Contrarily, the ATHOS-3 trial showed no significant difference in mortality at day 7 (HR 0.78; 95% CI 0.53 to 1.16; p= 0.22) and day 28 (HR 0.78; 95% CI, 0.57 to 1.07; p= 0.12). Notably, the use of normal saline as a placebo in ATHOS-3 may limit its results, given the adverse effects of fluid administration in patients who are not fluid-responsive. [2]
A 2018 systematic review evaluated 21 studies, including 16 prospective comparative trials and 5 post-hoc analyses, to determine the efficacy and safety of ATII, selepressin, and terlipressin in treating vasodilatory shock. When focusing on ATII, ATII increases blood pressure (BP) from baseline. However, the panel raises concerns with interpreting the results from the trials given the allowance of titration of open-label vasopressors in all trials making it difficult to discern the true effect of ATII on BP. Additionally, the panel analyzed post-hoc analyses of the ATHOS-3 trial to determine the mortality benefit of ATII in various subgroups. Mortality was significantly lower with AT2 versus placebo in patients requiring renal replacement therapy (RRT), (47% vs 70%; p= 0.012), those with acute physiologic assessment and chronic health evaluation (APACHE) II severity of illness scores > 30, and patients with baseline serum AT1–AT2 ratio above the median value of 1.63 pg/mL (HR 0.64; 95% CI 0.41-1.00; p= 0.047). [3]
A closer look at the aforementioned post-hoc analyses from the ATHOS-3 trial revealed patient populations that may benefit from the addition of ATII. Patients with more severe illness at baseline (APACHE II > 30 [n= 123]) had a significantly greater 28-day mortality in the placebo group compared to the angiotensin II group (70.8% vs 51.8%; HR 0.62; 95% C] 0.39 to 0.98; p= 0.037). A higher angiotensin I/II ratio was associated with significantly higher mortality in multivariate analysis (HR 1.78; 95% CI 1.25 to 2.53; p= 0.002) across the entire population in ATHOS-3. Additionally, risk of death in the placebo arm was significantly associated with an elevated angiotensin I/II ratio in multivariate analysis (HR 1.77; 95% CI 1.1 to 2.85; p= 0.019). Patients with acute kidney injury treated with renal replacement therapy at initiation of treatment (n= 45 in angiotensin II group, n= 60 in placebo group) had a significantly higher survival rate when treated with angiotensin II compared to placebo (53% vs. 30%; p= 0.012). Day 28 survival was also significantly higher in patients who received ≤ 5 ng/kg/min versus > 5 ng/kg/min (59% vs. 33%; HR 0.48; 95% CI 0.28 to 0.72; p= 0.0007). [4], [5], [6], [7]
A 2023 exploratory post-hoc analysis of phase 3 clinical trial data from the ATHOS-3 trial (see Table 4) evaluated the impact of baseline vasopressor dose on outcomes in patients with vasodilatory shock treated with AT II. The study analyzed 321 patients randomized to receive AT II or placebo in addition to standard-of-care vasopressors and stratified them by norepinephrine-equivalent dose (NED) at study drug initiation: low (≤ 0.25 µg/kg/min; n= 104) and high (> 0.25 µg/kg/min; n= 217). The primary outcome was the difference in 28-day survival between AT II and placebo in the low-NED subgroup. Patients receiving AT II in the low-NED subgroup had significantly lower 28-day mortality compared to placebo (HR 0.509; 95% CI 0.274 to 0.945; p= 0.03), whereas no survival benefit was observed in the high-NED subgroup (HR 0.933; 95% CI 0.644 to 1.350; p= 0.71). AT II was associated with higher response rates at hour 3 in both NED subgroups and greater reductions in vasopressor requirements. In the high-NED subgroup, AT II was associated with a higher likelihood of renal replacement therapy (RRT) discontinuation at day 7 (HR 2.97; 95% CI 1.06 to 8.36; p= 0.03). Serious adverse events were numerically lower in the low-NED AT II group compared to placebo, though not statistically significant. Overall, these findings suggest that initiating AT II at lower vasopressor doses may be associated with improved survival and hemodynamic benefits, however, further studies may be necessary to definitively confirm these results. [8]
Another post-hoc analysis of ATHOS-3 (see Table 5) evaluated the effects of ATII plus standard-of-care vasopressors (n= 9) in managing vasoplegia after cardiac surgery compared to placebo plus standard-of-care vasopressors (n= 7). Eligible patients included adults with septic or distributive shock who displayed refractory hypotension despite receipt of >0.2 µg/kg/min of NED, including vasopressin, for at least 6-to-48 hours before enrollment and experienced vasoplegia after cardiac surgery with cardiopulmonary bypass (CPB). Vasopressin was administered within 6 hours before randomization to 6 (66.7%) patients in the ATII group and 4 (57.1%) patients in the placebo group. Few patients had prior exposure to angiotensin-converting enzyme (ACE) inhibitors (3/16 [18.8%]) or ATII receptor blockers (1/16 [6.3%]). Median circulating levels of angiotensin I were elevated (306 pg/mL) relative to a previously reported group of healthy control volunteers (42 pg/mL), as was the median ratio of angiotensin I:angiotensin II (2.3 vs 0.4 in healthy control volunteers). ATII was associated with a significantly greater incidence of MAP response at hour 3 compared to placebo ( 88.9% vs 0%, p= 0.0021). The study found no difference in mortality between the two groups. Given the post-hoc nature of the study, these results are hypothesis-generating rather than definitive, as the original study was not designed to detect differences in this subgroup. [9]
A final post hoc analysis of the ATHOS-3 trial (see Table 6), published in 2025, evaluated the efficacy of ATII in patients with catecholamine-resistant vasodilatory shock and acute kidney injury (AKI). The trial encompassed participants from 75 intensive care units across North America, Australasia, and Europe. The investigation included patients across all stages of AKI, focusing on those randomized to receive either intravenous ATII or a placebo, with the primary outcome being 28-day mortality. Secondary outcomes entailed monitoring the MAP response and the number of days patients were alive and free from renal replacement therapy (RRT) up to day 7. From the cohort of 321 patients enrolled in ATHOS-3, 203 individuals, or 63%, presented with AKI at the time of randomization, predominantly at stage 3 (67%). The median age of participants was 63 years, and the median APACHE II score was 30, indicative of their critical condition. By day 28, mortality was recorded at 58% overall, with the ANGII group showing a reduction in mortality to 53% compared to 63% in the placebo group, though this difference was not statistically significant (hazard ratio [HR] 0.75; 95% CI 0.52 to 1.08; p= 0.121). However, in patients with stage 3 AKI, ANGII significantly lowered mortality rates to 48% versus 67% in the placebo group (HR 0.57; 95% CI 0.36 to 0.91; p= 0.024). Additionally, ANGII recipients were more likely to achieve a MAP response (p<0.001) and experienced more days alive and free from RRT (p<0.001), highlighting the potential benefit of ANGII in this severely ill population. Of note, this analysis was only available as an abstract, limiting a comprehensive analysis of these findings. [10]